Insomnia

MEDICAL PSYCHIATRY

Series Editors Emeritus

William A. Frosch, M.D.
Weill Medical College of Council University, New York,
New York, U.S.A.

Advisory Board

Jonathan E. Alpert, M.D., Ph.D. Siegfried Kasper, M.D.

Massachusetts General Hospital and Medical University of Vienna
Harvard University School of Medicine Vienna, Austria
Boston, Massachusetts, U.S.A.
Mark H. Rapaport, M.D.
Bennett Leventhal, M.D. Cedars-Sinai Medical Center
University of Chicago School of Medicine Los Angeles, California, U.S.A.
Chicago, Illinois, U.S.A.

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 Insomnia
Diagnosis and Treatment

Edited by

Michael J. Sateia
Dartmouth Medical School
Lebanon, New Hampshire, U.S.A.

Daniel J. Buysse
University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania, U.S.A.
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This book is dedicated to our families – Holly, Heather, and Caitlin; and
Sandy, Caitlin, Allison, and Evan – whose love and support allow
us to write about insomnia rather than experience it.
 Preface

As the field of sleep medicine has matured in recent decades, it has become increasingly appar-
ent that disruption or failure of normal sleep function, not unlike failure of other essential
physiologic functions, has sweeping adverse consequences. Chronic insomnia is arguably the
most common form of sleep disruption, although its significance as a serious health problem
has been, and continues to be, largely overlooked. Much of this neglect seems to arise from
the tacit assumption that this condition is, in effect, more a benign existential problem than a
disorder deserving serious medical attention. Yet, investigations of chronic insomnia over the
past 20 years underscore the importance of addressing this issue as a component of the patient’s
overall health care. Not only is it clear that chronic insomnia is associated with impairments
in quality of life and function, comparable to those seen in disorders such as major depression
and congestive heart failure, but emerging data also indicate that insomnia may be a significant
risk factor for development of major psychiatric and possibly medical disorders. The availabil-
ity of effective therapies that can produce clinically meaningful and durable improvement or
resolution of symptoms lends further weight to the importance of identifying insomnia.
Although a small and dedicated group of sleep researchers and clinicians have made sig-
nificant strides in addressing this problem, an enormous knowledge and awareness gap exists
among most health care providers with respect to insomnia. Although we have made sub-
stantial efforts to address this through educational means, clearly the work has only begun. A
necessary foundation of sound educational efforts is a detailed, accessible body of knowledge
that addresses the pathophysiology, evaluation, and treatment of the disorder. Although many
excellent books have been published on insomnia, somewhat surprisingly, there have been only
limited efforts to produce a comprehensive reference text in this area. Our hope is that this
volume will help to meet this need.
Insomnia is relevant to virtually all aspects of medicine. For this reason, researchers and
clinicians from all fields must have access to detailed information. The subject matter of this
book will certainly be of considerable interest and importance to all sleep medicine clinicians.
However, its relevance and utility should extend well beyond this audience. As data increasingly
underscore the important and complex interaction between insomnia and mental illness, it is
incumbent upon psychiatrists, psychologists, and other mental health workers to not only
identify but also actively intervene when chronic insomnia complicates psychiatric disease.
Although the evidence that compels effective management of insomnia in comorbid medical and
neurological disease is not yet as well developed as that for mental illness, there is, nonetheless,
ample basis for internists, family practice physicians, neurologists, and other specialists to
appreciate the significant role that insomnia may play in the pathogenesis and maintenance of
physical illnesses.
The past 20 years have seen enormous progress in our understanding of the nature and
characteristics of chronic insomnia and in our ability to accurately assess and effectively treat
the problem. These advances have profoundly affected our view of chronic insomnia—most
importantly, transitioning its position from that of “secondary” symptom of other disorders
to a condition comorbid with other disorders. This paradigm shift is important because most
chronic insomnia is, in fact, comorbid with other medical or psychiatric disease. This perspective
suggests that chronic insomnia exhibits its own unique and somewhat independent pathophys-
iology, which is not only influenced by comorbid disorders but also, in turn, has major influence
on those disorders.
viii Preface

This book is intended to provide the reader with a comprehensive and detailed overview
of the current research and state-of-the-art practice parameters related to insomnia in three
parts. The first section, Fundamentals, addresses the characteristics and consequences of chronic
insomnia and, in effect, speaks about the nature of the disorder and the question of why
it deserves medical attention. The Evaluation section provides the clinician with a detailed
description of causes and comorbidities and offers clinicians specific guidelines and tools for
evaluating the disorder in its varied and often complex presentations. Finally, the section on
Management represents what we believe to be the most detailed and comprehensive description
of treatment modalities for chronic insomnia that is currently available. Each of the chapters
in this book is authored by recognized experts in the field whose research and writing have
collectively defined this area of sleep medicine.
In the modern era, medicine has moved progressively toward a multideterminant model
of causation of disease and multimodal treatment. It has become increasingly apparent that
sleep is one of the critical determinants of health and well-being. It is no longer possible for
researchers to effectively study disease or clinicians to effectively treat it without considering
the potential role of sleep and circadian factors. We believe that this comprehensive volume
will serve to stimulate interest and further inquiry in this area by scientists and clinicians from
many fields, and will provide practitioners with a guide for the management of this common
malady.
We welcome your thoughts, comments, and suggestions on the text to help us prepare for
the Second Edition.

Michael J. Sateia
Daniel J. Buysse
 Contents

Preface . . . . vii
Contributors . . . . xiii

Section I. Fundamentals of Insomnia

1. Introduction: History, Definition, and Epidemiology 1
Michael J. Sateia

2. Subjective and Objective Daytime Consequences of Insomnia 10

Michael Bonnet and Donna Arand

3. Socioeconomic Impact of Insomnia 19

Damien Leger

4. Insomnia as a Risk Factor in Disease 31

Wilfred R. Pigeon

5. Psychological Models of Insomnia 42

Lisa S. Talbot and Allison G. Harvey

6. Sleep EEG in Patients with Primary Insomnia 50

Michael Perlis, Philip Gehrman, Mario Terzano, Kimberly Cote, and Dieter Riemann

7. Neurobiological Disturbances in Insomnia: Clinical Utility

of Objective Measures of Sleep 65
Slobodanka Pejovic and Alexandros N. Vgontzas

8. Brain Imaging in Insomnia 77

Eric A. Nofzinger

Section II. Evaluation of Insomnia

9. History Taking in Insomnia 84
Karl Doghramji and Scott E. Cologne

10. Evaluation Instruments and Methodology 89

Anne Germain and Douglas E. Moul

11. Insomnia Diagnosis and Classification 98

Daniel J. Buysse

12. Clinical Assessment of Insomnia: Primary Insomnias 113

Rachel Manber and Jason C. Ong

13. Clinical Assessment of Comorbid Insomnias: Insomnia in Psychiatric Disorders 126

Meredith E. Rumble and Ruth M. Benca
x Contents

14. Insomnia in Chronic Pain 139

Emerson M. Wickwire and Michael T. Smith

15. Insomnia Related to Medical and Neurologic Disorders 153

Brooke G. Judd and Glen P. Greenough

16. Substance-Induced Insomnia 165

Deirdre A. Conroy, J. Todd Arnedt, and Kirk J. Brower

17. Insomnia in Circadian Rhythm Sleep Disorders: Shift Work/Jet

Lag/DSP/ASP/Free-Running—Blindness 181
Robert L. Sack

18. Insomnia in Other Sleep Disorders: Movement Disorders 199

Michael H. Silber

19. Insomnia in Other Sleep Disorders: Breathing Disorders 210

Emerson M. Wickwire, Michael T. Smith, and Nancy A. Collop

20. Insomnia in the Elderly 224

Philip Gehrman and Sonia Ancoli-Israel

21. Pediatric Insomnia 235

Bobbi Hopkins and Daniel Glaze

Section III. Management of Insomnia

22. Overview of Treatment Considerations 256
Daniel J. Buysse

23. Role of Healthy Sleep Practices: Alcohol/Caffeine/Exercise/Scheduling 260

Leah Friedman, Jamie M. Zeitzer, and Martin S. Mumenthaler

24. Stimulus Control Therapy 268

Richard R. Bootzin, Leisha J. Smith, Peter L. Franzen, and Shauna L. Shapiro

25. Insomnia: Sleep Restriction Therapy 277

Arthur J. Spielman, Chien-Ming Yang, and Paul B. Glovinsky

26. Other Nonpharmacological Treatments of Insomnia 290

Daniel J. Taylor, Emily A. Grieser, and JoLyn I. Tatum

27. Cognitive Therapy for Insomnia 299

Colin A. Espie and Jason Ellis

28. Short-Term and Group Treatment Approaches 310

Christina S. McCrae, Natalie D. Dautovich, and Joseph M. Dzierzewski

29. Multimodal Cognitive Behavior Therapy 342

Colleen E. Carney and Jack D. Edinger

30. Cognitive-Behavior Therapy for Comorbid and Late-Life Insomnia 352

Kenneth L. Lichstein, Bruce Rybarczyk, and Haley R. Dillon

31. Pharmacology of the GABAA Receptor Complex 365

Alan N. Bateson
Contents xi

32. Benzodiazepine Receptor Agonists: Indications, Efficacy, and Outcome 375

Andrew D. Krystal

33. Benzodiazepine Receptor Agonist Safety 387

Timothy Roehrs and Thomas Roth

34. Off-label Use of Prescription Medications for Insomnia: Sedating Antidepressants,

Antipsychotics, Anxiolytics, and Anticonvulsants 397
W. Vaughn McCall

35. Melatonin in Sleep-Wake Regulation 410

Phyllis C. Zee and Kathryn J. Reid

36. Nonprescription Pharmacotherapies: Alcohol, Over-the-Counter, and Complementary

and Alternative Medicines 417
David N. Neubauer and Kelleen N. Flaherty

37. Current Advances in the Pharmacotherapy of Insomnia: Pipeline Agents 427

Michael J. Sateia

38. Clinical Trials and the Development of New Therapeutics for Insomnia 436
Gary K. Zammit

39. Practice Models 453

Michael J. Sateia

Appendix: Resources . . . . 463

Index . . . . 465
 Contributors

Sonia Ancoli-Israel Department of Psychiatry, University of California, San Diego, La Jolla,

California, U.S.A.
Donna Arand Dayton Department of Veterans Affairs Medical Center, Wright State
University, Wallace Kettering Neuroscience Institute, and Kettering Medical Center, Dayton,
Ohio, U.S.A.
J. Todd Arnedt Department of Psychiatry and Neurology, University of Michigan, Ann
Arbor, Michigen, U.S.A.
Alan N. Bateson Institute for Membrane and Systems Biology, Faculty of Biological Sciences,
University of Leeds, Leeds, U.K.
Ruth M. Benca Department of Psychiatry, University of Wisconsin-Madison, Madison,
Wisconsin, U.S.A.
Michael Bonnet Dayton Department of Veterans Affairs Medical Center, Wright State
University, Wallace Kettering Neuroscience Institute, and Kettering Medical Center, Dayton,
Ohio, U.S.A.
Richard R. Bootzin Departments of Psychology and Psychiatry, University of Arizona,
Tucson, Arizona, U.S.A.
Kirk J. Brower Department of Psychiatry, University of Michigan, Ann Arbor, Michigan,
U.S.A.
Daniel J. Buysse Neuroscience Clinical and Translational Research Center, University of
Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.
Colleen E. Carney Department of Psychology, Ryerson University, Toronto, Ontario, Canada
Nancy A. Collop Division of Pulmonary and Critical Care, Johns Hopkins University School
of Medicine, Baltimore, Maryland, U.S.A.
Scott E. Cologne American Sleep Medicine, St. Louis, Missouri, U.S.A.
Deirdre A. Conroy Department of Psychiatry, University of Michigan, Ann Arbor, Michigan,
U.S.A.
Kimberly Cote Department of Psychology, Brock University, St. Catharines, Ontario, Canada
Natalie D. Dautovich Department of Psychology, The University of Florida, Gainesville,
Florida, U.S.A.
Haley R. Dillon Department of Psychology, The University of Alabama, Tuscaloosa,
Alabama, U.S.A.
Karl Doghramji Jefferson Sleep Disorders Center and the Department of Psychiatry and
Human Behavior, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.
Joseph M. Dzierzewski Department of Clinical and Health Psychology, University of
Florida, Gainesville, Florida, U.S.A.
xiv Contributors

Jack D. Edinger Psychology Service, VA Medical Center, Department of Psychiatry and

Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, U.S.A.
Jason Ellis Northumbria Centre for Sleep Research, School of Psychology and Sports
Science, Northumbria University, Newcastle upon Tyne, U.K.
Colin A. Espie University of Glasgow Sleep Centre, Sackler Institute of Psychobiological
Research, Southern General Hospital, Glasgow, Scotland, U.K.
Leah Friedman Department of Psychiatry and Behavioral Sciences, Stanford University,
Stanford, California, U.S.A.
Kelleen N. Flaherty Department of Biomedical Writing, University of the Sciences in
Philadelphia, Philadelphia, Pennsylvania, U.S.A.
Peter L. Franzen Sleep Medicine Institute and Department of Psychiatry, University of
Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.
Philip Gehrman Department of Psychiatry, University of Pennsylvania, Philadelphia,
Pennsylvania, U.S.A.
Anne Germain Department of Psychiatry, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania, U.S.A.
Daniel Glaze Baylor College of Medicine, Texas Children’s Hospital Children’s Sleep Center,
Houston, Texas, U.S.A.
Paul B. Glovinsky Cognitive Neurosciences Doctoral Program, Department of Psychology,
The City College of New York, City University of New York, New York, and Department of
Medicine, Section of Psychology, St. Peter’s Hospital, St. Peter’s Sleep Center, Albany, New
York, U.S.A.
Glen P. Greenough Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, U.S.A.
Emily A. Grieser Department of Psychology, University of North Texas, Denton, Texas,
U.S.A.
Allison G. Harvey Department of Psychology, University of California, Berkeley, California,
U.S.A.
Bobbi Hopkins Baylor College of Medicine, Texas Children’s Hospital Children’s Sleep
Center, Houston, Texas, U.S.A.
Brooke G. Judd Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, U.S.A.
Andrew D. Krystal Insomnia and Sleep Research Laboratory, Department of Psychiatry and
Behavioral Sciences, Duke University School of Medicine, Durham, North Carolina, U.S.A.
Damien Leger Sleep and Vigilance Center, Hotel Dieu de Paris, Assistance Publique
Hopitaux de Paris and University Paris Descartes, Faculty of Medicine, Paris, France
Kenneth L. Lichstein Department of Psychology, The University of Alabama, Tuscaloosa,
Alabama, U.S.A.
Rachel Manber Psychiatry & Behavioral Sciences, Stanford, California, U.S.A.
W. Vaughn McCall Department of Psychiatry and Behavioral Medicine, Wake Forest
University School of Medicine, Winston-Salem, North Carolina, U.S.A.
Christina S. McCrae Department of Clinical and Health Psychology, University of Florida,
Gainesville, Florida, U.S.A.
Douglas E. Moul Department of Psychiatry, Louisiana State University at Shreveport School
of Medicine, Shreveport, Louisiana, U.S.A.
Martin S. Mumenthaler Department of Psychiatry and Behavioral Sciences, Stanford
University, Stanford, California, U.S.A.
Contributors xv

David N. Neubauer Department of Psychiatry, Johns Hopkins Bayview Medical Center,

Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.
Eric A. Nofzinger Sleep Neuroimaging Research Program, University of Pittsburgh School
of Medicine, Pittsburgh, Pennsylvania, U.S.A.
Jason C. Ong Department of Behavioral Sciences, Rush University Medical Center, Chicago,
Illinois, U.S.A.
Slobodanka Pejovic Sleep Research and Treatment Center, Department of Psychiatry, Penn
State University College of Medicine, Hershey, Pennsylvania, U.S.A.
Michael Perlis Department of Psychiatry, University of Pennsylvania, Philadelphia,
Pennsylvania, U.S.A.
Wilfred R. Pigeon Sleep and Neurophysiology Research Lab, University of Rochester
Medical Center, Rochester, New York, U.S.A.
Kathryn J. Reid Department of Neurology, Feinberg School of Medicine, Northwestern
University, Chicago, Illinois, U.S.A.
Dieter Riemann Center for Sleep Research and Sleep Medicine, Department of Psychiatry,
Freiburg University, Freiburg, Germany
Timothy Roehrs Sleep Disorders and Research Center, Henry Ford Hospital, and
Department of Psychiatry and Behavioral Neuroscience, School of Medicine, Wayne State
University, Detroit, Michigan, U.S.A.
Thomas Roth Sleep Disorders and Research Center, Henry Ford Hospital, and Department
of Psychiatry and Behavioral Neuroscience, School of Medicine, Wayne State University,
Detroit, Michigan, U.S.A.
Meredith E. Rumble Department of Psychiatry, University of Wisconsin-Madison, Madison,
Wisconsin, U.S.A.
Bruce Rybarczyk Department of Psychology, Virginia Commonwealth University,
Richmond, Virginia, U.S.A.
Robert L. Sack Oregon Health and Science University, Portland, Oregon, U.S.A.
Michael J. Sateia Department of Psychiatry, Dartmouth Medical School, Lebanon, New
Hampshire, U.S.A.
Michael H. Silber Center for Sleep Medicine and Department of Neurology, Mayo Clinic
College of Medicine, Rochester, Minnesota, U.S.A.
Shauna L. Shapiro Department of Counseling Psychology, Santa Clara University, Santa
Clara, California, U.S.A.
Leisha J. Smith Department of Psychology, University of Arizona, Tucson, Arizona, U.S.A.
Michael T. Smith Department of Psychiatry and Behavioral Sciences, Behavioral Sleep
Medicine Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.
Arthur J. Spielman Cognitive Neurosciences Doctoral Program, Department of Psychology,
The City College of New York, City University of New York, New York; Center for Sleep
Medicine, Department of Neurology, New York Presbyterian Hospital, Weill Cornell Medical
College, New York; and Center for Sleep Disorders Medicine and Research, Department of
Pulmonary Medicine, New York Methodist Hospital, Brooklyn, New York, U.S.A.
Lisa S. Talbot Department of Psychology, University of California, Berkeley, California,
U.S.A.
JoLyn I. Tatum Department of Psychology, University of North Texas, Denton, Texas, U.S.A.
Daniel J. Taylor Department of Psychology, University of North Texas, Denton, Texas, U.S.A.
xvi Contributors

Mario Terzano Department of Neurology, University of Parma, Parma, Italy

Alexandros N. Vgontzas Sleep Research and Treatment Center, Department of Psychiatry,
Penn State University College of Medicine, Hershey, Pennsylvania, U.S.A.
Emerson M. Wickwire Center for Sleep Disorders, Pulmonary Disease and Critical Care
Associates, Columbia, Maryland, U.S.A.
Chien-Ming Yang Department of Psychology, The Research Center for Mind, Brain &
Learning, National Cheng-Chi University, Taipei, Taiwan
Gary K. Zammit Clinilabs, Inc., Sleep Disorders Institute, Columbia University College of
Physicians and Surgeons, New York, New York, U.S.A.
Phyllis C. Zee Department of Neurology, Feinberg School of Medicine, Northwestern
University, Chicago, Illinois, U.S.A.
Jamie M. Zeitzer Department of Psychiatry and Behavioral Sciences, Stanford University,
Stanford, and Psychiatry Service, VA Palo Alto Health Care System, Palo Alto, California,
U.S.A.
c01 IHBK059-Sateia March 28, 2010 8:11 Char Count=

1 Introduction: History, Definition, and

Epidemiology
Michael J. Sateia
Department of Psychiatry, Dartmouth Medical School, Lebanon, New Hampshire, U.S.A.

The worst thing in the world is to try to sleep and not to.
F. Scott Fitzgerald

HISTORY
Fitzgerald succinctly captured the feelings of many chronic insomnia sufferers who labor nightly
to achieve the solace and restoration of a good night’s sleep. History is replete with examples of
the tragedies and anguish wrought as a result of insomnia. In one of the earliest known pieces
of literature, the Epic of Gilgamesh, the epic hero and ruler of the first known civilization is
beset by sleeplessness (1). In the biblical tale of Job, God inflicts insomnia on Job, causing him
to lament: “When I lie down, I say, ‘when shall I arise, and the night be gone?’ and I am full of
tossings to and fro unto the dawning of the day.”
The earliest recorded discussion of insomnia as a medical symptom can be traced to
Hippocrates (2), who recognized perturbations of sleep as a sign of disease. However, it is likely
that insomnia was being treated with opium and herbal preparations well prior to the rise of
Greek civilization (3). During much of the past two millennia, insomnia has been viewed as
a secondary phenomenon, attributable to a variety of causes. Disturbances of sleep have, for
millennia, been associated with an unquiet mind, in the form of guilt, vexation or rumination.
Examples of this are commonly cited in literature, such as in the works of Shakespeare, when
Romeo’s advisor, Friar Lawrence, notes: “Care keeps his watch in every old man’s eye, and
where care lodges, sleep can never lie.” Environmental factors such as noise, light, temperature,
or characteristics of the bed have been blamed. Benjamin Franklin, a noted insomniac, would
remove himself from bed and allow it to air so that the sheets might cool (4). Charles Dickens,
another insomnia sufferer, would sleep only in the exact middle of north-facing beds (5). Dickens
often wandered the streets of London during the night, providing a source of inspiration for
many of his characters and scenes. Insomnia became the subject of increasing medical attention
in Victorian England, when the queen herself was reportedly prescribed cannabis for sleep. An
article from the British Medical Journal of 1894 (6) lamented: “The hurry and excitement of
modern life is held to be responsible for much of the insomnia of which we hear; and most of
the articles and letters are full of good advice to live more quietly and of platitudes concerning
the harmfulness of rush and worry. The pity of it is that so many people are unable to follow
this good advice and are obliged to lead a life of anxiety and high tension.”
As Horne (5) points out in a 2008 essay, it is remarkable that, despite the widely held
notion that sleep disturbance was the product of psychological factors, “cures” for the affliction
were overwhelmingly pharmacological in nature. Opiates, alcohol, and herbals, such as valerian,
were likely used to treat insomnia in Sumerian and Greek civilizations, and continued to occupy
a central role in this respect (e.g., laudanum, a combination of opioid and alcohol) until the late
19th century when they gradually became supplanted by newer compounds such as bromides,
chloral hydrate, and later, barbiturates.
The conceptualization of insomnia in the first half of the 20th century was largely domi-
nated by the psychoanalytic view of insomnia as a psychoneurotic symptom, treatable, in theory,
through analysis. This view perpetuated the long-standing perception of insomnia as a symptom
secondary to psychological distress or other primary conditions. Nevertheless, the most widely
used therapies during this period were barbiturate and like compounds such as glutethimide
c01 IHBK059-Sateia March 28, 2010 8:11 Char Count=

2 SATEIA

or ethchlorvynol. Development of benzodiazepine drugs in the 1960s subsequently gave rise to

the current pharmacological approach to insomnia.
The view of insomnia as a secondary symptom has largely persisted, even to the present
day. However, as our understanding of the biological and psychobehavioral characteristics of
the condition has grown, greater emphasis has been placed on insomnia as a disorder in its
own right, with a pathophysiology that may be, in many respects, independent of the identified
“primary” condition. This view was elaborated in the NIH Consensus Statement (7) on chronic
insomnia, which recommended that the term “comorbid” replace “secondary” in describing
associated conditions. This important operational distinction is discussed later in this volume.

DEFINING INSOMNIA
For much of the modern era of sleep medicine, the field has suffered from a lack of a compre-
hensive, widely accepted and utilized definition of insomnia. This absence has resulted in a
considerable degree of heterogeneity in definitions and, hence, difficulties in comparing clinical
or research samples of “insomnia.” There are a number of components that may be considered
in a general definition of insomnia. These include: (1) symptom profile—most definitions have
historically included problems getting to sleep and staying asleep, the latter including early
awakening. There continues to be debate as to whether nonrestorative sleep complaints should
be included in this definition; (2) chronicity—most modern-day definitions have distinguished
between acute and chronic insomnia, although the exact durations that separate these have
varied significantly from as short as two weeks to as long as six months. Historically, some have
suggested that the term insomnia be reserved only for chronic disturbances; (3) subjective ver-
sus objective findings—although it has long been recognized that insomnia is in many respects,
a highly subjective experience, researchers and some clinical approaches have attempted to
define insomnia by means of objective parameters such as sleep latency, number of awaken-
ings, wake time after sleep onset or total sleep time. At present, quantitative, objective criteria
are employed primarily in research settings, while clinical diagnostic criteria rely solely on sub-
jective complaints; (4) frequency—there has been wide variability with respect to application
of frequency criteria. Presently, neither the Diagnostic and Statistical Manual of Mental Disor-
ders, fourth edition (DSM-IV) (8) nor the International Classification of Sleep Disorders, second
edition (ICSD-2) (9) include a frequency criterion; (5) presence of daytime consequences–while
it has long been understood that complaints of daytime symptoms and dysfunction are one of
the major complications of insomnia, inclusion of these consequences has not been a standard
component of many research criteria until recent years. Both DSM-IV and ICSD-2 include a
requirement of daytime dysfunction.
The modern-day definitions of insomnia can be traced to the 1979 publication of the
Diagnostic Classification of Sleep and Arousal Disorders (10). It is of note that this volume does
not, in fact, offer a general definition of insomnia but only describes features specific to each
particular diagnosis. The insomnia diagnoses are clumped within a single category of disorders
of initiating and maintaining sleep (DIMS). There are no specific diagnostic criteria other than
presence of a DIMS and descriptors of key characteristics that are focused largely on presumed
etiologies. The first edition of the International Classification of Sleep Disorders (11) did not
offer a general definition of insomnia, other than to describe degrees of severity in terms of “a
. . . complaint of an insufficient amount of sleep or not feeling rested.” ICSD-1 does include a
requirement of “a complaint of decreased functioning during wakefulness” with some (though,
curiously, not all) insomnia related diagnoses.
The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)
specifically includes difficulty initiating or maintaining sleep, as well as nonrestorative sleep
in its insomnia criteria. It also includes minimum one-month duration and a requirement that
the disturbance results in “clinically significant distress or impairment in social, occupational,
or other important areas of function.” The 2005 revision of the ICSD (second edition) was the
first to include explicit general criteria for insomnia (Table 1). The criteria include the unique
addition of a requirement of adequate opportunity and circumstances to sleep, drawing a
bright line between insomnia and insufficient sleep syndromes. All insomnia disorders must
be of at least one-month duration, excepting adjustment insomnia, which must be of less than
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INTRODUCTION: HISTORY, DEFINITION, AND EPIDEMIOLOGY 3

Table 1 Standardized Criteria for Defining Insomnia

A. A complaint of difficulty initiating sleep, difficulty maintaining sleep, or waking up too early, or sleep that is
chronically nonrestorative or poor in quality. In children the sleep difficulty is often reported by the
caretaker and may consist of observed bedtime resistance or inability to sleep independently.
B. The above sleep difficulty occurs despite adequate opportunity and circumstances for sleep.
C. At least one of the following forms of daytime impairment related to the nighttime sleep difficulty is
reported by the patient:
i Fatigue/malaise;
ii Attention, concentration, or memory impairment;
iii Social/vocational dysfunction or poor school performance;
iv Mood disturbance/irritability;
v Daytime sleepiness;
vi Motivation/energy/initiative reduction;
vii Proneness for errors/accidents at work or while driving;
viii Tension, headaches, and/or GI symptoms in response to sleep loss; and
ix Concerns or worries about sleep.

Source: From Ref. 9.

three months duration. These criteria also identify specific daytime consequences, which must
occur as a result of the sleep disturbance. A companion of sorts to the ICSD-2 criteria is the
Research Diagnostic Criteria (RDC) (12) for insomnia. The general criteria of the RDC are
essentially identical to those of the ICSD-2. The extensive review of criteria undertaken as
part of the development of the RDC examined the frequency with which various diagnostic
criteria were utilized for subject selection in the 165 insomnia papers selected. These data
are reproduced in Figure 1. Research studies have typically included objective PSG criteria as
criteria for inclusion in insomnia studies. This begs the question of whether objective criteria
should be applied to clinical populations as well. In research environments, such criteria allow
for establishment of more uniform and highly specific populations, essential to the research.
In the clinical setting, however, effective application of such objective criteria is fraught with
significant problems. These complications are best encapsulated by the oft-cited observation
that not every (objectively) poor sleeper has insomnia and not every insomniac has (objectively)
poor sleep. Indeed, there are many individuals who suffer great distress as a result of perceived
sleep disturbance who would not meet typical objective (e.g., PSG) criteria for “insomnia” (e.g.,
patients with paradoxical insomnia), while many others who would meet such criteria have no
insomnia complaints. Thus, degree of distress, perhaps to a greater extent than any objective
changes, seems to dictate the presence or severity of this condition.
Investigations of insomnia have, for some time, identified this discrepancy between objec-
tive findings and subjective perception of sleep in patients with insomnia as characteristic of
the condition (13,14). Persons with insomnia most often overestimate the degree of sleep dis-
turbance in comparison to objective (polysomnographic or actigraphic) criteria. Thus, sleep
latency, frequency of awakening and amount of wake after sleep onset are overestimated, while
total sleep time is underestimated. This discrepancy is observed at its greatest magnitude in
paradoxical insomnia, a condition in which sleep is objectively normal or near normal (by
standard PSG scoring criteria), while subjective perception suggests very little or no sleep.
While there is no well-established explanation for this discrepancy, emerging data on alter-
ation of biological and cognitive activity in the sleep of chronic insomnia patients (discussed in
later sections) may help explain why PSG-defined sleep may be misperceived as wake in this
population.

Nonrestorative Sleep
Nonrestorative sleep (NRS) represents a little-investigated complaint that has been catego-
rized in both ICSD-2 and DSM-IV with more standard insomnia symptoms of initiation and
maintenance problems. ICSD-2 references sleep that is “chronically nonrestorative and poor in
quality” (9). Thus, the affected individual is required to invoke a causal relationship between
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4 SATEIA

Sleep diary results

Insomnia samples
PSG vs subjective sleep estimates
Normal sleepers

Exclude primary sleep disorders

Sleep-related daytime sx

Exclude circadian disorders

PSG findings

Frequency criteria

Self-reported SOL, TST, etc.

Medication exclusions

Presence of DIMS sx

Psychiatric exclusions

Medical exclusions

Duration criteria

Diagnostic criteria

0 10 20 30 40 50
% of samples

Figure 1 Criteria used for Sample Selection. Source: From Ref. 12.

the poorly defined nocturnal disturbance and daytime symptoms. When complaints of non-
restorative sleep are associated with other insomnia complaints (trouble falling or staying
asleep), this etiologic leap may seem relatively straightforward. In the absence of these more
typical insomnia complaints, patients may experience “light” sleep (a vaguely defined sense of
partial/intermittent wakefulness) or no specific nocturnal complaints at all. In these cases, the
etiologic association would seem significantly more tenuous. Much of the available data on NRS
is epidemiologic in nature (15,16). The subject has also been recently reviewed (17). Although
the definitions applied in such studies typically include the criterion that the complaint occurs
“despite normal sleep duration,” this may not adequately account for individuals with longer
sleep requirements who are, in effect, sleep-deprived. Absent objective assessment of sleep, the
possibility of other, unidentified sleep disorders must also be considered. In this regard, it is
noteworthy that one survey of NRS (16) found that this group has a threefold higher rate of
excessive daytime sleepiness complaints, a finding more often associated with sleep disorders
other than insomnia. Many of the questions utilized to define NRS focus on morning symp-
toms (“not feeling rested on awakening,” “ease in getting started” or “waking up exhausted or
fatigued”), perhaps reflecting more of an issue of high sleep inertia in some, as opposed to truly
nonrestorative sleep.
The estimated prevalence of nonrestorative sleep is in the range of approximately 10%
(16). However, when the prevalence of NRS, in the absence of any other insomnia symptoms,
is examined, the prevalence drops to approximately 1% to 2%. Thus, it seems likely that there
is a subgroup of individuals who may manifest psychophysiologic disturbance and daytime
consequences similar to those of the more well-defined insomnia population, absent the usual
insomnia complaints. However, this remains poorly characterized and appears likely to repre-
sent a relatively small percentage of the total population of “insomnia” patients.
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INTRODUCTION: HISTORY, DEFINITION, AND EPIDEMIOLOGY 5

CONCLUSION
It seems clear that work remains in achieving a comprehensive and broadly applied definition
of insomnia. While insomnia definitions have varied considerably in the clinical and clinical
research arenas, even greater variability in definition can be found in the epidemiological
research on insomnia. This is discussed below. Although psychological and behavioral aspects
of insomnia will likely remain important components in defining the disorder, current research
in the biology of insomnia holds the promise that more physiologically based definitions may
hold greater sway as we move forward.

EPIDEMIOLOGY
The earliest identified epidemiologic study of insomnia in the modern era of sleep research was
published by Bixler and colleagues in 1979 (18). This study surveyed around 1000 residents of
the Los Angeles area and found a prevalence of “insomnia” of 42.5%. The survey relied solely
on respondents endorsing “insomnia” as a symptom. Since that time, epidemiologic surveys
have become progressively more sophisticated, including criteria that assess symptom profile,
frequency, severity, consequences and other characteristics (e.g., “dissatisfaction with sleep”)
that are considered germane in the current understanding of the disorder. With this increasing
refinement of definition, prevalence data have diminished from the remarkably high percentage
originally described by Bixler.
Detailed discussions of the epidemiology of insomnia have been published elsewhere
(19,20). The influence of varying criteria on prevalence of insomnia has also been reviewed
at length (21,22). Ohayon categorizes the approaches into four major categories: (1) insomnia
as a symptom, with or without frequency and/or severity criteria; (2) insomnia with daytime
consequences; (3) dissatisfaction with quality of sleep; (4) application of formal insomnia diag-
nostic criteria such as DSM-IV or ICSD (Fig. 2). Broadly speaking, use of a symptom criterion
alone expectedly produces the highest prevalence—roughly in the 30% to 40% range. Addition
of severity and/or frequency criteria reduces this to a range of approximately 15% to 25%.
Requirement of daytime consequences produces prevalence rates in the 10% to 15% range.
Similar, if perhaps, slightly lower estimates are observed when “dissatisfaction with quality or
quantity of sleep” is applied. Formal diagnostic criteria yield the lowest estimates—in the 5%
to 6% range.
As discussed above in the Definition section, identifying those characteristics that accu-
rately define this condition can be elusive. Currently, the clear trend in epidemiologic research
is toward requirement of daytime consequences and application of formal diagnostic criteria.
A survey (22) of nearly 25,000 Europeans found that 16.8% of those sampled reported one or
more symptoms of insomnia (difficulty with sleep initiation or maintenance, or nonrestorative
sleep). Addition of a one-month duration criterion reduces this to 15.8%, while further require-
ment of associated daytime consequences yields 11.1% meeting all three criteria. Quite similar
results were reported for a Canadian population (15), beginning with an initial criterion of
dissatisfaction with sleep (17.8%). Addition of an insomnia symptom requirement (sleep ini-
tiation and/or maintenance disturbance) yielded a prevalence of 11.2%. Addition of duration
and daytime consequences criteria further reduces this to 4% to 5%. The complete criteria in
both of the studies cited above approximate DSM-IV/ICSD criteria for chronic insomnia. While
some variability exists, most recent studies have reported similar prevalence when comparable
criteria are employed.

Risk Factors
Numerous factors are associated with higher rates of chronic insomnia. In almost all surveys,
insomnia is reported to be more frequent in women than in men (23–31). Explanations for
this are not clear, although hypotheses range from reporting bias to endocrine differences to
higher prevalence of certain mental disorders (e.g., depression) in women. Likewise, older age
has been found to be highly associated with chronic insomnia (24,25,32). This is certainly not
surprising in light of the multiple factors that also covary with age, including medical illness,
pain, medication use, and increased prevalence of other sleep disorders. In fact, some data
suggest that it is largely these covariates, rather than age itself, that are responsible for the
increased prevalence observed in later life (33).
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6 SATEIA

Insomnia symptoms

-Presence: 30–48%
-At least 3 nights/week or often
or always: 16–21%
-Moderately to extremely: 10–28%

Insomnia symptoms +
daytime consequences
9–15%

Dissatisfaction with sleep

quality or quantity
8–18%

Insomnia diagnosis
6%

Figure 2 Average prevalence of insomnia symptoms and diagnoses. Source: From Ref. 21.

Unemployment and socioeconomic deprivation have been strongly associated with

chronic insomnia (34). Various markers such as educational level and income have been
employed as socioeconomic markers (35). However, confounders such as higher rates of other
medical and psychiatric comorbidities, limited access to health care, medications, ethnicity,
and occupational status that covary with SE status must be considered in interpreting this
association.
Mental disorders are the most commonly associated comorbid conditions in chronic
insomnia. Early epidemiologic studies generally reported significant associations between
insomnia and depression and anxiety (18,25). Data from the 1989 National Institute of Men-
tal Health (NIMH) Epidemiologic Catchment Area study (36) found a prevalence of insomnia
(≥ 2 weeks of sleep initiation, maintenance or early awakening plus report to health profes-
sional or treatment or daytime consequences) of 10.2%. Forty percent of those had a comorbid
psychiatric disorder, predominantly major depression and anxiety disorders. A large-scale (N
= 5622) survey (31) of the French population found an overall prevalence of insomnia (initia-
tion, maintenance or nonrestorative sleep complaint of > 1 month plus daytime consequences)
of 18.6%. More than 40% of these individuals exhibited comorbid psychopathology (DSM-IV
Insomnia related to mental disorder = 16.6%; DSM-IV depression or anxiety disorder = 27.9%).
Pooled data from several European studies indicate that 48% of respondents meeting criteria
for insomnia also met criteria for a DSM-IV psychiatric disorder diagnosis (21).
The primary interpretation of this strong association between insomnia and mental disor-
ders was, for many years, that psychopathology is a key element in the genesis and maintenance
of chronic insomnia. While that interpretation remains valid, numerous epidemiologic studies
(36–38) exploring the chronological relationship between insomnia and psychiatric illness have
raised the important alternative hypothesis that chronic insomnia may be a key element in the
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INTRODUCTION: HISTORY, DEFINITION, AND EPIDEMIOLOGY 7

genesis and maintenance of psychiatric disorders. This issue is addressed in greater detail in
Chapter 4.
Numerous medical comorbidities have likewise been associated with insomnia. In most
cases, the characteristics of the relationship have not been well-investigated. Chronic pain is a
common condition frequently associated with insomnia (16). A multinational study of almost
19,000 persons found that 40% of those with insomnia complaints reported at least one chronic
pain problem. In this population, chronic pain was associated with greater difficulty getting
back to sleep and shorter duration of sleep, as well as more prominent daytime consequences.
Other medical conditions frequently associated with insomnia include lung disease, cardiovas-
cular diseases and various neurological disorders, especially degenerative diseases and stroke
(39–42). As with mental disorders, the causal relationship between these conditions is undoubt-
edly complex and is yet to be fully elucidated. Some recent studies (43,44) have explored
potential predisposition to cardiovascular disease as a result of chronic insomnia, but results
are preliminary and a causal link between chronic insomnia and incident hypertension is yet to
be clearly established.

DURATION AND COURSE

Chronic insomnia is variously defined as sleep disturbance that lasts longer than one to six
months. However, duration of chronic insomnia is typically measured in years or even decades.
The longitudinal course of insomnia has not been studied extensively. Early epidemiologic
studies (24,45,46) based on retrospective reports indicated that the vast majority of patients had
at least one-year duration, while approximately 40% reported durations of five years or more.
Subsequent longitudinal studies suggest that from 30% to 80% of chronic insomnia patients
show no significant remission over time.
More recent investigations confirm that most affected individuals suffer with this condi-
tion for very long periods. Three-year follow-up of a sample of nearly 400 individuals selected
for insomnia at baseline revealed that the problem was present for a minimum of one year in
almost 75% of the sample (47). Nearly half had the maximum three-year duration. Greater like-
lihood of persistence was associated with increasing severity and age as well as female gender.
A recent analysis of data from the long-term Zurich study (48) examined the course of insomnia
among young adults. Interview intervals ranged from two to six years over the study course.
Of subjects with insomnia duration of one month or longer, 30% had the same diagnosis at a
previous interview, while 99% had some insomnia diagnosis (shorter duration or intermittent
insomnia) previously. Thirty-five percent of one-month insomnia subjects had the diagnosis at
a subsequent interview and 82% had some type of insomnia diagnosis.
In assessing these data, one should bear in mind the fact that only a small percentage of
these patients are actually diagnosed and appropriately treated. Therefore, one can reasonably
assume that much of the chronicity reflects relatively low rates of spontaneous remission, rather
than refractoriness to treatment.

CONCLUSION
Chronic insomnia is a highly prevalent and unremitting condition characterized by complaints
of difficulty initiating or maintaining sleep or sleep that is not restorative. General agreement
exists that the definition must also include the presence of daytime symptoms attributable to
the insomnia. Women, older adults, and persons with psychiatric or medical comorbidities are
at increased risk for chronic insomnia. As discussed elsewhere, chronic insomnia may, in turn,
represent a risk for development of these comorbidities. The duration of chronic insomnia is
generally long, with many individuals experiencing fluctuating levels of sleep disturbance over
decades. Failure of patients to report the problem, and health care providers to identify and
treat it, contributes to persistence of the condition.

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2 Subjective and Objective Daytime Consequences

of Insomnia
Michael Bonnet and Donna Arand
Dayton Department of Veterans Affairs Medical Center, Wright State University,
Wallace Kettering Neuroscience Institute, and Kettering Medical Center, Dayton, Ohio, U.S.A.

The International Classification of Sleep Disorders Second Edition (ICSD-2) (1) requires both
poor sleep and daytime functional compromise for the diagnosis of insomnia. Patients report
numerous consequences of their insomnia, and the ICSD-2 lists the following as diagnostically
sufficient examples:
Fatigue or malaise
Poor attention or concentration
Social or vocational dysfunction
Mood disturbance
Daytime sleepiness
Reduced motivation or energy
Increased errors or accidents
Tension, headache or gastrointestinal symptoms
Continuing worry about sleep
Insomnia produces numerous medical, psychological, and economic deficits in addition to
changes in subjective state and performance, but only the latter two factors, specifically related
to the diagnostic criteria required for a diagnosis of insomnia, will be considered in this chapter.
A section reviewing subjective deficits will be followed by a section examining objective deficits.

SUBJECTIVE MOOD AND PERFORMANCE DECREMENTS

ASSOCIATED WITH INSOMNIA
Medications for sleep have historically been developed to produce efficacy based on decreas-
ing sleep latency or increasing sleep time at night. Mood and performance testing have been
conducted primarily to rule out hangover sedation rather than to demonstrate improvement of
the daytime symptoms reported by patients. In recent years, however, researchers have realized
that successful treatment for insomnia should both improve sleep parameters and reverse the
daytime consequences reported by patients (2). Numerous measures have been developed to
document subjective deficits in patients with insomnia. Categories that have been measured
include mood, anxiety or depression, quality of life, and work-related performance. Sections
reviewing significant subjective deficits will be followed by available data showing treatment
response.

Mood
Dysphoria is commonly reported by patients with insomnia. A number of studies have assessed
various mood components in these patients.

Sleepiness/Fatigue
The most commonly reported mood dimensions have been subjective fatigue and sleepi-
ness. In a review of studies prior to 2000 (3), it was reported that 7 of 12 studies using the
Stanford Sleepiness Scale in insomnia patients found significantly greater sleepiness in patients
as compared to controls. However, as the evaluation of insomnia has evolved, investigators
began to differentiate frank sleepiness (by asking patients if they would actually fall asleep in
a given circumstance using a questionnaire such as the Epworth Sleepiness Scale—ESS) from
fatigue (feeling tired or without energy but not likely to fall asleep). In recent years, the Stanford
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SUBJECTIVE AND OBJECTIVE DAYTIME CONSEQUENCES OF INSOMNIA 11

Sleepiness Scale has been used less frequently in insomnia patients, and a number of more
fatigue-related mood scales and measures have appeared (4). For example, in a study that
compared sleepiness measured by the ESS and fatigue measured by the Tiredness Symptoms
Scale (TSS), insomnia patients had sleepiness levels on the ESS that were nonsignificantly lower
than controls and significantly lower than sleep apnea patients whereas their TSS scores were
nonsignificantly higher than sleep apnea patients and significantly higher than controls (5).
These findings of lower sleepiness despite increased fatigue are consistent with objective sleepi-
ness data from the Multiple Sleep Latency Test. A recent review found that none of 12 studies
comparing objective daytime sleepiness in insomnia patients with controls found significantly
greater objective sleepiness in the insomnia patients (6). These findings suggest that sleepiness
and fatigue can be diagnostically differentiated if patients are given sufficient descriptive lati-
tude and that insomnia patients view their problem as more of a fatigue problem rather than
excessive sleepiness.
Fatigue has been measured from general mood scales such as the Profile of Mood States
(POMS), which has a specific fatigue scale, in addition to more recently developed specific scales
such as the Fatigue Severity Scale (FSS). Significant increases in fatigue have been reported in
insomnia patients in four (3,7–9) of seven studies (10–12).

Other Mood Changes

Insomnia patients frequently have more negative mood on a number of dimensions. Other
scales from the POMS that have been significantly different in insomnia patients compared
with controls include elevated Confusion, Tension/Anxiety, and Depression and reduced Vigor
(3,10–12).
Recent studies have begun to report changes in mood associated with insomnia treatment.
For example, studies of eszopiclone 2 and 3 mg have found that there was a significant increase in
daytime alertness, physical well-being, and ability to function but no improvement in morning
sleepiness at the end of treatment compared with parallel placebo groups in primary and
comorbid insomnia (13,14). Krystal et al. (15), in a six-month study of eszopiclone 3 mg, reported
significantly improved daytime subjective alertness and physical well-being in their treatment
group that continued until the end of medication administration compared with a parallel
placebo group. Another study (16) has shown that zolpidem extended release 12.5 mg prn
for six months was effective in reducing morning sleepiness (and ESS scores) and improving
concentration, with changes that were statistically significant for each of the six months of the
study (except for the sixth month for the ESS).

Anxiety and Depression

Most research studies have examined patients with primary insomnia, thereby excluding
patients with specific clinical mood disorders such as anxiety or depression. However, even
with exclusions for such clinical pathology, studies that have utilized traditional measures of
personality such as the Minnesota Multiphasic Personality Inventory (MMPI), Hamilton Depres-
sion Rating Scale, Beck Depression Inventory, and the depression scale from the POMS have
consistently shown that patients with primary insomnia have significantly elevated scores on
the depression subscale compared to controls. Nine of 12 studies reviewed reported significantly
higher scores in insomnia patients compared with controls (17–25) [negative studies (26–28)].
One of the studies found equivalent elevations in the MMPI in insomnia patients regardless
of whether their insomnia was psychologically based (psychophysiological insomnia) or med-
ically based (including insomnia with sleep apnea, periodic limb movements, or restless legs)
(24). However, these MMPI scale elevations typically do not place the insomnia patients into
the realm of clinical pathology, as such patients have typically been excluded.
Anxiety is also frequently elevated in patients with insomnia. Six of 12 studies have
reported significantly elevated anxiety in insomnia patients based on the MMPI (17,21,23–25,29)
[negative (18–20,26–28)] and two have reported elevations based on the Spielberger State-Trait
Anxiety Inventory (30,31). Studies have not reported decreases in anxiety or depression after
insomnia treatment. However, in clinically depressed patients, treatment of both depression
and insomnia has been shown to produce a more rapid improvement in depression (32).
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12 BONNET AND ARAND

Quality of Life
There are several means of assessing quality of life (QOL) in patients. Some studies have used
one or two specific questions whereas others have used QOL scales such as the Quality of
Life in Insomnia Scale (4). One QOL scale that has been widely used in diverse patient pop-
ulations is the Medical Outcomes Study Short Form (SF-36) (33). The SF-36 assesses physical
functioning, limitations due to physical health problems, bodily pain, general health percep-
tion, vitality, social functioning, limitations due to emotional health problems, and mental
health. Patients with insomnia reported decreased QOL compared with normal controls on all
dimensions of the SF-36 (P < 0.0001) (34,35) and SF-12 (36). One study (37) compared SF-36
results in a group of mild and severe insomnia patients with groups of patients diagnosed
with depression or congestive heart failure (CHF). Severe insomnia patients had numerically
greater loss of function than patients with CHF on all of the SF-36 scales except physical func-
tioning. Insomnia patients also reported more physical problems (the first four scales of the
SF-36) than patients with depression (37). Such findings suggest that the subjective dysphoria
and loss of function associated with insomnia is similar to that seen in other significant chronic
illness.
Research studies have also begun to examine changes in QOL with insomnia treatment.
One study found significantly improved ability to function during the day and physical well-
being throughout six months in patients receiving eszopiclone 3 mg compared with placebo in a
double-blind design (15). A study of eszopiclone 1 and 2 mg in elderly insomnia patients found
improved QOL on some subscales at the 2 mg but not the 1 mg dose over two weeks of medica-
tion administration (13). Another study (38) tracked the 3-item subscale of the Insomnia Severity
Index that deals with QOL and functioning in patients receiving indiplon 10 mg, indiplon 20 mg,
or placebo in a double-blind study and found that patients receiving either dose of medication
were significantly improved compared to the placebo group during each of the three months of
the study. The percentage of patients reporting minimal to no daytime impairment was signif-
icantly higher in the active treatment group (73%) versus the placebo group (60%). At the end
of the study approximately 2/3 of the patients in the medication treatment conditions scored
within the normal range on the complete Insomnia Severity Index compared with 38% in the
placebo group, also a significant difference (38). Finally, in a study that evaluated eszopiclone
3 mg or matching placebo under double-blind conditions for six months (39), the complete
SF-36 was administered at baseline and after one, three, and six months. At baseline, patients
had significantly lower values on the SF-36 Vitality, Social Functioning, and Mental Health
scales compared with healthy U.S. population norms. After six months of treatment, patients
taking eszopiclone had significantly improved on these three scales in comparison with the
insomnia patients receiving placebo and were at or above the U.S. population norms. QOL has
also been assessed in a behavioral treatment paradigm (40). In this study, patients with chronic
insomnia who had been treated with pharmacotherapy for 10 years on average were given
cognitive-behavioral therapy or no additional therapy (patients were allowed to either continue
or be withdrawn from their current sleeping medications). At intake, patients were found to
have significantly worse QOL compared with population norms, and this was significant for all
scales on the SF-36 for younger subjects (age 30–49). However, the oldest subjects (age 70–100)
were much closer to population norms and were significantly worse than those norms only
on physical functioning, mental health, vitality, and bodily pain. By the end of the six-month
trial, patients across all ages in the cognitive-behavioral therapy group had significantly better
scores than the control population on physical functioning, mental health, and limitations due
to emotional health problems. Unfortunately, these improvements occurred primarily because
QOL deteriorated in control patients rather than truly improving in the patients with behavioral
therapy.
The studies of QOL are consistent in showing that decrements in insomnia patients can be
reversed with return to normal levels after treatment for as long as six months (the duration of
study trials). There has also been improvement in parallel placebo groups, but improvement in
medication treatment groups has been significantly greater than that seen in the placebo groups.
Improved QOL has implications for decreased health care utilization and improved work per-
formance. One study has actually used QOL improvement as a basis for a determination of cost
effectiveness for long-term treatment of primary insomnia (41).
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SUBJECTIVE AND OBJECTIVE DAYTIME CONSEQUENCES OF INSOMNIA 13

Work Performance
Another means of assessing QOL is to assess job performance or career success in patients
compared to controls. One study found that self-reported poor sleepers in the Navy received
significantly fewer promotions and were less likely to be recommended for reenlistment (42).
Questionnaire studies have shown that subjectively identified patients with insomnia felt more
fatigued and irritated with their children and had more health care consequences on a number of
dimensions (43). Insomnia patients also reported consequences at work including significantly
more errors, significantly more accidents, more absenteeism, and poor efficiency (43,44). How-
ever, a recent study that attempted to replicate the finding of increased absenteeism in insomnia
patients found, in a logistic regression model, that absenteeism based on company sick leave
records was determined only by sex, profession, and depression (45). To some extent these
results may reflect a limitation of questionnaire studies of sleep problems (in which patients
with sleep apnea, other sleep pathology, or untreated depression may also be included in insom-
nia groups). Moreover, subjective responses to queries about accidents and sick leave further
confound results.
Fortunately, careful studies have begun to more clearly identify patients with primary
insomnia. One recent study used the Work Limitations Questionnaire (46) to assess time
demands, physical demands, mental demands, output demands, and work productivity loss
in primary insomnia patients given eszopiclone 3 mg or placebo in a double-blind design for
six months. Patients receiving medication were significantly improved compared with placebo
on all scales for the one to six month average score. Scores at the end of the study were in the
range of normal scores on all of the scales except time demands, but there was large variability.
In another study using the same questionnaire (47), patients given zolpidem extended release
12.5 mg versus placebo in a double-blind study for 12 weeks showed significant improvement
on the time demands and output demands scales at the end of the study. The magnitude of
improvement on these scales was similar in both studies.

OBJECTIVE MEASURES OF PERFORMANCE

Subjective measures clearly support the common perception of poor performance in insomnia
patients. However, it is also important to understand the extent to which these subjective reports
of poor performance are linked to objectively measured psychomotor performance. At least 21
studies have compared performance in patients with insomnia to matched controls on more than
30 different performance tasks (7–12,17–19,26,28,48–57). One review has compared the results
of these insomnia studies with those reported from sleep deprivation studies (one presumption
is that both insomnia patients and sleep deprived individuals have some accumulated sleep
loss) because many of the tests used to compare insomnia patients with normal sleepers have
been used and found sensitive in sleep deprivation studies (6). For convenience, that review
divided the many performance measures into several broad categories: memory, balance, math,
vigilance, hand/eye coordination, and reasoning tasks. These same categories were retained for
the current review.

Memory
Numerous memory tasks have been used to document differences between insomnia patients
and controls. Common short-term memory tasks that have been used include the Digit Symbol
Substitution Task (NS in seven of seven studies), digit span (NS in three of five studies), the
MAST (NS in six of seven reports from two studies), and simple short-term memory (NS in six of
nine studies). The nine studies reporting number of words recalled in an immediate memory task
were reviewed, and data from the four of those that included means plus standard deviations
in comparable patient and control groups were combined to calculate an effect size (58). From
those studies (7–9,53), mean words recalled from normals and insomnia patients were 10.8
and 8.4 words respectively (combined standard deviation of 2.69 with 105 and 185 Ss) giving a
combined t-value of t288 = 7.51 (P < 0.01) and effect size (ES) of 0.91. However, ESs for other types
of memory measures were lower (in the range of 0.28). In studies with long-term recall, insomnia
subjects performed significantly worse than controls in only one of four studies. More recently,
primary insomnia was associated with impairment of procedural memory in comparison to
controls (52). The number of studies showing significant results for various memory variables
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14 BONNET AND ARAND

is low, but the combination of studies with largely nonsignificant results to increase the sample
size produced a significant effect that also had a large ES. Therefore, examination of memory
effects in larger studies is indicated.

Balance
Two studies that have examined balance in insomnia patients and controls have both reported
statistically significant decreases in balance in insomnia patients (10,12) compared with controls,
and ES from the one study with data sufficient to calculate the statistic was 3.1 (12). One
implication of these results is a recent finding that insomnia, in elderly nursing home residents,
is associated with a greater risk of falls, and this risk is not based on the use of sleeping
medication (59). These data also imply that further examination of balance could be important.

Math
Computational ability has been infrequently examined in insomnia patients. None of the three
studies that have examined ability to perform additions have found significant decrements in
insomnia patients compared with controls.

Vigilance
True vigilance tasks and simple and choice reaction time tasks were included with vigilance
tasks. Two significant vigilance results were found from six studies; two significant 4-choice
reaction time results were found from four studies, and one significant simple reaction time
result was found from eight studies. Of studies reporting mean and standard deviation for
simple reaction time (10,11), reaction times from normals and insomnia patients were 290 and
364 msec, respectively (combined standard deviation of 256 msec with 56 Ss in both groups),
giving a small ES of 0.288. One study that reported nonsignificant differences for simple reaction
time in large groups (60) did report significantly slower response latencies for insomnia patients
compared with controls for responses to more complex decisions.

Hand/Eye Coordination
Hand/eye coordination tasks included tremor, card sorting, Purdue pegboard, tapping, line
tracing, trail making, and visual resolution. Of 13 total studies in this area, only one statistically
significant result, for the single study of line tracing (17), was found.

Reasoning
Four studies reported logical reasoning or proofreading in insomnia patients versus controls
but no statistically different results were reported.

Sleepiness/Alertness
Objective sleepiness/alertness is commonly measured with the Multiple Sleep Latency Test
(MSLT) or Maintenance of Wakefulness Test (MWT). A number of studies have examined the
ability of insomnia patients to fall asleep using the MSLT. These studies are of particular interest
because, if patients suffer mainly from reduced sleep at night, their daytime nap latencies
should be significantly reduced (61). However, if patients primarily suffer from physiological
hyperarousal, their daytime nap latencies should be increased. Twelve studies were found where
daytime nap latency was compared between insomnia patients and study controls (7,9,17–
19,26,49–51,62–64). Sleep latency was not significantly reduced in insomnia patients as compared
to controls in any study. Sleep latency was significantly increased in insomnia patients as
compared to controls in 6 of the 12 studies. Of the 12 studies, 7 used a relatively standard
protocol and reported both means and standard deviations for the groups. When the data for
these seven studies were combined, the average sleep latency for insomnia patients (N = 192)
was 13.5 (±4.9) minutes and for controls (N = 167) was 12.1 (±5.3) minutes. This difference was
statistically significant (t357 = 2.586, P = 0.01). The ES, based on these group data, was 0.27. The
t-value and ES value are both somewhat lower than in studies for which subjects were required
to meet both a subjective and objective sleep criterion to be included (6). In general, these data
are consistent with subjective data that show insomnia patients report increases in subjective
sleepiness and more specifically, fatigue, without objective sleepiness.
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SUBJECTIVE AND OBJECTIVE DAYTIME CONSEQUENCES OF INSOMNIA 15

SUMMARY
Extensive psychomotor performance and sleepiness data recorded from insomnia patients over
the past 25 years have shown that these patients have marginal decreases in performance. Of
functions assessed, decrements in balance accompanied by increased falls in elderly insomnia
patients are the most persuasive. Several individual studies and the pooled analysis of short-
term memory data do suggest the likelihood of some memory deficits in patients. Unfortunately,
objective performance indicators have only been reported in treatment studies in the negative
sense (absence of decrements shortly after awakening rather than improved performance during
the day). The large number of nonsignificant results along with the finding that insomnia
patients are significantly less sleepy than controls on the MSLT suggests that insomnia is not
the same as sleep deprivation. Since many of the tests used to compare insomnia patients with
controls have been selected secondary to their sensitivity to sleep deprivation, it is possible
that the psychomotor tests employed have not been the optimal measures for assessment of
impairment and that different or more specific tests might provide additional information. In
addition, the results from memory tests suggest that future studies of performance in insomnia
patients can benefit from larger sample sizes to more easily demonstrate deficits.
It is also the case that the picture of performance in patients with the insomnia is much
different when one examines objective performance measures than when one examines subjec-
tive measures such as mood or QOL. It will be important to reconcile the differences between
data sets that should reasonably be expected to correlate with one another. One means of doing
this is to compare objective and subjective results from within the same study. For example,
one study (8) both asked patients to subjectively rate their performance ability and employed
several objective performance measures. As expected, insomnia patients subjectively rated their
performance compared with their real capacity as significantly worse than did control subjects
with a large effect size (ES = 1.20). However, of eight objective performance measures including
memory tests, motor tests, reaction time, and executive function, insomnia patients performed
significantly worse than normals on only one of the four memory tests (digit span), and the
median ES for the performance tests was low (around 0.4). In the same study, insomnia patients
had reported a significantly longer subjective sleep latency compared to the controls (ES = 1.32)
while their objective PSG sleep latency was actually nonsignificantly shorter than the controls
(ES = −0.05). Similarly, the insomnia patients reported subjectively that their total sleep time
was significantly shorter than the controls (ES = 2.15) while their actual total sleep time was not
significantly different from the controls (ES = 0.4). These objective and subjective sleep data are
very consistent with the objective and subjective performance data reported above and suggest
that the same mechanism that results in patients subjectively reporting much worse sleep than is
corroborated objectively may also operate similarly when subjective performance is compared
with objective psychomotor performance measures.

CONCLUSIONS AND RECOMMENDATIONS FOR FURTHER RESEARCH

Patients with insomnia are differentiated from normal sleepers with a short sleep requirement
based on their complaint of daytime dysphoria and poor performance. Subjective report mea-
sures have consistently shown that insomnia patients have reduced QOL in all dimensions and
believe that their work and social performance is greatly limited. Recently, treatment studies
have begun to focus on QOL and have shown that pharmacological treatment and, possibly,
behavioral treatment can produce improvement in QOL with a return to baseline levels. The
inability to show consistent decrements in objective daytime alertness and performance has
limited more effective evaluation and treatment of insomnia for many years. Objective per-
formance deficits, like objective sleep deficits, have been difficult to identify in these patients.
A common limitation of these studies is smaller sample size (60). The ability to observe an
overall significant decrement in short-term memory performance by pooling over a number
of largely nonsignificant previous studies suggests that evaluation of memory and balance, at
least, in multicenter studies could provide evidence of significantly improved psychomotor
performance secondary to treatment. Furthermore, the extent to which the subjective and objec-
tive deficits reported by the patients are associated with partial sleep deprivation/sleepiness
versus hyperarousal requires additional investigation. In a study that correlated MSLT results
with sleep, demographic, and performance/mood variables (65), it was found that insomnia
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16 BONNET AND ARAND

patients with longer MSLT values (higher daytime alertness) also had longer subjective sleep
latency at night and higher anxiety scores on the POMS. Such findings link dysphoria and
poor subjective sleep with hyperarousal rather than sleepiness and suggest that performance
deficits in insomnia patients will be more apparent on psychomotor performance tasks that are
sensitive to central activation rather than sleepiness. Because many of the tests used in insomnia
research have evolved from sleep deprivation research, they may simply be inappropriate or
irrelevant for use in insomnia patients. The development of more appropriate and sensitive
tests for insomnia-related impairment may allow us to better define the relationship between
objective and subjective consequences of the condition.

ACKNOWLEDGMENT
This study was supported by the Dayton Department of Veterans Affairs Medical Center, Wright
State University School of Medicine, and the Sleep-Wake Disorders Research Institute.

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3 Socioeconomic Impact of Insomnia

Damien Leger
Sleep and Vigilance Center, Hotel Dieu de Paris, Assistance Publique Hopitaux de Paris and University Paris
Descartes, Faculty of Medicine, Paris, France

INTRODUCTION
Insomnia is now widely recognized as one of the major complaints associated with numerous
psychological and physical diseases in the general population and in primary care patients
around the world (1–4). Despite insomnia’s high prevalence, it is still frequently unrecognized
as a serious health threat by health professionals. One challenge is the fact that insomnia
is frequently considered as a symptom, rather than as a true disease, and it is not clear to
practitioners whether it is a symptom or a disease. Another challenge is that it is often difficult
for patients and for health professionals to understand when insomnia is severe enough to
require a treatment. In addition, there is still insufficient knowledge about the management of
insomnia. In the last decade, several consensus meetings about insomnia and its recognition,
diagnosis, and treatment have published recommendations (5–10). All these consensus groups
have underlined the effect of insomnia on public health and the need to better encompass the
consequences of insomnia on work, economics, and health-related quality of life (QOL).
The aim of this chapter was to carefully describe the possible links between insomnia and
public health concerns and to point out what are the certitudes and the missing data on the
consequences of insomnia on work, economics, and health-related QOL.

EPIDEMIOLOGY OF INSOMNIA AND CONSEQUENCES ON ECONOMICS

Insomnia is very prevalent in the general population, and this prevalence contributes to the
global economic impact of insomnia. In the last decade, several national and international
studies have underscored the universal presence of insomnia.
At the national level, to assess the prevalence of insomnia, Ohayon and Smirne (11)
conducted in 2002 a study with a representative sample of the U.K. population composed of
3970 individuals aged 15 years or older. In this study, insomnia symptoms were reported by
27.6% of the sample. Sleep dissatisfaction was found in 10.1% of the sample and insomnia
disorder was diagnosed in 7% of the sample. The use of sleep-enhancing medication was
reported by 5.7% of the sample. Leger et al. (12) in an epidemiological questionnaire survey
of a representative sample of the French population that included 12,778 individuals found a
prevalence of insomnia in 19% of the individuals surveyed, with 9% presenting severe insomnia
[at least two symptoms of insomnia according to the DSM-IV (Diagnostic and Statistical Manual
of Mental Disorders, 4th edition) definition]. Kim et al. (13), in a study with a representative
sample of the general population of Japan that included 3000 individuals, found a prevalence of
insomnia in 21.4% of the individuals. In the United States, the most recent study was conducted
in 2004 by the National Sleep Foundation on a representative sample of 1506 subjects older
than 18 years. Twenty-one percent of the sample complained of insomnia, according to the
ICSD (International Classification of Sleep Disorders) definition, but only 9% had insomnia
and daytime consequences (14). A compilation of the recent studies was conducted in 2002 by
Ohayon (1), who reported the prevalence of insomnia in one-third of the general population.
However, from 16% to 21% of the general population have insomnia only at least three times a
week, from 13% to 17% of the general population qualify their trouble as important or major,
and from 9% to 13% of the general population have insomnia and its daytime consequences.
International comparisons have also been made using the same protocol. They demon-
strated the universality of the insomnia complaint: Ohayon (15), in a survey of 25,580 indi-
viduals from seven European countries, observed that the prevalence of nonrestorative sleep
seems to follow a north-south line, with the United Kingdom having the highest prevalence
and Spain the lowest. He identified factors such as sleeping habits, climate, and cultural impact
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on responses to questionnaires to explain these differences (14). Soldatos et al. (2), in a survey
that included 35,327 questionnaires and subjects from 10 countries, found that 31.6% of subjects
had “insomnia” while another 17.5% could be considered as having “subthreshold insomnia.”
More recently, Leger et al. (3) in a survey comparing sleep disorders among representative
samples of 3962 North Americans, 5005 Europeans, and 1165 Japanese found that insomnia was
significantly higher in the United States (39%) than in Europe (28%) and Japan (21%).

SOCIODEMOGRAPHICS FACTORS CONTRIBUTING TO INSOMNIA

Almost all studies show an increasing prevalence of insomnia with age and a sex ratio in favor
of women (1–7). In a 12,778 sample, Leger et al. (12) found that severe insomnia was almost
twice as high for women as for men (12% vs. 6.3%; p < 0.0001). Older subjects have usually
more severe complaints than do younger subjects. In a representative sample (n = 5622) of
the general population of France aged 15 or older, Ohayon and Lemoine (16) found that the
prevalence of insomnia was more frequent (twice) in subjects 65 years of age or older compared
with subjects younger than 45 years. Moreover, in this last study, 47.1% of subjects older than
65 years reported three symptoms of insomnia compared with 32.2% of subjects younger than
44 years (p < 0.001). However, younger subjects (under 45 years) and females had significantly
more daytime consequences of insomnia than did older subjects and males.
There are few studies which support the link between perceived job stress and the preva-
lence of insomnia. Nakata et al. (17) surveyed 1161 male white-collar employees of a Japanese
electric equipment company by a mailed questionnaire. This study found an overall prevalence
rate of 23.6% for insomnia. Workers with high intragroup conflict [odds ratio (OR): 1.6] and
high job dissatisfaction (OR: 1.5) had a significantly increased risk of insomnia after adjusting
for multiple confounding factors. Low employment opportunities, physical environment, and
low coworker support were also found to be weakly associated with a risk of insomnia among
workers.
The prevalence of insomnia is also generally higher in persons of low socioeconomic status
(17). In the French population, the prevalence of insomnia has been found to be the highest in
the white-collar group (20, 8%) (12). A trend toward lower rates of insomnia in upper level
executives, in liberal professions, and in the farmers group was also found. In a cross-sectional
study including 4868 daytime white-collar workers, Doi et al. (18) similarly showed that poor
sleep was significantly more prevalent in white-collar workers (30–45%) than in the Japanese
general working population. Recently, Gellis et al. (19) investigated the likelihood of insomnia
and insomnia-related health consequences among a sample of at least 50 men and 50 women
in each age decade from 20 to 80+ years old and of different socioeconomic status. Results
indicated that individuals of lower individual and household education were significantly
more likely to experience insomnia, even after researchers accounted for ethnicity, gender, and
age. In addition, individuals with fewer years of education, particularly those who had dropped
out of high school, experienced greater subjective impairment because of their insomnia.

SEEKING HELP FOR INSOMNIA AND ACCESS TO TREATMENTS

Insomniacs, even severe insomniacs, often do not seek treatment. Years ago, a Gallup study
found that only 5% of insomniacs had ever visited a physician to discuss specifically their
sleeping problem and that only 21% had ever taken a prescription medication for sleep (20). In
France, 53% of severe insomniacs versus 27% of subjects with occasional sleep problems reported
that they had ever visited a doctor specifically for insomnia (p < 10−4 ) (21). Many individuals
with sleep dissatisfaction just watch television, read, use nonprescription medication, or drink
alcohol to promote sleep (1). In a survey in the Detroit area of a representative sample of 2181
adults aged between 18 and 45, Johnson et al. (22) found that 13.3% of the sample had used
alcohol as a sleep aid in the past year and 10.1% of the sample an over-the-counter prescription.
Fifteen percent of those who used alcohol as a sleep aid did it for at least one month; however,
the duration of use was short for the majority of users (<1 week). Only 5.3% of the sample
used a prescription medication. However, it was found that 10.8% of French adults regularly
used prescription medication to promote sleep (20). Recently, a consecutive sample (n = 700) of
U.S. adults attending a nonurgent primary care appointment was screened for sleep problems.
A follow-up mailed survey then assessed insomnia symptoms, daytime impairment, beliefs
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SOCIOECONOMIC IMPACT OF INSOMNIA 21

about sleep, medication use, sleepiness and fatigue, and medical help-seeking (23). Aikens
and Rouse conversely found that a high percentage (52%) of patients with probable insomnia
reported discussing this with a physician. Multivariate logistic regression analyses indicated
that discussing one’s probable insomnia with a physician was independently associated with
having a greater number of medical conditions [OR: 2.19 (95% CI: 1.13–4.22)], being more highly
educated [OR: 1.67 (95% CI: 1.11–2.51)], sleeping less per night [OR: 0.71 (95% CI: 0.52–0.96)],
and greater perceived daytime impairment due to insomnia [OR: 2.07 (95% CI: 1.06–4.03)].
Pires et al. (24) compared two studies carried out in Brazil in 1987 and 1995. They showed
that only 12.5% of the Brazilian insomniacs had sought medical help for their sleep problems
or had informed their physician of sleep problems during evaluation of other problems in
1987; this was even less (10.8%) in 1995. In a study carried out in the United States at five
managed care organizations, Hatoum et al. (25) found that only 0.9% of American patients
were seeing physicians due to sleep problems. Of these, only 11.6% were taking prescription
medications specifically for sleep problems and 21.4% were taking over-the-counter medications
for sleep. Moreover, the diagnosis of insomnia is not always followed by treatment. In Germany,
a Nationwide Insomnia Screening and Awareness Study (NISAS-2000) found that close to 50%
of all patients with insomnia did not receive a prescription for a specific insomnia therapy (26).

COMORBIDTY WITH DEPRESSION AND ANXIETY: RESPECTIVE IMPACT

ON ECONOMICS
Insomnia is associated with various medical and psychiatric conditions. It is easier to under-
stand how insomnia might result from a medical problem than to understand how insomnia
is a cause or a consequence of psychiatric diseases. Comorbidities with depression and anxiety
are estimated to occur in 35% to 60% of chronic insomniacs (1,7,11,21,27,28). Several longitu-
dinal studies have shown that insomnia may represent a substantial and statistical risk for the
development of depressive disorders (1,27). However, there is actually increasing evidence that
the coexistence of these two diseases reflects a common pathology rather than two separate
diseases. However, in order to clarify public health consequences due to insomnia, indepen-
dent of psychiatric disorders, it seems important to clearly identify insomniacs with psychiatric
diseases in the design of the studies. Depression and anxiety have indeed a well-documented
impact on economics and QOL (29–31).

INSOMNIA AT THE WORKPLACE

As previously stated, insomnia is very prevalent in adults and is therefore also frequently
found in professionals. There are very few studies that are specifically devoted to insomnia at
the workplace. However, it is commonly reported that insomnia affects daytime functioning and
working ability in professionals (32). Riedel and Lichstein (33) have, for example, recommended
using objective measures of work performance (absenteeism, promotion, etc.) to clarify the
impact of insomnia on daytime functioning. Insomnia is not a visible handicap in the workplace,
and it is difficult for insomniacs to explain to their colleagues and managers that they have had
a poor night and that they need to rest. Insomniacs have to face a regular work load, and
they often complain of difficulties in their professional life (35,36). However, there are few data
assessing the true impact of insomnia on daily work. It is essential that the impact of insomnia
on absenteeism and other work measures be evaluated in a real-world setting.

Absenteeism
In economic and epidemiological studies, overall measures of the respondent’s health appeared
to be the most important covariate of absenteeism (36,37). In a large, cross- sectional, national
probability sample of 1308 workers in the United States, Leigh (37) demonstrated that complain-
ing of insomnia was the most predictable factor of absenteeism from among 36 variables. In a
study comparing 80 insomniacs at work to 135 good sleepers, it was found that insomniacs had
double the control rate of absenteeism (21). Lavie (38) also found a higher rate of absenteeism
in insomniacs, which is significantly linked to a higher rate of work accidents in insomniacs. He
hypothesized that coworkers of the absentee insomniacs are more exposed to accidents because
of their work overload.
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However, these preliminary studies were based on general population samples: insomnia
was not always clearly defined and the groups of insomniacs were heterogeneous. Moreover,
the absenteeism data were mainly based on the patients’ declaration and not on objective data.
In a recent study (39), we specifically surveyed the absenteeism of a group of insomni-
acs at work compared to a matched group of good sleepers. Insomniacs showed almost twice
as much absenteeism as good sleepers. The difference between insomniacs and good sleepers
was particularly high for managers (OR = 2.29) and women (OR = 2.31). We believe that this
study is of particular interest because (i) we processed objective (rather than subjective) data
on absenteeism, (ii) insomnia was defined according to international classifications, (iii) sub-
jects with depression and anxiety were excluded, (iv) subjects were all full-time workers and
representative of the active population in the area, and (v) subjects with chronic disease (which
may interfere with sleep) and pregnant women were excluded from the study. Hence, in the
group studied here, it seems more probable that significant differences between insomniacs and
good sleepers reflect the impact of insomnia itself, rather than the effects of comorbidities. In
another study also assessing long-term absenteeism (including absence more than six months)
and comparing insomniac subjects (n = 986) with control subjects (n = 584), subjects with insom-
nia complaints (with or without mood or behavioral/physiologic sleep complaints) reported
poorer QOL and had a higher absenteeism rate than did controls (9.6 ± 31 vs. 5.8 ± 19 days;
p < 0.01). Logistic regression analysis of insomniacs with depressive complaints indicated that
absenteeism was more significantly associated with depression than insomnia itself (40).

Other Occupational Characteristics

The earliest study of this issue was conducted by Johnson et al. (41), who demonstrated that, in
a population of U.S. Navy workers, insomniacs performed more slowly and had poorer career
advancement than good sleepers. The difficulty of comparing the respective work loads of
insomniacs and good sleepers is a major concern in the discussion of these results. Insomniacs’
impairment at the workplace has been assessed by very few authors. Lavie, in a large and
detailed study of the lifestyle, health, sleep, and work habits of 1502 employees, concluded that
sleep habits directly affect the workplace. They showed that workers with daytime fatigue had
significantly more complaints of somnolence during work breaks (14.2% vs. 3.5%; p < 0.001),
higher frequency of napping at work (16.8% vs. 1.4%; p < 0.0001), and significantly less job
satisfaction (38) than other workers. However, this study was not directly focused on insomnia
but on sleep disorders. In a study comparing 240 severe insomniacs (SI) with 391 good sleepers
(GS), Leger et al. explored the consequences of insomnia on work (21). Fifteen percent of SI
versus 6% of GS (p < 0.001) reported having made errors at work over the past month, which
could have resulted in serious consequences. For 6% of SI versus 2% of GS, errors had occurred
more than once during the past month (p = 0.0032). Twelve percent of insomniacs versus 6% of
GS reported being late to work during the past month (p = NS). Moreover, 18% of SI versus 8% of
GS (p = 0.0004) felt that they had exhibited poor efficiency at work. Thirteen percent of SI versus
9% of GS reported difficulties completing complicated tasks at work (p = NS). In a recent work,
Daley et al. questioned 930 adults from the province of Quebec about sleep and professional
consequences. Reduced productivity was assessed by using the visual analogue scale (VAS).
Thirty-five percent of insomniacs versus 9.8% of the GS group reported reduced productivity
(42). These preliminary findings must be confirmed by more thorough and well-designed studies
which investigate insomniacs and GS working in the same field.

Accidents
The impact of sleep disorders on automobile accidents is a crucial issue from a public health
point of view. Public authorities and the media are well-informed on the risk of sleepiness at
the wheel during the night and on the effects of sleep debt and sleep pathologies (sleep apnea,
hypersomnia) on accidents. However, there are very few data on the risk of accidents due to
insomnia by itself.
Insomnia may impact the risk of accident in different ways: sleep deprivation, lack of
attention, and side effects of hypnotics. Motor vehicle accidents (MVA) and work accidents
(WA) have been the primary areas of investigation.
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SOCIOECONOMIC IMPACT OF INSOMNIA 23

In the French study comparing 240 SI with 391 GS (21), WA were found to occur eight
times more commonly over the past 12 months in SI (8%) than in GS (1%) (p = 0.0150), with an
average number of 0.07 (±0.25) accidents per SI versus 0.01 ± 0.11 per GS (p = 0.0550). There
was, however, no statistical difference for MVA over the past 12 months between the groups
(9% vs. 10%). The authors explained the discrepancy between WA and MVA by the fact that SI
may have avoided driving or driven shorter distance: 65.8% of SI versus 72.5% of GS drove a
car (p = 0.012). Lavie also showed a higher rate of WA in insomniacs (in their lifetime) than in
GS (52.1% vs. 35.6%; p < 0.01) (38). The rate of MVA due to fatigue (5% vs. 2%; p = NS) was
found to be slightly, but not significantly, increased in insomniacs.
Similarly, Daley et al., in a group of 930 adults in Quebec, did not find a different rate of
MVA in the last six months between insomniacs and GS. However, 23.5% of drivers reporting
an accident felt that insomnia played an important role in this event (42). Moreover, 39.5%
of participants described a link between their sleep difficulties and other types of accidents
(p < 0.001).
In Japan, in a study collecting data on occupational injuries in 1298 workers of small-
scale manufacturing firms, Nakata et al. (43) found that insomnia symptoms were significantly
associated with occupational injuries in both genders [OR = 1.64 (95%CI: 1.23–2.18)].
Regarding the effects of treatments on driving ability, it is usually generally held that
long-term half-life hypnotics (medium to long-term benzodiazepines and antihistamines) may
induce a risk of accidents, while driving, in the morning and a risk of falls in the night in
older adults. In Europe, the vast majority of hypnotics are labeled with a sign indicating
the possible risk of accidents due to the treatment. There are, however, very few published
studies on the effects of common hypnotics on driving ability. Partinen et al. (44) recently per-
formed a double-blind, randomized, placebo-controlled, three-treatment three-period crossover
study investigating the effects of zolpidem (10 mg) and temazepam 20 mg versus placebo in
18 insomniacs in a real-life condition on driving performance. After polysomnography at base-
line and each treatment night, patients underwent, a STISIM driving simulator test at 7:30 a.m.,
5.5 hours after drug intake. There were no differences between treatments for the primary out-
come measure (mean time to collision; baseline: 0.120 s, P: 0.124, T: 0.118, Z: 0.124; p ≥ 0.12
for all pairwise comparisons). No differences were recorded for speed deviation and reaction
time to tasks for the verum treatments; however, lane position deviation was greater after
administration of zolpidem in comparison with both placebo and temazepam (p = 0.025 and
0.05, respectively). They underlined the necessity to strongly advocate against the late intake of
hypnotics if patients intend to drive a car early the next morning. Using a mathematical model,
Menzin et al. calculated the potential effects of sleep medications on MVA and costs, and applied
the model to the French setting. They used the model of standard deviation of a vehicle’s lateral
position (SDLP) and hypothesized that compared with zaleplon, the use of zopiclone over 14
days would be expected to result in 503 excess accidents per 100,000 drivers (45).

COMORBIDITIES AND HEALTH CARE USE

Several studies have looked at the links between insomnia and general health status. Although
insomnia appears to be associated with poorer health status, it is difficult to know whether
insomnia is the result or cause of the poorer health status. Comorbid insomnia, which includes
not only psychological but also physical diseases, accounts for at least 50% of chronic insomnia.
It is likely that the high prevalence of comorbidity contributes to increased utilization of medical
services, including visits to doctors and other health professionals, intake of medications, and
the number and duration of hospitalizations.
Wereyer and Dilling (46) found a significantly higher average annual consultation rate
among mild and moderate SI than among those without sleep disorders (10.61 and 12.87 con-
sultations per year, respectively, vs. 5.25 per year for GS). They also reported a hospitalization
rate of 21.9% (SI) versus 12.2% (GS). Lavie (38) also found a higher rate of hospitalizations for
insomniacs, as did Kales et al. (47), who found an annual hospitalization rate of 15.7%. In the
study by Leger et al. (21), 18% of SI and 9% of GS had been hospitalized during the past 12
months (p = 0.0017), with an average of 0.17 (±0.40) hospitalizations for SI versus 0.11 (±0.45)
hospitalizations for GS (p = NS). The average duration of stay in hospital was 1.19 (± 3.45) days
for SI versus 0.76 (±3.83) days for GS (p = NS). Fifty–nine percent of SI and 49% of GS had
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24 LEGER

undergone a medical evaluation in the past six months (p = 0.0138), with an average of 2 (±3.0)
evaluations for SI versus 1.2 (±2.2) evaluations for GS (p = 0.0198). SI had had more blood
studies (48% vs. 34%; p = 0.0005) and radiological procedures (17% vs. 10%; p = 0.0142) than
GS. SI also had more outpatient visits and used more medications (particularly cardiovascular,
central nervous system, genitourinary, and gastrointestinal) than GS. However, there was no
difference in the use of analgesic medications, despite the fact that 46% of insomniacs versus 29%
of GS (p < 0.001) said that they were particularly sensitive to pain. This is an important point,
as pain may be an obvious cause of sleep disturbance. Katz and McHorney (48) have reported
that poor mental and physical health were far more prevalent among insomniacs than among
controls. Recently, Katz and McHorney (49) calculated the odds ratio between chronic diseases
and complaints of insomnia. Severe insomnia was strongly linked to current depression (OR =
8.2), as well as to congestive heart failure (OR = 2.5), obstructive airway disease (OR = +1.6),
and prostrate problems (OR = 1.6). Darko et al. (58) showed in a prospective study that fatigue
and sleep disturbance were frequent symptoms of advanced HIV infection and emphasized the
significance of these complaints in assessment of patients’ clinical status.
Finally, the fact that insomnia can be a risk factor for psychiatric diseases and alcoholism
(3–7,33) was also firmly demonstrated by Katz and McHorney (49). These findings have two
implications. First, insomnia seems to be associated with poorer health status; indeed, insom-
niacs should be routinely evaluated for psychiatric and somatic disorders. Second, although
we cannot conclude whether insomnia is the cause of or the result of worsened health status,
insomniacs are clearly at increased risk for certain diseases and a higher use of medical ser-
vices. Many of the findings reported to be consequences of insomnia are actually correlates.
Until a cause–effect relationship is established, correlate or comorbidity may be a more accurate
term to describe the relationship between insomnia and poor medical status. Finally, taking
care of insomnia may significantly reduce the severity of comorbidities as Dirksen and Epstein
(50) demonstrated: Women receiving cognitive-behavioral therapy for insomnia had significant
improvements in fatigue, trait anxiety, depression, and QOL.

COSTS OF INSOMNIA
At this time, there are very little published studies to address the economic consequences of
insomnia. The National Commission of Sleep Disorders Research (NCSDR) in the United States
estimated the direct cost of insomnia in 1990 to be $15.4 billion, extrapolating from available
data (51). However, in the judgment of the Commission, “the absence of hard epidemiological
data makes it impossible to calculate the precise cost of sleep disorders, but some data do exist
to show that the costs are substantial.” In 1988 Leger (52) examined, the cost of accidents related
to sleep disorders in the United States for the NCSDR and estimated its cost between $43.15
billion and $56.02 billion. Stoller (53) made an estimate of the total cost of insomnia in the United
States in 1988, based on a literature review on the economic costs and effects associated with
insomnia. Her cost estimate ranged from $92.5 billion to $107.5 billion (53). All consensus reports
agree on the lack of socioeconomic data to better understand the burden of insomnia on society.
One difficulty is the paucity of information about insomnia-related use of health care services.
Another is the degree of overlap between insomnia and many somatic and psychiatric diseases.
The following sections summarize the work that has been accomplished in the field and define
what could be undertaken to better understand the economic consequences of insomnia.
The economic impact of insomnia can be divided into direct costs, indirect costs, and
related costs. Direct costs of insomnia are charges for medical care or self–treatment that are
borne by patients, government, organized health care providers, or insurance companies. Indi-
rect costs refer to patient– and employer–borne costs that result from insomnia–related morbid-
ity and mortality. Related costs are other costs that can be rationally associated with the illness,
such as the cost of property damage resulting from accidents associated with insomnia.

Direct Costs of Insomnia

Direct costs of insomnia include those incurred for outpatient visits, sleep recordings, and
medications directly devoted to insomnia. There is very little knowledge about this kind of
cost. In 1999, Walsh and Engelhardt (54) estimated (using 1995 dollars) direct costs of insomnia
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SOCIOECONOMIC IMPACT OF INSOMNIA 25

to be $13.93 billion, which consisted of health care services ($11.96 billion), including nursing
home care ($10.9 billion), and medications/substances used for treatment ($1.97 billion). Leger
et al. (55) also made an estimate of the direct costs of insomnia in France in 1995 (based on 1995
dollars values). They gave a $2.067 billion value divided mainly into $1.75 billion for outpatient
visits and $310,59 million for substances used for insomnia. It was of particular interest to
observe the very limited costs of sleep centers in this estimate, $1.75 million. In both estimates,
the cost of prescriptions was very little compared with other costs. However, the direct costs
related to sleep disorders evaluation by practitioners seem to be a small part of the total cost of
insomnia. Recently, an update of the direct and indirect costs of untreated insomnia in adults
was made in the United States (56). With the help of a self-insurer, employer-sponsored plan,
the authors compared direct costs of insomnia (including inpatient, outpatient, pharmacy, and
emergency department costs for all diseases) for six months before the diagnosis of insomnia
or the first prescription of hypnotics was made. They compared 138,820 younger adults and
75,558 older adults with insomnia to control groups. After logistic regression they found $924
greater direct costs per six months for insomniacs versus controls and $1143 greater estimated
direct costs in older adult insomniacs.

INDIRECT COSTS OF INSOMNIA

The indirect costs of insomnia are the costs associated with the potential consequences of
insomnia on society, such as health problems, professional consequences (loss of productivity
and absenteeism), and accidents. The only estimate of the cost of accidents related to sleep
disorders ($46–$52 billion in 1988) was more focused on sleepiness at the wheel than on insomnia
(52). We previously reported that Johnson et al. demonstrated that insomniacs from a sample of
U.S. Navy men were slower at work and had poorer career advancement than did good sleepers
(41). On the basis of this last study, Stoller (53) estimated the loss of productivity due to insomnia
in the United States to be $41.1 billion in 1988 (53). The cost of absenteeism was evaluated among
nonmanagerial personnel and was estimated to be approximately $143 per day, or more than
$57 billion per year. We recently conducted a study on the indirect costs of absenteeism due
to insomnia in a sample of 369 employees of the Ile de France area with insomnia and 369
good sleeper professionals (57) The costs of absenteeism at work associated with insomnia were
estimated by comparing the two matched groups in terms of the number and duration of work
absences. We considered that work absences incurred costs relating to salary replacement and
loss of productivity: these were given a monetary value on the basis of the added value per hour
worked. The percentage of employees with at least one work absence was 50% and 34% for
insomniacs and GS, respectively. The work absenteeism [expressed in days, per employee, per
year ± confidence intervals (CI)] differed significantly between insomniacs and GS: 5.8 (±1.1)
and 2.4 (±0.5), respectively (p < 0.001). The extra cost (±CI) to the national health insurance
system of insomnia-associated absenteeism was estimated at €77 (±€39) per employee per year.
The extra cost (±CI) to employers was estimated at €233 (±€101) for salary replacement and
€1062 (±€386) for loss of productivity. Finally, employees themselves bore a cost (+CI) of €100
(€54). Ozminkowski et al. (56) also assessed the indirect costs of insomnia in their impressive
survey of 138,820 younger adults. Indirect costs included costs related to absenteeism from
work and the use of short-term disability programs. They found an average additional cost of
absenteeism over a 6-month period of $405 in patients eventually diagnosed with or treated for
insomnia (on a six-month period). The total short-term disability expenditures were, however,
$86 lower in insomniacs than in the control group.

Discussion About the Costs of Insomnia

Despite these several evaluations on the topic, the total costs of insomnia remain largely
unknown, and it is actually difficult to have a general view on the impact of insomnia on
economics. The studies on direct costs have been carried out only in two countries (54–57), and
it is difficult to apply these results to other parts of the world. The studies on indirect costs
are based on hypotheses that have limited empirical support and must be confirmed by larger
studies in more representative samples. The same degree of insomnia may not necessarily have
the same impact in different countries and there is a need for cross-cultural studies to better
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26 LEGER

understand the daily economic impact of diseases in insomniacs around the world. Future
studies might try to adopt economical values such as the national gross product for a better and
more comprehensive implication of the results at each country level.

QUALITY OF LIFE
There were very few studies specifically designed to assess the impact of insomnia on QOL. Most
of these were devoted to the impact of sleep disorders on the QOL of patients suffering from can-
cer. Some of the QOL studies have also been performed to explore the relationship of poor sleep
with diabetes, depression, Parkinson disease, chronic renal diseases with hemodialysis, and
HIV or chronic psychiatric diseases. QOL is also sometimes used to evaluate pharmacological
and nonpharmacological treatments of insomnia.

The Impact of Insomnia on QOL

The World Health Consensus report on sleep and health strongly recommends more studies
on the QOL of insomniacs (6). Surprisingly, until recently, there were relatively few works
specifically devoted to the subject (58–62). Four of them used the SF-36 [Short Form (36) Health
Survey] (58,59,61,62), a very widely used scale in QOL (63).
Zammitt et al. (62) used several instruments to evaluate the impact of insomnia on QOL in
a sample of 261 insomniacs compared to a control group of 101 GS. Insomniacs were recruited
by advertisements and had to fulfill the DSM criteria for insomnia. Individuals with criteria
of irregular sleep patterns, sleep apnea, restless leg syndrome, periodic limb movement dis-
orders, history of psychiatric illness, alcohol or substance abuse, epilepsy, and HIV-positive
infection were excluded from the study. They used the SF-36 and the QOL inventory, a 31-item
questionnaire specifically designed for the study which includes items related to sleep, cogni-
tive function, daytime performance, social and family relationships, and health. The authors
showed a significant difference between the two groups (p < 0.0001; MANOVA) on all eight
SF-36 subscales. Insomniacs reported more health concerns that limit physical activity, greater
interference of physical or emotional problems with normal social activities, more bodily pain,
poorer general health, less vitality, more emotional difficulties, and more mental health prob-
lems than did the GS group. Using the QOL inventory, they also found a significant impact on
the QOL of insomniacs. The authors suggested that the SF-36 can be used to assess differences
between subjects with insomnia and healthy controls and that the SF-36 may have clinical utility
as a measure of impairment associated with insomnia.
Leger et al. (64) also used the SF-36 to evaluate the QOL of three matched groups of 240 SI,
422 mild insomniacs, and 391 GS selected from the general population. They eliminated those
meeting DSM-IV criteria for anxiety and depression from the original group. They found that
SI had lower scores in eight dimensions of the SF-36 than did mild insomniacs and GS. Mild
insomniacs also had lower scores in the same eight dimensions than GS. No dimension was more
altered than the other. However, the mental health status and the emotional state were worse
in severe and mild insomniacs than in GS. This result demonstrates a clear interrelationship
between insomnia and emotional state, despite the fact that we had eliminated the subjects with
DSM-IV criteria of anxiety. The authors concluded that SF-36 was sensitive to the severity of
insomnia and seemed to be a reliable instrument to assess the impact of insomnia on QOL.
In a telephone interview study conducted as part of a five-year follow-up examination of
the Epidemiology of Hearing Loss Study, Schubert et al. (65) found the same kind of relationship
between the severity of insomnia and the decreased QOL in a group of 2800 older adults
(aged from 53 to 97 years). Participants were asked about symptoms of poor sleep. A response
of “often” or “almost always” was coded as positive for an insomnia trait. The SF-36 was
administrated to assess QOL of these subjects. Twenty-six percent of the population reported
one insomnia trait, 13% reported two, and 10% reported three. The eight domains of the SF-36
were found to be significantly decreased as the number of insomnia traits increased. The authors
concluded that insomnia is common among older adults and is associated with a decreased QOL.
Idzikowski (58) discussed the concept of QOL applied to sleep and introduced the fact
that short sleep is not necessarily deleterious but that abnormally shortened or fragmented
sleep can reduce an individual’s QOL. Smith and Shneerson (61) used the SF-36 in a sample of
IHBK059-03 IHBK059-Sateia March 28, 2010 8:19 Char Count=

SOCIOECONOMIC IMPACT OF INSOMNIA 27

223 subjects explored for snoring or daytime somnolence. They showed that the SF-36 score is
sensitive to sleep disruption.
Finally, Katz and McHorney (49) demonstrated that insomnia acts by itself on the QOL of
patients suffering from chronic illness. Insomnia was found to be severe in 16% and mild in 34%
of these patients. Differences between patients with mild insomnia versus no insomnia showed
small-to-medium decrements across SF-36 subscales ranging from 4.1 to 9.3 points (on a scale
of 100) and for severe insomnia from 12.0 to 23.9 points. Insomnia appeared in this study as an
independent factor of a worsened QOL to almost the same extent as chronic conditions such as
congestive heart failure and clinical depression.

Sleep in Comorbid Insomnia and QOL

In patients suffering from cancer, the quality of sleep has been recognized as a powerful factor
acting on the QOL (66). In a sample of 263 cancer patients undergoing chemotherapy, the authors
found that insomnia was negatively correlated to the QOL, probably by the way of depression.
Insomnia explained only 4% of the variance of QOL and depression 47%. Stark et al. (67) also
reported in 178 cancer subjects that insomnia was significantly and independently associated
with a deficit of QOL. They recommended that subjects with cancer be interviewed about sleep
to better discriminate subjects with anxiety. Lindley et al. (68) considered insomnia as a good
reflection of QOL in women following adjuvant therapy for early stage breast cancer. Treating
insomnia by cognitive-behavioral therapy in 72 women with breast cancer also statistically
significantly increased QOL, with a trend suggestive of lower depression at posttreatment (50).
In other chronic illness, several studies have shown that insomnia influences the QOL
of patients with Parkinson disease (69), hemodialysis patients (70), or patients with anxiety
and depression (71). In HIV infection, Nokes and Kendrew (72) also found that there was a
correlation between sleep quality (assessed by the Pittsburgh Sleep Quality Index) and positive
general well-being.

QOL in the Treatment of Insomnia

Goldenberg et al. (73) and Leger et al. (60) have shown that the QOL of insomniacs, as assessed
by questionnaires on professional, relational, sentimental, domestic, leisure, and safety aspects,
does not differ significantly from that of good sleepers. Walsh et al. (74) also reported an
improvement in the physical functioning, vitality, and social functioning dimensions of the
SF-36 of patients treated with eszopiclone versus placebo for the month one to six average (p
< 0.005). Baca et al. (75) also showed that zolpidem improved patients’ QOL assessed by a
questionnaire including four factors: social support, general satisfaction, physical and psycho-
logical well-being, and the absence of work overload/free time. However, to our knowledge,
there is no extensive survey comparing the effects of several hypnotics with well-validated QOL
instruments. Regarding nonpharmacological therapies, Quesnel et al. (76) showed the efficacy
of cognitive-behavioral therapy in insomnia in 10 women treated for nonmetastatic breast can-
cer. They found an improvement in sleep assessed by polysomnography and in the global and
cognitive subscales of the QLQ-C30. In a study comparing data from different studies using
cognitive-behavioral therapy on QOL, Dixon et al. (77) stated that after cognitive-behavioral
therapy intervention, statistically significant differences in SF-36 scores in favor of the interven-
tion were present for physical functioning, emotional role limitation, and mental health over
six months.
Insomnia affects the daily lives of patients. However, it is often difficult to evaluate the
impact of insomnia and the effect of treatments on patients’ everyday lives. QOL seems to
be a good way to better understand the complaints of insomniacs regarding their day-to-day
functioning. Several studies have shown the sensitivity of the SF-36 in evaluating the impact of
insomnia by itself or in relationship with other associated chronic diseases. We also recommend
the development of more accurate QOL tools specifically designed for insomnia.

HD-16: A Specifically Designed QOL Scale for Insomniacs

In many other chronic diseases, it has been shown that a disease-focused QOL instrument
was useful to accurately evaluate its impact on the daily lives of patients and to show the
efficacy of some treatments. In the field of insomnia, there is a need for specific instruments to
IHBK059-03 IHBK059-Sateia March 28, 2010 8:19 Char Count=

28 LEGER

better encompass the QOL of patients. This is why HD-16, a QOL scale specifically designed
for insomniacs, has been proposed (78). On the basis of interviews with SI patients, a 43-item
questionnaire on QOL has been built and tested on three groups composed of 240 SI, 422
mild insomniacs, and 391 GS. Ten steps led to the construction of a specific QOL scale. Five
dimensions have been validated as both relevant and independent from each other: physical
role, psychological role, social relationships with the others, cognitive (concentration, attention,
memorization), and energy. Sixteen items out the 43 initially tested were retained and were
found to be significantly different within the groups in each dimension. On the basis of these
16 items selected, we called the scale Hotel Dieu-16 (HD-16). The score’s specificity (correlation
score: 0.36) and reliability (Cronbach coefficient alpha: 0.78) were verified.

CONCLUSION
Insomnia affects the daily lives of millions of people around the world. The economic impact of
insomnia on society seems enormous. There is also increasing evidence linking insomnia to sev-
eral severe public health concerns: obesity, diabetes, depression, and cardiovascular diseases.
Besides the patients themselves, their family and work relatives are also affected by the conse-
quences of poor sleep. Public authorities are becoming increasingly focused on sleep education
and the protection of sleepers’ environment against noise. However, much work has to be done
to convince them that having good nights of sleep may deeply benefit individuals as well as
society.

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4 Insomnia as a Risk Factor in Disease

Wilfred R. Pigeon
Sleep and Neurophysiology Research Lab, University of Rochester Medical Center, Rochester, New York, U.S.A.

INTRODUCTION
As reviewed in the prior two chapters, insomnia can have a variety of daytime consequences for
the individual as well as present a considerable socioeconomic burden to society. As a disease
entity, insomnia also exists as an independent risk factor for psychiatric and medical illness,
compounding its consequences.
In this chapter, we will review the evidence that insomnia is “something that increases
a person’s chances of developing a disease.” This most common definition of risk factor will
be expanded to also include something that increases the chances for diminished treatment
response or in the case of adequate treatment response, increases relapse rates. It is important
to note that several definitions of the term risk factor exist and that the reader is often left
to determine what definition authors have in mind (if any). For that reason we also follow a
definition proffered by Beck (1) that additionally defines a risk factor as being part of the casual
chain, thus requiring temporal evidence, which can only be derived from longitudinal studies.
In the insomnia literature, there is a good deal of cross sectional data linking insomnia to a
variety of disease entities, which will be reviewed. Such studies, however, will be considered
as evidence that insomnia is a risk indicator that Burt (2) has defined as a probable or putative
risk factor.
Another matter of definition arises when reviewing the broad insomnia literature. Namely,
insomnia is not measured or defined in a consistent manner across studies. This is especially
true for data drawn from epidemiologic and community samples, but is also found in studies
in which sleep was not among the primary outcomes. Typically such investigations report on
single item measures of sleep complaints either developed for the study or embedded within
other instruments. For instance, the Hamilton Rating Scale for Depression (3) has three items,
one each pertaining to early, middle, and late night insomnia. Until recently, this item approach
to sleep or insomnia assessment had not been validated, but Manber et al. (4) have now shown
that, at least in a depressed sample, such approaches can be validated against the assessment of
insomnia via daily sleep diaries traditionally used by sleep researchers. This sleep outcome has
been called variably “insomnia” or “sleep disturbance.” The latter term has some merit when
the sleep items are few and very broad (e.g., one item that asks for a rating of sleep quality).
This chapter has adopted a convention of using the term “insomnia” in cases where there are
not validated measures of insomnia, but the sleep items are consistent with insomnia.

INSOMNIA AS A RISK FACTOR IN PSYCHIATRIC ILLNESS

In the psychiatric domain, there is a preponderance of data to suggest that insomnia is a risk
factor for new onset and recurrent major depressive disorder (MDD) (5). Less data are available
for the anxiety disorders, although insomnia is equally or more prevalent in anxiety, as compared
to mood disorders (6–9). As in the depression literature, available data suggest that subjects with
insomnia are more likely to have an anxiety disorder than those without insomnia (10).

Insomnia and Depression

Again, the largest body of evidence for a relationship between psychiatric illness and sleep
disturbances exists for the association between depression and insomnia. Both disorders are
highly prevalent and frequently co-occur in all age ranges and especially in older cohorts (11,12).
In the vast majority of these studies both female gender and increased age are associated with
higher prevalence rates. Cross sectional data allow not only for prevalence rate estimates for
each disorder, but also an estimate of how often the disorders co-occur. Longitudinal studies
meanwhile allow for the direct assessment of risk factors.
c04 IHBK059-Sateia March 28, 2010 8:20 Char Count=

32 PIGEON

Table 1 Prevalence Rates of Insomnia and Depression

In depressed, In insomnia,
Sample type Sleep Depressed Insomnia % with % with
Study (size) measures (%) (%) insomnia depression
Foley (119) Epid (9282) 5 sleep items 20 28 49 34
Weyerer (117) Comm (1536) 6 sleep items 7 16 47 24
Bixler (118) Comm (1006) 5–6 sleep 15 32 43 19
items
Mellinger (8) Comm (3161) 2 sleep items 5 17 71 21
Ohayon (120) Epid (5622) DSM criteria 6 17 57 18
Stewart (6) Epid (8580) Clinical 3 5 40 21
interview
Taylor (9) Comm (772) Sleep diaries 10 20 41 20
Ford (10) Epid (7954) 2 sleep items 5 10 42 23
Hohagen (121) PC (2512) DSM criteria 7 19 52 18
Total N 40,425 Weighted 9 16 49 26
averages
Abbreviations: Epid, epidemiologic sample; Comm, community-based sample; PC, primary care sample.

Prevalence Estimates for Insomnia and Depression

A number of community and epidemiologic studies have been conducted to determine the
prevalence of both insomnia and depression. While both disorders are variably defined across
studies, in general the prevalence of insomnia is approximately 16% and that of depression
is approximately 9%. The estimates are lower in studies with more stringent criteria, approxi-
mately 10% and 5% for insomnia and depression, respectively. Table 1 summarizes data from
nine such studies that also reported (or allowed the calculation of) the prevalence of depression
in only those subjects deemed to have insomnia and conversely, the prevalence of insomnia in
only those subjects deemed to be depressed.
For example, baseline estimates of prevalence rates from a study (n = 7954) based on
the National Institute of Mental Health Epidemiologic Catchment Area data were 10% for
insomnia and 5% for depression. Among those subjects with insomnia, 23% were depressed;
among subjects with depression, 42% had insomnia (10). Stewart et al. applied more stringent
diagnostic criteria than most prior studies to data from the Second National Survey of Psychiatric
Morbidity conducted in the United Kingdom (n = 8580). Their prevalence rate estimates were
5% for insomnia and 3% for depression (6). Among those subjects with insomnia 21% were
depressed, whereas among subjects with depression 40% had insomnia.
Overall, in a combined sample of 40,425 subjects, the prevalence of insomnia is nearly
twice that of depression. Perhaps more interesting is that the likelihood of having insomnia in
the context of depression is approximately twice that of having depression in the context of
insomnia. Such data suggest that insomnia may be considered a risk indicator for depression.

Longitudinal Studies of Insomnia and Depression

A number of longitudinal studies provide additional insight into the relationship between
insomnia and depression. One such study (13) sought to assess the course of depressive symp-
toms prior to a depressive episode by following patients with recurrent but remitted MDD for
up to 42 weeks with weekly administration of the Beck Depression Inventory (14). Subjects who
experienced a recurrence of depression were matched controls with no recurrence. Time series
data showed that the nonrecurrent group exhibited an elevated, but stable, level of insomnia
while the recurrent group exhibited an even higher level of sleep disturbance that began five
weeks prior to recurrence. The insomnia symptom cluster was the most prominent depressive
symptom cluster leading up to the depressive episode and reached its zenith at the week of
recurrence. This suggests that insomnia is both a risk factor for and a prodromal sign of a
recurrent depressive episode.
Most other longitudinal studies have assessed whether insomnia occurring at one or two
time points predicts depression at the second time point. These include several studies assessing
the onset of new depression over a one-year period. Two of these have found that insomnia
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INSOMNIA AS A RISK FACTOR IN DISEASE 33

posed an increased risk for the development of depression with odds ratios of 40 (CI: 19.8–80)
and 5.4 (2.6–11.3) respectively (10,15), while Dryman and Eaton found an increased risk of
depression [OR: 9.4(4.3–20.3)], but only in women (16).
While the above studies sampled populations of varying ages, others have focused on
younger adults. In a study that began with college-aged men, insomnia in college conferred
a relative risk of 2.0 (1.2–3.3) for developing depression at some point during the following
30 years (17). Breslau et al. (18) sampled 979 members of a health maintenance organization
who were 21 to 30 years old at baseline assessment and reassessed three years later. At baseline,
persons reporting two weeks or more of insomnia nearly every night at any point in their life
were at increased risk of developing new onset depression by the three-year follow-up [OR:
2.4(1.2–4.8)] than those with no history of insomnia even after controlling for prior depressive
symptoms.
In longitudinal studies performed in older cohorts, findings have been slightly mixed.
One study limited by power, found that in 147 patients with no prior history of depression,
the presence of persistent insomnia at baseline was associated with new onset depression one
year later (but only in females) (19). In a study of 524 community-dwelling elders, insomnia at
baseline and three years later was associated with depression at three years compared to those
with no insomnia or those with insomnia at one time point (20). In a reanalysis of this data
set including only subjects with activity limitations and no psychiatric morbidity at baseline,
baseline insomnia was not associated with depression three years later (21). Roberts et al. (22)
found that insomnia at baseline was associated with an increased risk of depression one year
later [OR: 2.5(1.7–3.7)] and insomnia at both time points carried an eightfold risk, though other
factors were more significant predictors. In older adults followed for 12 years (23), baseline
insomnia was an independent predictor of depression at 12 years in women only [OR: 4.1(2.3–
7.2)]. Brabbins (24) determined that in a sample of 771 elders, only initial insomnia (and not
middle of the night or early morning awakening) that occurred at both baseline and three years
was associated with the development of new depression at three years.
Finally, a meta-analysis of studies conducted in older adults found that sleep disturbance,
with an odds ratio of 2.6, was second to recent bereavement (OR 3.3) as a risk factor for late-life
depression (25). In summary, while there is a good body of evidence that suggest that both
incident and persistent insomnia predict new onset depression, the findings are not unanimous,
and insomnia is not the only significant risk factor. Taken as a whole these sets of longitudinal
studies support the insomnia as one risk factor for developing depression.
As Table 1 shows, insomnia and depression do not always co-occur, nor does one neces-
sarily presage the other across all cases. As is the case for any risk factor, insomnia is neither
a necessary condition for nor the sole pathway to depression, but it does, in fact, appear to be
part of the casual chain for many individuals. Two recent publications further this case with
respect to depression. Buysse et al. (26) were able to assess insomnia and depression from an
epidemiologic study in Zurich that included 6 time points over a 20-year span. In their analyses,
the presence of insomnia absent depression at each time point was strongly associated with the
presence of co-occurring insomnia and depression at the subsequent time point. A similar find-
ing occurred with respect to the presence of depression absent insomnia, though the findings
for insomnia were more robust. Departing from the epidemiologic data, Pigeon et al. assessed
insomnia in the context of a depression treatment trial of 1801 older adults in primary care
settings (26,27). They found that patients with insomnia that persisted across a baseline and
three-month assessment had a diminished treatment response at 6 and 12 months compared
to patients with insomnia at one or neither of the baseline and two-month time points. This
expands the notion of insomnia as a risk factor for depression to include comorbid insomnia as
a risk factor for unremitting depression.
While it is not the case that a putative risk factor must be demonstrated to improve a dis-
ease entity when it is removed, there are emerging data in this regard for insomnia in the context
of depression. Two uncontrolled studies have shown that patients presenting with stringent def-
initions of insomnia and depression who completed a course of cognitive-behavioral therapy
for insomnia had improvements in both sleep and depression (28,29). In addition two random-
ized, controlled trials have shown that treating insomnia and depression simultaneously has a
greater impact on both conditions than when treating the depression alone. One of these trials
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34 PIGEON

found that patients treated concomitantly with fluoxetine and eszopiclone exhibited less illness
severity over the course of an eight-week intervention and a faster time to recovery than sub-
jects treated with fluoxetine only (30) and the other that escitalopram and cognitive-behavioral
therapy for insomnia produced a higher rate of remission for depression and insomnia than
escitalopram alone (31). This set of studies supports the assertion that insomnia is a modifiable
risk factor for depression.

Insomnia in Other Mood Disorders and Related Conditions

Bipolar disorders must include at least one episode of mania to meet symptom criteria and are
far less prevalent than depressive disorders. Insomnia and/or sleep deprivation is often cited
by patients and practitioners as a precursor to manic episodes, though the empirical data are
relatively sparse in this area. There are nearly as many reviews on this topic as there are well-
designed studies and the reader is referred to these excellent reviews and theoretical discussions
(32–34). As Jackson (34) reports, five retrospective studies indicate that patients identify sleep
disturbance as a top prodromal sign of a manic episode, but not bipolar depression. As summa-
rized by Harvey (32) four studies have assessed sleep and bipolar symptoms prospectively on
a daily basis and found relationships between poor sleep and next-day worsening of manic or
depressive symptoms (though whether mania or depression was correlated with sleep varied
by study). These are limited data on which to call insomnia a risk factor for bipolar disorder
or for a manic episode, so that the field awaits more in the way of prospective data. This
would be important given the widespread belief that sleep disturbance is indeed a harbinger of
particularly a manic episode, but may lend itself to preventive intervention.
Complicated Grief Disorder is not a mood disorder per se, but is included in this section.
It occurs as a reaction to bereavement, the loss of a loved one by death. Between 10% to 20% of
persons experiencing bereavement have a complicated grief reaction (35). Current nosologies
do not include insomnia as a symptom, although sleep interference is included as one of
seven symptom criteria for a proposed diagnostic entity (36). Given that approximately 75%
of all deaths occur in persons ≥ 65 years old, bereavements, like insomnia, increase across the
lifespan (37) and may have some relationship to sleep. A prospective PSG study comparing
27 nondepressed elders with spousal bereavement to matched nonbereaved elders found the
only difference in groups to be elevated phasic REM activity and a slight decrement in slow
wave sleep in the bereaved group (38). In a meta-analytic review of studies in community-
dwelling elders, Cole and Dendukuri (25) determined that recent bereavement was the biggest
risk factor for depression. Across a number of smaller studies, sleep disturbance in the form of
difficulty sleeping and/or insomnia has been reported in one-third to one-half of subjects with
bereavement (36,39–43) and the level of sleep disturbance was higher than in that of control
groups without bereavement (41–43). There is no data to suggest, however, that insomnia
represents a risk factor for complicated grief following bereavement.
Suicide and suicidality may also be associated with insomnia. An early mention of this
association appeared in an article titled “Insomnia and Suicide” in a 1914 issue of The Lancet (44).
In it, C Ernest Pronger writes “For a long time past newspaper reports of suicide, associated with
insomnia, have attracted my attention. . .” and goes on to note how assessing and potentially
treating insomnia might prevent many calamities. Sadly, it has taken some time to take up this
call. Recent work includes a cross sectional study of 165 hospitalized suicide attempters in which
the vast majority endorsed one or more sleep complaints, with difficulty initiating sleep the most
commonly endorsed symptom (73%), but nightmares were the only independent predictor of
suicidality (45). Similarly, in 176 outpatients regression analyses revealed that insomnia and
nightmare symptoms were associated with both depressive symptoms and suicidality, but after
controlling for depressive symptoms, only nightmares were associated with suicidality (46).
Insomnia has also been found to be associated with suicidal thoughts in a sample of outpatient
chronic pain patients (47).
In a cross sectional study of 1362 high school students in China, both shorter sleep duration
and the presence of nightmares were significantly associated with reporting suicidality (48). In
one of two prospective studies, Bernert collected data from 14,456 community elders over a
10-year period during which time 21 individuals died by suicide. When matched to 20 randomly
selected controls, disturbances in sleep consistent with insomnia and independent of depression
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INSOMNIA AS A RISK FACTOR IN DISEASE 35

predicted an increased risk for eventual death by suicide (49). Goldstein et al. (50) assessed sleep
disturbances in 140 adolescent suicide victims and 131 controls with a psychological autopsy
protocol and semistructured psychiatric interview, respectively. Suicide completers had higher
rates of overall sleep disturbance, insomnia, and hypersomnia compared to controls within the
last week after controlling for affective disorders. These data suggest that insomnia is a risk
indicator for suicidality with some evidence that it is a risk factor for suicide.

Insomnia and Anxiety Disorders

Although sleep disturbances are more prevalent in anxiety disorders than they are in mood
disorders, far less research has been conducted in these areas with the possible exception
of posttraumatic stress disorder (PTSD). The Ford and Kamerow (10) catchment area study
reported that 24% of respondents with insomnia had an anxiety disorder and were six times
more likely to have an anxiety disorder than those without insomnia. Others have found anxiety
disorders in general population samples to be equally or more prevalent than depression in their
respective insomnia subsamples (6–9).

Insomnia and Posttraumatic Stress Disorder

Sleep disturbances are a common feature of PTSD in both the general population (51) and
in combat veterans (52). Interestingly, while nightmares have historically been considered the
hallmark of PTSD, insomnia is actually a more prevalent symptom. This has been shown in an
epidemiologic survey of the general population as well as in a clinical sample seeking treatment
for insomnia (51,53). In an assessment of the National Vietnam Veterans Readjustment Study
database (52), Nelylan found that insomnia was more frequent than nightmares in both combat
veterans with PTSD (90.7% vs. 52.4%) and combat veterans without PTSD (62.5% vs. 4.8%).
While these findings speak about the specificity of nightmares for PTSD, they also underscore
the extremely high prevalence of insomnia in trauma-exposed populations of 60% to 90%.
There remains considerable debate, and little data to come to a consensus, on whether insomnia
represents a risk factor for the development of PTSD. Harvey and Bryant found that 72% of
civilians experiencing a sleep disturbance within one month of their trauma went on to develop
PTSD (54). In what may be some of the only other prospective assessments of sleep acutely
following trauma (but prior to the development of PTSD), Mellman et al. have shown that the
nature of dream content (55) and disturbances in REM sleep (56) predict PTSD outcome.
Most of the work in PTSD and sleep has focused on characterizing the sleep of trauma
survivors. Therefore, while insomnia can be considered a risk indicator it remains to be shown
whether it is a risk factor. Nonetheless it remains the case that insomnia is a prevalent residual
symptom following otherwise successful treatment of PTSD (53) and that a handful of stud-
ies with stringent definitions of insomnia have shown that cognitive-behavioral interventions
specifically tailored to the sleep of PTSD populations have met with some success (57–60).

Other Anxiety Disorders

There is a relative paucity of sleep data in generalized anxiety disorder (GAD), which is sur-
prising given that sleep disturbance is one of the six DSM symptom criteria for its diagnosis,
two additional symptoms (irritability and fatigue) are often associated with insomnia, and both
GAD and insomnia tend to present with features of hyperarousal (61–63). In a report of 141
patients presenting to an insomnia clinic, GAD was the most common co-occurring psychiatric
disorder (7). Breslau et al. (18) reported cross sectional data from their large sample (n = 1007)
indicating that in the 167 respondents with insomnia, 36% had at least one anxiety disorder
as opposed to 19% in those with no insomnia. In the insomnia sample, the disorder specific
occurrences reported were: GAD 8%, panic disorder 6%, obsessive–compulsive disorder 5%,
and phobia 25%.

Substance Abuse Disorders

Substance abuse occurs in approximately twice as many individuals with insomnia as com-
pared to those without insomnia (10,15,18). In a sample of 172 alcoholics admitted to inpatient
treatment, patients with insomnia were more likely to report frequent alcohol use for sleep than
those without insomnia (55% vs. 28%) (64).
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36 PIGEON

Anecdotal reports also suggest that particularly in patients acutely recovering from alco-
holism, sleeping problems lead to relapse. This has been borne out in one study, where insomnia
and fragmented sleep were found to predict relapse in 20 abstinent alcoholics (65). In another
sample of 74 recently abstinent alcoholics, 60% with baseline insomnia versus 30% without
baseline insomnia relapsed to any use of alcohol within five months (64). Brower et al. (66) also
recently completed a small randomized controlled trial of gabapentin in 21 patients with active
alcoholism and comorbid insomnia. Albeit a limited sample size, those in the treatment arm
had a reduced time to relapse.
These data indicate that insomnia is a risk indicator for the development of alcoholism;
there is not enough data to posit such an assertion in other forms of substance abuse. The data
also suggest that insomnia represents a risk factor for relapse in alcohol dependence.

INSOMNIA AS A RISK FACTOR IN MEDICAL ILLNESS

In the medical domain there are a series of studies that suggest that poor sleep is a risk factor
for increased mortality, especially in the elderly (e.g., 24,67–69). Insomnia and/or short sleep
duration are also associated with increased mortality (70,71). In general, data with respect to
specific medical illnesses are less substantial than in the psychiatric domain.

Insomnia and Chronic Pain

Approximately 50% patients with diverse chronic pain conditions complain of significant sleep
disturbance, with some investigations finding sleep disturbance as high as 70% to 88% (72–75).
The directionality of this relationship is largely untested however. One exception comes from
Affleck et al. (76) who analyzed 30 consecutive days worth of daily sleep and pain diaries from
fibromyalgia patients and found that pain and sleep had a bidirectional influence on each other.
Experimental data in animals and humans suggest that sleep disruption or deprivation (not
insomnia) increases various types of pain sensitivity (77–79) or can produce or worsen pain
(80–82). As in some of the psychiatric literature, there are also some studies demonstrating that
treating insomnia in the context of chronic pain can improve insomnia (83) or both conditions
(84,85). The available data, therefore, while strongly implicating insomnia as a risk indicator
does not speak about the issue of risk factor directly.

Insomnia and Other Medical Conditions

A number of cross sectional studies have implicated sleep disturbance in conditions such as
gastrointestinal distress (86), recovery from and physical function and emotional well-being
after cardiac surgery (87–91), and Type II diabetes and glucose homeostasis dysregulation (pre-
diabetic syndromes) (92–94). There are also some longitudinal epidemiologic studies that have
assessed the relationship of insomnia to hypertension and cardiovascular disease. Suka et al.
used an annual health examination database of a Japanese telecommunication company and
followed 4794 men from a baseline assessment for up to four years or until they developed
hypertension (95). After adjusting for potential confounding factors, persistent complaints of
difficulty initiating sleep and difficulty maintaining sleep were significantly associated with
a significant increased risk of hypertension with OR 1.96 (1.42–2.70) and OR 1.88 (1.45–2.45),
respectively. Phillips and Manino (96) used 8757 participants without hypertension and 11,863
without cardiovascular disease from the Atherosclerosis Risk in Communities Study and fol-
lowed them from a baseline assessment to the development of disease or up to six years. Either
difficulty falling asleep or waking up repeatedly predicted a slight increased risk of hyperten-
sion [OR 1.2(1.03–1.3)] and endorsement of these two symptoms plus awaking tired or fatigued
increased risk of cardiovascular disease [OR 1.5(1.1–2.0)]. In a subsequent analysis of this data
set comparing single item sleep disturbances at Year 5 to subsequent hypertension incidence at
Year 11, these authors did not find any single item measure of insomnia to be associated with
subsequent incident hypertension (97). The above studies represent the first set of evidence that
favor insomnia as a risk factor in these conditions, but negative findings have been reported.

Insomnia and Immune Function

To date, the association between immunity and sleep has been evaluated primarily in terms of
whether plasma levels of either NK cells or sleep-related cytokines vary with sleep, sleep loss,
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INSOMNIA AS A RISK FACTOR IN DISEASE 37

sleep deprivation, or with clinical diagnosis (i.e., insomnia) (98–104). As reviewed by Krueger
et al. (101), numerous cytokines appear to have some relation to sleep. A small number of studies
have found that insomnia (as compared to good sleep) tends to be associated with altered innate
immunity. In general, insomnia is associated with decreased NK activity (105,106), and a shift in
the circadian distribution of IL-6 and TNF-␣ from the night to the daytime (107), despite higher
evening levels of Il-6 (107). Only one study has found that immune alterations are correlated
with self-report or PSG measures of disturbed sleep. Burgos et al. (108) found in patients with
insomnia that IL-6 secretion is inversely correlated with self-reported sleep quality and PSG-
measured SWS minutes. While intriguing none of these data point to insomnia as a possible
risk factor for subsequent disease.
Data from three adaptive immune system studies (as opposed to the innate immunity
studies above) are also suggestive. In a companion study to a clinical trail of an experimental
avian influenza vaccine (109), 46 patients receiving the active vaccine were assessed with the
Pittsburgh Sleep Quality Index (PSQI) (110). Compared to vaccine responders, the nonrespon-
ders had higher PSQI scores, poorer sleep efficiency, and shorter sleep duration. Cohen et al.
(111), in a study of 276 healthy adults, sought to assess whether social ties were related to
susceptibility to the common cold. All participants were infected with a live rhinovirus and
the development and severity of common cold symptoms were assessed. While the primary
hypothesis was borne out (greater social ties were protective against the development of cold
symptoms), several potential variables were found to moderate the relationship, including
decreased self-reported sleep efficiency. In a follow-up study designed to further test this asso-
ciation in 153 participants, these authors found that sleep durations under seven hours and
sleep efficiency under 92% immediately preceding exposure to a rhinovirus were each associ-
ated with significantly higher rates of infection (112). Thus, preliminary data exist demonstrates
that insomnia is a risk factor for infectious disease.

SUMMARY AND CONCLUSION

Insomnia is highly prevalent across a wide range of psychiatric and medical conditions with
considerable evidence that it is a risk indicator for the majority of these conditions. Moreover,
insomnia represents a risk factor for the development of highly prevalent disorders ranging
from mood and anxiety disorders to chronic pain and hypertension as well as for all cause
mortality and suicide. Finally, for many of these conditions, insomnia also represents a risk
factor for relapse or delayed recovery.
Authors who have been calling for an end to the notion of insomnia as a secondary
disorder (see for example, 113–116) have considerable evidence to draw upon to make their
case. The task now falls to the sleep community to continue its efforts to identify and possibly
treat insomnia across these many disease states.

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5 Psychological Models of Insomnia

Lisa S. Talbot and Allison G. Harvey
Department of Psychology, University of California, Berkeley, California, U.S.A.

The critical role of psychological processes in the cause and/or maintenance of insomnia has
received considerable attention over the past four decades. In this chapter, we begin by describ-
ing an influential overarching psychological theory, the three-P model. We then move on to
review several of the behavioral, cognitive, and hybrid models in chronological order.
A range of psychological processes may contribute to insomnia, including behavior, cog-
nition, affect, and personality. As will become evident, the bulk of the excellent work completed
thus far has targeted the behavioral and/or cognitive types of explanation. These theories vary
across a number of dimensions. First, several of the theories attempt to capture the entire life
course of the disorder, from its inception to its most chronic form, while others take a narrower
focus on just the maintaining or perpetuating factors. The former tend to be more general and
the latter tend to be more detailed or specific. Second, some of the theories examine several
types of explanation (e.g., the hybrid models) while others take on the task of delving into the
detail of one type of explanation. Other psychological processes, such as affect and personality
traits, may also be relevant but have been understudied. We will return to this topic later in this
chapter.

THREE P-MODEL
The three-P model, also referred to as the three-factor or Spielman model, is a diathesis-stress
theory that includes predisposing, precipitating, and perpetuating factors (1,2). The predispos-
ing factors can be biological (e.g., regularly elevated cortisol), psychological (e.g., tendency to
worry), or social (e.g., work schedule incompatible with sleep schedule). These factors represent
a vulnerability for insomnia. Precipitating factors, such as stressful life events, trigger the acute
onset of insomnia. The influence of precipitating factors diminishes over time. Perpetuating
factors, such as maladaptive coping skills or an extension of time in bed, contribute to the acute
insomnia developing into a chronic or longer term disorder. As the perpetuating factors serve
to maintain the insomnia, they are typically the targets of treatment. Importantly, the model
has been refined such that the three types of factors are dynamic over time (3). For exam-
ple, predisposing factors are not necessarily viewed as constant vulnerabilities in the refined
model (Fig. 1).
The unique feature of this model is that it provides a framework across types of explana-
tion; that is, this model is relevant to biological, cognitive, social, and other types of explanation.
However, in the early discussions of the model the behavioral processes were emphasized. In
particular, an important perpetuating factor was identified as extending sleep opportunity, or
lengthening the time in bed by going to bed earlier or getting up later. In this conceptualization,
this behavior results in a discrepancy between time in bed and ability to sleep. This theory has
resulted in a well-established therapy according to American Psychological Association criteria
(4), known as sleep restriction (5), as described in chapter 25.

STIMULUS CONTROL MODEL

The stimulus control model was proposed by Bootzin (6). It is founded upon the condition-
ing principle that a stimulus can elicit a variety of responses; the particular response elicited
depends on the conditioning history. Bootzin’s theory is that insomnia occurs when sleep stim-
uli, either temporal (e.g., bedtime) or environmental (e.g., bed or bedroom), are no longer
specifically paired with sleep, but instead have become paired with numerous other activities
(e.g., reading, working, being awake and anxious about not sleeping, etc.). That is, a condi-
tioning history in which the bed/bedroom was continually paired with nonsleep activities
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PSYCHOLOGICAL MODELS OF INSOMNIA 43

Perpetuating
INSOMNIA SEVERITY

Insomnia
Threshold Precipitating

Predisposing

TIME

Figure 1 Characteristics contributing to insomnia over time. Source: Adapted from Ref. 3.

leads to a new association of the bed/bedroom with not sleeping. In this model, individuals’
attempts to cope with insomnia may maintain and actually exacerbate the disorder through
strengthening such maladaptive associations. For example, an individual with insomnia may
lie in bed awake for long periods of time, believing it is better to get rest. Or the individual
may get up and do work in the bedroom when sleep is elusive. In both cases, the behavior
results in a lower likelihood that the sleep stimuli of the bed/bedroom will elicit the desired
response of falling asleep. The intervention arising from this theory is another that meets the
American Psychological Association criteria for a well-validated treatment (4), as described in
chapter 24.

HYBRID COGNITIVE-BEHAVIORAL MODEL (MORIN)

Morin’s hybrid cognitive-behavioral model of insomnia (7) is an integrative model that incor-
porates individual, temporal, and environmental variables. A central factor of this model is
hyperarousal. The hyperarousal can be cognitive affective, behavioral, or physiological. Con-
ditioning can exacerbate arousal; for example, after sleeping poorly for several consecutive
nights, an individual may begin to associate temporal (e.g., bedtime) or contextual (e.g., bed-
room) stimuli with the responses of worry and fear of poor sleep—both of which are arous-
ing. Such conditioning may occur at different rates among individuals, likely dependent on
such factors as predisposition to insomnia and current daytime problems (e.g., interpersonal
conflict).
In this model, individuals’ sleeplessness leads to worry and rumination, along with mis-
perceptions of sleep (e.g., distortions in how much time the individual believes he/she was
awake during the night). Morin’s model stipulates daytime consequences including fatigue and
mood disturbance, which then trigger further worry and other negative cognitions about sleep.
These negative cognitions play an important role in insomnia; for example, they may consist of
unhelpful beliefs about sleep (i.e., if I don’t get eight hours of sleep, I cannot function the next
day). Such negative cognitions lead to emotional distress, which further exacerbates the insom-
nia. The result of this cycle of conditioning, arousal, worry and rumination, misperception, and
daytime consequences is a sense of learned helplessness. The individual comes to believe that
the insomnia is uncontrollable and unpredictable.
According to this model, to attempt to cope with insomnia, individuals develop mal-
adaptive sleep habits such as excessive time in bed or daytime napping, which contribute to
the maintenance of insomnia through preventing the development of a regular sleep–wake
rhythm. Thus, in this model hyperarousal often serves as a trigger, but a multitude of factors
such as maladaptive sleep habits or negative cognitions perpetuate the negative cycle. It is
important to note that the consequences of sleeplessness can also serve as a further trigger
for the cycle; that is, there is a bidirectional relationship among the variables. This theory has
resulted in a form of cognitive-behavior therapy (7) that was manualized, tested, and shown
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44 TALBOT AND HARVEY

to be an empirically supported treatment according to American Psychological Association

criteria (4).

HYBRID COGNITIVE-BEHAVIORAL MODEL (LUNDH AND BROMAN)

Based on a detailed review of the existing empirical literature, Lundh and Broman (8) propose
that there are two different categories of psychological processes involved in insomnia: (i) pro-
cesses that interfere with sleep (e.g., cognitive, emotional, and physiological arousal, which may
be due to stressful events or emotional conflicts, and may be moderated by various personality
variables such as arousability, neuroticism, etc.) are referred to as sleep-interfering processes; and
(ii) processes that make the individual perceive or interpret his or her sleep patterns in a dis-
torted or otherwise dysfunctional manner (e.g., misperceptions of sleep, dysfunctional beliefs
about sleep quantity requirements and consequences of not meeting these requirements, dys-
functional beliefs about natural variations in sleep, misattribution of negative aspects of daily
functioning to poor sleep, attentional biases, etc.) are referred to as sleep-interpreting processes.
The central tenet of Lundh and Broman’s model is that insomnia is the result of vari-
ous combinations, and interactions, of sleep-interfering and sleep-interpreting processes. These
two kinds of processes have a bidirectional relationship. For example, sleep-interfering arousal
can lead to increasingly negative interpretations of sleep difficulties. Similarly, negative sleep-
interpreting processes (dysfunctional beliefs about need to sleep, worries about sleep, rumina-
tion about causes and effects of poor sleep, etc.) can contribute to increases in sleep-interfering
arousal.
Lundh and Broman argue that it is important to distinguish between these two types
of processes as they may require different forms of treatment. In some cases, sleep-interfering
processes may dominate and the treatment should focus on these (e.g., by emotional processing,
training in relaxation or mindfulness skills, or stimulus control and sleep restriction techniques);
in other cases sleep-interpreting processes may dominate, which require cognitive methods. In
still other cases, both kinds of processes may be equally involved, causing various kinds of
vicious cycles between cognition, behavior, and sleep-interfering arousal, and requiring both
kinds of treatment approaches.

NEUROCOGNITIVE MODEL
The neurocognitive model (9) extends behavioral models by explicitly allowing for the possibil-
ity that conditioned arousal may act as a maintaining factor in insomnia. In this model, arousal
includes somatic, cognitive, and cortical arousal. Somatic arousal corresponds to measures of
metabolic rate, cognitive arousal typically refers to mental constructs like worry rumination,
and cortical arousal refers to the level of cortical activation [primarily electroencephalography
(EEG) activity, though cortical arousal may also include all CNS arousal]. Cortical arousal is
hypothesized to occur as a result of classical conditioning and can lead to abnormal levels of
sensory and information processing and long-term memory formation.
In this model, the cortical arousal phenomena become linked to sleep continuity
disturbance and/or sleep state misperception (i.e., the individual judging that he was awake
for a longer duration than actually occurred). In particular, enhanced sensory processing
around sleep onset and during NREM sleep is thought to make the individual vulnerable
to environmental stimuli (e.g., a noise outside on the street) interfering with sleep initiation
and/or maintenance. Enhanced information processing (detection of, and discrimination
between, stimuli and the formation of a short-term memory of the stimulating event) during
NREM sleep may blur the distinction between sleep and wakefulness. That is, one cue for
“knowing” that one is asleep is the lack of awareness for events occurring during sleep.
Enhanced information processing may therefore account for the tendency in insomnia to
judge PSG sleep as wakefulness (i.e., sleep state misperception). Finally, enhanced long-term
memory (e.g., recollection of a stimulating event hours after its occurrence) around sleep onset
and during NREM sleep may interfere with the subjective experience of sleep initiation and
duration. Typically individuals cannot recall information from periods immediately prior to
sleep, during sleep, or during brief arousals from sleep. An enhanced ability to encode and
retrieve information in insomnia would thus be expected to influence judgments about sleep
latency, wakefulness after sleep onset, and sleep duration.
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PSYCHOLOGICAL MODELS OF INSOMNIA 45

PSYCHOBIOLOGICAL INHIBITION MODEL

Espie’s psychobiological inhibition model of insomnia (10) includes psychological (cognitive
and emotional), physiological, and environmental arousal in the maintenance of insomnia and
proposes that insomnia results from chronic inhibition of homeostatic and circadian processes.
This model of insomnia differs from many others in that the starting point is good sleep instead
of pathology. Espie posits that in good sleepers homeostatic and circadian processes are invol-
untary and naturally default to good sleep. To maintain the automaticity and plasticity of these
processes in good sleep, however, several critical component processes must occur, including
sleep-related stimulus control (e.g., regular sleep habits), daytime facilitation of nighttime sleep
(e.g., effective coping skills), sleep-related physiological dearousal, and sleep-related cognitive
dearousal.
According to this model, insomnia results when there is a failure of these automated sleep
activation and maintenance processes. In particular, inhibitory feedback from one or more of
the psychobiological processes disrupts the automaticity and plasticity of the system and thus
prevents normal sleep. For example, the automaticity of the process of sleep stimulus control
would be weakened if an individual developed a conditioned association of sleep-incompatible
activities (e.g., watching TV) with the bedroom environment. Another feature of this model is
that it accounts for the contribution of daytime factors; for example, disturbed daytime affect
could undermine cognitive and behavioral preparation for sleep.
Recently this model has been extended. Espie et al. (11) have proposed the importance
of an attention–intention–effort pathway to explain how insomnia develops and to describe
the critical factors that maintain it. Again, good sleep is considered to be a relatively automatic
process, but this automaticity can be inhibited by attempts to control the process including three
overlapping stages: (i) selective attention to sleep, (ii) explicit intention to sleep, and (iii) effort
to sleep. In the first stage, selectively “attending” to sleep involves shifting attentional focus
to sleep-salient stimuli, such as monitoring for signs inconsistent with sleep (12). The second
part of the pathway, explicitly “intending” to sleep, is explained in part by examining the
contrast whereby individuals who are good sleepers typically passively abandon wakefulness
and fall into sleep, whereas individuals with insomnia try to initiate sleep, such as through
thought control. This explicit intention—or the planning mode—is dysfunctional in that it
inhibits normal dearousal, and thus the intention paradoxically inhibits sleep. The final stage is
a further development of intention, whereby sleep “effort”—or the performing mode—includes
two related processes: (i) direct (i.e., trying to force sleep to come) and (ii) indirect (i.e., increasing
sleep opportunity, such as going to bed earlier). This final stage further inhibits sleep–wake
automaticity.
In sum, this model starts with an assumption of good sleep and posits that in insomnia
the automaticity of good sleep is interrupted via the attention, intention, and effort maintain-
ing processes. The role of the attention–intention–effort pathway in this model suggests that
cognitive-behavioral interventions that target and modify these processes may reduce insomnia
and restore normal sleep.

COGNITIVE MODEL
According to Harvey’s cognitive model of insomnia, insomnia is maintained by a cascade of
cognitive processes that operate at night and during the day. The five key cognitive processes
that comprise the cascade are worry (accompanied by arousal and distress), selective attention
and monitoring, misperception of sleep and daytime deficits, unhelpful beliefs, and counter-
productive safety behaviors (13). Two assumptions are made. First, the cognitive processes that
are proposed to operate at night apply equally to difficulty getting to sleep at the beginning of
the night and to difficulty getting back to sleep after waking during the night and to waking too
early in the morning. Second, the maintaining processes described can “kick in” at any point in
the model and as a consequence of either daytime or nighttime experiences.
This cognitive model suggests that worry in the night activates the sympathetic nervous
system thereby triggering physiological arousal and distress. This combination of worry, arousal,
and distress plunges the individual into an anxiety state (10). Research in cognitive psychology
indicates that when one is anxious the range of stimuli in the environment that is attended to
narrows (14) and attention is preferentially directed toward potential threats (15). On this basis
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46 TALBOT AND HARVEY

the model suggests that the anxious state leads people with insomnia to narrow their attention
and selectively attend to or monitor for sleep-related threats that might be internal stimuli (e.g.,
bodily sensations) and/or external stimuli (e.g., clock). As monitoring for threat increases the
chance of detecting random and meaningless cues that can then be misinterpreted (16) and
the aroused state means that there is likely to be an abundance of body sensations present to
be detected, monitoring is likely to provide further cause for worry. Hence, a vicious cycle is
established.
This model suggests that this cycle may help explain the robust finding that some indi-
viduals with insomnia overestimate the extent to which their sleep is inadequate. For example,
in the time perception literature time seems longer when the number of units of information
processed per unit of time increases (17). Hence, worry may distort the perception of how
long it is taking to get to sleep (18). Monitoring increases the chance of detecting random and
meaningless cues. These may then be misinterpreted as indicative of threat (16,19) that, in turn,
contributes to misperception of sleep and/or daytime functioning. Of course, if an individual
perceives they have not slept adequately a further cause for worry is established, thus fuelling
the vicious cycle.
It is proposed that there are two additional exacerbating processes operating at night. First,
unhelpful beliefs about sleep are likely to exacerbate worry (7). Second, in an attempt to cope
with the escalating anxiety caused by the processes described, individuals with insomnia often
make use of safety behaviors (20), such as drinking alcohol to reduce anxiety and promote sleep
onset. A safety behavior is an overt or covert action that is adopted to avoid feared outcomes.
The problem is that these behaviors (i) prevent the person experiencing disconfirmation of their
unrealistic beliefs and (ii) may make the feared outcome more likely to occur (20).
The same cognitive processes are suggested to be operating during the day. For example,
people with insomnia often worry during the day that they have not obtained sufficient sleep.
This worry, in turn, triggers arousal and distress, selective attention and monitoring for sleep-
related threats, misperception and the use of counterproductive safety behaviors. Each of these
processes serves to maintain the insomnia. In addition, worry, arousal, and distress are likely to
interfere with satisfying and effective daytime performance. Further, the use of safety behaviors
can contribute to distress and worsening of sleep, as well as preventing disconfirmation of
unhelpful beliefs.
It is suggested that these processes culminate in a real sleep deficit. Three points are relevant
here. First, when an individual suffers from a real sleep deficit it is conceived to be the product of
escalating anxiety that is not conducive to sleep onset (10) nor to effective daytime performance
(21). Second, misperception of sleep and a real sleep deficit can coexist. An individual may
report sleeping only two hours on a night but on polysomnography is shown to have slept
for four hours. In this example, the individual is misperceiving his sleep and suffering from
a serious real sleep deficit. Third, for the occasional individual with insomnia who thinks he
is not getting enough sleep but, in reality, is sleeping sufficiently (sleep state misperception),
the cognitive model suggests that such individuals will be at grave risk of getting trapped
into becoming progressively more absorbed by and anxious about their sleep problem. The
unfortunate consequence of this is that they are at high risk of developing a real sleep deficit.
The process of empirically validating predictions from this model is ongoing (see Ref. 22 for a
summary of evidence to date) and a treatment derived from the model has preliminary support
in an open trial (23).

UNDERSTUDIED PSYCHOLOGICAL PROCESSES: AFFECT AND PERSONALITY

Within the psychological level of explanation for causal and maintaining factors in insomnia,
the majority of the models reviewed have addressed behavioral and cognitive factors. How-
ever, it seems likely that other psychological processes, such as affect and personality, are also
important.
The role of affect is increasingly recognized to be important across a number of psychiatric
disorders (24). Following Gross (25), we use the term “affect” to include emotion (short-lived
responses that involve changes in the behavioral, experiential, autonomic, and neuroendocrine
systems), emotion episodes (emotions more extended in time and space), and mood (longer
duration responses than emotions, more diffuse than emotions).
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PSYCHOLOGICAL MODELS OF INSOMNIA 47

It is well established that insomnia is associated with psychiatric disorders characterized

by affect regulation difficulties, such as depression, bipolar disorder, and anxiety disorders
(26,27). However, there is minimal research on the role of presleep affect in insomnia. An
interesting untested hypothesis is that individual differences in ability to downregulate affect
could be a predisposing or perpetuating factor. One study that supports this hypothesis found
that individuals with insomnia rated the impact of daily minor stressors and the intensity of
major negative life events as higher than good sleepers (28). Furthermore, such individuals used
more emotion-oriented coping strategies and had greater presleep arousal than good sleepers,
while a path model indicated that emotion-focused coping indirectly negatively impacted sleep
by increasing both the impact of stress and presleep cognitive arousal.
While in the previously paragraph we suggest that affect can negatively impact sleep,
a further hypothesis is that the lack of sleep experienced by individuals with insomnia will
adversely impact next-day affect. Accumulating evidence has begun to provide support for this
possibility. For example, a number of investigators have examined daytime affect in individuals
with insomnia. Buysse et al. (29) used ecological momentary assessment, a technique in which
individuals report on their subjective experience in their natural context several times per
day, to assess daytime symptoms in insomnia patients. Results demonstrated that individuals
with insomnia endorsed lower positive moods and higher negative moods, including higher
depression and anxiety scores, compared to good sleepers. Additionally, Riedel and Lichstein
(30) reviewed studies examining daytime affective symptoms of insomnia. A small majority of
studies utilizing three measures of affect (Beck Depression Inventory, the State-Trait Anxiety
Inventory, and the Profile of Mood States) observed increases in depression and anxiety scores
in individuals with insomnia.
A study by Yoo et al. (31) with healthy participants provides additional, though indirect,
evidence for the possibility of insomnia affecting next-day affect. Healthy participants who were
sleep deprived for 35 hours or who had slept normally completed an emotional stimulus viewing
task (100 images varying in emotional intensity) in an event-related fMRI design. The two
groups showed amygdala activation to negative picture stimuli. This was an anticipated result
on the basis that the amygdala is involved in the generation of emotions and the development of
emotional memories. However, relative to those who slept normally, those in the sleep deprived
group exhibited more than 60% greater amygdala activity. Furthermore, this large increase was
associated with a loss of activity in the medial prefrontal cortex (MPFC). The MPFC exerts top–
down control on the limbic area (including the amygdala) and functions to modulate emotional
responses so that they are appropriate for the context. Thus, this study suggests that sleep
contributes to maintaining connectivity between the MPFC and amygdala, which is critical for
responding appropriately to next-day emotional challenges.
Hence, the research to date provides initial support for the hypothesis that insomnia
contributes to affective impairment and that affective impairment contributes to insomnia.
However, affective theories of insomnia have not yet been developed. Future research testing
the possibility that there may be a bidirectional relationship between affect and sleep may be a
wise investment.
There is also limited research on the role of personality in insomnia. A few studies have
found personality disturbances in individuals with insomnia, such as a higher score on the
Neuroticism scale of the Eysenck Personality Questionnaire (e.g., Ref. 32) and an “abnormal”
score on the Minnesota Multiphasic Personality Inventory (MMPI) (33–35). In particular, one
study that used the MMPI found that individuals with insomnia demonstrated personality
profiles suggestive of neurotic depression. Additionally, individuals with insomnia appeared to
handle conflicts and stressors through internalizing emotions (as opposed to through irritability
or hostility) (35). However, the research on this topic has been mostly correlational and thus the
question remains as to whether personality characteristics predispose individuals to insomnia
or result from insomnia.

CONTEXTUAL/ENVIRONMENTAL FACTORS
Context likely underlies the expression of and interaction between all the psychological factors
we have discussed, including behavior, cognition, affect, and personality. The role of context,
or environmental factors, is also understudied. Examples of potentially important contextual
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48 TALBOT AND HARVEY

factors include bed partners who may interfere with each other’s sleep through snoring, move-
ment, or dyssynchronous bedtimes. Other contextual factors include the noise and safety levels
of the environment that could lead to sleep disturbance and/or hypervigilance for threat.
Increased use of technology and busier schedules may also impact insomnia through increased
stress and poorer sleep habits.

CONCLUSION
A number of the important psychological models have been reviewed in this chapter, ranging
from behavioral to cognitive to several hybrid cognitive-behavioral models. These substantial
theoretical contributions have led to the development of numerous efficacious treatments (4),
but more work remains. In particular, future research on the role of emotion, personality, and
contextual factors could pave the way for even more successful treatments.

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26. Benca RM, Obermeyer WH, Thisted RA, et al. Sleep and psychiatric disorders: a meta-analysis. Arch
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6 Sleep EEG in Patients with Primary Insomnia

Michael Perlis and Phil Gehrman
Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

Mario Terzano
Department of Neurology, University of Parma, Parma, Italy

Kimberly Cote
Department of Psychology, Brock University, St. Catharines, Ontario, Canada

Dieter Riemann
Center for Sleep Research and Sleep Medicine, Department of Psychiatry, Freiburg University, Freiburg, Germany

INTRODUCTION
With the advent of the electroencephalographic study of sleep (1–3) and the more comprehensive
methodology of polysomnography (4), the era of the objective assessment of sleep had arrived.
Along with this technology, came the promise that sleep related complaints could be accounted
for by abnormal physiologic function during sleep. That is, it was believed that the simultaneous
and long duration monitoring of sleep continuity and sleep architecture along with pulmonary,
cardiac, motor, and cortical function would reveal the abnormalities that account for sleep initia-
tion and maintenance problems, the report of shallow and/or fragmented and/or nonrestorative
sleep, and/or the diurnal complaints of sleepiness and fatigue. To a large extent this promise was
realized for the complaint of shallow and/or fragmented and/or nonrestorative sleep, and/or
the diurnal complaints of pathologic sleepiness. The polysomnographic study of sleep revealed
that these complaints were, in large measure, directly related to sleep disordered breathing. The
promise, however, was not realized for the complaint of insomnia (sleep initiation and main-
tenance problems). In fact, the very effort to objectively measure sleep continuity disturbance1
raised more questions than it answered. That is, the objective assessment of sleep with electroen-
cephalography brought into sharp resolution that remarkable discrepancies existed between the
subjective and objective measure of sleep latency, wake after sleep onset, number of awakenings,
and total sleep time (4,5). Further, no evidence was obtained for physiologic abnormalities that
clearly accounted for difficulty initiating or maintaining sleep (e.g., abnormal REM pressure,
slow wave sleep deficiency, sleep onset related central apneic events, sleep induced cardiac or
CNS irregularities, etc.). At best some of these factors were found to be indicative of “Secondary
Insomnia” and particularly the sleep of patients with major depression (6,7).
The lack of obvious abnormalities resulted in a new program of research, one that was
focused on the effort to document that physiologic and/or cognitive hyperarousal is pathog-
nomic for primary insomnia2 . This program of research yielded a variety of findings and the-
ories, all of which provide partial support for the “hyperarousal hypotheses” (8). Interestingly,
these efforts also gave rise to a fundamentally new concept with respect to the etiology and
pathophysiology of insomnia—the concept that the primary defect in primary insomnia may
be less related to “hyperarousal” and more related to “the failure to inhibit wakefulness” (9).

1 Sleep Continuity refers to the collection of variables that correspond to sleep initiation and maintenance,
including Sleep Latency (SL), Wake After Sleep Onset (WASO), Number of Awakenings (NWAK), and Total Sleep
Time (TST). While the term is not formally part of the sleep lexicon, it has the heuristic value of being a global
term whose meaning may be contrasted with the class of variables that correspond to “Sleep Architecture”.
2 For the purposes of this chapter, the term “primary insomnia” is meant to be synonymous with psychophysio-
logic insomnia.
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SLEEP EEG IN PATIENTS WITH PRIMARY INSOMNIA 51

In this chapter, information will be provided regarding the findings from all of the
EEG based technologies including those from Polysomnography (PSG), Quantitative Elec-
troencephalography (QEEG), Cyclic Alternating Patterns analysis (CAPs) and Event-Related
Potentials (ERPs).

EEG SLEEP CONTINUITY MEASURES

When assessed with the sleep EEG, patients with primary insomnia, on average, do exhibit prob-
lems with initiating and maintaining sleep. The sleep continuity abnormalities, however, are
generally less severe than when assessed by self report (4,5,10–19). These incongruities appear
to various extents in at least two forms of primary insomnia including both psychophysiologic
insomnia and paradoxical insomnia (formerly referred to as sleep state misperception insom-
nia) but may or may not be characteristic of “secondary insomnia” [c.f. Perlis 2000 (19)]. These
“subjective-objective” discrepancies, it should also be noted, occur for when subjects are queried
about their state of consciousness when awakened from polysomnographically defined sleep.

Subjective vs. PSG Measures of Sleep Continuity

As noted above, patients with primary insomnia tend to overestimate how long it takes them
to fall asleep and the amount of time that they are awake over the course of the night when
compared with objective assessments. Good sleepers tend to estimate correctly how long it takes
them to fall asleep, and if a trend is evident, they tend to overestimate the amount of sleep they
obtain. Both patients with insomnia and good sleepers, when compared to polysomnographic
measures, tend to underestimate number of awakenings or number of nocturnal arousals.
This last finding may be an artifact of the manner in which sleep is scored. Most laboratories
score in 30-second epochs and thus intervals as brief as 16 seconds may be categorized as
wakefulness and/or as separate bouts of wakefulness. Such extremely brief awakenings may not
be recalled by either good sleepers or patients with insomnia (20,21) and/or in the case of patients
with insomnia may be perceived as continuous wakefulness. Figure 1 depicts “subjective-
objective” discrepancies as they occur in patients with primary insomnia, insomnia comorbid
with Depression, and in Good sleeper subjects (19,22).

The Perception of PSG Sleep

When awakened from polysomnographically verified sleep, patients with primary insomnia
more frequently report having been awake than good sleeper subjects (11,23–25). On average,
the patient with insomnia tends to identify PSG sleep as wakefulness 73% of the time. Good
sleepers identify PSG sleep as wakefulness between 45% and 50% of the time. These kinds of
findings vary as a function of number of sleep study nights, sleep stage from which the subject
is awakened, and the manner in which the subject is awakened. The discrepancy between PSG
sleep and subjective impression, however, is most evident for awakenings that occur shortly
after sleep onset(s) (26).

EEG SLEEP AND SLEEP ARCHITECTURE

While there is a long standing tradition of research regarding sleep architectural abnormalities
in psychiatry illness, especially major depression, there is remarkably little work on such abnor-
malities as they occur with primary insomnia. In the case of major depression, where there
are hundreds of studies over thousands of subjects, there appears to be a reasonably reliable
constellation of sleep architectural abnormalities including short REM Latency, a prolonged first
REM period, increased REM Density, increased REM percent, and diminished slow wave sleep
(SWS) (7).
The dearth of PSG studies in primary insomnia is partly related to at least three factors.
First, insomnia’s characterization as only a “symptom” discouraged the effort to characterize it
as a unique disease state. Second, studies conducted prior to 1990 (prior to the publication of
the ICSD or the DSM-IV) relied on definitions of insomnia that were nonstandard and study
protocols that did not have exclusions for medical and psychiatric illnesses and/or medications
known to affect PSG sleep. As a result, the findings were mixed, and when trends were available,
they were remarkably like those seen with major depression.
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52 PERLIS ET AL.

(S-O) SLEEP LATENCY

60
55
50
TIME IN MINUTES

45
40
35
30
25
20
15
10
5
0
PI MDD GS

(S-O) WAKE AFTER SLEEP ONSET

50
40
TIME IN MINUTES

30
20
10
0
–10
–20
–30
–40
–50
PI MDD GS

Figure 1 In both figures, time in minutes are difference scores between the group average subjective values
and the objective values. For example, if subjective SL = 90 and the objective SL = 30 then the difference score if
60 minutes. Accordingly, these difference scores represent the absolute magnitude of the “sub-ob discrepancies”
as seen in PI, MDD and GS subjects.

Third, insomnia’s characterization, prior to and after 1990, as a disorder of initiation and
maintenance of sleep (DIMS) came with the suggestion that sleep continuity disturbance was
the (vs. a) defining attribute of insomnia and thus many PSG studies of insomnia simply did
not contain sleep architecture data.
With these caveats in mind, the PSG findings in insomnia from 1975 to 1989 insomnia
were characterized by Benca and colleagues in 1992 (7). This metaanalytic study summarized
the results from 25 investigations in patients with insomnia. The findings for patients with
insomnia, and nine other psychiatric patient classifications, were expressed as whether they
significant differed from values calculated for healthy good sleepers. The results from this
study suggested that patients with insomnia exhibit reduced SWS%. REM% and REM latency
were found to be within normal limits. Data for stage 1 and stage 2 were not reported.
In order to assess whether these results are also typical of a more modern cohort, a set
of 17 studies from 1994 to the present was reviewed. All the studies included in this review
(1) used ICSD or DSM-IV definitions of insomnia, (2) reported one or more sleep architectural
findings, and (3) indicated that patients were medication free at the time of study. Most of
the studies for this review had small samples although there were two investigations with
samples of 100 or more subjects (27,28). Table 1 provides a list of these studies, their findings,
and study related information. The sleep architecture findings are summarized below by stage
of sleep.
Stage 1%: One study reported a statistical tendency (p < 0.10) for stage 1% to be increased in
patients with primary insomnia as compared to good sleepers (28). Fifteen studies report
no difference and one study does not provide data (29).
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SLEEP EEG IN PATIENTS WITH PRIMARY INSOMNIA 53

Table 1 Sleep Architecture Findings in Primary Insomnia

Authors Sample STG1 STG2 SWS REM RL Date Citation

Lichstein et al. 20 — — — — 1994 Sleep 17: 693–402
Bonnet & Arand 10 — ↓ — ↓ (↑) 1995 Sleep 18: 581–588
Lamarche & 6 — — — — — 1997 Sleep 20: 724–733
Ogilvie
Dorsey & 18 — — — — — 1997 Biol Psychiatry 41: 209–216
Bootzin
Edinger et al. 32 — — — 1997 Sleep 20: 1119–1126
Crenshaw & Physiology & Behavior 66:
Edinger 485–492
Stepanski et al. 10 — — — — — 2000 Sleep 23: 1–5
Edinger et al. 31 ↓ 2000 Physiology & Behavior 70:
127–134
Rosa & Bonnet 121 — — — — — 2000 Psychosom Med 62: 474–482
Edinger et al. 35 — — — — — 2001 Sleep 24: 761–770
Riemann et al. 10 — — — — — 2002 Psychiat Res 113: 11–27
Means et al. 52 — — — — 2003 Sleep Med 4: 285–296
Bastein et al. 20 — — 2003 J Psychosom Res 54: 39–49
Backhaus et al. 16 — — ↓ — — 2006 Biol Psychiat
Burgos et al. 11 — — — — — 2006 Brain Behav Immun 20:
246–253
Orff et al. 32 — — — — 2007 Sleep 30: 1205–1211
Bastien et al. 15 — — — ↓ 2008 Sleep 31: 887–898
Feige et al. 100 (↑) — — ↓ — 2008 J Sleep Res 17: 180–190
# supportive 1 1 2 3 1
studies

Stage 2: One study reported differences for this stage of sleep. Bonnet & Arand (1995) (30) found
that patients with insomnia exhibited a slight decrease in stage 2 percent. Fourteen studies
report no difference and two studies do not provide these data (29,31).
SWS: Two studies describe a reduction of SWS percent in insomniacs compared to controls
(29,32). Fourteen studies report no difference and one study did not provide these
data (33).
REM: Three studies described significantly reduced REM sleep percent in insomnia (28,30,34).
Eleven studies report no difference and three studies do not provide these data (29,31,33).
REM latency: One study described a statistical tendency for REM latency to be prolonged in
patients with insomnia (30). Seven studies report no difference (27–29,31,32,35–37) and
nine studies do not provide these data.
Apart from naturalistic studies, there are two investigations that probe the issue of SWS
deficiency and/or sleep homeostasis dysregulation as it occurs in patients with insomnia in
response to sleep deprivation. Besset and colleagues (38) conducted a study in which patients
with primary insomnia were subjected to a partial sleep deprivation protocol (three hour sleep)
and then allowed a recovery sleep period of 10 hour on the following night. Both the PI
and GS subjects exhibited increase in total sleep time and SWS percent. When compared to
good sleepers, the patients with PI exhibited a smaller increase in total sleep time (although a
comparable percent) and a smaller increase in SWS minutes (although a comparable percent).
Stepanski et al. (2000) (39) found that patients with primary insomnia, when sleep deprived for
approximately 36 hours, exhibited larger increases in total sleep time, but a smaller percentage
increase in SWS than good sleepers.
In sum, the most conservative interpretation of the findings to date is that patients with
insomnia do not exhibit reliably altered sleep architecture. If trends exist, they do so as cohort
effects or relative to probative conditions. With respect to cohort effects, the earlier generation
of studies tended to show reduced slow wave sleep percent as a feature of insomnia while
the later generation studies tend to show reduced REM percent. With respect to probative
conditions, there is mixed evidence that patients with insomnia exhibit a reduced capacity to
IHBK059-06 IHBK059-Sateia March 28, 2010 8:24 Char Count=

54 PERLIS ET AL.

generate SWS in response to sleep loss. Given these findings, clearly further research is needed
where such studies may benefit by having large samples, the use of both absolute and percent
time (differences may exist for the former where they do not for the latter), the application of
quantitative electroencephalographic techniques to quantify SWS activity, and/or the use of
challenge paradigms to resolve underlying abnormalities.

QUANTITATIVE ELECTROENCEPHALOGRAPHY
Quantitative electroencephalography (QEEG) refers to a group of mathematical techniques
used for detecting periodicities within time series data. The techniques include, but are not
limited to, power spectral analysis (PSA) and digital period analysis (DPA). As employed
within electroencephalography, the technique is used to deconstruct complex waveforms into
their constituent frequencies. In the case of PSA, quantification is accomplished by determining
the amount of voltage that occurs per bin and/or prespecified bandwidth. This technique and
related techniques have been extensively used to quantify delta frequency EEG in good sleepers
(during normal sleep or manipulations like constant routine schedules or sleep deprivation).
The technique has also been used to quantify high frequency EEG activity in the 14 to 45 Hz
range in both good sleepers and in patients with insomnia.
High frequency EEG was first observed in the waking state by Berger in 1937. He hypothe-
sized that such activity, observed during mental arithmetic, must be a “material concomitant of
mental processes” (40). In the last two decades, there has been substantial work indicating that
during wakefulness high frequency EEG activity in the beta (14–35 Hz) and gamma (35–45 Hz)
ranges is associated with attention in animals [e.g., (41,42)] and with attention, perception, and,
more generally, cognitive function in humans (43–58).
Recently, eight investigations have demonstrated that patients with insomnia exhibit an
unusual amount of beta EEG activity during polysomnographically-monitored sleep (59–66).
The majority of the investigations found that the increase in beta activity was apparent in
patients with insomnia compared to good sleeper controls for time period’s at/around sleep
onset and/or during NREM sleep. These findings were based on (1) EEG measurements from
central sites using monopolar or bipolar measures that included C3, Cz or C4, and O2, (2) relative,
as opposed to absolute, measures of power density, and (3) definitions of beta activity ranging
from 14 to 32 Hz. Three studies provided evidence that increased beta activity during sleep
occurs specifically in association with primary, as opposed to secondary, insomnia (63,64,66).
Two studies provided data to suggest that patients with insomnia also have more beta activity
during REM sleep (60,61). One study indicated that beta activity varies with clinical course given
nonpharmacological interventions (65). The most recent study of high frequency EEG activity
in patients with insomnia suggests that women with primary insomnia, but not men, showed
increased high-frequency and low-frequency EEG activity during NREM sleep compared to
good sleepers. Figure 2 represents the all night distribution of delta and beta activity in good
sleepers and in patients with primary insomnia.
While the data acquired from this measurement strategy appear to support the perspec-
tive that cortical arousal may be a biomarker for insomnia (and this is theoretically appealing
to the extent that the increased occurrence of beta and gamma activity is thought to be permis-
sive of increased sensory and information processing), the lack of replication across large scale
contemporary investigations (e.g., 67) and unpublished studies (Buysse D, personal commu-
nication, 2005; Perlis M, personal communication, 2005) suggests that this approach has some
limitations. In our hands, the occurrence of beta and gamma activity varies not only with trait
considerations (diagnostic category) but also appears to be mediated/moderated by a variety
of factors including:
r Whether or not the patient experiences a first night effect or a reverse-first night effect
(a precedent also exists in the published literature) (e.g., 68)
r Whether or not the patient experiences a good night’s sleep in relation to the amount of prior
sleep loss or amount of prior wakefulness (i.e., increased homeostatic pressure for sleep)
r The extent to which circadian dysrhythmia contributes to the insomnia (e.g., delayed sleep
phase syndrome subjects would be expected to show more beta/gamma activity when
attempting to sleep in a nonpreferred sleep phase)
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SLEEP EEG IN PATIENTS WITH PRIMARY INSOMNIA 55

DELTA * BETA1 WHOLE NIGHT

100 10
80 8
GOOD

BETA1
DELTA
SLEEPER 60 6
CONTROLS 40 4
20 2
0 0 0
42
84
126
168
210
252
294
336
378
420
462
504
546
588
630
672
714
756
798
840
882
924
966
SLEEP ONSET

100 10
80 8

BETA1
DELTA

PRIMARY 60 6
INSOMNIA 40 4
20 2
0 0
0
45
90
135
180
225
270
315
360
405
450
495
540
585
630
675
720
765
810
856
901
949
994
SLEEP ONSET DELTA BETA1

Figure 2 In both figures, (1) the left and right ordinates represent relative power [e.g., (beta power/total power)],
(2) the abscissa represents time (from sleep onset, in 30 second increments, to sleep offset), (3) the black boxes
represent delta power and the white boxes represent beta power, (4) the data are average plots for nine individuals
per group.

r Technical considerations regarding how the EEG signals are acquired (e.g., signals transmit-
ted over long cable runs may significantly alter the power spectrum)
r Ambient noise in the recording/sleep environment (e.g., sound, light, temperature, etc.)
The extent to which one or more of these factors obscure simple group contrasts under-
scores the need to identify a biomarker, probe, or challenge paradigm that provides for stable
group characterizations of the phenomena that contribute to the occurrence of and/or severity
of insomnia.

CYCLIC ALTERNATING PATTERN

The cyclic alternating pattern (CAP) is a periodic EEG activity of sleep that occurs spontaneously
throughout NREM sleep (69,70). CAP is characterized by repetitive slow (high amplitude bursts)
and fast EEG transients that are distinct from background EEG activity and recur at up to one
minute intervals (see Figure 3 for examples of NCAP and CAP). CAPs occur following cerebral
activation (phase A) and cerebral deactivation (phase B). A CAP cycle is composed of a phase A
and the following phase B. Two or more CAP cycles constitute a CAP sequence. CAP sequences
have no upper limits either on overall duration or on the number of CAP cycles. CAP sequences,
during the A Phase, may be further categorized into subtypes (71): A1 which is represented by
EEG synchrony; A2 which is a mixed signal (slow and fast rhythms); and A3 which is largely low
voltage fast frequency signal. CAP sequences, as opposed to NCAP, are thought to be indicative
of unstable sleep (72). NCAP and CAP sequences are illustrated below.
CAP sequences can be identified by computer assisted devices. In brief, the metrics of the
PSG derived CAP analysis is based on the quantification of CAP time (the time duration of all
CAP sequences) and CAP rate (the ratio between CAP time and NREM sleep time). To date,
CAP rate has been show to be correlated with self-reported sleep quality [in both good sleepers
(73) and in patients with insomnia] and with treatment outcome (74).
In the case of good sleepers (74), it was found that auditory stimulation across four sound
intensities (white noise at 45 dBA, 55 dBA, 65 dBA and 75 dBA) resulted in a linear increase
in CAP rate and these changes were significantly correlated with self reported sleep quality.
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56 PERLIS ET AL.

NCAP
Bipolar EOG
Fp2-F4
F4-C4
C4-P4
P4-02
C3-A2
EMG
Respiratory Flow
EKG

CAP
A B A B A B A B
Bipolar EOG
Fp2-F4
F4-C4
C4-P4
P4-02
C3-A2
EMG
Respiratory Flow
EKG

Figure 3 The letter designations “A” and “B” represent phase A and B CAPS. Fp2-F4, F4-C4, C4-P4, P4–02,
are bipolar EEG derivations. C3-A2 is a monopolar derivation (typically used for sleep scoring) EMG is mentalis
electromyogram EKG is an electrocardiograph tracing.

In the case of patients with insomnia (74), it was found that, under placebo conditions, patients
exhibited a significantly higher CAP rate than did controls (evident for subtypes A1 and A2 but
not A3). Treatment with several medications [zolpidem (10 mg), triazolam (0.25 mg), zopiclone
(7.5 mg), brotizolam (0.25 mg)] significantly reduced CAP rates, although only for subtypes
A1 and A2 (74). Finally, sleep quality was significantly improved by the use of hypnotics, and
improved sleep quality was significantly correlated with CAP rate.
These data suggest that “hyperarousal” within NREM sleep can be assessed in terms of
CAP rate and that the association of CAP rate with sleep quality suggests that this form of
arousal during sleep (or processes associated with this form of arousal) may undermine sleep’s
capacity to be restorative.

EVENT-RELATED POTENTIALS (ERPs)

ERPs are EEG-based brain potentials that occur in response to sensory stimulation and represent
the timing and extent of information processing. (75,76) They provide information on how
quickly a stimulus is identified and encoded and the degree of attentional resources allocated
to processing. ERPs vary predictably with changes in arousal and attention, (77) and have been
well described in healthy good sleepers. They have been used as an index of attention during
alert and drowsy wakefulness, at sleep onset and during sleep (77–81).
The most common ERP paradigm applied in sleep research is the auditory odd-ball task,
where a rare ‘deviant’ tone is presented at random in a train of frequently occurring ‘standard’
tone pips (75). EEG is then averaged over numerous trials for each stimulus category and
the ERP emerges as a series of peaks and troughs in a waveform which represent the brain’s
processing of the stimuli. ERPs elicited in this task between 50 and 350+ ms are most sensitive
to changes in arousal and attention (77,82). The earliest peaks, N1 and P2, are elicited by both
standard and deviant stimuli. N1 is a negative peak around 80 to 120 ms that represents early
sensory processing such as encoding (75,76,82). P2 is a positive wave around 175 to 225 ms,
which is thought to index the degree to which stimuli are inhibited or blocked (83). P300 is a
large amplitude positive wave, which peaks around 300 ms when the target stimulus has been
detected (84). The parietal maximum P300 wave generally reflects conscious detection of the
target and stimulus discrimination. One variation of the oddball task involves stimuli that are
presented rapidly. This elicits the mismatch negativity (MMN) waveform, which is thought to
reflect automatic processing of stimulus change in a repetitive stimulus stream or attentional
switching (85).
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SLEEP EEG IN PATIENTS WITH PRIMARY INSOMNIA 57

Based on ERP studies in good sleepers (77,80,81,85–94) one would expect signs of hyper-
arousal and/or deficits in inhibition in patients with insomnia to appear as larger N1, smaller
P2, and larger P300 amplitudes in wakefulness. One would also expect N350 to be smaller in
poor sleepers. Figure 4 represents the transition from wakefulness to sleep and the changes that
one would expect in patients with chronic insomnia.
To date, there have been two types of studies applying ERPs to investigate the phenomena
of insomnia: (1) a number of studies have examined information processing in patients with
insomnia during wakefulness (95–99) (2) two studies have investigated ERPs at sleep onset or
during early NREM sleep (34,100).

ERPs During Wakefulness

Early studies employing peak-to-peak measurement techniques reported equivocal results with
respect to N1 and P2 amplitude to varying stimulus intensities (95,98). More recent studies
employing baseline to peak measurement provide a clearer picture. Wang et al.(99) examined
MMN during wakefulness while performing a distracter task in patients with insomnia and
in good sleepers. Poor sleepers had larger amplitude MMN at frontal sites that was correlated
with depression and impulsivity scores. These findings reflect hyperactivity in the patient group,
which the authors suggested, was related to weak gating mechanisms.
Devoto et al. (96,97) proposed that waking hyperarousal may be more of a state-like phe-
nomena which would only be associated with a relatively poor night of sleep. To test this, they
investigated ERPs in the morning following a good and poor night of sleep in patients with
primary insomnia compared to good sleepers (99). Insomnia patients had larger P300 ampli-
tudes at Fz compared to good sleepers, but only following a poor night of sleep. Investigators
interpreted the enhanced P300 as cortical hyperarousal, and speculated that it was also present
in the pre-sleep and sleep period. As a follow-up, Devoto et al. (97) then repeated the study with
ERP recordings in both the evening (30 min before bed) and morning (30 min after awakening)
for one week at home (96). They again found that P300 at Fz was enhanced in the poor sleeper
group compared to good sleepers, for the worst but not best night of the week. The authors
concluded that hyperarousal varies night to night with quality of sleep, and that it begins in
the pre-sleep period. In a commentary, Colrain (101) pointed out the preliminary nature of
these data because of the small sample and effect sizes, and the atypical frontal distribution of
the peak.
Taken together, the studies during wakefulness suggest that there is evidence of hyper-
arousal or enhanced information processing and attention during wakefulness in patients with
insomnia. Given the paucity of research in this area, the preliminary nature of many of these
reports, and the disparate methodology, it would be appropriate to further investigate waking
ERPs in order to determine when hyperarousal is present in wakefulness (e.g., only the pre-sleep
onset period or all day; only surrounding subjectively bad nights or as a trait-like phenomena;
or only in some subtypes of insomnia).

ERPs at Sleep Onset and/or During Early NREM Sleep

There are only two published reports which have applied ERPs to the problem of insomnia by
investigating the period of time in which they report their sleep difficulties (34,100). Yang and Lo
(100) examined the first five-minute of stage 2 sleep and found that patients with insomnia had
larger N1 and smaller P2 amplitudes to deviant tones, and smaller N350 amplitude to standard
tones (100). These differences, which were not evident for whole night averages, were taken
to mean that there is an enhancement in attention and a reduction in the inhibitory process at
sleep onset. Although these findings are consistent with a view of hyperarousal, some caution
should be taken in interpretation because the sleep onset period itself was not examined (i.e., the
transition from wake to stage 1 to stage 2), ERPs were averaged from a brief five-minute period,
and K-complexes were not removed from the averages. Moreover, since N1 and P2 changes
were only noted for the rare deviant stimuli, replication is needed to establish reliability of
findings.
Bastien and colleagues investigated good sleepers and patients with psychophysiological
insomnia who had either sleep onset and/or sleep maintenance complaints (34). Waking ERPs
were recorded during evening and morning over four nights, whereas ERPs during sleep onset
IHBK059-06 IHBK059-Sateia March 28, 2010 8:24 Char Count=

58 PERLIS ET AL.

1A. Standard in Wake 2A. Deviant in Wake

−10.0 −10.0
−7.5 −7.5
N1 N1
−5.0 −5.0
−2.5 −2.5
µV 0.0 µV 0.0
2.5 2.5
5.0 P2 5.0 P2
7.5 7.5
10.0 10.0 P300

−100.0 0.0 100.0 200.0 300.0 400.0 500.0 600.0 −100.0 0.0 100.0 200.0 300.0 400.0 500.0 600.0
ms ms

1B. Standard at Sleep Onset 2B. Deviant at Sleep Onset

N350 N350
−10.0 −10.0
−7.5 −7.5
−5.0 N1 −5.0 N1
−2.5 −2.5
µV 0.0 µV 0.0
2.5 2.5
5.0 5.0
P2 P2 P300
7.5 7.5
10.0 10.0

−100.0 0.0 100.0 200.0 300.0 400.0 500.0 600.0 −100.0 0.0 100.0 200.0 300.0 400.0 500.0 600.0
ms ms

GS
PI

Figure 4 Theoretical ERP waveforms following standard and deviant stimuli in good sleepers (GS) and
patients with primary insomnia (PI) in an alert waking state (1A and 2A) and at sleep onset (1B and 2B).
Panel 1A: In attentive wakefulness, GS have a large N1 and a small P2 peak. PIs should have a larger N1 and
smaller P2 depicting heightened attention. PIs may also show the sleep-related N350 reflecting sleepiness. Panel
1B: At sleep onset in GS, N1 decreases to baseline while P2 increases in amplitude reflecting that attention is
disengaged. For PIs, it is expected that N1 might remain large and P2 small (similar to wakefulness) reflecting
failure to inhibit. Research shows a smaller N350 emerging at sleep onset in PIs compared to controls, reflecting
a failure of sleep inhibition processes. Panel 2A: N1 and P2 appear similar following the standard and deviant
stimuli in GS, but it is possible that early sensory processing of the deviant may differ for PIs. In GS, the large
P300 reflects conscious detection of the deviant in waking-attend conditions. Waking P300 has been reported by
Devoto et al to be larger in amplitude for PIs compared to GS reflecting hyperarousal. Panel 2B: In GS, P300 is
diminished at sleep onset (i.e., present in stage 1 when there is a behavioral response but absent in stage 2). For
PIs, it is theorized that P300 may be larger in early or late stage 1 or remain present in stage 2 sleep.

were investigated during a single night. Participants were instructed to ignore tones in a classic
oddball paradigm. In-wake, N1 to the standard tone was larger for patients than controls on
the fourth night at Pz, and larger on the fourth morning at both Cz and Pz sites. There were no
P2 or P300 differences. These data are in agreement with some previous reports of increased N1
in wakefulness reflecting hyperarousal and attentiveness (98,100). To examine the sleep onset
period, ERPs were averaged to stimuli presented from lights out to any sign of stage 2 sleep,
and the K-complexes were appropriately excluded from averages. The authors observed that
N350 was smaller in patients with insomnia compared to good sleepers at sleep onset, which
reflects a failure of the inhibition processes needed to initiate sleep. In addition, the authors
observed a smaller N1 to standards at Cz, and a larger P2 to deviants at Pz in patients with
IHBK059-06 IHBK059-Sateia March 28, 2010 8:24 Char Count=

SLEEP EEG IN PATIENTS WITH PRIMARY INSOMNIA 59

insomnia compared to good sleepers. These results are contrary to what would be expected
based on selective attention research, (77) and what has been found to date with waking ERPs
in patients with insomnia. Replication is necessary given that only a single sleep onset period
was observed, ERPs were collapsed across wake and stage 1, and results were not consistent at
all sites or apparent in both categories of stimuli.
The data from these two reports of ERPs at sleep onset and during early NREM sleep are in
agreement in some respects, but not others. It is thus important that this area be pursued through
further study. It is necessary that researchers collect enough ERP trials for reliable averaging (e.g.,
through more stimuli delivered, and more subjects or multiple nights). The findings on N350 are
most compelling to date; N350 may be a sensitive metric of deficits in information processing
associated with sleep initiation problems in particular. It will also be important to carefully select
patient samples, by ensuring they do not have comorbid medical conditions and by system-
atically investigating differences between qualitatively different types of insomnia (e.g., sleep
onset versus maintenance complaints). Finally, the sleep period itself needs to be more system-
atically investigated, particularly for those with sleep maintenance complaints, to investigate
information processing in NREM stages at various times of night and in REM sleep periods.

CONCLUDING COMMENTS
In many ways, the assessment of the sleep EEG in primary insomnia is in its infancy. This is
ironic in that that insomnia is likely to be the oldest established diagnostic entity of the various
sleep disorders and it was likely the first to be studied with most, if not all, EEG techniques.
This said, it is an inescapable fact that each methodological approach has been applied to the
problem of insomnia in only a few dedicated studies where each of the studies are generally
on very small samples. Thus, at this point in time, it is difficult to definitively say whether
subjects with primary insomnia reliably exhibit any form of abnormal sleep EEG and it is
nearly impossible to make claims about how the types (e.g., psychophysiologic, paradoxical,
idiopathic insomnia) subtypes (i.e., initial, middle, late or mixed insomnia) or the comorbid
insomnias (insomnia comorbid with psychiatric or medical illnesses) are similar to, or different
from, primary insomnia on EEG measures.
At the present time, the following claims can be made, albeit tentatively
r Sleep continuity disturbance as measured by PSG tends to be more normal than is measured
by self-report. This suggests that there is a tendency to report more insomnia severity
than exists or that patients are reporting phenomena that are not properly assessed by
polysomnography (102).
r Sleep architecture does not appear reliably altered in patients with primary insomnia, and to
the extent that trends are evident they exist as modest alterations to SWS and REM sleep. This
suggests that systems that are responsible for the regulation of these forms of sleep are not
related to sleep induction and maintenance. This said it seems likely that SWS (as it related
to sleep homeostasis) would be altered in insomnia (103). Resolution of effects within this
domain may require more than naturalistic studies but instead challenge paradigms that use
sleep deprivation, pharmacologic probes or treatment as ways of assessing the functioning
of these systems.
r QEEG abnormalities have been reported where the primary finding is in terms of elevated
beta/gamma frequency activity around sleep onset and during NREM sleep (104). These
findings have been interpreted as supporting that hyperarousal is a primary etiologic factor
in insomnia.
r CAP irregularities have been shown to be correlated with self-reported sleep quality and to
be associated with treatment outcome. These findings have been interpreted as supporting
that hyperarousal is a primary etiologic factor in insomnia.
r ERP activity appears to be altered in patients with insomnia. As compared to healthy controls,
patients with primary insomnia (during sleep onset and/or early NREM sleep) tend to
exhibit larger N1 and smaller P2 amplitudes to deviant tones, and smaller N350 amplitudes
to standard tones. These findings suggest that insomnia (around sleep onset and during
NREM sleep) is characterized by both elevated CNS activation and by an attenuation of the
processes that serve to inhibit sensory and information processing.
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60 PERLIS ET AL.

Given the tenuousness of the present sleep EEG findings, further studies are clearly
indicated. The problem with the “call” for further research is that there is a fundamental
disagreement about whether insomnia merits targeted research. The lack of merit owes to a
variety of factors including (1) the widespread belief that insomnia is only a symptom; and
(2) that insomnia, when considered a primary disorder, does not have significant medical,
psychiatric, personal or social consequences.
The former is a conceptual issue that has been under siege from within the sleep commu-
nity for nearly a decade (105,106). At present it is commonly held (within the sleep community)
that insomnia is disorder which, when it occurs with other medical and/or psychiatric illness,
is best characterized as a comorbid disorder. This change in perspective, which has yet to gain
wide spread acceptance outside the sleep community, carries with it the implication that fur-
ther research is warranted and likely to be fruitful with respect to the delineation of specific
biological correlates.
The latter is an empirical issue. That is, there needs to be enough research that demonstrates
the medical, psychiatric, personal or social effects of insomnia to persuade the larger science and
medical communities of the importance of conducting the research needed to reach a detailed
consensus view on the pathophysiology of insomnia based on sleep EEG techniques as well
as other approaches ranging from animal models to functional and anatomical imaging for
both global and regional activation in human subjects (107–109) and the profiling of specific
neurotransmitter system activity (110).

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7 Neurobiological Disturbances in Insomnia:

Clinical Utility of Objective Measures of Sleep
Slobodanka Pejovic and Alexandros N. Vgontzas
Sleep Research and Treatment Center, Department of Psychiatry, Penn State University College of Medicine,
Hershey, Pennsylvania, U.S.A.

INTRODUCTION
Insomnia is, by far, the most commonly encountered sleep disorder in medical practice. Its
prevalence varies considerably based on the definition used. While one-fourth to one-third of
the general population reports a complaint of difficulty falling and/or staying asleep, about 10%
present chronic complaints and seek medical help for insomnia (1–11). However, insomnia has
always been and still is an underrecognized and therefore undertreated problem, since about
60% of the people suffering from insomnia never discuss their sleeping difficulties with their
physicians (12,13).
Relatively little is known about the mechanisms, causes, clinical course, and consequences
of this highly prevalent chronic condition (14). Insomnia occurs more frequently in women as
well as in middle aged and older adults. Many studies have established that insomnia is highly
comorbid with psychiatric disorders and is a risk factor for the development of depression,
anxiety, and suicide (14,15). However, despite the evidence that insomnia has significant public
health implications, including impaired occupational performance, increased absenteeism at
work, higher health care costs, and decreased quality of life, there is a paucity of data linking
chronic insomnia with significant medical morbidity, for example, cardiovascular disorders.
This paucity may in part be due to our limited understanding of its neurobiology.

NEUROBIOLOGY OF INSOMNIA: THE HYPERAROUSAL MODEL

Early studies from the 1970s pointed to the presence of increased physiological activation in
insomnia patients before and during sleep (16). At about the same time, it was reported that
insomnia is associated with depression, anxiety, rumination, and inhibition of emotions (16).
These findings from biological and psychometric studies led to the formulation of the hypothesis
that insomnia is a disorder of physiologic and emotional arousal. These early studies have been
enhanced by more recent studies that evaluated various aspects of neurobiology in insomnia
patients and suggest that insomnia is a disorder of hyperarousal present through 24-hour
sleep/wake cycle rather than a disorder of sleep loss. In this section, we will review data
suggesting that hyperarousal may be a core neurobiological mechanism of chronic insomnia
and its degree is associated with objective measures of sleep.

AUTONOMIC CHANGES IN INSOMNIA

An early study comparing “good” and “poor” sleepers showed that the poor sleepers’ rectal
temperature and peripheral vasoconstriction were elevated during a 30-minute presleep period
as well as during sleep. Also, during sleep poor sleepers had more body movements and higher
skin resistance compared to controls (17). In two other early studies, insomniacs were found to
have higher levels of muscle tension compared to controls, as measured by frontalis EMG activ-
ity before sleep (18,19). Additionally, insomnia patients had lower levels of finger temperature
than controls prior to sleep; this is consistent with the inverse relationship between core body
temperature and distal peripheral temperature (18,20). Furthermore, a more recent study inves-
tigating core body temperature in aged insomniacs in comparison to controls showed increased
core body temperature prior to their habitual sleep onset time at home that persisted during
the wakeful constant routine night until early in the morning (21). Finally, in a group of insom-
nia patients with polysomnographically verified sleep disturbance, a significantly increased
pupil size was observed compared to controls indicative of sympathetic system activation (22).
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66 PEJOVIC AND VGONTZAS

In contrast, two other studies, in which diagnosis of insomnia was based on subjective measures
only, showed opposite results, that is, decreased pupil size (23,24). Overall, these studies show
that poor sleepers, particularly those with objective sleep disturbance, exhibit increased levels
of autonomic system activity compared to good sleepers before and during sleep.

HEART RATE
Heart rate variability is under the control of the sympathetic nervous system activity and
represents another measure of physiologic arousal in humans. An early study by Monroe (17)
showed significantly increased heart rate 30 minutes before sleep in insomniacs as compared
to normal sleepers. During sleep, their heart rate was slightly, but not significantly, faster.
Similarly, in another study insomniacs were found to have increased heart rate prior to sleep,
but these differences were not present during sleep (18). In contrast to these early studies, two
more recent studies found significant changes in nocturnal heart rate and heart rate variability
when comparing insomnia patients who also met objective criteria of sleep disturbance to
normal sleepers (25,26). Specifically, in a 36-hour laboratory study, sleep and EKG measures
were evaluated in insomnia patients and age-, gender-, and BMI (body mass index)-matched
controls. Heart period was decreased, that is, heart rate was increased, and heart rate variability
was decreased in all sleep stages in insomniacs as compared to good sleepers. Furthermore,
spectral analysis of heart rate variability revealed significant increase in low frequency reflecting
sympathetic system activity and decrease in high-frequency power reflecting parasympathetic
system activity in insomniacs as compared to controls. Those changes were present across
all sleep stages. The authors concluded that chronic insomniacs could be at higher risk for the
development of disorders associated with increased sympathetic system, such as coronary artery
disease (25). The other study assessed heart rate in chronic insomnia patients with objective sleep
disturbance and normal sleepers before sleep, during sleep, and in response to acute stress (i.e.,
stressful performance task given in the morning after a night of sleep recording) (26). Nocturnal
heart rate was significantly higher in insomniacs. The morning after no difference was found in
heart rate between the two groups, but there was a significant increase in heart rate during the
stressful performance task. The lack of significant increase in nocturnal heart rate in insomnia
groups in two early studies may be due to the fact that insomnia was defined only subjectively
in contrast to the two recent studies, in which insomniacs met both subjective and objective
polysomnographic criteria.

METABOLIC FUNCTION

Whole Body Metabolic Rate

Two recent studies by Bonnet and Arand investigated whole body metabolic rate in insomnia
patients by measuring overall oxygen consumption (VO2 ), which is considered an index of
whole body metabolic rate. In a study that assessed whole body VO2 for 36 hours in insom-
nia patients with polysomnographically documented sleep disturbance, VO2 was constantly
elevated at all measurement points in insomnia patients as compared to carefully matched con-
trols (Fig. 1) (27). The nocturnal increase remained significant even after eliminating from the
data set metabolic values from periods during the night that contained wake time or arousals.
The authors concluded that the chronic insomnia patients may suffer from a more general
disorder of hyperarousal that may be responsible for their daytime symptoms as well as poor
nighttime sleep. Another study assessed whole body VO2 in patients with “sleep state misper-
ception” (“paradoxical insomnia”), a condition in which patients perceive their sleep as poor
but whose polysomnographic parameters do not significantly differ from those of matched
controls (28). Whole body metabolic rate over the 24-hour period as measured by VO2 was
significantly increased in “sleep state misperception insomnia patients” compared to controls
but to a lesser degree compared to insomnia patients with polysomnographically documented
sleep disturbance (27,28). Additionally, in experimentally induced insomnia, by using 400 mg of
caffeine three times a day for seven consecutive days young healthy adults exhibited increased
whole body metabolic rate, reduced total sleep time and sleep efficiency, and increased wake
time after sleep onset, sleep latency, and MSLT values (29). Collectively, these studies yield the
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NEUROBIOLOGICAL DISTURBANCES IN INSOMNIA: CLINICAL UTILITY OF OBJECTIVE MEASURES OF SLEEP 67

340
INSOMNIACS
CONTROLS
320

300
VO2 (mL/min)

280

260

240

220

200
5 10 15 20 25 30 35
Time (hr)

Figure 1 Average best fit VO2 in groups of insomnia patients and normal controls as a function of time of day.
The data represent averaged best fit third degree polynomials. A marker has been added at the right and left
margin of both lines to indicate the group. The average t = 13.10, P < 0.0001.

conclusion that increased whole body metabolic rate is primarily present in insomnia patients
with objective short sleep duration.

Brain Metabolic Activity

Recently, functional neuroimaging techniques have been used to assess cerebral glucose
metabolism and changes in brain neurochemistry in different brain regions during sleep and
wakefulness in insomnia patients and healthy controls. In a study that compared PET imag-
ing data obtained from insomnia patients and healthy controls during wakefulness as well as
during nonrapid eye movement (NREM) sleep states, the patients showed significantly greater
cerebral glucose metabolism during NREM sleep and while awake (30). Additionally, insomnia
patients had a smaller decline in relative glucose metabolism from waking to sleep states in
regions that promote wakefulness, that is, ascending reticular activating system, hypothalamus
and thalamus, and reduced relative glucose metabolism in the prefrontal cortex during wake-
fulness. The authors concluded that disturbed sleep in insomnia patients is associated with
greater brain metabolism and that inability to fall asleep may be related to failure of arousal
mechanisms to decrease in activity from waking to sleep states. In another study, using PET
imaging technique, the same authors investigated the NREM sleep-related cerebral metabolic
correlates of sleep disturbance as measured by wake time after sleep onset (WTASO) in patients
with primary insomnia. Both objective and subjective WTASO were positively correlated with
relative metabolism in pontine tegmentum and in thalamocortical networks and this may be
the result of increased activity in arousal systems (31). Finally, a recent study reported a 30%
reduction of GABA in insomnia patients as compared to controls and a significant negative cor-
relation between GABA levels and WTASO in insomnia patients after adjusting for age, BMI,
and gender (32).
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68 PEJOVIC AND VGONTZAS

NEUROENDOCRINE CHANGES IN INSOMNIA

Hypothalamic–Pituitary–Adrenal Axis
Stress has been associated with the activation of the hypothalamic–pituitary–adrenal (HPA)
axis, while corticotrophin-releasing hormone (CRH) and cortisol, products of the hypothalamus
and the adrenals, respectively, are known to cause arousal and sleeplessness in humans and
animals. On the other hand, sleep, and particularly deep sleep, has an inhibitory effect on
the stress system, including its two major components, the HPA axis and the sympathetic
system (33).
In the past, few studies have assessed cortisol levels in insomnia patients and their results
were inconsistent. Two reported no difference between good and poor sleepers in urinary
24-hour cortisol or 17-hydroxysteroid (17-OHCS) excretion (34,35), whereas a third reported a
significantly higher 24-hour rate of urinary free 11-hydroxycorticosteroid (11-OHCS) excretion
in young adult poor sleepers as compared to young adult normal sleepers (36).
More recently, in a preliminary study that investigated the possible association between
chronic insomnia and the activity of the stress system, mean 24-hour urinary free cortisol
(UFC) levels, although within the normal range, were correlated positively with indices of sleep
disturbance, that is, total wake time (TWT) (37). In a following controlled study that tested
24-hour serial adrenocorticotropic hormone (ACTH) and cortisol level in young adult insomnia
patients and age- and BMI-matched healthy controls, ACTH and cortisol were significantly
higher in insomniacs (Fig. 2) (38). Within the 24-hour period the strongest elevations were
observed in the evening and during the first half of the night. Furthermore, within the group of
insomnia patients, the subgroup with high degree of objective sleep disturbance [percent of total
sleep time (%TST) <70] had higher amount of cortisol compared to the subgroup with low degree
of sleep disturbance (Fig. 3). Finally, pulsatile analysis revealed a significantly higher number of
ACTH and cortisol pulses in insomnia patients as compared to normal sleepers, while cosinor
analysis indicated a significant circadian rhythm without differences in the temporal pattern of
ACTH and cortisol secretion between the two groups. Hence, this study suggests that insomnia
is associated with an overall 24-hour increase in ACTH and cortisol secretion, which nonetheless
retains a normal circadian pattern. Based on these two studies the authors concluded that in
chronic insomnia (i) the activity of the stress system is directly proportional to the degree of
objective sleep disturbance and (ii) polysomnographic measures can provide a reliable index of
the biological impact and severity of chronic insomnia (37,38). Similarly, a recent study assessing
plasma cortisol levels in patients with severe chronic primary insomnia found that evening
and nocturnal cortisol levels were significantly increased in insomnia patients as compared to
controls (39). Finally, a study that investigated the effects of the tricyclic antidepressant doxepin
on nocturnal sleep and plasma cortisol levels in patients with primary insomnia showed that
doxepin improved sleep and reduced mean cortisol levels suggesting that beneficial effects of
the medication are at least partially mediated by the normalization of the HPA axis (40).
Contrary to the above findings, two studies found no increase in cortisol secretion in
insomnia patients. It appears that the difference between these two groups of studies is the
degree of polysomnographically documented sleep disturbance. For example, in a study by
Rodenbeck et al. (39) the correlation between area under the curve (AUC) of cortisol and
percentage sleep efficiency was 0.91 suggesting that high cortisol levels are present in insomnia
patients with an objective short sleep duration. In contrast, in a study by Riemann et al. (41),
in which no cortisol differences were observed between insomnia patients and controls, the
objective sleep of insomniacs was very similar to that of controls, that is, sleep efficiency of 88.2%
versus 88.6%. Furthermore, in a study that applied constant routine conditions, all indices of
physiological arousal were increased but not to a significant degree due to lack of power and
uncareful selection of controls (42,43). Interestingly, in this study a visual inspection of cortisol
data suggested an elevation of cortisol values of 15% to 20% in the insomnia group, a difference
similar to that reported in a study by Vgontzas et al. and is considered of clinical significance
(37,42).
Similar findings have been reported in a community sample investigating evening and
morning saliva cortisol levels in 393 children of ages 5 through 11 (44). A univariate analysis
controlling for BMI percentile, age, and gender demonstrated significantly higher morning
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NEUROBIOLOGICAL DISTURBANCES IN INSOMNIA: CLINICAL UTILITY OF OBJECTIVE MEASURES OF SLEEP 69

14 3.5 * 21:00–00:30
3.0

2.5

ACTH pmol/L
12 2.0

1.5

1.0

10 0.5

0.0
ACTH (pmol/L)

0
08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:00 02:00 04:00 06:00
Time (clock hours)

550
180 * 21:00–00:30
160
500
140
Cortisol nmol/L

120
450 100
80

400 60
40
20
Cortisol (nmol/L)

350 0

300

250

200

150

100

50

0
08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:00 02:00 04:00 06:00
Time (clock hours)

b
Figure 2 The 24-hour plasma ACTH (top) and cortisol (bottom) concentrations in insomnia patients (
) and
controls ( ). The thick black line on the abscissa indicates the sleep-recording period. Error bar indicates SE,
∗ P < 0.01.
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70 PEJOVIC AND VGONTZAS

24

22

20

18

16

14
Cortisol (µg/dl)

12

10

0
08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:00 02:00 04:00 06:00
Clock time

Figure 3 The 24-hour circadian secretory pattern of cortisol in insomnia patients with low TST () and high ( ) r
TST. The thick black line on the abscissa indicates the sleep-recording period. Error bar indicates SE, ∗ P < 0.05.

levels of cortisol in the insomnia group with objective low sleep efficiency than in both the
control group and insomnia group without objective low sleep efficiency. Evening cortisol
levels were also significantly higher in the insomnia group with objective low sleep efficiency
than in the insomnia group without objective low sleep efficiency. It appears that childhood
insomnia combined with objective low sleep efficiency is associated with high cortisol levels.
The findings of the 24-hour HPA axis activation in primary insomnia are consistent with a
disorder of central nervous system hyperarousal rather than one of sleep loss, which is usually
associated with no change or a decrease in cortisol secretion. Most of the studies investigating
the effects of sleep loss on cortisol secretion have found no change or decrease in the secretion of
cortisol after sleep deprivation. On the other hand, in studies that reported significant increase
of cortisol in the evening following the night of sleep loss, sleep deprivation was associated with
rather stressful experimental conditions, that is, lying in bed in a dimly lit room and receiving
calories through an IV catheter (45–51). Also, the higher evening cortisol levels reported in
studies where sleep was curtailed at the beginning of the night may represent a change of
the 24-hour secretory pattern, for example, a shift of the nadir point of cortisol secretion later
at night.

Catecholamines
Sympathetic system activation results in the release of norepinephrine from sympathetic nerve
terminals and in the secretion of epinephrine from the adrenals.
In an early study that investigated urinary epinephrine levels in middle-aged good and
poor sleepers no significant difference was found, although there was a trend toward higher
epinephrine levels in poor sleepers (35).
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NEUROBIOLOGICAL DISTURBANCES IN INSOMNIA: CLINICAL UTILITY OF OBJECTIVE MEASURES OF SLEEP 71

Wake time after sleep onset (min)

70 70 70
60 rxy = 0.49 P = 0.07 60 rxy = 0.58 P = 0.03 60 rxy = 0.53 P = 0.05

50 50 50
40 40 40
30 30 30
20 20 20
10 10 10
0 0 0
0 10 20 30 40 50 60 0 500 1000 1500 20 30 40 50 60 70 80 90 100
Norepinephrine (µg/24 hr) DOPAC (µg/24 hr) DHPG (µg/24 hr)

Figure 4 Correlation between wake time after sleep onset with 24-hour urinary NE, DHPG, and DOPAC.

About 10 years ago, Vgontzas et al. (37) in a preliminary study in young chronic insomnia
patients correlated 24-hour catecholamines levels with polysomnographic measures of sleep
architecture and continuity. Catecholamine metabolites, DHPG (dihydroxyphenylglycol), and
DOPAC (3,4-dihydroxyphenylacetic acid) were positively correlated with percentage stage 1
(%ST1) sleep and WTASO, while norepinephrine tended to be significantly positively asso-
ciated with %ST1 and WTASO and negatively associated with percentage slow wave sleep
(%SWS) (Fig. 4). In the same study, growth hormone (GH) was detectable in a small percent
of the participants suggesting that GH axis may be suppressed in chronic insomniacs. These
findings were further supported by a controlled study, which found that circulating levels of
norepinephrine during the nocturnal period were elevated in patients with primary insomnia
compared to patients with major depression and normal controls (52). Additionally, sleep effi-
ciency was negatively correlated with norepinephrine levels in insomnia patients but not in
the controls or depressives. Those findings together indicate that sympathetic nervous system
activity as measured by cathecholamines levels is increased in chronic insomnia patients with
objective sleep disturbance.
Finally, based on the previous reports that insomnia with objective short sleep duration
is associated with hypercortisolemia, increased catecholaminergic activity, and increased auto-
nomic activity (e.g., increased heart rate and 24-hour metabolic rate and impaired heart rate
variability), a recent study examined the relationship between insomnia and hypertension in a
large general population sample using objective measures of sleep, that is, polysomnography
(53). After controlling for age, gender, race, BMI, diabetes, smoking, alcohol use, depression,
and sleep disordered breathing, chronic insomnia with objective short sleep duration was found
to be associated with a high risk for hypertension suggesting that objective measures of sleep
duration of insomnia may serve as clinically useful predictors of the medical severity of chronic
insomnia.

IMMUNE SYSTEM CHANGES IN INSOMNIA

Proinflammatory Cytokines in Insomnia

Proinflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor ␣ (TNF ␣), are consid-
ered to induce sleepiness and fatigue (48,54–57). Insomnia patients frequently report daytime
fatigue and sleepiness, poor concentration, and inattention (16). In a study in which a potential
role of IL-6 and TNF␣ secretion in mediating daytime fatigue was investigated, 24-hour plasma
levels of IL-6 and TNF␣ were compared between insomnia patients and normal sleepers (58).
Although mean 24-hour circulating levels of cytokines were not different between the two
groups, IL-6 levels were elevated significantly in insomnia patients compared to controls in the
mid-afternoon and evening presleep period (5–11 p.m.). Furthermore, cosinor analysis of IL-6
levels showed a significant shift of the peak secretion from nighttime to evening in the insomnia
group (Fig. 5). Moreover, the characteristic circadian TNF␣ secretion with a peak close to the
sleep offset, which was found in the normal sleepers, was not present in the insomnia patients,
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72 PEJOVIC AND VGONTZAS

7 3.5

6
3.0

TNF (pg/mL)
IL-6 (pg/mL)

2.5
4

3 2.0

2
1.5

1
0.0
8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:00 02:00 04:00 06:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:00 02:00 04:00 06:00

Clock time Clock time

r
Figure 5 The 24-hour circadian secretory pattern of IL-6 (left) and TNF␣ (right) in insomnia patients () and
controls ( ). The thick black line on the abscissa indicates the sleep-recording period. Error bar indicates SE, ∗ P
< 0.05.

whereas their TNF␣ secretion was characterized by a regular 4-hour rhythm, a pattern that
was not present in the normal sleepers group. Based on these findings, the authors concluded
that chronic insomnia is associated with a shift of IL-6 and TNF␣ secretion from nighttime to
daytime, which may explain the daytime fatigue and performance decrements associated with
this disorder. Another recent study of IL-6 secretion in chronic insomnia patients of wide age
range showed a significant increase in nocturnal IL-6 levels in insomnia patients compared to
controls (59).
Cytokine secretion is elevated in disorders of “true” excessive daytime sleepiness defined
by falling asleep quickly in objective daytime sleep testing [multiple sleep latency test (MSLT)],
that is, sleep apnea and narcolepsy, and in healthy individuals experiencing daytime sleepiness
secondary to acute and short-term total or partial sleep loss. Cytokine peripheral levels are also
elevated in insomnia patients who experience “fatigue” but not true “sleepiness,” that is, not
falling asleep quickly in objective daytime sleep testing (48,49,54,56,60,61). What modulates the
effect of cytokines so that in one instance they are associated with true “sleepiness” and in
another with “fatigue”? Based on accumulated evidence, we proposed that it is the interaction
of cytokines and cortisol secretion that determines sleepiness versus fatigue (61). Specifically,
the hypersecretion and/or circadian alteration of the cytokines secretion associated with an
HPA axis activation may explain the fatigue and poor sleep associated with insomnia (38,58).
In contrast, hypersecretion and/or circadian alteration of the cytokines that is not associated
with HPA axis activation, that is, sleep deprivation in normal sleepers, may explain their true
sleepiness and poor sleep (48,49,58,62).

HORMONAL CHANGES ASSOCIATED WITH MIDDLE AGE AND MENOPAUSE

INCREASE VULNERABILITY TO INSOMNIA
The role of psychological characteristics, such as certain personality traits and inadequate cop-
ing mechanisms, as vulnerability factors increasing the susceptibility for insomnia is well-
documented. However, our knowledge on physiologic changes that may predispose to insom-
nia is very limited. The prevalence of insomnia increases during middle and old age. Up to
40% of the general population reports difficulties in falling or staying asleep in middle age in
contrast to about 20% of young subjects (16). It has been assumed that this increase is a result of
increasing prevalence of comorbid psychiatric and medical conditions. Recently, studies have
suggested that physiologic factors, such as age-related sleep changes, can also increase the
vulnerability to insomnia. In order to investigate if middle age is associated with increased
sensitivity to the sleep-disturbing effects of the HPA axis, a recent study examined the effects of
exogenous administration of CRH, a hormone with an arousing/waking effect, in middle aged
vs. young men. Although both middle aged and young men responded with similar elevations
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NEUROBIOLOGICAL DISTURBANCES IN INSOMNIA: CLINICAL UTILITY OF OBJECTIVE MEASURES OF SLEEP 73

of ACTH and cortisol, wakefulness increased significantly only in the middle-aged group (63).
This increase was more pronounced during the first half of the night. Moreover, CRH admin-
istration caused a significant reduction of SWS only in the middle-aged group. These findings
suggest that middle-aged men as compared with the young are more vulnerable to the arousing
effects of CRH. Therefore, the increased prevalence of insomnia in middle age may be the result
of deteriorating sleep mechanisms associated with increased sensitivity to arousal-producing
stress hormones, such as CRH and cortisol, rather than to increased life stresses during this
period. This suggests that a middle-aged individual compared with a young individual is at a
significantly higher risk of developing insomnia when faced with equivalent stressors.
Disturbed sleep also is a common complaint of women entering the menopause phase of
life. A recent study investigating the objective sleep patterns associated with menopause and
hormonal replacement therapy (HRT) in a large population sample found that the objective
sleep of postmenopausal women without HRT was worse than that of men matched for age and
postmenopausal women on HRT (64). Specifically, menopause appears to have a negative effect
on sleep latency (SL) and SWS, that is, postmenopausal women without HRT had a longer SL
and less SWS than women on HRT and compared with men. SL was not significantly different
between premenopausal women and men as well as between menopausal women with HRT and
men. However, postmenopausal women without HRT had significantly longer SL compared
to men and compared to women with HRT. Furthermore, postmenopausal women without
HRT were less likely to have SWS compared to those with HRT. These objective findings are
consistent with the complaint of poor sleep in some postmenopausal women as well as the
symptomatic relief reported by those on HRT (65–72). These data are also consistent with early
epidemiological findings from a large community cohort in which there was a greater increase
of prevalence of insomnia in women compared to men in middle age, a difference that could
not be explained by changes in the prevalence of psychiatric disorders such as depression or
anxiety (73).

CONCLUSION
Consistent data from numerous biological studies conducted over the 30-year period and
assessing different physiological domains including autonomic nervous system status, heart
rate, sympathetic system and HPA axis activity, whole body and brain metabolic rate, and
immune system basal activity suggest that (i) insomnia is a disorder of physiologic hyper-
arousal present throughout 24-hour sleep–wake cycle and (ii) insomnia and sleep loss are two
distinct states. Central nervous system hyperarousal, either as preexisting and/or induced by
psychiatric pathology and worsened by stressful events, as well as aging- and menopause-
related physiological decline of sleep mechanisms appears to be at the core of this common
sleep disorder. Finally, there is emerging evidence that the levels of physiologic hyperarousal
are directly related to the degree of polysomnographically documented sleep disturbance in
insomnia patients, suggesting that objective measures of sleep duration in insomnia may be a
useful marker of the biological severity of the disorder.

ACKNOWLEDGMENTS
We thank Barbara Green for overall preparation of the manuscript and Athanasia F. Vgontzas
for editing of the manuscript.

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8 Brain Imaging in Insomnia

Eric A. Nofzinger
Sleep Neuroimaging Research Program, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION
Clinically, insomnia patients describe overactive minds that do not turn off at night to allow
them to sleep. This chapter will review brain imaging studies that comment on whether or
not there is abnormal brain function in insomnia patients that may in some way relate to
their difficulty sleeping. Interpretations will be aided by review of relevant preclinical studies
of the neurobiology of sleep and recent neuroimaging studies in healthy humans across the
sleep/wake cycle. The organization of this paper will follow a systems neuroscience view of a
hierarchical arousal network in the central nervous system. Abnormalities in any component of
this interactive system may produce insomnia complaints. Finally, evidence will be presented
as to the location where interventions may impact on regional brain function in insomnia
patients.

BRAINSTEM, HYPOTHALAMUS, AND BASAL FOREBRAIN

Preclinical research has identified the basic, or most primitive, circuits in the brain that are
responsible for promoting arousal (1,2). A major component of this network is the brain-
stem reticular core, a diffuse network of predominantly glutamatergic long-projecting neu-
rons and a smaller collection of presumed local circuit GABA neurons. Additional components
include a collection of nuclei in the brainstem tegmentum dorsal to the reticular formation
that include cholinergic and monoaminergic (serotonergic, noradrenergic, and dopaminergic)
neurons. These nuclei send rostral projections that are parallel and interconnected with those
of the brainstem reticular core. Cholinergic nuclei are also clustered rostrally in the basal fore-
brain including septal nuclei and the diagonal band of Broca. Recent attention has focused
on the hypothalamus playing a significant role in arousal and in homeostasis. Specifically, the
tuberomamillary histaminergic neurons and the perifornical hypocretin neurons in the posterior
hypothalamus have extensive interconnections and interactions with the basic arousal systems.
Human sleep neuroimaging studies in healthy subjects support the involvement of these
basic arousal networks in NREM sleep. Blood flow has been shown to negatively correlate
with the presence of NREM sleep in the pontine reticular formation (3–5) and in the basal
forebrain/hypothalamus (3,5). Reduction of activity in this network from waking to sleep is
consistent with their role in promoting arousal and potentially in initiating sleep.
Human sleep neuroimaging studies in insomnia subjects support the involvement of
these basic arousal networks in disturbances in NREM sleep (6). Nofzinger et al. investigated
the neurobiological basis of poor sleep in insomnia. Insomnia patients and healthy subjects
completed regional cerebral glucose metabolic assessments during both waking and NREM
sleep using [18 F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). Healthy
subjects reported better sleep quality than did insomnia subjects. The two groups did not differ
on any measure of visually scored or automated measure of sleep. A group × state interaction
analysis confirmed that insomnia subjects showed a smaller decrease than did healthy subjects
in relative metabolism from waking to NREM sleep in the brainstem reticular core and in the
hypothalamus. This study supports the concept that persistent activity in this basic arousal
network may be responsible for impaired objective and subjective sleep in insomnia patients.
In terms of interventions, the mechanism of action of sedative hypnotics may be primarily
on these basic arousal systems. For example, Kajimura et al. (7) assessed regional cerebral blood
flow during NREM sleep in response to triazolam, a short acting benzodiazepine sedative
hypnotic. They found that blood flow in the basal forebrain was lower during NREM sleep
following triazolam administration than following placebo.
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78 NOFZINGER

A recent study aimed to determine if eszopiclone, a nonbenzodiazepine cyclopyrrolone,

reversed the pattern of brainstem, hypothalamus, and basal forebrain abnormalities found in
insomnia patients (8). In this study, 106 subjects were screened, 23 received in person assess-
ments and 12 met DSM-IV criteria for primary insomnia. Of these, 8 subjects (4 women/
4 men, mean age + s.d. = 35 + 13 years) completed two weeks eszopiclone 3 mg qhs open label
treatment. Pre and posttreatment assessments included sleep diary, three nights of polysomnog-
raphy, and waking and NREM sleep [18 F]-FDG PET scans. Paired t-tests were performed on
subjective and EEG sleep data. Voxel-based repeated measures ANCOVA (group = pre vs. post,
repeated measure = regional cerebral metabolism in waking and sleep, covarying for global
metabolism) were performed on cerebral metabolic data. From pre to posttreatment, insomnia
patients showed improvements in all subjective measures of sleep, sleep quality, mood, and
next morning alertness [e.g., Pittsburgh Sleep Quality Index Total = 11.9 + 2.5 pre vs. 7.5 + 2.3
posttreatment, paired t(7) = 3.86, P = 0.006]. Patients showed increases in stage 2 sleep and REM
latency and decreases in stage delta sleep from pre to posttreatment. Brain imaging analyses
showed that the reduction in relative metabolism in an arousal network from waking to NREM
sleep was greater following eszopiclone treatment than before. Specific regions included the
pontine reticular formation and ascended into the midbrain, subthalamic nucleus, culmen of
the cerebellum, and thalamus. Related neocortical areas showing this interaction included the
orbitofrontal cortex, superior temporal lobe, right paracentral lobule of the posterior medial
frontal lobe, right precuneus, dorsal cingulate gyrus, and portions of the frontal lobe. Compar-
isons involving only sleep, but not wake, revealed similar regions of posttreatment reductions
in relative metabolism. These results demonstrate that eszopiclone reverses a pattern of cen-
tral nervous system hyperarousal in insomnia patients. This effect is most pronounced during
NREM sleep, at a time when the concentration of eszopiclone in the brain, when given prior to
sleep, should be highest. The inhibitory actions of eszopiclone, and likely similar nonbenzodi-
azepine sedative hypnotics and potentially the benzodiazepine sedative hypnotics, then, that
are likely responsible for the sedating properties of these medications, appear to be largely on
a CNS arousal neural network within sleep that includes the pontine and midbrain reticular
activating system.

LIMBIC AND PARALIMBIC SYSTEM

Behaviorally, maintaining an alert brain serves broader functions than a simple homeostatic one
related to sleep at night. It allows an individual to adapt in an efficient manner to a variety of
salient events in real time while awake. Importantly, the basic biology of arousal can be modified
by neural systems that regulate emotional and goal-directed behavior. These systems may play
an important role in modulating or perpetuating the increased arousal of insomnia patients.
This is especially true given the significant epidemiologic and neurobiological overlaps between
insomnia and mental disorders.
The results of preclinical, healthy human, and depressed human neuroimaging studies
support the importance of two neural systems in emotional behavior (9). A more ventrally
located system, with important contributions from the amygdala, has been shown to be fun-
damental to the initial experience of emotions and to the automatic generation of emotional
responses. The function of this system is a reactive one in response to emotional stimuli. Other
structures related to this system include the anterior insula, ventral striatum, and ventral regions
of the anterior cingulate cortex and ventral prefrontal cortex. A more dorsally located system,
with important contributions from the dorsolateral prefrontal cortex, has been shown to be fun-
damental to the conscious, planned regulation of emotional behavior in light of future behavior.
The function of this system is one of planning behavior in response to emotional stimuli. Other
structures related to this system include the hippocampus and dorsal regions of the anterior
cingulate cortex. A primary structure in the ventral system is the amygdala. It has been shown
to participate in the sensory component of emotional behavior and in the initial organization of
a reactive emotional response. In humans, the amygdala shows increased activation in response
to a variety of emotional stimuli including fearful (10), and sad (11) faces, threatening words (12),
and fearful vocalizations (13). A reactive “motor” role for the amygdala includes the recruit-
ment and coordinating of cortical arousal and vigilant attention for optimizing sensory and
perceptual processing of stimuli associated with underdetermined contingencies (14).
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BRAIN IMAGING IN INSOMNIA 79

Recent work shows that the amygdala is anatomically connected with and functionally
modulates effects on the brainstem centers involved in arousal and sleep regulation (15,16).
Similarly, other components of the ventral emotional system such as the ventral striatum, the
subgenual anterior cingulate cortex, and the ventromedial prefrontal cortex are known to have
both anatomical and functional relationships with brainstem centers thought to play a role in
behavioral state regulation in addition to the primary roles they each play in cortical arousal
(17,18).
Human sleep neuroimaging studies support a role for the ventral emotional system in
sleep processes. Blood flow has been shown to negatively correlate with the presence of NREM
sleep in the anterior cingulate (3–5), the amygdala (5), and in the orbitofrontal cortex (3–5). These
changes suggest that components of the ventral emotion system play a role in modulating sleep
or in the manifestation of sleep. Declining function in the amygdala raises the possibility that
this structure modulates activity in core structures involved in regulating arousal.
Human sleep neuroimaging studies support the role for components of the ventral emo-
tion system in pathological sleep associated with both depression and insomnia. Nofzinger
et al. (19) used [18 F]-FDG PET to define regional cerebral correlates of arousal in NREM
sleep in 9 healthy and 12 depressed patients. They assessed EEG power in the beta high
frequency spectrum as a measure of cortical arousal. They then correlated beta power with
metabolism in NREM sleep. They found that beta power negatively correlated with sleep quality.
Further, beta power positively correlated with ventromedial prefrontal cortex metabolism in
both group of depressed and healthy subjects. They concluded that elevated function in the ven-
tromedial prefrontal cortex, an area associated with obsessive behavior and anatomically linked
with brainstem and hypothalamic arousal centers, may contribute to dysfunctional arousal.
Nofzinger et al. (6) investigated the neurobiological basis of poor sleep in insomnia. Insom-
nia patients and healthy subjects completed regional cerebral glucose metabolic assessments
during both waking and NREM sleep using [18 F]-FDG PET. Healthy subjects reported better
sleep quality than did insomnia subjects. A group × state interaction analysis confirmed that
insomnia subjects showed a smaller decrease than did healthy subjects in relative metabolism
from waking to NREM sleep in the insular cortex, amygdala, hippocampus, anterior cingulate,
and medial prefrontal cortices. This study supports the notion that persistent overactivity in a
limbic/paralimbic level of the arousal system contributes to the nonrestorative sleep in insomnia
patients.
Pharmacotherapy for insomnia may have some of its mechanism of action on these limbic
and paralimbic structures, especially the psychotropic medications. When Kajimura et al. (7)
assessed regional cerebral blood flow during NREM sleep in response to triazolam, they also
found that blood flow in the amygdaloid complexes, in addition to basal forebrain, was lower
than following placebo. While not always consistent, several neuroimaging studies show that
serotonergic antidepressants tend to lower, or inhibit, brain function (blood flow or metabolism)
in ventral limbic and paralimbic cortex including the amygdala (20,21), perhaps via actions on
5-HT1 postsynaptic receptors given their high density in these areas (22). Inhibiting hyper-
arousal in this limbic/paralimbic emotional neural network could benefit insomnia patients.
Recent studies have focused on the role of sleep in memory consolidation utilizing both
cognitive neuroscience and brain imaging of the hippocampus. Nissen et al. (23) compared
sleep-related consolidation of procedural memory in seven patients with primary insomnia
and seven healthy controls. Performance on a mirror tracing task was measured before and
after sleep. Performance in the mirror tracing task before sleep did not differ between the
groups. Both groups performed significantly better in the recall condition after sleep. Healthy
controls showed an improvement of 42.8% ± 5.8% in the mirror tracing draw time, whereas
patients with insomnia showed an improvement of 20.4% ± 14.8% (multivariate analyses of
variance test session × group interaction: F3,10 = 10.9, P = 0.002). These preliminary findings
support the view that sleep-associated consolidation of procedural memories may be impaired
in patients with primary insomnia.
Another study focused on morphology of the hippocampus in insomnia patients (24).
Morphometric analysis of magnetic resonance imaging brain scans was used to investigate
possible neuroanatomic differences between patients with primary insomnia compared to good
sleepers. MRI images (1.5 Tesla) of the brain were obtained from insomnia patients and good
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80 NOFZINGER

sleepers. MRI scans were analyzed bilaterally by manual morphometry for different brain areas
including hippocampus, amygdala, anterior cingulate, orbitofrontal and dorsolateral prefrontal
cortex. Patients with primary insomnia demonstrated significantly reduced hippocampal vol-
umes bilaterally compared to the good sleepers. None of the other regions of interest analyzed
revealed differences between the two groups. While replication of the findings in larger samples
is needed to confirm the validity of the data, these pilot data raise the possibility that chronic
insomnia is associated with alterations in brain structure. The integration of structural, neu-
ropsychological, neuroendocrine, and polysomnographic studies is necessary to further assess
the relationships between insomnia and brain function and structure.

THALAMUS AND NEOCORTEX

In many respects, maintaining efficient thalamocortical activity during waking could be con-
ceptualized as a primary function of sleep. The best way for the neocortex to maintain adequate
daytime function is for an individual to sleep well at night. At the macroscopic level, sleep has
been shown to discharge a wake-dependent sleep drive as measured by EEG spectral power
in the delta frequency band. At the molecular and neuronal levels, hypothetical functions of
sleep include the restoration of brain energy metabolism through the replenishment of brain
glycogen stores that are depleted during wakefulness (25) and the downscaling of synapses
that have been potentiated during waking brain function (26). These restorative components of
sleep are recognized to have regional selectivity. Slow wave sleep rhythms have both thalamic
and cortical components (27). Decreases in brain activity from waking to NREM sleep are most
pronounced in frontoparietal cortex. An anterior dominance of EEG spectral power in the delta
EEG spectral power range has been reported (28). A frontal predominance for the increase
in delta power following sleep loss has also been reported (29). This region of cortex plays a
prominent role in waking executive functions that are preferentially impaired following sleep
deprivation (30). These sleep deprivation-induced cognitive impairments have been related to
declines in frontal metabolism after sleep loss (31). Further, recent topographic EEG studies
during NREM sleep before and after training on a task revealed slow wave activity increases
in regions of cortex known to involve the task (32). Evidence such as this suggests that NREM
sleep is important for prefrontal cortex function. As such, the alterations in NREM sleep in
insomnia patients may relate to alterations in prefrontal cortex function.
Prefrontal cortex function may play a role in insomnia in several respects. As noted
above, there are significant epidemiologic links between insomnia and disorders of emotion.
The dorsolateral prefrontal cortex (DLPFC) is a primary structure in the dorsal emotional
neural system. This structure has been shown to play an important role in executive function,
including selective attention, planning, and effortful regulation of affective states (9). The DLPFC
maintains the representation of goals and the means to achieve them. It sends bias signals to
other areas of the brain to facilitate the expression of task-appropriate responses in the face
of competition with other responses (33). Davidson et al. has emphasized the importance of
left-lateralized PFC regions in approach-related appetitive goals and the right in behavioral
inhibition and vigilant attention (14). The DLPFC is not only responsible for recruiting or
inhibiting limbic regions as appropriate to performing tasks (e.g., Davidson et al.) (34) but
appears to be modulated by early limbic processing (35). A related component of the dorsal
emotional system is the dorsal anterior cingulate cortex (9). This region has been associated with
conflict monitoring (e.g., it is particularly active during conditions when one must arbitrate
quickly between two likely responses) (36). Given its role in the executive aspects of emotional
behavior, an abnormal increase in vigilant functions of the prefrontal cortex function could lead
to insomnia, whereas deficient executive behavior could be a consequence of inadequate sleep
resulting from insomnia.
Functional neuroimaging studies have revealed reliable global decreases in cerebral
metabolism or blood flow from waking to NREM sleep (e.g., Nofzinger et al.) (37). Region-
ally, studies across several laboratories and using various imaging methods have demonstrated
that between waking and NREM sleep there are relative reductions in activity in heteromodal
association cortex in the frontal, parietal, and temporal lobes as well as in the thalamus. Sleep
deprivation (31) is associated with global declines in absolute cerebral metabolism. Region-
ally, these declines are most notable in frontoparietal cortex and in the thalamus. Alertness and
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BRAIN IMAGING IN INSOMNIA 81

cognitive performance on a sleep deprivation-sensitive serial addition/subtraction test declined

in association with the sleep deprivation-associated regional deactivations. These studies
demonstrate that reductions in global brain function and especially in prefrontal cortex function
are important for the restorative function of sleep. Inadequate sleep in insomniacs may lead to
a deficit in prefrontal cortex function.
Nofzinger et al. (6) investigated regional cerebral glucose metabolism in insomnia patients
and healthy subjects during both waking and NREM sleep using [18 F]-FDG PET. Insomnia sub-
jects scored worse on measures of daytime concentration and fatigue consistent with prefrontal
cortex impairment. Insomnia patients showed increased global cerebral glucose metabolism
during sleep and wakefulness suggesting an increased vigilant or attentive function of the
neocortex consistent with hyperarousal. A group × state interaction analysis confirmed that
insomnia subjects showed a smaller decrease than did healthy subjects in relative metabolism
from waking to NREM sleep in the thalamus, the anterior cingulate, and medial prefrontal cor-
tices suggesting a persistence of thalamocortical arousal even within sleep in insomnia patients.
While awake, in relation to healthy subjects, insomnia subjects showed relative hypometabolism
in a broad region of the frontal cortex bilaterally, left hemispheric superior temporal, parietal
and occipital cortices, and the thalamus. Their daytime fatigue may reflect decreased activity in
prefrontal cortex that results from inefficient sleep.
Several interventions may alter activity in the prefrontal cortex in a beneficial manner for
insomnia patients. For example, Lou et al. (38), assessed regional brain function associated with
Yoga Nidra, a meditative state in which there is a loss of conscious control and an increased
awareness of sensory experience. In their study, they found reduced blood flow during medita-
tion in an attentional network that included the DLPFC and anterior cingulate cortex, as well as
increased blood flow in posterior sensory and associative cortex associated with visual imagery.
Cognitive approaches to the treatment of insomnia may have similar mechanisms of action
in prefrontal areas. Serotonergically active antidepressants also increase brain function (blood
flow or metabolism) in dorsal paralimbic and DLPFC (21,39). Increasing activity in prefrontal
cortex may reverse prefrontal deficits in insomnia patients leading to improved daytime cog-
nitive function. Alternatively, further increasing an already metabolically overactive prefrontal
cortex may increase attentive and vigilant functions, thereby producing further insomnia, a not
uncommon side effect of SSRI therapy in either depressed or insomnia patients.
A recent study documented prefrontal hypoactivation in insomnia as predicted from the
background review above. Although subjective complaints about daytime cognitive functioning
are an essential symptom of chronic insomnia, abnormalities in functional brain activation have
not previously been investigated. This study investigated functional brain activation differences
as a possible result of chronic insomnia, and the reversibility of these differences after nonmed-
icated sleep therapy. Twenty-one insomniacs and 12 carefully matched controls underwent
functional magnetic resonance imaging (fMRI) scanning during the performance of a category
and a letter fluency task. Insomniacs were randomly assigned to either a six-week period of
nonpharmacological sleep therapy or a wait list period, after which fMRI scanning was repeated
using parallel tasks. Task-related brain activation and number of generated words were con-
sidered as outcome measures. Compared to controls, insomnia patients showed hypoactivation
of the medial and inferior prefrontal cortical areas (Brodmann Area 9, 44, 45), which recov-
ered after sleep therapy but not after a wait list period. These studies support the hypothesis
that insomnia interferes in a reversible fashion with activation of the prefrontal cortical system
during daytime task performance.

SUMMARY
Cerebral metabolic studies, in light of preclinical work, suggest that there are hierarchical levels
of arousal that may be disturbed in insomnia. Further, interventions may have their effects at
different levels of a hierarchical arousal neural network. Additional work is needed to clarify
the degree to which alterations in these levels of arousal distinguish insomnia patients from
other sleep disorders, or the degree to which distinct levels may be disturbed in individual
patients. Additional work is also needed to match interventions for the treatment of insomnia
with the levels of arousal that are unique to the individual patient.
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82 NOFZINGER

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normal emotion perception. Biol Psychiatry 2003; 54:504–514.
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repeatedly presented emotional stimuli. Neuroreport 2001; 12:379–383.
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9 History Taking in Insomnia

Karl Doghramji
Jefferson Sleep Disorders Center and the Department of Psychiatry and Human Behavior, Thomas Jefferson
University, Philadelphia, Pennsylvania, U.S.A.

Scott E. Cologne
American Sleep Medicine, St. Louis, Missouri, U.S.A.

INTRODUCTION
A comprehensive history is the cornerstone of the evaluation process in insomnia. This fact
deserves special emphasis in the case of insomnia, since less than half of primary care physicians
obtain a sleep history despite being confronted with a complaint of insomnia (1). In this chapter,
we will assume that an insomnia complaint has already been established; nevertheless, it is
noteworthy that only a minority of insomnia complaints are actually captured during patient–
physician encounters. Even severe insomnia remains undetected by physicians in 60% of cases
(2,3). Therefore, active inquiry about sleep disturbances is especially important since 70% of
insomnia sufferers do not raise the problem with their physicians (4).
The history should be explored in a systematic fashion. Although a variety of formulations
have been described in the history-taking process, empirical studies of the optimal method are
lacking (5).

THE PRIMARY COMPLAINT

The complaint may involve difficulty in initiating sleep, multiple nocturnal awakenings, dif-
ficulty in reinitiating sleep, early morning awakening, or a combination of these. The nature
of symptoms can change with the progression of time as a complaint of initial insomnia, for
example, progresses into a sleep maintenance difficulty. In one study, the nature of symptoms
changed in over half of patients with insomnia over the course of four months (2).
The onset and duration of the difficulty should be carefully assessed. Acute bouts of
insomnia are commonly experienced, yet long lasting insomnias are presumed to be of greater
clinical relevance since they may pose a greater risk for daytime consequences. Such distinctions
have not, however, been subjected to empirical validation. Additionally, a State-of-the-Science
conference held in 2005 underscored the variability in the definitions of acute and chronic
insomnia, with minimum durations for chronic insomnia ranging from 30 days to as long as
6 months (6). Most cases of insomnia are chronic by the time of presentation; in a survey of
community dwellers, the history of insomnia spanned 9.3 to 13 years (7).
The temporal pattern of insomnia can also be relevant. Insomnia tends to recur episodically
over time; hence, the frequency and duration of episodes should be assessed. The frequency
of nights affected per week during each episode can also indicate degree of severity. In the
national sample described above, 36% of 1000 adults reported a current sleep problem, of
which 27% indicated that sleep problems occurred occasionally and 9% reported difficulty
sleeping on a frequent basis; insomnia episodes typically lasted 4.7 days. Those with chronic
insomnia reported that sleep problems affected over half of the nights in an average month
(16.4 days).
Events or circumstances that may have precipitated the insomnia, such as the occurrence
of a medical or psychiatric illness, job loss, or shift work, should be identified. Subsequent
complications, such as poor sleep hygiene practices and development of anticipatory anxiety
regarding sleep, may have perpetuated the difficulty. From the standpoint of future treatment,
it is useful to understand the type of interventions that have already been attempted and the
effectiveness and side effects of each of these.
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HISTORY TAKING IN INSOMNIA 85

SLEEP PATTERNS
The list below summarizes critical elements of the sleep/wake history
1. Bedtime
2. Sleep latency
3. Nocturnal awakenings; number and duration
4. Final morning awakening
5. Out-of-bed time
6. Number, time, and duration of daytime naps
7. Levels of sleepiness and fatigue as the day progresses
Characteristic disturbances in these areas can point to certain circadian rhythm distur-
bances such as delayed sleep phase syndrome and sleep hygiene impairments such as spending
excessive time in bed while awake, among others. It is also useful to ascertain each of these
parameters not only for the “average” day, but also for a sequence of days, as such a tempo-
ral record can demonstrate variability in sleep patterns over time that can, in turn, contribute
to poor sleep. The assessment of variability between workdays/schooldays, weekends, and
vacations can be useful. Poor sleepers characteristically do not maintain rigorous sleep/wake
schedules. Identification and correction of this variability is a primary element of sleep hygiene
education and other cognitive-behavioral techniques.

DAYTIME SYMPTOMS, HABITS, AND BEHAVIORS

Insomnia is associated with a variety of daytime symptoms (see chapter 3 for a detailed dis-
cussion of daytime symptoms). Typically, their severity covaries with the perceived degree of
impairment in nocturnal sleep. However, in some patients, the degree of abnormality in sleep
latency or maintenance may be modest, yet the patient may complain that sleep is unproductive
and nonrestorative. It is, therefore, important to independently explore daytime symptoms. In
order to understand their nature and magnitude, it is useful to initially ask the patient to elab-
orate on these symptoms in an open-ended fashion, and to follow-up with specific questions
regarding each area of concern. Insomnia patients more frequently report a variety of psycholog-
ical symptoms during the day, including feeling depressed, hopeless, helpless, worried, tense,
anxious, irritable, lonely, and lacking in self confidence, than do controls (8). They report feeling
tired and sleepy. They also report cognitive difficulties such as memory impairment, difficulty
with focusing and attention, and mental slowing. They suffer from impairments in reaction
time (9). They report decrements in coping, accomplishing tasks, mood, personal relationships,
and family and social life (4). Many report work-related impairments (10). Sleep difficulties are
associated with traffic accidents (11).
Daytime behaviors can modulate sleep patterns. Those that are relevant include the
amount and timing of exercise, as intense exercise too close to bedtime can disrupt sleep (12).
Long periods of bed rest, inactivity, and excessive napping can foment circadian rhythm distur-
bances. Exposure to bright light can be helpful in establishing circadian cycling and, conversely,
lack of sufficient light exposure can disrupt sleep. Frequent travel and shift work can disrupt
sleep and contribute to daytime sleepiness. It is useful to understand the patient’s preferred
social and occupational activities, as this information can be helpful in devising a daily structure
that promotes consistent sleep scheduling.

SLEEP-RELATED BEHAVIORS AND HABITS

The behaviors in which the patient engages during the few hours prior to bedtime, during
bedtime hours, and just after morning awakening can modulate the degree of sleep difficulty,
and, in some cases, cause it. These include the consumption of caffeine and alcohol prior to
bedtime; smoking; eating large meals or excessive fluid intake within three hours of bedtime;
exercising within three hours of bedtime; utilizing the bed for nonsleep activities such as work,
telephone conversations, or the internet; working and conducting other emotionally taxing
activities up to the point of bedtime, without a transitional “down” time; clock watching prior
to falling asleep or during nocturnal awakenings; exposure to bright light prior to bedtime or
following nocturnal awakenings; excessive worrying at bedtime; keeping the bedroom too hot
or too cold; exposure to noise from external sources such as cars and airplanes or from internal
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86 DOGHRAMJI AND COLOGNE

sources such as family members or a television set; and being disturbed by the movements of
a bed partner. Aerobic exercise increases body temperature, which may contribute to reduced
sleep propensity in the immediate postexercise period. This is followed by a drop within four to
six hours which, in turn, can promote sleep continuity (13). Certain behaviors are compensatory
and intended to address the sleep difficulty, but have a detrimental effect nevertheless. These
include strategies for catching up on lost sleep such as going to bed too early and staying in
bed for extended periods of time after awakening. A similar strategy includes staying in bed
for extended periods of time after nocturnal awakenings.

SYMPTOMS OF COMORBID DISORDERS

Insomnia is often comorbid with other psychiatric, medical, and neurological conditions. There-
fore, it is often helpful to inquire about certain symptoms that may indicate the presence of
comorbid disorders as a contributing factor to the insomnia complaint. An exhaustive list of the
disorders and their symptoms is beyond the scope of this chapter, and readers are referred to
chapters 14 to 17 on comorbid insomnias. In Table 1, we refer to specific disorders and symptoms
that occur primarily during, or surrounding, sleep. For many of these symptoms, interviewing
a bed partner can be highly productive, as bed partners are typically more aware of symptoms
that arise while the patient is asleep.

Table 1 Symptoms of Specific Selected Sleep Disorders

Sleep disorder Symptoms

Obstructive sleep apnea syndrome Snoring
Breathing pauses during sleep
Choking
Gasping
Morning dry mouth
Morning headaches
Restless legs syndrome Irresistible urge to move the extremities
Limb paresthesia
Onset of symptoms during periods of rest and in the evening or at
bedtime
Relief of symptoms with movement
Periodic limb movement disorder Twitching and repetitive movements of the extremities during sleep
or just prior to falling asleep
Congestive heart failure Paroxysmal nocturnal dyspnea
Orthopnea
Chronic obstructive pulmonary disease Dyspnea
Pain from various disorders Pain
Gastroesophageal reflux Epigastric pain or burning
Laryngospasm
Acid taste in mouth
Sudden nocturnal awakenings
Prostatic hypertrophy Frequent nocturia
Nocturnal seizures Thrashing in bed
Loss of bladder or bowel control
Nocturnal panic attacks Sudden surges of anxiety
Tachycardia
Diaphoresis
Choking
Laryngospasm
Posttraumatic stress disorder Vivid dreams and nightmares Recurring dreams
Major depression Depressed mood
Anhedonia
Attention deficit hyperactivity disorder Excessive physical activity and shifting attention
Psychophysiological insomnia “Trying” to fall asleep
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HISTORY TAKING IN INSOMNIA 87

MEDICATIONS
A history of current and prior medications is always of relevance. The list should include not only
prescribed medications, but also over-the-counter agents, nutraceuticals, herbals substances,
dietary supplements, and even foods. Their effects, side effects, dosages or quantities, and timing
of administration should be recorded. Allergies to medications should also be recorded. The
effects of psychotropic and pain medications on sleep are reviewed in chapters 13 and 14 of this
book.

SUBSTANCES
It is useful to determine the type and extent of use of various substances. Chronic and excessive
use may lead to substance use disorders, including abuse or dependence. The effects of sub-
stances on sleep are reviewed in chapter 16 of this book. Of particular relevance are stimulants
such as caffeine, amphetamines, and cocaine. Sedatives such as alcohol, at low dosages, can
help with sleep initiation, yet chronic and excessive use may lead to disturbed sleep and the
complaint of insomnia (14,15).

PAST MEDICAL, PSYCHIATRIC, AND SURGICAL HISTORY

Comorbid disorders should be reviewed, along with their dates of onset, types of treatment, and
results of treatment. Surgeries and hospitalizations should also be evaluated. Major disorders
can affect sleep by virtue of their psychological impact such as anxiety and depression, through
pain and discomfort, as well as by direct effects on sleep and wakefulness. For a review of these
disorders and their effects on sleep, please see chapters 13–16.

FAMILY HISTORY
Certain sleep disorders have a hereditary component. In the case of restless legs syndrome, 50%
of primary cases have a positive family history (16). Other comorbid disorders such as obstruc-
tive sleep apnea may demonstrate familial predisposition by virtue of inherited metabolic or
anatomical conditions. Fatal familial insomnia is a relatively rare disorder in which family
history is clearly key.

SOCIAL AND OCCUPATIONAL HISTORY

Disruption in interpersonal relationships, family, job, and hobbies can cause anxiety, leading
to insomnia. Such stresses, especially job loss, can also lead to insomnia by causing erratic
sleep/wake hours.

PRIOR MEDICAL DOCUMENTS

Prior polysomnographic studies and other laboratory tests are especially relevant to the evalu-
ation and should be carefully reviewed as part of the overall assessment.

CONCLUSIONS
A thorough history provides the clinician with critical information for the formulation of a dif-
ferential diagnosis and establishes the foundation for therapy. As already indicated, approaches
to the clinical history have not been subjected to empirical validation and, indeed, it is difficult
to imagine how a single process might apply to all clinicians and patients. However, this chapter
has provided a framework upon which the history-taking process can be organized. Therefore,
we recommend that clinicians tailor the guidelines and principles that have been provided to
develop history-taking strategies that are most appropriate for their work styles and patient
types in the evaluation of insomnia.

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3. Schramm E, Hohagen F, Kappler C, et al. Mental comorbidity of chronic insomnia in general practice
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nights’ sleep among individuals with primary insomnia. Sleep 2008; 31(5):599–607.
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population. J Gen Intern Med 1995; 10:25–32.
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10 Evaluation Instruments and Methodology

Anne Germain
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.

Douglas E. Moul
Department of Psychiatry, Louisiana State University at Shreveport School of Medicine,
Shreveport, Louisiana, U.S.A.

INTRODUCTION
Epidemiological studies (1,2) have shown that the most prevalent form of insomnia occurs
concurrently with other medical, psychiatric, or sleep disorders. For researchers studying the
psychophysiological and neurobiological mechanisms underlying insomnia, however, primary
insomnia offers the advantages of being uncomplicated by other conditions. While not entirely
homogenous, primary insomnia also offers the advantage of providing a group of relatively
uncomplicated patients to evaluate treatment efficacy in clinical trials. Nevertheless, the dif-
ferential diagnosis and evaluation of insomnia in epidemiological and treatment effectiveness
studies require similar measurement approaches for insomnia and relevant domains, to thor-
oughly characterize the populations of interest. While most insomnia measurement scales and
methods described here are derived from instruments developed to study primary insomnia,
the goal of capturing insomnia as a distinct and addressable measurement problem remains the
same, irrespective of the cause of insomnia. In this chapter, we discuss evaluation measures and
methods that have been widely used, and that are validated, reliable, and/or recommended
by expert consensus on insomnia measurements (3). These methods are amenable to different
purposes for the evaluation of insomnia: clinical evaluation, research assessments, and epi-
demiological studies. As such, we first discuss the requirements and constraints of these three
contexts in relation to the evaluation of insomnia. Selected measures of insomnia reviewed here
include clinician-administered scales, self-report questionnaires, sleep diaries, and actigraphy.
Polysomnography (PSG) has been used widely as a screening method to rule out other sleep
disorders that may masquerade as insomnia (e.g., sleep apnea, periodic leg movement disor-
der), as a quantitative measurement of sleep disturbances, and as an objective outcome measure
in treatment efficacy studies. However, PSG is not a clinically recommended measurement
method to diagnose insomnia (4). Additionally, PSG does not quantify all features of insomnia,
which also include sleep dissatisfaction, daytime impairments, and related symptoms. These
latter daytime symptoms may partially explain the modest relationships between subjective
and objective sleep measures in patients with sleep disorders (5).
In addition to assessing the nighttime features and daytime symptoms of insomnia, mea-
suring insomnia requires the evaluation of exclusionary criteria of insomnia. Therefore, mea-
sures that do not assess insomnia are also required to enhance the ability to discriminate insom-
nia from other sleep or psychiatric disorders, and to determine whether insomnia is present in
a primary or comorbid form.

MEASUREMENT OF INSOMNIA IN CLINICAL, RESEARCH, AND

EPIDEMIOLOGICAL STUDIES
The needs and constraints of insomnia measurement vary depending on the requirements of
a given application. For the clinician, primary tasks in responding to a patient’s complaint of
insomnia are to establish a provisional diagnosis, identify differential diagnoses, initiate treat-
ment(s), and monitor outcomes. For the most part, provisional and differential diagnoses are best
accomplished through clinical interviewing conducted by an expert clinician. Self-report ques-
tionnaires, actigraphy, and sleep diaries can be helpful in increasing the efficiency of obtaining
an accurate diagnosis. Some questionnaires focus on psychological difficulties common among
insomnia patients, and may aid in differential diagnoses, especially in distinguishing primary
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90 GERMAIN AND MOUL

insomnia from a comorbid insomnia related to depression or other psychiatric disorders. If the
goal is to derive a “caseness” decision for screening purposes, then some questionnaires with
clinical cut-off scores may assist with population-level management efforts. Outcome measure-
ment is an additional area where questionnaires may help both the clinician and the patient
measure progress with treatment.
For the clinical researcher, self-report instruments, actigraphy, and PSG can document
the relative success of treatments of insomnia. Detailed clinical interviews to accurately select
research participants are essential in obtaining replicable and robust findings. For research
methods and instruments, reliability, validity, precision, and sensitivity to change are highly
desirable, since these instrument characteristics decrease the number of subjects needed to
convincingly answer a research question. An additional task for research is theory testing.
To test theories, the items in questionnaires need to relate directly to the concepts proposed
in a theory of insomnia onset, maintenance, or therapy. For example, if a theory proposes
that particularly anxious thoughts contribute to sustaining insomnia, then the theory-related
questionnaire should ask about the presence and frequency of these thoughts.
Two differing types of epidemiological studies also guide choices of questionnaire. For
analytic epidemiological studies, the goal is to pursue causal theories of insomnia by assessing
potential risk factors. For such analytic studies, questionnaires for primary insomnia need to
be quite detailed and elaborate, since primary insomnia is a diagnosis of exclusion. Similarly,
risk factors also need to be queried with high specificity, so that the relationships derived in
the statistical analysis are not susceptible to measurement errors and biases. The second kind of
epidemiological study is largely descriptive. For such an effort, the main goal of measurement
is to estimate the population burden of chronic insomnia. Here it may be possible to use one
of the instruments listed below to derive some estimate of prevalence. This kind of description
will be helpful to health policy planners and services researchers in planning for health resource
utilization.

MEASURES OF INSOMNIA

Clinician-Administered Scales for Insomnia

As described in the previous chapter, the use of unstructured yet detailed clinical interviews
combined with a thorough review of sleep history is widely used for diagnosis and screening
for insomnia in clinical and research contexts. Semistructured interviews are used in-house
by research teams and by clinicians to standardize evaluation procedures, but the reliability
of these in-house measures has not been thoroughly assessed and the measures are typically
not widely distributed. Structured interviews are available (6,7) but not easily accessible (8),
nor have they been updated with recent nosologies for insomnia disorders (6). Currently, a
reliable clinician-administered gold standard measure for insomnia remains to be developed
and validated.

Self-Report Questionnaires
Whether they are used alone or in conjunction with clinical assessment measures and methods,
self-report questionnaires of insomnia are by far the most common method for assessing insom-
nia in clinical, research, and epidemiological contexts. There are numerous insomnia scales or
single-item measures that have been developed and used across different types of studies (9).
Some self-report instruments are specifically designed to assess the frequency and/or severity
of sleep and wake symptoms of insomnia. Since instruments vary in their popularity, format,
ease of scoring, and psychometrics, clinicians and researchers can make the best choices when
considering instruments’ characteristics in relation to their specific measurement goals and tar-
get populations. Other more global assessments of sleep quality and sleep patterns have been
widely used in clinical, research, and epidemiological sleep studies, and are also described here.
These instruments may have a role in settings where the population studied contains a variety
of sleep disturbances other than chronic insomnia.
The Insomnia Severity Index (ISI) (10,11) is a seven-item questionnaire that assesses sub-
jective severity of insomnia symptoms, degree of satisfaction with sleep, nature and salience
of daytime impairments, and concerns caused by the sleep difficulties. Each item is rated on a
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EVALUATION INSTRUMENTS AND METHODOLOGY 91

0 to 4 point scale. A cut-off score of 14 has been shown to optimize sensitivity and specificity.
Scores from zero to seven reflect no clinically significant insomnia; scores from 8 to 14 reflect
subthreshold insomnia; scores from 15 to 21 reflect clinically significant insomnia of moderate
severity; and scores from 22 to 28 reflect clinically significant, severe insomnia. The ISI is consid-
ered to be one of the best standards for evaluation of treatment efficacy in clinical research (3).
Because of its brevity, the ISI can also be comfortably included in large epidemiological studies.
Drawbacks of the ISI include its lack of items specifically focusing on nighttime symptoms and
its dependence on the cognitive theory of insomnia. The ISI has not yet been studied with Item
Response Theory (IRT) methods.
The Spielman Insomnia Symptom Questionnaire (12) contains 13 100-mm visual analog scales
evaluating the frequency of some nighttime features of insomnia, daytime consequences, and
behavior characteristics of insomnia. The questionnaire items are addressed using a visual
analog scale that ranges from “never” at the far left side of the scale (0 mm) to “always” at the
far right (100 mm). The individual items refer to symptoms and events during the week prior to
completing the questionnaire. The total questionnaire score is the average of the 13-item scores
measured as the distance in millimeters from 0 to 100 on each scale. It has been used in clinical
trials, but has not been studied psychometrically in relation to depression, anxiety, or fatigue
scales. It has a Cronbach’s alpha of 0.92, based on data studying the Pittsburgh Insomnia Rating
Scale (PIRS) (5). Clinical cut-off scores have not been determined.
The Pittsburgh Insomnia Rating Scale, 20-item version (PIRS-20) (13,14) is derived from
the original 65-item version of the PIRS. From the original study of insomnia patients and
control subjects, these 20 items were selected based on both their classical and item response
characteristics, to include daytime and nighttime items, excluding the influence of depressive
or anxiety symptomatology. The PIRS-20 focuses on sleep and wake symptoms as they occurred
in the week prior to completion of the instrument. It does not discriminate between primary or
comorbid insomnia. The PIRS-20 assesses the intensity of distress related to 12 nighttime and
daytime symptoms of insomnia on a 0 (not at all bothered) to 3 (severely bothered) scale; four
items on quantitative sleep parameters (e.g., sleep latency, sleep durations) also scored on a 0
to 3 scale, and four items evaluating quality, regularity, and depth of sleep on a 0 (excellent) to
3 (poor) scale. The total score is the simple sum of the item scores, which provides an index of
insomnia severity. A score higher than 20 (out of a maximum of 60) appears to be a useful cut-
off for clinical insomnia (15). The PIRS-20 has a Cronbach’s alpha of 0.95, and has a test–retest
reliability of 0.92. It responds robustly to clinical change (6). Of note, two items of the PIRS-20,
items #9 (lack of energy because of poor sleep) and #18 (satisfaction with your sleep) comprise the
PIRS-2, which can serve as an ultrashort severity questionnaire for screening or epidemiological
purposes. On the PIRS-2, a score equal to or higher than 2 (out of maximum of 6) may serve
as an index of clinically meaningful insomnia. The PIRS-20 was designed as a comparatively
theory-neutral instrument for scaling insomnia severity.
The Athens Insomnia Scale (AIS) (16) is an instrument for measuring insomnia based on the
diagnostic criteria of the International Classification of Diseases, 10th Edition (17). The AIS refers
to symptoms as they occurred in the past month. It has five-item and eight-item versions, with
scores being the simple sum of the item scores. It contains eight items that ask about daytime
and nighttime symptoms, but without containing items that ask about specific time lengths
associated with sleep. A cut-off score of 6 on the AIS can serve as a clinical case definition for
chronic insomnia. The Cronbach’s alpha of the five- and seven-item versions is 0.87 and 0.89,
respectively (16). Its test–retest reliability was 0.89 at a one-week interval. The AIS has not been
evaluated for its correlation against dimensions of depression, anxiety, or fatigue scaling, but
has served well as an outcome measure.
In most epidemiological studies, insomnia is more common among women than men,
particularly during and after the perimenopausal transition. As part of the Women’s Health
Initiative (WHI), researchers utilized the five-item Women’s Health Initiative Insomnia Rating
Scale in a very large sample of middle-aged women (18,19). The period covered by the rating
scale is the four weeks preceding the completion of the questionnaire, and the score is a simple
sum of item scores. Fatigue items were selected out of the questionnaire. This questionnaire
correlated only 0.21 with the Center for Epidemiology Studies Depression scale (20). Clinical
cut-offs were not described but the scale did serve as a useful outcome measure of sleep quality
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92 GERMAIN AND MOUL

in a trial of hormone replacement in perimenopausal women. This instrument appears to be

valid for middle-aged women, but has not been studied for use in evaluating men’s symptoms.
Other self-report questionnaires have been widely used and have proven informative
in clinical, research, and epidemiological studies of insomnia. While the following scales do
not exclusively focus on insomnia, they have high predictive power and/or provide relevant
information in the evaluation and treatment of insomnia. Among these, the Pittsburgh Sleep
Quality Index (21) is the best known and most widely translated into other languages. It is a
19-item self-report measure that assesses seven components of sleep quality (i.e., subjective sleep
quality, sleep latency, duration, efficiency, disturbances, use of sleep medication, and daytime
dysfunction). Each component is rated on a 0 to 3 scale referring to the composite score derived
from the frequency of each disturbance, where 0 = not in the past month, and 3 = three or
more times a week, with a global score range from 0 to 21. A cut-off score of 5 has been shown
to discriminate between good and bad sleepers. The PSQI has acceptable internal consistency
(Cronbach’s alpha = 0.83) and test–retest reliability (r = 0.85).
As part of the psychometrics effort in the Medical Outcomes Survey, from which the 36-item
short form (SF-36) was developed, Hayes and Stewart (8,9) developed a 12-item questionnaire
designed to measure sleep/wake functioning in large populations. This measure asks about
symptoms in the past month. The scoring algorithm is complicated, but readily available (10).
This scale has been well studied psychometrically. It was constructed with several sleep/wake
domains considered. Minimum Cronbach’s alpha estimates for its four sleep disturbance items
were 0.80; that for two-item sleep adequacy scaling was 0.76, and that for daytime somnolence
was 0.63. It includes two time period items, as well as several items related to sleep disordered
breathing. It has not been examined in relation to correlations against anxiety, depression, or
fatigue symptoms. Clinical cut-off scores have not been described.
The Sleep Hygiene Awareness and Practices Scale (22) is a 32-item questionnaire that evaluates
the knowledge and practice of behaviors that promote or interfere with sleep and can contribute
to perpetuation of insomnia. The frequency of individual habits and behaviors is rated for an
average number of days during one week. The disruptive effects of these habits and behaviors
are also rated on a scale from 1 (very beneficial for sleep) to 7 (very disruptive for sleep).
However, psychometric performance of this instrument is not known, and has not been tested
in anxious or depressed samples. Clinical cut-off scores are not described.
The Dysfunctional Attitudes and Beliefs About Sleep questionnaire (DBAS) (11,23,24) can be
used to evaluate cognitions and beliefs about sleep that may contribute to poor sleep habits
and/or bedtime and daytime worries about insomnia. This instrument has been shown to be
sensitive to treatment-related improvements in sleep and insomnia (25). Two forms exist: the
long, 30-item version (11), and the short, 10-item version (23,24). Items of the DBAS assess the
degree to which one disagrees or agrees with statements related to the causes and consequences
of sleep disruption using 100-mm visual analog scales. Scores on both versions are highly
correlated, and both versions have acceptable internal consistency coefficients (11,23,24). Scores
are sensitive to treatment-related improvements in sleep and insomnia symptoms. Although
scores discriminate among patients with insomnia and good sleepers, cut-off scores are not
provided.
Finally, one of the NIH Roadmap Initiatives, called the Patient-Reported Outcomes
Management Information System (26) (http://www.nihpromis.org/default.aspx), focuses on
patient-reported outcomes (PROs). The effort includes development of a sleep–wake func-
tioning item bank. Using item response theory techniques, separate short form question-
naires for sleep and wake functioning have been developed for use alongside the other
instruments within the PROMIS family (Global Health, Fatigue, Pain, Emotional Distress,
Physical Function, among others). These forms are now available on the PROMIS website
(http://www.nihpromis.org/default.aspx), which also provides item parameters for use by
clinicians and researchers who may wish to use the functionality of this internet-based system
of measurement. Further work is ongoing for the refinement of these items and their associ-
ated short forms. The Cronbach’s alpha values for the sleep and wake disturbance item banks
are 0.97 and 0.95, respectively. Individual items have been calibrated for their IRT indications
in great detail, and have been inspected for differential item response functioning. While the
PROMIS sleep–wake scales do not specifically focus on insomnia symptoms, they nevertheless
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EVALUATION INSTRUMENTS AND METHODOLOGY 93

provide a psychometrically advanced brief measure of sleep and wake function that can easily
be translated into clinical, research, and epidemiological contexts.

Sleep Diaries
Sleep diaries are a widely used method to gather nightly information on sleep–wake tim-
ing, patterns, and sleep disturbances prospectively over one or two weeks. Because of the
prospective nature of data collected with sleep diaries, recall bias is minimized compared to
retrospective clinical interviews or self-report questionnaires. Sleep diaries also provide more
information regarding night-to-night variability compared to PSG recordings that can only be
practically collected over two nights. Sleep diaries typically collect information about quantita-
tive sleep parameters, including sleep latency, number and duration of nocturnal awakenings,
sleep timing, and total sleep time, and qualitative assessments of sleep quality and feelings
upon awakenings. Many sleep diaries also include items aimed at gathering information of
daytime habits and behaviors that can influence sleep and wake functions, such as napping or
use of alcohol, stimulants, or medications.
Sleep diaries can be useful for screening purposes, but are a complementary piece of
information necessary for diagnostic purposes. For clinical and research purposes, sleep diaries
provide valuable longitudinal data that have been shown to closely correlate with PSG sleep
measures (27,28), and that are sensitive to change related to pharmacological and behavioral
insomnia treatments (12,29).
Numerous sleep diary formats have been used, but sleep diaries do not have an estab-
lished form that has been validated or standardized for use across clinical or research settings.
Nevertheless, they are typically of two common formats: the graphic format [Fig. 1A] and the
text format [Fig. 1B]. These sleep diaries are typically distributed and used in pencil-and-paper
formats, which do not allow for verification that the diary was indeed completed at the expected
time of day, every day. The use of electronic versions of sleep diaries using handheld comput-
ers, web-based dairies, and interactive voice response systems eliminates such undesirable
retrospective reporting.

Actigraphy
Actigraphs are wrist bracelets worn on the nondominant hand that record objective rest and
activity patterns continuously for several consecutives days and nights, with minimal inter-
ference with one’s daily and nightly routines. The bracelet detects and stores the number of
movements per one-minute epoch. The rest–activity patterns are then downloaded and used
as proxies for episodes or sleep and wakefulness. Algorithms code and classify the actigraphic
data collected to derive estimates of sleep latency, total sleep time, wake time after sleep onset,
and sleep fragmentation. Actigraphy is cost-effective (3,4,30–33). While actigraphy has been
used in insomnia research, for example (30,33–35), its use in clinical practice remains controver-
sial. Actigraphy can be used as a screening measure, and can complement clinical evaluation.
However, actigraphy is neither sufficient nor necessary for either diagnostic purposes or mech-
anistic studies of insomnia. It is practical for use in monitoring adherence and for monitoring
and displaying treatment-related changes in sleep.

Assessing Other Domains Relevant to Insomnia

As previously mentioned, evaluating and accurately characterizing the nature of insomnia
complaints and daytime features requires evaluation of other relevant domains.
Medical history reviews and physical examinations should be included in research and
clinical settings for accurate screening, diagnosis, and treatment planning. Other sleep disorders
can also present as, or co-occur with, insomnia. Obstructive sleep apnea (OSA), restless legs
syndrome, periodic leg movement disorder, and circadian disorders are all commonly described
as insomnia by patients and research participants. Several self-report questionnaires can be used
to estimate the likelihood of OSA using severity of daytime sleepiness, such as with the Epworth
Sleepiness Scale (36,37), or a combination of predictive factors for OSA as with the Multivariate
Apnea Index (38). Fatigue is another important domain that can be evaluated and quantified
using self-report questionnaires such as the Multidimensional Fatigue Inventory (39), or Fatigue
Severity Scale (40).
c10 IHBK059-Sateia March 17, 2010 9:29 Char Count=

SLEEP DIARY Name:

Midnight

Sleep Quality
p.m. a.m.

Noon
Date Afternoon Evening Morning

12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11

M
T
W
Th
F
Sa
Su
M
T
W
Th
F
Sa
Su
Instructions: Use the symbols below to indicate your Comments
sleep times in the grid. Rate your sleep quality each
night from 0 (poor) to 10 (excellent).
= Go to bed
= Get out of bed
= Actual sleep

The Pittsburgh Sleep Diary

SLEEP DIARY BEDTIME KEEP BY BED SLEEP DIARY WAKETIME KEEP BY BED
Please fill out this part of the diary last thing at night. Please fill out this part of the diary first thing in the morning:

day date day date

Today, when did you have: breakfast went to bed last night at
(if none, write ‘none’) lights out at
lunch
minutes untill fell asleep
dinner finally woke at
How many of the following did you have in each time period?
(if none, leave blank) Awakened by (check one): alarm clock/radio
before or after breakfast after lunch after someone whom I asked to wake me
with before/with before/with dinner noises
breakfast lunch dinner just woke
caffeinated drinks After falling asleep, woke up this many times during the night (circle)
alcoholic drinks 0 1 2 3 4 5 or more
total number of minutes awake
cigarettes
woke to use bathroom (circle # times)
cigars/pipes/plugs
0 1 2 3 4 5 or more
(of chewing tobacco)
awakened by noises/child/bedpartner (circle # times)
Which drugs and medications did you take today? (prescribed & over the counter) 0 1 2 3 4 5 or more
name time dose awakened due to discomfort or physical complaint (circle # times)
0 1 2 3 4 5 or more
just woke (circle # times)
0 1 2 3 4 5 or more
Ratings (place a mark somewhere along the line):
What exercise did you take today? (if none, check here) Sleep Quality:
very very
bad good
start end type
start end type Mood on Final Wakening:
very very
How many daytime naps did you take today? (if none, write 0) tense calm
give times for each: Alertness on Final Wakening:
very very
start end start end sleepy alert

Figure 1 Sleep diaries. (A) Graphic sleep diary. Patients/participants are asked to indicate time in and out of
bed by arrows pointing down and up, respectively, and to mark time spent asleep during the night or during the
day by side arrows pointing to the start and end time of sleep. Hours of the day and night are provided at the top
of the chart. Sleep quality using a 10-point Likert scale can also be logged. (B) Pittsburgh (text) sleep dairy. The
bedtime section is completed in the evening, prior to bed time, and collects information about daytime habits and
behaviors that can influence sleep. The morning wake time section is completed upon awakening in the morning
and inquires about timing of bed time and wake time, sleep latency, number and duration of nocturnal awakenings,
and feelings upon final awakening. Source: From Ref. 51.
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EVALUATION INSTRUMENTS AND METHODOLOGY 95

Finally, evaluating psychiatric health and psychiatric symptoms is an important compo-

nent of the measurement of insomnia. Unstructured clinical interviews or clinician-administered
scales such as the Structured Clinical Diagnostic Interview for DSM-IV (SCID) (41) and the
Hamilton Rating Scale for Depression (42) or for Anxiety (43) are highly recommended (3) and
necessary in treatment efficacy and mechanistic studies. Self-report measures of depression and
anxiety such as the Beck Depression Inventory (44–46), Inventory of Depressive Symptomatol-
ogy (47), Beck Anxiety Inventory (48), and the Spielberger State-Trait Anxiety Inventory (49) can
provide screening information regarding conditions comorbid with insomnia and contribute to
refining intervention plans or clinical referrals.

METHODOLOGICAL ISSUES
In selecting instruments for use in the clinic or in research studies, it is important to select
ones that are best suited to the precise measurement goals of the effort and the expected case
prevalence in the studied population. No single instrument is appropriate for all applications.
If the measurement goal is to find as many cases as possible, then an instrument with a high
sensitivity (# of cases/# test-positives) will be best. If the goal is to be sure that the identified
cases really are true cases, then an instrument with a high specificity (# of noncases/# test-
negatives) will be better. However, before deciding on the basis of sensitivity and specificity
alone, consideration of the expected population prevalence in the setting of measurement should
also be modeled with the sensitivities and specificities. With very high prevalence, it may not
be especially informative to use any questionnaire, since virtually everyone will be a case. With
very low prevalence, most of the test-positives will turn out to be false positives. Calculating
the positive and negative predictive values will be helpful.
If the measurement goal is mainly to scale the severity of symptoms, then other consider-
ations come into play. An ideal scale will behave like a thermometer, where only one dimension
of phenomenology is measured and accuracy is uniform at each point along the scale. Often,
semantically based scales have mixtures of dimensions. For example, people often think of
depression and insomnia together. However, when measuring symptoms of depression and
insomnia, it is best to have one scale for sad mood, another for insomnia, and as little correlation
between the two scales as possible. Separating symptom dimensions avoids confounding one’s
measurements. Accuracy of measurement can also present difficulty. In traditional severity
scales, the estimate of severity is the sum of the item scores in the scale. This method, using
what are called short forms, works reasonably well, but may not afford the greatest accuracy
of measurement. A newer general method, IRT, estimates severity as a point along a latent
dimension of severity. This estimator makes the most use of each item’s semantic severity to the
respondent. For example, the PIRS item “Your satisfaction with your sleep” is less severe than
the item “Lack of energy because of poor sleep.” Judging how strongly a person endorses the
second item even when first is strongly endorsed provides greater measurement accuracy than
the summary score from the two items. Based on this principle, it is possible to use a computer
algorithm to estimate symptom severity using only a few items, rather than deploying an entire
short form. This method is called “computer-adapted testing,” and is likely to be increasingly
used as more is learned about the item characteristics of sleep-related symptom questions in
population studies.

CONCLUSION
Insomnia is a prevalent complaint, whether primary or comorbid with other psychiatric, med-
ical, or sleep disorders. The evaluation of both primary and comorbid insomnia requires cap-
turing both the nighttime symptoms and the daytime consequences of insomnia, whether
the context is clinical, experimental, or epidemiological in nature. The evaluation of insomnia
also necessitates the evaluation of other sleep disorders, psychiatric symptoms, and medical
conditions that can be comorbid to or a risk factor for insomnia. Unstructured and struc-
tured clinician-administered interviews, self-report measures, actigraphy, and sleep diaries are
diverse assessment methods and tools that complement each other, and provide a comprehen-
sive assessment of nighttime and daytime symptoms of insomnia. Not all measures, however,
are amenable to all research contexts. For example, sleep dairies may be required for clinical
trials, but may be difficult to implement in epidemiological studies.
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96 GERMAIN AND MOUL

The assessment and measurement of insomnia requires further empirical validation work
in different areas. There is a clear need for developing and validating a reliable clinician-
administered gold standard for the assessment of insomnia that closely parallels the diagnostic
criteria for insomnia. Guidelines and recommendations for the selection of self-report measures
are available (3,50), and a combination of tools is often necessary to fully cover the different
domains of insomnia symptoms and related impairments and distress. Sleep diaries are also
numerous, but the need to achieve consensus on the most effective format and content items
has not yet been addressed. Actigraphy provides the advantages of allowing for objective
measurements over extended periods with minimal burden to the participant, but data collection
parameters and sleep–wake scoring algorithms vary widely, and few have been validated
against PSG or sleep diary measures in patients with insomnia.
In summary, the selection of tools to assess insomnia in a given context (e.g., experimental
mechanistic study vs. clinical trial vs. epidemiological population study) will be strongly guided
by the research aims to be achieved and by the feasibility of using different measurement meth-
ods. The growing use of advanced measurement methods, such as computerized adaptive test-
ing, can increase the sensitivity, specificity, and practicality of insomnia measurements and pro-
vide tools that enhance comparability of findings across study contexts and across populations.

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11 Insomnia Diagnosis and Classification

Daniel J. Buysse
Neuroscience Clinical and Translational Research Center, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION
Classification in medicine serves several purposes. In the clinical arena, disease classification is
used to identify individuals with a consistent set of symptoms and signs. This permits condi-
tions of a similar type or etiology to be recognized and discriminated from other conditions,
and helps to guide therapeutic interventions. In serving these functions, classification provides
a sort of “shorthand” for communication among professionals. Additionally, classification is
important for administrative functions such as medical record-keeping and billing. Within the
research arena, classification provides consistency in the identification of “cases” for scien-
tific investigation into epidemiology, course, etiology, pathophysiology, and treatment. Ideally,
the conceptualization and classification of disorders informs research into their etiology and
treatment, and such research leads back to refinements of conceptualization and classification.
Generalizations regarding etiology and treatment efficacy depend on reliable and valid diag-
noses. In this chapter, we will briefly review some general aspects of disease classification, and
present an overview regarding classification of insomnia, highlighting findings from empirical
research studies.

Definitions
At the most basic clinical level, symptoms are defined as complaints or other subjective evidence
presented by the patient. Signs are objective indicators of a health, illness, or functioning. Thus,
“difficulty falling asleep” is a symptom; polysomnographic sleep latency value of 32 minutes
is a sign. A syndrome is a characteristic set of symptoms and/or signs, which often follow
a characteristic clinical course. An illness or disorder typically encompasses the elements of a
syndrome, but also includes the connotation of suffering and a deviation from the normal state
of function. Finally, the term disease includes all the elements of a syndrome, but also connotes a
particular etiology. The etiology and pathophysiology of different diseases may vary widely. For
instance, diseases may be defined in terms of morbid anatomy (e.g., mitral stenosis), cellular
pathology (e.g., cancer), molecular pathology (e.g., porphyria) or an infectious agent (e.g.,
tuberculosis). A diagnosis is the determination of the nature of a case of illness or disorder, derived
from the Latin verb meaning “to recognize”. More commonly, diagnosis refers to the label placed
on a specific case of disease, illness or disorder. A nosology is a classification system of diseases, an
organizational structure comprising a set of specific diagnoses. Classification systems may use
categorical or dimensional models of disorders and diseases, or some combination of the two (as is
the case with sleep disorders classifications). A categorical model assumes that individuals with
a disorder/disease differ in some fundamental, noncontinuous way from the remainder of the
population, allowing a clean distinction between affected and unaffected individuals. In sleep
medicine, narcolepsy is an example of a disease, which can be classified in categorical terms;
an individual either has narcolepsy or does not. In dimensional disease models, affected and
unaffected individuals are seen as coming from a single population, with affected individuals
exceeding a specified threshold. In sleep medicine, sleep apnea is an example of a disorder
based on a dimensional threshold.
According to these definitions, insomnia may best be seen as a symptom or a disorder
rather than a true disease. Sometimes “insomnia” is used to refer to an isolated complaint
(symptom); in other cases, it is used to indicate a disorder, i.e., a consistent set of symptoms
and signs which causes distress or impairment, but for which no precise etiology has been
defined. Whether as a symptom or disorder, insomnia is most often conceptualized in dimen-
sional rather than categorical terms, which may help to explain why the percentage of affected
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INSOMNIA DIAGNOSIS AND CLASSIFICATION 99

individuals may vary from study to study, and why there is occasionally confusion as to whether
an individual should be considered to have a disorder at all. However, the ultimate goal of clas-
sification, even in insomnia diagnosis, is to assign individuals to discrete diagnostic categories
for purposes of clinical management or research investigation.
Finally, many disorders and diseases can have variable presentations of symptoms and
signs. For some diseases, pathological structure is the only criterion; cancer is an example. For
other diseases, even those with known pathophysiology, symptoms and signs can quite vari-
able; systemic lupus erythematosus and multiple sclerosis are two common examples in which
the pathophysiology is known, but specific manifestations vary considerably from one individ-
ual to another. Finally, disorders without established pathophysiology or etiology, defined by
symptoms and signs alone, can be highly variable among individuals. For instance, two indi-
viduals who meet the criteria for major depressive disorder may have virtually no symptoms in
common. Insomnia disorders encompass a similar wide degree of variability. For instance, the
criteria for general insomnia disorder according to the International Classification of Sleep Dis-
orders, Second Edition (ICSD-2) encompass individuals who present with sleep onset difficulty
and irritability as well as individuals with nonrestorative sleep and daytime fatigue.

Key Attributes of Classification Systems

A classification system for insomnia diagnoses should possess several key attributes. First,
the system should be reasonably easy to use. Complex diagnoses or classification systems are
unlikely to be widely used, even if they accurately describe disorders or diseases. Second, for
administrative reasons, classifications for insomnia should conform to or be compatible with
widely accepted disease classifications, such as the International Classification of Diseases and
the International Classification of Functioning, Disability and Health. Third, classifications and
diagnoses must have acceptable reliability, which refers to the extent to which diagnoses are
reproducible, either among multiple raters (inter-rater reliability), within a single rater (intra-
rater reliability) or across time (test-retest reliability). Third, classifications and diagnoses should
have acceptable measures of validity, defined as the extent to which a diagnosis serves its pur-
pose of case identification, clinical prediction, or communication. The goals of classification and
diagnosis sometimes differ in clinical and research settings. In clinical settings, an important
goal is to have diagnostic and descriptive coverage for all or most cases, leaving very few
cases, which cannot be classified. As a result, optimal clinical categories are often fairly broad.
Research applications often benefit from more narrow diagnostic categories to ensure homoge-
nous samples for pathophysiological and treatment research. Thus, the goal of classification in
clinical practice is to diagnosis and treat patients, whereas the goal of classification in research
is often to study a specific disease or disorder.

Classification Systems for Insomnia

Multiple systems have been proposed for classifying insomnia symptoms and disorders, with
changes over time that reflect the prevailing zeitgeists. Most important has been an evolution
in thinking about insomnia with regard to its conceptualization as a symptom or a disorder,
and with regard to the nature of causality. Some of the earliest classifications describe insomnia
as a symptom, not a disorder (1,2). Clinicians were encouraged to identify the symptom of
insomnia in order to identify and treat underlying causes, most often emotional distress or frank
psychiatric disorders. The implication was that treating the underlying condition would lead
to resolution of insomnia. However, establishing causality or even the temporal relationship
between insomnia and other disorders can be difficult, imprecise, and ineffective (3,4). For
instance, insomnia and fatigue are the most common residual symptoms of depression, (5) and
even when painful medical conditions such as arthritis are identified and treated, insomnia
may persist (6,7). Thus, more recent conceptualizations suggest that it may be more appropriate
to think of insomnia as a disorder that is frequently comorbid with, rather than secondary to,
other conditions. This view was emphasized in the 2005 NIH State of the Science Conference
on insomnia (8).
Another common method of classifying insomnia, also exemplified by the 1983 NIH Con-
sensus Conference on Insomnia, (1) was to classify insomnia by its duration: Transient, defined
as less than two weeks; short-term, lasting for two to four weeks; and chronic, lasting greater
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100 BUYSSE

than four weeks (1). This type of classification, however, is recognized as being an intermediate
step toward more specific etiologically-based diagnoses, which often differ in their duration. For
instance, transient insomnia complaints are often associated with situational, environmental, or
medical stresses, and chronic insomnia is more often associated with psychiatric disorders, cir-
cadian rhythm disorders, or primary dysregulation of sleep-wake mechanisms. Duration-based
insomnia disorders are to some extent recognized in more formal nosologies such as ICSD-2
in disorders such as adjustment sleep disorder, with a duration of less than three months, and
idiopathic insomnia, with a lifelong course. Empirical evidence and epidemiological studies
also address potential subtypes based on duration. A Gallup Poll conducted for the National
Sleep Foundation suggested that approximately 30% of adults complained of transient, short-
term, or recurrent insomnia, and 10% complained of chronic problems (9). The cross-sectional
national Comorbidity Survey Replication study demonstrated a more bimodal distribution of
insomnia duration, with approximately 20% of patients reporting symptoms of less than four
weeks duration, and approximately 30% reporting symptoms for greater than one year (10).
Some longitudinal studies suggest a continuum of insomnia duration, including occasional
insomnia, repeated brief insomnia, and more persistent forms (11,12). Studies with follow-up
intervals of one to three years suggest that insomnia symptoms persist in approximately 50% to
80% of individuals, depending on the definition of insomnia symptoms (13,14). Other data sug-
gest that more severe forms of insomnia have greater chronicity. A three-year follow-up study
demonstrated remission in approximately 40% of individuals with insomnia symptoms, whereas
approximately 80% of individuals with insomnia syndrome had a chronic course (15). Data from
the Wisconsin Sleep Cohort indicate that approximately two-third of individuals with insomnia
symptoms have persistent symptoms at 3 and 10 year follow-up (16). Therefore, some empirical
data support the distinction between duration-based insomnia subtypes. However, duration in
itself provides little guidance in terms of appropriate interventions, but merely points toward
likely contributing factors that can be specifically addressed.
Another common, but informal, method for classifying insomnia is by the specific symp-
tom presentation: sleep onset insomnia, sleep maintenance insomnia, or nonrestorative sleep.
Epidemiological and survey data demonstrate that sleep maintenance insomnia is consistently
the most prevalent symptom, and early morning awakening the least common.(17) Moreover,
symptom types vary with age, with sleep onset insomnia and nonrestorative sleep being rela-
tively more common in younger adults, and sleep maintenance insomnia being more common
with increasing age [e.g., (17,18)]. However, such studies also demonstrate the high rate of cooc-
currence of individual symptoms, and the strong correlation between them. For instance, in the
National Comorbidity Survey Replication, each of the symptoms correlated with each of the
others with r values of 0.65 to 0.84 (10), and up to 80% of insomnia patients have more than one
symptom when followed longitudinally (16). Moreover, longitudinal studies demonstrate that
individuals’ specific symptom type frequently changes over time (16,19). Insomnia symptom
types may provide clues to specific contributing factors such as Restless Legs Syndrome or
subclinical circadian phase delays (20) in individuals with sleep onset complaints. Symptom
patterns are also considered in selecting specific treatments. For instance, a patient who presents
with predominantly sleep onset complaints may be an appropriate candidate for a short-acting
benzodiazepine receptor agonist, and a patient with predominantly sleep maintenance com-
plaints may benefit from a longer-acting agent. However, because of the frequent cooccurrence
of symptoms and their poor stability over time, symptom subtype does not appear to be an
adequate basis for diagnostic classification. Formal diagnostic classifications for insomnia have
been proposed as part of more comprehensive sleep disorders nosologies. These classifications
distinguish different insomnia disorders on the basis of specific sleep symptoms, other clinical
features (e.g., duration, polysomnographic features), and the presence or absence of other sleep,
general medical, and psychiatric disorders. Table 1 outlines the major classification systems for
sleep disorders used the past 30 years: the diagnostic classification of sleep and arousal disorders
(DCSAD) (2); the international classification of sleep disorders (ICSD) (21,22); the International
Classification of Sleep Disorders, 2nd Edition (ICSD-2) (23); the Diagnostic and Statistical Man-
ual of Mental Disorders, Third Edition Revised (DSM-III-R) (24); and Fourth Edition (DSM-IV)
(25); and the International Classification of Diseases, 9th Edition, Clinical Modification (ICD-
9CM) (26) and 10th Edition (27). These classification systems differ substantially in terms of their
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Table 1 Diagnostic Classifications for Sleep Disorders

International
Diagnostic and Statistical International
Statistical Manual Classification of Statistical
Diagnostic of Mental Diseases and Related Classification of

8:26
Classification of International International Disorders, Diagnostic and Health Problems, Diseases and
Sleep and Arousal Classification of Classification of 3rd Edition Statistical Manual of 9th Edition, Clinical Related Health
Disorders Sleep Disorders Sleep Disorders, 2nd Revised Mental Disorders, 4th Modification Problems, 10th

Char Count=
(DCSAD) (2) (ICSD) (21,22) Edition (ICSD-2) (23) (DSM-III-R) (24) Edition (DSM-IV) (25) (ICD-9-CM) (26) Edition (ICD-10) (27)

r Disorders of r Dyssomnias r Insomnia r Dyssomnias r Primary sleep r Sleep disturbances r Sleep disorders
Initiating and – Intrinsic r Sleep-related – Insomnia disorders (organic) (organic)
maintaining – Extrinsic breathing disorders disorder – Dyssomnias r Specific disorders r Sleep disorders
sleep (DIMS) – Circadian rhythm r Hypersomnias of – Hypersomnia – Parasomnias of sleep of due to emotional
r Disorders of sleep disorders central origin disorder r Sleep disorders nonorganic origin causes
excessive sleep r Parasomnias r Circadian rhythm – Sleep–wake related to another
(DOES) r Sleep disorders– sleep disorders schedule mental disorder
r Disorders of the associated with r Parasomnias disorder r Sleep disorders due
sleep–wake mental, neurologic, r Sleep-related r Parasomnias to medical disorder
schedule or medical movement r Substance-induced
r Parasomnias disorders disorders sleep disorder
r Proposed sleep r Isolated symptoms,
disorders apparently normal
variants, and
unresolved issues
r Other sleep
disorders

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organizational schemes, the number of specific diagnoses, and their reliance on specific criteria.
An overview of these features is presented in Table 2. Specific insomnia diagnoses within each
classification are outlined in Table 3.
The DCSAD, the first widely used classification of sleep disorders, includes four major
categories of disorders: Disorders of Initiating and Maintaining Sleep (DIMS or insomnias), Dis-
orders of Excessive Sleepiness (DOES or hypersomnias), Disorders of the Sleep/Wake Schedule,
and Parasomnias. This classification is easy to use, given its symptom-based organization. The
number of individual categories is large, and approximately 30 diagnoses could conceivably
include a complaint of insomnia. The DCSAD provides useful clinical descriptions of each dis-
order. However, it also has some important limitations. First, specific clinical and polysomno-
graphic criteria are not included, which necessitates considerable clinical judgment in establish-
ing a diagnosis and is likely to decrease reliability. Second, the symptom-based approach makes
sense clinically but leads to duplicate listings for a single disorder. For instance, periodic limb
movement disorder can produce either insomnia or hypersomnia, so the diagnosis was listed
twice in the classification, in both the DIMS and DOES sections.
The ICSD is a successor to the DCSAD, published in 1990. It differs from the DCSAD clas-
sification in two major ways. First, the organization of disorders is by presumed etiology rather
than symptom presentation. Second, the ICSD includes specific clinical and polysomnographic
criteria, severity ratings, and both “minimal” and “complete” diagnostic criteria for each dis-
order. The three major categories of sleep disorders in ICSD are dyssomnias, parasomnias, and
secondary sleep disorders. Dyssomnias are disorders in which the major signs and symptoms
relate to sleep and/or wakefulness. The dyssomnias are further subdivided into intrinsic dys-
somnias, in which some abnormality of brain function is thought to underlie the symptoms
and signs; extrinsic disorders, in which some external factor leads to the sleep complaint; and
circadian rhythm sleep disorders, which are thought to result from abnormal entrainment or
misalignment of the circadian system with external time cues. Secondary sleep disorders are those
associated with, and presumed to be causally related to, mental, neurologic, and medical disor-
ders. In contrast to dyssomnias, secondary sleep disorders occur within a context of broader set
of symptoms and signs of the “primary” disorder. Of the 84 diagnoses in ICSD, approximately
43 may be associated with insomnia complaints, including those in Dyssomnia and Secondary
Sleep Disorder categories. ICSD defines insomnia as in general as a “complaint of an insuffi-
cient amount of sleep or not feeling rested after the habitual sleep episode.” Daytime symptoms
associated with insomnia, such as restlessness, irritability, anxiety, fatigue, and tiredness, are
described in the severity criteria, rather than in the insomnia disorders themselves.
Although the ICSD has several advantages compared DCSAD, it also has some limitations,
many of which apply to other classifications as well. First, diagnoses are based largely upon
expert opinion, although literature reviews were also used. Second, for most sleep disorders,
the exact pathophysiology remains unknown, despite the broad pathophysiological orientation,
which drives ICSD. Third, most specific diagnostic criteria in the ICSD have not been rigorously
tested against alternative criteria, being based largely upon expert opinion. Fourth, there is
some concern that the ICSD’s large number of categories may represent a form of pseudo
precision. For instance, Reynolds and colleagues (28) argued that sub-typing chronic insomnia
into different disorders may be premature, given the uncertain validity of concepts such as
sleep state misperception, environmental sleep disorder, and inadequate sleep hygiene. Finally,
the specific diagnostic criteria for certain disorders have been questioned by expert interest
groups within those areas. For instance, alternative criteria had been proposed for the diagnosis
of restless leg syndrome and periodic limb movements, (29) sleep apnea syndromes, (30) and
narcolepsy (31,32).
ICSD-2 was published in 2005. The framework of ICSD-2 departs substantially from
ICSD in two major ways. First, ICSD-2 groups sleep disorders into eight major categories
based on major symptom presentation and presumed etiology (Table 2). Insomnia is one of
these categories, and 11 specific insomnia diagnoses are grouped in that section. Brief descrip-
tions of these diagnoses are presented in Table 3. Second, ICSD-2 specifies general criteria for
insomnia which apply to all diagnoses within the Insomnia section (Table 4). The important
elements of this definition are (1) a sleep-related insomnia complaint; (2) adequate oppor-
tunity and circumstances to sleep, clearly demarcating insomnia from problems related to
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8:26
Table 2 Diagnostic Classifications for Sleep Disorders

DCSAD (2) ICSD (21,22) ICSD-2 (23) DSM-III-R (24) DSM-IV (25) ICD-9-CM (26) ICD-10 (27)

Char Count=
Derivation Expert opinion Expert opinion, Expert opinion, Expert opinion Expert opinion, Expert opinion Expert opinion
literature reviews literature reviews literature reviews
Major organizing Symptoms Presumed Symptoms, Symptoms Presumed Presumed Presumed
feature pathophysiology/ Presumed pathophysiology/ pathophysiology/ pathophysiology/
etiology pathophysiology/ etiology etiology etiology
etiology
Breadth of Narrow Narrow Narrow Broad Intermediate Broad Broad
categories
Number of specific 68 88 81 15 25 18 15
disorders
Polysomnographic No Yes, for some Yes, for some No No No No
criteria disorders, but not disorders, but not
insomnia insomnia

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Table 3 ICSD-2 Insomnia Disorders

Adjustment r Insomnia temporally associated with an identifiable stressor

insomnia (acute r Sleep disturbance expected to resolve when the acute stressor resolves or when the
insomnia) individual adapts
r Sleep disturbance lasts for less than three months
Psychophysiological r Insomnia present for at least one month
insomnia r Evidence of conditioned sleep difficulty and/or heightened arousal as indicated by
one or more of the following:
(1) Excessive focus on and heightened anxiety about sleep
(2) Difficulty falling asleep in bed at desired bedtime or during planned naps, but not
during monotonous activities when not intending to sleep
(3) Sleep better away from home than at home
(4) Mental arousal in bed (intrusive thoughts or inability to cease sleep-preventing
mental activity)
(5) Heightened somatic tension in bed, perceived inability to relax the body
Paradoxical r Insomnia present for at least one month
insomnia r One or more of the following:
(1) Chronic pattern of little or no sleep most nights with rare nights of relatively
normal amounts of sleep
(2) Sleep-log data show an average sleep time well below normative values
(3) Consistent marked mismatch between objective findings from polysomnography
or actigraphy and subjective sleep estimates
r At least one of the following:
(1) Constant or near constant awareness of environmental stimuli throughout most
nights
(2) Conscious thoughts or rumination throughout most nights while maintaining a
recumbent posture
r Daytime impairment consistent with that reported by other insomnia subtypes, but
much less severe than expected given the extreme level of sleep deprivation
Idiopathic insomnia r Course of the disorder is chronic, as indicated by each of the following:
(1) Onset during infancy or childhood
(2) No identifiable precipitant or cause
(3) Persistent course with no periods of sustained remission
Due to mental r Insomnia present for at least one month
disorder r Mental disorder has been diagnosed according to standard criteria
r Insomnia is temporally associated with the mental disorder (may appear a few days
or weeks before the emergence of the mental disorder)
r Insomnia is more prominent than that typically associated with the mental disorders,
as indicated by marked distress or an independent focus of treatment
Inadequate sleep r Insomnia present for at least one month
hygiene r Inadequate sleep hygiene practices indicated by at least one of the following:
(1) Improper sleep scheduling (frequent daytime napping, highly variable bedtimes
or rising times, excessive amounts of time in bed)
(2) Use of alcohol, nicotine, or caffeine, especially in the period preceding bedtime
(3) Mentally stimulating, physically activating, or emotionally upsetting activities too
close to bedtime
(4) Frequent use of the bed for activities other than sleep
(5) Failure to maintain comfortable sleeping environment
Behavioral insomnia r Sleep onset association type includes each of the following:
of childhood (1) Falling asleep is an extended process that requires special conditions
(2) Sleep onset associations are highly problematic or demanding
(3) In the absence of the associated conditions, sleep onset is significantly delayed
or sleep is otherwise disrupted
(4) Nighttime awakenings require caregiver intervention for the child to return to
sleep
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INSOMNIA DIAGNOSIS AND CLASSIFICATION 105

Table 3 ICSD-2 Insomnia Disorders (Continued )

r Limit-setting type includes each of the following:
(1) Difficulty initiating or maintaining sleep
(2) Stalls or refuses to go to bed at an appropriate time or refuses to return to bed
following a nighttime awakening
(3) Caregiver demonstrates insufficient or inappropriate limit setting to establish
appropriate sleeping behavior in the child
Due to drug or r Insomnia present for at least one month
substance r One of the following applies
(1) Current ongoing dependence on or abuse of a drug or substance known to have
sleep-disruptive properties either during use or intoxication or withdrawal
(2) Current ongoing use of or exposure to a medication, food, or toxin known to have
sleep-disruptive properties in susceptible individuals
r Insomnia temporally associated with the substance exposure, use or abuse, or acute
withdrawal
Due to medical r Insomnia is present for at least one month
condition r Coexisting medical or physiologic condition known to disrupt sleep
r Insomnia associated with the medical or physiologic condition (began near the time
of onset, or with significant progression of the medical or physiologic condition and
varies the severity of this condition)

Source: From Ref. 23.

behaviorally-induced insufficient sleep or environmental disturbance; and (3) the presence of at

least one type of daytime impairment related to the sleep disturbance. The general criteria for
insomnia were derived from Research Diagnostic Criteria for Insomnia, (33) discussed further
below. The ICSD-2 general criterion for insomnia includes not only complaints of difficulty
initiating or maintaining sleep, but also complaints of “sleep that is chronically nonrestorative
or poor in quality.” Nonrestorative sleep has traditionally been included among insomnia com-
plaints, although significant uncertainty exists regarding whether this symptom is similar to
other symptoms of chronic insomnia with regard to precursors, precipitants, pathology and
associated factors.
The subtypes of insomnia and diagnostic criteria in ICSD-2 are similar to those in ICSD,
with a few exceptions. The ICSD diagnosis of Sleep State Misperception is renamed Paradoxical
Insomnia in ICSD-2. More importantly, the ICSD diagnoses related to childhood insomnia, i.e.,
Limit-setting Sleep Disorder and Sleep-onset Association Disorder, were merged into a single
diagnosis in ICSD-2 called Behavioral Insomnia of Childhood. This diagnosis was moved from
the ICSD section of Extrinsic Sleep Disorders to the ICSD-2 section of Insomnia. Finally, ICSD-2

Table 4 ICSD-2 General Insomnia Criteria

(A) A complaint of difficulty initiating sleep, difficulty maintaining sleep, or waking up too early or sleep that
is chronically nonrestorative or poor in quality. In children, the sleep difficulty is often reported by the
caretaker and may consist of observed bedtime resistance or inability to sleep independently.
(B) The above sleep difficulty occurs despite adequate opportunity and circumstances for sleep.
(C) At least one of the following forms of daytime impairment related to the nighttime sleep difficulty is
reported by the patient:
(i) Fatigue or malaise
(ii) Attention, concentration, or memory impairment
(iii) Social or vocational dysfunction or poor school performance
(iv) Mood disturbance or irritability
(v) Daytime sleepiness
(vi) Motivation, energy, or initiative reduction
(vii) Proneness for errors or accidents at work or while driving
(viii) Tension, headaches, or gastrointestinal symptoms in response to sleep loss
(ix) Concerns or worries about sleep

Source: From Ref. 23.

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brings the “secondary” insomnia disorders due to mental disorder, medical disorder, or sub-
stance abuse, into the insomnia section. Although ICSD-2 identifies insomnia disorders within
a single section, clinicians must also be mindful of the fact that many, in fact most, other major
sections within the nosology also contain diagnoses that may include an insomnia complaint as
one element of the clinical presentation. For instance, insomnia complaints are ubiquitous in the
circadian rhythm disorders and common among breathing and movement disorders as well.
Even patients with narcolepsy often report insomnia, occasionally as a presenting complaint.
Insomnia symptoms associated with these other major sleep disorders may coexist with major
insomnia diagnoses (primary or comorbid), requiring that both disorders be targeted effectively
in treatment.ICSD-2 employs the terminology of “insomnia due to. . .” in identifying what have
historically been referred to as “secondary” insomnia conditions. As discussed above, current
evidence suggests the importance of moving away from the concept of secondary insomnia and
toward that of comorbid insomnia.
The DSM-III-R and DSM-IV were designed as classifications of mental disorders but also
include sleep disorders sections. DSM-III-R includes two major sections of sleep disorders, dys-
somnias and parasomnias. The dyssomnias include insomnia disorder, hypersomnia disorder, and
other dyssomnias; within insomnia disorder are three subtypes, related to another mental dis-
order, related to a known organic factor, and primary insomnia. In DSM-IV, the major divisions
of sleep disorders are arranged differently, and include a small number of additional categories.
DSM-IV major divisions are Primary Sleep Disorders, which include dyssomnias and parasom-
nias; sleep disorders related to another mental disorder; sleep disorder due to a general medical
disorder (including insomnia type); and substance-induced sleep disorder (including insomnia
type). Thus, there is some homology between the organization of DSM-III-R and DCSAD, and
between DSM-IV and ICSD. The main difference between the psychiatric and sleep medicine
classifications is in the number of specific categories and the breadth of these diagnoses. For
instance, DSM-IV includes only one diagnosis for chronic “primary” insomnia unrelated to
mental, medical, or substance-induced sleep disorders (primary insomnia). This category sub-
sumes more specific ICSD categories such as psychophysiological insomnia, inadequate sleep
hygiene, idiopathic hypersomnia, adjustment sleep disorder, and environmental sleep disorder,
both in theory and in practice (34). Like the ICSD, DSM-IV was derived from expert opinion and
literature reviews, and the organization is based broadly on presumed pathophysiology. Also
like ICSD, it includes clinical criteria, but unlike ICSD, it does not include specific polysomno-
graphic criteria or severity descriptors. Although DSM-IV is appropriate for and appears to be
well- accepted by the psychiatric community, it is not widely used by sleep disorders specialists.
ICD-9CM and ICD-10 include two broad categories of sleep disorders, those of organic
origin, and those of nonorganic origin (due to emotional causes). In ICD-10, Organic sleep disorders
include insomnia, hypersomnia, circadian disorders, sleep apnea, and narcolepsy. Sleep disorders
due to emotional causes include insomnia, hypersomnia, circadian rhythm disorders, sleepwalk-
ing, sleep terrors, and nightmares. Specific diagnostic descriptions are provided only for the
nonorganic sleep disorders. The distinction between organic and nonorganic is largely arbitrary
and may be difficult to operationalize in clinical practice. Therefore, ICD-9CM and ICD-10 are
not widely used clinically for descriptive purposes. However, the diagnosis codes from ICD-
9CM have been cross-referenced to ICSD, ICSD-2, and DSM-IV, and these codes are widely used
for billing and records keeping purposes.
Although it was developed specifically as a research tool, the Research Diagnostic Criteria
for Insomnia (RDC-I) (33) used a rigorous review process and consensus to evaluate reliability
and validity data for various insomnia disorders. More than 400 published research studies of
insomnia were examined to determine how often various criteria were used in the selection
and characterization of study samples, and cross-referenced these actual study selection criteria
against the specific DSM-IV or ICSD diagnosis which was said to be studied. For example, actual
selection criteria included the use of specific insomnia diagnoses, insomnia duration, medical,
psychiatric, and medication exclusions, self-reported symptoms, and polysomnographic find-
ings. Based on this literature review and a consensus process, the work group developed research
criteria for those diagnoses with the greatest empirical support. This led to the development
of research diagnostic criteria for general insomnia disorder, nine specific insomnia disorders,
and normal sleepers. The nine specific disorders include primary insomnia, insomnia due to
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INSOMNIA DIAGNOSIS AND CLASSIFICATION 107

a mental disorder, psychophysiological insomnia, paradoxical insomnia, idiopathic insomnia,

insomnia related to periodic limb mvement disorder, insomnia related to sleep apnea, insomnia
due to medical condition, and insomnia due to drug or substance. Note that these disorders
include categories included in ICSD and in DSM-IV. Beyond the provision of specific diagnostic
criteria, the rigorous process of the RDC-I influenced the development of insomnia disorder
categories included in ICSD-2.
In summary, existing classifications for insomnia disorders show similarities and differ-
ences, and have their own strengths and weaknesses. The ICSD-2 is currently most widely used
by sleep disorders specialists.
A survey conducted in 1996, prior to the introduction of ICSD-2, examined the use of
various sleep disorders classifications in clinical practice (35). This survey indicated that 91.7% of
participating sleep disorders centers used the ICSD for establishing clinical diagnoses, consistent
with center accreditation standards at the time. However, clinicians rated the organizational
structure of ICSD and DCSAD significantly more favorably than that of ICD-9 or DSM-IV, and
DCSAD was ranked more favorably than ICSD. Thus, clinicians seemed to prefer the intuitive
symptom-based structure of DCSAD. The “fit” of each classification to actual patients was
also rated more highly for ICSD and DCSAD compared to ICD-9 and DSM-IV. In terms of
“ease of use”, clinicians rated the DCSAD as being simpler than ICSD. These data indicate that
clinicians use the diagnostic classification systems available, but seem to find a symptom-based
system easier to use. Although this survey preceded the introduction of ICSD-2, it is worth
noting that the overall organization of ICSD-2, with six major diagnostic clusters, resembles the
organization of DCSAD more than that of ICSD.

Reliability
Reliability is a measure of the extent to which diagnoses are reproducible across time (test-retest
reliability), across multiple ratings by a single rater (intra-rater reliability), and among different
raters (inter-rater reliability). Several sources of variance contribute to reduced reliability. First,
test-retest reliability may be low because patients’ actual clinical state may change from one
time to another. Inter-rater reliability may be imperfect because the judgments of one clinician
will not perfectly match those of another. In addition, both types of reliability may suffer
from measurement error, either in the sensitivity of particular questions asked of a patient,
or of physiological measures such as EEG sleep studies. Similarly, the interpretation of specific
measurements may vary across raters and over time. Finally, the specific criteria used to establish
a diagnosis may be imprecise. Table 5 summarizes data on inter-rater and test-retest reliability
for insomnia diagnoses using various diagnostic criteria. The table illustrates that the total
number of reliability studies and the total number of insomnia patients assessed has been small.
The most rigorous work has been conducted with ICSD-2 and DSM-IV, although publication of
peer-reviewed findings is pending at this time.
Although not a measure of reliability per se, one would expect similar patterns of insomnia
diagnoses to be made at different sleep medicine centers. A field trial for DSM-IV examined
diagnostic patterns in five sleep disorders centers found similar overall patterns of diagnoses,
but significantly different relative frequencies for specific diagnoses (36). For instance, some
sites made frequent diagnoses of insomnia related to another mental disorder, and very few

Table 5 Interrater Reliability and Convergent Validity for Insomnia Diagnoses

Total number Number of

Reference DSM-III-R/DSM-IV ICSD ICSD-2 of subjects insomnia subjects
(37) 0.91a – 68 54
(36) 0.35–0.56a – 216 216
(38) 0.25a 0.22a 41 41
(39) 0.71a 0.68a 31 31
(40,41) 0.09–0.68b 0.15–0.68b 333 333
a
Values reported are kappa values for interrater reliability.
b
Values reported are correlation values for diagnostic ratings across pairs of raters. The reported range of values represents
values for different specific diagnoses.
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108 BUYSSE

diagnoses of Primary Insomnia, whereas other sites had the opposite pattern. This study also
examined diagnostic patterns of two different interviewers at each site, one a sleep specialist
and one a nonsleep specialist clinician. The two types of interviewers had similar patterns of
overall diagnoses, but nonspecialists tended to make more diagnoses of insomnia due to a
medical condition, whereas sleep specialists tended to make more diagnoses such as delayed
sleep phase syndrome.
Other studies have examined more traditional measures of inter-rater reliability. Schramm
et al (37) used a structured diagnostic interview to establish DSM-III-R insomnia diagnoses in
a sample of 68 patients with complaints of sleep disturbances. The overall kappa value for
insomnia disorders was 0.91, indicating excellent inter-rater agreement. With regard to specific
types of insomnia, kappa values ranged from 0.84 to 0.86 for insomnia related to a mental
disorder, insomnia related to a known organic factor, and primary insomnia. Of note, the kappa
for primary insomnia was derived from a total of only 10 cases, which again makes the reliability
of this estimate uncertain.
The DSM-IV field trial included 216 patients clinically referred for a sleep disorder and
evaluated by two interviewers, one an experienced sleep specialist and one a nonsleep specialist
clinician. The two raters used their “usual clinical interview” to assess patients. Kappa values for
the primary diagnosis ranged from 0.35 to 0.56 across the five sites, indicating only moderate
diagnostic agreement. Kappa values for specific diagnoses were somewhat worse, ranging
from 0.28 to 0.59 for primary insomnia and 0.34 to 0.60 for insomnia related to another mental
disorder. The lower degree of inter-rater reliability in this study likely related to the use of clinical
interviews, rather than structured interviews, and clinicians who varied in their sleep expertise.
However, videotaped interviews for a subset of 41 patients were reviewed by sleep specialists
at each of the five sites. The overall kappa value for DSM-IV and ICSD diagnoses ranged from
0.22 to 0.25, in the fair to poor range(38). Thus, it appears that different raters, even among sleep
specialists, make use of clinical information in different ways to establish diagnoses.
Another small study (39) examined inter-rater agreement for DSM-III-R and ICSD diag-
noses in 31 clinically referred patients with insomnia, with diagnoses based on clinical and
polysomnographic information rather than direct interview with the patients. A kappa value
of 0.71 was found for DSM-III-R diagnoses, and 0.68 for ICSD diagnoses, within the moderate
to very good range of reliability.
No published studies have formally assessed the test-retest reliability of insomnia diag-
noses. The study by Schramm and colleagues described above indicates that test-retest reliability
was assessed, but the interval between interviews was only one to three days. In addition, this
study combined elements of both a test-retest and inter-rater reliability study.
More recent preliminary data from a two-site study examined the reliability and validity of
DSM-IV and ICSD-2 insomnia diagnoses in 333 patients.(40) Each patient was interviewed by six
sleep specialists, using various combinations of clinical interview, structured interview, and PSG
information. Inter-rater correlations for DSM-IV diagnoses were highest for disorders that might
be considered secondary or comorbid forms of insomnia, such as alcohol-induced, insomnia
related to another mental or medical disorder, breathing-related sleep disorder, and circadian
rhythm sleep disorder, with inter-rater r values of approximately 0.40 to 0.70. DSM-IV primary
insomnia and other forms of insomnia were least reliable, with r values of approximately 0.10
to 0.30. Among ICSD-2 diagnoses, highest reliability was associated with insomnia related to a
mental or medical disorder, restless legs syndrome, idiopathic insomnia, delayed sleep phase
syndrome, and obstructive sleep apnea (r values approximately 0.34–0.68); lowest reliability
was seen for paradoxical insomnia. Some ICSD-2 insomnia diagnoses were never chosen. The
authors conclude that reliability and validity of some, but not all, DSM-IV and ICSD-2 diagnoses
was supported, and that the former nosology may have too few categories, and the latter too
many. Further data from this study indicated that use of a structured diagnostic interview
was associated with greater reliability against “gold standard” diagnoses than standard clinical
interviews.(41)
In summary, available data suggest moderate inter-rater reliability for insomnia diagnoses
using DSM-IV, ICSD, and ICSD-2 criteria. Test-retest reliability has yet to be adequately assessed.
The finding of significant differences among sleep disorder centers and the diagnoses they
establish, and the low rates of inter-rater agreement among sleep specialists at different sites,
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INSOMNIA DIAGNOSIS AND CLASSIFICATION 109

suggest that different investigators apply the diagnostic criteria for insomnia disorders in very
different ways. Data from a small number of studies also suggest moderate improvements in
reliability with the use of structured interview and/or PSG data.

Validity
Validity is a measure of the extent to which a diagnosis serves its purposes of case identification,
clinical prediction, or communication. Several types of validity are commonly investigated. Face
validity or ecological validity describes how reasonable a diagnosis is based on clinical experience;
in other words, does the diagnosis make sense and reflect a condition seen in the real world?
Construct validity refers to the degree to which a diagnosis (or other measurement scale) measures
the theoretical, etiological, or pathological construct it is designed to measure, and is often
inferred from discriminant and convergent validity. Descriminant validity relates to how well
specific features discriminate one diagnosis from other diagnoses. Convergent validity refers to
the degree to which one diagnosis or set of diagnostic criteria relates to similar diagnoses or
criteria. Predictive validity assesses the degree to which a diagnosis corresponds with a particular
natural history or treatment response.
A large number of studies have been reported which describe distinctive clinical features
or polysomnographic features of one type of insomnia diagnosis compared to other insomnia
diagnoses. For instance, traditional polysomnographic and clinical characteristics that distin-
guish “chronic insomnia” from the insomnia of depression (42,43) or “objective insomnia”
from “subjective insomnia” (44,45) have been evaluated. Other analyses have demonstrated
quantitative EEG sleep differences between subjects with psychophysiological insomnia, para-
doxical insomnia, insomnia associated with depression, and good sleepers (46,47). Two studies
have also demonstrated similarities and differences in the 24-hour metabolic rate patterns of
psychophysological and paradoxical insomnia patients, both of whom differed from controls
(48–50). However, confirmatory analyses and replications have been infrequently reported with
all of these analyses. Likewise, the sensitivity, specificity, or receiver-operating characteristic
curves of specific polysomnographic or clinical features have not been described for one subtype
of insomnia versus another. By contrast, such studies have been conducted for measures such as
reduced REM latency in depression (51,52). Perhaps partly as a result of infrequently-replicated
findings, current clinical recommendations do not support the use of polysomnography for
diagnosis in most patients with insomnia (53,54).
Another method of assessing construct validity is to determine how clinical and
polysomnographic features empirically cluster, and to match such empirical clusters to clinical
diagnoses. Hauri (55) reported a cluster analysis of psychological tests, clinical interview, and
three nights of polysomnography in 89 insomnia patients and 10 controls compared to DCSAD
diagnoses. Factor analysis identified 26 factors derived from these assessments, and subsequent
cluster analysis provided empirical validation for the category of persistent psychophysiolog-
ical insomnia, insomnia associated with affective disorder, and childhood onset (idiopathic)
insomnia. However, six other clusters did not readily correspond to existing DCSAD diagnoses.
A similar study used questionnaire data, polysomnographic data, and interview data to derive
15 factors in 113 insomnia patients and 39 healthy controls (39). The 14 empirically-identified
clusters did not correspond strongly with either DSM-III-R or ICSD diagnoses. Caution is war-
ranted given the small number of patients and controls relative to the large number of factors
in both of these studies.
Construct validity, focusing on distinctions between primary insomnia and insomnia
related to another mental disorder, was also addressed in the DSM-IV field trial described
above (56). Clinicians were asked to rate factors they thought might contribute to the individual
patients insomnia complaint regardless of diagnosis, then assigned a primary diagnosis and
up to three secondary diagnoses for each patient. Patients with insomnia related to a mental
disorder were identified as having less evidence of poor sleep hygiene and negative conditioning
than patients with primary insomnia. Conversely, patients with primary insomnia were felt
to have significantly less psychiatric disturbance contributing to their insomnia. These data
support the distinction between the insomnia subtypes of primary and psychiatric insomnia,
and suggest that additional criteria reflecting sleep hygiene and conditioning factors may help
to improve the reliability of these diagnoses.
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Clinicians also use diagnostic judgments to make treatment decisions. Further data
from the DSM-IV field trial (38) showed that the pattern of diagnostic recommendations for
different specific insomnia diagnoses do in fact differ in significant ways. Specifically, treatment
recommendations for ICSD diagnoses of psychophysiological insomnia, delayed sleep phase
syndrome, inadequate sleep hygiene, insomnia related to mood disorder, and obstructive
sleep apnea syndrome have very distinct patterns of treatment recommendations. Treatment
recommendations are not equivalent to treatment outcomes, but these data do provide some
support for the notion that clinicians believe their diagnoses have predictive validity in the
clinical setting.
Finally, the two-site study of DSM-IV and ICSD-2 diagnoses described above also
addressed questions of convergent validity using multitrait/multi-method matrices based on
the diagnoses of six raters (57). These analyses demonstrated strong validity indices for ICSD-2
idiopathic insomnia, moderate indices for psychophysiological insomnia, environmental sleep
disorder, and inadequate sleep hygiene, and low indices for paradoxical insomnia. DSM-IV
primary insomnia had lower validity indices than all ICSD-2 diagnoses except paradoxical
insomnia. These findings suggest that specific diagnostic criteria may improve the reliability
and validity of insomnia diagnoses, in contrast to the broad and nonspecific criteria used in
DSM-IV primary insomnia.

Summary and Future Directions

Although insomnia has long been recognized as one of the fundamental forms of disordered
sleep, approaches to its classification and diagnosis have varied considerably. The best current
evidence suggests that insomnia is a disorder of brain function rather than a disease per se,
and that it exists on a continuum of healthy to disordered sleep. Approaches to classification
of insomnia have shifted over the past 30 to 40 years. Insomnia was long held to be exclu-
sively a symptom of other underlying conditions, most often mental disorders. Subsequently,
insomnia was conceptualized as existing in both primary and secondary forms. Most recently,
as exemplified in the 2005 NIH State of The Science Conference, insomnia has been viewed as a
disorder that is frequently comorbid with other conditions, but not necessarily caused by those
conditions. This change in conceptualization has been mirrored to some extent by sleep disorder
nosologies more than the past 30 years. During this time, considerable debate has continued
regarding the issue of “lumping versus. splitting” insomnia disorders, about whether to include
quantitative criteria in insomnia diagnoses, and about how to best define insomnia subtypes
(e.g., by symptom presentation, duration, and/or presumed etiology).
Inter-rater reliability for insomnia diagnoses has generally been only fair to moderate for
any of the diagnostic systems, although few published studies have been adequately powered
to address this issue. Structured interviews improve diagnostic reliability. Although numerous
studies have been published that lend support to the validity of insomnia as a disorder of
sleep and arousal relative to “normal” sleep, few of these studies have been replicated, and
no biological marker can be said to exist for insomnia. The best available evidence to support
the validity of specific insomnia diagnoses is for idiopathic insomnia and comorbid insomnia,
particularly insomnia comorbid with mental disorders. Both reliability and validity of insomnia
diagnoses are improved with the inclusion of more specific diagnostic criteria; this observation
may be useful as a way to increase the reliability of “primary” insomnia.
Clinicians should consider several additional factors when using any insomnia diagnostic
system. While accurate diagnosis represents an important step in the assessment and manage-
ment of the insomnia patient, it is not an end in itself. Most chronic insomnia is multifactorial in
nature and some patients may satisfy criteria for more than one insomnia diagnosis. Moreover,
a number will also satisfy criteria for other, noninsomnia diagnoses such as obstructive sleep
apnea or a parasomnia. Therefore, it is essential that the clinician thinks in multifactorial terms
and carefully consider the rich and complex interaction among various diagnoses and other
contributing issues.
In the future, work on insomnia symptoms, pathophysiology, and biological markers will
need to be conducted and replicated in much larger samples, and across multiple sites. Only
studies of this sort can hope to identify reliable clinical and biological markers of insomnia.
Insomnia classification will also be aided by the inclusion of genetic analyses in combination
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INSOMNIA DIAGNOSIS AND CLASSIFICATION 111

with careful clinical and physiological phenotyping. Such studies would also help to fulfill the
goals of personalized medicine, by permitting an examination of treatment response in relation
to carefully characterized patient phenotypes.

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12 Clinical Assessment of Insomnia:

Primary Insomnias
Rachel Manber
Psychiatry & Behavioral Sciences, Stanford, California, U.S.A.

Jason C. Ong
Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois, U.S.A.

DEFINITION OF PRIMARY INSOMNIA

Primary insomnia is a diagnostic category in the psychiatric classification of the Diagnostic and
Statistical Manual for Mental Disorders, Fourth Edition [DSM-IV (1)]. It is characterized by (a)
difficulty initiating or maintaining sleep or nonrestorative sleep of at least one month duration
that (b) causes significant distress or impairment in an important area of functioning and (c)
does not occur exclusively in the context of another sleep disorder, or (d) mental disorder,
and (e) is not due to the direct physiological effects of a substance. The American Academy
of Sleep Medicine Work Group proposed a slightly refined Research Diagnostic Criteria (RDC)
for primary insomnia (2). Under the RDC, an “insomnia disorder” that includes the presence
of nocturnal symptoms and its associated waking complaints is distinguished from “insomnia
symptoms,” which include the nocturnal complaints only. As is true for the DSM-IV diagnosis,
the RDC also requires that a primary insomnia disorder does not occur exclusively in the context
of another medical, psychiatric or substance abuse disorder, or, if another disorder is present,
the course of the insomnia disorder shows some independence from the temporal course of
that disorder (2). This minor difference in criteria not withstanding, the diagnostic assessment
of primary insomnia requires ascertaining the presence of an insomnia disorder and ruling out
comorbidities that might be the primary reason for the reported sleep difficulties.
The epidemiology of insomnia is discussed in detail in chapter 2. Briefly, the prevalence
of insomnia disorders is approximately 10%, with roughly 2:1 ratio of women to men (3–5).
Epidemiological studies estimate the prevalence of primary insomnia at approximately 1%
(3,4). Among individuals seen in sleep clinics with a complaint of insomnia, primary insomnia
is diagnosed in approximately 25% (6,7). The prevalence of all insomnia disorders, including
primary insomnia, increases with age.

Primary Insomnia Subtypes

The International Classification of Sleep Disorders, Second edition [ICSD-2 (8)] includes four
adult diagnostic categories that can be considered subtypes of primary insomnia (2) and are
therefore particularly relevant when assessing chronic insomnia. These include psychophysio-
logical insomnia, paradoxical insomnia, idiopathic insomnia, and inadequate sleep hygiene.

Psychophysiological Insomnia
Psychophysiological insomnia is a primary insomnia subtype characterized by heightened
sleep-related arousal or the presence of associations that are incompatible with sleep. According
to the ICSD-2, the prevalence of psychophysiological insomnia is 12% to 15% among individuals
presenting to a sleep center, regardless of chief complaint. Evidence for psychophysiological
insomnia include any one of the following: (i) excessive focus on and heightened anxiety about
sleep during the day (e.g., avoiding evening events for fear that such events might interfere with
sleep, worrying about sleep during the day); (ii) relative ease of falling asleep during relatively
monotonous activities (e.g., watching TV, reading, etc.) when not intending to sleep; (iii) ability
to sleep better away from home than at home; (iv) intrusive thoughts in bed or inability to calm
the mind; (v) heightened somatic tension in bed reflected by a perceived inability to relax the
body. Sleep-related arousal that is prominent during the intended sleep period may be cognitive
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114 MANBER AND ONG

(e.g., racing thoughts or difficulty calming the mind when trying to sleep), emotional (anxiety
or agitation while in bed or anticipatory anxiety prior to bedtime), and/or physiological (e.g.,
muscle tension). Sleep-related arousal can also be evidenced by excessive preoccupation with
sleep during the day.

Paradoxical Insomnia
Paradoxical insomnia (formerly “sleep state misperception” or “subjective insomnia”) is a sub-
type of primary insomnia characterized by a profound mismatch between subjective and objec-
tive sleep estimates. Evidence for paradoxical insomnia include any one of the following: (i)
reporting a chronic pattern of little or no sleep most nights with rare nights during which rel-
atively normal amounts of sleep are obtained; (ii) sleep log data during one or more weeks of
monitoring show an average sleep time well below published age-adjusted normative values,
often with no sleep at all for several nights per week. Typically there is an absence of daytime
naps following such nights; (iii) a marked mismatch between objective findings from PSG or
actigraphy and subjective sleep estimates. Patients with paradoxical insomnia report levels of
daytime impairments that are similar to what is reported by other primary insomnia subtypes
but much less severe than would be expected given the extreme level of sleep deprivation
reported.
While there are no established criteria for a discrepancy threshold between subjective
perception and objective findings, various definitions have been used in research. Krystal et
al. defined paradoxical insomnia in patients with insomnia complaints based on PSG-defined
total sleep time (TST) and sleep efficiency (SE) (9,10). The criteria were age dependent, taking
into account shorter sleep durations in older adults. PSG sleep was deemed “normal” if TST
was ≥6.5 hours. In those with TST between 6 and 6.5 hours, sleep was defined as “normal”
based on their age. For those <60 years old, SE% had to be >85% and those ≥60, SE% had
to be >80%. Individual differences in time estimates and the perception of sleep states (11)
are at the core of a debate on the validity of paradoxical insomnia as a distinct diagnostic
category. Those supporting the validity of the paradoxical insomnia diagnosis (12) claim that
the underestimation of sleep time is unique to a subset of individuals with primary insomnia.
Others claim that underestimation of sleep time is a generic characteristic of insomnia with
some exhibiting larger discrepancy than others (13). According to the ICSD-2, the prevalence of
paradoxical insomnia is less than 5% among individuals presenting to sleep centers, regardless
of chief complaint. A survey of 11 sleep centers in the United States found that 9% of patients
with insomnia received a diagnosis of subjective (now paradoxical) insomnia (6).

Idiopathic Insomnia
Idiopathic insomnia is a subtype of primary insomnia with an onset during infancy or child-
hood, no identifiable precipitating event, and a persistent course with no periods of sustained
remission (8). The RDC specifies an onset prior to age 10 (2). According to the ICSD-2 the preva-
lence of idiopathic insomnia is less than 10% among individuals presenting to sleep centers,
regardless of chief complaint. The diagnosis of idiopathic insomnia requires assessment of the
age of onset of the first insomnia episode and its course. A typical statement volunteered by
individuals with idiopathic insomnia is “I have always had problems sleeping.”
The possibility that some cases of idiopathic insomnia might be related to a delayed
sleep phase should be considered. Children with a delayed sleep phase might be predisposed to
developing sleep onset difficulty because they are expected to sleep at times when their circadian
clocks are generating strong activating signals. Early and repeated associations of efforts to
sleep with heightened arousal may fuel a pattern of insomnia that persists into adulthood. As
adults, these individuals might continue to express a preference for delayed sleep schedules but
experience sleep difficulties even when allowed to choose their preferred sleep schedule, which
precludes a diagnosis of delayed sleep phase syndrome. If their insomnia is primary, they will
meet criteria for idiopathic insomnia. This suggests that a delayed sleep phase might constitute
a predisposition for idiopathic insomnia. Though this possibility has not been directly tested, it
is supported by evidence that children with ADHD and chronic sleep onset insomnia (> 1 year)
have a delayed melatonin rhythm (14).
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Inadequate Sleep Hygiene

Inadequate sleep hygiene is a primary insomnia subtype associated with at least one poor
sleep hygiene practice that is not better explained by another sleep disorder (8). Sleep hygiene
practices are sleep-related behaviors that have the potential to interfere with sleep. Although
there is no agreement as to the specific behaviors that fall into this category, the core behaviors
are those that are essential to the diagnosis of inadequate sleep hygiene disorder, which include
irregular sleep schedule, frequent napping, spending excessive time in bed, consuming alcohol,
nicotine, or caffeine in amounts or at times that will likely disrupt sleep, and routinely engaging
in activating activities at bedtime (8). The RDC does not include a diagnostic category of
inadequate sleep hygiene (2). Inadequate sleep hygiene practices are common in all forms of
primary insomnia yet a diagnosis of inadequate sleep hygiene is merited only if the patient
does not meet criteria for another ICSD-2 defined insomnia subtype. According to the ICSD-2,
the prevalence of inadequate sleep hygiene is 5% to 10% among individuals presenting to sleep
centers, regardless of chief complaint.
The assessment of sleep hygiene practices is essential for determining if inadequate sleep
hygiene disorder is present. In addition, because poor sleep hygiene practices are common
among patients with primary insomnia, information about sleep hygiene practices aids case
conceptualization and identifies targets for intervention.

DIAGNOSTIC ASSESSMENT
Diagnostic assessment of primary insomnia is based primarily on a clinical interview. Sleep
diaries and self-report questionnaires are often used to supplement the interview and are
administered either before the initial interview to facilitate the intake evaluation or after
the initial interview to clarify diagnostic issues that arise during the initial assessment (see
chapter 11). Routine polysomnography is not indicated for the initial diagnosis of primary
insomnia. Polysomnography is indicated when sleep disordered breathing or periodic limb
movement disorder is suspected, when the diagnosis is uncertain, and when violent injurious
behavior during sleep is present (15).

Diagnosis of Primary Insomnia

Figure 1 provides a schematic diagram of the algorithm for diagnostic assessment of primary
insomnia. At the first level, the assessment is focused on determining if the complaint of insom-
nia is a symptom or a disorder. An insomnia symptom is a complaint of difficulty falling asleep,
difficulty staying asleep, awakening too early, or nonrestorative sleep despite adequate oppor-
tunity and circumstance for sleep (16). A diagnosis of an insomnia disorder requires that the
insomnia symptoms are also associated with significant waking distress or impairment, indicat-
ing that the nocturnal symptoms are clinically significant and merit clinical attention. Daytime
symptoms of insomnia include preoccupation with sleep, mood disturbances, decreased vigor,
impaired performance, and fatigue.
Once an insomnia disorder has been diagnosed, the next step is to ascertain duration of
the current episode and determine if the disorder is primary; that is, the disorder is not related
to another sleep, mental, or medical disorder or to substance use. Important sleep disorders
that need to be ruled out include sleep disordered breathing, restless legs syndrome, a circadian
rhythm disorder, or narcolepsy (a disorder of excessive daytime sleepiness that is often asso-
ciated with disturbed sleep). A thorough evaluation of current medical and mental disorders
is therefore essential for differential diagnosis of primary insomnia versus insomnia related to
other disorders or substances. The most common medical disorders associated with poor sleep
are those associated with dyspnea and those associated with pain (for a review see chapters
15 and 16). The most common psychiatric comorbidities are depressive illnesses, generalized
anxiety disorder, and adjustment disorder with anxiety. When current comorbid conditions
exist, the clinician should assess the temporal relationship between the insomnia disorder and
the comorbid condition(s), both in terms of relative onset and in terms of changes in disease
severity. Questionnaires quantifying depression and anxiety severity can complement the clin-
ical assessment but are sometimes difficult to interpret in the context of an insomnia disorder.
For example, an elevated score on a depression symptom severity questionnaire alone does
not provide sufficient data to determine if a comorbid depressive disorder is present because
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116 MANBER AND ONG

Complaint of difficulty
Prolonged
initiating or
sleep
maintaining sleep
onset latency

Is it a clinical Frequent or
problem? prolonged
awakenings
after
YES NO sleep onset
Phenotypes
(nocturnal
symptoms)
Insomnia Insomnia
disorder symptoms
Early morning
awakenings

Does it
occur exclusively
in the context of another
disorder or substance
use? Nonrestorative
sleep
NO YES

Primary Comorbid
insomnia insomnia

Are there
features related
to presumed
etiology?

Psychophysiological Paradoxical Idiopathic Inadequate sleep Primary insomnia

insomnia insomnia insomnia hygiene subtypes

Figure 1 A schematic diagram for the diagnostic assessment of primary insomnia and its subtypes. This algo-
rithm provides a general guideline for differential diagnosis of primary insomnia.

insomnia and depressive disorders share symptoms, such as poor sleep, poor concentration,
and low energy.

Assessing Nocturnal Symptoms and Sleep-Related Behaviors

The initial focus of a diagnostic assessment is naturally on the presenting problem. Details
about sleep onset latency, wake time after sleep onset, early morning awakening, estimated
TST, and the refreshing value of sleep provide indications of the severity and specific nature
of the presenting problem. This aspect of the assessment can be facilitated by administering
sleep questionnaires and/or sleep diaries prior to the initial assessment visit. Both the self-
report and the interview provide information about habitual sleep patterns. Specific aspects
to assess are the habitual timing and variability of getting into and out of bed, lights out, and
final awakening. These data together with the frequency and duration of daytime naps allow
the clinician to ascertain if irregular sleep schedule and excessive time in bed are present. Both
are relevant to the diagnosis of inadequate sleep hygiene and constitute important therapeutic
targets for insomnia disorders. These data also inform the clinician to what extent circadian
rhythm tendencies play a role in the patient’s presentation (see section of circadian rhythm
tendency below).
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Table 1 A Chronological Assessment of Nocturnal and Daytime Symptoms of Insomnia

Time Sample of interview questions Targets for assessment

Presleep What is your presleep routine? When is Presleep arousal, circadian factors,
your last meal? When is your last sleep hygiene
alcoholic beverage? Do you engage in
any self-soothing activities? When do you
stop your work-related activities?
Bedtime What time do you go to bed during the week Conditioned arousal, behaviors
and weekends? What goes on in your associated with bedtime, sleep effort,
mind when you are not able to sleep? pattern of medication use
When do you take your sleep medication?
Where do you do your work?
Middle of the night What do you do in the middle of the night Medications, reactions to nocturnal
when you cannot sleep? Do you look at awakenings, strategies for going back
the clock frequently throughout the night? to sleep, sleep hygiene
Do you eat in the middle of the night?
Morning/rise time How difficult is it to wake-up and get out of Circadian factors, difficulty rising, early
bed in the morning? When do you get out morning awakenings
of bed on the weekends?
Daytime Do you take naps during the day? Have you Sleep-related cognitions, fatigue,
made changes to your daytime activities sleepiness, napping behaviors, sleep
following a night of poor sleep? Do you hygiene
take any substances to help stay awake
during the day?

One practical way to gather these essential data is to ask the patient to describe in detail
specific sleep-related behaviors in the chronological order they occur throughout the evening
and night, starting with the presleep routines and progressing through the sleep period to the
patient’s morning rise time. Table 1 summarizes the type of information that can be obtained
relative to this time line and how it pertains to case conceptualization, as discussed below.
For better understanding of the patient’s insomnia experience, the clinician should pay atten-
tion to and, if necessary, probe the patient’s emotional reactions and behavioral responses
in coping with insomnia. Knowledge of the patient’s routine evening activities, particularly
the hour or two before bedtime, allows the clinician to determine if activities at bedtime are
likely to be interfering with sleep. This information is relevant to the diagnosis of inadequate
sleep hygiene and it identifies specific sleep-interfering activities that need to be addressed in
treatment.
Details about the consumption of substances, such as alcohol, nicotine, and caffeine should
include the amount and timing of such consumption and their potential for disrupting sleep.
The same holds true for prescription and over the counter medications and herbal preparations
taken to promote sleep. Other behaviors that can interfere with sleep and should therefore be
assessed include, clock watching (17), a sedentary lifestyle, and absence of sufficient stimulation
during the day. The latter is particularly important to assess in institutional older adults.

Assessing Daytime Symptoms of Insomnia

Daytime symptoms of insomnia include fatigue or malaise, attention, concentration, or memory
impairment, social or vocational dysfunction or poor school performance, mood disturbance or
irritability, daytime sleepiness, motivation, energy, or initiative reduction, proneness for errors
or accidents at work or while driving, tension, headache, or gastrointestinal symptoms, or
concerns or worries about sleep (8). Nonrestorative sleep is associated with greater daytime
impairment than other pure insomnia phenotypes (18,19). Table 1 includes information for
assessing these daytime symptoms.
The distinction between sleepiness and fatigue is often not clear to insomnia patients.
Patients tend to use the terms sleepiness and fatigue interchangeably. In the context of sleep
medicine, sleepiness is usually defined as the propensity to sleep onset and fatigue as an index
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118 MANBER AND ONG

of low energy that may be influenced by psychological and physiological factors. Objectively
measured daytime sleepiness using the Multiple Sleep Latency Test (MSLT) indicates that
following habitual sleep, individuals with primary insomnia are not abnormally sleepy, with
sleepiness scores comparable to that of good sleepers (20–22). Interestingly, when individuals
with primary insomnia are sleep deprived to 80% of their habitual sleep time, objectively
determined daytime sleepiness, as measured with the MSLT is increased (23).
Research suggests that the severity of reported daytime symptoms is impacted by the sub-
jective perception of poor or insufficient sleep. Semler and Harvey manipulated the perception
of sleep by providing individuals with primary insomnia “feedback” about the results of the
actigraphic recording of their sleep in a random counter balanced fashion. Regardless of the
actual observed sleep, participants reported more sleepiness during the day when they were
told that they slept poorly on the previous night (24).

CASE CONCEPTUALIZATION
Beyond establishing a diagnosis of primary insomnia and its subtypes, the goal of the clinical
assessment is reaching a case conceptualization and formulating a treatment plan. To that end the
clinician considers etiological models and theories of insomnia while listening and inquiring for
further information from the patient. We therefore present a prevailing model of insomnia, the
diathesis-stress model, and the arousal/activation theories and discuss how to assess features
relevant to these theories. We also discuss the relevance and assessment of circadian tendency
and treatment history in primary insomnia.

A Diathesis-Stress Model of Insomnia

This model posits that insomnia emerges when a precipitating event is superimposed on pre-
morbid predisposition and persists as a result of perpetuating factors (25). Predisposing factors
may include psychologically based (e.g., personality traits) or biologically based (e.g., low
parasympathetic tone) diathesis for insomnia. Precipitating factors include the triggers of an
insomnia episode, such as psychosocial stressors or physical illness. About 75% of people with
insomnia can identify a trigger of their insomnia, most commonly health issues and stress
related to family or work situations (14). Perpetuating factors are maladaptive responses to dis-
turbed sleep. They serve to maintain insomnia even after the resolution of the precipitating event
and lead to a cyclical pattern of chronic insomnia. Examples of perpetuating factors are: extended
time spent in bed, poor bedtime habits, compensatory daytime naps, increased sleep effort, and
conditioning factors. This model is presumed to apply to the different insomnia subtypes and
is not specific to primary insomnia.
It is therefore important to understand how these three processes are expressed in each
individual patient. Information on precipitating factors can be gathered by inquiring about the
circumstances surrounding the onset of the current episode of insomnia, including psychosocial
stressors (e.g., going through a divorce, loss of a job) and change in health status (e.g., onset
of thyroid disorder). These historical events provide insights into patients’ stress reactivity and
susceptibility to sleep disturbance. Understanding the context of the onset and precipitants
of the insomnia episode can also facilitate communication with the patient when explaining
the diathesis-stress model of insomnia at the onset of treatment and when discussing relapse
prevention toward termination of treatment. The assessment of perpetuating factors typically
focuses on the patient’s reactions to the initial insomnia episode, including changes in sleep-
related behaviors (such as staying in bed longer than before) and current sleep-interfering
cognitions. Questions might include: What have you done to try to improve your sleep? What
do you do in the middle of the night when you cannot sleep? How do you cope during the day?
Are you trying to take naps? What goes on in your mind when you are not able to sleep? Have
you made changes to your daytime activities following a night of poor sleep? Understanding
factors that perpetuate sleep is particularly relevant in the context of psychological treatments
as these factors are important therapeutic targets for cognitive-behavioral therapy of insomnia.

Cognitive and Emotional Arousal

Sleep-related cognitive and emotional arousal is a key feature of primary insomnia, regard-
less of subtypes. It is a diagnostic feature of one specific subtype of primary insomnia,
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psychophysiological insomnia, but it is frequently an associated feature across subtypes of pri-

mary insomnia. Compared with controls, individuals with primary insomnia have higher scores
on trait arousability measures (26). Cognitive intrusions are also prominent among patients with
insomnia disorders. Studies of analog and clinical samples conclude that sleep onset difficul-
ties, particularly at the beginning of the night, are related to cognitive intrusions (27). These
studies focused primarily on the period before initial sleep onset and concluded that, compared
with good sleepers, intrusive thoughts are more prevalent in people with insomnia and their
content is more laden with negative emotions, including rumination over the day’s event, wor-
rying about future events, and other anxious thoughts (for a review see Ref. 28). The intrusive
thoughts may involve active problem solving, monitoring current sleep–wake state, or reacting
to environmental stimuli (29). Two studies that examined cognitive activity in the middle of the
night had similar findings (30,31). Thoughts about sleep and worries about the consequences
of poor sleep are also common among patients with primary insomnia and often contribute to
increased sleep effort (trying hard to sleep), which in turn perpetuates insomnia. The body of
research on the role of cognition in insomnia has lead some to propose a cognitive model of
insomnia (32) and others to examine mindfulness-based stress reduction as an intervention for
insomnia aimed at reducing arousal and activation (33).
Assessment of sleep-related cognitions, most notably sleep effort, provides a window
to the level of cognitive arousal experienced by the patient. While nondisturbed sleep occurs
effortlessly, chronic insomnia is associated with increased sleep effort and increased preoccu-
pation and apprehension related to obtaining optimal sleep, which increase arousal/activation
and hinder sleep. During the interview the clinician should pay attention to overt and covert
cognitions and behaviors that are manifestations of increased sleep effort. Attention should also
be given to the coping strategies the patient uses, as many strategies serve to perpetuate insom-
nia either directly or by increasing cognitive arousal. To supplement the information about
cognitive arousal that is obtained during the assessment interview one can use questionnaires
developed to assess beliefs and attitudes about sleep, presleep cognition, and sleep effort that
are discussed elsewhere in this book.

Cortical Arousal and Autonomic Activation

Individuals with primary insomnia have high cortical arousal and autonomic activation. Com-
pared with controls, individuals with primary insomnia have higher cortical activity during
non-REM sleep as indexed by EEG activity in the 14 to 45 Hz range Z range (34), higher 24-hour
metabolic rate (21), higher metabolic activity during sleep in brain areas associated with acti-
vation (35), and higher sympathetic and lower parasympathetic tone as indexed by measures
of heart rate variability (36). The latter was tested only in individuals with primary insomnia
whose disturbed sleep was confirmed with polysomnography. Together these studies suggest
increased arousal and activation at the cortical, autonomic, and cognitive levels among people
with primary insomnia relative to normal sleepers. Using event-related potential methodol-
ogy, a recent study provides additional support of the hyperarousal/hyperactivation theory of
primary insomnia (37). This study found enhanced attention and reduction of the inhibitory
process that normally facilitates sleep onset in the beginning part of sleep (37).
It is not entirely clear whether increased arousal or activation is the cause or consequence
of having an insomnia disorder (28). A series of experiments conducted by Bonnet and Arandt
support the causative theory. These researchers compared objective measures of daytime sleep
propensity in subjects with primary insomnia and in research volunteers whose insomnia was
induced by caffeine, people whose sleep was manipulated in the sleep laboratory to resem-
ble sleep of yoked individuals with primary insomnia, and in healthy controls whose sleep
was not manipulated. The results indicate that the sleep propensity of people with primary
insomnia was similar to that of people with caffeine-induced insomnia and lower than the sleep
propensity of those with laboratory-induced insomnia, who were, in turn, lower than normal
controls (21,2338). Taken together these results were interpreted as evidence of a causative
role of arousal in primary insomnia (21,23,38). These results also provide evidence that the
daytime consequence of sleep disturbance associated with insomnia might be different from
daytime sequelae of externally induced sleep deprivation of similar magnitude. Additional sup-
port for the contention that heightened arousal plays a causative role in insomnia comes from
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120 MANBER AND ONG

preliminary findings from a naturalistic follow-up after an open-label behavioral intervention

for insomnia (39). The study found significantly greater presleep arousal and sleep effort at the
end of treatment among participants who experienced at least one insomnia episode during
the 12-month follow-up period than those who did not experience an insomnia episode during
the follow-up period.

Circadian Contributions
Circadian factors are relevant to the presentation of primary insomnia both in terms of differen-
tial diagnosis and case conceptualization. For example, it has been suggested that individuals
who present with sleep onset difficulties and no sleep maintenance problems have a delayed
sleep phase. Their temperature rhythm markers were approximately 2.5 hours later than the
respective phases of the good sleepers and their usual bedtimes fell within the “wake main-
tenance zone” (phases of the body’s temperature rhythm during which sleep onset is seldom
selected by free running subjects) of their temperature rhythm (40). However, the generalizabil-
ity of this finding is not clear as this study did not report whether the participants with sleep
onset difficulty met criteria for primary insomnia disorder or delayed sleep phase syndrome. The
salient feature differentiating between insomnia and circadian rhythm sleep disorder, delayed
type, is that in the latter case sleep initiation and maintenance are normal when sleep occurs
during the patient’s preferred time (8). It has also been suggested that individuals with pri-
mary insomnia presenting with early morning awakenings have a two to four hours advanced
melatonin rhythm phases (41), and that this phase advance causes early arousal from sleep in
these patients. The salient feature differentiating between insomnia and circadian rhythm sleep
disorder, advanced type, is that in the latter case the patient typically experiences early evening
sleepiness that is usually absent in primary insomnia (8).
In a clinical setting it is most practical to assess the patient’s circadian tendencies either
during the interview or by using validated questionnaires. In the absence of a full syndrome of
delayed sleep phase, some patients with primary insomnia experience their best sleep during
the second half of the night and report prolonged time to feel fully awake after rise time.
These two symptoms suggest a natural evening chronotype that needs to be considered when
recommending bedtime and rise time. Similarly, in the absence of a full syndrome of advanced
sleep phase, some patients with primary insomnia present with an early bedtime, involuntary
evening “naps,” and very early wake-up times. Since comorbid psychiatric disorders that are
associated with early morning awakening have been ruled out during the diagnostic portion
of the assessment, these symptoms suggest a morning chronotype. Other circadian rhythm
considerations concern irregular sleep schedules. The strength of the signal for optimal timing
of sleep delivered by the suprachiasmatic nucleus is weakened when sleep–wake schedules
change dramatically or frequently, as is the case in professions that require multiple shifts in
time zones (e.g., airline industry and other jobs that require frequent changes in time zones)
and in professions that involve varying shifts. Therefore, information about the patient’s work
schedule and travel patterns should be obtained.

Nocturnal Symptom Phenotypes

Classification of insomnia based on specific nocturnal symptoms [difficulty initiating sleep,
difficulty maintaining sleep, waking up too early (early morning awakenings), or nonrestora-
tive sleep] might be considered phenotyping of insomnia. Determining the specific primary
insomnia phenotype might be relevant to pharmacological treatments of insomnia. For exam-
ple, short acting hypotonic medications might not be ideal for individuals presenting with early
morning awakening. However, the relevance of assessing phenotype for treatment matching
has not been well studied. A few studies of cognitive-behavioral therapy for insomnia have
targeted specific insomnia phenotypes. For example, Edinger et al., Morin et al., and Sivertsen
et al. (42–44) focused on sleep maintenance insomnia and Jacobs et al. (45) targeted sleep onset
insomnia. However, these studies did not modify CBT to specifically address the distinct phe-
notypes. Moreover, most studies demonstrate efficacy of CBT in samples consisting of mixed
phenotypes, suggesting that phenotypes of insomnia might not be very relevant to cognitive-
behavioral therapy for insomnia. Of note, however, is the possibility that the early morning
awakening and nonrestorative sleep phenotypes might require specific modification of CBT or
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other specific treatment approaches. To the best of our knowledge no treatment outcome studies
tested the efficacy of CBT or pharmacological treatments for these two insomnia phenotypes.
The distribution of the four phenotypes has been studied in epidemiological studies and
surveys of the general population and clinic samples (46,47), but due to variations in nosology
and study criteria specific findings for primary insomnia are unclear. Inference from these
studies to primary insomnia cannot be made because the samples that were studied included
individuals that did not meet criteria for an insomnia disorder and/or those whose insomnia
disorder might be related to other medical or psychiatric conditions. The extant literature
suggests that the pure early morning awakening phenotype is the least common among people
with a probable insomnia disorder (4) and that the most common presentation in clinic samples
(45,48) and in population surveys consists of more than one of the four nocturnal symptoms
(4). One could infer from these studies that mixed symptoms are likely to be the most common
presentation among individuals with primary insomnia. However, to the best of our knowledge,
estimates of the symptom distribution among those who meet criteria for primary insomnia are
lacking.
Nonrestorative sleep is the least studied nocturnal symptom of insomnia disorder. This
nocturnal symptom is most commonly defined by reports of feeling unrefreshed upon awaken-
ing. Unlike sleep maintenance phenotype, whose prevalence increases with age, nonrestorative
sleep is not associated with increasing age (6); it is more common among people younger than
55 years (18). Nonrestorative sleep has been studied mostly in individuals with medical dis-
orders associated with fatigue, such as fibromyalgia, chronic fatigue, temporomandibular joint
disorder, and irritable bowel syndrome (49) and in patients with other sleep disorders, such as
sleep apnea (8). There is a fourfold increase in the prevalence of nonrestorative sleep among
those with mood disorders (18). We were unable to find any study of nonrestorative sleep among
individuals with primary insomnia and it is not clear if nonrestorative sleep exists in a pure
form (i.e., without other nocturnal symptom) among individuals with primary insomnia (50).

Past and Present Treatments

Implementation and response to current and past treatments provide valuable information to
the clinician, particularly when the patient reports past treatment failures. For pharmacological
treatments, targets for assessment include the dose, frequency, and time of ingestion for all
prescription medications and over-the-counter remedies taken to improve sleep. Is the medi-
cation taken on schedule or as needed? How does the patient decide if and when to take the
medication or how much of the medication to take? This aspect of the assessment process is
particularly relevant when making treatment choices. Response and side effects associated with
past medications prescribed for sleep further inform a physician about the most appropriate
next step in managing the patient with primary insomnia. For past pharmacological treatments
these include the following: How well did the medication control the nocturnal symptoms
of insomnia? Did efficacy remain optimal or diminish with continued use? How has the fre-
quency and dose changed over time? Has morning sedation been a problem? What were the
side effects? It is also important to evaluate psychological factors associated with medication
use, such as ambivalence about using sleep medications and psychological dependence. These
factors may complicate the presentation of patients with primary insomnia who still qualify for
this diagnosis despite chronic nightly use of sleep medications.
Many insomnia patients are interested in nonpharmacological approaches to remedy
their sleep problem and follow recommendations provided in books, magazines, and the inter-
net. Relevant information about these previous attempts includes what was tried, how it was
implemented, and the effectiveness of each strategy that was tried. Knowledge of these past
experiences can help the insomnia therapist deliver some of the very same recommendations in
a manner that is more likely to be adhered to and most likely to be effective. Patients presenting
to a tertiary setting frequently report that they have tried “everything.” Knowing specific details
of previous approaches can inform the insomnia therapist of misunderstanding and adherence
issues that have hindered response. For example, a patient might have gotten out of bed when
unable to sleep, a component of stimulus control, but have done so expecting results on the
first night, and since the procedure is rarely effective when used for a single night, has sub-
sequently abandoned the practice. Using this information, the therapist can set more realistic
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122 MANBER AND ONG

expectations and encourage the patient to try implementing the full set of stimulus control
instruction consistently for at least two weeks.

POLYSOMNOGRAPHIC FINDINGS
Comparisons of PSG-defined sleep parameters in primary insomnia relative to controls gen-
erally report minimal to modest differences. Average differences are less than 38 minutes for
TST and less than 42 minutes for total wake time, with many studies detecting no significant
difference (42). Individual differences in the perception of sleep states (11) might explain the
inconsistency in the results from these, usually small, studies. In general, sleep time misper-
ceptions are larger when subjective estimation of time awake after sleep onset is longer (51).
Overestimation of time awake is associated with a complaint of nonrestorative sleep and the
conviction that one’s sleep difficulty is organically based (52). The severity of distress and day-
time complaints of people with insomnia is not fully explained by the severity of the disruption
in sleep.
Macro architecture of sleep in individuals with primary insomnia is only slightly different
from that of good sleepers, with more time spent in stage 1 sleep, less time spent in stages 3 and
4, and more stage shifts (53). The micro architecture of sleep, as determined by spectral analyses
of the EEG, reveals increases in fast frequency EEG (beta) among people with primary insomnia
relative to controls (34). Krystal et al. found that individuals with paradoxical insomnia also have
lower delta and greater alpha and sigma EEG activity during non-REM sleep than noninsomnia
control subjects and that less delta EEG activity predicted greater deviation between subjective
and PSG estimates of sleep time (2). These finding might suggest that the origins of the sleep
complaints in patients with paradoxical insomnia are related to high cortical arousal during
sleep (10,54).
Objectively defined sleep onset and sleep discontinuity parameters are not in high agree-
ment with subjective recollections of sleep experiences provided by the patient. Only 12% of
patients with insomnia (less than half of which were likely to have experienced primary insom-
nia) provide estimates of their TST that are congruent (off by no more that 15 minutes) relative
to their PSG-defined TST (55). Approximately 44% had estimates that were lower than PSG TST
by at least 60 minutes (55). Overestimation of sleep difficulties is common in all types of insom-
nia. It is more pronounced in people with paradoxical insomnia. For example, Edinger and Fins
found that patients diagnosed with sleep state misperception (paradoxical insomnia) had actual
(PSG defined) sleep times that were at least twice as large as their subjective time estimates,
whereas those with psychophysiological insomnia or inadequate sleep hygiene estimated their
sleep times more accurately, at a median of 88% of the objective (PSG) estimates (52).

MANAGEMENT OF PRIMARY INSOMNIA

Both pharmacological and nonpharmacological approaches are effective in the management of
primary insomnia. Hypnotic medications are generally considered the pharmacological treat-
ment of choice and cognitive-behavior therapy for insomnia (CBT-I) is the nonpharmacological
treatment of choice. The preponderance of the evidence indicates that the two treatment modali-
ties have comparable efficacy at the end of treatment and that the benefits of CBT-I are of greater
long-term durability (43,44). (Please see the relevant chapters in part III of this book for a more
through review of evidence.)
Most patients with primary insomnia are appropriate candidates for pharmacotherapy
and for CBT-I. There is currently no information on how to best match patients to treatments
and no conclusive evidence regarding the efficacy of specific treatments for insomnia pheno-
types or subtypes. Patient preference often guides treatment but there has been little research
on the impact of patient preference on outcome in primary insomnia. One study that evaluated
treatment preference (CBT-I and pharmacological modalities) in a sample of patients that sub-
sequently received group CBT-I found that it is more relevant to adherence to CBT-I than to
outcome (56).
Beyond patient preference, the assessment provides useful information when considering
treatments for primary insomnia. For example, in choosing the best pharmacological approach
(e.g., short-acting vs. long-acting or controlled-release medication) to treat primary insomnia,
the prescribing clinician should consider the average time spent in bed and the part of the night
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CLINICAL ASSESSMENT OF INSOMNIA: PRIMARY INSOMNIAS 123

most affected (early middle, and/or late) as well as the pharmacokinetics of sleep inducing
medications and over the counter preparations that the patient is using at the time of the
assessment. The assessment also provides useful information when considering CBT-I. For
example, habitual sleep times guide the initial time in bed prescription associated with sleep
restriction. Evaluation of chronotypes can also help the insomnia therapist chose the optimal
time in bed window. For example, the optimal bedtime for a patient who describes himself as
a night owl will be later than what would be recommended for a patient who describes herself
as a morning person. The information gathered in the assessment can aid in choosing the order
and relative emphasis of the various CBT-I treatment components, allowing the therapist to
work through compliance issues thus improving adherence with treatment recommendations.

CONCLUSION
The goal of this chapter was to provide an overview of the assessment process relevant to
the diagnosis, case conceptualization, and treatment of the patient with primary insomnia.
Evaluation of nonprimary forms of insomnia disorder necessitates additional assessments,
discussed elsewhere in this book. However, the diathesis-stress model of insomnia applies to
insomnia disorders other than primary insomnia, thus rendering much of the content of this
chapter relevant to the assessment of other insomnia disorders.

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13 Clinical Assessment of Comorbid Insomnias:

Insomnia in Psychiatric Disorders
Meredith E. Rumble and Ruth M. Benca
Department of Psychiatry, University of Wisconsin-Madison, Madison, Wisconsin, U.S.A.

INTRODUCTION
Insomnia and psychiatric disorders frequently occur together. Epidemiological studies have
demonstrated that between approximately 25% and 50% of individuals with insomnia in the
general population meet criteria for insomnia comorbid with a psychiatric disorder, including
most commonly the psychiatric comorbidities of depressive disorders, anxiety disorders, and
substance use disorders (1–3). Sleep difficulties are a common symptom of many psychiatric
disorders and in some cases treatment of the psychiatric disorder may lead to improvement or
resolution of the sleep difficulties. However, insomnia commonly persists despite treatment of
the psychiatric illness (e.g., Ref. 4) and can cause significant distress to the patient as well as an
adverse impact on the course of the psychiatric disorder.
Mounting evidence suggests a dynamic and potentially bidirectional relationship between
insomnia and psychiatric disorders. For example, longitudinal research has demonstrated that
individuals with insomnia but without a comorbid psychiatric illness at baseline are at a signifi-
cantly higher risk for developing future depressive, anxiety, and substance abuse or dependence
disorders (1,5–8). Not only is insomnia a risk factor for the onset of psychiatric disorders, but it
has also been shown that insomnia can increase the risk for relapse and exacerbation of psychi-
atric symptoms. For example, individuals with residual insomnia symptoms after treatment for
depression are at a higher risk of relapse of depression than those without residual insomnia
(9). Conversely, treatment of insomnia may improve the course of a depressive episode; recent
research has demonstrated how individuals with depression and insomnia who receive both
general treatment for depression as well as insomnia-specific treatment (e.g., fluoxetine with
eszopiclone or escitalopram with cognitive-behavioral therapy for insomnia) have significantly
greater improvements in depressive symptoms than those who only receive general treatment
for depression (10,11).
Given this dynamic relationship, it is essential to assess both insomnia and psychiatric
symptomatology in patients with either an insomnia or psychiatric complaint so that appropri-
ate treatment planning and implementation can occur. The focus of the current chapter is to pro-
vide recommendations regarding the assessment of insomnia comorbid with psychiatric issues.
The first section of this chapter will discuss the assessment of psychiatric disorders commonly
occurring with insomnia (i.e., depressive disorders, bipolar disorders, generalized anxiety dis-
order, panic disorder, posttraumatic stress disorder, and schizophrenia), including a description,
associated sleep complaints, characteristic abnormalities detected in sleep electroencephalogra-
phy (EEG), and possible screening measures for each psychiatric disorder. The second section
will review the assessment of important factors commonly contributing to insomnia in patients
with psychiatric disorders, including behavioral factors, the effects of psychotropic medications,
and other sleep disorders. With the aim of promoting more standardized insomnia assessment
in clinical practice and facilitating a connection between clinical and research settings, the stan-
dardized insomnia assessment recommendations for research developed by Buysse et al. (12)
will be used as a guide whenever possible. Of note, assessment of insomnia related to substance
issues is not covered in this chapter as this particular comorbidity is covered in chapter 16.

ASSESSMENT OF PSYCHIATRIC DISORDERS COMMONLY OCCURRING

WITH INSOMNIA
Psychiatric disorders commonly associated with insomnia include depressive disorders, bipo-
lar disorders, generalized anxiety disorder, panic disorder, posttraumatic stress disorder, and
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CLINICAL ASSESSMENT OF COMORBID INSOMNIAS: INSOMNIA IN PSYCHIATRIC DISORDERS 127

schizophrenia. Despite their high prevalence, psychiatric disorders often remain undiagnosed,
untreated or undertreated in patients who present with insomnia (13). Factors that can contribute
to the lack of diagnosis and treatment include: (a) attribution of psychiatric symptomatology to
sleep problems (e.g., “If I could only sleep, then I would be fine.”); (b) lack of physician training
in psychiatric assessment; (c) insufficient time during clinic visits to assess psychiatric symp-
toms in busy clinical practices; and (d) limited reimbursement for assessment and treatment of
psychiatric disorders.
Descriptions of the psychiatric disorders commonly occurring with insomnia are provided
below. In addition, associated sleep complaints, characteristic abnormalities in sleep EEG, and
suggested screening questions and measures to potentially identify patients at risk for specific
psychiatric disorders are described below and summarized in Table 1. It should be noted
that the basic sleep patterns outlined below, including both sleep complaints and objective
abnormalities in sleep EGG, should not be used as definitive diagnostic markers. The sleep
patterns described are not necessarily present in all individuals with a particular psychiatric

Table 1 Basic Sleep Patterns, Screening Questions, and Screening Questionnaires for Common Psychiatric
Disorders Comorbid with Insomnia

Psychiatric Screening
comorbidity Basic sleep patterns Screening question(s) questionnaires
Depressive disorders • Sleep continuity • “Have you been feeling • Beck Depression
disturbances depressed or down?” Inventory II (17)
• REM sleep abnormalities • “Have you lost interest • Inventory of
• SWS deficits in things you usually Depressive
enjoy?” Symptomatology
Self-Report (18)
• Geriatric Depression
Scale (21)
Bipolar disorders • Sleep continuity • “Have you felt so high, • Mood Disorders
disturbances ‘hyper’, or irritable that Questionnaire (23)
• REM sleep abnormalities people told you that
• SWS deficits you were not your
normal self?”
Generalized anxiety • Sleep continuity • “Have you been • State-Trait Anxiety
disorder disturbances anxious or worried?” Inventory, trait
version (29)
• Penn State Worry
Questionnaire (30)
Panic disorder • Sleep continuity • “Have you ever had a • Brief Panic Disorder
disturbances panic attack when you Screen (36)
• Nocturnal panic attacks suddenly felt anxious
with related fears of going or experienced a lot of
to sleep physical symptoms?”
Posttraumatic stress • Sleep continuity • “Have you experienced • Posttraumatic Stress
disorder disturbances any traumas in your Diagnostic Scale (42)
• REM sleep abnormalities life?”
• Nightmares/flashbacks
with related fears of going
to sleep
Schizophrenia • Sleep continuity • If psychotic symptoms • If psychotic symptoms
disturbances are observed and are observed and
• NREM sleep spindle there is no diagnosis, there is no diagnosis,
deficits in the vertex region an immediate referral an immediate referral
for psychiatric for psychiatric
assessment is assessment is
recommended recommended
Abbreviations: REM, rapid eye movement; SWS, slow wave sleep; NREM, nonrapid eye movement.
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128 RUMBLE AND BENCA

diagnosis and similar sleep abnormalities may be seen in individuals without those disorders,
including healthy, normal individuals. Likewise, the screening questions and measures outlined
below should not be used to make specific diagnoses but instead to identify individuals at greater
risk for particular psychiatric disorder. Further psychiatric assessment is recommended for any
case where clinical suspicion for possible psychiatric disorder is increased based on clinical or
objective sleep abnormalities and/or positive screening questionnaires.
When treating an individual with insomnia and a known psychiatric disorder, the screen-
ing measures outlined below can also be used to track psychiatric symptom severity along with
insomnia symptom severity so that intervention can be better guided. For example, if increases
and decreases in psychiatric and insomnia symptom severity seem to correspond, treatment
could focus more prominently on the psychiatric disorder. Other the other hand, if insomnia
symptom severity remains high in the context of low psychiatric symptom severity, treatment
could center more on insomnia.

Depressive Disorders
Major depressive disorder is characterized by the presence of at least one major depressive
episode (14). The starting criterion for a major depressive episode is the presence of depressed
mood or anhedonia for two weeks or longer. Other symptoms include: (a) significant weight
loss or weight gain, (b) insomnia or hypersomnia, (c) psychomotor agitation or retardation, (d)
fatigue or loss of energy, (e) feelings of worthlessness or guilt, (f) decreased ability to concentrate,
and (g) recurrent thoughts of death and suicide. Five or more symptoms must be present
with at least one of these symptoms being depressed mood or anhedonia. Major depressive
episodes also cause clinically significant distress or impaired social or occupational functioning.
Dysthymic disorder is diagnosed in individuals with chronic depressive symptoms for at least
two years who have significant impairment in functioning, but do not meet full criteria for a
major depressive episode.

Basic Sleep Patterns

Patients who are depressed typically complain of insomnia, including difficulty falling asleep,
difficulty staying asleep, early morning awakenings, nonrestorative sleep, and decreased
amounts of sleep. A minority of patients report hypersomnia or increased sleepiness and/or
sleep amounts, and some individuals with mood disorders may report periods of both insomnia
and hypersomnia (5). Common polysomnographic abnormalities in individuals with depres-
sion include sleep continuity disturbances, such as prolonged latency to sleep onset, increased
wakefulness during sleep, and early morning awakenings, resulting in decreased amounts of
total sleep time and more fragmented sleep (15,16). One of the more specific changes in sleep
architecture associated with depressive disorders is alteration in rapid eye movement (REM)
sleep patterns. Reduced latency to REM sleep is the most commonly described alteration, but
other findings include increased duration of the first REM sleep period, increased rapid eye
movements during REM sleep periods, and increased percentage of REM sleep. Finally, indi-
viduals with depression also have deficits in slow wave sleep (SWS), including decreased total
amounts of SWS, decreased proportion of SWS, and less SWS during the first nonrapid eye
movement (NREM) sleep period (15,16).

Possible Screening Measures

Given the particularly strong association between insomnia and depressive disorders, all indi-
viduals with complaints of insomnia should be assessed for depression. There are two general
screening questions that can be helpful as an initial assessment of depression: “Have you been
feeling depressed or down?” and “Have you lost interest in things you usually enjoy?” Patients
who endorse either of these symptoms should be assessed more carefully for depression.
There are also a number of validated self-report screening measures available to assess
depressive symptoms in insomnia (12), including the Beck Depression Inventory II (BDI-II;
17) and the Inventory of Depressive Symptomatology Self-Report (IDS-SR; 18). The BDI-II is a
21-item self-report scale that reflects DSM-IV criteria and takes approximately 5 to 10 minutes
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CLINICAL ASSESSMENT OF COMORBID INSOMNIAS: INSOMNIA IN PSYCHIATRIC DISORDERS 129

to complete. Each item is rated on a 4-point scale ranging from 0 to 3 and summed into a
single score ranging from 0 to 63. Severity of depression based on scores is as follows: 0–13
minimal, 14–19 mild, 20–28 moderate, and 29–63 severe. A cut-off score of 18 or higher yielded
a sensitivity of 94% and a specificity of 92% when predicting a diagnosis of major depressive
disorder as diagnosed by the Patient Health Questionnaire (PHQ, 19) in a sample of primary
care patients (20).
The IDS-SR is a 30-item self-report scale that includes all DSM-IV symptom domains for
a major depressive episode. This measure takes approximately 15 to 20 minutes to complete.
Each item is rated on a 4-point scale ranging from 0 to 3 and summed into a single score ranging
from 0 to 84. Depression severity ranges are as follows: 0 to 11 normal, 12 to 23 mildly ill, 24
to 36 moderately ill, 37 to 46 moderately to severely ill, and 47 to 84 severely ill. In a sample
of outpatients with and without current symptomatic major depressive disorder as determined
by diagnostic interview, a cut-off score of 18 or higher revealed a sensitivity of 100% and a
specificity of 94% (18).
In comparison to the BDI-II, the IDS-SR is a longer measure that takes more time to
complete; however, this measure also offers the benefits of assessment of a larger number of
depressive symptoms, a wider score range, better detection of depression in less severely ill
populations, and easy accessibility (www.ids-qids.org; 18). Furthermore, the IDS-SR has four
items specifically assessing sleep compared to only one item on the BDI-II.
In addition to these two scales, the Geriatric Depression Scale (GDS; 21) may be helpful
for assessment of depressive symptoms in older adults with insomnia (12). The GDS is a 30-item
self-report scale and each item is answered by circling yes or no. Some of the items are reversed
scored, and then the items are summed into a single score ranging from 0 to 30. In one of the
original validation studies for the GDS, a cut-off score of 11 yielded a sensitivity rate of 84%
and a specificity rate of 95% (22). There are two main benefits of using this measure for older
adults. First, the GDS is in a simpler format with yes/no questions in comparison to items with
4-point scales. Second, the scale does not include physical symptoms that may mimic depressive
symptoms in older adults, such as motor retardation, which could result from a chronic medical
condition rather than depression.

Bipolar Disorders
Bipolar disorders are characterized by the occurrence of at least one manic or mixed episode (14).
Criteria for diagnosis of a manic episode include abnormally elevated or irritable mood, lasting
one week or longer, accompanied by three or more of the following symptoms (four or more
if only irritable mood): (a) grandiosity, (b) decreased need for sleep (usually with significantly
decreased amounts of total sleep), (c) talkativeness, (d) racing thoughts, (e) distractibility, (f)
increased goal-directed activity, and (g) excessive involvement in pleasurable activities with
potential for negative consequences. Mixed episodes are diagnosed when the patient meets
criteria for both a manic episode and a depressive episode simultaneously. Both manic and mixed
episodes cause clinically significant distress or impaired social or occupational functioning.
Hypomanic episodes are of lesser severity and associated functional impairment.

Basic Sleep Patterns

Patients meeting criteria for bipolar disorder often report a decreased need for sleep during peri-
ods of mania or hypomania. These patients also commonly have insomnia complaints, including
difficulty falling asleep, difficulty staying asleep, and nonrestorative sleep. As for polysomno-
graphic abnormalities, individuals with bipolar disorder demonstrate similar patterns as indi-
viduals with depression, including sleep continuity disturbances, REM sleep abnormalities, and
SWS deficits (15).

Possible Screening Measures

A standard screening question for mania is, “Have you felt so high, ‘hyper’, or irritable that
people told you that you were not your normal self?” For patients in whom mania is suspected,
one instrument that can be used to screen for manic and hypomanic symptoms is the Mood
Disorders Questionnaire (MDQ; 23). The MDQ is a 13-item self-report scale with two additional
items assessing whether any of the endorsed symptoms have occurred together and the degree
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130 RUMBLE AND BENCA

of impairment associated with symptoms. The first 13 items are answered in a yes/no response
format and scores range from 0 to 13. Using a cut-off of seven or more endorsed symptoms,
one study demonstrated a sensitivity of 58% and a specificity of 93% in a primary care clinic
sample with and without bipolar disorder as determined by a diagnostic interview (24). Using
this same cut-off and similar methods, sensitivity was higher and specificity was lower (73%
and 90%, respectively) in a psychiatric clinic sample (23).

Generalized Anxiety Disorder

Generalized anxiety disorder (GAD) is characterized by excessive and uncontrollable worry
and anxiety about a number of events or activities (14). In addition, this worry and anxiety
occurs most days for at least six months and is associated with three or more of the following
symptoms: (a) restlessness, (b) increased fatigue, (c) difficulty concentrating, (d) irritability, (e)
muscle tension, and (f) difficulty falling asleep, staying asleep, or nonrestorative sleep. GAD
also causes clinically significant distress or impaired social or occupational functioning.

Basic Sleep Patterns

Individuals with GAD often report difficulty falling asleep and staying asleep (25). In addition,
polysomnographic studies have shown a variety of sleep continuity disturbances, including
prolonged sleep latency, decreased sleep efficiency, early morning awakenings, and decreased
total sleep time (26–28). In contrast to those with mood disorders, individuals with GAD do not
typically demonstrate changes in REM sleep patterns (15).

Possible Screening Measures

To screen for GAD, patients may be asked, “Have you been anxious or worried?” Self-report
screening questionnaires assessing anxiety symptoms include the trait version of the State-
Trait Anxiety Inventory (STAI-T; 29), which has been recommended for measuring anxiety in
individuals with insomnia (12). The STAI-T is a 20-item self-report scale commonly used in
insomnia research that measures feelings of anxiety (12). Individuals rate various anxious and
nonanxious feeling states on a scale from 0 (not at all) to 3 (very much so). Some items are
reverse scored, and then all items are summed into a single score ranging from 20 (mild) to 80
(severe) with no cut-off scores.
Although the STAI-T is used regularly in research setting to measure anxiety symptoms,
more specific measures are available to assess possible GAD symptoms. One of these measures is
the Penn State Worry Questionnaire (PSWQ; 30), a 16-item self-report scale that was designed to
assess the frequency, excessiveness, and generalizability of worry (the main DSM-IV diagnostic
criteria for GAD). Each item is rated on a 5-point scale ranging from 1 (not at all typical) to
5 (very typical), and the measure takes approximately five minutes to complete. Some items
are reversed scored, and then all items are summed into a single score ranging from 16 to 80.
Individuals with GAD usually have a score of 60 or higher. However, one study examining the
screening utility of the PSWQ in a sample of individuals with and without GAD as determined
by diagnostic interview found that a cut-off score of 45 provided the most optimization with a
sensitivity of 99% and a specificity of 98% (31).

Panic Disorder
Patients with panic disorder experience repeated panic attacks, which are sudden occurrences
of extreme anxiety accompanied by at least four of the following symptoms: palpitations,
sweating, trembling, shortness of breath, choking, chest pain, nausea, dizziness, derealization
or depersonalization, fear of losing control or dying, numbness or tingling, and chills or hot
flushes (14). Agoraphobia, which is the fear of being in a place from which escape or help might
not be possible should a panic attack ensue, often develops as a secondary feature. Panic attacks
usually occur while awake, but may arise during sleep. Panic attacks occurring during sleep
can be differentiated from night terrors since patients are usually awake and alert during panic
attacks and remember them the next day, whereas they do not always fully awaken during a
night terror or confusional arousal and are less likely to remember them. Night terrors are also
more frequently associated with a frightening dream than are panic attacks.
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CLINICAL ASSESSMENT OF COMORBID INSOMNIAS: INSOMNIA IN PSYCHIATRIC DISORDERS 131

Basic Sleep Patterns

Patients with panic disorder can have increased insomnia complaints. Some studies comparing
objectively recorded sleep in patients with panic disorder to normal controls have demonstrated
abnormalities related to decreased sleep continuity (32,33), including prolonged sleep latency
and difficulties maintaining sleep. Patients with panic disorder also can develop fears of going
to sleep due to anticipation of possible nocturnal panic attacks (34). Polysomnographic studies
have demonstrated that nocturnal panic attacks most frequently occur when transitioning from
stage 2 to SWS (35). Unlike patients with mood disorders, patients with panic disorder do not
demonstrate REM sleep abnormalities.

Possible Screening Measures

A common screening question for panic disorder is, “Have you ever had a panic attack when
you suddenly felt anxious or experienced a lot of physical symptoms?” The four-item version of
the Anxiety Sensitivity Index (ASI), the Brief Panic Disorder Screen (BPDS), is a brief scale that
assesses fear of anxiety-related bodily sensations or consequences (36) and can be used to screen
for panic disorder. Each item on the four-item ASI is rated on a 5-point scale ranging from 0 to
4. All items are summed into a single score ranging from 0 to 16. In a sample of outpatients with
anxiety disorders as determined by a diagnostic interview, a cut-off of 11 revealed a sensitivity
of 78% and a specificity of 73% (36).

Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) develops in individuals who have experienced a traumatic
event and is characterized by re-experiencing the event in flashbacks, intrusive recollections of
the event, or recurrent dreams of the event (14). PTSD is also characterized by increased arousal
and avoidance of stimuli associated with the trauma. Symptoms must be present longer than one
month and cause clinically significant distress or impaired social or occupational functioning
to meet diagnostic criteria for PTSD.

Basic Sleep Patterns

Patients with PTSD often complain of nightmares as well as difficulties initiating and main-
taining sleep. The majority of polysomnographic research has demonstrated REM sleep abnor-
malities in PTSD patients, particularly disruption of REM sleep continuity and increased REM
density (37–39). On the other hand, there have been mixed results for insomnia disturbances in
that only some studies have demonstrated sleep initiation and maintenance difficulties (40,41).

Possible Screening Measures

When screening for PTSD, one frequently used question is, “Have you experienced any traumas
in your lifetime?” As for screening questionnaires, the Posttraumatic Stress Diagnostic Scale
(PDS; 42) is a 49-item self-report scale that assesses the severity of PTSD symptoms. This scale is
divided into four parts. The first part assesses what types of traumas occurred in the person’s life,
and the second part has the patient identify the most bothersome trauma and when it occurred.
The third part has patients rate the frequency of 17 PTSD symptoms on a 4-point scale ranging
from 0 to 3. The final part assesses the degree to which PTSD symptoms impact functioning.
In a psychiatric outpatient sample of individuals with and without PTSD as determined by
diagnostic interview, Sheeran and Zimmerman (43) found that a simple cut-off score of 15 or
higher on the third part of the questionnaire described above yielded a sensitivity of 89% and a
specificity of 76%.

Schizophrenia
Schizophrenia is a chronic illness characterized by the presence of a constellation of symptoms
that are associated with significant social or occupational dysfunction (14). The lifetime preva-
lence is 1% and death results from suicide in about 10% of cases. Positive symptoms include
disorganization of speech and behavior, as well as psychotic features such as delusions and
hallucinations. Negative symptoms consist of affective flattening, alogia (poverty of speech and
its content), and avolition (decrease in goal-directed activity). Depressed mood, loss of interest
or pleasure in normally pleasurable activities, anxiety, and irritability also may be present.
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132 RUMBLE AND BENCA

Basic Sleep Patterns

Patients with schizophrenia commonly will complain of sleep initiation or maintenance difficul-
ties and poor sleep quality even when treated with antipsychotic medication (44,45). In addition,
it is important to note that sleep difficulty in the context of discontinuation of antipsychotic med-
ications is often an early symptom of relapse (46). Objective assessment of sleep demonstrates
problems with sleep initiation and maintenance (47,48) as well as decreased REM sleep latency
and SWS, but these findings are less consistent (47). Finally, using 256-electrode high-density
EEG recording during sleep, a recent study found a significant deficit in NREM sleep spindles
in the vertex region of the scalp in patients with schizophrenia when compared to both control
participants and participants with a history of depression (49). Interestingly, a deficit in sleep
spindles suggests a possible abnormality in the thalamic reticular nucleus and thalamocortical
system, which, in turn, may represent a novel biological marker of schizophrenia.

Possible Screening Measures

Screening questionnaires are typically not used to identify patients at risk for schizophrenia, in
contrast to mood and anxiety disorders, although several questionnaires are available to assess
severity of symptomatology. Given the nature and severity of schizophrenia, however, the
majority of standardized measures for schizophrenia, such as the Brief Psychiatric Rating Scale
(50) or Positive and Negative Syndrome Scale (PANSS; 51), are designed to be given by mental
health professionals trained in administering these instruments. Therefore, screening measures
are more difficult to administer in nonmental health care settings. In the event that a patient
presents with psychotic symptoms and does not currently have a psychotic disorder diagnosis,
immediate referral to a mental health professional for further assessment is recommended.

ASSESSMENT OF FACTORS COMMONLY CONTRIBUTING TO INSOMNIA IN PATIENTS

WITH PSYCHIATRIC DISORDERS
If a psychiatric disorder is present, that disorder should be treated to remission if possible,
since sleep problems are generally worse in patients who are suffering from acute or inade-
quately treated episodes of illness. However, a thorough assessment of the sleep complaint is
also warranted in the case of insomnia comorbid with psychiatric issues as even in remitted or
optimally treated psychiatric patients insomnia frequently persists and can be a risk factor in
relapse or exacerbation of the psychiatric illness. Particular factors that commonly contribute
to insomnia in patients with psychiatric disorders include behavioral factors, the effects of psy-
chotropic medications, and other sleep disorders. These factors should be of particular focus
when assessing insomnia in this population. Each of these factors is discussed below, including
recommendations for assessment and treatment, and is summarized in Table 2. Certainly, in
addition to the factors discussed below, psychiatric disorder-specific factors that may be con-
tributing to insomnia, such as nocturnal panic attacks in panic disorder, should be assessed and
considered in the overall treatment plan.

Behavioral Factors
Behavioral factors are always important to assess in the context of insomnia. Furthermore,
given that individuals with insomnia comorbid with depressive and/or anxiety disorders have
been shown to report significantly higher levels of sleep-inhibitory behaviors (e.g., napping,
smoking more than one pack of cigarettes a day, using caffeine within four hours of bedtime,
and not relaxing prior to bedtime) than individuals with primary insomnia (52), assessment
of behavioral factors in psychiatric patients with insomnia complaints is paramount. These
patients often have a lack of daily structure, irregular bedtimes and wake-up times, and incon-
sistent patterns of activity and exercise. They also are prone to spend excessive amounts of time
in bed sleeping and attempting to sleep. Finally, they frequently engage in daytime napping
and accidental dozing, as well as use of caffeine, tobacco, alcohol, and/or recreational drugs.
Collectively, these behaviors that commonly occur in reaction to both sleep loss and psychiatric
symptoms can then perpetuate sleep difficulties through circadian disruption, homeostatic dys-
regulation, weakened associations between the bedroom and sleeping, and increased arousal.
Furthermore, some of these behaviors, particularly daytime napping and accidental dozing,
may be exacerbated by sedating psychiatric medications.
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CLINICAL ASSESSMENT OF COMORBID INSOMNIAS: INSOMNIA IN PSYCHIATRIC DISORDERS 133

Table 2 Key Areas and Screening and Assessment/Treatment Recommendations for Factors Commonly
Contributing to Insomnia in Patients with Psychiatric Disorders

Screening Assessment/treatment
Factors Key areas recommendations recommendations
Behavioral factors • Lack of daily structure • Patient’s description of a • Cognitive-behavioral
• Irregular sleep schedule typical day and night therapy for insomnia with
• Lack of exercise • Sleep Hygiene Practice an individual trained in
• Excessive time in bed Scale behavioral techniques
• Daytime napping • Sleep logs
• Accidental dozing • Activity logs
• Substance use • Actigraphy
Psychotropic • Antidepressants • Regular follow-up on • Assess time of day
medications • Antipsychotics sleep-related side medication is taken,
• Stimulants effects when prescribing dose and half-life
any of these medications • Consider alternative
agents if possible
Primary sleep • OSA • OSA: screen for obesity, • If OSA or PLMD
disorders • PLMD upper airway suspected, referral for a
• RLS obstruction, snoring, diagnostic sleep study
• Delayed sleep phase witnessed apneas, poor and consultation with
sleep quality, and sleep specialist
excessive daytime • If RLS, referral to a sleep
sleepiness specialist for
• PLMD: screen for legs consultation
twitching or jerking at • If delayed sleep phase,
night light therapy,
• RLS: screen for chronotherapy,
uncomfortable or odd melatonin, and/or
sensations in legs stimulus control
• Delayed sleep phase:
sleep logs
Abbreviations: OSA, obstructive sleep apnea; PLMD, periodic limb movement disorder; RLS, restless legs syndrome.

As part of the assessment, patients should describe a typical day and night. Questionnaires
and/or daily monitoring with sleep logs and/or actigraphy can also provide information about
sleep habits. The Sleep Hygiene Practice Scale (SHPS; 53), may be a particularly useful instru-
ment for this population, which is especially prone to poor sleep hygiene. This measure has
demonstrated good evidence of validity as it discriminates patients meeting criteria for insom-
nia from those who do not (52,53). Patients can engage in self-monitoring by completing sleep
logs (e.g., 54) and/or activity logs (e.g., 55). An assessment of the 24-hour rest-activity pattern
over days or weeks may also be assessed through the use of actigraphy devices, particularly if
the patient’s psychiatric issues significantly limit his or her ability to appropriately self-report
sleep and waking patterns.
Patients who exhibit sleep-related behaviors that are counterproductive to promoting
sleep (e.g., large amounts of time in bed awake, a variable sleep schedule, daytime napping
or dozing, alcohol use to facilitate sleep) may benefit from cognitive-behavioral therapy for
insomnia (CBT-I; see chapters 24–30). Several recent research studies have demonstrated the
efficacy of CBT-I for insomnia comorbid with depression, showing not only improvements in
sleep outcomes, but also improvements in depressive symptoms (11,56).

Effects of Psychotropic Medications

Psychopharmacological agents commonly used to treat psychiatric disorders, including antide-
pressants, antipsychotics, and stimulants, act on neurotransmitter systems involved in sleep-
ing and waking, including 5-hydroxytryptamine, acetylcholine, dopamine, histamine, and
norepinephrine. These various actions may result in improvement of insomnia, exacerba-
tion of insomnia, and/or increased daytime sleepiness (57). The potential effects of different
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134 RUMBLE AND BENCA

medications on sleep within each class are reviewed below. When evaluating the psychiatric
patient with insomnia, it is important to consider the contribution of these medications to sleep
complaints. The care provider should also verify that the patient is taking the medication at the
appropriate time of day and at the appropriate dosage. If sleep-related side effects are clinically
significant and timing and dosage have been optimized, it is recommended that other agents
be tried whenever possible.

Antidepressants and Their Effects on Sleep

A majority of commonly prescribed antidepressants decrease sleep continuity. These include
selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, sertraline, paroxetine, citalo-
pram), dual reuptake inhibitors (e.g., venlafaxine, duloxetine), buproprion, some tricyclics (e.g.,
imipramine, desipramine, and clomipramine), and monoamine oxidase inhibitors (58–60). In
addition, SSRIs, venlafaxine, and particularly monoamine oxidase inhibitors have been shown
to suppress REM sleep. REM sleep suppression is clinically important as patients can experience
vivid dreams and nightmares (i.e., “REM sleep rebound”) when discontinuing such medications
abruptly or even simply missing a dose.
On the other hand, some antidepressants are sedating and are frequently used to treat
insomnia comorbid with depression; these include trazodone, tricyclic antidepressants (e.g.,
amitriptyline, doxepin), mirtazapine, and nefazodone. However, sedating antidepressants often
lead to increased daytime sleepiness because of their long half-lives. As noted above, tricyclic
antidepressants suppress REM sleep (58,60) and thus cause REM sleep rebound and disrupted
sleep on nights not taken.

Antipsychotics and Their Effects on Sleep

Antipsychotic medications are often sedating, and patients may be most bothered by this side
effect (61). Typical antipsychotic agents that are high-milligram, low-potency agents, such as
chlorpromazine and thioridazine, tend to produce greater sedation than low-milligram, high-
potency agents, such as haloperidol and thiothixene (47). Newer atypical antipsychotics vary in
the sedative effects, with clozapine and olanzapine being particularly sedating and aripiprazole
and ziprasidone somewhat less so. In addition, newer atypical agents, such as clozapine and
olanzapine, tend to enhance sleep continuity (57,62,63). Similarly, quetiapine has been shown
to decrease sleep onset latency and waking time, increase total sleep time, and have no impact
on SWS, REM sleep latency, or REM density (64); risperidone has been shown to decrease total
wake time, improve sleep quality, and increase SWS (57,63). As a result, these medications are
often administered at higher doses at bedtime to aid in sleep and minimize daytime sedation.

Stimulants and Their Effects on Sleep

Stimulants are increasingly used for attention deficit disorder/attention deficit hyperactiv-
ity disorder, depression, and fatigue (65). Not surprisingly, the effects of stimulants, such
as methylphenidate, amphetamine, and modafinil, are decreased total sleep time, increased
arousals, and suppressed REM sleep (65). In patients with significant insomnia who may require
them for psychiatric reasons, these medications should be used in the lowest doses possible and
dosing later in the day should be minimized or avoided if possible.

Other Sleep Disorders

When assessing insomnia in a patient with a known psychiatric illness, insomnia related to
another primary sleep disorder should also be considered, particularly insomnia related to
obstructive sleep apnea (OSA), sleep-related movement disorders, including periodic limb
movement disorder (PLMD) and restless legs syndrome (RLS), or circadian rhythm disorders.
Psychiatric medications may precipitate or exacerbate these disorders. If OSA or PLMD is
suspected, a referral for a diagnostic sleep study is recommended. Patients with suspected RLS
should be referred to a sleep specialist for consultation. Patients with circadian rhythm disorders
may benefit from a referral to an individual trained in behavioral sleep medicine.
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CLINICAL ASSESSMENT OF COMORBID INSOMNIAS: INSOMNIA IN PSYCHIATRIC DISORDERS 135

Obstructive Sleep Apnea

OSA is a common sleep disorder in which the upper airway collapses repeatedly during sleep
causing pauses in breathing, arousals, and sleep fragmentation. OSA is associated with obesity
and/or upper airway obstruction related to enlarged tonsils or other anatomic features, and
individuals with OSA often complain of snoring, poor sleep quality, and excessive daytime
sleepiness. Although OSA is more typically associated with excessive daytime sleepiness, OSA
is also frequently comorbid with insomnia; about half of patients with OSA also complain
of clinically meaningful insomnia (66). OSA can also be comorbid with psychiatric disorders;
one study showed that almost one in five individuals with major depression had a breathing-
related sleep disorder and approximately one in five with a breathing-related disorder had
major depression (67). Overlapping symptoms among OSA, insomnia, depression, and other
psychiatric disorders include fatigue, decreased attention/concentration, lack of motivation,
and decreased enjoyment. Importantly, one must also consider how psychiatric medication can
indirectly exacerbate OSA through weight gain (e.g., atypical antipsychotics, antidepressants,
mood stabilizers) and muscle relaxation (e.g., benzodiazepines, barbiturates) (e.g., 68). Psychi-
atric patients with suspected OSA should not be given barbiturates, and sedating medications
should be avoided or used with caution.

Sleep-Related Movement Disorders

Sleep-related movement disorders, including PLMD and RLS, are important to keep in mind
when assessing insomnia within the context of a psychiatric disorder. PLMD is characterized by
repeated contraction of the anterior tibialis muscles during sleep, resulting in leg movements,
kicks, or twitches during sleep. If frequent or severe enough, they may lead to arousals and frag-
mented sleep. RLS is characterized by uncomfortable or odd sensations, mostly in the legs, that
are accompanied by an urge to move. They tend to occur most commonly in the evening, when
the patient is sitting or lying down, but may also occur at other times of day when the patient
is sedentary. Furthermore, movement typically relieves these sensations temporarily. RLS is
differentiated from akathisia, which is most commonly a side effect of neuroleptic antipsychotic
medication, in that akathisia usually is experienced as restlessness throughout the body that
does not demonstrate a circadian pattern or abate with movement (69). The presence of RLS
and/or PLMD may prolong sleep onset latency or extend nocturnal awakenings.
Notably, many psychiatric medications can increase periodic limb movements (PLMs)
and restless legs symptoms, including SSRIs, serotonin-norepinephrine reuptake inhibitors,
and both typical and atypical antipsychotics. For example, a recent study found that approx-
imately 9% of individuals experienced new onset or exacerbation of restless legs symp-
toms after starting newer antidepressants (e.g., SSRIs or dual reuptake inhibitors) (70). The
pharmacological mechanisms thought to be associated with these symptoms are the reup-
take inhibition of 5-hydroxytryptamine and dopamine antagonism. Agents such as bupro-
prion, with significant dopaminergic activity, are thought to be less likely to exacerbate these
symptoms (71,72).

Circadian Rhythm Disorders

Circadian rhythm disorders involve a mismatch between the 24-hour day and the endogenous
circadian rhythm, which is generated by the master pacemaker within the suprachiasmatic
nucleus of the hypothalamus. Various factors can entrain the human circadian rhythm, includ-
ing light, melatonin, and social cues (e.g., mealtimes, start time for work). The most common
circadian disorder is delayed sleep phase, which consists of profound insomnia at sleep initiation
and then marked difficulty waking up in the morning. Delayed sleep phase occurs frequently in
adolescents and young adults and is thought to be related to developmental changes in the cir-
cadian clock (73). Delayed sleep phase has also been observed to occur more frequently in mood
disorder populations; several studies have suggested that patients with bipolar disorder may
have greater rates of delayed sleep phase than individuals with schizophrenia or individuals
without a psychiatric diagnosis, as seen by a significantly higher preference for “evening-
ness” and significantly delayed sleep times (74,75). If delayed sleep phase is suspected, it is
recommend that patients engage in self-monitoring by completing sleep logs (e.g., 54) to con-
firm a regular pattern of extreme sleep initiation difficulties (e.g., several hours) and delayed
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136 RUMBLE AND BENCA

wake-up times. Treatment for delayed sleep phase disorder includes morning bright light
therapy for less significantly delayed sleep patterns and chronotherapy for more significantly
delayed sleep patterns (76). Treatment may also include melatonin administration and/or other
behavioral techniques, such as stimulus control therapy (77), if sleep-inhibitory behaviors are
present (76).

SUMMARY
Insomnia and psychiatric disorders frequently occur together. Furthermore, mounting evidence
has shown that insomnia is a risk factor for future onset and/or relapse and exacerbation
of psychiatric disorders, particularly depression. Therefore, the assessment of both sleep and
psychiatric symptomatology in individuals with either an insomnia or a psychiatric complaint is
essential. Psychiatric disorders commonly occurring with insomnia include mood, anxiety, and
psychotic disorders; these have effects on both subjective insomnia as well as affecting objective
sleep EEG patterns. Screening questions and tools are often helpful to identify psychiatric
disorders in patients with insomnia and to monitor the severity of psychiatric symptoms during
the course of treatment. Other factors commonly contributing to insomnia in psychiatric patients
include behavioral factors, the effects of psychotropic medications, and other sleep disorders.
An understanding of the comorbidity between sleep and psychiatric disorders as well as ways
to better screen, assess, and monitor both insomnia and psychiatric disorders should lead to
more optimal management and outcome in insomnia patients.

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14 Insomnia in Chronic Pain

Emerson M. Wickwire
Center for Sleep Disorders, Pulmonary Disease and Critical Care Associates, Columbia, Maryland, U.S.A.

Michael T. Smith
Department of Psychiatry and Behavioral Sciences, Behavioral Sleep Medicine Program, Johns Hopkins
University School of Medicine, Baltimore, Maryland, U.S.A.

INTRODUCTION: DEFINITION, PREVALENCE, AND COSTS OF CHRONIC PAIN

The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory
and emotional experience associated with actual or potential tissue damage, or described in
terms of such damage” (1). Pain is the most common health-related complaint in the United
States, accounting for over 80% of all doctor office visits (2). While acute pain serves a critical
biologic survival mechanism, signaling injury, pain can develop from an acute, beneficial sensory
phenomenon to a pathological, intractable condition. More than half of U.S. adults report
experiencing some form of chronic pain during the past year and 50% of these individuals
report pain lasting longer than one year (2). Chronic pain accounts for over $70 billion annually
in health care costs and lost workplace productivity (2).
Chronic pain is often described as pain that persists beyond the expected time of healing,
but the factors associated with the transition from acute to chronic pain are poorly understood
and likely involve complex genetic, behavioral, societal, and peripheral and central nervous sys-
tem interactions. Disorders associated with chronic pain are often classified by their presumed
primary etiology, for example, inflammatory pain (e.g., rheumatory arthritis), nociceptive pain
resulting from active stimulation of pain sensing neurons (i.e., nociceptors), and neuropathic
pain, resulting from injury to nociceptors (e.g., postherpetic neuralgia). These categories, how-
ever, are not mutually exclusive, and chronic pain conditions often involve some combination of
these classic categories of pain. Moreover, many chronic pain conditions such as fibromyalgia,
irritable bowel syndrome, temporomandibular joint disorder, and others, are idiopathic, having
no identifiable peripheral insult or pathology that explains the magnitude of pain and suffering.
Increasingly, data from neuroimaging and psychophysiologic studies implicate dysfunc-
tional central pain processing mechanisms in the etiology and maintenance of many chronic
pain disorders, particularly the idiopathic syndromes. A complex network of descending opi-
oidergic and serotonergic systems have been shown to inhibit and facilitate afferent nociceptive
input from second order neurons in the dorsal horn through key centers in the periaqueductal
gray and the rostral ventral medulla (3). These systems are often dysregulated in chronic pain
disorders, leading to a state of central sensitization, such that ascending pain signals are aug-
mented at the level of the spinal cord (4). Specific higher order brain regions, often referred to as
the pain neuromatrix, include the thalamus, anterior cingulate nucleus, insula, and prefrontal
cortices, regions that are known to directly regulate brain stem pain modulatory centers (5).
Individual differences in the functional integrity of these systems predict individuals at risk
for the development of chronic pain (6). Many of the CNS systems involved in pain process-
ing, particularly the limbic system, thalamus, and prefrontal cortices, are also critical to both
affect and sleep regulation. It is therefore not surprising that both mood impairments and sleep
disturbance are common to the experience of chronic pain. Moreover, both negative mood and
sleep disturbance are increasingly identified as independent risk factors for the development
of chronic pain syndromes (7–10), possibly contributing to a top–down pain amplification by
impairing pain modulatory centers in the brain stem and spinal cord.
The vast majority of individuals with chronic pain report significant sleep problems,
including delayed sleep onset, increased nocturnal awakenings, greater wake after sleep onset,
and poorer quality sleep, relative to pain-free individuals (11). Evidence also suggests the
possibility that rates of other intrinsic sleep disorders such as sleep disordered breathing may
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140 WICKWIRE AND SMITH

(1) Traditional Linear View

PAIN AROUSAL INSOMNIA

(2) Reciprocal View (Moldofsky, 1975)

COPING

AROUSAL
PAIN
INSOMNIA

DEPRESSION

Figure 1 Reciprocal relations between sleep and pain.

be elevated in chronic pain patients (e.g., Ref. 12). Although it is commonly assumed that sleep
disturbance associated with pain is primarily a consequence of pain, experimental and cross
sectional evidence spanning over half a century, as well as emerging longitudinal data, support
a bidirectional relationship between sleep and pain. Indeed, for patients with chronic pain
a vicious cycle often develops, with pain disrupting sleep and poor sleep further exacerba-
ting pain.
Importantly, mood disturbance and psychological distress are common among chronic
pain patients (13). Evidence consistently supports elevated rates of both depression and anx-
iety in chronic pain populations, and as demonstrated in Figure 1, it is now known that the
sleep–pain relationship is often mediated by cognitive and affective processes. This suggests
that thorough assessment of emotional disturbance and sleep disorders is especially important
in the evaluation and management of patients with chronic pain conditions. Further, despite
high prevalence rates of insomnia complaints in patients suffering from chronic pain condi-
tions, systematic empirical treatment approaches are not well developed and therefore clinical
management can be especially challenging.
The purpose of this chapter is to review the relation between chronic insomnia and chronic
pain. To this end, we will briefly summarize the literature evaluating the effect of experimental
sleep disturbance on pain sensitivity, as well as the effects of the administration of pain during
sleep to provide important background information. We will next consider evidence supporting
prospective and reciprocal relations between sleep disturbance and pain. Sleep complaints in
several common chronic pain conditions will be reviewed, and key findings from the extant
clinical trials literature, including pharmacological and cognitive-behavioral approaches, will
be discussed. The chapter concludes with clinical recommendations and suggestions for future
research.

EXPERIMENTAL AND LONGITUDINAL RELATIONS BETWEEN SLEEP AND PAIN

Effects of Experimental Sleep Disruption on Pain

In the first third of the 20th century, researchers proposed a relation between sleep disruption
and pain processing. Copperman (14) observed decreased skin sensitivity to touch and pain
following 60 hours of sleep deprivation, with greater sleep loss being associated with lower
pain thresholds. Nearly 40 years later, Moldofsky et al. evaluated the relation between sleep
and pain by using auditory tones to disrupt slow wave sleep and REM sleep in uncontrolled
studies of healthy subjects. They reported next day increases in musculoskeletal tenderness
after SWS but not REM disruption, noting that the patterns of muscle tenderness resembled
symptoms of fibrositis (fibromyalgia) (15,16). These authors were among the first to suggest a
vicious cycle between sleep disturbance and chronic pain, with pain impairing sleep and poor
sleep enhancing pain and disturbed mood. Since these reports in the mid-1970s, researchers
have continued to evaluate the effects of sleep disruption on pain. Although results have been
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INSOMNIA IN CHRONIC PAIN 141

somewhat mixed (17), in aggregate these findings support a bidirectional, causal relationship
between sleep and pain sensitivity (18). More recent studies have reported increased sensitivity
to mechanical stimuli following 40 hours of total sleep deprivation (19), a 24% decrease in
mechanical pain threshold, and an increase in inflammatory skin flare response following SWS
disruption among women (20). Recent well-controlled experiments found that restriction to four
hours of sleep and REM disruption (but not NREM disruption) caused thermal hyperalgesia
(21). In a controlled study of 32 healthy females, sleep continuity disturbance induced via
forced awakenings, but not simple sleep curtailment, impaired descending pain inhibitory
functions and induced spontaneous reports of pain (22). While not enough systematic research
is yet available to conclusively explain which types of sleep disruption or loss alter various
dimensions of central pain processing, it is clear that insufficient sleep contributes to pain
amplification and induces pain even in the absence of peripheral input.

Effects of Pain Administration During Sleep

A second line of experimental research has evaluated the effects of painful stimuli administered
during sleep. All of these studies have found noxious stimuli to induce sleep microarousals
(increases if high frequency EEG activity, often accompanied by autonomic changes) and con-
current decrease in slow wave activity (23–25). For example, Drewes et al. (24), administered
painful stimuli to both muscles and joints and found decreased delta activity and increases
in the alpha, beta, and sigma ranges. Other studies have found painful stimuli administered
during sleep to produce transient tachycardia (26) as well as cortical arousal even in the absence
of frank awakenings (25). These EEG findings are consistent with EEG profiles observed in
chronic pain patients, which often show decreased slow wave sleep and increased alpha activ-
ity without frank awakenings. However, the stimuli administered in these studies were of brief
duration (i.e., one millisecond) and therefore cannot be considered representative of clinical
pain conditions, which are characterized by persistent pain of greater duration (23,24,27,28). In
studies that have employed painful stimuli of greater duration, a dose–response relationship
has been observed between stimuli duration and cortical arousal (24,26–28).
Despite the ability of noxious stimuli of sufficient intensity to fragment sleep, it should be
noted that in healthy subjects the data also indicate that the nociceptive system is attenuated.
The intensity of stimulation required to evoke arousal is much higher than the intensity of
stimulation required to reach pain threshold during testing conducted when awake (27,28). It
remains unknown whether chronic pain patients also have attenuated pain processing during
sleep or whether this process itself becomes disrupted as part of neuroplastic changes associated
with chronic pain. Although painful stimuli during sleep have not yet been administered in
chronic pain populations, EEG arousal responses to painful stimuli suggest that sleep distur-
bances observed in chronic pain may in part be caused by pain itself and may not always reflect
independent sleep or mood disturbance.

Longitudinal Relationship Between Sleep and Pain

Longitudinal clinical studies support a reciprocal relationship, such that pain interferes with
sleep and disturbed sleep is associated with next day or longer-term increases in pain (29–34).
Supporting the reciprocal nature of sleep–pain interactions, an increasing number of longitu-
dinal studies suggest that poor sleep is an independent risk factor for increased pain severity
(22,29,32,34,35). For example, in a sample of 333 hospitalized burn patients, insomnia complaints
and pain severity were assessed at discharge and 6, 12, and 24-month follow-up (9). Individuals
with sleep onset insomnia had significantly less improvement in pain symptoms and increased
pain severity at follow-up, even after controlling for premorbid pain, pain severity at discharge,
mental health, and total burn surface area. Similarly, burn pain during hospitalization predicted
future insomnia complaints (9), although to a lesser extent. Hence the relationships between
sleep and pain appear to be long term, prospective, and reciprocal. In a microlongitudinal
study designed to assess these reciprocal relationships over multiple nights, Edwards et al. (36)
recently reported results from a naturalistic telephone survey of representative sample of 971
U.S. adults in the general population. Over a one-week period, daily reports of sleep dura-
tion (<6 hours or >9 hours) were associated with greater next-day pain; in a reciprocal model
daily pain reports were similarly although less strongly predictive of sleep duration that night
(36). In addition to these self-report data, Drewes et al. (30) administered PSG to 35 patients
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142 WICKWIRE AND SMITH

with rheumatoid arthritis and found that time awake in bed predicted morning stiffness, joint
tenderness, and subjective pain ratings six months later. Similarly, baseline ratings of pain and
morning stiffness predicted nocturnal wake time as well as changes in sleep architecture at six
months (30).

INSOMNIA IN CHRONIC PAIN CONDITIONS

Consistent with this experimental and longitudinal evidence, data obtained from clinical sam-
ples also support a strong relation between sleep disturbance and pain. High rates of sleep
disturbance have been found in numerous chronic pain conditions, with insomnia being the
most common presenting symptom. For example, large-scale studies consistently suggest that
at least 50% or more of patients with osteoarthritis (OA) report significant difficulty initiating or
maintaining sleep (37–42). Among cancer patients, high rates of insomnia complaints, depres-
sive symptoms, and health anxiety have been reported (43). Because persistent pain, mood
disturbance, and sleep complaints and nearly ubiquitous in these populations, a review of all
chronic pain conditions is beyond the scope of this chapter. The following section, however,
provides a brief overview of sleep in three broad categories of chronic pain conditions that are
frequently seen in general clinical practice and highlight the complexities of sleep–pain interac-
tions: (i) inflammatory and autoimmune conditions, (ii) idiopathic pain disorders (functional),
and (iii) neuropathic pain syndromes.

Inflammatory and Autoimmune Conditions Associated with Chronic Pain

Patients with inflammatory and autoimmune conditions consistently report sleep disturbance.
For example, adult rheumatoid arthritis (RA) patients frequently complain of sleep disruption,
including decreased arousal threshold and increased time awake in the middle of the night. PSG
findings have tended to corroborate these self-reports. For example, relative to healthy controls,
RA patients have been found to have increased sleep fragmentation (44–50) and higher arousal
indices as measured via PSG (45,48,49). Similarly, several studies have reported increased wake
after sleep onset in RA (45,48). Importantly, evidence supports a relation between these sleep
disturbances and pain severity in RA, with higher arousal indices and greater wake after sleep
onset having been positively associated with self-reported pain and morning stiffness among
adults (30,44,49). Not surprisingly, high frequency EEG activity (e.g., alpha intrusion) has also
been consistently documented in the sleep of RA patients (44–50).
Data are more limited among other autoimmune conditions but also suggest disturbed
sleep among patients with these diseases. For example, in a PSG study of 27 consecutive clinic
patients with systemic sclerosis (scleroderma), results demonstrated decreased sleep efficiency,
decreased REM sleep, increased SWS, and increased arousals, relative to normative data (51).
This study also reported a high rate of periodic limb movement disorder and restless legs syn-
drome, indicating clinicians should actively assess and consider referral for these disorders in
scleroderma. Likewise, persons with the autoimmune inflammatory disease sarcoidosis expe-
rience fatigue, insomnia, and daytime sleepiness, and PSG evidence supports both sleep apnea
and periodic limb movements as common comorbid sleep disorders (52,53). Normalizing sleep
in autoimmune diseases, inflammatory diseases, and other illnesses involving dysregulation of
the immune system, such as cancer, may prove a critical and currently under appreciated com-
ponent of disease management. Growing evidence from sleep deprivation studies suggests that
insufficient sleep has detrimental consequences on immune system function, including caus-
ing elevation in proinflammatory cytokines, which sensitize nociceptors, thereby augmenting
clinical pain and contributing to fatigue (54).

Idiopathic Pain Disorders

Idiopathic pain disorders are a group of highly comorbid syndromes with overlapping symp-
toms including chronic widespread pain, fatigue, psychological distress, and motor dysfunction.
Neuroendocrine abnormalities and mild cognitive impairment can also be present. Common
idiopathic pain conditions include fibromyalgia, irritable bowel syndrome, temporomandibu-
lar joint disorder, tension headache disorders, chronic pelvic pain, and interstitial cystitis
(55,56). Although these disorders typically have no clear peripheral pathology, evidence sug-
gests that they share a common central nervous system substrate characterized by heightened
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INSOMNIA IN CHRONIC PAIN 143

processing of noxious input. As a result, there is a great deal of overlap in symptoms between
these conditions, which have been increasingly referred to as “central sensitivity syndromes”
(57). Patients diagnosed with one of these disorders frequently meet diagnostic criteria for other
syndromes in this cluster of conditions associated with intractable pain (58,59).
Subjective and objectively measured sleep disturbances are highly prevalent in these pop-
ulations and may exacerbate symptoms through increased psychological distress or disturbed
processing of noxious inputs (e.g., Ref. 22). In clinical settings, sleep disruption is among the
most common of all symptoms reported in idiopathic pain disorders. For example, fibromyalgia
(FM) has a consistent and well-replicated relation with disturbed sleep (11), with the majority of
patients reporting difficulty maintaining sleep and characterizing their sleep quality as shallow
and nonrestorative (60). Complaints of impaired sleep continuity in FM have been verified by
PSG, including increased sleep onset latency (61), increased nocturnal arousals (62–64), more
time awake during the night (62), greater sleep fragmentation (65), decreased sleep efficiency
(64,66,67), and increased alpha intrusion during NREM sleep (64,68).
Patients with myofascial temporomandibular joint disorder (TMD) report similar sleep
disturbances, and recent evidence suggests high rates of diagnosed sleep disorders in this pop-
ulation, including insomnia, obstructive sleep apnea, and sleep bruxism (69a,69b). Polysomno-
graphically measured decrements in sleep efficiency have also been linked to psychophysical
measures of impaired pain inhibitory processes in TMD (70). Sleep fragmentation has been
shown to decrease endogenous pain inhibitory capacity, and dysfunction of these same descend-
ing pain inhibitory systems has been implicated in pathophysiologic models of idiopathic pain
disorders (71).
Sleep disturbance and headache disorders, the most common category of episodic pain
disorder, are also highly comorbid. Insomnia is the most common sleep complaint in this
population (72) with over one half of all headache patients reporting difficulty initiating or
maintaining sleep, early morning awakening, or nonrestorative sleep (73). Boardman et al. (74)
surveyed 2662 adults living in the United Kingdom and found that after controlling for age and
gender, sleep disturbance was monotonically related to headache complaints. Similarly, Ohayon
(75) analyzed data from a large-scale telephone-based survey and found a significant associa-
tion between morning headache and insomnia. Other studies have documented differences in
sleep complaints between patients with migraine or tension-type headache, with tension-type
headache generally being more strongly associated with complaints of insomnia (76,77). Among
patients with tension-type headache, insomnia has also been associated with poorer prognosis
(77). Patients with migraine have changes in the quality of sleep several days before the onset
of a migraine attack, but have largely normal sleep patterns outside the attacks (78). Cluster
headaches (attacks of severe unilateral orbital, supraorbital or temporal pain) frequently occur
during sleep and are believed to be directly associated with chronobiologic mechanisms and
sleep stage shifts. In addition to insomnia, sleep disordered breathing has often been linked
to morning headaches, and current guidelines indicated that headache management should
identify and treat sleep disorders, which may improve or prevent headaches (72). In general,
the particularly strong association between sleep disturbance and central sensitivity syndromes
suggests the possibility that sleep disturbances may play an integral role in the pathophysiology
and clinical course of these syndromes. Research aimed at determining how treatment of sleep
disturbances in these conditions alters pain and related symptoms is needed.

Neuropathic Pain Syndromes

Neuropathic pain syndromes are particularly treatment-refractory chronic pain conditions asso-
ciated with damage to peripheral nerves. Like other intractable pain disorders, however, neu-
roplastic changes in pain processing systems play an integral role in their pathophysiology and
maintenance. In addition to sensory loss associated with denervation, neuropathies also para-
doxically involve positive symptoms, most commonly pain that is often qualitatively described
as “burning” or “shooting.” Spontaneous paresthesias/dysesthesias, hyperalgesia (exaggerated
response to a noxious stimulus), and allodynia (in which previously non-noxious stimuli are
perceived as painful) are common consequences of peripheral nerve damage. Allodynia can
be particularly disruptive to sleep, and affected patients will often report that even light touch
stimulation of the affected area by bed sheets can trigger exquisite pain. Common neuropathic
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144 WICKWIRE AND SMITH

pain conditions include diabetic neuropathies, complex regional pain syndrome, demyelinating
diseases, virally mediated neuropathies (e.g., HIV and postherpetic neuralgia), spinal cord
injuries, and iatrogenic nerve damage due to chemotherapies for cancer. Although there
are many causes of neuropathic pain, treatment targeting neuropathic pain most commonly
includes agents that stabilize cell membranes (e.g., Na+ and K+ channels) associated with
aberrant nerve conduction. Anticonvulsant medications with sedating properties are commonly
used and may improve sleep.
As is the case with other types of chronic pain, mood disturbance is common among
patients experiencing neuropathic pain (79), and not surprisingly, many patients also complain
of sleep disturbance. In one of the few systematic studies of sleep in neuropathic pain disorders,
Zelman et al. (80) compared self-report sleep data from 255 patients with painful diabetic
peripheral neuropathy (DPN). These authors found that relative to the general population (P <
0.001) and patients with chronic medical diseases (P < 0.05), patients with painful DPN reported
significantly poorer sleep. The DPN group also reported greater sleep disturbance than subjects
with postherpetic neuralgia. Average daily pain and anxiety and depression symptoms were
all associated with poorer sleep in this cross sectional study. With increasing prevalence of
obesity and diabetes worldwide and an estimated U.S. diabetes prevalence of 11.2% by the year
2030 (81), these data indicate that systematic research to assess and treat sleep and pain in this
population is a health priority.

TREATMENT OF COMORBID INSOMNIA AND CHRONIC PAIN

The available experimental and longitudinal data strongly suggest the sleep–pain relationship
is best described as bidirectional or reciprocal. Given this data, it is somewhat surprising that
few clinical trials designed to determine analgesic efficacy and effectiveness have included sleep
as a major outcome.

Pharmacologic Treatments for Sleep Disturbance in Chronic Pain

Several early studies have tested the short-term effects of benzodiazepine receptor agonists
(BZRAs) on sleep and pain (44,82,83). These studies included patients with FM and RA, and
results indicated that BZRAs improved sleep but had minimal impact on pain. Negative findings
with respect to pain, however, are likely a function of very small sample sizes, insufficient
treatment durations, and no follow-up investigation. Clinical trials designed to study the effects
of these agents over longer periods of time (months rather than days) are needed.

Pharmacological Treatments for Pain and Effects on Sleep

Historically, sedating antidepressants have often been prescribed to treat comorbid chronic pain
and insomnia. Older drugs, including tricyclic antidepressants, can be effective in improving
sleep parameters when administered in doses lower than typically prescribed for treatment
of depression (84). Nonetheless, given the ubiquitous overlap between sleep complaints and
mood disturbance, it should be noted that it is not entirely clear whether these improvements are
independent of changes in depressive symptoms (85). More recently, research has also evaluated
the effectiveness of newer antidepressant compounds, particularly the selective serotonin and
norepinephrine inhibitors. Fishbain et al. (86) pooled data from three double-blind, randomized,
placebo-controlled clinical trials investigating the treatment of DPN with duloxetine. Results
indicated that reductions in sleep interference were associated with less daily pain and less
severe night pain. Clinicians should be cautioned that some patients may experience insomnia
as a side effect of antidepressant medications.
In clinical practice, anticonvulsants have also often been prescribed for sleep disturbance
within the context of chronic pain, and some evidence supports their effectiveness. Gordh
et al. (87) conducted a randomized, double-blind, placebo-controlled trial of gabapentin among
120 traumatic nerve injury patients across nine treatment centers. Despite null findings for
the primary outcome variable of pain intensity, gabapentin was associated with significant
decreases in pain-related sleep interference. Similarly, Tolle et al. (88) found pregabalin to be
associated with significant reductions in pain-related sleep interference in neuropathic pain.
Arnold et al. (89) also reported significant improvements in self-reported sleep parameters in
FM patients following 14 weeks of pregabalin administration.
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INSOMNIA IN CHRONIC PAIN 145

Finally, some recent evidence also supports the use of weak opioid agonists for comorbid
pain and sleep disturbance. In two large (N > 1000) posthoc studies of extended-release tramadol
in adults with OA, significant improvement in self-reported sleep parameters were reported as
early as one week and maintained throughout treatment (90). In another study of OA patients,
Kivitz et al (91) reported that 40 and 50 mg, but not 10 mg, extended-release oxymorphone
improved self-reported sleep.

Effects of Cognitive-Behavioral Therapy for Pain on Sleep

Like cognitive-behavioral treatments for insomnia, CBT interventions for pain typically include
multiple components. These are likely to include training in relaxation, developing coping skills,
and addressing maladaptive beliefs, and behavioral activation strategies including increasing
physical activity, setting goals, and scheduling pleasurable activities. These protocols differ
notably from typical CBT-I prescriptions, which are more likely to include sleep hygiene edu-
cation, stimulus control, and sleep restriction. Relaxation is a shared component of the two
approaches. Whereas treatment effects for CBT-I tend to be moderate to large, the impact of
CBT-P on pain outcomes is more limited. Astin et al. (92) reported effect sizes of 0.20, and Morley
et al. (93) found only slightly higher effect at 0.29. The effects of CBT-P on outcomes such as
coping and self-efficacy are notably higher and in the moderate range and tend to increase over
time (92,93).
Given the well-known relation among sleep complaints, pain severity, and mood distur-
bance, it is surprising that effects of CBT-P on sleep are generally not reported in treatment
studies of chronic pain conditions (94). The studies that have considered these effects present a
mixed picture. An early study (95) reported improvements in sleep complaints roughly equal to
reductions in pain at posttreatment and six-month follow-up. Similarly, Singh et al. (96) reported
improvements in sleep, pain, and depression following a treatment that included mindfulness
meditation and movement therapy in FM patients. Thieme et al. (97,98) have reported similar
results using operant behavioral and cognitive-behavioral approaches. Several clinical recom-
mendations have been made in the literature. Based on a comprehensive literature review,
Thieme et al. (99) recommended operant behavioral and cognitive-behavioral approaches to
pain management, both of which have been associated with improvements in sleep. Dalton et
al. (100) have described a tailored CBT-P for use in cancer pain patients and found that this
approach was associated with a reduction in pain-related interference with sleep.
At the same time, a number of studies have detected no improvements in sleep following
CBT-P. Among RA patients, two studies have failed to detect any improvement in sleep despite
improvements in pain, self-efficacy, movement, and joint involvement (101,102). Whereas find-
ings have been similar in adolescents with FM (103), Redondo et al. (104) employed a CBT-P and
failed to find improvement in either pain or sleep in adults with FM. Others have also failed to
detect improvement in sleep complaints following CBT-P among FM patients (105). Although
CBT-P appears promising for improving sleep in patients with chronic pain, further research is
needed before any clear conclusions can be drawn.

Effects of Cognitive-Behavioral Therapy for Insomnia in Chronic Pain Conditions

Although most CBT-I literature has excluded patients with comorbid conditions, a number of
investigators have applied cognitive-behavioral models of insomnia to understanding insomnia
in patients with chronic pain. Maladaptive coping strategies and compensatory sleep behaviors
such as napping, spending excessive time awake in bed, and following an inconsistent sleep–
wake schedule are common in patients with pain and may worsen insomnia. At the same
time, pain patients are likely to catastrophize, or ruminate on the potential worst-case scenario
outcomes of their condition. Similarly, Smith et al. (106) reported increased levels of presleep
arousal and attention to bedroom stimuli such as temperature and noise among patients with
chronic pain. These thought processes were more robust predictors than pain ratings of sleep
complaints. Cognitive therapy techniques designed to manage these catastrophic cognitions
may be particularly helpful in treating insomnia associated with chronic pain.
Early case reports of sleep restriction and stimulus control in chronic pain found large
improvements in both subjective and objectively measured sleep onset latency and time awake
in bed, and these changes were maintained at two- and six-month follow-up (107,108). Although
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146 WICKWIRE AND SMITH

mood improved concurrent with sleep, no changes were detected in subjective pain ratings. In
a sample of cancer patients, Cannici et al. (109) found that PMR led to a significant, 90-minute
reduction in diary-reported sleep onset latency, an improvement that was maintained at follow-
up. Again, no improvements in pain were observed, although baseline pain ratings in this
sample were low. A study of mixed diagnosis outpatients demonstrated that CBT-I could be
effective even when the primary cause of sleep disturbance was believed to be medical or psy-
chiatric (110). Moderate effect sizes were reportedly observed for improvements in wake time
after sleep onset, sleep efficiency, and sleep quality ratings, and these changes were maintained
at three-month follow-up (110). Others have reported similar results (111). Among older adults
with mixed medical comorbidities including OA, CBT-I is associated with improvements in
diary-reported but not actigraphically measured sleep onset latency, sleep efficiency, and sleep
quality (112,113). In addition to these studies employing standard cognitive-behavioral treat-
ment for insomnia, other studies have evaluated the impact of adding sleep education to routine
medical care. For example, Calhoun and Ford (114) employed a randomized, placebo-controlled
design and found that adding cognitive-behavioral instructions for improved sleep was asso-
ciated with a significant reduction in headache complaints among 43 women with migraine.
Further, improvement in headache symptoms was related to the number of changes in sleep
behaviors reported. Although changes in sleep parameters were not reported, this study is
nonetheless notable for the association of a sleep-focused intervention and reductions in report
of chronic pain.
At least two randomized clinical trials have evaluated using CBT-I exclusively in chronic
pain conditions. In the first of these, Currie et al. (115) reported improvements in the CBT-I
condition relative to wait-list control in both diary and actigraphic measures of sleep latency,
wake after sleep onset, sleep efficiency, and sleep quality. As is found in CBT-I for primary
insomnia, effect sizes were large (in the range of 0.80), and treatment gains were maintained at
three months. Although no significant group differences were observed in total sleep time, the
CBT-I group tended to have larger gains that increased during the three-month follow-up period.
More recently, Edinger et al. (116) employed an active control group to test the effectiveness
of CBT-I in FM patients with chronic insomnia. Relative to the control condition, CBT-I was
associated with improvements in diary-based measures of sleep onset latency, sleep efficiency,
and total wake time. Actigraphy-measured sleep latency was also significantly improved in
CBT-I relative to control. In addition, reductions in night-to-night sleep variability were also
observed in the CBT-I group.
Preliminary evidence suggests effectiveness of standard CBT-I for improving sleep in
patients with chronically painful conditions, although further research is needed. Several impor-
tant limitations must also be noted. Only one of the aforementioned studies (116) employed
a credible control condition. Thus, it cannot be concluded that observed changes were due to
specific treatment elements rather than nonspecific factors such as therapist contact. It is par-
ticularly challenging to develop credible placebo control conditions for cognitive-behavioral
interventions. Sleep hygiene, often employed as a control condition, has been associated with
improvements in insomnia complaints (117), further highlighting the need for new approaches
to experimental design in this area.

Relation Between Improved Sleep and Pain Complaints

Although they were not designed to address the issue, the Currie et al. (115) and Edinger
et al. (116) studies provide some insight into the effect of improved sleep on pain complaints.
For example, Currie et al. (115) reported a nonsignificant trend toward reduced pain com-
plaints in the CBT-I group relative to wait-list at three-month follow-up. This study suggests
that reductions in pain associated with improved sleep may be delayed. Although follow-up
data were not reported in the Edinger et al. (116) study, it is common for studies evaluating
cognitive-behavioral interventions for insomnia and pain, as well as other conditions, to find
that treatment effects improve over time. Presumably, patients continue to learn and behavior
change becomes more permanent with repeated practice. The issue of improvement over time is
particularly important to CBT-I, as sleep restriction and stimulus control reduce total sleep time
during the acute treatment phase before total sleep time is gradually extended. In the Currie
et al. study, total sleep time had increased an additional duration of 24 minutes at three-month
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INSOMNIA IN CHRONIC PAIN 147

follow-up, concurrent with the nearly significant reduction in pain. This result raises the possibil-
ity that noticeable analgesic effects may require increases in consolidated sleep time. However,
participants in the sleep hygiene condition of the Edinger et al. (116) study reported significantly
reduced pain even by posttreatment, while those in the CBT-I condition did not. Posthoc anal-
yses of this data revealed that a subset of patients in the sleep hygiene group actually restricted
their sleep opportunity. These individuals reported reduced time in bed and total wake time,
and also showed significant reductions in pain. In summary, although much remains to be
learned, two studies suggest that improving sleep might reduce clinical pain, although these
effects may require time for sleep consolidation to occur. Aggressively treating insomnia asso-
ciated with chronic pain conditions clearly has the potential to improve sleep, pain, mood, and
quality of life.

CLINICAL RECOMMENDATIONS
In clinical practice, a majority of patients suffering from chronic pain will report numerous
overlapping symptoms including difficulty sleeping and psychological distress. Due to the
numerous reciprocal relationships among these symptoms, their casual interactions are difficult
to disentangle. Clinicians treating patients with chronic pain conditions will find themselves
facing chicken-or-egg dilemmas in diagnosis: Are the patients having trouble sleeping because
they are in pain, or do they are in pain because they are hardly sleeping? These relationships
are likely to be dynamic and may change within the patients, requiring frequent re-evaluation
for the treatment plan. It is strongly recommended that clinicians working with patients with
chronic pain conditions adopt a biopsychosocial perspective for assessment and conceptual-
ization. Treatment will frequently require flexibility on the part of the clinician, and providers
will often be asked to employ a balanced treatment approach that addresses multiple com-
plaints simultaneously. A multidisciplinary approach is highly desirable if not essential. Finally,
because enhancing motivation is such an important component of many treatment approaches,
an empathetic, patient-centered approach to maximize treatment outcomes is often most pro-
ductive, as many chronic pain patients have experienced multiple frustrations in their search
for pain relief.
When chronic pain patients seek care for their sleep disturbance, several areas must be
addressed as part of a thorough biopsychosocial assessment (118,119). We review the primary
categories below. In addition, medical records including current medications and previous sleep
study results should be requested and reviewed.
r Sleep disturbance. In addition to thoroughly assessing insomnia complaints, the diagnostic
priority should be to discern sleepiness from fatigue and whether referral for an overnight
sleep study is warranted. Sleep disorders other than insomnia (e.g., sleep disordered breath-
ing, restless legs) will require additional evaluation and treatment. Of note, actigraphy has
recently been validated as a measure of sleep in patients with TMD and may be a useful
adjunct in patients with chronic pain conditions (123).
r Mood states and psychiatric distress. Psychological distress is likely to impair patients’ ability
and motivation to care for themselves, undermining the self-efficacy that patients need to
engage in routine self-care. Numerous validated screening instruments exist for the most
common psychiatric disorders, including depression and anxiety, and clinicians should
also inquire about suicidal ideation/behavior, which is not only elevated in chronic pain
populations (120), but has also been linked to insomnia in chronic pain patients (121).
r Cognitive processes and thought content. Many patients with chronic pain report increased
somatic focus and engage in catastrophic thinking, which predicts poorer functional out-
comes. Clinicians should seek to understand these thought processes, which can be effec-
tively addressed using cognitive restructuring, and patient attitudes that can similarly be
explored and modified in treatment. For example, many pain patients perceive that exer-
cise will exacerbate their pain experience. In reality, gradually building toward consistent
moderate exercise is among the most reliable treatments associated with improvements in
physical function and improved mood among chronic pain patients. Patient beliefs about
the relations between their pain and sleep disturbance can also guide treatment planning.
Treatment acceptability and readiness to change are other important areas for assessment.
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148 WICKWIRE AND SMITH

r Social function. Understanding a patient’s social support network is necessary to encourage

their increased social interaction. Chronic pain patients are likely to experience depression
and negative affect, and as a result many patients disengage from once-pleasurable activities.
In addition to helping patients stay engaged, increasing social activity can be a good way
to facilitate physical (e.g., exercise class) as well as intellectual activity among patients (e.g.,
playing bridge, book club).
r Coping. Because the strategies patients use to cope with pain can also have a detrimental
impact on sleep (e.g., decreasing physical activity, staying in bed all day, etc.), it is important
for clinicians to understand what patients do when they are in pain. This discussion often
creates an excellent opportunity to discuss with the patient the relation between their sleep
disturbance and pain, and to collaboratively decide on a treatment approach and objectives.
In terms of conceptualization and treatment, the blend of shared symptoms between
sleep disturbance and chronic pain can make it difficult to determine which conditions to treat
first. Providers should weigh and discuss with the patient the above factors as well as the
patient’s readiness to change and engage in potentially demanding cognitive-behavioral treat-
ments. Clinical experience suggests that treatments that incorporate principles of motivational
interviewing (122) are likely to be among the most effective at treating patients with chronic
conditions. In addition, all treatments begin with comprehensive psychoeducation regarding
the etiology and overlap between distinct but co-occurring disorders and symptoms.

CONCLUSIONS AND FUTURE DIRECTIONS

Sleep disturbances, particularly insomnia, are ubiquitous in patients suffering from most types
of chronic pain. Although more research is needed, the available data indicate that the sleep–
pain relationship is best described as reciprocal. Thus, aggressive evaluation and treatment of
sleep disturbance in chronic pain is recommended. While some data suggest that interventions
designed to treat pain may have some impact on pain-related sleep disturbance, the findings are
mixed. Conversely, although additional data are needed, pharmacologic and behavioral inter-
ventions developed for primary insomnia improve sleep in chronic pain disorders. It is unclear
whether improvements in sleep will translate into improvements in pain. Future research aimed
at developing hybrid treatments that simultaneously maximize analgesia and improve sleep
is needed, as are studies with sufficiently long follow-up periods and sample sizes necessary
to determine how improving sleep in chronic pain might impact both pain and psychological
symptoms.

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15 Insomnia Related to Medical and

Neurologic Disorders
Brooke G. Judd and Glen P. Greenough
Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, U.S.A.

Medical and neurological disorders frequently have a significant impact on sleep, affecting
overall well-being and quality of life. Further, the lack of restful or sufficient sleep may exacerbate
the underlying disease itself. Numerous investigators have demonstrated increased prevalence
of insomnia in subjects with somatic diseases (1–7). Furthermore, a National Sleep Foundation
survey found that participants’ perception of their sleep quality was highly associated with their
number of medical conditions (6). Although prevalence rates are variable, there is consensus that
rates of chronic insomnia are higher in clinical populations than in the general population. While
numerous disease processes may be associated with insomnia and poor sleep, some medical and
neurological disorders have more consistent associations with sleep-related complaints. Chronic
pain syndromes are also highly associated with insomnia and sleep disturbance, although this
is not included in this chapter as it is discussed more fully in chapter 14.

MEDICAL DISORDERS

Chronic Obstructive Pulmonary Disease

Multiple studies have noted a high frequency of insomnia complaints in patients with chronic
obstructive pulmonary disease (COPD) (8–13). In addition to higher frequency of subjective
sleep complaints, patients with COPD have been found to have decreased total sleep time,
increased arousals, and decreased rapid eye movement (REM) sleep, compared with matched
controls without COPD (8,14). The etiology of the sleep architecture abnormalities and subjective
complaints is likely multifactorial: Typical daytime symptoms of COPD such as cough, excessive
mucus production, and breathlessness may also occur during sleep and cause sleep disruption.
The alveolar gas exchange abnormalities associated with COPD are accentuated in sleep, during
which time the normal ventilatory responses to hypercapnia and hypoxemia are blunted. During
REM sleep, the ventilatory responses are blunted even further. Sleep-related hypoxemia has been
postulated as a contributing factor to the poor sleep quality, as one study did correlate arterial
oxygen desaturation with sleep fragmentation, particularly during REM sleep (8). It is not
clear, however, that oxygen supplementation improves objective or subjective sleep abnorma-
lities (8,15).
Medications used to treat COPD may also contribute to insomnia complaints and poor
quality sleep. In particular, theophylline and the inhaled ␤-agonists have stimulant properties
that could affect sleep quality. Alternatively, the inhaled anticholinergic agent, ipratropium
bromide, has been shown to improve sleep quality in patients with COPD, perhaps related to
improved respiratory status (16).
Patients with COPD may also have coexistent sleep apnea (also known as the overlap
syndrome). Patients with overlap syndrome had more severe desaturations during sleep and
worse sleep quality than patients with only one of these disorders (17). This too may contribute
to sleep disruption in COPD, and treatment of sleep apnea may also help to improve sleep
quality in these patients.
Treating insomnia in patients with COPD is similar to treating insomnia in the general
population, although with a few additional considerations. First, as noted above, some of the
medications used to treat COPD may contribute to sleep disruption and may present obstacles
to treatment. It may be possible to alter the timing of the more stimulating medications so that
they are less likely to interfere with sleep. Identifying and treating any concurrent sleep apnea
is also an important consideration.
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154 JUDD AND GREENOUGH

Medical treatment of insomnia in patients with COPD is also an option, although again
with some special considerations. Benzodiazepines are commonly prescribed for insomnia,
although they may pose additional risk in patients with COPD. A large number of studies
(18) have reviewed the effects of the benzodiazepines on respiratory function in both normal
individuals as well as those with COPD, with variable results. Most, though not all, studies
demonstrated detrimental effects on a variety of respiratory parameters in patients with and
without lung disease. Studies have been performed with the non-benzodiazepine benzodi-
azepine receptor agonist (BzRA) zolpidem (19–21), suggesting that there is not a significant
impairment in respiratory parameters when administered to patients with COPD, although
studies are limited in number and results must be interpreted cautiously. It remains reasonable
to recommend that these medications may be used with caution in patients with underlying
respiratory abnormalities, although the non-benzodiazepine BzRAs may be a better choice than
standard benzodiazepines in this population. Recent studies have demonstrated the safety of
ramelteon in patients with mild to moderate as well as severe COPD (22,23), although there
is little information on the use of other designated sedative hypnotics in this specific group of
patients.

Diabetes Mellitus
Sleep disturbances are common among individuals with diabetes due to a number of factors.
There is a strong association between impaired glucose tolerance, insulin resistance, obesity, and
sleep disordered breathing (24,25), increasing the likelihood of insomnia complaints related to
nocturnal respiratory disturbances. Beyond this, however, are other factors that lead to increased
insomnia complaints in diabetics and higher rates of hypnotic use (6,26,27).
Rapid changes in glucose levels during sleep have been postulated to cause awakenings
in type 1 diabetics (28). Poor sleep in type 2 diabetics has been associated with poor glycemic
control, with an inverse correlation between hemoglobin A1C and sleep efficiency (29). Thus,
maintaining more constant levels of glucose control may help improve sleep quality in diabetic
individuals.
Leg discomfort may also contribute to disrupted sleep in diabetics. Individuals with dia-
betes have not been found to have an increased risk for developing restless legs syndrome
(26,30). Diabetic peripheral neuropathy with associated pain and paresthesias can lead to dis-
turbed sleep (27,31) and treatments aimed at alleviating these symptoms may be helpful in
improving sleep.

Chronic Kidney Disease

Chronic kidney disease (CKD) is associated with a high prevalence of disorders of sleep and
wakefulness with estimates that range anywhere from 40% to 80%, depending on the assess-
ment method and the type of population studied (32). There are numerous factors that can
contribute to sleep–wake disturbances in this patient population, including biochemical and
pathophysiological mechanisms, psychological problems, lifestyle, and treatment-related fac-
tors. Dialysis status and the role of uremia-related factors may play a role in poor sleep. A
number of studies have attempted to correlate insomnia symptoms with numerous abnormal
biochemical markers in CKD including altered melatonin levels, although there have been no
consistent findings (33–35). One study (36) compared sleep disturbance complaints (including
insomnia) with timing of dialysis (morning, afternoon or evening), finding no difference in sleep
complaints with a dialysis shift. There has been evidence that insomnia complaints improve
(though not resolve) after kidney transplantation (37,38), although it is not clear if this is due
to improvements in biochemical markers or the other numerous factors that may contribute to
insomnia in chronic illness.
Restless legs syndrome (RLS) is elevated in CKD and may contribute to insomnia com-
plaints. A study that evaluated the association of RLS, insomnia, and quality of life in postrenal
transplant patients (39) found that patients with RLS were three times more likely to have
insomnia than those without RLS (29% vs. 9%). Patients with CKD also appear to be at an
elevated risk for sleep apnea syndromes (40,41), and may be less likely to present with classic
signs or symptoms such as elevated body mass index or snoring (42,43). The clinician therefore
needs to be aware of the increased risk of comorbid sleep disorders, ask appropriate questions
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when obtaining a history, and consider polysomnography even if the patient does not report
typical symptoms of sleep disordered breathing, as an occult respiratory or motor disorder may
be contributing to insomnia symptoms.
Treatment of insomnia related to CKD is complex, given the multiple factors that may
contribute to the symptoms. Further, extra care and caution has to be exercised when treating
insomnia in this group of patients, given the potential altered metabolism of medications and
potential interactions with the numerous medications often used in this population. Surprisingly
little work has been done evaluating the use of sedative hypnotics in patients with CKD, despite
their high prevalence of insomnia complaints. One analysis identified a 15% higher mortality rate
in dialysis patients using benzodiazepines or zolpidem (44), although this did not further discern
between the two medication classes or identify specific risks associated with these medications.
The non-benzodiazepines, zaleplon, zolpidem, and zopiclone, are increasingly used to treat
insomnia in the general population. As their primary mode of metabolism is hepatic and renal
function does not contribute significantly to their excretion, these medications may be safer to
use in patients with kidney disease. Both zolpidem (45) and zaleplon (46) have been evaluated in
clinical studies involving patients with CKD and were found to be safe and effective; however,
these were both small studies and sedative hypnotics should be used with caution given the
numerous potential confounding factors in this population. Nonpharmacological interventions
may also be appropriate and a recent study by Chen et al. (47) did demonstrate improvements
in subjective sleep quality in a small group of peritoneal dialysis patients who underwent
cognitive-behavioral therapy for insomnia.

Human Immunodeficiency Virus Infection

Sleep disturbances have been recognized as a prominent complaint in patients with human
immunodeficiency virus (HIV) infection even in the earliest clinical reports of the disease (48).
Multiple factors have been postulated to contribute to disturbed sleep and insomnia, although
it remains unclear how much of the disturbance is due to the disease process itself and how
much is due to other associated factors such as medications, concurrent illnesses, and the
psychological effects of living with chronic illness. Of particular interest in patients with HIV
infection as well as cancer patients is the observation that sleep deprivation results in alterations
of immune system function (49–51), which may have implications in the recuperative process
from infections and other illnesses.
Numerous studies have evaluated polysomnographic data in patients with HIV infection.
These are described in detail in a review by Reid and Dwyer (52). While initial studies suggested
an increase in slow wave sleep in HIV infection, this has not been confirmed in later studies. In
fact, polysomnographic abnormalities have been inconsistent, with variable reports in regards
to percentage of sleep stages, including slow wave sleep and REM, as well as spindle density.
Thus, it does not appear that there is a definite change in sleep architecture that is associated
with HIV infection.
The role of the multiple endogenous substances involved in sleep regulation, including
neurotransmitters, hormones, and cytokines, has been evaluated in this population. For exam-
ple, it is well documented that many changes occur in the hypothalamic-pituitary-adrenal axis
in HIV infection (53–55). This subsequently leads to alterations in other substances such as
growth hormone and other hormones, as well as multiple cytokines. These alterations may
also contribute to sleep disturbance although there is no evidence at this point that targeting a
particular chemical derangement will improve sleep.
Medications are another potential contributing factor in HIV-associated insomnia and
antiretroviral therapy is often reported to include insomnia as an adverse effect. In general,
however, multiple studies have not confirmed a class effect of the retroviral drugs (52). One
notable exception is the nonnucleoside reverse transcriptase inhibitor efavirenz, a medication
associated with a high number of neuropsychiatric complications. Studies with this medication
have more clearly demonstrated an increased risk of sleep disturbance and insomnia com-
plaints (56,57).
The factor most strongly associated with HIV infection and insomnia is underlying psy-
chological morbidity. Given the strong relationship between psychiatric illnesses and insom-
nia in addition to the high prevalence of depression and anxiety in HIV infection, this
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156 JUDD AND GREENOUGH

association should not be surprising. Stage of illness has not necessarily correlated with insom-
nia symptoms. Asymptomatic seropositive patients with depression have been found to have
a high likelihood for insomnia in clinical studies (52,58). Conversely, cognitive impairment
due to Acquired Immune Deficiency Syndrome-related central nervous system involvement
associated with more advanced disease is also highly predictive of insomnia (48).
Treatment of insomnia in this population may thus provide further challenges, given the
multiple possible contributors to the sleep symptoms.

Malignancy
Sleep disturbance constitutes a significant source of suffering in patients with cancer, although
prevalence rates vary depending on the type of cancer and method of assessing symptoms. Much
of the work investigating insomnia and cancer has been with breast cancer patients. In this group,
using standardized criteria as defined by Savard and Morin (59) insomnia rates were found to
be double that of the general population. As with the general population, sleep disturbances
can significantly impact quality of life in cancer patients. Women with metastatic breast cancer
rated sleep in the highest quartile of quality of life items (59) and patients undergoing radiation
therapy ranked sleep disturbance as one of the 10 most troubling difficulties of their illness
(60). However, despite the distress associated with insomnia, many patients do not report the
problem to their health care providers, perhaps assuming it is an inevitable aspect of their
illness or that nothing can be done for the symptoms. In fact, one study found that almost 85%
of cancer patients with sleep disturbance did not discuss the problem with their provider (61).
The same study also noted that approximately half of the patients experienced their symptoms
on a nightly basis.
Although the nature of the sleep disturbance may be as heterogeneous as the underlying
illness, frequent awakenings appear to be the most commonly reported disturbance, described
in multiple studies (62–66). In Davidson’s survey (66), 52% of patients attributed their insomnia
to “intrusive thoughts” and 45% attributed their sleep disturbance to physical discomfort.
Although there is limited objective evaluation of sleep in cancer patients, the studies available
would generally concur with subjective reports demonstrating decreased sleep efficiency and
increased awakenings on polysomnography (67) as well as actigraphy (68,69).
As with many of the other illnesses discussed in this chapter, the etiology of insom-
nia related to cancer is likely multifactorial. Physical symptoms, psychological distress, and
medications may all play a role in the sleep disturbance and may be targets for treatment.
Cancer-related fatigue is also a highly prevalent and persistent problem in patients with cancer,
as well as cancer survivors. Roscoe et al. (70) provides a detailed description of the interrela-
tionship between fatigue and sleep disturbance in cancer patients. The relationship between the
two may be bidirectional. The fatigue may be due at least in part to the poor sleep, although
other factors such as cytokines associated with tumors have also been reported as possible con-
tributors to cancer-related fatigue. However, the fatigue may cause patients to extend their sleep
opportunity, spending excessive time in bed with subsequent reductions in sleep efficiency and
worsening feelings of poor sleep. Thus, measures aimed at improving daytime fatigue may also
help with the nocturnal disturbance.
Treatment of insomnia in cancer has typically focused on pharmacologic agents, although
there have been a number of studies demonstrating the effectiveness of cognitive-behavioral
therapy for insomnia (CBT-I). This is particularly important, given that insomnia symptoms can
persist for several years after the end of treatment. More recent studies (71,72) in particular have
modified CBT-I to meet the special needs of cancer patients, more specifically using strategies
to help cope with fatigue (such as encouraging physical activity) and employing education and
cognitive restructuring to address the fatigue.

NEUROLOGICAL DISORDERS

Neurodegenerative Diseases
As the pathophysiology of neurodegenerative diseases becomes better understood there has
been a shift in classification. Traditional classification systems were based on clinical symptom
complexes. More recently many neurodegenerative diseases can be classified as tauopathies or
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INSOMNIA RELATED TO MEDICAL AND NEUROLOGIC DISORDERS 157

synucleinopathies based on which protein is dysfunctional. Interestingly this breakdown seems

to correlate with sleep symptoms as well. Patients with tauopathies and synucleinopathies may
be afflicted with different sleep disorders or complaints. In general, the characteristic sleep
disturbance in the tauopathies appears to be insomnia and circadian dysfunction as opposed
to REM sleep behavior disorder (RBD) and hypersomnias in the synucleinopathies (73). That
being said, insomnia is still a significant problem in Parkinson’s disease (PD), the most common
synucleinopathy.

Tauopathies
The prototypic tauopathy is Alzheimer’s disease (AD). AD is the most common form of demen-
tia. Short-term memory loss, the hallmark of the disease, tends to be progressive. Other areas
of impairment include executive dysfunction, language, abstraction, and mood. The classic
pathologic findings in this disorder include extracellular plaques of the peptide ␤-amyloid and
intracellular neurofibrillary tangles composed of the protein tau. The most prominent biochem-
ical change is the loss of choline acetyltransferase activity. This enzyme is responsible for the
production of acetylcholine in cholinergic neurons.
Patients with AD exhibit abnormal sleep architecture on polysomnography. These changes
generally reflect lower quality sleep with a reduction in sleep efficiency and total sleep time and
an elevation in stage one sleep along with an increased number of arousals and awakenings (73).
The formed elements of sleep, K-complexes, and sleep spindles may also be reduced. Late in
the disease, a decrease in REM sleep percentage and a prolongation of the latency to REM sleep
develop (73). Cholinesterase inhibitors used to treat dementia have been shown to increase REM
sleep in nondemented patients and may have the same effect in AD patients. Reports of vivid
dreaming in AD patients on cholinesterase inhibitor support this notion (74). The cholinesterase
inhibitor, donepezil, may lead to insomnia whereas this does not appear to be the case with
rivastagmine and galantamine (74).
Degeneration of neurons in the suprachiasmatic nucleus and decreased melatonin secre-
tion may lead to circadian rhythm disruption in AD (75). Circadian rhythm abnormalities
characteristic of this disorder include daytime sleepiness and nocturnal wakefulness (75).
Patients with dementia may develop the irregular sleep–wake type circadian sleep disorder
(76). This disorder is characterized by a lack of clearly defined sleep and wake periods with
at least three sleep episodes in a 24-hour period. The severity of dementia has been correlated
with the severity of the circadian rhythm disturbance (77). Other factors such as medications
that lead to confusion, lack of environmental cues (e.g., limited light exposure), other medical
conditions (e.g., pain), psychiatric conditions (e.g., depression), and inadequate sleep hygiene
(e.g., time spent in bed watching television) may exacerbate or mimic the circadian rhythm
disruption. Use of sleep logs and actigraphy can help provide diagnostic clues. This disrup-
tion of the circadian pattern of sleep and wake is particularly important, as the majority of
caregivers point to nocturnal problems as a factor in their decision to institutionalize elderly
relatives (78).
Sleep disordered breathing may lead to an insomnia complaint. An association between
AD and obstructive sleep apnea (OSA) has been demonstrated. The APOE4 allele commonly
associated with AD has also been associated with OSA (79).
When considering therapies for insomnia in AD patients one must first consider the etiol-
ogy. Addressing the underlying problem driving the insomnia may then lead to improvement
in the symptom of insomnia. For example, a delirium secondary to a medical condition or
medication could be the driving force behind the insomnia in an AD patient (74). A primary
sleep disorder such as RLS or OSA should be addressed directly if possible before addressing
the symptom of insomnia. Assuming these conditions have been met, symptom management
of insomnia can be undertaken. Information on the use of sedative hypnotics in AD patients
is sparse. There are limited data to suggest that the short acting benzodiazepine, triazolam,
and the BzRA, zolpidem, may help with insomnia in AD patients (74). Concerns, however,
about adverse events such as unsteadiness, falls, and worsening of cognitive impairment have
limited their usage. A meta-analysis of hypnotic use in people aged 60 or over concluded
there were small improvements in the sleep quality but an increased risk of adverse events
(80). Antipsychotic medications have been used off-label as hypnotics, especially if nocturnal
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158 JUDD AND GREENOUGH

agitation is also present. The safety of these medications for this purpose, however, remains
largely unexplored with some evidence to suggest increased cerebrovascular adverse events
(81,82), cognitive decline (83), and mortality (84) in patients with dementia. Because of the
reduction in melatonin secretion that is greater than expected for age in AD, melatonin supple-
mentation has been attempted as a therapy (85). Studies evaluating melatonin replacement’s
effect on sleep in elderly and AD patients have been mixed (85). In 2003, a multicenter, ran-
domized, double-blind, placebo-controlled clinical trial suggested no benefit of melatonin up
to 10 mg on actigraphically derived measure of sleep in an AD population (86). This may be
explained by the observation that the number of melatonin-1 receptor containing neurons in the
suprachiasmatic nucleus in patients with AD is reduced (85). The data on the use of ramelteon, a
melatonin-1 and 2 receptor agonist, is limited (85). Phototherapy may be helpful in the manage-
ment of the circadian disruption in patients with AD but the specifics on the timing, duration,
and intensity have yet to be determined (75). Some success has been achieved through a combi-
nation of environmental and behavioral changes in nursing home residents. Such changes have
included increased daytime bright light exposure, avoidance of daytime time in bed, structured
bedtime routines, and increased physical activity as well as sleep hygiene education for the
caregiver (87,88).
Progressive supranuclear palsy (PSP), another tauopathy, is a disorder characterized by
parkinsonism, dystonia, gait disturbance, and a supranuclear gaze palsy (impaired voluntary
vertical eye movements initially). Insomnia is common in this disorder and tends to be more
severe than the insomnia in AD or PD (89,90). Insomnia in PSP disorder correlates most closely
with motor impairment and to a lesser degree with cognitive or eye movement impairment
(90,91). Polysomnographic findings demonstrate a reduced sleep efficiency of 58% in one study
(90). The etiology of the insomnia complaint may be a direct result of brain stem pathology,
immobility, depression, dysphagia, and/or nocturia (90,92). Sleep-related breathing disorders
and REM sleep behavior disorder are probably not common in PSP but data are limited (89,90).
Besides the reduced sleep efficiency, other polysomnographic findings in PSP include reduced or
absent eye movements, poorly formed or absent sleep spindles and K-complexes, and increased
alpha activity in stage 1 and 2 sleep (90). Corticobasal degeneration, another tauopathy, has been
associated with periodic limb movements and REM sleep behavior disorder in case reports only
(89). Little is known about sleep in this rare disorder.

Synucleinopathies
Parkinson’s disease is characterized by a resting tremor, bradykinesia, masked fascies, loss of
postural reflexes, and an increased incidence of depression. The hallmark pathologic finding is
loss of dopaminergic neurons in the substantia nigra in the brainstem. Sleep complaints and
problems are multiple in this disorder and are more common with more severe disease (93).
The frequency of reported sleep problems in PD varies among studies from 25% to 98% (93).
RBD is seen in one-third of newly diagnosed patients with PD (76). Hypersomnia, whether it
is from the disease process itself, the dopaminergic agents used to treat PD or coexistent sleep
disorders known to cause excessive sleepiness, is common in PD (94–96). The frequency of the
RLS and OSA appears to be elevated in PD as well and may lead to insomnia and/or daytime
sleepiness (94).
While the sleep complaints are multiple in patients with PD the two most problematic
appear to be sleep maintenance insomnia and nocturia (93). Almost two-thirds of PD patients
complain of sleep onset difficulties but almost 90% may complain about sleep maintenance
issues (97). Akathisia, dystonia, freezing, tremor, nocturia, muscle cramps, and off period-
related urinary incontinence and pain can all play a role in insomnia in PD (94). Some of the
medications used to treat PD, such as selegiline or the dopamine agonists, can be alerting
and contribute to insomnia. The depression associated with PD may also be associated with
insomnia complaints (96).
Polysomnographic findings in patients with PD include decreased sleep efficiency,
increased wake after sleep onset, sleep fragmentation, decreased SWS, decreased REM sleep,
decreased sleep spindles, and increased EMG activity. Findings consistent with RBD such as
REM sleep without atonia may also be present (97). Periodic limb movements consistent with
RLS as well as obstructive respiratory events consistent with OSA may also play a role in sleep
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INSOMNIA RELATED TO MEDICAL AND NEUROLOGIC DISORDERS 159

disruption in PD and have been demonstrated at an increased frequency on polysomnography

in this population (94,98).
Treatment of specific sleep disorders, such as OSA, RLS with or without periodic limb
movements or RBD, can be undertaken directly and may lead to improved symptom control.
Treating the parkinsonian symptoms at night can also be helpful in improving nocturnal mobil-
ity among other symptoms. That being said one must be aware that dopaminergic agents,
particularly at higher doses, may be arousing (75). Improving sleep quality theoretically may
also lead to improvement in mobility and motor function especially in the morning. This is based
on the observation that some patients with PD experience improved mobility upon awakening
from a night of sleep (99).
Dementia with Lewy Body Disease is a degenerative disorder characterized by parkin-
sonism, dementia, and hallucinations. The sleep problem most closely associated with this
disorder is RBD (76). Multisystem atrophy (MSA) is a disorder characterized by parkinsonism,
autonomic dysfunction, and cerebellar signs. MSA is also strongly associated with RBD in that
90% of patients with MSA have RBD (76). MSA patients may also have fragmented sleep on the
basis of sleep disordered breathing that may manifest in various forms with nocturnal stridor
being the most characteristic (89).

Fatal Familial Insomnia

Fatal familial insomnia (FFI) is a fatal progressive prion disease characterized by sleep onset and
maintenance insomnia with lapses from quiet wakefulness into a sleep-like state with dream
enactment (76). It is inherited in an autosomal dominant fashion although sporadic cases have
been reported. Thalamic hypometabolism is characteristic on PET scans (100). Pathologic find-
ings include reactive gliosis of the anterior and dorsomedial thalamic nuclei and neuronal loss
and reactive astrogliosis in the inferior olives (76). Patients homozygous for the defect have a
rapid course with a mean 9 to 10 month survival whereas patients heterozygous for the defect
have a mean disease duration of 30 months (100). Age of onset is typically in the fifth and sixth
decades of life. Early symptoms include apathy and drowsiness. Other characteristic symptoms
include dream enactment, dysautonomia (pyrexia, salivation, tachycardia, tachypnea, hyper-
hydrosis, and dyspnea), and motor symptoms (dysarthria, dysphagia, tremor, myoclonus, and
dystonia) (76). Polysomnographic features include reductions in SWS and sleep spindles. Stage
one sleep and REM sleep predominate (76). There is no directly effective medical therapy.
Treatment is limited to supportive measures.

Cerebrovascular Disease
Strokes have been associated with a number of disorders of sleep and wake. Insomnia com-
plaints, specifically, are common in the poststroke period. Approximately 2/3 of ischemic stroke
patients had insomnia early on and that insomnia persisted for at least 18 months in almost
half of the patients in one study (101). Damage to specific regions of the brain may lead to an
insomnia complaint. Inversion of the sleep–wake cycle with nocturnal agitation and daytime
hypersomnolence may occur in association with subcortical, thalamic, thalamomesencephalic,
and large tegmental pontine strokes (102). Two patients with locked-in syndromes had pro-
longed periods of polysomnographically confirmed insomnia lasting over one month. One had
a pontomesencephalic stroke and the other had a bilateral basal pontine stroke with extension to
the pontine tegmentum (102). Insomnia in the poststroke period may be related to depression.
Depression is a well-documented consequence of stroke (103). Just as in nonstroke patients,
sleep disordered breathing may lead to an insomnia complaint (102). Inadequate sleep hygiene
(i.e., extended periods in bed) secondary to a lack of mobility or independence may lead to
insomnia. Other causes of insomnia in the poststroke period include other medical disorders,
other sleep disorders, medications, inactivity, and environmental disturbances (104). Directly
treating any underlying disorder such as depression or pain that could be leading to insomnia
may also lead to improvement in the insomnia. No large-scale trials of therapy for insomnia
in stroke populations have been undertaken. If pharmacotherapy is used one must take into
account the respiratory suppressant effects as sleep-related breathing disorders are common in
poststroke populations (102).
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160 JUDD AND GREENOUGH

Multiple Sclerosis
Multiple sclerosis (MS) is a disorder characterized by central nervous system demyelination.
Difficulty initiating or maintaining sleep is a complaint in approximately 40% of MS patients
(105). This insomnia in MS may have multiple possible causes such as pain, nocturia, medica-
tions, depression, or classic sleep disorders such as RLS and periodic limb movement disorder
(106). Depression may be present in up to 50% of patients with MS and a symptom of that
depression may be insomnia (107). Pain is also very common in MS and may take different
forms such as neuropathic pain or pain related to muscle spasm. Nocturia or urinary inconti-
nence related to a spastic bladder is also very common in MS and may also disrupt sleep (106).
Immunomodulating medications such as interferon and steroids that are commonly used in MS
have been associated with insomnia (106). Addressing the underlying etiology of the insomnia
is the principal means of treatment in MS.

Traumatic Brain Injury

Traumatic brain injury (TBI) has been associated with a wide spectrum of sleep disorders and
complaints both soon after the trauma and chronically. Patients hospitalized after TBI are likely
to have insomnia complaints (108). While hypersomnias may be a more common complaint in
chronic TBI populations, insomnia still is a frequent complaint (109). Ouellet et al. (110) found
that 50% of TBI patients, 7.8 years on average after their trauma, had an insomnia complaint
while almost 30% met diagnostic criteria for an insomnia syndrome. There are multiple potential
causes for insomnia in chronic TBI including posttraumatic mood disorder, sleep disordered
breathing, periodic limb movements, narcolepsy and parasomnias (109) as well as pain from
other injuries. Evidence for a posttraumatic circadian rhythm disorder has been mixed (111).
Recently, Ayalon et al. (112) have provided evidence of either a delayed sleep phase syndrome
or irregular sleep–wake pattern in 36% of mild TBI patients with an insomnia complaint.
From a therapeutic standpoint, cognitive-behavioral therapy has been shown efficacious in
treating insomnia in TBI. Concerns have been raised about side effects in TBI populations
with benzodiazepines. Non-benzodiazepine receptor agonists have fewer complications in non-
TBI populations so it has been theorized that this would also be the case in TBI populations
(113). There is little data on the subject of pharmacotherapy for insomnia in patients with TBI.
Lorazepam and zopiclone had similar effects on insomnia and daytime cognition in a population
with stroke or brain injury (114).

CONCLUSION
A wide range of medical and neurologic diseases have been associated with insomnia com-
plaints. The etiology of the insomnia in these conditions varies with the condition and is also
often multifactorial. The pathologic process of the disease itself may directly lead to the insomnia
complaint as may be the case in AD. Other symptoms or problems attributable to the condition
such as pain, impaired respiration or immobility may also lead to insomnia. In chronic diseases
in particular, the insomnia may be associated with a coexistent mood disorder, rather than
directly with the neurologic or medical disorder. Some of the medications used to treat medi-
cal and neurological disorders can also lead to insomnia, such as ␤-agonist inhalers in COPD.
Primary sleep disorders, such as OSA or the RLS, among others, may occur more frequently in
patients with certain conditions. These primary sleep disorders may manifest as an insomnia
complaint. Therapy for insomnia in medical or neurologic disease is often highly dependent on
the etiology of the insomnia.

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16 Substance-Induced Insomnia
Deirdre A. Conroy
Department of Psychiatry, University of Michigan, Ann Arbor, Michigan, U.S.A.

J. Todd Arnedt
Department of Psychiatry and Neurology, University of Michigan, Ann Arbor, Michigan, U.S.A.

Kirk J. Brower
Department of Psychiatry, University of Michigan, Ann Arbor, Michigan, U.S.A.

EPIDEMIOLOGY OF SUBSTANCE-INDUCED INSOMNIA

Substance-induced insomnia (SII) is characterized by disruption of sleep and adverse daytime
consequences during periods of use or withdrawal from illicit drugs, prescription medications,
or licit substances (i.e. alcohol, caffeine, toxins or food items). SII does not result exclusively
from substance abuse, but can also develop over time through repeated exposure to a prescribed
dosage of a medication. SII is found in approximately 0.2% of the general population, but can
comprise up to 3.5% of the sleep disorders clinic population (1). Not unexpectedly, rates are
considerably higher in patients presenting for substance abuse treatment. Up to 91% of alcohol-
dependent patients, for example, have symptoms of insomnia (2).
Nearly all substances can disrupt sleep and a number of toxins and food allergies can lead
to insomnia. A complete description of all potential sleep-disruptive substances is outside the
scope of this chapter. Here, we focus on the illicit and licit substances most commonly associated
with substance-induced insomnia.
Individuals with insomnia may use substances to either self-medicate (e.g. with alcohol
or hypnotics) or to treat the side effects of a poor night’s sleep. According to the National Sleep
Foundation’s (NSF) 2008 Sleep in America poll, 8% percent of the respondents reported current
use of alcohol to help them fall asleep (3). It has also been found that a much higher percentage
of patients diagnosed with insomnia use alcohol as a sleep aid, with 15% to 28% reporting the
use of alcohol to fall asleep (4). In addition, 58% of respondents to the NSF survey reported that
they were at least somewhat likely to use caffeinated beverages such as coffee, soda, or tea to
cope with sleepiness during the day (3).
The evolution of SII can be difficult to establish. This chapter focuses on how substance use
directly affects sleep, but the reverse should also be considered. One can have insomnia before
developing substance abuse or dependence. In a longitudinal epidemiological study, Breslau
et al. (5) found that young adults that had insomnia at baseline were twice as likely to develop
an alcohol use disorder, seven times more likely to develop an illicit drug use disorder, and
twice as likely to develop nicotine dependence 3.5 years later (5). These findings raise important
questions about the cyclical nature of insomnia and SII.
SII is a relatively understudied area. As will be evident in the evaluation and treatment
sections of this chapter, the majority of research has focused on alcohol-induced insomnia to
the exclusion of other substances. Much more research is needed on these other substances that
can lead to chronic sleep difficulties.

Alcohol

Intoxication
Acute administration of alcohol to normal healthy volunteers decreases sleep onset latency
(SOL) (6–8), prolongs rapid eye movement onset latency (ROL) (9) and increases slow wave sleep
(SWS) in the first half of the night (6,7,10). In the second half of the night, stage 1 (N1) sleep, wake-
fulness, and the percentage of REM sleep increase (6), while SWS decreases (6,7,10) (Table 1).
 IHBK059-16
Table 1 Effect of Substances of Abuse on Sleep and Wakefulness

166

IHBK059-Sateia
Sleep Sleep Sleep
continuity architecture disorders Sleepinessa

Substance of Abuse SOL TST SE ROL REM SWS S1 SDB PLMS MSLT MWT
ALCOHOL
Intoxicationb ⇓6–8 ⇓8,13c ⇑8 ⇑9 ⇓7,9,14,15 ⇑6–8,15,16 ⇓8 ⇑15,17d ⇑18 ⇑11
⇓19

March 28, 2010

Withdrawal ⇑20 ⇓16 ⇑21 ⇓22,23 ⇑16 ⇓10,22 ⇑24 ⇑25 ⇓14f
⇓16 ⇑21e ⇔16
NICOTINE
Intoxication ⇑26–28 ⇓26 ⇓26 ⇑29 ⇓26 ⇔26 ⇔26 ⇔26 ⇓30 —
Withdrawal ⇑31 31–33 27,31g ⇓31 ⇑27,31 ⇑32h ⇓ ⇓31 ⇑33j ⇓33
⇓27g ⇑ ⇓ 31⇓ ⇔

8:35
⇓ 33⇔ 32,33i

CAFFEINE

Char Count=
Intoxication ⇑34,35 ⇓34,36 ⇓34,35 ⇓34k ⇔34k ⇓35,36l ⇑36 ⇑34,37
⇔ ⇔
Withdrawal 34 ⇔34 ⇔34 ⇔34 ⇔34 34 ⇔34 ⇔34

MARIJUANA
Intoxication ⇑38 ⇑38m ⇑38 ⇑38 ⇓40 ⇑40,41 ⇑38m ⇓38
⇓ ⇓ ⇓39 ⇓
Withdrawal ⇑42 ⇑43 ⇓42,43 ⇓41

OPIOIDS
Intoxication ⇑44 ⇔45,46 ⇔45,46 ⇑46 ⇓46–49 ⇓45–47 ⇑48 ⇑46,47,50
⇓44 ⇓47 49 ⇔51
⇓46 ⇓45
Withdrawal ⇑52 ⇑49,52,53 ⇔52
⇓

MDMA “ECSTASY”

CONROY ET AL.
Intoxication ⇔54 ⇓55 ⇓54 ⇓54 ⇑56 ⇑57
⇑
Withdrawal ⇑57 ⇓57 ⇓57j ⇓57 ⇑57j ⇔57 ⇑57
 IHBK059-16
SUBSTANCE-INDUCED INSOMNIA

IHBK059-Sateia
COCAINE
Intoxication ⇑58 ⇓58 ⇓58 ⇑58 ⇓58 ⇑59 ⇔58
⇔60
Withdrawal ⇓58,59g ⇓ ⇓62,63 ⇓62,65 ⇑62,64 ⇓59,61 ⇑61 ⇓65
⇔61 59,62– ⇔ 61 ⇔63 ⇔63n
⇑59e 64e ⇑59g
⇑

March 28, 2010

58,59g
AMPHETAMINES
Intoxication ⇑66–68
Withdrawal ⇑64 ⇓64 ⇓64g ⇓64 ⇓64g ⇓64 ⇑64

GHB
Intoxication ⇑69 ⇓69 ⇑69 ⇓69 ⇓69 ⇑69 ⇓69 ⇑70 ⇑69

8:35
⇑
Withdrawal

Char Count=
a
Decrease in sleep onset on the MSLT indicates more sleepiness.
b
Alcohol’s effects on sleep stages change from the 1st half to the 2nd half of the night.
c
Increased number of wake periods in sleep.
d
Only in men.
e
Late withdrawal (>3 weeks).
f
Increased SOL during first 75 min after consumption.
g
Early withdrawal (<3 weeks).
h
Wetter et al (2000) shows SWS decreases at day 3 but then increases from day 3–10.
i
Initially increased, but decreased over time.
j
Not significant.
k
Decreased shortly after caffeine intake but increase with late caffeine (see Table 1, pg. 530 of Bonnet and Arand 34).
l
During the first 1/3rd of the sleep period.
m
Depending on dose of THC and CBD variables; include dose and time into withdrawal.
n
Pace –Schott et al (63) is a binge abstinence protocol.
⇑= Increase, ⇓= Decrease, ⇔= No change, = No data. Abbreviations: MSLT, Multiple Sleep Latency Test; MWT, Maintenance of Wakefulness Test. PLMS, Periodic Limb Movements in Sleep;
REM%, Rapid Eye Movement percentage; ROL, Rapid Eye Movement Sleep Latency; S1, Stage 1 sleep; SDB, Sleep Disordered Breathing; SE, Sleep efficiency; SOL, Sleep onset latency; SWS,
Slow Wave Sleep; TST, Total sleep time.

167
IHBK059-16 IHBK059-Sateia March 28, 2010 8:35 Char Count=

168 CONROY ET AL.

Figure 1 The reciprocal relationship between

insomnia and alcoholism. Insomnia may lead to
increased alcohol consumption by self-medication.
Increased alcohol consumption can have neuro-
toxic effects on the same neurotransmitters that
are involved in sleep regulation. Both insomnia and
high alcohol intake may lead to alcoholism. Insom-
nia can persist despite treatment and can lead to
relapse. Treatment of insomnia may facilitate absti-
nence. Studies are ongoing.

Tolerance to alcohol’s acute effects can develop quickly, within one week in healthy volunteers
(11), resulting in increased alcohol intake to derive the same sleep-promoting effects. Insomnia
may persist even after alcohol use has stopped and treatment has been initiated. In fact, an esti-
mated 36% to 91% of patients in early recovery from alcohol dependence complain of insomnia
(2,12) Figure 1 provides a schematic describing the bidirectional relationship of alcohol use and
sleep disturbance.

Withdrawal
Polysomnographic (PSG) irregularities during alcohol withdrawal have been well characterized.
There is typically an increase in SOL (14,22), a decrease in SWS percentage (%) (16,22) and an
increase in REM sleep (16). Returning to drinking was found to temporarily increase SWS or
decrease REM sleep; however, upon repeat withdrawal, these changes reverted to baseline or
below baseline levels (71).
Sleep architecture (SWS and REM) and sleep continuity (sleep latency, total sleep time,
sleep efficiency) during withdrawal have been studied extensively as predictors of relapse
(22). Reduced SWS percentage was implicated in some early studies, (10,72) but these findings
were only partially replicated in a larger sample (22). REM variables have been consistently
linked to relapse in alcoholic patients (23). Increased REM pressure and reduced ROL, have
been shown to differentiate relapsers from abstainers after follow-up as long as six months
(22,73). A recent study using spectral EEG analysis found evidence for increased hyperarousal
in the REM sleep of alcoholic patients who relapsed within three months compared to abstinent
alcoholics and controls (74). In addition to the consistent REM findings, most clinical studies
have also identified sleep continuity measures, (increased SOL and reduced TST) as being
strongly predictive of relapse (21,22). Sleep disturbances during withdrawal can persist for up
to two years (16).
Comparisons between subjective and objective data may highlight important perceptual
distinctions in SII. Alcohol dependent patients with insomnia who overestimated SOL and
underestimated wake time after sleep onset (WASO) were more likely to relapse (75).
Several mechanisms have been proposed to explain the sleep disruptive properties of alco-
hol. Sleep-generating systems in the brain, including the GABAergic system, adapt to chronic
alcohol administration by downregulation, whereas arousal-generating systems involving glu-
tamate and other neurotransmitters are upregulated. During alcohol withdrawal, dysregulated
neurotransmitter systems such as these are postulated to disrupt sleep (71). One study found
that alcoholics’ homeostatic response (measured via SWS and delta power) to partial sleep
deprivation was impaired compared to controls (76). Circadian rhythm mechanisms are also
disturbed by alcohol (77–79). Insomnia may also be related to alcohol-related sleep disordered
IHBK059-16 IHBK059-Sateia March 28, 2010 8:35 Char Count=

SUBSTANCE-INDUCED INSOMNIA 169

breathing (SDB) (18) or periodic limb movements in sleep (PLMS) (25,80), both of which are
elevated in alcoholic patients.

Nicotine
Nicotine increases catecholamines, vasopressin, growth hormone, ACTH, and endorphins in
the brain, which can disturb sleep. The average cigarette contains 8 to 9 mg of nicotine, but
the amount delivered varies because smokers can adjust dose by puffing volume, depth, rate
or intensity. Many studies, therefore, have employed the nicotine patch to better regulate dose-
dependent effects.

Intoxication
Smokers (particularly females (81)) report more difficulty sleeping compared to nonsmokers
independent of health, demographics, behavioral, and psychological variables (81). Laboratory
studies show that nonsmokers with a nicotine patch took longer to fall asleep, had shorter TST,
lower sleep efficiency (SE), and lower REM sleep % compared to participants with a placebo
patch (26).
Depression history is associated with differences in REM sleep during nicotine exposure
and withdrawal. A randomized controlled trial found that depressed nonsmokers wearing
nicotine patches showed increased REM sleep and short-term mood improvements compared
to nondepressed nonsmokers (29). The increased REM sleep persisted during withdrawal in
depressed patients, while REM sleep in nondepressed patients decreased (32).

Withdrawal
Sleep and mood disturbances have been documented for up to one year following smoking ces-
sation. Heavy smokers (mean smoking history of 24 years) were studied across a smoking week
and a withdrawal week. During the withdrawal week, smokers had more arousals, awakenings,
and stage changes compared to the smoking week (33). In the first long-term study across one
year of abstinence, seven former smokers underwent PSG at months 1, 2, 4, 6, 9, and 12. There
was a reduction of REM latency, N1 sleep, and SWS coupled with an increase in REM sleep
and N2 sleep (31). Interestingly, depression measures were increased and correlated with REM,
ROL from sleep onset and N2, and stage shifts (31). The authors posit that the increases in REM
sleep and levels of depression may be due in part to an increased sensitivity of serotonergic
neurons during withdrawal.

Caffeine
Caffeine, a phosphodiesterase inhibitor with a half-life ranging from three to seven hours, pro-
motes wakefulness by blocking adenosine receptors (82) and is the most widely used substance
for counteracting the daytime effects of sleep loss.

Intoxication
Caffeine attenuates the progressive increase in sleepiness across the day and reduces the quality
of recovery sleep (83), but effects vary depending on an individual’s history of caffeine con-
sumption (84). Administration of caffeine at bedtime has been shown to prolong SOL, shorten
TST, and reduce total SWS and S4 sleep in a dose-dependent manner (34,35,85) During sleep
deprivation, low to moderate caffeine doses (100–200 mg) have been found to increase stage 1
sleep and reduce the slow component of EEG power (0.75–2.0 Hz) relative to placebo; during
recovery sleep, fast EEG components (11.25–20.0 Hz) were enhanced (35). Higher caffeine doses
during sleep deprivation (300 mg) reduce TST, increase S1 sleep, and reduce SWS in the first
third of the night (36).
Low-dose caffeine improves daytime performance more than placebo (86). Concomitant
subjective sleepiness data has been more variable. For example, a recent double-blind parallel-
group design using a forced desynchrony protocol found that low doses of repeated caffeine
(0.3 mg per hour) across an extended 28.57 hour “day” reduced objective sleepiness compared
to placebo, but increased subjective sleepiness (86).
Chronic caffeine use can lead to a physiological state of hyperarousal, a common charac-
teristic in patients with insomnia. One study used caffeine to model insomnia by giving repeated
IHBK059-16 IHBK059-Sateia March 28, 2010 8:35 Char Count=

170 CONROY ET AL.

doses of 400 mg of caffeine to healthy volunteers across one week. The study reported prolonged
SOL, reduced S4, and shortened TST (34). Metabolic rate measured via VO2 also increased, con-
sistent with the hyperarousal theory of insomnia. A later study by the same group examined
electrocardiograms (ECGs) during sleep in 15 healthy volunteers who took 400 mg of caffeine a
half-hour before bedtime. Heart rate variability, defined as the integration of the low frequency
(LF)/high frequency (HF) ratio band was significantly higher during REM sleep in the caffeine
group than in the placebo group. The investigators interpreted this finding as suggestive of a
predominance of sympathetic nervous system activity and an increased risk for adverse cardiac
events (87).

Withdrawal
Withdrawal from chronic caffeine use is associated with distinct physiological and subjective
withdrawal symptoms, due in large part to the hypersensitivity of adenosine receptors during
abstinence (82). Within 12 to 16 hours into caffeine withdrawal, sleepiness, lethargy, headaches,
decreased alertness, depressed mood, irritability, and mental fogginess may occur (83,84). With-
drawal symptoms usually dissipate within 3 to 5 days, but can last as long as one week (88).
In summary, the ability of caffeine to attenuate decrements in performance across prolonged
wakefulness makes it a highly desired substance. However, caffeine can contribute to impair-
ments in sleep if consumed in close proximity to bedtime and withdrawal can be associated
with impairment in cognitive functioning.

Marijuana
The psychoactive ingredient in marijuana, delta-9-tetrahydrocannabinol (THC), binds to type
1 cannabinoid (CB1 ) G protein-coupled receptors located in the nociceptive areas of the brain,
spinal cord, and peripheral nervous system (89).

Intoxication
Overall, THC effects on sleep have been found to be variable, owing to variability in methodol-
ogy and samples studied (see also Table 1 –substance table).
Marijuana can induce sleep (38) and decrease REM sleep (40). Administration of THC at
doses of 10, 20, and 30 mg prior to sleep onset decreased SOL after subjects reported achieving a
“high” (90). When large doses (15 mg) of cannabidiol (a major component in marijuana thought
to have minimal psychoactive effects) were added to THC and administered to participants
before sleep, the amount of wakefulness in the night increased (38). Conflicting evidence exists
with respect to the acute effect of THC on SWS [for review see Schierenbeck et al. 2008 (91)].
Some studies have reported an increase in stage 4 (S4) (40) sleep, while others have reported a
decrease in overall SWS (38).

Withdrawal
Sleep disturbance is one of the most common symptoms associated with marijuana with-
drawal. Other common symptoms may include strange dreams, depression, chills, and irri-
tability. Among 1735 frequent users of marijuana (>21 occasions in a single year), 235 (13.5%)
reported difficulty sleeping during withdrawal (92). Laboratory studies show prolonged SOL
(42) and decreased SWS% (42,43) during withdrawal. REM sleep rebound has been documented,
but only in withdrawal from higher doses of THC (70–210 mg) (43). One study tracking common
cannabis withdrawal symptoms, including sleep problems, in 36 cannabis-dependent subjects
reported that these symptoms were not predictive of relapse after an approximately 26-month
period (93).

Opioids

Intoxication
Opioids, (e.g. methadone, morphine, heroin) are perceived as sedating, but can disrupt sleep
quality. In healthy adults, morphine sulfate and methadone have been found to reduce SWS
(45,47) and REM sleep (48,49) When compared to naltrexone in a group of recovering addicts,
methadone patients had increased SOL (44) and WASO and reduced TST (44), SWS (47), and
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SUBSTANCE-INDUCED INSOMNIA 171

REM sleep (44). Heroin-dependent patients detoxified with methadone reported even greater
sleep problems than those maintained on methadone during the first months of heroin absti-
nence (94). Sleep disturbance, increased dreams, and nightmares were also associated with
opioids in palliative care patients (95).

Withdrawal
Abstinent morphine-dependent patients showed a dose-related effect of morphine on sleep
with decreases in TST, SWS, and REM sleep (96). Methadone-maintained patients had more
awakenings (44) lower sleep efficiency (SE), and lower SWS (47) than controls. One early study
of six male heroin-dependent prisoners compared sleep for three months prior to methadone
induction, during titration and stabilization of 100 mg daily of methadone, and finally up to
22 weeks after withdrawal. During methadone administration, awake time during the night
decreased and delta bursts increased significantly (53). Across 22 weeks of abstinence, wake-up
time decreased further while REM sleep and delta sleep increased significantly (53).
Animal data suggest that opioids may disrupt sleep by decreasing GABA neurotrans-
mission in the pontine reticular nucleus (97). Symptoms of insomnia may also result from
opioid-induced central sleep apnea (46,47,98), occurring in about 30% of chronic users (99).

“Ecstacy” (±) 3, 4- Methylenedioxymethamphetamine (MDMA)

MDMA (3, 4 –methylenedioxymethamphetamine), or “ecstasy” is a stimulant with hallucino-
genic properties and commonly called a “club drug”. It stimulates the release and inhibits the
reuptake of serotonin (5HT), among other effects on various neurotransmitter systems, which
can generate feelings of elation and pleasure (56,100). This abrupt surge in neurotransmitters
can acutely affect sleep as well as regulation of mood, aggression, sexual activity, and sensi-
tivity to pain. The repeated surge in serotonin levels can have neurotoxic effects with possible
implications for sleep, circadian rhythms, anxiety, impulsivity, cognitive deficits, and mood
disorders (57).

Intoxication
Persistent use of ecstasy shortens TST and impairs NREM sleep, particularly S2 sleep (100,101).
An early study examined the effects of MDMA on the sleep of 23 MDMA abstinent users
compared to age- and sex-matched controls with no history of use (55). The MDMA users
had a 19-minute reduction of TST and a slightly shorter ROL than controls (60 minutes versus
75 minutes). In a more recent study, alpha-methyl-para-tyrosine (AMPT), which decreases brain
catecholamines, was administered to abstinent MDMA users to determine whether AMPT
would differentially affect sleep and cognitive performance in abstinent users. Results showed
that exposure to AMPT at 4 PM and 10 PM before a 12 AM bedtime resulted in a trend towards
decreased TST, ROL and significantly lower S2 sleep (102).
MDMA exposure has lasting effects on circadian rhythms in animal experiments. Rats
exposed to MDMA had alterations in sleep and circadian pattern of activity (wheel running) for
up to five days after dosage. In addition, SWS was still altered after one month (103). In vitro
administration of MDMA to rat brain slices impaired the resetting ability of cells in the SCN to
a serotoinin receptor agonist 20 weeks after initial exposure (60).

Cocaine
Cocaine is a stimulant that blocks reuptake of DA, NE, and 5HT and can cause increased energy
and euphoria.

Intoxication
Acute administration of cocaine in a laboratory setting causes sleep impairment, including
increased SOL by several hours, decreased SE, and decreased REM sleep (58). In chronic cocaine
users, administration of cocaine actually increased SWS during cocaine administration (59).
Spectral analyses of the sleep EEG showed that during binge periods, slower EEG bandwidths,
e.g., delta and theta, were higher than the faster bands, e.g., sigma and beta (59).
IHBK059-16 IHBK059-Sateia March 28, 2010 8:35 Char Count=

172 CONROY ET AL.

Withdrawal
Sleep disturbance is one of the most common symptoms of cocaine withdrawal, reported in
71% of a sample of recovering cocaine addicts (20). Sleep quality appears to change from early
abstinence (≤3 weeks) to late abstinence (>3 weeks). Early abstinence in cocaine withdrawal
is associated with decreased SOL (59), increased TST (58,59,62), shortened ROL (61,62), and
increased REM% (62). Late abstinence is associated with prolonged SOL (59,62), decreased TST
(63) and decreased SE (63).
Finally, there appears to be a discrepancy between objective sleep and subjective percep-
tion of sleep during early withdrawal from cocaine. Subjective ratings, including overall sleep
quality, feeling well rested, depth of sleep, and mental alertness all increased over protracted
abstinence in one study, but objectively measured sleep did not (59). Other studies have found
that despite deterioration of sleep quality across cocaine abstinence, estimates of sleep quality
improved (104) or remained unchanged (63). The authors posit that this finding may reflect a
dysregulation of homeostatic sleep drive in chronic cocaine users. Similar discrepancies between
objective and subjective measures have been documented in early abstinence from alcohol (74).
While cocaine is a known stimulant of monoamine neurotransmitter systems via reup-
take blockade, animal studies suggest that circadian mechanisms may also be involved in its
rewarding effects, if not sleep impairment per se (105,106).

Amphetamines
The exact mechanisms of how amphetamines, a major class of stimulants, increase EEG arousal
are uncertain, but are thought to involve adrenergic or dopaminergic transmission (107).
Increased alertness is also highly dependent on the dose and the type of amphetamine.

Intoxication
D-amphetamine is three times more potent than L-amphetamine and 12 times more potent than
L-methamphetamine in increasing wakefulness and reducing SWS (108). Three studies have
examined the effect of amphetamines on daytime sleepiness using the Multiple Sleep Latency
Test (MSLT). All three showed prolonged SOL on nap opportunities across the day (66–68). Sleep
deprivation appears to increase the drug-seeking behaviors associated with amphetamines.
Another similarly acting stimulant, methylphenidate, was chosen more often (88% of days)
after a four-hour time in bed time than it was after an 8-hour time in bed (29%) (68).

Withdrawal
Early amphetamine withdrawal is associated with initial long bouts of sleep and reports of
poor quality sleep. Sleep records obtained by nurses’ observations in abstinent amphetamine-
dependent subjects showed an initial increase in TST followed by reduced TST across 20 nights
following cessation of use (109). Sleep questionnaires given to 21 patients in the first three weeks
of methamphetamine withdrawal showed that TST (day and night) peaked on the fifth day of
abstinence (110). One study evaluated objective sleep parameters across acute (days 3–10) and
subacute withdrawal (days 11–14) in stimulant abusers. From acute to subacute withdrawal,
stimulant abusers had less TST and REM sleep. However, subjective reports of sleep improved
across abstinence. Another study found that self-reported SOL, number of awakenings in the
night, quality of sleep, clear-headedness on awakening, satisfaction with sleep, and depth of
sleep all improved significantly across the three weeks of continued abstinence (110).

EVALUATION

Preliminary Assessment
SII may have varying clinical presentations depending on the patient’s age, gender, weight,
genetics, psychological traits and states, and health status. For example, stimulant-induced
insomnia may be diagnosed more in younger patients (typically adolescents) whereas SII due
to alcohol or hypnotics may be found more in older patients. Substances may also have indi-
rect effects by exacerbating preexisting medical conditions (e.g. caffeine may worsen gastroe-
sophageal reflux disease, which can disrupt sleep).
IHBK059-16 IHBK059-Sateia March 28, 2010 8:35 Char Count=

SUBSTANCE-INDUCED INSOMNIA 173

When assessing substance-using patients for insomnia, several principles should be borne
in mind. First, substances may not be the only cause of the insomnia. Other medical or psychiatric
disorders, sleep-impairing medications, inadequate sleep hygiene, and dysfunctional beliefs
about sleep may play a role. This issue is particularly relevant to patients with substance use
disorders, who have high rates of co-occurring psychiatric and medical disorders. It should
be assumed that substances are part of the problem, even if not necessarily the only cause of
insomnia. Second, PSG should be considered if there is high suspicion of other sleep disorders,
particularly sleep apnea and periodic limb movement (PLM) disorder. Third, assessment of
sleep complaints is aided by asking patients to keep a sleep log for two weeks during early
recovery after acute substance withdrawal symptoms have subsided. Sleep logs have several
advantages, including an assessment of sleep patterns over time, documenting improvement
with abstinence, and engaging the patient in the treatment process.

Differential Diagnoses
In addition to other medical or psychiatric disorders, differential diagnoses of SII include inad-
equate sleep hygiene and psychophysiological insomnia. To distinguish SII from these two
disorders, specific inquiry about substance tolerance, dosage escalation, rebound insomnia in
the absence of the substance, fear of not sleeping (or staying awake) without the substance,
and sporadic use of hypnotics, will help distinguish SII from other sleep disorders. Use of the
Diagnostic and Statistical Manual or the ICSD can be used to diagnose SII, but certain diagnostic
criteria may vary (see Table 2).
Inadequate sleep hygiene is characterized by daily activities that are not compatible with
maintenance of quality sleep. This diagnosis is appropriate when the timing of substance use is
incompatible with the preferred sleep time. For example, a patient’s use of alcohol or nicotine in
the hours before bedtime is clearly associated with the sleep disturbance. However, SII should
be considered if the sleep problem began or got worse after initiation of the substance use or the
sleep difficulties improve markedly during periods of abstinence, or the individual feels unable
to sleep without the substance. Some of the distinguishing characteristics of psychophysiological
insomnia are the perpetuating factors that serve to maintain the insomnia, i.e., heightened
arousal in bed. Substance use may have contributed to poor sleep in the acute and early stages
of the insomnia, but when the maladaptive thoughts and behaviors persist even after the patient
stops using the substance, the diagnosis is more consistent with psychophysiological insomnia

Table 2 Diagnostic Criteria for Substance-Induced Sleep Disorders

A. SUBSTANCE-INDUCED SLEEP DISORDERS DSM-IVa ICSD-2b

Must identify sleep disturbance as:
Insomnia due to drug or substance


Hypersomnia due to drug or substance


Parasomnia due to drug or substance


Mixed due to drug or substance

Circadian rhythm sleep disorder due to drug or substance

Central sleep apnea due to drug or substance

B. SUBSTANCE-INDUCED INSOMNIA
Meets the criteria for insomnia

Insomnia developed within one month of substance exposure, use or abuse, or acute


withdrawal
There is current ongoing dependence on or abuse of a substance known to disrupt


sleep either during use or withdrawal or there is exposure to a toxin known to disrupt
sleep.
Insomnia is temporally associated with the substance use, exposure or withdrawal


Insomnia is not better accounted for by a sleep disorder that is not substance induced,


medical, neurological, or mental disorder
a
DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, DSM-IV-TR: Diagnostic
and Statistical Manual of Mental Disorders, 4th ed, Text Revision, American Psychiatric Association, Washington DC, 2000.
b
ICSD-2, International Classification of Sleep Disorders, 2nd edition (1).
IHBK059-16 IHBK059-Sateia March 28, 2010 8:35 Char Count=

174 CONROY ET AL.

than SII. Therefore, a timeline with respect to the use of the substance(s) and the onset of the
insomnia is important to obtain.
Finally, insomnia may predate the substance use/dependence; however, there must be
convincing evidence based on the sleep history that the sleep disturbance and substance
use/abuse are intricately related.

TREATMENT

Pharmacological Treatments
Special considerations are required when considering hypnotic therapy with patients recovering
from substance dependence. First, physicians who treat patients with a history of substance
abuse or dependence are reticent to prescribe medications for sleep. This is especially true for
the Schedule IV hypnotics (including benzodiazepine receptor agonists), which are first-line
agents for insomnia in nonabusing patients with insomnia, but their reluctance to prescribe
may also generalize to other available hypnotics. A recent postal survey of addiction medicine
physicians found that less than one-third of alcoholic patients with sleep disturbances during
the first three months of recovery were offered a sleep medication (111). Second, although the
most widely used hypnotic agents have low addiction potential for most patients with insomnia
(112), the benzodiazepine receptor agonist medications have moderate to high abuse liability
in patients with a history of substance abuse and dependence (113).
We outline the most commonly available hypnotic medications and their efficacy for
substance-induced insomnia below. These studies have been conducted almost exclusively
with alcohol-dependent patients. Pharmacological treatment options for patients with other
types of substance use disorders are needed.

Benzodiazepines and Benzodiazepine Receptor Agonists (BzRAs)

Benzodiazepines and other benzodiazepine receptor agonists (e.g., zolpidem) are safe, effica-
cious, sedative-hypnotics and often the medications of choice for treating transient insomnia
in non-SII patients (114). They also may have beneficial effects on sleep during subacute alco-
hol withdrawal (115), but confer increased risk for sedative-hypnotic abuse in patients with
a history of substance abuse or dependence (116–118). Accordingly, most addiction treatment
specialists recommend against the use of sedative-hypnotics in alcoholic patients (except for
benzodiazepines during acute alcohol withdrawal), because of their abuse potential, withdrawal
effects, rebound insomnia, and potential for overdose when mixed with alcohol (119–122).

Anticonvulsants
Anticonvulsant agents do not lower seizure threshold, which makes them appealing for treating
insomnia in the substance-abusing population. At least two anticonvulsants—carbamazepine
and gabapentin-–have been studied specifically for their effects on sleep in alcoholics. Carba-
mazepine was superior to lorazepam for treating sleep disturbance associated with acute alcohol
withdrawal (123). Gabapentin has the advantages of sleep promotion, non-liver metabolism,
noninterference with metabolism or excretion of other medications, and it does not require blood
monitoring for therapeutic concentrations, hepatotoxicity, and hematological toxicity. Further-
more, it has a favorable side effects profile, low abuse potential, and is not protein-bound.
It exerts its CNS effects by binding to alpha-2-delta receptors, resulting in voltage-sensitive
calcium channel inhibition (124).
Gabapentin may improve the sleep of recovering alcoholic patients (125–127). Karam-
Hage and Brower (125) found that self-reported sleep quality improved after four to six weeks
of treatment with gabapentin (mean dose 953 mg/day) in 15 of 17 consecutively evaluated
alcoholic patients with persistent insomnia. A recent placebo-controlled study, however, found
that, while six weeks of gabapentin 1500 mg nightly delayed the onset to heavy drinking,
no subjective or objective sleep differences were found between the gabapentin and placebo
groups (128). Although gabapentin and pregabalin, a newer anticonvulsant agent, increase SWS
in healthy control subjects, similar evidence is lacking in patients with alcohol dependence.
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SUBSTANCE-INDUCED INSOMNIA 175

Antidepressants
Trazodone is the most frequently prescribed medication for sleep by addiction medicine physi-
cians (111). It is effective acutely in the treatment of depressed patients with insomnia (129–132)
and has been used safely in several samples of alcoholics (126,133). In a placebo-controlled study
of trazodone in 16 abstinent alcoholic patients, trazodone significantly reduced wake time after
sleep onset (WASO) and improved SE compared to placebo, but only improvements in WASO
were sustained at night 28. Depression scores were also more improved in the trazodone group
(134). A recently completed study also found superior sleep outcomes of trazodone vs. placebo
more than 12 weeks of treatment in alcohol-dependent patients, but heavy drinking was higher
in the trazodone-treated group compared to the placebo group (135).

Antipsychotics
Quetiapine is an atypical antipsychotic with sedative effects (136) that has been used as a
treatment for insomnia in alcohol-dependent patients. In one of the only studies in substance
users, Monnelly et al (137) found that alcohol-dependent veterans who reported difficulty
sleeping and were treated with 25 to 200 mg of quetiapine had an increased number of days
of abstinence and fewer hospitalizations, but no subjective or objective sleep measure was
included. Moreover, any benefit of quetiapine for use in this population must be weighed
against its potential for akathisia (138) and increased PLMs when used to promote sleep (136).

Other Hypnotics
Melatonin is a sleep-promoting agent that may be particularly useful to treat circadian rhythm
disorders (139). Because the manufacturing and quality of melatonin is not currently regu-
lated in the U.S., the melatonin receptor agonist, ramelteon, may be a better candidate for
study. Over-the-counter remedies such as antihistamines, valerian root extract (from the herbal
plant, Valeriana officinalis), and melatonin have not been widely evaluated in substance-abusing
patients, although they are commonly used.

Nonpharmacological Treatments for Substance-Induced Insomnia

Few studies have evaluated the efficacy of nonpharmacological sleep treatments for substance-
induced insomnia. An initial study compared progressive muscle relaxation to no treatment
in 22 alcoholic inpatients with insomnia (140). At the end of treatment, the relaxation group
reported better sleep quality on a nonvalidated 10-point rating scale.
The benefits of cognitive behavioral therapy for insomnia (CBT-I) for reducing relapse in
alcoholic patients have been studied. Currie and colleagues (141) randomized sixty alcoholic
outpatients to individual CBT therapy (5 sessions more than 7 weeks), self-help manual with
telephone support calls, or wait-list control. Patients in both active treatment groups reported
greater improvements than controls on diary measures of sleep quality and sleep continu-
ity at posttreatment and follow-up, but no differences in relapse rates were found (141). An
uncontrolled trial of an individual eight-session cognitive behavioral therapy for insomnia
found posttreatment improvements in both sleep quality and daytime functioning and no one
relapsed to drinking (142).
The use of CBT-based interventions has also been explored in adolescent users of alco-
hol, marijuana, hallucinogens, cocaine, opioids, and stimulants. A six-session multicompo-
nent behavioral sleep intervention (stimulus control, bright light therapy, sleep hygiene, cog-
nitive therapy, mindfulness-based stress reduction) improved sleep, reduced aggression, and
decreased drug use after one year in adolescents who had received treatment for substance
abuse (143,144). These findings indicate that CBT-I may be efficacious for improving sleep and
daytime functioning in adolescents and adults with SII. More controlled trials of nonpharmaco-
logical sleep interventions are needed and the relationship between improved sleep and future
substance use remains to be more clearly elucidated.

CONCLUSIONS
There are a number of licit and illicit substances that can lead to SII. Although substance-
induced sleep problems improve with continued abstinence, persistent sleep problems may
occur for at least two reasons. First, long-lasting alterations to the sleep centers of the brain may
IHBK059-16 IHBK059-Sateia March 28, 2010 8:35 Char Count=

176 CONROY ET AL.

occur due to chronic drug exposure. Second, chronic sleep disturbance is typically associated
with multiple perpetuating causes and substance use may be just one of many reasons for sleep
complaints. Assessment should consider the many causes of sleep disturbance. Pharmacological
and nonpharmacological treatments to target insomnia associated with substance use disorders
do exist, but many are either inappropriate or have been inadequately tested in this patient
population. More well-controlled studies are needed to characterize the phenomenology of
sleep during recovery, to determine the efficacy of monotherapy and combined approaches to
sleep treatment in patients with addiction, and to evaluate the impact of such treatments on
relapse and recovery.

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17 Insomnia in Circadian Rhythm Sleep

Disorders: Shift Work/Jet Lag/DSP/ASP/
Free-Running—Blindness
Robert L. Sack
Oregon Health and Science University, Portland, Oregon, U.S.A.

INTRODUCTION
Circadian rhythm sleep disorders (CRSDs) arise from either an alteration in the function of the
circadian timing system or a misalignment between the circadian rhythm of sleep propensity
and the requirements of the environmental or socially structured sleep schedule. There are six
recognized CRSDs: (i) delayed sleep phase disorder (DSPD), (ii) advanced sleep phase disorder
(ASPD), (iii) irregular sleep–wake disorder (ISWD), (iv) free-running disorder (FRD), also called
nonentrained or non–24-hour sleep–wake disorder, (v) jet lag disorder (JLD), and (vi) shift work
disorder (SWD). Insomnia (difficulty falling asleep or staying asleep) is a major symptom of all
the CRSDs, as well as sleepiness and dysphoria while awake. To meet the full diagnostic criteria
for a sleep disorder, the symptoms must be persistent and involve a significant impairment in
social, occupational, or other areas of function.

DIAGNOSTIC CONSIDERATIONS
Although the formal diagnostic criteria developed by the American Academy of Sleep Medicine
(AASM) (1) are intended to distinguish clinical disorders from normal variability, the dividing
line is not always sharp. Symptoms are likely to occur in otherwise unaffected people if the
circadian system is significantly challenged, as in long distance jet travel or shift work. There is
ambiguity about the relevance of the formal diagnostic criteria to a clinical population since the
criteria have rarely been used in research studies (2,3). In any case, the principles of treatment
are similar whether the symptoms are mild (subclinical) or more severe. The clinician needs
to judge whether a patient meets criteria for a formal diagnosis and decide how aggressive
treatment should be.

EPIDEMIOLOGY AND CONSEQUENCES

Data on the epidemiology of CRSDs are quite limited, but considering that millions of people
work unconventional schedules and travel across time zones, the prevalence of SWD and JLD
must be high. In addition, many young people have a tendency for DSPD, and older people,
for ASPD, whether or not they meet full criteria.
Although CRSDs are common, patients with these disorders do not seek medical attention
as frequently as patients with other sleep disorders. There could be a number of reasons. Patients
with SWD and JLD often accept their symptoms as an inevitable burden of their circumstance,
which will ultimately remit when their situation changes. Patients with DSPD or ASPD may
consider their sleep pattern as so ingrained in their makeup that it would be very difficult to
change. Perhaps a more important reason that these patients do not present to the sleep clinic
is a lack of public awareness regarding the safe and effective treatments that are available. It
is unfortunate that severely affected patients may suffer recurrent educational or occupational
failure, or endure lifelong impairment, when simple treatments are available. The theme of this
chapter is that the therapy of CRSDs can be based on well-developed principles derived from
circadian science.

CIRCADIAN MISALIGNMENT: THE UNDERLYING PATHOPHYSIOLOGY OF CIRCADIAN

RHYTHM SLEEP DISORDERS
Although the CRSDs have different etiologies, they share a common pathophysiology; namely,
a misalignment between the endogenous circadian rhythms and the desired (or required) time
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182 SACK

for sleep. This misalignment in timing can arise from either exogenous or endogenous factors
(or both). For example, in JLD and SWD, rhythms are misaligned because of an externally
imposed shift in the timing of sleep. In the other CRSDs, misalignment is hypothesized to
involve abnormalities of the circadian system itself; for example, in DSPD the intrinsic circadian
period may be unusually long, and in ASPD, unusually short; or there may be subsensitivity to
the usual circadian time cues. In ISWD associated with dementia, the amplitude of the circadian
signal may be diminished. However, the distinction between exogenous and endogenous factors
is not always sharp; for example, an “owl” (a person with a tendency for DSPS) may have no
problem with insomnia until the requirements of a new job involve going to bed earlier and
getting up earlier.
The opponent process model of sleep regulation, as formulated by Edgar et al. (4), readily
explains the consequences of circadian misalignment. The model postulates that, during the
day, homeostatic sleep drive accumulates in proportion to the duration of prior wakefulness
(Fig. 1). However, the accumulation of sleep drive is not manifest as sleepiness during the day
because it is counteracted (opposed) by a circadian alerting process. As bedtime approaches,
this circadian alerting process wanes, the accumulated sleep drive is unopposed, and normally
a person becomes sleepy and ready for bed. Whether the circadian system actively promotes
sleep at night, or simply does not oppose it, is debated by circadian scientists. During sleep,
the accumulated sleep drive is discharged, and in the morning the cycle begins again. These
homeostatic and circadian processes are normally synchronized with each other and with the
24-hour solar and social day–night cycle.

Day Night Day Night

SL SL
EE Work EE
PD PD
RIV time RIV
E E

Work Sleep Work Sleep

time time time time
S S
NES NES
A LERT A LERT
L OF L OF
VE VE
LE LE
AL
AL

GN
GN

SI
SI

G
G

IN IN
RT E RT
E
AL AL

9 AM 3 PM 9 PM 3 AM 9 AM 3 PM 9 PM 3 AM 9 AM

Figure 1 The opponent process model of sleep regulation on a conventional sleep schedule. The opponent
process model proposed by Edgar et al. (4) is illustrated in a double-plotted hypothetical diagram. According to
the model, the level of alertness (sleepiness) is a vector sum derived from the opposing forces of sleep drive,
which accumulates in proportion to the duration of prior wakefulness (shown as a downward force), and an alerting
signal, generated by the circadian pacemaker in the SCN (shown as an upward force). During the day, sleep drive
accumulates, but is counteracted by the opposing alerting signal. In the early evening, the alerting signal peaks
and, even though sleep drive is strong, initiating sleep is difficult. Prior to bedtime, the alerting signal recedes,
sleepiness emerges, sleep commences, and sleep drive dissipates. At the time of final awakening, sleep drive is
at a minimum. After sleep inertia has receded, the daytime level of alertness is restored to a normal zone.
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INSOMNIA IN CIRCADIAN RHYTHM SLEEP DISORDERS 183

Day Night Day Night

Sleep Work Sleep Work

time time time time

SL
EE SLE
PD EP
RIV DR
E IVE

NESS S
ERT TNES
AL LER
F A
O F
L

L
L
VE

NA
NA

L
VE
LE

IG
IG

LE
S S
NG NG
TI TI
ER ER
AL AL

9 AM 3 PM 9 PM 3 AM 9 AM 3 PM 9 PM 3 AM 9 AM

Figure 2 The opponent process model of sleep regulation in a night shift worker. This diagram illustrates the role
of the opponent process on alertness in a night shift worker that has made no circadian adaptation. Daytime sleep
is undermined and shortened by the circadian alerting process: consequently, overall sleep drive is increased due
to insufficient, nonrestorative sleep. Furthermore, the timing of work is coincident with a recession of the alerting
signal; consequently, the accumulated sleep drive is unopposed by the SCN alerting. With the combination of a
high burden of sleep drive and a lack of circadian alerting, sleep may be very difficult to resist toward the end of
the night or on the drive home.

When homeostatic and circadian processes are out of alignment, the inappropriately timed
circadian alerting process interferes with sleep. Depending on the relationship of the circadian
alerting signal to the timing of attempted sleep, there can be difficulties getting to sleep, staying
asleep, as well as waking up too early. Moreover, during the intervening periods of wake, the
circadian alerting signal is weak or absent, and does not sufficiently counteract the accumulated
sleep drive (or may actively promote sleep) resulting in unwelcome sleepiness and dysphoria.
A multitude of physiological processes are driven by the circadian pacemaker, including
cyclic variations in core body temperature, melatonin, and cortisol secretion, as well as glucose
and lipid metabolism. These abnormalities in circadian synchrony may increase the risk for
cardiovascular and metabolic disorders.
In addition to these endogenous mechanisms, sleep at nonstandard times can be inter-
rupted by ambient noise and light, as well as pressing social obligations. Furthermore, there
is an unavoidable degree of sleep deprivation associated with sudden transitions in the sleep
schedule as occur in SWD and JLD. The various consequences of circadian misalignment as
exemplified in SWD are illustrated in Figure 2 and discussed in the accompanying legend.

DIAGNOSTIC ASSESSMENT
The treatment of CRSDs needs to be preceded by a careful history to rule out other primary
sleep disorders and to characterize behavior patterns (e.g., ill-timed recreational or social activ-
ities) or other factors (e.g., chronic illness, medication side effects, caffeine intake) that may be
exacerbating the problem. Difficulty falling asleep or waking up too early may suggest a CRSD,
but other causes of sleep onset or maintenance insomnia need to be considered, especially
psychophysiological insomnia as well as anxiety and depressive disorders.
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A sleep diary is always a useful assessment instrument when a CRSD is suspected. Data
should be collected for at least two weeks and include the times of “light’s off” and “light’s
on,” estimated sleep latency, final awakening, and the recording of medications, alcohol use,
or other factors that influence sleep. Actigraphy, if available, is extremely useful to corroborate
diary data and to provide objective assessment of sleep timing and quality. The Morningness–
Eveningness scale (5) can corroborate the preference for a delayed or advanced sleep schedule,
but cannot replace a clinical interview and evaluation.
An indicator of internal circadian timing (“hands on the clock”) would provide the most
objective way to evaluate the alignment between sleep and circadian phase. However, the two
methods most frequently used in the research setting—the timing of melatonin secretion and
the core body temperature rhythm under constant conditions—have not been applied clinically.
Measuring onset of melatonin secretion in the evening either in serial plasma or saliva samples
(dim light melatonin onset or DLMO) (6) would be feasible in a sleep laboratory, but the
melatonin assay is not readily available as yet. The constant routine protocol (7) required for
valid measurements of core temperature rhythms is very labor intensive and not suitable for
the clinical setting.

GENERAL PRINCIPLES OF TREATMENT

It is important to set realistic goals for treatment that the patient is clearly motivated to accom-
plish. For example, some patients with DSPD have a strong preference for their atypical schedule
and may have difficulty understanding why others do not accommodate it. If the problem is
impacting the family, they should be involved in the treatment as well.
There are three general treatment strategies that have been used to treat CRSDs: (1)
prescribed sleep scheduling, designed to either improve the alignment between sleep and the
underlying rhythms, or to minimize the consequences of misalignment. (2) Pharmacotherapy
(using hypnotic or alerting medication) aimed at counteracting the symptoms of insomnia
and/or sleepiness that are generated by circadian misalignment. (3) Circadian phase shifting
(“resetting the body clock”); that is, realigning circadian rhythms with the desired sleep schedule
by administering appropriately timed bright light exposure or melatonin. Combining two or
more of these intervention strategies may be warranted. Circadian phase shifting is a treatment
that is quite specific for CRSDs and therefore its basis, derived from circadian science, will be
explained in more detail.

Phase Shifting with Appropriately Timed Light Exposure

In all mammals, the fundamental intrinsic circadian rhythm is generated by the activity of
clock genes that regulate a translational–transcription feedback cycle within individual neu-
rons of the suprachiasmatic nucleus (SCN) in the hypothalamus. The output of the SCN (the
circadian signal) represents the summation of rhythms generated by a population of SCN neu-
rons, and is usually slightly longer or shorter than 24 hours. Therefore normal synchronization
(entrainment) of the circadian pacemaker to the 24-hour day requires recurrent timing adjust-
ments (phase resetting) that, in turn, depend on exposure to relevant environmental time cues
(zeitgebers)—most importantly, the solar light/dark cycle. Signals from specialized photore-
ceptors in the retina carry information about the level of illumination directly to the SCN via a
retinal-hypothalamic tract that is separate from the visual pathway. If a person is isolated from
environmental times cues (or is totally blind, with no light perception), circadian rhythms will
typically “free-run” on a non–24-hour cycle reflecting the intrinsic period of the nonentrained
circadian pacemaker.
In nature, the solar light–dark cycle is the most potent environmental time cue for syn-
chronizing the circadian pacemaker, for humans, as well as most other species. If circadian
rhythms drift out of alignment, exposure to the solar light–dark cycle will normally provide a
corrective advance or delay, thereby maintaining a stable relationship of the circadian system
to the 24-hour day. Specifically, light exposure in the morning will reset the body clock to an
earlier time (cause a phase advance), while light exposure in the evening will reset the body
clock to a later time (cause a phase delay) (Fig. 2). These timing (phase)-dependent effects of
light exposure can be plotted as a light phase response curve (PRC). The magnitude of the phase
shifts is greatest around the inflection point of the PRC (around 5 AM in normally entrained
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INSOMNIA IN CIRCADIAN RHYTHM SLEEP DISORDERS 185

individuals) and is least (but not absent) with light exposure in mid-day [reviewed by Duffy
and Wright (8)].
Appropriately timed bright light exposure (3000–10,000 lux) has been shown to produce
robust phase shifts, but even modest intensities (100–550 lux) can produce substantial phase
shifts if subjects have been living in a constant dim light environment. Also, intermittent bright
light exposure can produce almost as much phase shifting as continuous exposure (9). Recently,
specialized nonrod, noncone photoreceptors, associated with the ganglion cells of the retina, that
are maximally sensitive to blue-green light, have been shown to be important for the circadian
phase resetting (10). Clinical trials are underway to determine if exposure to blue-green light
has advantages. Reports of phase shifting with light exposure to the skin (11) have not been
replicated (12,13).
People usually sleep at night, in a dark room, with eyelids closed; thus, the timing of sleep
structures (or “gates”) an individual’s exposure to the light/dark cycle and in this way sleep
can indirectly (but importantly) influence circadian timing. Because sleep and reduced light
exposure occur together, it has been difficult to determine if sleep itself, apart from its gating
effect on light exposure, influences rhythms. Other possible nonphotic time cues, for example,
timed physical activity, may have some influence on circadian rhythms, but are not as potent as
light exposure.
Timed light exposure as a treatment modality usually involves a bright artificial light
source (3000 to 10,000 lux). There have been some safety concerns with light of this intensity,
especially the possibility of phototoxic effects on the lens and/or the retina, but it can be argued
that the intensities are no greater than sunlight on a clear, sunny day. Nevertheless, bright light
sources should be used with caution in patients with ocular pathology (e.g., lenticular cataracts
or retinal degeneration). In early experiments with light therapy “full spectrum” sources that
included UV radiation were employed for light therapy, but UV wavelengths are unnecessary
and should be avoided (14). A diffuser panel placed over the light sources effectively filters UV
radiation.
In summary, the phase-resetting effects of light are dependent on intensity, timing, wave-
length, pattern (intermittent or continuous), duration, exposure history, and the level of contrast
with background light exposure. In clinical practice, it is customary to employ light exposure
from a commercially available light source that generates diffuse illumination with an intensity
of 3000 to 10,000 lux for 30 to 60 minutes, at a time of day that will promote the desired phase-
shifting effect. If light exposure is to be carried out on a regular basis, compliance will be poor
if it is not integrated into some other daily activity (e.g., eating, watching television, reading,
etc.). The light can be indirect; that is, patients do not need to fix their gaze at a light source.
Used in this way, timed bright light exposure appears to be safe within the parameters that have
been tested. Appropriately timed exposure to ordinary daylight, when feasible, can be just as
effective, and is less expensive than an artificial light source.
If the goal is to synchronize the circadian system to the desired (or required) sleep schedule,
appropriately timed light exposure should, in principle, be a helpful intervention for almost
all of the CRSDs, although it may be impractical or even impossible to implement in some
circumstances. Likewise, eliminating (or reducing) the unwanted effects of light on the circadian
system (by staying indoors or wearing goggles) has been shown to inhibit unwanted phase
shifting (15).

Phase Shifting with Timed Melatonin Administration

Melatonin is a hormone produced by the pineal gland at night, in the dark. Its effects on the
circadian system are opposite to light exposure, so it is useful to think of it as a “darkness
signal.” Hence, melatonin administration in the morning shifts rhythms later, while melatonin
administration in the evening shifts rhythms earlier (16) (Fig. 3). In other words, the mela-
tonin PRC is about 180 degrees out of phase with the light PRC. Melatonin administration to
both animals and humans has been shown to be sufficiently potent to entrain free-running
rhythms.
The use of melatonin and melatonin agonists to directly promote sleep (a soporific effect as
distinct from a phase-shifting effect) is discussed in a later chapter. In general, the soporific activ-
ity of melatonin appears to be more prominent with higher doses, and when it is administered at
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186 SACK

Night Day

Phase advance
(reset clock earlier)
Phase delay
(reset clock later)

Light PRC

Melatonin PRC

Phase advance
(reset clock earlier)
Phase delay
(reset clock later)
Endogenous
Melatonin
Profile

12 18 0 6 12
Circadian time

24 6 12 18
Approximate clock time

Figure 3 Schematic phase response curves (PRCs) for light and melatonin administration. The effects of light
and melatonin are dependent on the timing (phase) of administration, a relationship that can be plotted as a
phase response curve (PRC). Light exposure late in the day or melatonin administration in the morning will
cause the circadian clock to shift later (a phase delay); on the other hand, light exposure in the morning or
melatonin administration late in the day will cause the circadian clock to shift earlier (a phase advance). Both light
and melatonin PRCs have an inflection point, the crossover time between advances and delays. According to
convention, circadian time 0 is the beginning of the light phase (daytime) and circadian time 12 is the beginning
of the dark phase (nighttime).

those times of the day when endogenous melatonin is not being secreted. Sleep promoting and
phase-shifting effects may occur concurrently, depending on the timing and dose, and in some
instances, one or the other may be considered undesirable; for example, an early morning dose
of melatonin may promote an intended phase delay but an associated hypnotic effect would
be unwelcome. Likewise, melatonin taken at bedtime for sleep maintenance insomnia related
to an advanced circadian phase might exacerbate the problem by promoting a further phase
advance.
Appropriately timed melatonin and light exposure may have synergistic phase-shifting
effects (17), and melatonin can counteract, to some extent, the effect of light exposure on the
circadian system if light and melatonin are promoting shifts in opposite directions.
A variety of doses of melatonin have been used for phase shifting, and it appears that
the shape of a dose response curve for this effect is rather flat; that is, there is not a great deal
of difference between lower and higher doses. Timing of administration appears to be more
important than dose. Paradoxically, it is possible for a high dose to be less effective than a low
dose. In one report, a low dose (0.5 mg per day) was able to normally entrain a blind person with
free-running rhythms after a high dose (up to 20 mg) had failed (18). The authors suggested
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INSOMNIA IN CIRCADIAN RHYTHM SLEEP DISORDERS 187

that the higher dose overlapped both the advance and delay portions of the melatonin PRC,
canceling out a phase-resetting effect, while the lower dose targeted just the phase advance
region.
Melatonin is widely available in the United States as a “nutritional supplement” but has
not been approved by the FDA as a drug. Concerns have been raised about the purity of the
available preparations, as well as the reliability of stated doses. Labels that feature a GMP
seal, which stands for Good Manufacturing Practice, provide some assurance of the purity and
accuracy of stated doses.
Commonly available melatonin formulations of 3 mg produce blood levels that are at least
10-fold higher than physiological concentrations; however, no serious adverse reactions have
been attributed to these supra-physiological doses. Recently, a melatonin agonist, ramelteon has
been licensed as a hypnotic in the United States and other melatonin agonists are in development.
Animal studies suggest that ramelteon has phase-shifting effects that are analogous to melatonin
(19) but, at this time, no studies have been reported in humans.

Other Phase-Shifting Treatments

Timed vigorous exercise has been tested for its phase-shifting effects, but does not appear to
be as potent as appropriately timed light or melatonin administration. In some experiments,
animals have been entrained to the time of feeding, but this has not been demonstrated to be
effective in humans.

Prescribed Sleep Scheduling

It is sometimes possible to devise a sleep schedule, based on an understanding of circadian
physiology that will minimize or remediate CRSD symptoms for example. Some examples will
be provided under the sections regarding the treatment of DSPS and SWD.

Symptomatic Treatment

Counteracting Insomnia
As discussed above, the circadian pacemaker generates an alerting signal during the day (in
diurnal species) that counteracts the expression of accumulated homeostatic sleep drive (4).
During the normal time for sleep at night, this alerting signal is withdrawn. In CRSDs, there
is a mismatch so that the circadian alerting signal occurs during the desired (or required)
time for sleep, potentially generating insomnia, usually manifested as foreshortened sleep.
Hypnotic drugs or other treatments for insomnia can be used to counteract the unwelcome
clock-dependent alerting in patients with CRSDs.

Counteracting Excessive Sleepiness

Circadian misalignment can produce excessive sleepiness in at least two ways: (i) insomnia (see
above) shortens time asleep resulting in an accumulation of homeostatic sleep drive, (ii) the
activity of the circadian alerting process is reduced when the person desires to be awake.
Caffeine is the most widely used alerting agent in our culture and is effective in counter-
acting sleepiness from almost any cause, but if over-used, can worsen insomnia. Amphetamine-
related drugs are more potent than caffeine and may be indicated in some patients with
CRSDs. Modafanil is the only drug that has been specially approved by the FDA for a CRSD;
namely, SWD.
Having discussed the general principles of circadian biology and modalities of treatment,
the remainder of this chapter will focus on specific CRSDs.

DELAYED SLEEP PHASE SYNDROME

DSPD is characterized by a recurrent or chronic complaint of not being able to fall asleep at
a desired or conventional time, as well as an extreme inability to awaken when desired or
required [for a recent review, see Wyatt (20)]. When there are no constraints on the timing
of sleep, patients with DSPD may sleep quite normally, albeit at a delayed time frame. They
typically seek help when unable to conform to conventional work schedules or other social
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demands. A tendency for a delayed sleep schedule is very common in adolescence and young
adulthood, but this could reflect life style issues as well as a biological tendency.
DSPD is the most common CRSD diagnosis among patients presenting to a sleep disorders
center; nevertheless, these individuals represent but a small percentage of the patients who
would qualify for the diagnosis that is estimated to be between 360,000 to several million people
in the United States alone (20). The disorder is more common in men than women. Weitzman,
who first described the syndrome (21), originally proposed that a significant number of patients
with a diagnosis of sleep onset insomnia may, in fact, have underlying subsyndromal DSPD.
If true, it would imply that an appreciable subgroup of insomnia patients should respond to
circadian-based interventions.
It is often suggested that patients with DSPS have an intrinsic circadian period that is
longer than average and that is why they have such difficulty resetting their circadian pace-
maker (and sleep schedule) to an earlier time frame; however, other mechanisms; such as a
subsensitivity to the phase-advancing effects of light could explain the disorder. Okawa and
Uchiyama have recently published a detailed review of possible mechanisms (22).

Timed Light Exposure

Bright light exposure in the morning, on the advance portion of the light PRC, would be
expected to shift circadian rhythms to an earlier time, thereby correcting a pathological phase
delay. Although the evidence is limited, this hypothesis has been supported in a few clinical
trials. For example, Rosenthal et al. (23) in a cross-over design, compared bright light (2500 lux)
to dim light (300 lux) exposure, two hours per day (6 AM to 9 AM), for two weeks in 20 patients
with DSPD. The bright light treatment produced a greater benefit, as judged by self-report.
In addition, bright light produced a larger advance in the core body temperature rhythm and
increased morning alertness as measured with an MSLT.
The optimal intensity and duration of morning bright light exposure for DSPD remains
undefined, and practical, realistic arrangements need to be negotiated with the patient. In our
clinic, we aim for at least 3000 lux for at least 30 minutes, beginning shortly after awakening,
and integrated with other morning activities such as eating breakfast or applying makeup. We
provide a schedule on a spreadsheet that starts with the patient’s current sleep schedule, and
advances the timing of sleep and light exposure gradually (15 to 30 minutes, every few days).
Since advancing the circadian system in these patients is challenging, attempting to normalize
the schedule too quickly can lead to failure and frustration. Limiting light exposure in the
evening (when it has a delaying effect) may augment the response.
In clinical practice, an artificial light source may be unnecessary if the wake-up time
occurs after sunrise; simply going outside into sunlight for 20 to 30 minutes upon awakening
may provide the required exposure. Compliance with light therapy is a major challenge as
patients with DSPD because their notorious sleep inertia is reflected in their extraordinary
difficulty waking up in the morning when the light exposure is needed.

Timed Melatonin Administration

Melatonin administration in the afternoon or evening would be expected to shift rhythms
earlier, thereby correcting a pathological phase delay. In an early double-blind crossover study,
Dahlitz et al. (24) gave eight patients with DSPD melatonin (5 mg), or placebo at 22:00, five
hours before the average sleep onset time for four weeks. Melatonin treatment shifted sleep
onset times 82 minutes earlier (on average) and wake-up times 117 minutes earlier. In a large
(N = 61), open-label study, those receiving 5 mg of melatonin given at 22:00 for six weeks
reported significant benefit, but also a high rate of relapse when treatment was discontinued
(level 4) (25).
In a double-blind trial, Kayumov et al. (26) administered melatonin (5 mg between 19:00
and 21:00) for four weeks. Treatment normalized the melatonin rhythm, and significantly
reduced sleep onset latency as determined by PSG. However, total sleep time as measured
by PSG, was not improved, nor were self-reported measures of daytime alertness.
In a recent double-blind study, two doses of melatonin (0.3 and 3 mg) were administered
between 1.5 and 6.5 hours prior to the pretreatment DLMO for four weeks. Both doses advanced
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INSOMNIA IN CIRCADIAN RHYTHM SLEEP DISORDERS 189

the DLMO and CBT rhythm. On further analysis, the earlier the melatonin was administered
relative to DLMO, the larger was the phase advance.
The optimal time for melatonin administration would be at the peak of the phase advance
portion of the melatonin PRC, but until circadian marker such as the DLMO becomes clinically
available, appropriate timing has to be estimated. In our clinic, we provide the patient with a
schedule (like the one for light therapy) that initiates treatment (0.5 to 3 mg) at about three to
four hours prior to habitual bedtime, and then gradually shifts the timing of both melatonin
administration and bedtime earlier (15 to 30 minutes every few days).

Prescribed Sleep Schedule

The term chronotherapy was originally coined to describe a prescribed sleep schedule treatment
for DSPD in which patients are instructed to intentionally, and systematically, delay their sleep
several hours per day until it is aligned to a targeted bedtime (27). After the patient achieves
this goal, they are instructed to scrupulously maintain their new sleep schedule lest they relapse
and the procedure has to be repeated. Chronotherapy is based on the hypothesis that the human
circadian period is usually longer than 24 hours and might be exceptionally long in patients
with DSPD. This would account for the great difficulty DSPD patients have in shifting their
sleep schedule to an earlier time, and why delaying sleep would be easier.

Pharmacologic Symptom Control

Hypnotic medications have not been systematically tested for DSPS, and are not recommended
as monotherapy, but can be a reasonable adjunctive measure for those nights when the patient’s
sleep latency extends 30 minutes beyond the prescribed bedtime.

Combination Treatment
In our clinic, evening melatonin and morning bright light are often prescribed in tandem,
utilizing a schedule (provided by a computer-generated worksheet) that gradually advances
the timing of attempted sleep and the timing of both treatments by 15 to 30 minutes every
few days. These gradual shifts in schedule are based on an understanding that large circadian
“phase jumps” are difficult to achieve, especially phase advances, and therefore attempting
to shift sleep times too quickly may lead to failure and the abandonment of treatment. Once
the desired schedule is accomplished, maintenance treatment with light and melatonin can be
continued on a stable, fixed schedule.
Many patients with DSPS have a strong personal preference for being awake late at night
(e.g., they may enjoy the solitude at this time of day) and unless there is a serious consequence
such as failing in school or losing a job, they may not want to change their sleep schedule.
Consequently, cultivating patient motivation is important for the success of any treatment
for DSPD. With adolescents, a great deal of tension has often developed with their parents
regarding sleep schedules. In order to reduce unproductive blaming, an effort may be needed to
educate patients and their parents about the factors that regulate circadian rhythms and sleep,
attempting to frame the problem in a more dispassionate way.

ADVANCED SLEEP PHASE DISORDER

Advanced sleep phase syndrome (ASPD) is characterized by a sleep schedule that is persistently
several hours earlier than the conventional or desired time. ASPD is thought to be much less
common than DSPD, but may be underestimated because an early sleep pattern is less likely
to generate social conflicts. A familial form of ASPD has been described (28), associated with
a specific clock gene mutation that would be expected to shorten circadian period (29). In fact,
a member of the originally described family was studied in a temporal isolation facility and
found to have a circadian period less than 24 hours (28).
As normal people age, bedtimes, wake times and circadian markers often shift earlier
(30,31). Experimental treatment with timed bright light exposure has been tested in this pop-
ulation on the assumption that these patients have a variant of ASPD although the etiology
might be different from younger people; for example, older people may awaken early because
of a decrease in homeostatic sleep drive that results in a secondary phase advance due to early
morning light exposure.
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Timed Light Exposure

According to circadian principles, light exposure in the evening should counteract the tendency
for phase-advanced rhythms. A number of clinical trials have been conducted, and subjective
reports have been encouraging; however, PSG outcome data have been mixed. For example, one
group reported that bright light treatment (4000 lux for two hours in the late evening for 12 days)
produced a delay in the core body temperature rhythm of more than two hours and substantial
improvements in PSG-documented sleep efficiency and sleep architecture (32). However, in a
subsequent report the same group, using an identical protocol, reported comparable circadian
phase delays but no improvement in PSG monitored sleep (33). Another group reported that
two nights of late evening light therapy (2500 lux for four hours) produced both an acute delay
in circadian phase and continued benefits for sleep. In follow-up at one week and at four weeks,
improvement in wake after sleep onset (WASO) persisted (34).
In summary, late evening light exposure is likely to delay circadian phase, and can be used
in patients with ASPD. It may also be tried as an adjunctive treatment in patients with sleep
maintenance insomnia who may have a secondarily phase-advanced circadian rhythms due to
early awakening.

Timed Melatonin Administration

Although there are no systematic reports of melatonin administration for ASPD, it would
be expected to promote phase delays if administered in the latter half of the night or early
morning. The dose should be kept low (0.5 mg) in order to minimize unwanted soporific effects
and patients should be cautioned about the possibility of drowsiness that could carry over into
the daytime hours.

Prescribed Sleep Schedule

Chronotherapy (systematic sleep scheduling), shifting sleep around the clock in an advance
direction, was found to be effective in one case of ASPS (35).

Pharmacologic Symptom Control

If a patient with ASPS is unable to stay up to enjoy social or cultural activities in the evening, the
intermittent use of a low-dose, short-acting stimulant (e.g., methylphenidate 5 mg) to counteract
evening sleepiness may be justified. A short-acting hypnotic such as zaleplon could be used as
a middle-of-the-night sleeping aid for premature awakening. Neither of these treatments has
been systematically studied in clinical trials.

Combination Treatment
As with DSPD, a combination of the treatments can be employed as there are no known adverse
interactions.

SHIFT WORK DISORDER

Shift work is a term that applies to a broad range of nonstandard work schedules including
permanent night shifts, rotating shifts, intermittent night duty, and jobs that require an early
awakening from nocturnal sleep. Daytime sleep in night workers is shorter (4 to 6 hours in one
study) and less efficient (36). Day sleep insomnia is due, in large part, to circadian misalignment
although ambient light, noise, childcare duties, and social conflicts also play a role.
Rapidly rotating shifts clearly do not allow sufficient time for circadian adaptation, but
even permanent night workers typically undermine circadian adaptation by adopting a con-
ventional day active schedule on their days off. Shift workers appear to be at greater risk for
certain medical problems, including peptic ulcer disease, coronary artery disease, and obesity.
In addition, sleepiness on the job can lead to accidents that affect both the worker and other
people.
SWD is a clinical diagnosis that presumably applies to a subgroup of night workers who
fail to adapt to their atypical schedule (37); however, the difference between a normal response
to an unnatural sleep schedule and a diagnosable disorder is not easy to determine. Most of the
descriptive research studies on shift work have been done without regard to clinical diagnosis.
Furthermore, many of the interventional studies have been carried out in a laboratory setting
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with recruited volunteers as subjects. Therefore, the precise nature and boundaries of this
disorder remain rather undefined.
The degree to which night workers reset their circadian rhythms to match their daytime
sleep schedule appears to be quite variable and may depend on a number of factors, especially
baseline circadian phase and the pattern of light exposure. In general, realignment of rhythms
so they are congruent with a day sleep schedule improves the quantity and quality of sleep (36),
although one study of actual shift workers found an unexpectedly weak correlation between
sleep quality and work satisfaction (38). Even if phase congruence could be accomplished, some
night workers would find it undesirable because they would be out of phase on their days off.

Timed Light Exposure

Most night workers go to bed in the morning after their shift, so circadian adaptation requires
a phase delay. In a series of elegant experiments employing subjects on a simulated night shift
schedule, Eastman and colleagues have shown that individuals, who have an early circadian
phase while on a conventional schedule, will have greater difficulty re-entraining to a night
work schedule. They also showed that strategically timed bright light exposure during the
night can substantially facilitate adaptive phase days (39). Furthermore, wearing dark goggles
on the commute home, to block the phase-advancing effect of morning light exposure, also
facilitates phase delays. In recent studies, they demonstrated that 20 minutes pulses of bright
light, if presented in a gradually delaying pattern (one hour later per day), combined with dark
goggles worn on the morning commute, was a highly effective treatment regimen that was
practical and could be adapted by actual shift workers.
While complete resynchronization of the circadian clock to a nocturnally active schedule
is probably unrealistic, the Eastman group showed that phase delays that were sufficient to
move the temperature minimum into the first half of the sleep cycle could produce as much
benefit for sleep and alertness as more robust delays (40). In order to optimize the congruence
of circadian phase and sleep, night workers should go to bed as quickly as possible after they
get home.
There are only a few field studies of light treatment tested in actual shift workers, but they
have generally supported the findings derived from simulation studies. For example, Boivin
and James (41) treated 10 night duty nurses for the first six hours of their shift with intermittent
bright light exposure administered when the subjects were working at their nurse’s station.
The bright light treatment, combined with strategic light avoidance (by wearing goggles on
the commute home and sleeping in absolute darkness), produced robust phase shifts in the
melatonin and body temperature rhythms.
Despite these kinds of encouraging results, light treatment (or avoidance) has not been
widely adopted by night workers. For many occupations, bright lights are considered too
difficult and expensive to incorporate into the work environment, and may be unpleasant for
the worker. Wearing goggles on the morning commute may not be safe for people who are
driving home. These are not insurmountable obstacles, and with modification to the realities of
a particular setting, strategically patterning light exposure offers a potent nonpharmacological
treatment for SWD that is based on sound circadian science.

Timed Melatonin Administration

In one shift work simulation study, melatonin (0.5 or 3.0 mg) administered to subjects who went
to bed in the afternoon (7.5 hours earlier than their usual bedtime) potentiated a desired phase
advance (42). However, in another study in which melatonin (1.8 mg) was administered prior
to a morning (0830) bedtime, their was no augmentation of a desired phase delay (43).
A study from our program illustrates not only the efficacy, but also the complexity of
melatonin treatment for shift work sleep problems (44). Melatonin (0.5 mg) or placebo was
administered at bedtime for seven consecutive days at a time to permanent night nurses
(N = 24) who worked seven night shifts alternating with seven days off (7/70 schedule). In
other words, each subject received both a melatonin trial and a placebo trial for both a work-
week and a week-off (a four-week protocol). At the end of each week, DLMOs were assessed
to determine circadian phase. Nine of the subjects had similar phase shifts on melatonin com-
pared to placebo, and eight failed to shift with either treatment. Seven were specific melatonin
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responders; that is, they shifted with melatonin treatment but not with placebo. In summary, it
appears that some night workers do not need treatment, others fail melatonin treatment, and
some respond specifically to melatonin treatment.
Melatonin given just prior to daytime sleep may have both a direct hypnotic effect (perhaps
by counteracting the unwelcome daytime circadian alerting signal) as well as a circadian phase-
resetting effect. To date, there have been no studies comparing melatonin to a standard hypnotic
medication for daytime sleep.

Pharmacologic Symptom Control

Counteracting Insomnia
Hypnotic medications have been shown to promote daytime sleep in several simulated shift
work studies (45,46). However, it was somewhat surprising that the increase in total sleep time
did not necessarily counteract the circadian-mediated dip in nighttime alertness, as measured
with MSLT. In another study, treatment did not improve nighttime alertness as assessed by
MSLT, but did improve scores on the Maintenance of Wakefulness Test (MWT), suggesting a
differential effect on these two dimensions of sleepiness (47).
There is little question that hypnotic medications can lengthen daytime sleep in night
workers, but there is not yet a consensus as to when such treatment would be appropriate (or
inappropriate). For short runs or occasional night shifts, a short course of hypnotic medication
would seem consistent with the generally accepted guidelines for their use. The use of hypnotics
for permanent night workers is more controversial.

Counteracting Excessive Sleepiness

In the largest (N = 209) double-blind, placebo-controlled study of shift workers to date, Czeisler
et al. (48) tested modafinil (300 mg) as a treatment to counteract excessive sleepiness during
night work. At baseline, and then on three occasions, one month apart, MSLTs, clinical symptom
ratings, and simple reaction time performance testing were performed. Modafinil produced a
modest, but statistically significant, lengthening of nighttime sleep latency (1.7 ± 0.4 vs. 0.3 ± 0.3
minutes; P = 0.002). Self-rated symptom improvement occurred in 74% of those treated versus
36% on placebo. There were concomitant improvements in performance measures. Although
modafinil counteracted nighttime sleepiness, it did not restore alertness to a daytime level. It is
unknown whether a higher dose would have produced a more robust effect.
In several studies, caffeine has been shown to be an effective countermeasure for sleepiness
during night work or experimentally induced sleep deprivation (49,50).

Treating SWD with Prescribed Sleep Scheduling

Designing a shift work schedule, based on sleep and circadian science, can be considered a
form of prescribed sleep scheduling. However, there remains a lack of consensus as to the
optimal schedule for night work – all have advantages and disadvantages. For example, if a
rapidly rotating schedule minimizes time in a desynchronized state, then a schedule with more
consecutive days of shift work would provide an opportunity to achieve a degree of circadian
synchrony.
Because the human circadian period is longer than 24 hours, it is easier for most people
to phase shift in a delay direction than in an advance direction. This understanding of human
circadian physiology is consistent with the finding that a clockwise (delaying) shift work rotation
was better tolerated than a counterclockwise (advancing) rotation (51). In another example of
basing a work schedule on circadian physiology (15), Eastman et al. showed that gradual, rather
than abrupt, shifts in a night work schedule allowed the circadian system to adapt. This schedule
was designed with the understanding that the circadian pacemaker can be reset only an hour
or two per day however. Although consistent with circadian physiology, a gradually shifting
work/sleep schedule would be difficult to implement in most settings. In the “real world,”
circadian physiology is often secondary to other considerations in shift work scheduling; for
example, worker seniority status, labor-management relations, time-off preferences.
Prescribed napping, either before (prophylactic napping) or during a night shift (recuperative
napping), has been shown to improve alertness on the job, and has been used more extensively
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in Europe than in the United States. In order to minimize sleep inertia, naps should be kept
relatively brief.

Combination Treatment
Given the wide variety shift work schedules and the various desires of patients, treatment will
need to be tailored to meet the needs of the individual worker. For an occasional overnight duty
(e.g., 24-hour duty in the Emergency Room), phase resetting would not be possible or desirable.
A stimulant medication to maintain alertness during the shift and perhaps a hypnotic for
daytime sleep might be indicated. For workers on a steady night shift (who maintain a relative
nocturnal orientation on the their days off), promoting phase resetting with light exposure or
melatonin would be more logical. For a worker who is at risk for costly mistakes (e.g., a nuclear
power plant supervisor) more aggressive treatment may be required. Recently, Eastman et al.
have shown that using light treatment to reset rhythms to a compromise phase, along with
prescribed sleep scheduling, in between a night work and conventional schedule, may be the
best way to maximize sleep and alertness for both work days and days off. Some people are
very intolerant of shift work and may need a medical authorization to be excused.

JET LAG DISORDER

JLD results from crossing time zones too rapidly for the circadian system to keep pace. It can
take days or even weeks for the circadian system to resynchronize, depending on a number of
factors: (i) the number of time zones crossed, (ii) the direction of travel, (iii) the availability and
intensity of local circadian time cues upon arrival, and (iv) individual differences in circadian
adaptability or tolerance to circadian misalignment. Attempting to sleep in upright position in
an uncomfortable airplane seat adds the burden of sleep deprivation to the mix, and excessive
alcohol or caffeine intake while in transit can make it worse. Although JLD is naturally self-
limited, preventative measures and treatment can diminish its intensity and duration.

Timed Light Exposure

Numerous laboratory-based studies (which can be considered as jet travel simulations) have
shown that appropriately timed bright light exposure can accelerate circadian phase shifting.
So it makes sense, in most instances, to get as much sunlight after arrival at the destination as
possible, but there are possible exceptions (52). When traveling across eight time zones or more,
it would be prudent to avoid light in the early morning for the first few days, as it would be
illuminating the “wrong” portion of the light PRC; that is, delaying rhythms when an advance is
needed. Likewise, after a very long westward flight, it would make sense to avoid and advance
when a delay is needed. After a few days, there will be enough circadian adaptation (shift in
the light PRC) that light avoidance should be unnecessary. While light avoidance is rational,
it is difficult for travelers to do. Wearing dark sunglasses and staying in dimly lit hotel room
might help, but no studies have been done. After eastward flight of more than eight time zones,
an eight-hour advance would be needed for resynchronization to local time and some experts
suggest that it would be easier to promote a delay, even though this would involve up to a
16-hour phase shift (53).
Another approach is to use timed bright light exposure to reset the body clock in anticipa-
tion of jet travel. Aiming to develop a practical light treatment for use prior to eastward flight,
Eastman et al. (54) showed that shifting the sleep schedule earlier by one or two hours per
day, combined with bright morning light (5000 lux), advanced rhythms up to 1.8 hours in three
days. If a formal light treatment program is too difficult, getting up progressively earlier than
usual for a few days into a brightly lit environment should begin to advance rhythms before
eastward travel; staying up progressively later with exposure to bright light should begin to
delay rhythms for westward travel.

Melatonin Administration
The benefits of melatonin for jet lag have been demonstrated in a number of double-blind,
placebo-controlled studies (55). Improvement in sleep, accelerated phase shifting, and a decrease
in jet lag symptoms have been reported in various studies. Doses ranging from 0.5 to 10 mg
for up to three days prior to departure and up to five days upon arrival at the destination
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have been employed. Most of these studies have tested melatonin for eastward flight, when a
bedtime dose would promote a desired phase advance and might have a hypnotic effect as well.
With westward flight melatonin should be taken (according to the melatonin PRC) upon early
morning awakening in order to facilitate phase delays; if taken at bedtime, it could stimulate
the advance portion of the melatonin PRC and thereby inhibit clock resetting in the desired
delay direction. In order to minimize a sleep-promoting effect, a morning dose should be low;
for example, 0.5 mg.

Prescribed Sleep Scheduling

For brief trips, maintaining the home base schedule (if feasible) and avoiding phase shifts
is logical. Many travelers feel that immediately adopting local time upon arrival (not thinking
about what time it is back home) reduces jet lag symptoms, but this has never been systematically
studied.

Pharmacologic Symptom Control

Counteracting Insomnia
JLD-related insomnia is the result, not only of circadian misalignment, but also of attempting to
sleep in an upright, sometimes noisy, airplane seat, and later, in an unfamiliar hotel bed. Because
JLD-insomnia is self-limited, a short course of hypnotic medication can be readily justified. A few
studies that have tested hypnotics for this indication and they were shown to be generally safe
and effective (56). Occasional adverse events have been reported; for example, global amnesia
following the use of triazolam (and some alcohol) during flight (57). Also, hypnotic use during
a flight could increase immobility and raise the risk for deep vein thrombosis.

Counteracting Excessive Sleepiness

Many travelers increase their caffeine consumption as a countermeasure for JLD daytime sleepi-
ness, but this could exacerbate jet lag-induced insomnia. In a clinical trial of slow-release
caffeine (300 mg), daytime alertness was improved but the treated group also had longer
sleep latencies and more awakenings at night (58). In phase-shifting experiments that simulate
jet lag (as well as shift work), modafinil has been shown to improve daytime alertness, but
there have been no field trials to date. There appears to be relatively few contraindications to
its use.

Combination Treatment
Melatonin, for its phase-resetting effect, and a hypnotic medication, for insomnia, could be taken
together as there are no known adverse pharmacological interactions. The hypnotic effects might
be additive.

FREE-RUNNING DISORDER (NON–24-HOUR SLEEP DISORDER) – SIGHTED

In patients with FRD, the timing of sleep persistently delays by about 30 to 90 minutes per
day, expressing a free-running circadian cycle that is greater than 24 hours. FRD is uncommon
in sighted people, and the available literature consists mostly of single case reports. Most
of the cases have been young males. Some of these patients had a history of severe DSPD
prior to developing a free-running pattern, and the two disorders might well have similar
etiologies (22).

Timed Light Exposure

Bright light exposure was found to successfully entrain circadian rhythms in several case reports;
however, no placebo-controlled trials have been conducted (2).

Timed Melatonin Administration

There are reports of successful treatment with daily melatonin administration at the desired
bedtime (when it would be predicted to promote a corrective phase advance). The most common
dose was 3 mg and the duration of treatment ranged from one month to six years (2).
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Prescribed Sleep Scheduling

An early study of four children with FRD related to neurological disorders suggested that
increasing the regularity of sleep and potency of environmental time cues could improve the
sleep–wake rhythms (2).

Combination Treatment
Non–24-hour CRSD may be an extreme form of DSPS and similar treatment strategies can be
tried; for example, morning light exposure, evening melatonin administration, and intermittent
hypnotics (as described above).

FREE-RUNNING DISORDER (NON–24-HOUR SLEEP DISORDER) – BLIND

Although Non–24-hour CRSD is very rare in normally sighted people, about half of the totally
blind, those with no light perception, have free-running circadian rhythms (59). The recurrent
symptoms of daytime sleepiness and nighttime insomnia, when their rhythms are out of phase,
can be very burdensome.

Timed Melatonin Administration

Daily melatonin administration has been shown to entrain free-running rhythms in totally blind
subjects (60–63) and is the current treatment of choice. A physiological dose (0.5 mg) appears to
be as effective as a pharmacological dose (5 to 10 mg), and in some cases, more effective (18).

IRREGULAR SLEEP–WAKE DISORDER

Irregular sleep–wake disorder (ISWD) is characterized by a relative absence of a circadian
pattern, with sleep and wake randomly distributed over the night and day, mimicking the
pattern seen in animals with SCN lesions. The diagnosis is uncommon in healthy adults and is
usually associated with dementia [particularly Alzheimer’s disease (AD)], mental retardation,
or brain injury. In these cases, damage to the SCN is thought to underlie a circadian amplitude
(rather than phase) disturbance. Demented patients with ISWD cause their caretakers to lose
sleep, and consequently, and this is the most common reason these cases are brought to medical
attention. More rarely, the pattern is seen in otherwise normal individuals with either very poor
sleep hygiene or without apparent etiology. The goal of therapy is to consolidate sleep, as much
as possible, into a major nighttime bout.

Timed Light Exposure

Older adults living in an institutional setting are exposed to less daylight than elderly people
living in the community. In addition, the retina and optic nerve may be compromised. These
considerations have provided the rationale for using daytime bright light treatment (sometimes
combined with more intense social activity) for Alzheimer’s patients in nursing home settings.
Most studies of this treatment have found a modest beneficial effect (2), but the increased
attention associated with light therapy may explain some of results.

Timed Melatonin Administration

The nocturnal secretion of melatonin is reduced with normal aging; even greater reductions are
seen with AD, providing the rationale for melatonin treatment in this population. Several large
trials have been disappointing. For example, Singer et al. (64) randomized 157 AD patients to
2.5 mg sustained release melatonin, 10 mg of immediate release, or placebo. The primary
outcome variable was actigraphically monitored sleep. The protocol involved two to three
weeks of baseline measurement, eight weeks of treatment, and two weeks of placebo washout.
Neither formulation of melatonin was better than placebo.
More favorable results have been reported using melatonin (2 to 20 mg) for brain-injured,
mentally retarded children with ISWD (65). However, a trial of melatonin to improve the timing
and quality of sleep in young girls with Rett syndrome was negative (66).

Prescribed Sleep Scheduling

McCurry et al. (67) conducted a study in which family caregivers of AD patients were instructed
in the standard principles of good sleep hygiene, including regularized sleep schedules, and
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were provided training in behavior management skills. A control group received education
about dementia and caregiver support. Sleep was monitored actigraphically. The active treat-
ment group had fewer nighttime awakenings and a reduction in total wake time during the
night. These benefits persisted to six-month follow-up.

Pharmacologic Symptom Control

A number of studies have concluded that sedative–hypnotic drugs are inappropriately pre-
scribed or overprescribed to demented patients. On the other hand, no controlled studies of
benzodiazepine receptor agonists have been conducted to assess efficacy and safety in AD. A
clinical trial with one of the usual sedative/hypnotic drugs might be justified in difficult cases,
but may exacerbate confusion and disorientation. Stimulant medications during the day have
not been tested but might be justified in some individuals.

SUMMARY AND CONCLUSIONS

The symptom of insomnia in CRSDs is usually related to a misalignment of the circadian alerting
process and the sleep schedule. Understanding the basic principles of circadian physiology
can provide the basis for intervention. The delineation of the PRCs for light exposure and
melatonin administration has provided a scientific basis for resetting of the body clock so that
it is more congruent with the desired or required time for sleep. If clock resetting is impractical,
unsuccessful, or undesirable, insomnia (however unconventional the sleep–wake schedule) can
be counteracted with judicious use of hypnotic medications.

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18 Insomnia in Other Sleep Disorders:

Movement Disorders
Michael H. Silber
Center for Sleep Medicine and Department of Neurology, Mayo Clinic College of Medicine, Rochester,
Minnesota, U.S.A.

RESTLESS LEGS SYNDROME

Definition
Restless legs syndrome (RLS) is a major cause of comorbid insomnia. It is characterized by
four basic symptoms: an urge to move the legs, usually accompanied by unpleasant sensations;
worsening of symptoms by rest; relief of symptoms by activity; and worsening of symptoms in
the evening or night (1,2). The unpleasant sensations are typically described as creepy-crawly
or worm-like, but patients use varied descriptors and not uncommonly find it hard to label
the quality of the discomfort. A minority will describe the sensations as painful and some will
experience only the need to move without associated sensations. Usually the symptoms are
experienced bilaterally, but one limb may predominate, with discomfort sometimes alternating
between different sides. In some patients the symptoms may also be experienced in other areas
of the body, especially the arms (3). The urge to move is precipitated by physical rest such
as sitting or lying down and may be especially severe in prolonged situations of enforced
quiescence, such as traveling in a car or plane or sitting in a theater. Reduced alertness may
enhance the severity of RLS and, conversely, stimulating mental activities may help alleviate
the discomfort. Activities such as walking, stretching or bicycling result in relief but symptoms
recommence after the activity is discontinued. Soaking or massaging the affected limb may also
provide temporary relief. The characteristic circadian rhythmicity of RLS results in symptoms
frequently being most severe in bed, either before sleep onset or on waking during the night.

Additional Clinical Features

Three other features of the disorder may provide added confirmation of the diagnosis (1). First,
the probability of a correct diagnosis of RLS may be increased by the identification of a family
history of the disorder in a first degree relative. Second, a sustained therapeutic response to a
dopaminergic drug may provide indirect evidence that the diagnosis is correct. Third, RLS is
frequently accompanied by periodic limb movements of sleep (PLMS) with polysomnographic
studies showing their occurrence in 80% to 88% of patients (4). PLMS are repetitive contractions
of the legs during sleep with dorsiflexion of the ankle and flexion of the knee and hip. Each
movement typically lasts 0.5 to 10 seconds with an intermovement interval of 5 to 90 seconds
(2). PLMS are not confined to patients with RLS and may accompany a wide range of other sleep
and neurological disorders, including obstructive sleep apnea (5), narcolepsy (6), REM sleep
behavior disorder (7), and Parkinson’s disease (8). They may also occur in isolation, either as an
asymptomatic phenomenon especially in older people (9–11), or rarely as a primary disorder
causing sleep disruption.

Diagnostic Assessment
The diagnosis of RLS can be made in most patients by obtaining a careful history and diagnostic
testing is not generally needed. Polysomnography to detect PLMS has low sensitivity and speci-
ficity and immobilization tests (12) to detect periodic limb movements of wakefulness are rarely
used clinically. Other potentially confusing conditions have different clinical features, usually
allowing easy differentiation. Nocturnal leg cramps abruptly awaken the patient with severe
pain in a palpably contracted muscle. Arthritis pain is localized to joints and the discomfort of
a sensory peripheral neuropathy is predominantly felt in the feet. While neurogenic pain may
be worse at night or at rest, it is not generally associated with an urge to move. Fibromyalgia is
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200 SILBER

accompanied by tender muscle trigger points in a characteristic distribution. Discomfort from

transient compression neuropathies is associated with numbness and tingling and is confined to
specific peripheral nerve distributions. Jiggling of the legs during wakefulness is not associated
with an urge to move and can be voluntarily discontinued without discomfort. Akathisia, most
commonly associated with neuroleptic use, is neither worse at rest nor relieved by movement.
Painful legs and moving toes syndrome is a rare disorder characterized by typical wandering
toe movements.
Epidemiology
The prevalence of RLS has been identified as 5% to 10% in a variety of population based
epidemiological studies (13–17). In one study based on a primary care practice, 6.6% of patients
described RLS occurring more than three times a week (18). The incidence of RLS increases
with age but symptoms may develop as early as childhood. RLS is twice as frequent in women
as in men and is especially frequent during pregnancy. At least 50% of patients have a family
history of a relative with the disorder, especially if symptoms started early in life (4,19). The
genetics of RLS are complex and much further work will be needed to fully understand the
hereditary underpinnings of the disorder. Studies have shown linkage to sites on five different
chromosomes (12q, 14q, 9p, 20p and 2q) with four reports suggesting an autosomal dominant
inheritance pattern and one an autosomal recessive pattern (20–24). Genome wide studies have
suggested an association of RLS or PLMS with a number of genes on chromosomes 2p, 6p and
15q, some of which affect spinal motor neuron connectivity or the development of spinal cord
sensory pathways (25,26).
Associated Conditions and Pathogenesis
A number of acquired factors are associated with RLS. The best studied is that of iron deficiency,
with studies showing a relationship between RLS severity and low or low- normal serum ferritin
concentration (27,28). Even in RLS patients with ostensibly normal systemic iron stores, CSF
ferritin levels are lower than in normal controls (29). MRI (30) and pathological (31) studies
have also revealed lower concentration of iron in the basal ganglia in RLS. Current hypotheses
link low cerebral iron stores to dopamine deficiency. The exact nature of the relationship is
uncertain, but iron is a cofactor for tyrosine hydroxylase, the rate-limiting step of dopamine
synthesis, and is also necessary for the functioning of the dopamine D2 receptor. RLS is also
associated with chronic renal failure, but the exact pathophysiology has not been determined. In
one study, 23% of 138 dialysis patients had definite RLS (32). RLS has been linked to peripheral
neuropathy, especially in patients with older onset disease and no family history of the disorder
(33). Evidence of small fiber neuropathy has been detected in some RLS patients by measurement
of intraepidermal nerve fiber density on skin biopsy (34). It has been suggested that Parkinson’s
disease may also predispose to the development of RLS (35).
Insomnia in Restless Legs Syndrome
RLS is classified as a sleep disorder (2) because patients frequently report difficult initiating
and maintaining sleep. This observation gives rise to the question of how frequently RLS actu-
ally causes insomnia and what form the sleep disturbance takes. Controlled and uncontrolled
questionnaire and polysomnographic studies have addressed these issues.
Uncontrolled, questionnaire studies of the consequences of RLS on sleep have been
reported in sleep clinic, primary care practice and population settings. In a large, clinic-based
study of 133 consecutive RLS patients, 84.7% reported difficulty falling asleep and 86% difficulty
staying asleep (4). Of 55 patients in a sleep clinic practice, insomnia was reported in 67% of those
with onset at ≤20 years of age and 55% of those with onset >20 years of age (36). RLS patients
with symptoms at least twice a week and at least some negative impact on quality of life were
studied in primary care centers in the USA and four European countries (37). Of 551 patients,
88% reported at least one sleep-related symptom (including inability to fall asleep, inability
to stay asleep and disturbed sleep). A sleep latency of 30 minutes or longer on symptomatic
nights was reported by 68.6%, while 60.1% reported waking three or more times a night. Sleep
disturbances were rated the most troublesome symptom in 43.4% of patients. A population
based study of 15,391 subjects in the USA and five European countries revealed 416 (2.7%)
respondents with moderate or severe RLS causing at least moderate distress and occurring a
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INSOMNIA IN OTHER SLEEP DISORDERS: MOVEMENT DISORDERS 201

minimum of twice weekly (17). Sleep-related symptoms were noted by 75.5% of patients, with
48.1% describing difficulty falling asleep, 39.2% difficulty staying asleep, 60.6% experiencing
disturbed or interrupted sleep and 40.1% insufficient sleep. The most troublesome symptom
was listed as sleep disturbance by 37.8% of patients.
Several controlled, population-based studies of RLS symptoms have been reported. A
study of 1000 randomly selected adults from Norway and 1005 from Denmark revealed a
prevalence of RLS of 11.5% (38). Of those subjects indicating that insomnia was usually or
always present, 23% had RLS compared to 9.3% of those indicating insomnia to be sometimes
or never present. Multivariate analysis demonstrated that RLS was significantly associated
with insomnia that was always present (odds ratio 2.75), usually present (odds ratio 3.16) and
sometimes present (odds ratio 1.71). Depressive mood did not correlate significantly with the
presence of RLS. Of 1000 randomly selected Swedish adults, 5% were diagnosed with RLS
(39). Symptoms of insomnia were described by 51% of the RLS patients compared to 24.3%
of the controls (p = 0.0001), whereas depressed mood was present in 18% of the RLS patients
compared to 6.7% of the controls (p = 0.01). As part of the 2005 National Sleep Foundation Poll,
1506 randomly selected United States adults were interviewed. RLS was identified in 9.7% of
the sample (40). Compared to controls, RLS subjects were more likely to sleep <6 hours a night,
to endorse symptoms of insomnia, to stay up longer than they planned more than a few nights
a week and to take >30 minutes to fall asleep.
A few polysomnographic (PSG) studies of RLS patients have addressed the question of
sleep disruption. In an uncontrolled study of 133 consecutive patients with RLS (4), the mean
PSG sleep latency was 20.5 minutes and the mean sleep efficiency was 75%. A mean of 7.4
awakenings per night greater than two minutes was reported. The PSG findings correlated with
the patients’ subjective reports. The mean sleep latency for those complaining of difficulty falling
asleep was 22.9 minutes compared to 10.6 minutes for those reporting no initial insomnia. The
mean sleep efficiency was 73.2% for those complaining of difficulty maintaining sleep compared
to 86.4% for those reporting no sleep maintenance problems. The periodic limb movement index
did not, however, correlate with patients’ complaints of sleep onset or maintenance insomnia, the
number of objective awakenings or sleep efficiency, suggesting that periodic limb movements
are not the primary cause of the sleep disturbances in RLS patients. In a study of the effects
of ropinirole on moderate to severe RLS, baseline PSG data was reported for 59 patients (41).
Mean preintervention sleep efficiency was 81.2% for the drug group and 81.9% for the placebo
group. However, preintervention mean sleep latency was relatively short: only 16.7 minutes for
the drug group and 8.9 minutes for the placebo group.
A small controlled PSG study of 12 RLS patients compared to 12 controls showed increased
wake time after sleep onset (mean 92.4 minutes compared to 36.2 minutes), reduced sleep
efficiency (73.2% compared to 86.6%), shorter total sleep time (326.3 minutes compared to
383.3 minutes) and more awakenings (12.2 compared to 7.4) (42). A larger controlled PSG
study of 45 RLS patients and controls showed that the patients had significantly reduced
sleep efficiency (80% compared to 87.6%), higher arousal index (23.4 compared to 12.4), more
awakenings (26.8 compared to 20.8) and more wake after sleep onset (15.6% compared to 7.9%)
(43). Percentage stages 2 and REM sleep were significantly reduced in the RLS group and REM
latency was prolonged. Sleep onset latency did not differ between the groups, but latency to 10
minutes persistent sleep was significantly longer in the RLS subjects (41.6 minutes compared to
25.4 minutes).
In summary, questionnaire and PSG studies show conclusively that untreated RLS causes
serious disruption of sleep. In population based studies, approximately one half to three quar-
ters of RLS patients describe sleep-related symptoms, with higher percentages reported in
studies based on primary care or specialist practices. Both sleep onset and sleep mainte-
nance difficulties are described. In objective PSG studies, sleep maintenance difficulties are
confirmed, with reduced sleep efficiency together with increased arousals and awakenings.
Conventionally calculated sleep latency is less consistently prolonged but latency to sustained
sleep lengthens, suggesting that many patients fall asleep rapidly but wake shortly thereafter
with recurrence of symptoms. While there is limited data on the role of periodic limb move-
ments, one study suggests that they do not significantly contribute to the sleep disturbances of
RLS (4).
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Management of Restless Legs Syndrome

Insomnia due to RLS is generally managed by treating the underlying disorder. Nonpharma-
cological approaches (44) include iron replacement when systemic iron deficiency is detected,
usually indicated by a low or low-normal serum ferritin concentration. Ferrous sulphate, fer-
rous fumarate or ferrous gluconate may be used in combination with Vitamin C to enhance
absorption. Mental alerting activities and physical exercise may alleviate symptoms adequately
in mild cases of RLS. Dopaminergic agents have been shown in controlled trials to be very
effective in relieving RLS and are the first line of therapy in patients with severe enough disease
to require daily therapy (45). Levodopa, the first drug shown to be effective, is rarely used
currently except on an intermittent basis because of the high risk of inducing daytime aug-
mentation, defined as the worsening of symptoms earlier in the day after an evening dose of
medication. The nonergot dopamine agonists pramipexole and ropinirole, both approved by
the U.S. Food and Drug Administration for RLS treatment, are most widely prescribed. Poten-
tial side-effects include daytime sleepiness and the development of impulse control disorders,
such as compulsive gambling or excessive shopping (15). Other agents shown to be effective
include gabapentin and opioids, such as oxycodone (44). Benzodiazepines may also help to
relieve symptoms.
Do the therapeutic agents, which reduce restless legs, also help the associated insomnia?
Most information comes from studies of dopaminergic drugs. In four large multicenter, con-
trolled studies of 202 to 380 patients with moderate to severe RLS (46–49), the effects of ropinirole
after 12 weeks administration were compared to those of placebo using the Medical Outcomes
Study (MOS) sleep scale domains. In all studies there was a significant improvement in sleep
disturbance, sleep adequacy and sleep quantity with the drug. The mean degree of improve-
ment in sleep time ranged between 0.3 and 1.3 hours. A similar study of 345 patients treated
with pramipexole or placebo showed significant decrease in the severity of sleep disturbance
and increased satisfaction with sleep after six weeks use of the drug compared to placebo (50).
The effects of levodopa were assessed in a crossover trial of 32 patients with RLS (51). Quality of
sleep, refreshment after sleep, sleep latency, and sleep duration assessed by questionnaire were
all improved with the drug compared to placebo. Sleep latency was shortened by a mean of
25.2 minutes and total sleep time lengthened by a mean of 0.9 hours. A combination of regular
release and slow release levodopa before bed resulted in significantly better quality of sleep,
longer time asleep and fewer awakenings compared to regular release levodopa alone (52). In
a PSG study of 29 patients taking ropinirole for RLS and 30 taking placebo, adjusted mean
total sleep time increased by 20.5 minutes and sleep efficiency by 4.3% but these changes did
not reach statistical significance. In contrast, mean sleep latency fell significantly by a mean of
6.1 minutes (41). In summary, RLS patients report definite benefit in sleep from dopaminergic
agents. Little additional objective PSG data is available.
In a controlled PSG study of the effect of gabapentin on 22 RLS patients compared to 22 on
placebo, significantly increased total sleep time (0.5 hour) and sleep efficiency (9.8%) were noted
in the drug group but sleep latency was not significantly different (53). Interpretation of studies
of the effects of other agents on sleep is limited by small numbers of patients and inconsistent
diagnostic criteria, especially lack of distinction between RLS and PLMS. A crossover study of
11 RLS patients showed that oxycodone resulted in significantly higher sleep efficiency than
placebo (mean difference 24.7%) (54). A crossover study of clonazepam (6 patients) showed
significantly better quality sleep by questionnaire with the drug compared to placebo (55).
The Medical Advisory Board of the Restless Legs Syndrome Foundation has developed
an algorithm for the management of RLS, based on classifying the disorder into intermittent,
daily and refractory forms (56). Intermittent RLS can be managed by nonpharamacological
therapies or intermittent use of levodopa, low-potency opoids or benzodiazepines. Daily RLS
is usually treated with dopamine agonists, but gabapentin or low-potency opioids can be used.
Refractory RLS is defined as RLS in which the use of a dopamine agonist has failed due
to inadequate response, intolerable side effects, or development of tolerance or uncontrollable
augmentation. Options include substituting another dopamine agonist, changing to gabapentin,
adding a second drug, or using a high potency opioid. There are several practical considerations
regarding the management of insomnia associated with RLS. It is important that dopamine
agonists be administered one to two hours before the usual onset of symptoms to allow for
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INSOMNIA IN OTHER SLEEP DISORDERS: MOVEMENT DISORDERS 203

adequate absorption. In particular, the drugs should not be given at bedtime to patients whose
symptoms are maximal in bed before sleep onset. If the initial dose is given in the afternoon
or early in the evening, a second dose before bed may be needed. In patients who have both
RLS and primary insomnia, a benzodiazepine agonist may be helpful, either as a first-line or
supplementary drug. Similarly, gabapentin is generally sedating and may be helpful in these
circumstances.

PERIODIC LIMB MOVEMENT DISORDER

Periodic Limb Movements of Sleep

PLMS are motor phenomena recordable during polysomnography and frequently visible to bed
partners and other observers. The original definition by Coleman has been recently modified
(57,58), based on new quantitative approaches (59). A PLM lasts 0.5 to 10 seconds with minimum
amplitude of 8 ␮v increase in anterior tibial surface electromyographic voltage above the resting
EMG. A minimum of four leg movements, separated by 5 to 90 seconds between onsets of
successive movements, must occur in succession to be considered PLMS.
PLMS may accompany a wide range of other disorders. As discussed above, more than
five PLMS/hr are found in 80 to 88% of RLS patients (4). PLMS are found in 80% of patients
with narcolepsy and 71% of patients with REM sleep behavior disorder (6). They appear to
be common in association with obstructive sleep apnea (5,60). They occur more frequently in
Parkinson’s disease than in controls (61). In addition, PLMS are frequently seen in asymptomatic
older subjects. A study of 100 normal subjects using a cut-off of 30 movements over the course
of a night found that no subjects younger than 30 years, 5.2% of subjects 30 to 49 years old
and 29% of subjects older than 49 years, had PLMS (10). In a study of 100 community dwelling
subjects aged 60 years or older, 58% showed PLMS ≥5/hr (11). A similar community-based
study of 420 volunteers found that 45% had five or more PLMS/hr (9).

Periodic Limb Movement Disorder and Insomnia

In view of the association of PLMS with multiple other disorders and the high frequency
of PLMS in normal older subjects, the clinical significance of PLMS alone has been a matter
of confusion and controversy (6,62–64). The term periodic limb movement disorder (PLMD)
has been used in widely different ways but was standardized in the second edition of the
International Classification of Sleep Disorders (ICSD) (2). In order for a diagnosis of PLMD to
be made, PLMS must be present on PSG at a frequency of >5/hr in children and >15/hr in
most adult cases. In addition, there must be a clinical sleep disturbance or complaint of daytime
fatigue not better explained by any other current sleep, medical, neurologic, mental or substance
use disorder or the use of medications. Thus PLMS in the setting of RLS should not be diagnosed
as PLMD and considerable caution should be exercised in diagnosing PLMD in the setting of
sleep apnea or narcolepsy. But how common is true PLMD and, in particular, how frequently
do PLMS alone cause insomnia?
In an early study of 441 successive patients seen at an academic sleep center, 53 had 40 or
more PLMS during a night of PSG monitoring. There was no significant difference between the
frequency of insomnia diagnosed in the patients with PLMS (18%) compared to the frequency
in patients with diagnoses of narcolepsy, sleep apnea or other hypersomnias. Similarly, the
frequency of insomnia as the chief complaint (17%) was no higher than that of excessive daytime
sleepiness or other disorders (65). Of 1692 patients seen in an academic sleep center, 67 had
PLMS in the absence of RLS. There was no association between the PLM arousal index and
sleep efficiency on the PSG but wake time after sleep onset was increased in the PLMS patients.
However, no association was found between the presence of PLMS and complaints of insomnia,
sleepiness, or unrefreshing sleep (66). In a study of 22 older subjects with insomnia or depression,
no significant associations were found between the PLM index and total sleep time or wake time
after sleep onset on PSG, or subjective measures of insomnia (67). The PLMS index was similar
in 20 middle-aged patients complaining of insomnia compared to 20 age and gender matched
controls (6). A group of 61 patients referred for insomnia or hypersomnia with PLM index
of five or greater and RLS, sleep apnea and narcolepsy excluded was compared to 61 control
patients, mainly with sleep apnea. Symptoms of insomnia or sleepiness predicted neither the
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204 SILBER

presence nor severity of PLMS (68). No association was found between sleep quality assessed
on a standardized questionnaire and the PLMS index in 78 patients with PLMS (narcolepsy
and sleep apnea patients excluded). There was also no association detected in a subgroup of 22
patients diagnosed with primary insomnia (69). A study of 34 patients with daytime sleepiness
and PLMS showed no correlation between the PLMS index and mean latencies on a multiple
sleep latency test (70).
Similar results have been found in studies of normal subjects. In a study of 100 com-
munity dwelling older subjects, the presence of PLMS was not significantly associated with
complaints of insomnia or sleepiness, nor with any abnormal sleep log measurements (11).
However, in a similar study of 420 subjects, PLMS were associated with complaints of reduced
sleep satisfaction (9). Seventy healthy middle-aged subjects were assessed by PSG and sleep
questionnaires. There was no association between PLMS severity and any PSG measure, includ-
ing sleep latency and sleep efficiency. Sleep quality assessed with the Pittsburgh Sleep Quality
Index was significantly lower in men with higher numbers of PLMS but not for women (71).
Another approach to understanding the significance of PLMS comes from analysis of
arousals. In a detailed study of 10 patients complaining of insomnia or sleepiness, including
six with RLS, the relationship between PLMS and arousal phenomena was assessed. Of 3916
EEG arousals occurring 10 seconds before or after the onset of a PLMS, 49.2% occurred before
leg movements, 30.6% simultaneous with leg movements and 23.2% after leg movements.
Alpha activity was significantly higher during the 10 seconds before movements compared to
the 10 seconds after movements. These data suggest that PLMS may be manifestations of an
underlying arousal disorder rather than the primary cause (72). Six patients with RLS were
treated with levodopa or placebo and the effect on PLMS and arousals assessed. Levodopa
resulted in a significant reduction in the PLMS index compared to placebo but the frequency of K-
alpha complexes remained unchanged, suggesting that the leg movements were not responsible
for the arousals (73). Transient increases in heart rate (74,75) and changes in EEG theta and delta
activity (74) have been reported following PLMS, even when unassociated with EEG arousals.
However, the clinical relevance, if any, of these physiologic changes has not been established.
Thus, in summary, there is little data to suggest that PLMS alone play an important role
in causing insomnia or sleepiness in the absence of other sleep disorders. PLMD appears to
be a rare condition and should be diagnosed with care. A sustained response of the primary
complaint of insomnia or hypersomnia with the use of dopaminergic agonists can result in
increased confidence in the correctness of the initial diagnosis (62). However, while it may
seem intuitive to treat PLMD with drugs known to improve RLS and the associated PLMS, no
controlled clinical trials of any agents for pure PLMD have been reported (76), apart from studies
using clonazepam (77) and ropinirole (78) for a single night compared to a night with placebo.

SLEEP-RELATED BRUXISM
Sleep-related bruxism (tooth grinding or clenching) is associated with either tonic contraction
of the masseter muscle or rhythmic masticatory muscle activity (RMMA), a series of repetitive
contractions at approximately 1 Hz each lasting 0.25 to 2 seconds (57). Bruxism can occur in any
stage of sleep, but occurs most frequently in light NREM sleep. Bruxism is common, but in order
to qualify as a disorder, not only must the patient report or be aware of tooth grinding sounds or
tooth clenching in the night, but one or more clinical consequence must occur. According to the
second edition of the ICSD, these are abnormal wear of the teeth; jaw muscle discomfort, fatigue
or pain and jaw lock on awakening; and masseter muscle hypertrophy. In adults the prevalence
of sleep related tooth grinding has been estimated at 8% in a Canadian sample of 2,019 subjects,
with prevalence dropping from 13% at ages 18 to 29 years to 3% at ages 60 years and older (13).
In a European sample of 13,057 subjects, the prevalence of sleep-related bruxism was 8.8% in
women and 7.5% in men (79). Prevalence was 5.5% in the 15 to 18 year age group, 8.8% to 10.5%
in adults aged 19 to 64 years and 3% in subjects older than 64 years. It should be understood
that these figures (13,79) reflect the motor phenomenon alone and not its consequences. In the
European study, the prevalence of bruxism as a disorder using the ICSD (second edition) criteria
was also assessed (79). Overall prevalence was 4.6% in women and 4.1% in men with the lowest
prevalence (1.1%) in subjects older than 64 years and maximal prevalence in those age 19 to 44
years (5.8%).
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INSOMNIA IN OTHER SLEEP DISORDERS: MOVEMENT DISORDERS 205

It should be noted that the ICSD criteria for bruxism do not include any resultant changes
in sleep or wakefulness. In an age and gender matched PSG study of 18 patients with bruxism
and 18 controls, there was no significant difference in total sleep time, sleep efficiency, sleep
latency or arousals between the two groups (80). In a similar study of six patients and six
controls, again no significant differences in total sleep time, wake time after sleep onset or
sleep latency were noted (81). A further PSG study of 10 patients and 10 controls also failed to
detect any differences between sleep duration, sleep efficiency and arousals (82). In a European
study of 13,057 subjects, the disorder of sleep bruxism was not associated with insomnia disorder
diagnoses but tooth grinding was associated with perception of disrupted sleep in a multivariate
model (79). In a study of 917 subjects, mostly shift workers, frequent occurrence of bruxism was
associated with symptoms of difficulty initiating sleep and disrupted sleep (83) Thus, there is no
evidence that bruxism, either as a motor phenomenon or an arbitrarily defined disorder, causes
significant insomnia. It is possible that there may be an association with perceived disrupted
sleep, but other data suggests that bruxism may actually be the result of sleep fragmentation
rather than its cause.
In a study of 10 patients with bruxism, a significant increase in EEG alpha band activity
was seen in a four second window preceding the onset of RRMA (82). Similarly, during the
10 heart beats preceding onset of RRMA, the mean heart rate significantly increased. These
findings suggest that a microarousal occurred before the start of an episode of bruxism and thus
may have been instrumental in its causation. Similarly, in a study of six patients with bruxism,
EMG activity commenced during phase A of the cyclic alternating pattern and especially during
subtype A3 (81). Phase A indicates a state of arousal and subtype A3 specifically suggests the
presence of microarousals. The results of these studies match with the clinical observation that
episodes of bruxism sometimes occur with arousals from episodes of obstructive sleep apnea.
Because the major consequences of bruxism are related to dental damage and not to sleep
disruption, management usually involve the use of oral appliances rather than medications.

RHYTHMIC MOVEMENT DISORDER

Rhythmic movement disorder (RMD) consists of stereotyped, rhythmic and repetitive move-
ments of large muscles during drowsiness or sleep. The movements take the form of rocking
the head or body from side to side or from front to back, resulting in alternative names of head
banging, body rocking or jactatio capitis nocturna. The movements are common in infancy and
early childhood and in some people persist into later childhood or adulthood. The movements
occur at a frequency of 0.5 to 2 Hz and are easily recognizable on a PSG and video recording
(57). The ICSD (second edition) definition of RMD requires the movements to be predominantly
sleep related, occurring near bedtime or when the person appears drowsy or asleep. In addi-
tion, the movements must interfere with normal sleep, significantly impair daytime function or
result in self-inflicted injury that would require medical treatment (2). However, whether RMD
actually disturbs sleep is controversial.
Rhythmic movements occur during light NREM sleep, especially stage N2, as well as
during REM sleep (84), but also frequently occur during drowsiness before sleep onset and
following arousals from sleep. Many patients will explain that they have used the soothing and
rhythmic nature of the movements to induce sleep, usually from early childhood onwards. In a
questionnaire study of 1413 children aged 6.2 to 10.9 years, RMD was significantly associated
with a complaint of sleep onset insomnia (odds ratio 2.4), but causation could not be determined
(85). Further studies of the clinical consequences of the phenomenon are needed, but at present
there is little evidence that rhythmic movements cause insomnia. Unless there is a risk of body
injury or the sleep of a bed partner is disrupted, RMD generally does not need treatment
although associated primary insomnia may need to be independently addressed. No trials of
therapy for RMD have been reported, although the use of benzodiazepines such as clonazepam
has been suggested (86).

SLEEP RELATED LEG CRAMPS

Leg cramps are painful contractions of muscles of the leg or foot with resultant tightness or
hardness. The pain is relieved by stretching the muscle, often induced by standing on the affected
leg (2). Sleep-related leg cramps wake patients abruptly from sleep. While cramps can occur in
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206 SILBER

some neuromuscular disorders, idiopathic cramps are common, especially in older persons (87).
Their pathophysiology is uncertain. Leg cramps, when frequent, can cause clinically relevant
arousals and may precipitate periods of sleep maintenance insomnia. However, no systematic
studies of these potential consequences have been reported.
Treatment of leg cramps can be challenging. While quinine has been recommended, con-
trolled trials have shown at most modest benefits. A meta-analysis showed a relative risk
reduction of only 21% with frequent side effects reported, especially tinnitus (88). The potential
for more serious complications of therapy, such as thrombocytopenia and cardiac arrhythmias,
should also be noted. Gabapentin and verapamil have been suggested as alternative possible
therapies, but adequate trials have not been performed (89).

SUMMARY
Restless legs syndrome is a common disorder and is one of the most important causes of
comorbid insomnia. It can usually be diagnosed clinically with a careful history. The pathogen-
esis is not fully understood, but involves genetic factors, low brain iron stores and dopamine
deficiency. Population studies show that 50% to 75% of RLS patients complain of insomnia,
confirmed by PSG studies showing reduced sleep efficiency, increased arousals and prolonged
latency to sustained sleep. Appropriate treatment of RLS can be a vital component in managing
insomnia.
Periodic limb movements of sleep accompany RLS but probably play little role in the
sleep disturbances. True periodic limb movement disorder is uncommon and, in the absence
of other disorders, rarely results in insomnia. Bruxism, while common, has not been shown
to cause sleep disruption, but may sometimes occur as a motor phenomenon accompanying
arousals from other causes. Rhythmic movement disorder consists of rhythmic movements of
large muscle groups but there is little evidence that the movements cause sleep disruption. On
the contrary, they may be seen as a sleep induction technique by patients with other causes of
insomnia. Sleep related leg cramps are little understood and their severe pain can disrupt sleep.
Treatment can be challenging.

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19 Insomnia in Other Sleep Disorders:

Breathing Disorders
Emerson M. Wickwire
Center for Sleep Disorders, Pulmonary Disease and Critical Care Associates, Columbia, Maryland, U.S.A.

Michael T. Smith
Department of Psychiatry and Behavioral Sciences, Behavioral Sleep Medicine Program, Johns Hopkins
University School of Medicine, Baltimore, Maryland, U.S.A.

Nancy A. Collop
Division of Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore,
Maryland, U.S.A.

INTRODUCTION
Recent years have seen a rapidly growing interest in the frequent co-occurrence of insomnia
disorder and sleep related breathing disorders (SRBD) (1). The two conditions were once con-
sidered orthogonal, or insomnia was considered a symptom of SRBD. However, evidence from
clinical, research, and population samples, as well as clinical experience, consistently suggest
that insomnia disorder and SRBD co-exist as distinct disease entities and warrant independent
treatment in many patients. The purpose of this chapter is to review the association between
insomnia and SRBD, the two most common sleep disorders among adults. The chapter begins
with a review of the causes and consequences of SRBD, followed by a discussion of the liter-
ature regarding the cooccurrence of chronic insomnia and SRBD. Treatment of these disorders
when they are comorbid is considered, along with the potential interactions among treatments,
including pharmacological approaches. Clinical recommendations and suggestions for future
research are offered.

DEFINITION OF SLEEP-RELATED BREATHING DISORDER

Upper airway obstructive SRBD exists on a continuum from narrowing of the upper airway to
snoring to complete obstruction. Snoring, the least severe form, occurs when air is forced through
the restricted space of a narrowed airway, causing the surrounding tissues to vibrate. As the air-
way becomes increasingly more restricted, increased work of breathing, even in the absence of
actual flow decrement or oxyhemoglobin desaturation, may result in repetitive arousals. Such
events are classified as respiratory effort-related arousals or RERAs. Hypopneas are partial
restrictions of airflow due to obstruction. A hypopnea is defined as ≥ 30% reduction in airflow
followed by ≥ 4% reduction in oxyhemoglobin saturation and/or an EEG arousal. At the most
severe end of the SRBD continuum, frank obstructive apnea occurs when the upper airway com-
pletely collapses during sleep. As presented in Figure 1, several consequences result from these
obstructive events. First, significant hypoxemia may develop. Second, increased respiratory
effort results in frequent EEG arousals, causing sleep fragmentation, a nonrestorative pattern
of sleep, and daytime symptoms (See below). Each of these outcomes has been associated with
negative health effects. Further, even without distinct hypopneas and apneas, increased airway
resistance and flow limitation during sleep [Upper Airway Resistance Syndrome (UARS)] has
been identified as a distinct sleep-related breathing disorder (2) and is associated with negative
health consequences.
Although Obstructive sleep apnea (OSA) accounts for more than 95% of apnea cases,
central sleep apnea, characterized by the absence of both effort and airflow, is not uncommonly
observed in certain populations such as congestive heart failure patients or opioid users. For
the purposes of this Chapter, we will focus most of our discussion on OSA.
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INSOMNIA IN OTHER SLEEP DISORDERS: BREATHING DISORDERS 211

60.00s 60.00s
4:15:00 AM 4:15:05 AM 4:15:10 AM 4:15:15 AM 4:15:20 AM 4:15:25 AM 4:15:30 AM 4:15:35 AM 4:15:40 AM 4:15:45 AM 4:15:50 AM 4:15:55 AM

EDGL

EDGR
S2 S2

D1A2

C3A2
Resp Arousal

EMGch
ECG

EMGat
Hypopnea (21.15s)
NCPT

AFth
Chest

Abd
98

98

97
97

97
97

97

97

97
Desaturation (27.00s) [7.0 %]
97

97

97
97

97
97

97
97

97

97
97
97

97
97
97
97
97
97

97

97

96

96

96
96

96
96

96
96
SpO2
96

95
95

95
94
94
94

94
94
92

92
9

91
9

9
9

9
9

9
9

90
91
Figure 1 Hypopnea This figure shows a polysomnographic recording of an obstructive hypopnea lasting 21
seconds. Airflow (NCPT and AFth ) is decreased but effort (Chest and Abd) increases as the event proceeds.
The event is terminated with an arousal from sleep and oxygen saturation falls by 7%. Abbreviations: EOGL ,
EOGR, electrooculogram; O1 A2 , Occipital electroencephalogram; C3 A2 ,Central electroencephalogram; EMGch ,
Chin electromyogram; ECG, Electrocardiogram; EMGat , Anterior tibialis (leg) electromyogram; NCPT, Airflow as
measured by a nasal cannula pressure transducer; AFth , Airflow as measured by a thermocouple; Chest Abd,
Respiratory effort of chest and abdomen; SpO 2, Pulse oxygen saturation.

Sequelae of SRBD
The short and long-term health consequences of OSA can be severe. Common short-term symp-
toms of OSA include excessive daytime sleepiness, irritability, depressed mood, poor execu-
tive function including cognitive and memory impairment, and other performance deficits.
For example, a recent review reported that 23 of 27 studies found a significant relation
between OSA and risk for motor vehicle accident (3). Equally striking are the long-term disease
correlates of OSA. Well-documented relationships exist between OSA and hypertension, stroke,
cardiovascular death, and overall mortality (4).
Of particular relevance to health care professionals working with insomnia patients is
the complex and often subtle presentation of SRBD. Symptoms of OSA can include restless or
nonrestorative sleep, rapid weight gain, lethargy, excessive daytime sleepiness, reduced libido,
irritability, difficulty concentrating, and hyperactivity in children. Such complaints can easily
be mistaken for numerous psychological or medical disorders, including depression, anxiety,
attention deficit hyperactivity disorder and cognitive impairment (5). At the very least, to
maximize diagnostic accuracy, routine assessments across medical and psychological disciplines
should include the question, “Do you snore?”

Epidemiology of SRBD
Obstructive sleep apnea (OSA) is the second most common sleep disorder, with overall pop-
ulation prevalence estimates ranging from 3% to 7% (6). Men suffer OSA at roughly two to
three times the rate of women (7), although clinic referrals display a greater gender discrepancy,
with five or more times as many men being referred for evaluation than women. Perhaps due
to decreasing patency in the upper airway and changes in the pharyngeal structure (8,9), the
prevalence of OSA increases steadily with age until the sixth decade of life, when a plateau
appears to be reached (7). Although obstructive apnea increases with age for both genders, in
women, menopause is associated with significant increases in incidence. In addition to age and
gender, members of certain ethnic and socioeconomic groups are also at increased risk relative
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212 WICKWIRE ET AL.

to the general population. Although additional data is needed, African-Americans younger

than 25 years or older than 65 years in age have been found to have higher rates of OSA than
middle-aged African-Americans or members of other racial or ethnic groups (10,11). Similarly,
after controlling for age, body mass, and other factors, Asians are at increased risk for the devel-
opment of OSA (12,13), perhaps due to differences in craniofacial structures (14). High rates of
snoring have been reported among both Hispanic men and women (15).

Causes of SRBD
The exact cause of OSA is unknown. However, certain anatomical and behavioral factors have
been consistently associated with this condition (16). There also appears to be a genetic predis-
position for obstructive sleep apnea (17). Craniofacial structures differ across racial groups, and
these differences have also been associated with higher prevalence of OSA. In terms of behavior,
weight gain has consistently been associated with increased prevalence of the disorder. In one
community-based longitudinal study, individuals whose weight increased by 10% were found
to have a 32% increase in AHI and were at six times the risk for development of moderate or
severe obstructive sleep apnea, relative to individuals whose weight remained constant (18).
Other factors may also contribute to development or exacerbation of OSA. Alcohol consumption
decreases muscle tone in the upper airway and can precipitate apneic episodes in otherwise
normal breathing individuals, or worsen the severity of apneic events and oxyhemoglobin desat-
uration in patients with established OSA (19). Smoking and exposure to second-hand smoke
have been associated with snoring and obstructive sleep apnea (20). (Readers are referred to
reference #7, Punjabi 2008, for a detailed review of the epidemiology of OSA.)

Clinical Presentation of SRBD

Most patients referred for evaluation of SRBD do not recall their repeated airway obstructions
and arousals during the night. Although some patients do awaken choking or gasping for
air, a majority of referred individuals present based on complaints of fatigue and daytime
sleepiness or concerns expressed by a bed partner about their snoring and breathing pauses
during sleep. Not surprisingly, daytime sleepiness impacts many areas of a patient’s life, and
complaints of difficulty concentrating and staying awake at work are common. Sleep-deprived
individuals report poor cognitive functioning and mood disturbance. Relationship difficulties
are also common complaints, due to both nighttime disturbance (i.e., sharing a bed with someone
who snores loudly) as well as conflict caused by increased irritability during the day. SRBD has
also been associated with decreased libido and impotence.

Assessment of SRBD
An overnight sleep study, or polysomnogram (PSG), is usually performed to confirm the diag-
nosis. The PSG is a test that records a number of parameters during sleep: brain activity (via
electroencephalogram); electrical activity of muscles (via surface electromyography); eye move-
ments (via electrooculogram); leg movement; heart rate and rhythm; airflow, snoring; blood
oxygen saturation; and chest and abdominal movement. Most sleep centers also use video
recording, which allows treatment providers to observe sleeping position, body movements, or
other unusual behaviors during sleep.
A diagnosis of sleep apnea is made based on the number of breathing “events” (i.e., apneas
and hypopneas) observed during the night, which are calculated into an apnea-hypopnea index
(AHI—the number of events/hr of sleep time). Unfortunately, there is a lack of consensus in
interpreting the significance of the AHI, and this is reflected in inconsistent diagnostic cutoffs
among various sleep centers. Centers for Medicare and Medicaid Services (CMS) define mild
sleep apnea as having an AHI between 5 and 15 events/hr, with an associated daytime com-
plaint; an AHI of 15 to 30 is labeled moderate disease severity, and individuals with an AHI
greater than 30 are described as having severe sleep apnea (21). In terms of prevalence estimates
and determining the relationship between SRBD and insomnia, the sensitivity of these cutoffs
is important and can lead to notably divergent results, as will be discussed below.
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INSOMNIA IN OTHER SLEEP DISORDERS: BREATHING DISORDERS 213

Treatment of SRBD
Depending on disease severity and individual patient characteristics, most SRBD patients are
currently treated using one of four approaches. For mild cases of OSA, conservative treatment
includes weight loss, careful monitoring of symptom progression, and mechanical interventions,
such as sleeping with additional pillows or sewing a tennis ball into the back of a t-shirt, to
prevent the patient from sleeping on his or her back. The next least invasive approach involves
the use of a customized oral appliance designed to keep the airway open by pulling the lower
jaw forward. In a recent metaanalysis, Lim and colleagues (22) reported significant reduction
in disease severity when use of an oral appliance was compared to a control condition. Surgical
alternatives such as uvulopalatopharyngoplasty (UPPP) represent the most invasive treatments.
Although surgery may be effective in certain carefully selected patients, a recent review (23)
found insufficient evidence to support the use of surgical treatment approaches in SRBD.
Continuous positive airway pressure (CPAP) is the currently the most commonly
employed and “gold standard” treatment for SRBD and an overwhelming majority of SRBD
patients are treated using positive airway pressure therapy. CPAP consists of small machine
that generates a prescribed level of air pressure, delivered to the upper airway via a hose and
mask that covers the nose or nose and mouth. The air pressure functions as a pneumatic splint,
pushing the airway open and allowing the patient to breathe normally. CPAP is the most effec-
tive first-treatment available. The major challenge to successful long-term therapy is patient
adherence. Careful follow-up and resolution of complicating factors is required to achieve com-
pliance. Readers are referred to Reference (24) for review of minimally invasive treatments of
SRBD as well as modifiable psychological factors related to CPAP adherence.

RELATION BETWEEN INSOMNIA AND SRBD

Guilleminault (25) first documented comorbid insomnia and sleep related breathing disorder
35 years ago. With few exceptions, studies of the phenomenon since then have employed
one of two designs. Nine reports have retrospectively reviewed charts of patients referred to
sleep disorder centers for evaluation of suspected sleep apnea, and several other studies have
considered the relations between insomnia and SRBD among older adults. Here the issue of
diagnostic criteria is particularly important. Although both SRBD and insomnia complaints
increase over the lifespan, there is a lack of consensus regarding the relation between various
SRBD cutoffs and functional impairment among older adults. Studies by Krakow and Gold have
considered the co-occurrence of insomnia disorder and SRBD in specific patient populations
including trauma survivors and women with fibromyalgia. Not surprisingly these studies have
varied in patient demographics, criteria for insomnia complaints, and criteria for OSA diagnosis.

Prevalence of Insomnia Complaints Among Patients Referred for Evaluation of SRBD

A majority of studies reporting on the cooccurrence of insomnia and SRBD have retrospectively
analyzed charts of patients referred to a sleep disorder center for suspected SRBD. All studies
evaluating these patient populations have utilized some form of screening questionnaire to
identify insomnia complaints, and none has included a diagnostic interview. Table 1 presents a
summary of these studies.
Of the clinic studies, Smith et al. (28) conducted the most thorough assessment of insomnia
complaints. In a retrospective review of 105 consecutive patients referred for suspected SRBD,
these authors required four criteria for a diagnosis of insomnia: a score of 15 or greater on the
Insomnia Severity Index (34), complaint duration of at least six months, objective sleep onset
latency or wake after sleep onset of at least 30 minutes (as documented by PSG), and a daytime
complaint. Thirty-nine percent of SRBD patients met criteria for moderately severe insomnia.
Unfortunately, the AHI threshold used to define OSA was not included in this report.
In a representative study, Krell and Kapur (31) assessed subjective sleep latency, noc-
turnal awakenings, and early morning awakenings via three individual items, scored on a
four-point scale. Just more than half of patients diagnosed with OSA (AHI > 10) reported at
least one insomnia-related complaint. In this study, among the patients with SRBD the most com-
mon complaint was difficulty maintaining sleep (36.4%), followed by difficulty initiating sleep
(29.4%) and early morning awakening (28.9%). Interestingly, a significantly greater percentage
(81.5%) of patients without SRBD (i.e., AHI < 10) reported at least one insomnia complaint,
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214 WICKWIRE ET AL.

Table 1 Retrospective Chart Review Studies of Insomnia Complaints in Patients Referred for Evaluation of
SRBD

Insomnia Prevalence of
References N criteria OSA criteria insomnia Major findings
26 358 Questionnaire RDI > 5 OI in women: Profile of SRBD-related
items 27.9%; OI in men: sleep disturbances
21.9% may differ b/t men
and women, (e.g.,
women more SOL
complaints than men
but not snoring or
EDS; Women also
complain ↑ EDS and
↑ SOL together,
more often than men.
27 157 4 questionnaire AHI > 5, 42% ≥1 complaint: OI: ↓ AHI; MI: ↑ EDS;
items AHI > 15 OI (6%), MI results similar w/AHI
(26%), EMA > 5 and AHI > 15
(19%)
28 105 ISI > 15, self-report, chart 39% Suspected OSA: 2x
duration > 6 review (AHI likely INS; INS +
mo, SOL or not reported) SRBD vs. SRBD
WASO > 30 alone: ↑ depression,
m on PSG ↑ anxiety, ↑ stress
29 357 3 questionnaire AHI > 10 OI: 15.6% if AHI > OI: ↓ SRBD; lie awake
items 60, 18.2% if AHI w/intense thoughts: ↓
> 30, 20.9% if SRBD; MI: ↑ SRBD
AHI > 10; MI:
73.9% if AHI >
60, 62.9% if AHI
> 30, 58.2% if
AHI > 10
30 231 3 questionnaire AHI > 5 50% INS + SRBD vs SRBD
items alone: ↑ SOL (65 vs
17 m), ↓ TST (5.6 vs
7.2 h), ↑ psych probs
31 255 3 questionnaire AHI > 5, 54.9% ≥1 INS: ↓ SRBD; INS: ↑
items AHI > 15 complaint: OI pain, psych probs,
(33.4%), MI RLS, PLMS; AHI >
(38.8%), EMA 10 vs AHIÃ10: ↓ INS
(31.4%) (51.8% vs 81.5%)
32 119 4 questionnaire AHI > 5 33% NOA, 21% OI: ↓ AHI vs MI or no
items EMA, 16% insomnia; MI is most
WASO, 9% SOL common complaint in
SRBD; many SRBD
pts have OI
33 232 3 questionnaire AHI > 5 37% > 1 complaint: Patients reporting
items OI (16.6%), MI maintenance
(23.7%), EMA insomnia were less
(20.6%) adherent to CPAP
prescription at
clinical follow-up.
Insomnia complaints
were unrelated to
AHI.
Abbreviations: INS, insomnia; SRBD, sleep related breathing disorder; OI, onset insomnia; MI, maintenance insomnia; EMA,
early morning awakenings; SOL, sleep onset latency; WASO, wake after sleep onset; NOA, number of nocturnal awakenings;
PSG, polysomnogram; AHI, apnea-hypopnea index; ISI, insomnia severity index; RLS, restless legs syndrome; PLMS, periodic
limb movements.
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INSOMNIA IN OTHER SLEEP DISORDERS: BREATHING DISORDERS 215

Table 2 Sleep Related Breathing Disorder in Insomnia Patients

References Study design N Insomnia criteria Prevalence of SRBD

35 RCT 45 older adults TST < 6.5 h, SOL or WASO 40% had RDI > 10, 35.6%
> 30 m, 6 m duration had RDI < 5, 24.4% had
RDI between 5–9
36 RCT 80 older adults SOL or WASO > 30 m 29% had AHI > 15, 43%
w/daytime complaint for 6 had AHI > 5
m duration
38 chart review 394 older 30 m SOL; >20 m WASO, 67% had AHI > 5; 15.7%
women 3x/wk, >1 m duration, + had UARS
insomniacs daytime complaint; >30 m
SOL at least 1x/wk as
measured by actigraphy

including significantly more difficulty initiating sleep (66.7%), maintaining sleep (59.2%), and
early morning awakenings (51.8%).
Other investigators have reported an inverse relationship between insomnia complaints
and severity of SRBD. Gold et al. (29) analyzed data collected from 357 consecutive patients,
including 220 OSA (AHI > 10) patients and 137 patients diagnosed with UARS. Insomnia
complaints were quantified using three Likert items from an intake questionnaire. Consis-
tent with previous findings (31), greater sleep onset latency was associated with less severe
SRBD. Similarly, Chung (27) also found that complaints of onset insomnia were associated with
lower respiratory disturbance. In this study, an insomnia complaint was reported by 42% of
157 patients diagnosed with OSA (AHI > 5). Individuals with more severe SRBD likely expe-
rience greater daytime sleepiness, which may explain the inverse relationship between SRBD
and onset insomnia. We will return to this issue in a later section.

SRBD Among Older Adults with Complaints of Insomnia

As indicated previously, a PSG is not necessary for a diagnosis of insomnia and is in fact often
denied for insurance reimbursement. Therefore, PSG data is not typically available for clinic
patients whose primary presenting complaint is insomnia. Further, because of the cost involved
in administering PSG, insomnia researchers typically screen potential participants for the most
common signs of OSA: excessive daytime sleepiness, snoring, choking during sleep or waking
gasping for air. As a result most research evaluating SRBD among insomnia patients has been
conducted within the context of controlled insomnia research.
In one of the earliest studies to administer PSG to insomniacs, 40% of 45 recruited older
adults were found to have OSA (AHI>10) while 35.6% had no OSA (AHI > 5; (35) (Table 2).
Similarly, even after screening out obvious cases of OSA, 29% to 43% (based on AHI cutoffs
of 5 and 15, respectfully) of older adults recruited for an insomnia study were diagnosed with
previously undetected OSA (36). Guilleminauilt, et al (37) found 67% of 394 postmenopausal
women complaining of insomnia had OSA (AHI>5), and an additional 15.7% were diagnosed
with UARS. In aggregate, these data suggest high rates of SRBD in older adults complaining of
insomnia.
Among the general population the picture is less clear. In a large-scale study of more than
1700 participants, Bixler (39) found no differences in AHI based on insomnia status. Similarly,
Gooneratne et al. (40) matched 99 older adults with insomnia with 100 controls. Based on
two PSG nights, fewer insomniacs (29.3%) than controls (38.0%) were diagnosed with OSA
(AHI>15). Although the later finding may be related to sleepiness associated with SRBD, these
discrepant findings warrant more detailed consideration.

Consequences of Comorbid SRBD and Insomnia

Beyond determining the prevalence of comorbid insomnia and SRBD, it is important to evaluate
how the two disorders may interact. In terms of sleep disruption, there appear to be additive
effects of insomnia and SRBD. Individuals with both insomnia and SRBD report worse habitual
sleep than patients with only SRBD (28), and several studies have documented worse sleep
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216 WICKWIRE ET AL.

during the PSG evaluation. In the Smith et al. (28) study, individuals with both insomnia and
SRBD experienced lower sleep efficiency and total sleep time, as well as more time awake in
bed. This finding is consistent with Krakow et al. (30), who observed that patients with both
insomnia and OSA (AHI>5) reported significantly longer SOL (17 m vs. 65 m), shorter TST
(5.6 h vs. 7.2 h), and lower SE (75% vs. 92%) as measured during PSG.
A similar pattern emerges in daytime performance. Patients with both insomnia and SRBD
report significantly more depression, anxiety, and stress than did patients with only SRBD (28).
Gooneratne et al. (40) found that individuals with both insomnia and SRBD had slower psy-
chomotor reaction times and greater functional impairment, including daytime sleepiness as
measured by MSLT, than did patients with SRBD alone. At least one study has found no signif-
icant differences between individuals with insomnia and SRBD versus individuals with insom-
nia alone (35); however, small samples size in this study limited power to identify differences
between groups.

Central Sensitization: A Potential Shared Mechanism Between Insomnia and OSA

Although traditionally conceptualized as distinct disorders, insomnia and SRBD have recently
been proposed to share a common pathogenesis. For example, Gold et al. (29) suggest that
mild SRBD can result in inspiratory flow limitation and increased alpha intrusion into the
sleeping EEG. The result is a chronic hyperarousal similar to that experienced by insomniacs.
This hyperarousal is believed to account for the increased SOL among patients with mild SRBD.
Additional data support this hypothesis. Chung (27) found that individuals who experi-
enced extended sleep latencies reported less daytime sleepiness, while patients who reported
nocturnal awakenings and more time awake in the middle of the night were more likely to be
sleepy both by subjective and objective measures. In this study (n = 157), only 6% of participants
reported extended SOL, while WASO and NOA were reported by 26% and 19% of participants,
respectively.
In a sample of trauma survivors presenting for complaints of insomnia and PTSD-related
nightmares, 40 of 44 had AHI>15 (41). Similarly, 95% of patients who underwent PSG had an
AHI>15 (42). In this study, SRBD, psychophysiological insomnia, and nightmares accounted
for 37% of variance in PTSD symptoms, suggesting that sleep complaints are more complex
than simply a symptom or complaint related to psychological distress.

TREATMENT OF COMORBID INSOMNIA AND OSA

SRBD in Insomnia and/or Insomnia in SRBD

Although the true prevalence of SRBD cooccurring with chronic insomnia is not known, the
above literature review and clinical experience indicates that the two disorders coexist in a
substantial number of patients. Yet very little research has been conducted to develop appro-
priate treatment approaches when both disorders are present. The lack of systematic research
is likely due in part to the fact that the two disorders have traditionally been conceptualized
as orthogonal. Researchers developing insomnia therapies routinely exclude patients with the
diagnosis of sleep apnea to avoid confound and visa versa.
This mutual exclusion is unfortunate, as clinical experience suggests that insomnia and
SRBD often interact in complex ways that may compromise outcomes for the treatment of either
condition. For example, patients with chronic insomnia who present with subclinical anxiety
and more focused on sleep and the consequences of poor sleep, may be less likely to adhere
to CPAP interventions and experience the PAP device as sleep interfering. Conversely, patients
sometimes perceive insomnia as a stigmatization associated with mental health problems. They
therefore may be more inclined to over-attribute all their sleep problems to SRBD, and neglect
needed insomnia interventions. A recent study by Machado and colleagues highlights the fact
that chronic insomnia, left unaddressed, may be associated with poor outcome in patients
with sleep related breathing disorder (43). These authors conducted telephone interviews of
188 clinic patients previously treated for OSA with a mandibular device. Although a majority
reported subjective improvement, 20 individuals were identified as treatment nonresponders
who perceived a lack of improvement. These patients were matched on age, gender, and OSA
severity with 20 “improved” patients from the same sample. In a multivariate logistic regression
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INSOMNIA IN OTHER SLEEP DISORDERS: BREATHING DISORDERS 217

model, insomnia symptoms were the only predictors of nonimprovement. Similarly, in a sample
of 232 patients referred for evaluation of SRBD and seen in clinical follow-up, complaints of sleep
maintenance insomnia at baseline independently predicted poorer rates of CPAP acceptance
at follow-up (33). This study was the first to provide empirical support for the very common
clinical phenomenon of patients ascribing difficulty acclimating to CPAP to difficulty initiating
or maintaining sleep.
Only a few pioneering studies (summarized in Table 3) have explored the use of behavioral
interventions for insomnia in patients with SRBD, or interventions for SRBD in patients with
insomnia. In perhaps the first related study, Guilleminault and colleagues (47) subdivided a
sample of older adult females with chronic insomnia into those with upper airway resistance
syndrome versus those with no sleep related breathing disorder. None of the sample met criteria
for obstructive sleep apnea, however. Half of the subjects with UARS received either CPAP or
turbinectomy and the other half received a six-week CBT-I intervention. The group without
UARS received either CBT-I or a sleep hygiene education control condition. Interestingly none
of the groups showed improvement in Epworth sleepiness scores, and all groups showed
improvement in sleep quality, PSG sleep latency, and PSG wake after sleep onset time. This
suggests that CBT-I alone may have some long-term benefit for patients with UARS. Only
the group receiving CPAP or turbinectomy demonstrated significant reduction in fatigue and
actigraphic measure of arousal at six months. This indicates that in select cases intervening
on upper airway resistance may be a critical intervention to add to traditional interventions
for insomnia. Another major finding from the study was that subjects who underwent CBT-I
outperformed the sleep hygiene control groups as well as the SRBD treatment only groups
on PSG measures of sleep latency and total sleep time. While this study did not contrast a
treatment package that combined CPAP or turbinectomy with CBT-I, the differential gains with
both interventions suggest that a combination approach may prove superior.
The only other studies exploring treatment approaches to patients with chronic insomnia
and signs/symptoms of sleep related breathing disorder were conducted by Krakow and col-
leagues (45). In the only study of patients meeting criteria for obstructive sleep apnea, Krakow
and colleagues (45) conducted a chart review of patients who had initially presented with
symptoms of insomnia but who had achieved only partial remission of insomnia symptoms
from standard CBT-I. Nineteen patients subsequently underwent PSG and an adequate CPAP
titration trial. Comparing the titration night PSG against the diagnostic baseline, these authors
found that CPAP was associated with decreased sleep latency, decreased sleep wake transitions
and increased percentage of REM sleep.
In a prospective open label study of trauma survivors with OSA and insomnia, Krakow
and colleagues (45) studied outcomes at the end of CBT-I. Patients without complete cure from
CBT-I were then enrolled in a CPAP or mandibular positioning device (MPD) arm with outcomes
assessed three months posttreatment. Only subjects showing good adherence to CPAP or the
MPD (one subject had turbinectomy) were included in the analyses. At the end of CBT-I, all
groups demonstrated subjective improvement in insomnia. Improvement increased further at
three months on all measures. Of particular interest is that the vast majority of insomniacs
(88%) treated for sleep related breathing disorder demonstrated subclinical levels of insomnia
symptoms at three months posttreatment. This suggests that insomniacs refractory to insomnia
therapies may benefit from further evaluation and treatment of sleep related breathing disorder.
More recently, Krakow and colleagues (46) studied the effects of an external nasal dila-
tor strip in normal weight, sleep maintenance insomniacs reporting some symptoms of sleep
disordered breathing. Subjects were randomly assigned to four weeks of nasal dilator strips
versus a contact educational control condition. At one month, the nasal dilator group showed
large differential effects on self-reported insomnia severity and improvements in sleep quality.
Moderate but significant improvements were observed on measures of quality of life, sleepiness
impact, and diary symptoms of sleep related breathing disorder. While this study is suggestive,
conclusions must be tempered as no diagnostic PSGs were conducted and there was no placebo
condition. Since only subjective measurements were conducted with no blinded placebo con-
trol, it remains possible that these data might be a function of expectancies for improvement or
lack of improvement. This said, the effect sizes were large and future placebo controlled studies
using objective measurement and diagnosis is warranted.
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IHBK059-Sateia
218
Table 3 Studies Treating Sleep Related Breathing Disorder in Patients with Chronic Insomnia
References Sample Design Endpoints OSA criteria Major findings Comments
44 Two groups of Post Clinical Trial, 4 Baseline & 6 mo No OSA, AHI < 5 No group showed improved combined RX of CBT-I
+UARS RX, although

March 28, 2010

menopausal females conditions: Note: mean baseline sleepiness (ESS)
with chronic insomnia: - VAS Sleep Quality & ESS ≈7.9 all groups, All groups ↑SQ & TST (ACT not tested may hold
a. UARS + CPAP (n = Fatigue i.e., normal baseline &PSG) particular promise
1. With UARS 15) or - Actigraphy (7 days) level of sleepiness. All groups ↓PSG SL & PSG Unclear whether 4
(n = 62) Radiofrequnecy / - PSG WASO groups randomly
2. Without UARS turbinectomy (n = Therapy for UARS (Group A) allocated
(n = 68); Mean Age 15) ↓VAS fatigue and actigraphy
= 62 b. UARS + CBT-I (6 arousal index with only turbinate
weeks, n = 32)

8:56
sig. ↓ relative to B,C, & D
c. No UARS + CBT-I CBT-I > PSG SL reductions
(n = 34) CBT-I in non UARS had > ↑PSG
d. No UARS + Sleep

Char Count=
TST
hygiene Waitlist

45 Study 1: Chronic Study 1: Uncontrolled, Study 1: PSG sleep AHI ≥ 5 plus daytime Study 1: Compared to DX night, Highly selected groups
Insomnia, failed CBT-I chart review comparing continuity & architecture SX CPAP Night : ↓ Sleep-wake of treatment compliant
with sleep apnea CPAP titration night Study 2: Self-report transition; ↓ AHI; ↓ SL↑ REM% subjects and lack of
(N = 19) versus DX night sleep quality, insomnia Study 2: Both CBT-I and SRBD Rx control limit
Study 2: Trauma Study 2: Open label trial severity, & sleepiness phase demonstrated improvement conclusions &
survivors with insomnia, CBT-I followed impairment @ baseline, on all measures. ↓ Insomnia generalizability
refractory to CBT-I, and sequentially by SRBD post CBT-I and @ 3 mo: severity post SRBD RX @ 3 mo
compliant with SRBD RX (CPAP, 3 mo, oral ISI, PSQI, FOSQ FU 88% achieved nonclinical ISI
RX (N = 17) appliance, score after SRBD RX
turbinectomy)
46 Nonobese, Sleep Randomized controlled Baseline and 4 wk. Self-reported SX Nasal dilator strips associated Lack of PSG diagnosis
maintenance insomnia clinical trial of nasal Primary outcomes: consistent with mild to with large (effect sizes >1) of SRBD, a placebo
with self-reported dilators strips (4 wk (n = Self-report sleep quality, moderate, reductions in insomnia severity condition, and objective
mild-moderate sleep 42) vs. contact, SRBD insomnia severity, & uncomplicated SRBD. ISI, and improvements in sleep measurement limits
related breathing education control sleepiness impairment No PSG assessment. quality. conclusions.
disorder symptoms (n = 38) (ISI, PSQI, FOSQ, and Moderate improvements in
(N = 80) quality of life QLSEQ) sleepiness impact and quality of
Secondary Outcomes: life FOSQ.

WICKWIRE ET AL.
prospective diaries of Diary data revealed self-reported
sleep-related SX improvement in sleep quality and
sleep related breathing symptoms
Abbreviations: FOSQ, Functional outcomes of sleep questionnaire; ISI, Insomnia severity index; PSQI, Pittsburgh Sleep Quality Index; QLSEQ, Quality of Life Enjoyment and Satisfaction Questionnaire.
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INSOMNIA IN OTHER SLEEP DISORDERS: BREATHING DISORDERS 219

Drug Effects on OSA

Many drugs can have an adverse effect on SRBD patients. Drugs that depress the central nervous
system often result in worsening SRBD. The literature on this subject comes predominantly
from the study of anesthesia in OSA patients. The worsening of OSA when CNS depressants
are used is due to respiratory depression with resultant changes in neuromuscular tone and
loss of protective reflexes. Caution should be utilized when considering the use of any sedative,
narcotic or hypnotic drug in OSA patients.

Sedatives
Benzodiazepines including diazepam and midazolam, have been shown to preferentially reduce
upper airway muscle tone more than diaphragmatic muscle tone (48–50) This is thought to
worsen OSA due to the imbalance of muscle tone. Benzodiazepines also reduce the arousal
threshold so patients may have longer events prior to arousing from sleep. Finally, these medi-
cations likely also reduce hypoxic and hypercapneic ventilatory responses.

Alcohol
Many patients with insomnia use alcohol to induce sleep. Alcohol has numerous effects on sleep,
both in terms of breathing and architecture. Alcohol induces deep (slow wave) sleep but as the
alcohol wears off, REM sleep rebound occurs, although this rebound is typically fragmented
by arousal and awakenings (51). In addition to its effects on sleep, alcohol is a respiratory
depressant and has been shown in several studies to induce sleep apnea in susceptible persons,
and worsen the degree of apnea in patients known to have the disorder (19,52,53). Specifically,
alcohol has been shown to cause selective reduction in genioglossus and hypoglossal motor
nerve activity increased edema of the nasal mucosa, and reduction of the arousal response
(54–57). These depressant effects have been shown to occur even with levels of alcohol below
the “legal blood alcohol concentration” (58).

Narcotics
There are a number of case reports describing adverse events in OSA patients following surgery
in which narcotics were used for pain control (59–62). In general, most textbooks and guidelines
suggest caution in prescribing opioids to OSA patients due to their respiratory depressive
effects. In fact, however, there are relatively few studies that have actually examined the use of
these drugs in OSA (63).

Hypnotics
Medications specifically formulated as sleep aids have been studied in relation to their effects
on SRBD. Trials are usually short (1–5 nights) and placebo-controlled. Table 4 lists many of the
trials that have evaluated hypnotic use in patients with OSA. Some of the trials evaluated using
hypnotics while patients were on CPAP, to determine if the CPAP requirements changed when
under the influence of those drugs.
In general, the newer hypnotic agents (zolpidem, eszopiclone/zopiclone, zaleplon,
ramelteon) appear to have minimal effects on OSA. Typically, apnea-hypopnea indices do not
change significantly and changes in oxygen saturation are minimal and likely not clinically sig-
nificant. Some of the older agents, which were in the benzodiazepine class, did show some more
significant changes in AHI and oxygen saturation, but these were not dramatic. Of particular
interest, use of a hypnotic in one study did not show any improvement in CPAP usage, although
patients were unselected and insomnia complaints not utilized as a screen for enrollment. (Ref
61, Table 4)
In summary, it appears that some medications (benzodiazepines, opioids) should be used
with caution in OSA patients unless they are undergoing concomitant treatment with CPAP.
Further studies should be performed to determine their effects under that condition however.
Alcohol should also be avoided in OSA patients around the sleep hours, as it clearly worsens
SRBD. Using CPAP following alcohol ingestion does not appear to change CPAP efficacy-–but
again, more study is needed (76). Finally, the newer hypnotic agents appear to be relatively safe
to use in OSA patients although, again, caution should be exercised in patients with severe OSA
or with other respiratory disorders.
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220 WICKWIRE ET AL.

Table 4 Studies Investigating Effects of Medication on Respiration

References Intervention Trial type N Length Findings

64 Triazolam (0.25 mg) R/DB/PC/CO 12 1 nt ↑ NREM AHI, ↓ SpO2
nadir
65 Flurazepam (30 mg) R/DB/PC 20 1 nt ↑ # apnea and apnea
duration, ↑degree of
SpO2 desaturation
66 Nitrazepam (5, 10 mg) R/DB/PC/CO 11 1 nt each No difference between
dose doses in AI or
SpO2 nadir
67 Temazepam (15–30 mg) R/PC 15 8 wks No difference in AHI
68 Eszopiclone (3 mg) R/DB/PC/CO 21 2 nts No difference in AHI or
SpO2
69 Zolpidem/CPAP (10 mg) R/PC vs 16 1 nt each No improvement in CPAP
standard usage with zolpidem
care
70 Zolpidem/CPAP (10 mg) R/DB/PC/CO 72 4 wks No difference in AHI,
ODI, or SpO2 nadir
71 Zolpidem (10 mg) DB/PC/CO 10 1 nt ↑ AHI (3 vs 1.5), no
difference in SpO2
parameters
72 Zolpidem (20 mg)/ R/DB/PC/CO 12 1 nt each ↓ SpO2 nadir and mean
Flurazepam (30 mg) drug low SpO2 with
zolpidem
73 Zopiclone (7.5 mg) R/DB/PC 8 7 nts No difference in AHI or
SpO2
74 Zaleplon/CPAP (10 mg) R/ PC/CO 15 5 nts No difference in AHI,
↓ SpO2 nadir
75 Ramelteon R/DB/PC/CO 26 1 nt No difference in AHI or
mean SpO2
Abbreviations: R, randomized; DB, double blind; PC, placebo-controlled; CO, crossover.

CLINICAL RECOMMENDATIONS
Patients experiencing both sleep related breathing disorder and insomnia are likely to be seen
in a variety of health care environments. In each setting, health care providers should inquire,
at minimum, about difficulty initiating and maintaining sleep, as well as snoring and witnessed
apnea. The diagnostic priority should be to distinguish sleepiness from fatigue, while keeping in
mind that patients with comorbid insomnia disorder and SRBD will be likely to report complex
symptoms that may involve sleepiness and fatigue. Further, patient self-reports will be affected
by their knowledge of sleep and sleep disorders. Due to the nature of insomnia as a subjective
and highly distressing condition, patients may self-diagnose with insomnia when in reality,
SRBD or other factors play an equal or larger role in the overall sleep pathology. In addition, the
influence of social desirability factors must not be overlooked. For some patients, both male and
female, insomnia may be a more socially acceptable condition than snoring and sleep apnea,
or the opposite may be equally true. Practitioners are encouraged to consider their patients’
symptom and disease awareness and to elicit as much corroborating information as necessary
to reliably discern sleepiness from fatigue.
In terms of treatment, the overlap between insomnia and SRBD presents the equally
challenging dilemma of selecting the first targets for treatment. Not surprisingly, there are a
number of factors for providers to consider: severity of sleep complaints, comorbid medical or
psychiatric conditions, and patient preference or readiness for demanding treatments such as
CBT-I or CPAP, to name just a few although clinical judgment should guide the decision-making
process, there are a few rules of thumb. Regardless of the severity of insomnia complaints,
patients who report sleepiness while driving, who have fallen asleep unexpectedly during
daytime hours, or who exhibit other overt signs of sleepiness should be referred for a sleep
study, especially if they snore or have witnessed apneas during sleep. Similarly, if patients
describe chronic problems falling asleep or staying asleep, referral to behavioral sleep medicine
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INSOMNIA IN OTHER SLEEP DISORDERS: BREATHING DISORDERS 221

specialist should be considered. A recent report (77) of combined insomnia and poor CPAP
adherence documented the psychoeducation, motivational approach (78), and give and take
often necessary when treating patients with complicated presentations.
CONCLUSIONS AND FUTURE DIRECTIONS
Insomnia is the second most common medical complaint after pain, and sleep related breathing
disorder is the second most common sleep disorder. Health care providers in all areas, including
physicians, psychologists, nurses, social workers, and especially sleep medicine professionals,
will see patients with combined insomnia and sleep related breathing disorder. In terms of
practice, accurate assessment is essential to ensure patients receive state of the art, appropriate
treatment. Students and health care providers should be trained in the basics of assessing fatigue
and sleepiness and realize that symptoms of both insomnia and SRBD can appear as other
medical or psychological disorders. Future research will help illuminate any potential shared
mechanisms underlying comorbid insomnia and SRBD and guide the further development and
refinement of effective treatments.

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20 Insomnia in the Elderly

Philip Gehrman
Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

Sonia Ancoli-Israel
Department of Psychiatry, University of California, San Diego, La Jolla, California, U.S.A.

INTRODUCTION
Insomnia is the most common sleep-related complaint in the elderly and its prevalence increases
with age. In one study of more than 9000 older adults, 42% reported difficulty falling or staying
asleep (1). The high frequency of insomnia has led to a popular myth that disturbed sleep is a
part of the normal aging process. In fact, it is the factors associated with aging, but not aging per
se, that contribute to poor sleep. Therefore, it is not surprising that insomnia is so prevalent in
the elderly given the multiplicity of both internal and external factors that can have a negative
impact on sleep.
Aside from the increased prevalence, insomnia is of particular concern in the elderly
because of its related consequences. In addition to the sequelae seen in younger adults, such
as problems with concentration and poor quality of life, insomnia in older adults is associated
with greater risk of falls, difficulty with ambulation and balance, and visual impairment, over
and above the effects of medications (2,3). The increased fall risk is particularly concerning
since this is a strong predictor of nursing home placement (4). Compared to older adults
without sleep complaints, those with insomnia demonstrate slower reaction times and greater
cognitive dysfunction in domains such as memory (5). Thus age-related cognitive decline can
be exacerbated by insomnia. Perhaps most significantly, disturbed sleep increases the risk of
all-cause mortality, even after controlling for important covariates (6).
It is important to keep in mind the definition of insomnia. For an individual to receive
a diagnosis of insomnia (7,8) there must be both disturbed sleep and a subjective complaint
that the disturbance is associated with daytime distress or impairment. Not all individuals with
disturbed sleep meet criteria for insomnia. Although this phenomenon occurs at all ages it may
be particularly salient for older adults who might not express distress over poor sleep because
of the belief that it is just a natural consequence of aging. Fichten and colleagues separated
subjects in a study of older adults into three groups defined as good sleepers, poor sleepers
with a sleep-related distress, and poor sleepers without distress (9). The largest groups consisted
of clear good and poor sleepers (i.e., reported sleep quantity and rating of sleep-related distress
were in agreement). However, there was also a sizeable group who had disturbed sleep based on
quantitative criteria but who did not complain of poor sleep. The field of sleep research contains
a number of studies of ‘insomnia’ that did not assess for distress or impairment and hence
can only be considered studies of ‘disturbed sleep’ or ‘insomnia symptoms’ which represents a
more heterogeneous phenotype. As such an effort will be made in this chapter to use the term
insomnia only for studies that utilized this criterion.

AGE-RELATED CHANGES IN SLEEP/WAKE PROCESSES

Sleep Architecture
There are both quantitative and qualitative changes in sleep changes with age. Polysomno-
graphic studies of older adults that did not focus exclusively on those with insomnia complaints
found longer sleep onset latency, decreased total sleep time, and greater number of awakenings
during the night, despite greater time spent in bed (10). There is an associated change in the
distribution of sleep stages with more time spent in lighter stages N1 and N2 and less time spent
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INSOMNIA IN THE ELDERLY 225

in REM sleep. There is also a gradual decline in slow wave sleep (SWS), beginning earlier in life
during young and middle adulthood, resulting in reduction of delta wave amplitude (11). The
fact that these sleep changes occur with age irrespective of complaints of poor sleep has led to a
popular myth that sleep need declines with age. However, evidence suggests that it is not sleep
need but rather sleep ability that changes (12).
There are also changes in sleep/wake patterns during the day. The frequency and duration
of napping increase with age (13). This trend is maintained even within the elderly population
such that “old old” individuals reported more napping than the “young old” (14). Napping is
often a coping strategy used to compensate for poor sleep as suggested by data demonstrating a
relationship between nighttime sleep fragmentation and increased daytime napping (15). There
are some data to indicate that napping can improve daytime functioning. For example, Monk
and colleagues found that an afternoon nap decreased objective sleepiness as measured on the
Multiple Sleep Latency Test (16). However, this same study found that napping was associated
with reduced total sleep time and earlier wake times the following night. It has been argued
that daytime napping reduces homeostatic sleep drive that has accumulated prior to the nap, so
at bedtime there is less drive available to initiate and maintain sleep, although data examining
this relationship are mixed (13).

Homeostatic Processes
Age-related changes in sleep architecture are likely a reflection of changes in underlying brain
processes for sleep and wakefulness. According to current models of sleep/wake regulation,
arousal state is determined by homeostatic (process S) and circadian (process C) mechanisms
(17). The homeostatic process is a drive for sleep that accumulates during wakefulness and is
discharged during sleep. Insomnia, in particular sleep onset complaints, could be produced
by an insufficient build-up of sleep drive such that at bedtime sleep-promoting processes are
weaker than those promoting wakefulness. Sleep maintenance complaints, on the other hand,
could be the result of a decline in process S during sleep that is too rapid. This would create
a situation in which there is not sufficient sleep drive to keep the individual asleep in the
latter part of the night, particularly after the minimum of core body temperature when the
drive for wakefulness increases. There is evidence that homeostatic processes change with age.
Delta activity during sleep is a marker of sleep drive, so the age-related decline in SWS can
be interpreted as indicating reduced drive (18). Theta EEG activity, which acts similarly as
a marker of homeostatic drive during wakefulness (19), has been found to decline with age
although this may reflect an overall decline in EEG power across frequency bands and not
a decline in homeostatic drive (20). Sleep deprivation experiments also provide evidence of
reduced homeostatic drive in the elderly. Following a period of sleep deprivation, and therefore
enhanced accumulation of sleep drive, good sleepers exhibit subsequent recovery sleep that is
of longer duration and is characterized by greater delta EEG activity compared to baseline sleep.
In contrast, studies of individuals with insomnia have found reduced rebound in delta activity
following sleep deprivation compared to good sleepers, although the effects on total sleep
time were mixed (18). In contrast to research on the accumulation of sleep drive in insomnia, no
studies have examined the rate of decline of slow wave activity during the night. Given the high
prevalence of sleep maintenance complaints in the elderly this possible etiological mechanism
need to be explored.

Circadian Rhythms
The second sleep/wake regulatory process is circadian rhythmicity. Most physiological pro-
cesses follow predictable rhythmic patterns with a periodicity of approximately 24 hours. These
circadian rhythms are generated endogenously by the suprachiasmatic nucleus (SCN) of the
hypothalamus and are influenced by environmental factors that act as zeitgebers or ‘time cues,’
both of which can change with age. There is a substantial body of research documenting age-
related changes in circadian rhythms in humans and various animal species. Some have even
speculated that deterioration of circadian rhythms may be a central component of the aging
process (21). Early free-running studies in animals (22) and humans (23) suggested that there
is a decrease in the intrinsic period of circadian rhythms. The human data have been criticized,
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226 GEHRMAN AND ANCOLI-ISRAEL

however, because of more recent findings that demonstrate that self-selected light exposure
during free-running protocols affects estimates of period derived from these studies (24). In
a more recent constant routine study comparing core body temperature rhythms in younger
and older subjects, Czeisler and colleagues found almost identical periods in the two groups
(25). This and similar studies suggest that, at least in humans, there is no decrease in period
associated with aging.
A second age-related change is a decrease in the amplitude of the circadian rhythms,
including in the rhythm of body temperature, melatonin, urinary electrolytes, and prolactin
(10). In one study younger subjects had an average core body temperature amplitude that was
40% greater than in older subjects (26). Data on the amplitude of rest-activity rhythms, which
are less of a ‘pure’ measure of circadian rhythmicity, are mixed (e.g., 27).
A phase advance of circadian rhythms has been consistently found in older compared to
younger adults. During constant routine studies, a phase advance of approximately 90 minutes
was found in older adults (10). These results are in accordance with those found for circadian
rhythms of melatonin (28) and cortisol (29) in older adults. This phase advance manifests as
difficulties with sleepiness in the evening prior to the desired bedtime and early morning
awakenings with difficulty returning to sleep (see below).
Lastly, there is some evidence that there is a desynchronization of circadian rhythms with
age. Wever found that 70% of subjects between the ages of 40 and 70 years became internally
desynchronized during free running compared to only 22% of younger subjects (30). In another
study, it was found that 18% of younger subjects met criteria for desynchronization of rhythms
compared to 50% of older adults (31).
There are several etiological pathways for the age-related decline in circadian rhythmicity
including reductions in endogenous circadian drive, environmental cues, and entrainment.
Swaab et al. found that the volume of the SCN decreased by 41% with age in subjects more than
80 years of age (32). In animals, lesions that destroy a large portion of the SCN are sufficient
to cause disruptions in circadian rhythms that produced nocturnal wakefulness and daytime
napping, similar to sleep changes seen in aging (33). Recently Malatesta and colleagues found
evidence for changes in CLOCK protein activity in older compared to younger animals (34),
suggesting that there may be age-related declines in the fundamental molecular pathways that
generate circadian rhythms.
According to the “environmental hypothesis,” deficient zeitgebers, which entrain endoge-
nous rhythms to the external environment, are the cause of disrupted circadian rhythms in aging
(35). Bright light plays an important role as a zeitgeber and studies have found that many older
adults receive very little exposure to bright light. One study reported that older adults were
exposed to bright light (>1000 lux) for only 35 minutes/day compared to 102 minutes in
younger adults (36). In a study of community-dwelling elderly, investigators reported that the
median duration of exposure to light more than 1000 lux was only 4% (37). Exposure to bright
light is the strongest, but not the only environmental cue that can entrain circadian rhythms.
Older adults have also been shown to have less exposure to other zeitgebers such as physical
activity (36).
Whereas light acts as the primary zeitgeber during the day, melatonin plays an important
role in sleep/wake regulation at night. A number of investigators have reported age-related
decreases in melatonin production. Kennaway and colleagues conducted a meta-analysis of
these studies and found a decrease of peak plasma melatonin levels of 36% and 43% in adults age
50 to 65 and 65 to 80, respectively, compared to adults between the ages of 20 and 35 (38). Several
theories have been proposed to explain the decline in melatonin with age including decreased
beta-adrenergic receptors in the pineal, increased clearance of melatonin in the brain, and
reduced exposure to bright light (39). Recent data also suggest that there is an age-related decline
in responsiveness of the SCN to melatonin (40). However, data on the relationship between
melatonin production and insomnia complaints in the elderly are very mixed. Lushington and
colleagues found no differences in urinary melatonin metabolites between elderly with sleep
maintenance insomnia and good sleepers (41). The therapeutic effects of exogenous melatonin
on insomnia have been equally variable, with several large controlled studies failing to find any
significant benefit (42). The relationship between melatonin and sleep in older adults is clearly
complex and further research will be necessary to untangle the intricacies.
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Aging may be associated with a failure of the entrainment process itself. Light exposure
affects activity of the SCN via the retinohypothalamic tract, which is the primary neural pathway
by which bright light entrains circadian rhythms. Once photic (light-related) information reaches
the SCN it induces the expression of immediate early genes, such as c-fos and jun-B, at times
of day that correspond to the phase response curve to light (43). Sutin et al. found that there
was an age-related decrease in the response of immediate early genes to photic stimuli (44)
suggesting a possible site of molecular changes with age that impact the entrainment of circadian
rhythms.
The results of these and other studies suggest that there are definite changes in circadian
rhythms with age that reflect a variety of etiological pathways. Coupled with the changes in
homeostatic processes, it is clear that increasing age is associated with a greater vulnerability to
insomnia due to alterations in basic sleep/wake regulation. This is consistent with the concept
of predisposing factors in Spielman’s 3-P’s model of insomnia (45). Increased vulnerability to
insomnia in older adults can interact with precipitating events that trigger an episode of disturbed
sleep.

CORRELATES OF INSOMNIA IN THE ELDERLY

Several prior chapters have addressed the most common correlates of insomnia that act as
precipitating factors including medical illness, psychiatric illness, and the effects of medications
and substances. The mechanisms by which these factors contribute to insomnia are not thought
to change with age except to the extent that older adults may be more vulnerable to their effects
due to the previously reviewed changes in sleep/wake regulatory processes. The difference in
the elderly is the higher prevalence of these factors compared to younger adults.

Medical Factors
Advancing age is associated with, on average, a greater number of physical health problems.
In the 2003, National Sleep Foundation poll of sleep in older adults it was found that the likeli-
hood of disturbed sleep increased in parallel with increases in the number of medical conditions
reported (46). This relationship exists across a wide range of medical conditions including car-
diac and pulmonary disease, but the strongest relationships are found in conditions associated
with pain. Sleep maintenance is particularly affected with 81% of arthritis patients and 85% of
chronic pain patients reported difficulty staying asleep (47). Aside from pain, chronic medical
conditions more prevalent in the older adult such as nocturia secondary to an enlarge prostate,
shortness of breath in congestive heart failure or chronic obstructive pulmonary disease, and
neurological damage related to cerebrovascular accidents or dementia can negatively impact
sleep in other ways (48–50). As the number of medical conditions increases these factors can
have a cumulative effect on sleep.

Psychiatric Disorders
Psychiatric illness is a frequent comorbidity with insomnia. Insomnia is a diagnostic criterion for
major depression and generalized anxiety disorder, and sleep disturbance is a common correlate
of psychopathology in general (51). The relationship between insomnia and depression/anxiety
is bi-directional. The onset of psychiatric illness is often associated with a worsening of sleep.
However, several longitudinal studies have now found that insomnia in psychiatrically healthy
individuals is a risk factor for later development of psychopathology, particularly depression
and anxiety (52). The prevalence of psychiatric illness is lower in the elderly compared to
younger and middle-aged adults (53) so the higher rate of insomnia in the aged population is
not a consequence of greater psychopathology. Although insomnia often occurs in the context
of psychiatric illness (so called ‘secondary insomnia’) data are emerging that resolution of the
illness is often not associated with an improvement in sleep (54). It appears that over time the
insomnia develops into an independent condition requiring sleep-specific interventions. It is
likely that a portion of the elderly insomnia population first experienced disturbed sleep in the
context of psychopathology earlier in life, with perpetuation of the insomnia over time despite
the absence of ongoing comorbid psychopathology.
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228 GEHRMAN AND ANCOLI-ISRAEL

Dementia
Although the prevalence of psychopathology in general declines with age, there is an increase
in dementia (53), which is often associated with insomnia. In one study of community dwelling
adults with dementia, between 19% and 44% complained of disturbed sleep (55). Polysomno-
graphic studies have documented lower sleep efficiency, greater nocturnal awakenings, and
more time spent in lighter stages of sleep compared to nondemented older adults (10). Fragmen-
tation of sleep at night is accompanied by disruption of wakefulness during the day. Patients
with dementia often sleep during the day, with one study of institutionalized patients with
Alzheimer’s dementia finding that patients were rarely asleep for a full hour at night or awake
for a full hour during the day (56). Insomnia can exacerbate the difficulties of providing care
for an individual with dementia because they may be awake and wandering around during the
night. Pollak and Perlick found that disturbed sleep was one of the primary reasons caregivers
cited for decisions regarding institutionalization (57). During the day, cognitive functioning
may be further impaired as a result of poor sleep.
It is not clear if the sleep disturbance is the result of neurological damage associated with
the dementia or if it is related to the other factors such as pain or depression (58). Many of the
age-related changes in sleep/wake processes are magnified in dementia including deterioration
of the SCN (32) and reduced circadian rhythmicity of melatonin (59) and activity (60). There is
often also a paucity of exposure to zeitgebers, particularly bright light. Campbell et al found that
community-dwelling elderly with mild Alzheimer’s dementia received, on average, less than
30 minutes of bright light exposure per day (61). The situation is even worse for those in nursing
institutions that are often dimly lit (62). Increased prevalence of sleep disordered breathing (SDB)
and periodic limb movements in sleep (PLMS) in patients with dementia further complicates
the situation (63).

Sleep Disorders
In the older adult, primary sleep disorders also contribute to the decreased ability to get sufficient
sleep, and may present with a primary complaint of insomnia. SDB is characterized by recurrent
apneic events throughout the night due to obstruction of airflow or reduced respiratory effort.
Reduced blood oxygen triggers an arousal that stimulates a resumption of normal airflow.
These arousals are often very brief and are typically not remembered the next day; however
they often can lead to full awakenings. Even if each awakening is brief, their cumulative impact
can be experienced as a sleep maintenance problem. This may be further compounded by
increasing difficulty returning to sleep in some individuals. The apnea/insomnia comorbidity
is particularly relevant in older adults, as both conditions occur with higher prevalence than
in younger adults. In a randomly selected community sample of older adults Ancoli-Israel and
colleagues found that 81% had an apnea hypopnea index (AHI) of at least five events/hr (64).
Even at a more stringent cutoff of 20 events/hr, 44% of the samples were categorized as having
SDB. These rates are considerably higher than in young and middle aged adults. In one case-
control study of older adults with insomnia complaints there was an additive impact of daytime
functioning such that impairment was greatest in subjects with both conditions compared to
those with only one or zero conditions (65). Rates of SDB are even higher in the portion of
the elderly population with dementia (see below). The gold standard treatment for SDB is
continuous positive airway pressure (CPAP), with oral appliances and upper airway surgery as
alternatives. There is currently little known regarding the impact of CPAP treatment on insomnia
for individuals with both conditions, although it is unlikely that CPAP alone will eliminate
difficulties falling or staying asleep (see Collop chapter for further discussion of this issue).
Similarly, the prevalence of PLMS, the core feature of periodic limb movement disorder
(PLMD), and restless legs syndrome (RLS) increases with age. Rates of the disorders in the
elderly have been found to be as high as 45% for PLMS (66) and between 9% and 20% for RLS
(67). PLMS are characterized by repetitive limb movements throughout the night, usually in the
legs. As in sleep disordered breathing, PLMS can cause repetitive awakenings from sleep and
lead to a complaint of sleep maintenance insomnia. RLS, on the other hand, is associated with
uncomfortable, tingling sensations in the legs during rest and/or an irresistible urge to move
the legs. This typically occurs in the evening or at night, especially when sitting or lying down.
The sensations are only relieved with movement. The discomfort of RLS can interfere with sleep
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INSOMNIA IN THE ELDERLY 229

onset and make it more difficult to fall back to sleep when awake during the night. PLMD and
RLS are currently treated with medications that either target the leg movements directly or
reduce the arousal threshold. Dopaminergic agents are the most commonly prescribed class of
medications (see Chapter 18).
A third sleep disorder common in the older adult is advanced sleep phase (ASP), as
described above. Patients with ASP get sleepy early in the evening and awaken early in the
morning hours. Two scenarios are likely to occur. In the first scenario, the older adult, although
sleepy, may force himself/herself to stay awake to a more “acceptable” bedtime, yet still awaken
between 3:00 AM and 5:00 AM. This results in daytime sleepiness and perhaps daytime napping.
In the second scenario, the older patient falls asleep after dinner while reading or watching
television and then has a difficult time falling asleep when going to bed later in the evening.
That patient still awakens early in the morning. These patients then complain of both difficulty
falling asleep and difficulty staying asleep, both of which really result form the advanced phase
and poor sleep habits. This type of “insomnia” is best treated with light therapy (see below).

Medications and Substances

With the high rates of medical and psychiatric disorders in older adults it is not surprising
that they also have a higher rate of both prescription and over the counter medication use.
Although most medications do not have wake-promotion as their primary clinical effect, many
have alerting side effects that can interfere with sleep. The timing of dosing and pharmacoki-
netic properties of a medication will determine its potential impact on sleep. Medications taken
at night and those with long half-lives have the greatest potential to impact sleep. Some of the
classes of medications known to negatively affect sleep include: ␤-blockers, bronchodilators, cor-
ticosteroids, decongestants, diuretics, and other cardiovascular, neurological, psychiatric, and
gastrointestinal medications. A number of medications can have sedating effects and promote
sleep when taken at night, but can have a negative impact when taken during the day. Daytime
dosing of sedating medications can produce intentional or unintentional sleep episodes during
the day and disrupt both homeostatic and circadian process (see section on napping). Despite
the well known alerting or sedating effects of many medications, many prescribers fail to take
this into consideration when determining the appropriate dosing strategy. With polypharmacy
often the norm for older adults, the chances of medications having a negative impact on sleep
are high.
The effects of alcohol on sleep are well documented. Although alcohol can facilitate
sleep onset, there is often a disruption of sleep later in the night (68). Many individuals are
unaware of this negative effect and use alcohol to self-medicate for disturbed sleep. Studies have
found that older adults are more likely than their younger counterparts to use alcohol for this
purpose (69).

TREATMENT OF INSOMNIA IN THE ELDERLY

There are several options for the treatment of insomnia in the elderly. These treatments are
covered in more detail in other chapters but each will be described here with emphasis on
application with elderly patients.

Pharmacologic
The first line treatment of insomnia has traditionally been pharmacologic. A wide range of med-
ications has been used to treat insomnia including sedative-hypnotics, antihistamines, antide-
pressants, antipsychotics, and anticonvulsants. Commonly used medications include those that
are indicated for the treatment of insomnia or off-label medications, used due to their sedating
side-effects. There are no data available in the elderly to support the use of agents other than
sedative-hypnotics so those medications should be used cautiously, if at all. The 2005 State of the
Science Conference on Insomnia concluded that antihistamines, antidepressants, antipsychotics
and anticonvulsants all have more risks than benefits associated with them and should not be
used for the treatment of insomnia (70).
Sedative-hypnotic medications can be classified as benzodiazepines (e.g., temazepam),
nonbenzodiazepine receptor agonists (i.e., zaleplon, zolpidem, zolpidem MR, eszopiclone),
or melatonin receptor agonists (i.e., ramelteon). Pharmacologic treatment has the advantage
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230 GEHRMAN AND ANCOLI-ISRAEL

of rapid treatment response but there are important disadvantages including potential resid-
ual daytime sedation, dependence, tolerance, and withdrawal. Daytime sedation is especially
important to consider in the elderly who may be at increased risk of falls. Several studies
have found an association between use of benzodiazepines and other psychotropic drugs
and an increased risk of falls (71) although there are limited data regarding the use of the
newer sedative-hypnotic medications. Brassington and colleagues attempted to separate the
risks posed by medications from those due to disturbed sleep in a large sample of community-
dwelling elderly (2). Their results suggested that sleep problems rather than the medications was
associated with an increased risk of falls. A recent study by Formiga et al followed adults older
than age 89 years and found no difference in use of benzodiazepines between those that fell and
those that did not (72). These mixed results suggest that caution is warranted when prescribing
sedative-hypnotic medications for the elderly, especially with the older benzodiazepines and
longer-acting agents. Other factors that need to be factored into decisions for pharmacologic
treatment in the elderly are drug interactions given the high prevalence of polypharmacy, and
possible age-related changes in drug metabolism and excretion that may narrow the therapeutic
index. While there have been few studies of the effect of the older benzodiazepines or sedating
antidepressants in older adults, the newer sedative hypnotics have been shown to be safe and
effective in older patients with insomnia.
Given some of the problems associated with sedative-hypnotic medications, there has
been interest in the use of exogenous melatonin as a treatment for insomnia, particularly in
the elderly. There have been a number of randomized trials of melatonin in the elderly, both
with and without dementia, including a large multisite trial of 157 patients with Alzheimer’s
disease (42). Although some studies have found beneficial effects on sleep (ex. 73), a 2005 NIH
Consensus Conference on Insomnia concluded that there was not sufficient evidence of efficacy
(74). Melatonin receptor agonists, such as the drug ramelteon, may have more potent hypnotic
properties because they selectively bind to MT1 /MT2 receptors with a 1,000-fold greater affinity
than melatonin (75).

Cognitive-Behavioral Treatment
Although pharmacologic management is the most commonly employed treatment option, the
risks of side effects and potential need for long-term use suggest that alternative approaches may
be desirable, either alone or in combination with hypnotic medications. Cognitive-behavioral
treatment of insomnia (CBT-I) is a nonpharmacologic approach that uses a collection of strategies
to break the cycle of insomnia and reestablish a healthy sleep/wake pattern. The first component
of CBT-I is sleep hygiene, a set of habits and practices in which patients can engage in order to
promote healthy sleep. Some sleep hygiene guidelines that are particularly relevant for older
adults include reducing daytime napping and engaging in regular physical activity. For many
patients with insomnia, the bed and bedroom are not a cue for sleep because nonsleep activities
such as reading and watching TV takes place in bed. McCrae and colleagues assessed sleep
hygiene practices in community-dwelling older adults and found that those with insomnia
did not engage in a greater number of poor sleep hygiene practices, but may have been more
susceptible to their sleep-disrupting effects (76). Stimulus control is designed to reestablish an
association between the bed and sleep by eliminating sleep-incompatible activities in bed (77).
Often, patients with insomnia believe they can achieve a reasonable amount of sleep by spending
excessive time in bed, but this results in a low sleep efficiency. The technique of sleep restriction
has patients curtail time spent in bed in order to increase sleep efficiency (78). The rationale
behind this approach is that reducing time in bed will lead to an acute reduction in total sleep
time and hence an accumulation of homeostatic sleep drives. Over the course of several weeks
the increased sleep drive leads in increase in sleep efficiency. As sleep efficiency improves, the
patient is allowed to increase time in bed. There has been concern about using sleep restriction
in the elderly due to the potential sleep-deprivation related increased risk of falls. To minimize
this risk, a variant of sleep restriction, called sleep compression (79), can be used that reduces
time in bed more gradually. Patients with insomnia often report that they have difficulty in
sleeping because of excessive mental activity. Cognitive strategies are designed to alter both the
content and process of mental activity in order to facilitate sleep (80). Although there are several
cognitive techniques available, a commonly-used approach is to help patients identify distorted
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INSOMNIA IN THE ELDERLY 231

beliefs about sleep that are strongly held (ex: “I must get 8 hours of sleep in order to function
the next day.”) During the night when there is difficulty with sleep initiation, these thoughts
are activated and exacerbate the disturbance. Patients are taught to challenge these distorted
patterns of thinking, which, over time, can lead to changes in patterns of sleep-related thinking.
Meta-analyses of studies testing the efficacy of CBT-I have demonstrated significant
improvement in symptoms comparable to pharmacotherapy (81,82) including an analysis lim-
ited to studies in the elderly (83). A particularly noteworthy study by Morin and colleagues
compared CBT-I with temazepam in older adults with insomnia with a follow-up of two years
(84). Outcomes were comparable across treatment groups by the end of the active treatment
phase. However, CBT-I produced more durable improvements that were significantly better
than pharmacotherapy alone on follow-up assessment. This study also raises the question of
whether pharmacotherapy and CBT-I should be combined in order to capitalize on the quicker
treatment response of mediation and the long-lasting effects of CBT-I. They found, however,
that the combined treatment group had worse outcomes long-term than CBT-I alone (84).
More research is needed to determine if a combined treatment approach can be an efficacious
option.

Light Therapy
Aging is associated with changes in the circadian system, as described previously. Treatment
strategies that target the circadian system may therefore improve insomnia in the elderly. Given
that bright light is the most potent zeitgeber, exposure to bright light, (ie, light therapy) should
strengthen rhythms. There have been a number of studies of light therapy in elderly with
insomnia related to circadian rhythm disturbance. The specific timing of light therapy can
produce a phase delay, phase advance, or no shift in phase. The advanced sleep phase commonly
seen with aging can be treated with evening light exposure (85). Bright light should be avoided
in the morning in these individuals, which may necessitate wearing sunglasses when outside.
Although a delayed sleep phase is less common in the elderly, morning bright light exposure is
effective for producing a phase advance (85).

SUMMARY
In summary, many older adults suffer from insomnia. There is an increased vulnerability to
insomnia due to changes in basic sleep/wake processes, as well as a number of factors that
can contribute to disturbed sleep. Treatment options are generally consistent with those used in
younger adults, but there are additional considerations when working with the elderly.

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21 Pediatric Insomnia
Bobbi Hopkins and Daniel Glaze
Baylor College of Medicine, Texas Children’s Hospital Children’s Sleep Center, Houston, Texas, U.S.A.

INTRODUCTION
Pediatric insomnia is defined as a “repeated difficulty with sleep initiation, duration, consolida-
tion, or quality that occurs despite age appropriate time and opportunity for sleep and results in
some form of daytime functional impairment for the child and/or the family” (1). The etiology
of the insomnia varies based on age and is frequently multifactorial. Factors contributing to
insomnia in children vary, but include bedtime resistance, inability to fall asleep easily, fre-
quent or prolonged night awakenings, early morning awakenings, circadian rhythm disorders,
parasomnias, sleep-related movement disorders, and sleep-related breathing disorders (2,3).
Children with insomnia and decreased sleep duration are more likely to have difficulties
with attention, hyperactivity, excessive daytime sleepiness, interpersonal relationships, and
health (4,5). Tantrums and behavior issues are more likely to occur in young children with
sleep problems compared to those without sleep problems. Up to 20% of school-aged children
with sleep difficulties have failed at least one year of school (6). Depression and anxiety are
increased in children with sleep problems (7). When children do not sleep well, their families do
not sleep well. Mothers of infants with sleep problems are more likely to report depression (8).
For every one-hour reduction in the number of hours of sleep per night, the odds of childhood
obesity increase by 41% (9). Unfortunately, children with early sleep difficulties are more likely
to have problems sleeping when they are older (2). Therefore, early diagnosis and treatment is
paramount to a child’s success.

THE DEVELOPMENT OF NORMAL SLEEP

Identification and diagnosis of insomnia in children requires knowledge about the normal
development of sleep in children. Pediatric sleep patterns evolve with age. The average number
of hours of sleep in a 24-hour period decreases from 14.2 hours as an infant to 8.1 hours as an
adolescent (10).

Infants and Toddlers (0–2 Years)

During the first three months of life, infants typically sleep three to four hours at a time,
achieving between 16 to 17 hours of sleep in a 24 hour period (11). However, over the course
of the first year, most infants develop a diurnal sleep pattern with the majority of their sleep
being consolidated during the night with an accumulated two to three hours of napping during
the day (12). By nine months of age, 70% of children sleep throughout the night (13). At one
year of age, most children sleep between 13 to 16 hours in a 24-hour period with the majority of
the sleep consolidated during the night and with two daytime naps (12). By 18 months of age,
children change from two daytime naps to one daytime nap (10).
Parents of infants report frequent nighttime awakenings and early morning awakenings
(14). Observational studies have shown that normally developing infants wake intermittently
throughout the night and most will vocalize with the awakenings (15). Infants who are put into
their beds awake are more likely to be able to self-regulate or “self-soothe” themselves back
to sleep without intervention following an awakening and this skill increases with age (15).
Self-soothers have longer periods of consolidated sleep and an increased amount of quiet sleep
than non self-soothers (15).
Parent-infant interaction, environment, and childhood illnesses all impact the develop-
ment of the infant’s sleep habits. The presence of parents at sleep onset and provision of food
or drink at a nighttime awakening are associated with a greater likelihood of sleep difficulties
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236 HOPKINS AND GLAZE

in infants (16,17). Maternal separation anxiety is associated with increased night waking (18).
Frequent nocturnal awakenings are associated with increased accidental injury in toddlers (19).

Young Children (3–6 Years)

At three years of age a child sleeps approximately 12 hours in a 24 hour period decreasing to
approximately 11 hours in a 24 hour period by three years of age (10). The majority of the sleep
is consolidated during the night. Although 50% of children take a daytime nap at three years of
age, daytime naps become shorter and less frequent with age with only 8% of children napping
at five years of age (10).
In this age range many children experience bedtime issues, including refusal to go to bed
or to sleep. In a study of children four to six years of age, 17.3% were reported to take more than
30 minutes to fall asleep and 10.1% were reported to have “too much energy to sleep” at least
once per week (2). Night awakenings tend to decrease with age, but 15.6% of parents report
night awakenings to be at least a weekly problem for their children (2).

School-Aged Children (7–12 Years)

The total number of hours a child sleeps in a 24-hour period decreases further from an average
of 10.6 hours at 7 years of age to approximately 9.3 hours at 12 years of age (10). Children in this
age range no longer take routine naps (10). The frequency of problematic night awakenings con-
tinues to decline with under 10% of children 11 to 12 years of age experiencing difficulties more
than one time per week (2). However, sleep initiation insomnia remains problematic with 13.1%
of 7 to 10 year olds and 15.3% of 11 to 12 year old children taking more than 30 minutes to fall
asleep at least one time per week (2). Inadequate sleep hygiene starts to contribute to insomnia
in this age group. Television decreases sleep efficiency and computer games prolong the time to
go to sleep in school-aged children (20). Adjustment and psychophysiologic insomnia as well
as insomnia secondary to other medical or mental disorders become more prevalent at this age.

Adolescents (13–18 Years)

Adolescents typically require between eight to nine hours of sleep per night, but in reality, many
achieve less than 8 hours of sleep per night (10,21). Adolescents tend to go to bed and sleep at later
times, but are obligated to rise early for school (21). In a large population study of adolescents
aged 15 to 18 years, 14.1% reported difficulty initiating sleep, 10.5% reported early morning
awakenings, and 8.4% reported disrupted sleep (22). Insufficient sleep syndrome and sleep onset
insomnia in adolescents are associated with lower school performance (21,23). A significantly
increased number of adolescent girls 11 to 14 years of age report difficulties initiating and
maintaining sleep compared to boys of the same age or younger children (24). Adolescent
somatic, interpersonal, and psychological function are negatively influenced by insomnia (25).

EPIDEMIOLOGY
Insomnia is a common problem for children and the etiology tends to vary based on age. Up
to 40% of infants and up to 50% of preschool aged children have difficulty initiating sleep or
frequent night awakenings (26–30). Of school-aged children 4 to 12 years, 15% take longer than
30 minutes to fall asleep and 12% experience frequent nighttime awakenings more than once
per week (2). Approximately one quarter of adolescents have symptoms of insomnia (31).
Family history plays a role in the development of insomnia. Of persons with childhood-
onset insomnia, 55% have a positive family history (32). Persons with mood disorders who
are homozygous for the Clock 3111C variant are more likely to have difficulties initiating and
maintaining sleep and are more likely to have early morning awakenings (33).
Insomnia occurs more frequently in children with neurological and psychiatric disor-
ders. More than 40% of toddlers with developmental delays or autism suffer from insomnia
(34). Children with autism and sleep difficulties have more affective problems compared to
those children with autism who were considered to be good sleepers (35). Children with
attention-deficit/hyperactivity disorder and sleep onset insomnia have delayed sleep phase
and delayed melatonin release compared to children with attention deficit and hyperactivity
disorder (ADHD) and no difficulties initiating sleep (36).
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PEDIATRIC INSOMNIA 237

CLASSIFICATION OF PEDIATRIC INSOMNIA

Since the publication of the second edition of the International Classification of Sleep Disorders,
there have been no large scale studies examining the prevalence of the different classifications
of insomnia in the pediatric population. Table 1 summarizes the various types of insomnia
and provides information as it pertains to children. Children are susceptible to the same types
of insomnia reported in adults, but behavioral insomnia of childhood is unique to these age
groups.

Behavioral Insomnia of Childhood

Up to 30% of infants, toddlers, and preschool aged children have difficulties going to bed or
with frequent night awakenings (29). When these issues are persistent and significant enough
to affect the child and/or the family, and are related to a behavioral etiology, this is referred to
as behavioral insomnia of childhood. The condition may be the result of several factors. First,
sleep difficulties in young children may be related to neurodevelopmental maturation or an
underlying genetic predisposition to insomnia (64). Second, the parent-child interaction as well
as the parents’ personal characteristics play a role in the child’s ability to learn “self soothing”
techniques (16–18,64). Third, the environment (e.g., cosleeping in some cultures) in which the
child sleeps may contribute to sleep difficulties (64).
Children may display one of two types of behavioral insomnia: sleep onset association type
or limit-setting type (37). The two types may occur independently, but frequently occur together.
Children with sleep-onset association type of behavioral insomnia have significant difficulty falling
asleep without a specific routine, environment, or object (37). Common routines include rocking,
feeding, or massaging to go to sleep. Some children learn to go to sleep only in their parents’
room or when riding in the car. Certain objects, such as blankets, can be used to help develop
a positive sleep association. However, some object associations may become problematic if
the object is not available at all times for sleep or if the object is easily lost during the night
(e.g., pacifiers). Sleep onset association often results in frequent nighttime awakenings requiring
parental intervention (37).
Children with limit setting type of behavioral insomnia refuse to go to bed either at the
initial bedtime or following nighttime awakenings (37). Children may bargain with their parents,
citing a variety of reasons including thirst, hunger, or fear to avoid going to bed. Insufficient
or variable limit setting by parents in the face of these challenges results in persistent and
progressive resistance to sleep on the part of the child (37).

DIFFERENTIAL DIAGNOSIS
Before diagnosing a patient with a specific type of insomnia it is important to evaluate the
patient for other sleep disorders which could present in a similar fashion.
Delayed sleep phase syndrome is a common disorder, which typically presents during ado-
lescence. It is characterized by difficulty falling asleep until later than the desired bedtime.
Once asleep, the patient sleeps for normal durations, if allowed, often waking late in the day
(37). Teenagers may experience problems initiating sleep at conventional hours and insufficient
sleep because of early awakening to meet school start times. Treatment for delayed sleep phase
syndrome may include chronotherapeutic approaches to reset the circadian clock, use of bright
light upon awakening and dim light prior to bed, melatonin, and/or pharmacotherapy (65).
(Chapter 18)
Restless leg syndrome and periodic limb movement disorders are increasingly recognized in
children. Children with restless leg syndrome may have difficulty initiating and maintaining
sleep. Older children and adolescents may have sleep disturbances dating back to infancy
(66). Periodic limb movements in sleep may contribute to decreased REM sleep and increased
arousals (67). Because of the chronic nature of both of these disorders, they may mimic idiopathic
insomnia if left untreated. These disorders have been associated with low serum ferritin (68).
Treatment strategies are poorly studied in children, but may include dietary (iron supplement,
decrease caffeine), sleep hygiene, and pharmacologic agents (68).
Obstructive sleep apnea is associated with snoring, gasping and coughing during sleep,
and early morning headaches. It can contribute to frequent arousals from sleep and
night awakenings, mimicking insomnia. First line treatment is often tonsillectomy and
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238 HOPKINS AND GLAZE

Table 1 Summary of ICSD Second Edition Classification of Insomnia: Pediatric Associations

All forms of insomnia share basic criteria:(37)

r Difficulty initiating or maintaining sleep, early morning awakenings, or nonrestorative sleep
r The patient has an age appropriate opportunity to sleep
r Sleep difficulties contribute to daytime impairment
r Sleep difficulties are not better explained by a sleep disorder, psychiatric, or medical condition.
Insomnia Classification (37) Pediatric Associations
Adjustment Insomnia
r Symptoms present for less than 3 mo r Pediatric prevalence unknown
r Identifiable stressor r Not well studied in children
r Symptoms resolve after removal of or r Potential stressors for children:
adaptation to the stressor ◦ Change in family (divorce, death, move)
◦ School-related challenges (tests, tryouts, big
game)
◦ Relationships (difficulty with friends, bullies,
children who are abused)

Psychophysiologic Insomnia
r Symptoms present for > 1 mo r Not well studied in children
r Anxiety associated with sleep r 46% of adults with chronic insomnia cite adverse
r Trouble sleeping in bed, but able to fall events in childhood with persisting insomnia (38)
asleep in other places not typically meant r Anecdotally, children frequently present with
for sleep or away from home longstanding difficulty initiating sleep accompanied by
r Heightened arousal when trying to go to anxiety associated with sleep and hyperarousal when
sleep in bed. These children (and their families) become
excessively focused on their inability to sleep.
r Can give rise to multiple problems involving sleep
hygiene including sleeping during class or taking an
afternoon nap, use of media, and use of substances
both to stay awake and to promote sleep.

Paradoxical Insomnia
r Symptoms present for at least 1 mo r Pediatric prevalence unknown, but thought to be
r Report of chronic, severe, almost nightly rare (37)
sleep deprivation r Be aware of discrepancies between parent and child
r Increased awareness of environmental sleep time reporting.
stimuli and/or conscious thoughts r If this diagnosis is considered, sleep diaries combined
r Daytime impairment is less than expected with actigraphy may be helpful.
given the severity of the reported sleep
deprivation
r There may be a discrepancy between
subjective sleep logs and objective
measures (actigraphy, polysomnography)

Idiopathic Insomnia
r Persistent unremitting insomnia starting r Prevalence for 15–18 yr = 0.7%; In younger ages, the
during infancy or childhood prevalence is unknown (22)
r Diagnosis of exclusion, no cause identified r In a small sample of adults reporting onset of
insomnia as a child, more reported neurological
conditions including dyslexia, hyperkinesis, abnormal
electroencephalograms, or “minimal brain damage”
compared to persons with adult onset insomnia (32).
r Consider behavioral insomnia of childhood in younger
children.
r Older children may develop inadequate sleep hygiene,
medication dependence, or features of
psychophysiologic insomnia (39).
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PEDIATRIC INSOMNIA 239

Table 1 Summary of ICSD Second Edition Classification of Insomnia: Pediatric Associations (Continued )

Insomnia Because of Mental Disorder

r Symptoms present for > 1 mo r Prevalence in the pediatric population is > 50% in
r A mental disorder is present. children presenting to a sleep disorders clinic (40)
r The insomnia is associated with the mental r Children with a comorbid psychiatric disorder present
disorder with insomnia an average of two years earlier than
r The insomnia is significant enough that it children without psychiatric disorders (41).
requires treatment separate from the r Children with anxiety and depression have prolonged
treatment for the mood disorder sleep latencies (7).
r Children with bipolar disorder have decreased sleep
efficiency, more frequent nocturnal awakenings, and a
decreased need for sleep (42,43).
r Almost 30% of unmedicated children with ADHD have
difficulties with sleep onset (44,45).

Inadequate Sleep Hygiene

r Symptoms present > 1 mo r Prevalence in the pediatric population is 1%–2% (22)
r At least one: r Parents may have developmentally inappropriate
◦ Developmentally inappropriate sleep expectations for sleep times. In addition, children who
schedule do not sleep well at night, may fall asleep in class
◦ Use of substances (caffeine, alcohol, during the day or take developmentally inappropriate
nicotine, illicit drugs, or supplements naps after school making it harder to fall asleep at
prior to bed) night.
◦ Mentally or physically stimulating activity r Media: including television, computers, video games,
prior to bedtime and cell phones. Use of media is associated with
◦ Activities other than sleep in the bed decreased sleep duration, less time in bed, and
◦ Uncomfortable sleeping environment feeling sleepier the next day (46,47).
r Environment (cosleeping, noise, room temperature
(should be < 75◦ F), pets, allergens) (48)

Behavioral Insomnia of Childhood

r Sleep onset association type: r Prevalence in infants, toddlers, and preschoolers:
◦ Sleep initiation requires special 20%–30% (49)
circumstances r Common sleep associations:
◦ Without the special conditions, sleep is ◦ Feeding, pacifiers, blankets, stuffed animals,
delayed and/or interrupted parental presence during sleep
◦ Sleep associations are problematic for r Common limit-setting difficulties:
the family ◦ Children come out of their room and bargain: i.e.,
◦ Awakenings require the caregiver to need a drink, hungry, monsters, need a hug, need
intervene the light readjusted, one more book
r Limit-setting type ◦ Look for limit setting difficulties at other times of
◦ Difficulty initiating or maintaining sleep the day as well
◦ Child refuses to go to bed or stay in bed
◦ The caregiver is not able to adequately
set limits for the child

Insomnia Due to Drug or Substance

r Symptoms present for > 1 mo r Prevalence in children 12–17 yr old: 17.8% (50)
r Dependence on, abuse of, or exposure to a r Prescription Medications: steroids, stimulants
drug, substance, medication, food, or toxin (44,51,52)
that results in sleep disturbances r Caffeine: Adolescents with a high caffeine intake are
r Insomnia relates to the ingestion of the drug 1.9 times more likely to report difficulty sleeping than
or substance adolescents with a very low caffeine intake.
Additionally, students with a high caffeine intake were
more likely to report being tired during the day (53).
r Of 13,831 adolescents 12–17 yr of age surveyed,
alcohol, nicotine, and illicit drug use were all
associated with a higher rate of reported sleep
difficulties (50).

(Continued)
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240 HOPKINS AND GLAZE

Table 1 Summary of ICSD Second Edition Classification of Insomnia: Pediatric Associations (Continued )

Insomnia Due to A Medical Condition

r Symptoms present for > 1 mo r Pediatric prevalence unknown
r Medical condition known to result in sleep r Discomfort during sleep
disturbances ◦ asthma (54), reflux (55,56), juvenile rheumatoid
r Insomnia fluctuates with changes in arthritis (57,58)
condition severity or activity r Neurological disorders
◦ seizures (59), autism spectrum disorders
(60,61), cerebral palsy (62), and Angelman’s
syndrome (63).

This table was paraphrased in part from the ICSD 2nd Edition Classification of Insomnia. (37) For a full discussion of the criteria
for the various types of insomnia, please see this resource.
Source: From Ref. 37.

adenoidectomy, but treatment of allergies, weight loss, and positive airway pressure are options
as well (69).
Disorders of arousal include confusional arousals, sleep terrors, and sleepwalking (37). Par-
ents may believe that their child is fully aroused and describe the children as having insomnia.
However, children with disorders of arousal usually appear confused during the event and do
not remember the event of the next day. Management of disorders of arousal usually involves
reassuring the parents, ensuring that the child has an age appropriate amount of sleep, tak-
ing appropriate steps to ensure safety, and screening for other primary sleep disorders, which
may provoke events. However, in some cases, children require behavioral or pharmacologic
therapies (70).

EVALUATION
In general, all children should be screened for sleep problems. A parent report or a child or
adolescent’s self- report of sleep difficulties requires a thorough characterization of the sleep
problem and related factors (Table 2). This should include determination that the child or adoles-
cent has a developmentally and age appropriate opportunity to sleep. The history should include
details about the bedtime routine and the parent’s and the child’s response to night awakening.
Evaluation of the quality of sleep is also important. The clinician should determine if the child
awakes refreshed, if there are additional sleep disorders such as obstructive sleep apnea and
periodic limb movement disorder, and if there are medical or psychiatric conditions that may
disrupt sleep. Because some medications contribute to insomnia, a list of over-the-counter, pre-
scription, and illicit drugs should be obtained. In addition, identification of previous treatment
techniques, medications, and the duration of the time that they were used are necessary. The
clinician should also characterize significant daytime symptoms including excessive daytime
sleepiness, irritability, hyperactivity, and difficulty with concentration. Older children should be
interviewed separately from their parents to discuss safety at home and at school, exposure to
nicotine, alcohol, and illicit drugs, and to determine if there is an underlying psychiatric disorder.
The general physical examination should screen for medical disorders such as reflux,
asthma, and pain that may contribute to insomnia. Polysomnography is not typically indi-
cated unless there is concern for obstructive sleep apnea or periodic limb movement disorder
contributing to insomnia. A two-week sleep diary or actigraphy can help to better delineate
bedtimes, sleep times, and wake times. These tools can help distinguish between delayed sleep
phase syndrome and paradoxical insomnia.

MANAGEMENT
Management of pediatric insomnia depends on the underlying etiology. A discussion regard-
ing realistic developmentally appropriate bedtime, wake time, naptime, and sleep hygiene
(Table 3) should be considered for all children. The majority of cases of behavioral insomnia of
childhood are best managed through behavioral interventions including teaching new positive
sleep habits (49). In select cases, pharmacologic treatment may be used on a short-term basis
in combination with the behavioral interventions. For example, if a child’s insomnia is severe
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PEDIATRIC INSOMNIA 241

Table 2 Patient History

Ensure that the patient has a r What time does your child go to bed?
developmentally appropriate r What time does your child go to sleep?
number of hours of sleep in a 24 hr r What time does your child wake for the day?
period r Does your child take any naps?
r How many hours of sleep does your child receive in a 24 hour
period?
r How many awakenings does your child have per night?
r How long are the awakenings?

Bedtime resistance r What is the prebed routine?

r Does your child require the presence of a parent to go to sleep?
r Does your child feed prior to going to sleep?
r Does your child bargain to avoid going to bed?
r What is the parent’s response to refusal to go to bed or nighttime
awakening?

Is there evidence for adjustment or r Does the patient lay awake at night worrying about going to
psychophysiologic insomnia? sleep?
r Does the patient appear tired, but have difficulty going to sleep
once he/she goes to bed?
r Does the patient sleep better when not sleeping in his/her own
bed?
r Was the sleep difficulty provoked by a stressful event?

Screen for primary sleep disorders r OSA

◦ Snoring or pauses in breathing during sleep?
r RLS
◦ Abnormal feelings in the legs or feet that are relieved with
rest?
r Restless sleep?
r Delayed sleep phase syndrome
r If allowed to go to bed when you want, will you go right to sleep?
If so, how long do you sleep until you wake up on your own?

Screen for medical disorders r Asthma

r Gastroesophageal reflux disease
r Seasonal allergies
r Pain
r Other disorders

Screen for mental disorders r Anxiety

r Depression
r Bipolar disorder
r Post traumatic stress disorder (previous or current history of
trauma, child abuse, bullying)

Medications/Substances r Does the child take any medications known to result in

insomnia?
r Does the child take any medications to treat insomnia?
r Does the child use nicotine, alcohol, or illicit drugs?

Diet r Caffeine?
r Eating prior to going to bed

Daytime symptoms r Excessive daytime sleepiness

r Attention difficulties
r Hyperactivity
r Mood changes
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242 HOPKINS AND GLAZE

Table 3 Sleep Hygiene for Children

Sleep Routine
r Determine the latest time the child can wake up and still get to school on time. Make this the wake up
time. This should be observed consistently even on weekends until the sleep problem resolves.
r Determine the developmentally appropriate number of hours of sleep and count backwards from the wake
up time. This is the new bedtime. This should be observed consistently even on weekends until the sleep
problem resolves.
r Schedule developmentally appropriate nap times if indicated.
r Create a calm prebedtime routine that fits with the child and the family. This should be started 30–60 min
prior to the expected bedtime.
r Children should be allowed to fall asleep alone to avoid sleep-onset association with parents.
r Expose the child to bright light upon awakening and dim light for one hour prior to bedtime.
r Discontinue use of all media (TV, computer, video games, cell phones, texting) 30 min prior to bed. Media
may need to be removed from the child’s room.
r Discuss the parents’ response to night awakening (young children) and the child’s response to night
awakening (older children).

Lifestyle Changes
r The child should get plenty of exercise during the day. However, vigorous activity should be limited during
the hour prior to bedtime.
r Some children take a bath directly prior to bed. This is acceptable if it is a warm, calming bath. However, if
the child is young and the bath is fun and exciting, the parents should consider moving the bath to earlier
in the evening or in the morning.
r Keep the child’s bedroom temperature below 75◦ F.
r Remove environmental barriers to sleep if possible (i.e., pets, other siblings, noise, potential sources for
allergens).

Dietary and Medication Changes

r Eliminate caffeine from the diet or at least curtail consumption in the hours prior to bed.
r Children may have a snack prior to bed if hungry.
r Limit fluid intake 30 min prior to bedtime.
r Unless medically indicated, from 7 mo of age on, children should not eat or drink after bedtime to avoid
symptoms of gastroesophageal reflux and bladder distention that can result in arousal of the child. If a
child is still drinking from the bottle, wean down the amount and the frequency until the bottle can be
discontinued.
r Ensure that the child is not receiving medications containing alcohol or caffeine that could interfere in the
child’s sleep.
r Consider adjustment of other medications the child is receiving if they are contributing to insomnia (i.e.,
stimulants for ADHD).

Source: Adapted from Ref. 48.

enough to significantly affect the family’s ability to implement the recommended behavioral
interventions, medication may be used to improve the patient’s sleep and bring about behavioral
changes sooner (3). Additionally, there are some children with neurological or medical disorders
who require long-term pharmacologic treatment for insomnia. Unfortunately, research evalu-
ating the safety and efficacy of pharmacologic agents in the treatment of pediatric insomnia is
lacking (71).

Behavioral Interventions

Behavioral Insomnia of Childhood

Because of the serious impact sleep disorders can have on a child’s daytime functioning and
the potential for long term difficulties with sleep, The American Academy of Sleep Medicine
set forth practice parameters for the treatment of behavioral insomnia of childhood (49). These
parameters are based on the combined results from 52 studies evaluating the effectiveness of
behavioral interventions for behavioral insomnia of childhood in children primarily five years of
age and younger. Almost all (94%) of the studies reveal that behavioral interventions including
unmodified extinction, graduated extinction, positive routine, faded bedtime with response cost,
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PEDIATRIC INSOMNIA 243

Table 4 Treatment of Behavioral Insomnia of Childhood

Unmodified Extinction r The child is placed in their bed at a prescribed bedtime.

r The parent leaves the room and does not respond to signaling.
However, parents must respond to illness or danger.
r The child is allowed out of their bed/room at a prescribed wake time.

Modified extinction r The child is placed in their bed at a prescribed bedtime.

r The parent remains in the room but does not interact with the child.
r The child is allowed out of their bed/room at a prescribed wake time.

Graduated extinction r The child is placed in their bed at a prescribed bedtime.

r The parents respond to signaling after a set period of time.
r The parental response should be brief and the parent should leave the
room immediately after evaluating the child.
r The duration between the parental responses should be gradually
extended (5, 10, 15 minutes).

Positive routines r Provide the patient with a specific bedtime and wake time.
r Prior to bed the family should develop a brief, calm routine to be
performed every night prior to bed.

Faded bedtime with response r The child is put to bed close to the time of their current sleep onset.
cost r After the child starts to go to sleep easily at this time, the bedtime is
advanced (moved earlier) by 15 min. Once the child is falling asleep
easily the bedtime is advanced again.
r This process is repeated until the desired bedtime is achieved.
r If the child is not falling asleep easily, the child is removed from the bed
briefly and then placed back in bed.

Scheduled awakenings r The patient is awakened 15–30 min prior to their nocturnal awakenings.
r The time between scheduled awakenings should be increased over
time.
r Parents respond to their children during these awakenings with their
typical routine.

Parental education r Help families establish age appropriate consistent bedtimes, wake
times, and nap times.
r Remind families to avoid creating an association that requires parental
involvement.

Source: Adapted from Ref. 49.

scheduled awakenings, and parental education are effective in correcting bedtime resistance and
night wakings (64). (Table 4)
Extinction techniques are designed to decrease unwanted behaviors (49). Unmodified
extinction involves putting the child to bed at a prescribed time and leaving the child in the
room, ignoring the child’s signaling (crying) until it is time to wake in the morning. The parents
should remain extremely consistent in their responses to bargaining and night waking and
avoid positive reinforcement for unwanted behaviors. However, if the parent is concerned
that the child is ill or hurt, he/she is encouraged to investigate. Parents should be aware that
once positive sleep habits are established, illness or a change in routine (i.e., vacation) may
result in reemergence of the unwanted behavior. Consistently ignoring the child’s signaling
will help the child reestablish self-sufficient sleep. Some families find listening to the signaling
(crying) of their child stressful and may be unable to ignore their child for a sufficient amount
of time to allow the technique to work. A modification of the extinction technique involves the
family staying in the room with the child, but not interacting with the child (64,72). Graduated
extinction is another technique that may decrease parental stress. This technique involves the
parent ignoring the child’s behavior for a predetermined period of time (i.e., 5 minutes) and
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244 HOPKINS AND GLAZE

then checking on the child. When the parent checks on the child, the interaction should be
minimal and last less than 15 seconds to avoid reinforcing negative behavior. The periods
of time between checking on the child are gradually increased (i.e., 5 minutes, 10 minutes,
15 minutes) (64).
Difficulty with the extinction techniques may be encountered when the child does not stay
in his/her room. This can be counteracted by confining the children to a space using the crib or
closing the door of the room. Parents should ensure that the rooms are safe by covering electrical
outlets and removing hard toys and climbable surfaces. If the parent is concerned about the child
being in the room alone, securely attached stacked baby gates, half doors, or cameras will allow
parents to be able to see in the child’s room. Extinction techniques are effective if performed
with consistency and result in decreased bedtime problems, decreased night awakenings, and
improved sleep continuity (64).
Positive bedtime routines help to encourage appropriate behaviors. The family should
create a positive, but calm prebed routine. This routine may consist of a warm relaxing bath,
reading books, listening to music, etc. Dim light during the prebed routine is recommended
(48). The goal of this technique is to help the child slowly decrease their activity and to create a
positive association with bedtime (64).
For those children who have difficulty initiating sleep, the faded bedtime with response
cost may be beneficial. The child is put to bed close to the time when they typically fall asleep.
Once the child is going to sleep easily at the later time, the bedtime is advanced by 15 minutes
until the goal bedtime is reached. If the child does not fall asleep, the child is removed from bed
for a specific period of time and then placed back in bed. Children should wake up at a specific
time each morning. Naps, other than developmentally appropriate prescribed naps, should be
avoided (64).
Children with frequent night awakenings may benefit from scheduled night awakenings
to ultimately improve the amount of consolidated sleep. Children are put to bed at their usual
time, but are awakened by the parent about 15 to 30 minutes prior to the typical time of the
nighttime awakening. Parents are allowed to respond to the awakening with their usual routine.
Over time, the period between the scheduled awakenings is increased (64).
Parental education has been used in several studies starting as early as the prenatal
period. This technique focuses on educating parents on appropriate bedtimes, parental role in
sleep initiation, and response to nocturnal awakenings and is geared toward preventing the
development of unwanted behaviors (64). Early maternal sleep education is associated with
long-term decreased incidence of maternal depression and decreased sleep problems in their
children (73).
One behavioral technique has not been proven to be more effective than another in the
treatment of behavioral insomnia of childhood (64). Unmodified extinction may produce results
faster than scheduled awakenings (74). More than 80% of children treated with behavioral
techniques improved and had lasting effects for three to six months (64). No adverse sec-
ondary effects have been identified in participating children and parental energy and mood are
reported to improve following the implementation of the behavioral interventions (64,75,76).
The practitioner should consider the unique situation for the child and the family before
prescribing a particular technique and many practitioners combine techniques for maximum
efficacy (64).

Behavioral Interventions for Other Types of Insomnia

Children with insomnia not related to behavioral insomnia of childhood may respond to other
behavioral techniques that have classically been used to treat adult insomnia (65). Stimulus
control is a highly effective technique that is used to develop specific stimuli for sleep (77,78).
Children are asked to use their bed only for sleeping and to avoid staying in bed when they are
unable to go to sleep (65). This technique helps children identify their bed and bedroom with
sleep and decrease the association with other things, which preclude sleep (78). Sleep restriction
is often used in conjunction with stimulus control (65). This technique involves decreasing
the amount of time a child spends in bed to the amount of time the family estimates that the
child actually sleeps (but no less than six hours in children). The morning wake time remains
constant and the initial bedtime is later, in order to produce the appropriate time in bed. When
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PEDIATRIC INSOMNIA 245

the child falls asleep easily, the bedtime is then advanced by 15 minutes every four to seven
days. This process continues until the child achieves a developmentally appropriate amount
of sleep.
Parents may wish to incorporate positive reinforcement (i.e. sticker chart) to encourage
children to participate in the various treatment techniques. Children with mood disorders
or ADHD often complain that they cannot stop thinking when they go to bed. Relaxation
techniques have also been found helpful to decrease physiologic arousal as well as provide
a focus for their attention as they try to go to sleep (78). Combinations of these techniques
along with sleep education and sleep hygiene are reported to result in significant improvement
in sleep latency, night awakenings, and sleep duration in adolescents receiving treatment for
substance abuse (78).

Pharmacologic Interventions
Despite a lack of research support and FDA approval for pharmacologic treatment of pediatric
insomnia, multiple medications have been used by both physicians as well as parents without
physician guidance to help children sleep. Up to 25% of children 0 to 18 months of age have
been prescribed medication to help them sleep (79). In a large cross-sectional study between
1993 and 2004, 18,640,820 pediatric patient visits (aged 0 to 17 years) for sleep related difficulties
were evaluated (80). Physicians prescribed nutritional counseling for 7% and behavioral therapy
for 22%. However, 81% of patients were prescribed a medication (33% antihistamines, 26% ␣2
agonists, 15% benzodiazepines, 6% nonbenzodiazepines, 6% antidepressants). Nineteen percent
of patient visits received both pharmacological and behavioral treatment (80). In a separate
study, more than 75% of practitioners had recommended nonprescription medications at least
once for pediatric insomnia. Antihistamines were the most frequently recommended over the
counter medication. Fifteen percent of practitioners reported prescribing melatonin or herbal
remedies (81).
Due to the lack of controlled, well-powered studies evaluating the safety and efficacy of
hypnotics in children, pharmacotherapy should be reserved for those children who experience
significant negative consequences as a result of their chronic sleep difficulties, children requiring
a rapid solution to their insomnia, and/or children who have a disorder (e.g., neurological con-
dition) that precludes appropriate response to behavioral interventions (71). Pharmacotherapy
should be paired with a behavioral intervention for maximum efficacy (48). Choice of the med-
ication is guided by whether the patient has trouble initiating or maintaining sleep, comorbid
conditions, and the individual characteristics of the medication (Table 5). Caution is advised
with regard to the use of any agents which promote sleep in children. These agents should
not be combined with other central nervous system depressants or used in high doses due to
concern for respiratory depression. Commonly prescribed medications are discussed below.
This discussion is not meant to be a comprehensive review of these medications and readers are
encouraged to check manufacturer prescribing guidelines for dose recommendations, cautions,
and potential side effects prior to recommending these medications.

Antihistamines
Antihistamines including diphenhydramine hydrochloride and hydroxyzine are the most com-
monly prescribed agents in the treatment of pediatric insomnia (80). These medications compete
with histamine at H1 -receptors, promoting mild sedation at the prescribed dosing (82). They
have been reported to decrease sleep latency and nighttime awakenings (83). However, in a ran-
domized placebo controlled trial evaluating sleep disturbance in infants aged 6 to 15 months,
diphenhydramine hydrochloride showed no improvement compared to placebo (97). In addi-
tion, antihistamines may lead to insomnia in some children, may interfere with sleep quality, and
may contribute to daytime drowsiness (82). These medications are not recommended for chil-
dren less than two years of age (98). Persons taking antihistamines regularly develop tolerance
resulting in decreased effectiveness of the medication with chronic use (99).

␣ 2 -adrenergic receptor agonists

Clonidine, a ␣2 -adrenergic receptor agonist, acts at the brainstem and decreases noradrenergic
output (85). This decreased activity is thought to be responsible for sedation, but the exact role
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246 HOPKINS AND GLAZE

Table 5 Pharmacotherapy

Antihistamines (48,71,82) Mechanism of action

r H1 -receptor blocker
r ↓ sleep latency
Side effects
r May impair sleep quality
r Paradoxical insomnia in children
r Morning sedation
r Daytime sleepiness
r Anti-cholinergic side effects
Diphenhydramine (83) Pharmocodynamics and pharmacokinetics
r Maximum sedation: 1–3 hr
r Duration: 4–7 hr
Pediatric dosing
r Oral dosing 30 min prior to bed:
r 2–12 yr: oral: 1 mg/kg/dose (max 50 mg),
r > 12 yr: 50 mg
Available formulations
r Chewable tablet
r Strip
r Liquid
r Capsule
r Injection (for in hospital use without alternative administration)
Hydroxyzine (48,84) Pharmacodynamics and pharmacokinetics
r Time to peak concentration: 2 hr
r Half life increases with increasing age:
◦ 1 yr old = 4 hr
◦ 14 yr old = 11 hr
◦ adults = 3 hr
Pediatric dosing
Oral dosing for preoperative sedation
r Children: oral 0.5 mg/kg 30 min prior to bed
Available formulations
r Capsule
r Tablet
r Syrup
r Suspension
r Injection
␣2 -adrenergic receptor agonists Mechanism of action
(48,71,85,86) r Central acting
r Stimulates ␣2 -adreno receptors
r Decreased noradrenergic activity
r Results in decreased REM sleep
Side effects
r Sedation
r Hypotension
r Bradycardia
r Rebound hypertension if discontinued abruptly
r Insomnia
r Dizziness
r Fatigue
Clonidine (85) Pharmacodynamics and pharmacokinetics
r Onset of action: 30–60 min
r Serum half-life:
◦ Infants: 44–72 hr
◦ Children: 8–12 hr
◦ Adults: 6–20 hr
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Table 5 Pharmacotherapy (Continued )

Pediatric dosing
r No recommendations are available for pediatric sedation
r Study in children with ADHD: 50–800 ␮g (mean 157 ␮g) (87)
Available formulations
r Tablet
r Transdermal patch
Melatonin (88) Mechanism of action and effects on sleep
r Phase shift
r Hypnotic
Side effects
r Morning sedation
r Dysphoria
r Regulation of growth hormone and gonadotropic hormone
secretion
Pharmacokinetics and pharmacodynamics
r Rapid absorption
r Peak plasma level at 1 hr
Pediatric dosing
r No recommendations for dosing in children are available.
r Start with low dose 0.5 or 1 mg 1–5 hr prior to bedtime and
increase q 1–2 wk up to a maximum of 10 mg.
r Consider controlled release formulations for night awakenings
Available formulations
r Rapid release
◦ Tabs
◦ Spray
◦ Sublingual
◦ Liquid
r Controlled release
◦ Tabs
Benzodiazepines (48,71) Mechanism of action:
r GABA agonist
Side Effects
r Drowsiness
r Confusion
r Paradoxical excitement
r Decreased respiratory rate
r Apnea
r Hypotension
r Bradycardia
r Abrupt discontinuation is associated with seizures
Diazepam (48,89) Pharmacodyndamics and pharmacokinetics
r Half-life
◦ Infants: 40–50 hr
◦ Children: 15–21 hr
◦ Adults: 20–50 hr
Pediatric dosing
r 0.04–0.25 mg/kg at bedtime
Available formulations
r Oral
r Rectal
(Continued)
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248 HOPKINS AND GLAZE

Table 5 Pharmacotherapy (Continued )

Clonazepam (48,90) Pharmacodynamics and pharmacokinetics

r Onset of action: 20–60 min
r Half-life:
◦ Children: 22–33 hr
◦ Adults: 30–40 hr
Pediatric dosing
r Initial dose: 0.01 mg/kg at bedtime
r Max dose: 0.025 mg/kg
Available formulations
r Tablet
r Wafers
Lorazepam(71,91) Pharmacodynamics and pharmacokinetics
r Onset of action: oral: within 60 min
r Duration of action: 8–12 hr
r Half-life:
◦ Infants: 8–73 hr
◦ Children: 6–17 hr
◦ Adults: 10–16 hr
Pediatric dosing
r 0.05 mg/kg at bedtime
Available formulations
r Tablet
r Solution
r Injection
Nonbenzodiazepine hypnotics (92) Mechanism of action
r Enhances GABA activity at the benzodiazepine1 -receptor.
Side effects
r Paradoxical effects if dose is too low or high
r Dizziness
r Headaches
r Somnolence
Zolpidem (93) Pharmacokinetics and pharmacodynamics
r Time to maximum concentration: 1.1 hr
r Half-life: 2.1 hr
Pediatric dosing
r 0.25 mg/kg prior to bedtime with max dose of 20 mg
Available formulations
r Regular
r Controlled release
Antidepressants Tricyclic Mechanism of action
Antidepressants (71,94) r Increases presynaptic serotonin and norepinephrine by blocking
their reuptake
Side effects
r Cardiovascular side effects requiring cardiac evaluation prior to
prescribing these medications
r Anticholinergic effects
Imipramine (94) Pharmacokinetics and pharmacodynamics
r Peak serum concentration: 1–2 hr
r Mean half-life:
◦ Children: 11 hr
◦ Adults: 16–17 hr
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Table 5 Pharmacotherapy (Continued )

Pediatric dosing
r No recommendations are available for pediatric sedation
r For enuresis > 6 yr
◦ 10–25 mg PO at bedtime
r For depression
◦ 1.5 mg/kg/day with max dose of 5 mg/kg/d divided
1–4 times/day
◦ Monitor carefully doses > 3.5 mg/kg/day
Available formulations
r Capsule
r Tablet
Amitriptyline (95) Pharmacokinetics and pharmacodynamics
r Peak serum concentration: 4 hr
r Half-life in adults: 9–25 hr with mean of 15 hr
Pediatric dosing
r No recommendations are available for pediatric sedation
r For depression
◦ Children: 1 mg/kg/day divided in 3 doses
◦ Adolescents: 25–50 mg/day
Trazodone (96) Mechanism of action
r Inhibits reuptake of serotonin
r ␣-adrenergic blockade
Side effects
r Blurred vision
r Prolonged priaprism
r Postural hypotension
r Drowsiness
Pharmacokinetics and pharmacodynamics
r Peak serum concentration: 1–2 hr
r Half-life: 5–9 hr
Pediatric Dosing
r Not FDA approved for depression or sedation in children
r Children 2–18 yr of age
◦ 1.5–2 mg/kg/day in 3 divided doses
◦ Max dose 6 mg/kg/day
r Adolescents
◦ 25–50 mg/day with max of 150 mg/day in divided doses
r Adults
◦ 150 mg/day in 3 divided doses with max of 600 mg/day
This table serves as an outline of medications that have been used to treat pediatric insomnia. It is not comprehensive and
providers are encouraged to look at manufacturer prescribing information for side effects, and cautions prior to recommending
any of these medications to a patient.

in sedation is unclear (71). Clonidine has primarily been used to promote sedation in children
with ADHD (71). The benefit in this patient population is thought to relate to clonidine’s effect
on both ADHD symptoms as well as the side effect of sedation (87). One study found that the
degree of drowsiness decreases with time, which may mean that the dose required inducing
sedation, will increase over time (100).
Clonidine has also been found to reduce sleep latency and night awakening in children
with autism spectrum disorders (101). Despite the fact that clonidine has not been studied in
healthy children without comorbid disorders, general pediatricians commonly prescribe cloni-
dine for children with difficulty initiating sleep (102). Some children will experience insomnia
with this medication (85). Anecdotally, rebound insomnia appears to occur approximately
four to six hours following administration of the medication. Caution is recommended when
prescribing clonidine due to adverse effects such as dysphoria, bradycardia, hypotension, and
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250 HOPKINS AND GLAZE

rebound hypertension (71). The FDA recommends a thorough cardiac evaluation prior to the
initiation of this medication due to concern regarding sudden cardiac death (85). Because of the
side effect profile and lack of research in normal healthy children, clonidine is not recommended
for insomnia in healthy children (71).

Melatonin
Melatonin has been used to treat insomnia in adults as well as children. In vivo, levels increase
with darkness and decrease with light, playing a role in the circadian rhythm of sleep and
wakefulness (71). As with many medications used to treat insomnia in children, large studies
have not been performed to determine efficacy or safety. In a small randomized double blind
placebo controlled trial, short term use of melatonin was reported to be effective for phase
advancement, decreasing sleep latency, and increasing total sleep duration in children with
chronic insomnia (103). It has also been found to be efficacious in special patient populations
including children with blindness, intellectual disabilities, Angelman syndrome, Rett syndrome,
and autism (63,104–107). Although many studies evaluating the short-term efficacy in various
pediatric populations are available, studies evaluating the pharmocokinetics and long-term
safety and efficacy have not been performed in children. Significant adverse effects have not
been documented, but daytime somnolence has been reported (88). In addition, several children
have reported vivid dreams, but this warrants further study. There is an association between
melatonin and regulation of growth hormone and gonadotropic hormone (88,108). Therefore,
the practitioner should inform families of the theoretical risk of affecting these hormones in
children. Recommended dosing for children is not available. Based on studies in children, doses
of 0.5 mg up to 10 mg have been reported to be effective (48). Melatonin can be used prior to
bedtime as a hypnotic or up to four hours prior to bedtime as treatment for delayed sleep phase.
Controlled release melatonin is available for children with difficulties with both sleep initiation
and maintenance (109).

Benzodiazepines
Benzodiazepines bind to the ␥ -aminobutyric acid (GABA) receptor complex and modulate
action of GABA at the receptor site. As a result, benzodiazepines not only induce sleep and
decrease partial arousals during sleep transitions, but also contribute to decreased muscle tone
and decreased anxiety (71,110). Choosing a specific benzodiazepine depends on the patient’s
specific sleep disturbance. Patients with difficulty initiating sleep may benefit from a ben-
zodiazepine that is rapidly absorbed with a short half-life. A benzodiazepine with a longer
half-life may be chosen to treat nighttime or early morning awakenings (71). Although effec-
tive in treating insomnia, benzodiazepines may be associated with tolerance, rebound partial
arousals, and daytime somnolence (71). In addition, discontinuation following longer-term use
in children may result in increased insomnia in addition to anxiety, agitation, diarrhea, fever,
sweating, and tachypnea (111). In children, benzodiazepines have primarily been used to treat
disorders of arousal such as sleep terrors and confusional arousals (71). However, controlled
clinical trials using benzodiazepines in children do not exist. They are not approved for seda-
tion in children (71). Due to the significant side effects associated with benzodiazepines, these
medications are not recommended for patients with preexisting CNS depression, decreased
pulmonary function, apnea, or those patients taking medications that contribute to CNS
depression (48).

Other benzodiazepine receptor agonists (BzRAs)

BzRA hypnotics are selective GABA agonistic modulators that effect the benzodiazepine1 -
receptor resulting primarily in sedation, with presumably less muscle relaxant, anti-anxiety
and other effects of nonselective benzodiazepines (71,92). Previously, these hypnotics such
as zolpidem have not been well studied in children. However, a recent study evaluated the
pharmacokinetics of zolpidem in children (93). The effect on sleep was variable and included
paradoxical effects when the dose was too low or too high. Zolpidem has been reported to
increase the proportion of stage 3 NREM sleep as well as REM sleep without increasing the total
sleep time in pediatric burn patients (112). In children, short-term side effects are considered to
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PEDIATRIC INSOMNIA 251

be mild and self-limited (93). Common side effects in adults include dizziness, headaches, and
somnolence (92).

Antidepressants
Antidepressants have been prescribed for insomnia associated with depression or anxiety in
adults (113). Studies evaluating the safety and efficacy of antidepressants in children are not
available. Caution is advised when prescribing antidepressants to children due to the black box
warning regarding increase risk of suicide in children taking these medications (114).
Tricyclic antidepressants are thought to decrease arousal from sleep but may also impair
deep sleep as well as REM sleep (71,113). Most studies in adults have not found lasting sleep
associated benefits from treatment with tricyclic antidepressants (113). In children, imipramine
hydrochloride is prescribed most frequently for control of nocturnal enuresis and it has been
reported to be beneficial in decreasing disorders of arousal such as sleep terrors and confusional
arousals in children (71). Side effects include dry mouth, orthostatic hypotension, and cardiac
dysrhythmias (71).
Trazodone is a 5-HT2 -receptor antagonist with weak ␣2 -receptor antagonism (113). It
is associated with an increase in total sleep time, increase in the percentage of slow wave
sleep, and a decrease in arousals in adults (115). In a group of adolescents with depression
it was found to minimally decrease the time for insomnia resolution compared to fluoxetine
alone (116). Side effects of trazodone include sedation, dizziness, psychomotor impairment, and
priaprism (117).
Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake
inhibitors (SNRIs) are not generally used as primary sleep-promoting agents (113). Positive
effects on insomnia may result as part of the treatment of an underlying mood disorder.

SUMMARY
Pediatric insomnia is common and the etiology is often multifactorial. It has significant con-
sequences for children as well as their families. Behavioral insomnia of childhood is the most
common etiology of sleep disturbance in young children. Older children are susceptible to the
other types of insomnia seen in adults. In adolescents, delayed sleep phase is an especially
common cause of sleep initiation problems and morning sleepiness. A comprehensive history
and evaluation is important to determine the exact etiology for a child’s insomnia. Treatment
is based on parental education, a discussion of sleep hygiene, and behavioral techniques. For
select children who need pharmacologic intervention, medications are available, but must be
used with caution.

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22 Overview of Treatment Considerations

Daniel J. Buysse
Neuroscience Clinical and Translational Research Center, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania, U.S.A.

As reviewed in the first two sections of this volume, insomnia is a prevalent health problem in
the general population and in medical practice. Advances in our understanding of the origins
and evaluation of insomnia have been paralleled by advances in clinical treatment, reviewed in
this final section.
The treatment of insomnia falls into two major categories; psychological-behavioral treat-
ments, and pharmacologic treatments. Other treatments that do not fall into these categories,
such as bright light, exercise, and various somatic treatments, have also been examined. How-
ever, these are far less developed than the psychological-behavioral and pharmacologic treat-
ments, and for that reason are not reviewed in this volume.
The efficacy of psychological-behavioral treatments and pharmacological treatments has
been well established. Published reviews have systematically evaluated the evidence for effi-
cacy of psychological-behavioral treatments, and suggest that standard treatments such as
multicomponent cognitive behavioral therapy lead to both statistically and clinically significant
improvements in patients with primary and comorbid insomnias (1,2). Similarly, published
metaanalyses regarding benzodiazepine receptor agonist therapy demonstrate the efficacy of
this approach (3,4). Greater variability is evident in reviews of the efficacy of pharmacologic
treatments; some of these have suggested more limited benefits relative to observed adverse
effects, particularly among the elderly (5). Although it is often difficult to compare behavioral
and pharmacologic treatment studies because of differences in study design, available evidence
suggests that the two types of treatment are broadly comparable in their efficacy (4). Individual
studies have sometimes indicated larger treatment effects for behavioral versus pharmacologic
treatments (e.g., 6,7), but small sample sizes and methodologic features that favor one treatment
or another make such studies difficult to conduct and interpret.
Despite the proven efficacy of behavioral and pharmacologic treatments for insomnia,
a number of important questions remain. Early studies have begun to address some of these
questions, as indicated in subsequent chapters. These questions fall into four general areas.

INSOMNIA AND ITS MEASUREMENT

What is the etiology and pathophysiology of insomnia? As described in previous chapters in this
volume, significant advances have been made in our understanding of the psychological and
neurobiological underpinnings of insomnia. However, there is no definitive evidence that sup-
ports any single theory of insomnia. Likewise, no biological or neurophysiological markers have
demonstrated adequate sensitivity and specificity. Improving our understanding of the causes
of insomnia can only lead to more specific treatments for this condition.
What are the most appropriate outcome measures to use in the treatment of insomnia? Insomnia
symptoms can be assessed in a variety of ways, including patient report instruments, diaries,
polysomnography, and actigraphy. Even self-report outcomes have typically focused on “quan-
titative” outcomes such as sleep latency, wakefulness after sleep onset, and total sleep time.
Whether these measures adequately capture the core insomnia experience is open to ques-
tion. The development of patient report outcomes is increasingly using qualitative research
methods to ensure that insomnia assessment instruments capture those dimensions most
salient to patients themselves. Thus, more qualitative self-report outcomes may complement
polysomnography and other objective sleep outcomes in the future. Another important trend in
insomnia outcome measures is increasing emphasis on both sleep and waking aspects of the dis-
order. As exemplified in the Research Diagnostic Criteria for Insomnia (8) and the International
Classification of Sleep Disorders, Second Edition (ICSD-2) (9), increased emphasis has been
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OVERVIEW OF TREATMENT CONSIDERATIONS 257

placed on the measurement of waking symptoms of insomnia, including objective measure-

ment of neuropsychological impairments. Thus, greater sophistication in both self-report and
objective indicators of sleep and wake function in insomnia may lead to a better understanding
of treatment effects.

BEHAVIORAL TREATMENTS
What are the effective elements of multimodal cognitive behavioral therapy for insomnia (CBT-I)?
Although the efficacy of CBT-I is now well demonstrated, treatments can be made more efficient
if they focus on those elements that have the greatest efficacy. In order to identify these elements,
dismantling trials are needed to compare the various components of CBT-I.
What is the minimal effective “dose” of behavioral treatment? One objection sometimes raised
to the more widespread use of CBT-I and other behavioral treatment is the effort required
to provide six to eight individual treatment sessions. Some evidence already suggests that a
smaller number of treatments may have similar efficacy (10,11). Although the ideal number of
sessions is likely to vary for different individuals, further evidence is needed to clarify the range
of effective treatment duration.
How can we most effectively disseminate behavioral treatments for insomnia? Recognizing the
efficacy of behavioral treatments for insomnia, we must also confront the mismatch between
the number of trained behavioral sleep medicine specialists and the number of individuals in
the population who experience insomnia. As outlined in this section, early evidence suggests
that alternate forms of treatment and treatment delivery may be part of the answer. Briefer,
more focused treatments, the use of group therapy, and the use of self-guided treatments such
as internet-based therapy may all provide useful methods for dissemination. These methods
must also be accompanied by additional efforts toward education of other health professionals
and building the workforce of trained behavioral sleep medicine practitioners.

PHARMACOLOGIC TREATMENT
What are the viable targets for new pharmacotherapies? Sleep–wake regulation is complex, and
the number of neurotransmitters and neuromodulators involved is large. The good news is
that this creates a number of viable targets for insomnia therapy; the bad news is that no single
neurochemical is sufficient to reliably alter sleep–wake balance and treat insomnia. Nevertheless,
the long standing reliance on benzodiazepine receptor agonists is likely to give way to a greater
variety of treatments, including those affecting targets such as histamine, orexin, and serotonin
receptors.
What are the ideal delivery systems? Insomnia pharmacotherapy has been provided only in
the form of oral tablets or capsules. Alternate delivery systems, including transdermal systems,
sublingual, and nasal delivery systems may all be feasible for insomnia treatments. These
systems are currently under investigation; their place in the pharmacotherapy armamentarium
remains to be seen.
What is the optimal duration of treatment? Until the last five to ten years, the widespread
assumption was that insomnia pharamacotherapy should be restricted to short term. As evi-
dence is accumulated regarding the longer term efficacy of pharmacotherapy agents, as well as
the chronic nature of insomnia, reasonable questions emerge regarding the optimal length of
pharmacotherapy. Although it seems undesirable to consign a patient to lifelong pharmacologic
treatment, there is currently very little evidence suggesting how to optimize the duration of
treatment.

GENERAL TREATMENT CONSIDERATIONS

How can we match treatments to specific patients? Very little evidence currently guides practition-
ers in terms of selecting behavioral or pharmacologic treatments for a specific patient, much
less the specific treatment within these broad categories. Understanding how to match treat-
ments in patients requires studies with large numbers of subjects, and well-characterized treat-
ments and patients. Nonetheless, such efforts are important in order to reduce the time and
expense of treatment in real-world clinical settings.
What are the optimal forms of combination and sequenced treatments? Although the efficacy of
behavioral and pharmacologic treatments is well established, the circumstances under which
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258 BUYSSE

Clinical state
and circumstances

Clinical expertise

Patients’
preferences Research evidence
and actions
Figure 1 The optimal management of insom-
nia patients depends on research evidence, the
patientí s clinical state, circumstances, and pref-
erences, and the practitioner’s clinical expertise.
Source: From Refs. 12 and 13.

these treatments should be combined, or when patients should be treated sequentially with
the different modalities is largely unknown. Identifying the most effective treatment sequences
will help to address the problem of treatment nonresponse and residual symptoms, which have
heretofore received little attention.
How does treatment affect insomnia and its comorbidities? Convincing evidence indicates that
insomnia is a risk factor for mental disorders, and newer evidence suggests that insomnia may
be a risk factor for, or worsen the experience, of medical conditions such as hypertension and
chronic pain. An important question for future research is whether treating insomnia leads to
reduced risk for adverse health outcomes, and whether it actually improves the symptoms of
comorbid medical and psychiatric disorders.
Can we develop effective evidence-based treatment guidelines for insomnia? Basic evidence
regarding treatment efficacy is available for behavioral and pharmacologic treatments, although
more sophisticated evidence, such as treatment matching and optimal sequencing strategies,
is not. Initial treatment guidelines have been developed for insomnia, but a larger empirical
database is clearly needed to make these guidelines more meaningful and effective in clinical
practice. While there is clearly a need for evidence-based guidelines in insomnia, it is also impor-
tant to consider patients’ preferences in the selection of treatments as well. As Haynes wrote,
“the term evidence based medicine was developed to encourage practitioners and patients to
pay due respect—no more no less—to current best evidence in making decisions” (12) or, as
stated even more succinctly by DaCruz, “evidence does not make decisions, people do” (13).

SUMMARY
Many components of the effective treatment of insomnia have been addressed by previous
research, as presented in detail in this section. However, many other questions remain. The
optimal treatment of insomnia patients will depend on the continued collection of new research
evidence, as well as understanding and respect for the patient’s clinical state, preferences and
actions, and the practitioner’s expertise (Fig. 1).

ACKNOWLEDGMENT
Supported in part by NIH grants MH024652, AG020677 and AR052155.

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23 Role of Healthy Sleep Practices:

Alcohol/Caffeine/Exercise/Scheduling
Leah Friedman
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, U.S.A.

Jamie M. Zeitzer
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, and Psychiatry Service,
VA Palo Alto Health Care System, Palo Alto, California, U.S.A.

Martin S. Mumenthaler
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, U.S.A.

INTRODUCTION
Everyday behaviors can have a profound impact on sleep and modification of these behaviors is
considered a useful nonpharmacologic approach in treating many manifestations of insomnia.
Four behaviors commonly targeted in such treatments are the amount and daily timing of
alcohol and caffeine consumption, the nature, amount and timing of physical exercise, and the
scheduling of sleep and wake.
Most codified nonpharmacologic treatments for insomnia have included regulation of
some or all of these behaviors as treatment components [e.g., scheduling in stimulus control
(1)] or bundled with other recommended daily health practices as an independent behavioral
treatment called “sleep hygiene” [e.g., (2)]. Sleep hygiene has also been used as a control
treatment for other nondrug approaches [e.g., (3,4)]. The components of sleep hygiene vary but
the basic paradigm is consistent: the prescription of some practices thought to improve sleep
and the limitation or prohibition of others thought to harm sleep.
Although there have been studies of sleep hygiene as a package, it is difficult to test
the validity of sleep hygiene as a stand-alone treatment because there is no formal consensus
as to what components should be included nor have the instructions for these components
been standardized (5). Stepanski and Wyatt (5) have suggested that given the inconsistency in
the components of sleep hygiene treatments, evidence for specific health practices should be
reviewed independent of one another. Thus, we will review the extant research on the effects of
alcohol, caffeine, exercise and scheduling on sleep quality and quantity and, when available, the
effects of modifying these behaviors on disturbed sleep. In this chapter, the impact of routine
alcohol and caffeine use as components of inadequate sleep hygiene is discussed. Abuse of
these substances, and others, as primary causative factors in insomnia is discussed in detail in
Chapter 17.

ALCOHOL
Most nonpharmacologic treatments for insomnia advise patients to limit alcohol intake or
abstain from alcohol before bedtime. In some of the published techniques, the instructions are
vague [e.g., the patient is advised to “moderate alcohol consumption and eliminate ‘night caps’”
(6) or “practice light to moderate use of alcoholic beverages” (7)] though some are more specific,
such as those endorsed by a recent American Academy of Sleep Medicine wellness booklet: “Do
not drink alcoholic beverages within four to six hours of bedtime” (8).
The soporific effects of alcohol have long been known; witness the drunken sleep of Noah
in Genesis. Because of its initial sleep-inducing effects, alcohol is frequently used to self-medicate
insomnia. Alcohol is a global depressant of the central nervous system (CNS) and acts through
the inhibitory GABA-A receptor complex to increase the length of time it is opened after its
chloride channel is activated by GABA. Notably, this same receptor complex is also modulated
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by barbiturates and benzodiazepines, though these act at receptor complex sites distinct from
those at which alcohol acts (9).
Alcohol is undoubtedly the most commonly used sleep-promoting substance (10), but
the worm in this apple is that the sedative effects are transient. After intake before bedtime,
even in healthy individuals without insomnia, alcohol reduces sleep onset, increases nonrapid
eye movement (NREM) and reduces rapid eye movement (REM) sleep early in the night. This
seeming immediate benefit of alcohol vanishes relatively quickly since alcohol is metabolized
rapidly (at the approximate rate of one glass of wine or a half-pint of beer per two hours).
The second part of the night after evening alcohol ingestion is characterized by light, disturbed
sleep, with more REM sleep and associated increased dream or nightmare recall and sympathetic
arousal, including tachycardia and sweating (11). Gastric irritation, headache, and a full bladder
may also be among the effects that interrupt sleep in the latter part of the night. The negative
impact of alcohol on sleep can continue long after blood alcohol concentrations reach zero,
and lead to the so-called “hangover effect” (7). This may reduce overall vigor and daytime
alertness, leading to daytime sleep and a subsequent disruption of nighttime sleep due to sleep
fragmentation. In addition to the sleep-specific effects, alcohol increases the risk of nocturnal
falling (10) that may lead to an increase in injuries in certain vulnerable populations (e.g., older
individuals).
A further complication of alcohol intake late in the day is its impact on breathing, particu-
larly during sleep, in those who have compromised ventilation (7). In individuals with mild or
moderate sleep apnea, even moderate blood alcohol levels (0.07 gms/dL) can increase the fre-
quency of obstructive apneas and the mean sleep heart rate (12). In addition to the acute effects
of alcohol on sleep, chronic alcohol intake is likely to affect sleep as well. The amplitude and
incidence of K-complexes are reduced in older alcoholics (13) and this effect may be reversible
through extended alcohol abstinence. Although the incidence and prevalence of chronic alcohol
use as a factor contributing to insomnia is not known, a community-based survey found that
those who met insomnia criteria reported more than twice as much use of alcohol over the
course of a week than age and sex-matched controls not meeting criteria (14).
In sum, while alcohol is often used as both a short- and long-term self-treatment for
insomnia, in addition to being used in an unrelated recreational fashion, it has overall detri-
mental effects on sleep as it changes both the timing and nature of sleep-related physiology, the
consequence of which for long-term health is unknown.

CAFFEINE
If alcohol is the most widely used substance to self-medicate nocturnal sleeplessness, caffeine
is the most commonly used substance to self-medicate excessive sleepiness. While not quite
antediluvian, Chinese folklore dating from the third century reports a tale regarding the alerting
effects of caffeine (in tea). According to the tale, a Chinese general cut off his eyelids in order to
stay awake and a tea tree sprang up from the site where the eyelids fell to the ground (15).
Although the specific details vary, almost all behavioral insomnia treatments caution
against drinking caffeinated beverages late in the day. Some narrowly address coffee and tea
while others include chocolate and caffeinated soft drinks (16). Hygiene directions for limiting
caffeine intake vary from very stringent instructions (e.g., avoid caffeine use completely for four
weeks, followed by limiting caffeine use to three cups of coffee prior to 10 AM) (7) to more liberal
approaches [e.g., caffeine (should) be discontinued four to six hours before bedtime] (17).
Caffeine is a mild CNS stimulant that acts through the inhibition of A1 and A2A adenosine
receptors (18). As adenosine receptors are present throughout the brain, it has been difficult to
specify the location or locations at which caffeine inhibition acts to induce wakefulness. While
still controversial, the cholinergic basal forebrain is likely one such locus (19). Both coffee and
tea are beverages with high caffeine content; a standard cup of coffee has approximately 80
mg of caffeine while a similar sized drink of tea contains approximately 40 mg of caffeine (20).
There is, however, very large variation in the caffeine content of coffees and teas, ranging from
<0.05 mg/mL in decaffeinated coffees and teas to more than 3.5 mg/mL in some espressos
(21,22). Caffeine is also present in carbonated colas, pepper drinks, citrus drinks, root beers, cold
teas, and the growing market segment of energy drinks. The caffeine content of these drinks
can range from 0 (these are naturally uncaffeinated—the caffeine is added as a supplement) to
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262 FRIEDMAN ET AL.

120 mg in some energy drinks (23). Other less commonly imagined sources of caffeine include
chocolate (∼10–30 mg/43 g bar) and both sleepiness-specific (e.g., caffeine pills, ∼200 mg) and
nonspecific medications (e.g., migraine and diet medication, ∼30 mg) (24,25). Worldwide, tea is,
however, second only to water as the most widely consumed beverage (26). Because of its utility
as a stimulant, and no doubt because of its relatively low cost, near ubiquitous availability, and
apparent health safety both acutely and chronically, (18) caffeine is used extensively as a benign
drug to maintain alertness. The per capita consumption in the United States has been estimated
at 200 mg/day (20).
Contrary to alcohol, caffeine delays sleep initiation. Caffeine also increases the proportion
of sleep spent in lighter stages (N1 and N2), while reducing both slow wave sleep (N3) and total
sleep time, increases the time to first REM period, and increases the number of changes between
sleep stages (18). Caffeine ingestion even early in the day can have objectively quantifiable
effects on nocturnal sleep (27) possibly by disrupting the effects of adenosine, one hypothesized
mechanism underlying homeostatic sleep pressure (19). Individuals may be unaware of these
nocturnal effects as ingestion of low doses of caffeine during the daytime may fail to induce an
increase in subjective alertness during the day, but can still disrupt sleep at night (26). Daytime
caffeine ingestion can also lead to significant amounts of caffeine being present in the blood
when attempting to initiate sleep, as the half-life of caffeine is approximately 4.5 hours (25) and
its metabolites, notably theophylline, have potent inhibitory effects on the same A1 and A2A
adenosine receptors as does caffeine (18).
There is wide inter-individual variability in sleep responses to caffeine, with some indi-
viduals being more sensitive to the effects of caffeine than others (28,29). There is likely a genetic
component to this variability as a common genetic polymorphism in the adenosine A2A receptor
is related to both the subjective and objective effects of caffeine on sleep (29). The issue of caf-
feine sensitivity, however, is complex as a number of studies have shown that individuals both
with and without insomnia self-regulate caffeine intake such that those who rated themselves
as ‘caffeine sensitive’ would drink fewer caffeinated beverages (29,30). A further complexity is
that the change in sleep onset behavior that can be associated with mild caffeine intake may
be innately more worrisome, and therefore be perceived as more disruptive of sleep, for some
individuals than for others (31). The anxiety or worry associated with a delayed sleep onset
may exacerbate the mild sleep disruption that would have otherwise occurred after exposure
to a low dose of caffeine. Caffeine use is also associated with a subjective increase in tolerance
to the alerting effects of caffeine that is not accompanied by a change in metabolism or objective
effects on performance (32–34). This can lead to increasing caffeine intake during the day in an
effort to increase subjective alertness, which will secondarily increase caffeine levels during the
night, potentially disrupting sleep.
Given the complexities of interindividual difference in caffeine metabolism and sensitivity,
as well as issues of tolerance and subjective response to caffeine-induced alertness, it is not
surprising that there are no specific consensus instructions related to moderating caffeine intake
in individuals with insomnia. It should be noted that the International Classification of Sleep
Disorders, second edition (ICSD-2) makes diagnostic distinctions regarding both caffeine and
alcohol use. Persons whose use of either alcohol or caffeine is inappropriate in relation to their
sleep would be diagnosed as having insomnia due to inadequate sleep hygiene; whereas those
who are dependent on caffeine or alcohol or use them excessively would be assigned a diagnosis
of insomnia due to substance abuse (35). Education about the sources and possible long-lasting
effects of caffeine should be part of any nonpharmacologic treatment of insomnia.

EXERCISE
For more than 25 years, regular, daily exercise has been suggested as a component of nonphar-
macologic methods for treating insomnia (2). Exercise is still promoted widely as a nonpharma-
cologic method for improving the quality and quantity of sleep (8,36).
One metaanalysis of the acute effects of exercise on sleep, found support for small to
moderate effects of acute exercise on slow wave sleep, REM sleep latency, total time spent in
REM sleep, and total time asleep (37). Despite these findings, as Driver and Taylor note, the
sleep-promoting effect of exercise in both normal and clinical populations has not yet been
conclusively demonstrated (38).
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One hypothesized mechanism of the effects of exercise on sleep involves the production
of heat during exercise and subsequent cooling. In theory, this exercise-induced cooling could
enhance the normal sleep onset related cooling mechanisms that appear essential for normal
sleep induction and maintenance (39). The temperature-sensitive neurons in the hypothalamus
(40) that can respond to cooling and are sleep active may be the ultimate physiologic mechanism
responsible for exercise-induced changes in sleep. This would also help explain why exercise
that increases core temperature, when scheduled too close to the onset of sleep, can lead to
sleep disruption (41). Even passive forms of cooling (e.g., hot bath followed by evaporative
cooling several hours before intended bedtime) have been suggested as being beneficial to sleep
onset (42).
Another hypothetical mechanism underlying the effects of exercise on sleep is exercise
induction of cytokines, notably interleukin-6 (43). Low concentrations of cytokines, associated
with mild to moderate exercise, can promote drowsiness while elevated concentrations are
associated with intense exercise and increased wake. There are many other changes in endocrine
activity associated with exercise that may also underlie the changes associated with sleep (e.g.,
endorphins, cortisol).
One of the problems in assessing the effects of exercise on sleep is the variation in the
length, intensity, and timing of exercise, as well as the efficacy of acute and chronic exercise
routines. Each of these, as well as sex, age, and overall fitness level are likely to impact the effects
of exercise on sleep (44). Understanding the specific mechanism, by which exercise improves
sleep in individuals with insomnia, as well as in individuals without insomnia, will be a critical
step in understanding how to maximize its effects. The timing of exercise may also lead to an
indirect effect, which is greater exposure to daylight when the exercise intervention is scheduled
to take place outdoors (e.g., tennis, walking, jogging) (45). In older individuals whose reduced
daytime light exposure may lead to circadian-associated sleep problems (see below), outdoor
exercise may be especially important.
While there is yet to be a definitive link established between exercise and improved sleep,
there is sufficient evidence to suggest that there is a likely connection. A better understanding
of the mechanistic connection between the two will lead to an improved, more thoughtful
recommendation of exercise as a nonpharmacologic treatment of insomnia.

SCHEDULING
Bon vivant that he was, it is questionable whether Ben Franklin followed his own “early to bed,
early to rise” advice but he certainly was on to something important as chronic insomnia is
often associated with irregular sleep timing (30). Regularity in time-in-bed scheduling supports
the entrainment of sleep and wake to the basic daily alternation of day and night. Regular sleep
and wake patterns lead to regular exposure to light. Light is the primary zeitgeber (Gm., time
cue) of the circadian timing system. Thus, regular sleep and wake patterns lead to regular dark
and light exposure that leads to a regular position of the circadian clock relative to sleep and
wake. Such a pattern leads to circadian timing that is maximally supportive of proper sleep
and wake (46,47). Not only does regularly timed light exposure lead to a proper entrainment of
the circadian system, but it also maximizes circadian amplitude (48), which may be especially
important in older individuals who may have an innately decreased amplitude of their circadian
clock (49,50).
Given the nature of agricultural work in pre-industrial times, an inherent tie existed
between the daily alternation of light and dark and peoples’ work and sleep schedules. The
invention of the electric light likely accelerated our movement away from a natural light/dark
exposure and highly regular entraining signals for the circadian system. In our advanced tech-
nological society, there are fewer built-in factors that support a consistently followed daily
schedule. Advances in science and technology have led to great latitude in the timing of work
and play, much of which can theoretically occur now at any time of the day. Twenty-four hour
access to supermarkets and computers and businesses maximizing utilization of equipment and
space by scheduling work around the clock are just a few examples of infrastructure changes
that weaken the practice of fixed day/night schedules. This circumstance is thought to contribute
to the high prevalence of insomnia in modern societies and is also likely linked to decreased
daytime alertness (51,52).
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Scheduling or timing is in some sense at the core of the other health practices discussed in
this chapter. As seen above, a major concern regarding the consumption of alcohol, and caffeine,
and exercise practices is their timing in relation to sleep. Notably, the question is not necessarily
how much, but when. From its earliest formulations [e.g., (53)] to the most recent formulation of
approved guidelines for treatment of insomnia (54), the admonition to keep a regular schedule
has been included in nonpharmacological treatments for insomnia. An important caveat is that
regularity or scheduling alone is not sufficient, however, for patients to get adequate amounts
of sleep. It is necessary for them to allocate sufficient time in bed to get an adequate amount of
sleep (52). The various nonpharmacologic methods used for treating insomnia have different
instructions relating to regular sleep schedules. Stimulus control, given its goal of strengthening
the association between bed and sleep, has a very flexible into bedtime. A central stimulus con-
trol instruction is to get into bed “only when sleepy.” On the other hand, the morning instruction
is to set a standard fixed wake-up time (1). Cognitive behavioral therapy for the treatment of
insomnia also prescribes adherence to a standard rise time (55). The essential treatment mech-
anism in sleep restriction therapy involves scheduling. The time allotted in bed is manipulated
in order to build up sufficient sleep debt so that there will be adequate homeostatic pressure for
sleep during the scheduled time in bed. Although the restriction of time in bed to the amount
of time the individual actually sleeps is the central mechanism of sleep restriction therapy,
the regularity of sleep schedules is intrinsic to this therapy, even if not emphasized (56). Sleep
restriction therapy, along with some of the other nonpharmacologic treatments for insomnia,
also proscribe daytime napping. Not only does this increase the likelihood of being able to
maintain a regular nocturnal sleep schedule, but it also reduces daytime exposure to darkness.
The human circadian system is sensitive to light during the daytime (57) and the change in light
exposure through napping may also deleteriously influence the position of the circadian clock.

CONCLUSION
The benefit of each specific health practice described above remains to be definitively answered.
The most recent consensus guidelines for the treatment of insomnia concluded that “although
there is insufficient evidence of the effectiveness of sleep hygiene as an insomnia treatment the
general principles of sleep hygiene should be included in other behavioral treatments,” and for
the most part they have been (54).
Although the effectiveness and determination of the optimal parameters of the four health
practices described in this chapter are still in question, the overall evidence from our reading
of the research literature and our clinical experience is sufficient for us to suggest following
the four basic health practices discussed above. At worst, the suggested practices appear to do
no harm. At best, if any or all of these health practices have been the source of an individual’s
sleep problem or have exacerbated it, correcting these practices may help. Finally, they are all
supportive of good general mental and physical health independent of their effects on sleep
and this indirectly supports good sleep.
We suggest the following:

1. The collection of baseline sleep logs, which is widely recommended as a first step in behav-
ioral treatments, can generate helpful information as to what should be treatment targets.
For example, when patient information reveals regular late afternoon and evening use of
caffeine, this should be explored as a source of sleep disruption and insomnia complaints
(58). Many who have used these techniques have noted that in the process of collecting these
self-report data, individuals often become aware that some of their behavior is antithetical
to good sleep. This awareness helps increase compliance.
2. Limit evening drinking of alcoholic beverages to ONE alcoholic drink with dinner and NO
alcoholic drinks within three hours of bedtime. Information about alcohol and its paradoxical
effects on sleep initiation and sleep maintenance should be disseminated.
3. Limit caffeine (tea, coffee, cola, caffeinated soft drinks, chocolate) use no more than two
cups taken no later than lunchtime. The impact of caffeine metabolism should be explained
such that individuals with insomnia understand that what is a great boost in the daytime
is a negative at night. There are decaffeinated drinks that many have substituted for that
habitual beverage that people reflexively take throughout the day.
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4. Schedule some form of moderate (or greater) physical activity (walking, swimming, jogging,
gardening) for at least 30 min every day to be completed no later than four hours before
bedtime. Most people are aware of the importance of exercise for their general health, and
if only because exercise improves health it should contribute to good sleep. This exercise
is also likely to synergistically support circadian variation in core body temperature and
contribute to good sleep.
5. Set a sleep schedule that fits with usual habits as recorded by two weeks of sleep log
information. Once a realistic schedule is determined, the alarm should be set for the same
time, seven days a week. The evening into-bed-time can be scheduled within a one-hour
time frame to allow for that essential phone call or must-see TV program. If there are special
events that result in delayed bedtime, keep the alarm set at its regular time and wake as
usual. Keeping the same wake time instead of sleeping-in ensures the buildup of sufficient
homeostatic sleep pressure to maintain sleep the next evening and does not disrupt the
normal light exposure in the morning that is critical for keeping sleep rhythm coupled to
circadian rhythm.
Two parting thoughts: “Bad sleep hygiene is seldom the sole cause of any sleep problem,
but rare is the sleep problem that is not partially maintained by poor sleep hygiene,” (2) and, as
another early sleep hygiene investigator noted, “. . .removing the [sleep hygiene] abuses from
the daily routines of abusers is. . .probably. . .a good idea” (59).

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24 Stimulus Control Therapy

Richard R. Bootzin
Departments of Psychology and Psychiatry, University of Arizona, Tucson, Arizona, U.S.A.

Leisha J. Smith
Department of Psychology, University of Arizona, Tucson, Arizona, U.S.A.

Peter L. Franzen
Sleep Medicine Institute and Department of Psychiatry, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania, U.S.A.

Shauna L. Shapiro
Department of Counseling Psychology, Santa Clara University, Santa Clara, California, U.S.A.

Stimulus control therapy (SCT) for insomnia is based primarily upon an operant conditioning
model of the development and maintenance of insomnia in which falling asleep is conceptu-
alized as an instrumental act emitted to produce the reinforcement, sleep. Difficulty in falling
asleep, then may be due to inadequate stimulus control (1). This could be either because of the
lack of discriminative stimuli that facilitate sleep or the presence of stimuli that are associated
with activities that interfere with sleep.
The role of stimuli in facilitating or interfering with sleep is not the only learning principle
that affects sleep. Pavlovian conditioning is also important in that the bed and bedroom can
become cues for the anxiety and frustration associated with trying to fall asleep (1). Internal
cues, such as mind racing, anticipatory anxiety, and physiological arousal can become cues for
further arousal and sleep disruptions (2). SCT aims to reduce cues associated with arousal as
well as cues that are discriminative stimuli for activities that are incompatible with sleep.
Stimulus control therapy was designed to help individuals suffering from insomnia to
strengthen the bed and bedroom as cues for sleep, to weaken the bed and bedroom as cues
for arousal, and to develop a consistent sleep–wake schedule to help maintain improvement.
Stimulus control therapy for the treatment of insomnia was proposed by Bootzin in 1972 (3).
The instructions were expanded during the next few years (1,4) and have remained unchanged
to the present. The six instructions that comprise SCT are as follows:

1. Lie down to go to sleep only when you are sleepy.

2. Do not use your bed for anything except sleep; that is, do not read, watch television, eat,
or worry in bed. Sexual activity is the only exception to this rule. On such occasions, the
instructions are to be followed afterward when you intend to go to sleep.
3. If you find yourself unable to fall asleep, get up and go into another room. Stay up as
long as you wish and then return to the bedroom to sleep. Although we do not want you
to watch the clock, we want you to get out of bed if you do not fall asleep immediately.
Remember the goal is to associate your bed with falling asleep quickly! If you are in bed
more than 10 minutes without falling asleep and have not gotten up, you are not following
this instruction.
4. If you still cannot fall asleep, repeat step 3. Do this as often as is necessary throughout the
night.
5. Set your alarm and get up at the same time every morning irrespective of how much sleep
you got during the night. This will help your body acquire a consistent sleep rhythm.
6. Do not nap during the day.

While the instructions are concerned mainly with sleep onset, they may also be used
with individuals with sleep maintenance problems by repeating instructions three and four
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STIMULUS CONTROL THERAPY 269

during mid-night awakenings. Each of the instructions stated above is important in reestab-
lishing the bed and bedroom as cues for sleep rather than wakefulness. It is important that the
rationale for each instruction be described to patients in detail. Although the instructions seem
straightforward, they may be difficult for patients to follow, and if the reasons behind the
instructions are unclear, compliance may be even more challenging.
Instruction 1: The first instruction is designed to help individuals become more aware
of their bodies’ cues for sleepiness. Frequently, individuals with insomnia decide to go to bed
because of clock time as a result of a calculation of how much sleep they feel they must have
before awakening in the morning. This may produce increasing anxiety as sleeplessness persists
coupled with excessive time in bed for the amount of sleep that is obtained.
Initially, individuals with insomnia may rarely use internal cues of sleepiness. Thus,
instruction one should be viewed as a goal to be achieved gradually over the first few weeks
rather than as an imperative to be started immediately. Becoming sensitive to internal cues of
sleepiness will aid patients in determining an appropriate time to go to bed based on sleepiness,
not on the clock. Going to bed when sleepy will also make it easier for patients to fall asleep
more quickly.
Instruction 2: Instruction two is intended to help strengthen the cues of the bed and
bedroom with sleep and weaken the cues of bed and bedroom with arousal and wakefulness.
Often individuals with insomnia will engage in activities in bed that interfere with falling
asleep, such as reading, watching television, talking on the phone, text-messaging, or working.
This behavior establishes the bed and bedroom as conditioned stimuli for wakefulness. By
prohibiting any activity associated with arousal, other than sexual activity, from taking place in
the bed and bedroom, the second instruction of SCT serves to reduce the bed and bedroom as
cues for wakefulness, and reestablish them as cues for sleep.
Patients are typically asked to engage in activities associated with arousal in a different
room in the house. For example, if a patient typically thinks about and plans the following day’s
activities as they are lying in bed, he or she would be asked to do this planning in another room
before going into the bedroom. This may help individuals with insomnia create a new bedtime
routine that is better suited to facilitate sleep onset.
Instructions 3 and 4: The third and fourth instructions are core elements of SCT. Instructing
patients to get out of bed, if they are not sleeping, limits them from being awake in bed and
further strengthens the association between the bed and bedroom and sleep. While SCT is
focused primarily on sleep onset problems, instruction four is incorporated for use with sleep
maintenance issues. Getting out of bed to engage in other activities when unable to sleep can also
give individuals a sense of control over their insomnia. This makes the problem less distressing
and more manageable for the patient.
There are a few important issues in successfully implementing these instructions. First,
how long should someone with insomnia be in bed before getting out of bed? The instructions
place a premium on getting out-of-bed quickly, within 10 minutes. However, some individuals
with insomnia become anxious by such a recommendation and will constantly check the clock
to see if it is time to get out of bed. To avoid that, patients are typically instructed to turn the face
of the clock away from them, so that clock checking does not occur. If time-pressure produces
increased anxiety, the third instruction is often modified to put emphasis on the internal cues of
frustration and anxiety rather than on how much time has passed. Thus, while it is permissible
to be in bed while in the process of falling asleep, the patient should get out of bed at the first
signs of frustration with not falling asleep.
Importantly, however, it is not permissible to stay in bed for long periods of time waiting
to fall asleep (such as 45, 60 minutes, or longer) even if not frustrated. The goal of the SCT
instructions remains to associate the bed and bedroom with falling asleep quickly. Research has
indicated a quarter-hour rule (staying in bed before falling asleep no more than 15 minutes) is
manageable and effective in producing improved sleep in those with insomnia (5).
Second, once up, how long should the patients stay awake and what should they do?
A good clinical rule of thumb is that patients should stay out-of-bed long enough to feel that
they might successfully be able to fall asleep if they return to bed. This is an opportunity to
practice paying attention to internal cues of sleepiness and using them as a guide. Generally,
this means staying awake at least 15 or more minutes before trying to go to sleep again. As for
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270 BOOTZIN ET AL.

the activities to be engaged in, patients should be encouraged to do something relaxing and
enjoyable.
Because of the increasing evidence that even room light can alter sleep-wake circadian
schedules (e.g., 6), we have placed additional emphasis on keeping lights dim when out-of-
bed during the night. Reading with a reading light and watching television from a distance
are acceptable. We discourage patients from doing anything on the computer, even checking
email, since the amount of light from the monitor when sitting close to it is brighter than most
individuals realize and activities done on the computer are usually arousing.
Finally, many adults with sleep maintenance problems elect to start the day at 4 AM or
5 AM rather than return to the bed for additional sleep. This is not a wise strategy since even
30 or 60 minutes of additional sleep increases alertness and reduces fatigue during the day. As
long as the usual final wake-up time is maintained, returning to bed is recommended when
there is 45 minutes or more until wake-up time.
Instruction 5: One of the goals of instruction five is to set a more consistent wake-up time
for all seven days of the week, with less than one hour of discrepancy between days off and
workdays. Keeping a consistent wake time helps establish a more regular sleep schedule. Many
people with insomnia stay in bed later in the morning in hopes of catching up on the sleep
they missed the night before. However, irregular schedules weaken the association between
the cues of the bed and bedroom and sleep. Maintaining regular sleep schedules has been
found to reduce daytime fatigue and sleepiness (7). Consequently, a regular schedule helps
both strengthen cues for sleep and reduce daytime problems associated with sleep disturbance.
Instruction 6: The final instruction encourages patients to maintain more regular sleep
patterns by not napping during the day. In addition, the lack of daytime naps after a poor
night’s sleep when following SCT allows the homeostatic drive for sleep to build throughout
the day, making it more likely that the patient will successfully fall asleep faster the next night.
This strengthens the cues of the bed and bedroom with falling asleep and provides a success
experience for the patient to help maintain compliance with the instruction.
It should be emphasized that we are not opposed to all naps. Instruction six is intended
to increase the likelihood that SCT will successfully change a dysfunctional sleep pattern. With
some individuals, such as the elderly, however, it may be wise to have a brief nap (30 min or
less) scheduled at the same time every day. It is the irregularity of napping that produces and
maintains irregular sleep schedules.

EFFECTIVENESS OF STIMULUS CONTROL THERAPY

There have been numerous reviews and meta-analyses of the effectiveness of cognitive behav-
ioral treatments for insomnia. In 1999, a review (8) and practice guidelines (9) identified SCT as
the only psychological and behavioral treatment to meet the highest standard for recommenda-
tion. In 2006, the American Academy of Sleep Medicine (AASM) published an update of both
the review of the literature (10) and evidence-based practice parameters for psychological and
behavioral treatment of insomnia (11). While most of the newly added studies included in the
review investigated multicomponent cognitive behavioral treatments for treating insomnia,
the AASM recommendations maintained that SCT is an “effective and recommended therapy in
the treatment of chronic insomnia” (11, p.1417) and endorsed some additional single-treatments
as well.

MULTICOMPONENT TREATMENTS CONTAINING STIMULUS CONTROL THERAPY

A commonly employed multicomponent package combines stimulus control instructions, sleep
restriction, sleep education, and cognitive therapy. This combination of interventions lends
itself well to clinical settings in which adults of all ages are seen. Case series studies have found
this combination to be as effective in clinical settings as in controlled outcome studies (12–15).
Despite differences in which specific variables improve, as well as the degree of improvement,
all case series studies have reported significant improvement in primary sleep variables.
For example, Morin, and colleagues (13) reported that improvement ranged from 42%
to 50% on the main target symptoms of sleep onset latency, wake after sleep onset, and early
morning awakening. There was a statistically significant, but modest 8%, gain on total sleep time
(from 325 minutes at baseline to 350 minutes after therapy). In contrast to the small improvement
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STIMULUS CONTROL THERAPY 271

in total sleep time found by Morin and colleagues (13) Perlis, and colleagues (15) found a 29%
improvement in total sleep time along with a 56% reduction in wake after sleep onset and a
34% reduction in sleep onset latency.
Other studies have focused on the comparison of cognitive behavioral treatment for
insomnia (CBTi) with pharmacotherapy and for patients who have poor sleep despite using
medication. One study compared a CBTi intervention (including stimulus control instructions)
to zopiclone and placebo for the treatment of insomnia in older adults (16). Participants who
received CBTi improved on measures of sleep efficiency, amount of slow wave sleep, and time
spent awake during the night at both posttreatment and six-month follow-up assessments.
Participants in the drug and placebo groups did not show similar improvements. Another
study evaluated the effectiveness of CBTi for continuing insomnia in older adults who were
dependent on sedative-hypnotic medications (17). Participants were assigned to either a CBT
group, which included stimulus control instructions, or a placebo group. The group that received
CBTi showed clinically significant and subjective improvement on measures of sleep quality,
whereas the placebo group did not.
In multicomponent treatment studies, it is difficult to identify which components are
most effective. Harvey, Inglis, & Espie (18) surveyed 90 participants at the one year follow-up
to determine which of 10 components of their cognitive-behavioral insomnia treatment were
associated with changes in sleep measures. The combination of stimulus control and sleep
restriction was the best predictor of improved sleep latency and total sleep time, and cognitive
restructuring, a form of cognitive therapy, significantly predicted a reduction in wakefulness.
Relaxation, although most commonly endorsed by patients, did not predict improvement on
any variable. Likewise, sleep hygiene was unrelated to changes in sleep.
It should be stressed that it is important to include components in multicomponent treat-
ments that have been evaluated and found effective as single interventions. All of the multicom-
ponent treatments discussed here used SCT as a core element. From a theoretical perspective
it is easy to see how different components might cover a broader range of problems, but it is
desirable to empirically test that proposition by comparing a single component, such as SCT,
against a multiple component intervention.

NEW TREATMENT DIRECTIONS INVOLVING STIMULUS CONTROL THERAPY

New directions in insomnia treatment include ways of delivering treatment so that more patients
can be helped more quickly, bringing treatments into the bedroom, developing new treatments
that can accelerate improved sleep, and integrating mindfulness meditation with SCT and other
cognitive-behavioral treatments.

Reaching More Patients

Among the methods that have been evaluated are the use of group treatments (19,20), the
internet (21), the telephone (22), mass media including television (23), and self-help tapes and
books (24,25). Multicomponent treatments are almost always used and the specific treatment
components vary from study to study.
Although improvement on sleep measures has been demonstrated, there appears to be
a trade-off between the number of insomniacs who might be reached and the magnitude of
treatment effects (26). For example, individual and group treatments tend to produce larger
effects than mass media treatments. An additional problem when self-help methods such as
tapes, books, and television are employed is that there is no professional assessment of the sleep
problems. Consequently, comorbid disorders may go untreated resulting in potentially less
effective treatment for the sleep problem as well. It may be more effective to include self-help
materials within the context of professional care so that a thorough assessment can be completed.
Because insomnia has been associated with increased future risk for physical and psychi-
atric disorders, there has been increased interest in extending insomnia treatment to primary
care facilities where professional assessment can be provided (e.g., 27). Baillargon, Demers, and
Ladouceur (28) reported that stimulus control instructions could be used effectively by family
physicians. Eighty percent of the patients who completed the treatment for insomnia reduced
their sleep onset latency and six of seven who had been on hypnotics reduced or stopped taking
hypnotics.
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272 BOOTZIN ET AL.

In a thorough study incorporating treatment of insomnia as part of a local health service

in Scotland, visiting nurses were trained to provide a multicomponent CBTi for insomnia (29).
One hundred and thirty-nine insomniacs participated in a clinical trial that compared multi-
component CBTi with a self-monitoring control condition. CBTi produced significantly reduced
sleep latency and wakefulness during the night. These improvements were maintained at a
one-year follow-up. Total sleep increased significantly during follow-up and 84% of patients
initially using hypnotics remained medication-free.
An example of an attempt to develop abbreviated treatment using self-help materials
and professional assessment was reported by Edinger and Sampson (30). They designed two
25-minute sessions combined with take-home pamphlets and audiotapes that reinforced the
information provided during the sessions. The abbreviated CBTi intervention produced 50%
improvement in WASO in 52% of the patients and produced substantial improvement on more
than half of the patients on an insomnia symptom questionnaire.
Following Edinger and Sampson, there have been a number of investigations that have
reported improved sleep as a result of abbreviated multicomponent treatment, in which SCT was
one of the core components, with different populations of individuals with sleep disturbances.
They include an evaluation of a two session and two telephone follow-up multicomponent
behavioral treatment (combining SCT with sleep restriction, another behavioral intervention
for insomnia) in older adults with insomnia who have psychiatric and medical comorbidities of
aging (31,32), a three session multicomponent insomnia treatment in a family medicine clinical
setting (33), a brief (two individual sessions and two telephone follow-ups) multicomponent
intervention for older adults provided by rural care providers who were trained in a two-
day workshop (34), and a brief multicomponent intervention of family caregivers of cancer
patients (35).
The abbreviated treatments produced improved sleep comparable to that found in longer
studies. An advantage of these abbreviated treatments is that they all involve individual contact
between the clinician and the patient that allows for the tailoring of treatment to the individual
problems of the patients. Many of these brief CBTi interventions are discussed in greater detail
elsewhere in this section

Bringing Treatment into the Bedroom

Cognitive-behavioral treatments for insomnia are fundamentally self-help treatments. Clini-
cians provide a thorough assessment of the nature of the sleep problems and prescribe changes
in activities and life-style at home. Although both subjective and objective measures of sleep
can be obtained, there is not usually any means of providing an objective measure of whether
the patients are adhering to the treatment recommendations.
As an example, consider the stimulus control instruction to get out-of-bed quickly if the
individual with insomnia has not yet fallen asleep. Many individuals with insomnia are not
good judges of whether or not they have been asleep. Would they be helped by a monitor
on the bed-table that would provide a signal about when to get out-of-bed? Due to advances
in the technologies of sleep-wake detection, there are a number of alternatives available to
provide feedback to patients in the bedroom including using auditory signals to which the
sleeper responds if awake, actigraphy, or single-channel electroencephalographic-based sleep-
wake detection. The sleep-wake detection monitor can be combined with algorithms to provide
feedback about when to get out-of-bed when following stimulus control or other cognitive-
behavioral instructions. Although there are preliminary data to indicate that systems like this
can be helpful in the treatment of insomnia (e.g., 36), randomized control treatment outcome
studies have yet to be published.

Accelerating Improvement
In the previous section, we discussed how technology might be used to accelerate improvement.
In this section, we describe an entirely new approach to help the individual with insomnia to
relearn to fall asleep quickly. In Intensive Sleep Retraining, individuals with insomnia were
invited into the sleep laboratory during which participants received 40 hours of sleep depriva-
tion and were given 50 opportunities, one each half hour, to fall asleep for no more than four
minutes (37). These sleep opportunities began two hours before the participants usual bedtimes
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STIMULUS CONTROL THERAPY 273

and continued for 25 hours. The idea being evaluated was whether those who had difficulty
falling asleep quickly could learn to do so when given 50 trials at falling asleep when sleep
deprived.
On average, across the 50 trials, the participants were able to fall asleep quickly and fell
asleep in 6.9 minutes as measured by polysomnography. Posttreatment assessment indicated
substantial improvements in sleep onset latency, wake after sleep onset, and total sleep time, as
well as on broader measures of fatigue and vigor, cognitive anticipatory anxiety, and self-efficacy
for sleep. These improvements were maintained at the six week follow-up assessment.
In a subsequent clinical trial, 68 insomnia participants were randomly assigned to four
treatment conditions: (1) Sleep hygiene control, (2) Intensive Sleep Retraining, (3) Four-week
SCT, and (4) Combined Intensive Sleep Retraining and SCT (38). Preliminary analyses indicate
that the three active treatment conditions were all more effective than the sleep hygiene control.
ISR produced improvement faster than SCT but both reached the same degree of improvement.
The combined treatment provided both faster initial treatment gains plus additional improve-
ment that led to trends for the best overall outcomes.

Integrating Mindfulness Meditation with Stimulus Control Therapy

Mindfulness meditation has been a recently added component in multicomponent treatments
for insomnia. Mindfulness is defined as the awareness that arises out of intentionally attending
in an open, accepting and discerning way (39), and involves formal meditation practices to
cultivate this awareness, as well as principles for applying this awareness to one’s moment to
moment experience.
In the first systematic study for insomnia in adolescents, we developed a manualized,
small-group treatment to improve sleep, daytime sleepiness, and emotional distress (40) in
teens with a substance-abuse treatment history. In this population, and more generally in clinical
practice with adults, we have found mindfulness-based principles and practices to be effective
for reducing mind-racing and other arousal associated symptoms of insomnia. Our multicom-
ponent treatment consisted of six 90 minute weekly small group sessions, with the first session
dedicated to sleep education and sessions two to six split each session into cognitive-behavioral
sleep intervention and a modified Mindfulness-Based Stress Reduction (MBSR) program.
The cognitive-behavioral sleep treatment consisted of SCT, special emphasis on regulariz-
ing sleep–wake schedules across both school and weekend days, the use of bright light therapy
to advance circadian sleep-wake schedules, and cognitive therapy. The MBSR treatment con-
sisted of instruction in meditation practices and application of mindfulness into one’s daily life.
The teens who completed at least four of the six treatment sessions were considered completers
and showed pre to posttreatment improvement (p <0.05) in daily sleep diary variables includ-
ing sleep onset latency, number of awakenings, wake after sleep onset, total sleep time, sleep
efficiency, and ratings of sleep quality (40) as well as in emotional regulation, e.g., reductions in
aggressive ideation and actions (41).
Although reductions in substance use were not a primary target of this treatment devel-
opment study, improvement in substance use through the three month follow-up was seen in
female completers, but not in female noncompleters, or male completers or noncompleters.
In our study, the multicomponent sleep treatment was instituted after the outpatient sub-
stance abuse treatment was completed. This was done to separate the effects of the sleep
treatment from those of the substance abuse treatment. It is possible, however, that combining
the two treatments would enhance the effectiveness of the substance abuse treatment since
the additional cognitive and emotional resources available to the teens as a result of improved
sleep are likely to enhance resources available for comorbid problems, including substance
abuse. In this regard, recent research has found that CBTi produces improvement in comorbid
depression even in the absence of direct treatment for depression (42). The same emotional
benefit that occurs from CBTi for depression may also occur for those with substance abuse
problems.
Another multicomponent development study that integrated mindfulness principles
and practices with SCT with cognitive-behavioral treatment components has shown simi-
larly encouraging results for adults with insomnia (43). Twenty-seven adults with insomnia
completed a multicomponent group treatment that consisted of SCT, sleep restriction, sleep
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274 BOOTZIN ET AL.

education, sleep hygiene, and MBSR in an integrative framework. The treatment was delivered
in 6 weekly sessions lasting 90 to 120 minutes.
There were statistically significant changes in both sleep measures (total wake time, sleep
onset latency, wake after sleep onset, number of awakenings, sleep efficiency, and ratings of sleep
quality) and measures of arousal (cognitive and somatic presleep arousal and the Hyperarousal
Scale). Overall clinical significance was demonstrated using intent-to-treat analyses of the
30 participants who attended the first session. At posttreatment, 87% of the sample would
no longer meet the inclusion criteria and 15 of the 30 participants showed a 50% or greater
reduction in the primary sleep outcome measure of total wake time.
In the study of substance-abusing adolescents, frequency of mindfulness meditation prac-
tice, but not duration of practice, was significantly related to improvement in total sleep time
and to improvement in self-efficacy about sleep problems (44). Similarly, in the adults with
insomnia study, frequency of meditation practice, but not duration, was significantly related
to reductions in the Hyperarousal Scale (43). Both studies suggest that emphasis should be
placed more on the frequency than the duration of mindfulness meditation practice. Further,
both studies indicate that mindfulness meditation may make a contribution to improvement of
sleep problems and reduction in arousal in multicomponent treatment studies for insomnia.

CONCLUSION
Stimulus control therapy for insomnia is a behavioral treatment that has been consistently
documented to be effective in the treatment of insomnia, whether delivered as a single-
component treatment or part of a multicomponent behavioral or cognitive-behavioral inter-
vention. Although the six instructions of SCT are relatively straightforward, individuals fare
better when a rationale is provided.
Recent studies have focused on multicomponent treatments and new components such
as the use of bright light to change circadian rhythms and the use of mindfulness meditation to
reduce symptoms of arousal are strong additions. Recent studies have also suggested that even
brief interventions that include SCT improve insomnia, which may be important for treating
the vast numbers of people with insomnia symptoms. Some method for helping patients find
the appropriate level of care will need to be considered.
The development of entirely new treatments based on SCT such as Intensive Sleep Retrain-
ing and using technology to bring treatment into the bedroom is exciting. We can be justifiably
proud of how much progress has been made in developing and evaluating cognitive and behav-
ioral treatments for insomnia. Nevertheless, many challenges in prevention, public policy, as
well as treatment, remain. Effective treatments and new directions are very welcome.

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25 Insomnia: Sleep Restriction Therapy

Arthur J. Spielman
Cognitive Neurosciences Doctoral Program, Department of Psychology, The City College of New York, City
University of New York, New York; Center for Sleep Medicine, Department of Neurology, New York
Presbyterian Hospital, Weill Cornell Medical College, New York; and Center for Sleep Disorders Medicine and
Research, Department of Pulmonary Medicine, New York Methodist Hospital, Brooklyn, New York, U.S.A.

Chien-Ming Yang
Department of Psychology, The Research Center for Mind, Brain & Learning, National Cheng-Chi University,
Taipei, Taiwan

Paul B. Glovinsky
Cognitive Neurosciences Doctoral Program, Department of Psychology, The City College of New York, City
University of New York, New York, and Department of Medicine, Section of Psychology, St. Peter’s Hospital,
St. Peter’s Sleep Center, Albany, New York, U.S.A.

THE DEVELOPMENT OF SLEEP RESTRICTION THERAPY

The practical and theoretical roots underlying the development of sleep restriction therapy
(SRT) in 1987 (1) are readily traced: foremost, two decades of research into the physiological and
cognitive consequences of sleep deprivation under various paradigms had led to solid findings
regarding the effects of deprivation or restriction on sleep itself. These findings suggested that
disturbed sleep might in some instances benefit from restricted bedtime. Second, psychological
theories of the genesis and persistence of emotional distress provided a framework for under-
standing how attitudes and anxieties about sleep might harden into chronic insomnia. This
work suggested that an intervention able to break the vicious cycle of anticipatory anxiety lead-
ing to sleeplessness leading to increased anticipatory anxiety could be of great benefit even if it
could only be tolerated in the short term. Third, the new field of chronobiology was burgeoning,
and its findings beginning to find clinical application. There was much greater appreciation of
how the timing of bedtime affects the ability to fall and stay asleep. Finally, while pharmaco-
logic treatment for insomnia with benzodiazepines and other medications was gaining wide
acceptance, pitfalls and inadequacies associated with such treatment were becoming apparent,
fueling the search for effective behavioral interventions.
In the early 1970s, two behavioral approaches specifically formulated for the management
of insomnia took their place alongside progressive muscle relaxation (2), hypnosis and other
therapies that had long been employed to alleviate various anxiety disorders. At a time when
learning theory was ascendant, stimulus control instructions (3) introduced proscriptions and
prescriptions designed to foster the association of bedroom cues with rapid sleep onset. Sleep
hygiene (4) shared a focus on concrete behaviors, attempting to shape common-sense prac-
tices that strengthen mechanisms regulating sleep. SRT was clearly influenced by the direct,
prescriptive and behavior-focused nature of these two pioneering therapies.
With regard to basic research, many studies had explored the effects of sleep deprivation
and partial sleep deprivation (also known as sleep restriction). These studies followed a long
tradition in the biological sciences, one that sought to better understand a particular function by
removing or restricting access to it. The consequences of depriving organisms of sleep were anal-
ogous to depriving them of the objects of other “drive behaviors” such as food and water. Just
as increased hunger and thirst led to greater efforts to find food and water, increased sleepiness
led to greater efforts to find a safe place in which to sleep. Sleep regulation was therefore concep-
tualized as under homeostatic control. In this view, under conditions of deprivation a negative
feedback system is activated that produces an increase in appetitive features. Consummatory
behaviors such as eating, drinking, and sleeping restore the homeostatic balance.
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278 SPIELMAN ET AL.

The SRT instruction to spend less time in bed (TIB) effectively reduces total sleep time.
This partial sleep deprivation in turn activates a homeostatic response (5). The composition of
sleep stages across the night known as “sleep architecture” is changed; sleep becomes deeper
as it becomes more compact (6,7). Light NREM stage 1 sleep and wakefulness are reduced
under the pressure of sleep restriction. The amount of deep NREM slow wave sleep (currently
designated stage N3) remains the same but increases as a proportion of total sleep time. REM
sleep changes are more inconsistent. Some studies show a decrease in REM % of total sleep
time and REM minutes while other studies show REM% remains the same. The heightened
homeostatic response triggered by reducing sleep time also leads to shorter sleep latencies. All
of these changes recommended sleep restriction as a means of addressing both sleep-onset and
sleep-maintenance insomnia.
The near immediacy of SRT’s initial effects provides another boon to treatment: it inter-
rupts the circular, self-fulfilling prophecies concerning the prospects for sleep that ultimately
maintain chronic insomnia. At the time SRT was developed theorists were beginning to
understand how psychological dynamics could account for both the appearance of distress and
its perpetuation. Within the realm of sleep, for example, individuals who tend to internalize
psychological problems were seen to have heightened emotional arousal, which in turn
produces trouble sleeping (8). The poor sleep provides a new focus for concern, increasing
emotional distress and further exacerbating the sleep disturbance. This circularity of cause and
effect, called cyclical psychodynamics, represented a major theoretical integration of behavior
therapy and psychodynamics and captured the imagination of clinicians (9). Responding to this
insight, SRT attempted to short-circuit the apprehensive worry about poor sleep that served to
maintain that very condition.
By the late 1970s human circadian rhythm organization was under intense investigation.
The importance of a habitual wake-up time and morning exposure to temporal cues for purposes
of entrainment were widely appreciated. In an early clinical application of chronobiology,
individuals with severe difficulty falling asleep reported much shorter sleep latencies when
they went to bed later than usual on weekends (10). Going to bed later and setting a fixed
wake-up time, staples of SRT, are in line with this chronobiological understanding that sleep
onset is typically more rapid later at night, and that providing regular temporal cues helps
stabilize the sleep–wake cycle.
The improved safety and effectiveness of the benzodiazepines over earlier hypnotic med-
ications encouraged more individuals to seek treatment for chronic sleep disturbance. While
helpful in reducing sleep latency and promoting sustained sleep, these agents were not without
significant limitations especially when used chronically and upon discontinuation (11). Chronic
use of hypnotics with long elimination half-lives was prone to produce daytime hangover while
agents with short half-life were associated with morning anxiety or early morning awakening.
Memory problems and moodiness were reported as well. Finally, the development of drug
tolerance and dependence were of concern.
Thus by the early 1980s, the time was ripe for new approaches to insomnia treatment.
Behavioral therapies for a wide range of psychological problems were showing much promise.
A deepening understanding of the circadian organization of life was starting to shape clinical
interventions. There was much room for improvement in the pharmacological management
of insomnia. Finally, the nascent specialty of behavioral sleep medicine, fostered in newly
established sleep disorders centers as well as academic departments, was for the first time
conceiving of insomnia as not merely the symptom of various underlying problems, but as a
worthy target for systematic treatment trials. SRT drew upon all of these developments.
In the years since its introduction, SRT has been deployed as a stand alone treatment in
a number of studies (Table 1), often in a form slightly modified from its original description.
It was quickly incorporated into the multicomponent treatment known as cognitive behavior
therapy for insomnia (CBT-I; Table 2). The effectiveness of CBT-I for a wide range of insomnias
has been consistently demonstrated; it is now considered the frontline treatment for insomnia
(12). The 2006 American Academy of Sleep Medicine’s Practice Parameters for the treatment
of insomnia rates SRT as a Guideline (13). The Practice Parameters deemed CBT-I a Standard,
describing its behavioral components as follows:
3.6 Cognitive behavior therapy, with or without relaxation therapy is effective and recom-
mended therapy in the treatment of chronic insomnia. [4.2, 4.6] (Standard) . . . The behavioral
 c25
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INSOMNIA: SLEEP RESTRICTION THERAPY
Table 1 Studies of SRT and modified SRT: Summary of methods and results
Treatment Mean Treatment No. of
Author(s) condition N Age Format Sessions Measures Med. F/U Results
Spielman et al. SRT (no control 35 46 Individual 8 weekly Call-ins Sleep Hypnotics: 12 36 wks Both post-treatment & F/U: TST↑,

March 28, 2010

(1,14) condition) sessions log ISQ Antidep: 1 SOL↓, TWT↓, SE↑, ISQ↓
Anxiolytic:1
Alcohol: 2
No med: 19
Morin et al. SRT 1 case 49 Inpatient 12 days Sleep log No med. 4 mons Post-treatment: TST from 2.5 h to 6:23
(15) (depressed individual inpatient h F/U: 7 h
patient with
chronic pain)

13:55
Friedman et al. 1: Modified SRT SRT:10 RT:12 69.7 Individual 4 weekly Call-ins BZD: 4 No 3 mons SRT: Post-treatment: TST↑, SOL↓,
(16) 2: Relaxation sessions med: 18 WASO↓, SE↑; F/U: maintain
therapy (RT) treatment effects except for SOL RT:
TST↑ & SOL↓, but no effect in the

Char Count=
other variables
Brooks et al. Nap mod. SRT 9 67.7 Individual 4 weekly Actigraph No med N/A Actigraph: TST↑, SOL = , WASO↓,
(17) (no control sessions Sleep log SE↑ Sleep log: TST = , SOL↓,
condition) WASO↓, SE↑
Riedel et al. 1: Self-help 25 subjects for 67.4 1:Self-help 1:2 Video Sleep log No med 2 mons 1: TST↑, SOL = , WASO↓, SE↑, sleep
(18) Video each groups Video viewing Rating scale satisfaction↑, SSS↓; all effects
(Modified 2:Video + sessions 2:4 SSS maintained at F/U 2: TST = , SOL↓,
SRT-sleep Individual weekly WASO↓, SE↑, sleep satisfaction↑,
compression + sessions SSS↓; all effects maintained and
Sleep TST↑ at F/U 3: TST = , SOL↓,
Education) 2: WASO↓, SE↑, SSS↓
VIDEO +
therapist
guidance
3:Waiting- list
control
Bliwise et al. 1: Modified SRT 16 subjects for 68.7 Individual 4 weekly Call-ins N/A 3 mons 1: Post-treatment: TST = , SOL↓; F/U:
(19) 2: Relaxation both groups sessions + a TST↑ 2: Similar to SRT, but TST
Therapy (RT) wrap-up improved less at F/U
session
Friedman et al. 1: Modified SRT 1:12 64.2 Individual 4 weekly Actigraph No med. 3 mons Actigraph: Post-treatment: no sig.
(20) + sleep 2:12 session + a Sleep log effects, TST↓; F/U: TST = Sleep
hygiene 3:13 wrap-up log: Post-treatment: SE↑ for both
2: Nap mod. session SRT conditions; F/U: SE↑ for all
SRT + sleep conditions
hygiene
3:Sleep hygiene

279
(Continued)
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280
Table 1 Studies of SRT and modified SRT: Summary of methods and results (Continued )
Treatment Mean Treatment No. of
Author(s) condition N Age Format Sessions Measures Med. F/U Results

March 28, 2010

Riedel & Modified SRT 22 67.96 Individual 6 weekly Sleep log ESS No med. N/A TST = , SOL↓, No. awakening↓,
Lichstein sessions WASO↓, SE↑, ESS =
(21)
Lichstein et al. 1:SRT (sleep 1: 24 68.03 Individual 6 weekly Sleep log No med. 1 year SOL: decreased for all conditions,
(22) compression) 2: 27 sessions maintained for SRT only
2:Relaxation 3: 23 No. of awakenings: decreased for both
(RT) treatment groups, maintained for
3:Placebo SRT only

13:55
desensitization WASO: decreased for all groups both
(PL) post-treatment and at F/U
TST: interact w/ fatigue level
High fatigue: increased at

Char Count=
post-treatment and F/U for RT, at
F/U for PL; no diff for SRT
Low fatigue: increased at
post-treatment for RT, at F/U for
SRT; no diff for PL
SE: interact w/ fatigue level
High fatigue: increased at
post-treatment and F/U for RT &
SRT; increased at F/U for PL
Low fatigue: increased at F/U for SRT;
increased at post-treatment for PL;
no diff for RT
Abbreviations: TST, total sleep time; TWT, total waking time; SOL, sleep onset latency; WASO, wake after sleep onset; No. Awakening, Number of awakenings; SE, sleep efficiency; ISQ, Insomnia Symptom Questionnaire; SSS,
Stanford Sleepiness Scale; ESS, Epworth Sleepiness Scale; post-tx, post treatment; F/U, follow-up.
Friedman et al. (16): The SRT was modified. Subject tolerance was weighed heavily in the assignment of the allowed TIB at start of treatment. TIB was not reduced for failure to reach criterion.
Friedman et al. (20): Modified SRT-Subject tolerance was weighed heavily in the assignment of the allowed TIB at start of treatment. TIB was not reduced for failure to reach criterion. Patients were given weekly increments of TIB
according to a fixed algorithm based on their initial TST. TIB is only increased by getting into bed earlier at the beginning of the sleep period. The algorithm for determining increased TIB was based on patients’ reported sleepiness
and their initial TIB. All patients received seven-hours TIB by the end of the 4th treatment week.
Nap modification SRT-Optional daytime naps were included. Patients were encouraged to take a 30-min nap daily within a 1:00 to 3:00 PM window.
Brooks et al. (17) : Mandatory daytime naps were included in the protocol because some subjects object to SRT due to daytime sleepiness.
Riedel et al. (18): Sleep compression allows patients to gradually reduce TIB to more closely match TST, and the prescribed TIB is not increased in response to higher SE. During the first session, patients were advised to reduce

SPIELMAN ET AL.
TIB by one-half of the difference between baseline TIB and baseline TST. During session 2 and 3, TIB was further reduced by one-fourth of the difference between baseline TIB and baseline TST.
Bliwise et al. (19): TIB was extended when the floating mean SE over the preceding five days equaled or exceeded 85%. Flexibility in the procedure was employed in the assignment of initial TIB.
Riedel & Lichstein (21): During the first session, patients were recommended to reduce TIB by one-fifth of the difference between baseline TIB and TST. Over the next four sessions, gradual reductions of TIB were recommended to
approach baseline TST.
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INSOMNIA: SLEEP RESTRICTION THERAPY 281

Table 2 Studies of Insomnia Utilizing Sleep Restriction Therapy as Part of Cognitive Behavior Therapy
(a partial list)

Authors Techniques Patient

Morin et al. (23) CBT (Cognitive Therapy, Sleep Restriction, Late-life insomnia
Stimulus Control)
Morin et al. (24) CBT (Cognitive Therapy, Sleep Restriction, Sleep Primary late life insomnia
Hygiene, Stimulus Control)
Mimeault & Morin (25) CBT (Cognitive Therapy, Sleep Restriction, Primary insomnia
Stimulus Control)
Verbeek et al. (26) CBT (Cognitive Therapy, Sleep Restriction, Sleep Chronic insomnia
Hygiene, Relaxation Therapy, Stimulus Control)
Currie et al. (27) CBT (Cognitive Therapy, Sleep Restriction, Secondary insomnia
Relaxation, Stimulus Control,)
Perlis et al. (28) CBT (Cognitive Restructuring, Sleep Restriction, Primary insomnia
Sleep Hygiene, Relapse Prevention, Stimulus
Control)
Espie et al. (29) CBT (Cognitive Restructuring, Sleep Restriction, Chronic insomnia
Sleep Information, Sleep Hygiene, Relaxation,
Stimulus Control)
Perlis et al. (30) CBT (Cognitive Restructuring, Sleep Restriction, Primary and secondary
Sleep Hygiene, Relapse Prevention Stimulus insomnia
Control)
Edinger et al.. (31) CBT (Cognitive Therapy, Sleep Restriction, Sleep Chronic primary insomnia
Education, Relaxation, Stimulus Control)
Harvey et al. (32) CBT (Cognitive Restructuring, Sleep Restriction, Nonspecified insomnia
Relaxation, Sleep Hygiene, Stimulus Control,)
Currie SR, et al. (33) CBT (Cognitive Restructuring, Sleep Restriction, Comorbid insomnia and pain
Relaxation, Sleep Hygiene, Stimulus Control,)
Rybarczyk et al. (34) CBT (Cognitive Therapy, Sleep Restriction, Secondary insomnia
Relaxation, Stimulus Control,) (geriatric)
Edinger & Sampson (35) CBT (Cognitive Therapy, Sleep Restriction, Seep Primary insomnia
Hygiene, Stimulus Control)
Ouellet & Morin (36) CBT (Cognitive Therapy, Sleep Restriction, Sleep Insomnia associated (TBI)
Hygiene, Stimulus Control)
Morin et al. (37) CBT (Cognitive Therapy, Sleep Restriction, Benzodiazepine withdrawal,
Stimulus Control) older insomnia
Morgan et al. (38) CBT (Cognitive Treatments, Sleep Restriction, Chronic insomnia, long-term
Sleep Hygiene, Relaxation, Stimulus Control) hypnotic drug users
Currie et al. (39) CBT (Cognitive Therapy, Sleep Restriction, Sleep
Hygiene, Stimulus Control)
Perlis et al. (40) CBT (Cognitive Restructuring, Sleep Restriction, Primary insomnia
Sleep Hygiene, Relapse Prevention, Stimulus
Control)
Jacobs et al. (41) CBT (Cognitive Therapy, Sleep Restriction, Primary Insomnia
Relaxation, Stimulus Control)
Dopke et al. (42) CBT (Cognitive Therapy, Sleep Restriction, Sleep Insomnia associated with
Hygiene, Relaxation, Stimulus Control) psychiatric disorders
Stiefel& Stagno (43) CBT (Cognitive Therapy, Sleep Restriction, Insomnia with chronic pain
Imagery Training, Relaxation, Stimulus Control)
Rybarczyk et al. (44) CBT (Cognitive Therapy, Sleep Restriction, Comorbid, older insomnia
Stimulus Control)
Savard et al. (45) CBT (Cognitive Therapy, Sleep Restriction, Sleep Insomnia secondary to breast
Hygiene, Stimulus Control) cancer
Sivertsen et al. (46) CBT (Cognitive Therapy, Sleep Restriction, Sleep Chronic primary Insomnia
Hygiene, Relaxation, Stimulus Control) (older adults)
Ouellet & Morin (47) CBT (Cognitive Restructuring, Sleep Restriction, Insomnia associated (TBI)
Sleep Hygiene, Fatigue Management, Stimulus
Control)
Dirksen & Epstein (48) CBT (Cognitive Therapy, Sleep Restriction, Sleep Insomnia secondary to breast
Hygiene, Stimulus Control) cancer
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282 SPIELMAN ET AL.

component may include therapies such as stimulus control therapy, sleep restriction, or relax-
ation training.
The review paper (49) accompanying the Practice Parameter paper highlights a dozen
key treatment studies supporting the efficacy of CBT-I. Only six of these studies incorporated
Relaxation Therapy as part of the multicomponent therapy, whereas in all twelve of the studies
SRT was a component.

THE RATIONALE FOR SLEEP RESTRICTION THERAPY

Restricting TIB, the cornerstone of SRT, is certainly counterintuitive to the expectations of most
insomnia sufferers, who generally believe they need more sleep, not less. Patients with chronic
insomnia tend to respond to SRT prescriptions with a mixture of disbelief and curiosity—a
mindset which turns out to be surprisingly open to fair appraisal of the rationale for treatment
(Table 3).
A key component of this rationale involves the well-known effects of mild sleep loss
as well as the less appreciated ramifications of extending time in bed. From experience, most
patients will understand that the drive to sleep is increased by partial sleep deprivation. Most
have encountered the occasional night of “recovery sleep” when a chain of poor nights is finally
broken with a night of deeper and more satisfying sleep. The problem is typically that once the
accrued sleep debt is paid off, poor sleep begins anew. SRT modulates this haphazard pattern.
It restricts sleep over a sufficient span of nights and precludes recovery sleep so as to promote
more consistently shorter sleep latencies, as well as more consolidated, deeper sleep. These
gains are of course delivered along with the likelihood of increased daytime sleepiness and
fatigue. Patients are forewarned of this sleepiness, but reassured that sleep generally becomes
more reliable within a few weeks of SRT, and that as TIB is increased in response to increasing
sleep efficiency, daytime functional deficits will diminish.
While the deepening and consolidating of sleep produced by SRT are clearly advanta-
geous, even the increased daytime sleepiness that typically results from this intervention has
its benefits. People who contend with chronic insomnia commonly report that they “never feel
sleepy” or “have lost the ability to sleep”. The welling up of sleepiness during the day, even
if ill-timed, provides evidence that the sleep system is not irrevocably broken, and holds out
promise that it may soon be harnessed in the service of sleeping well at night.
The scientific literature also provides information about what might be expected when
individuals extend their TIB, as opposed to restricting it. This knowledge can be used to counter
the tendency of many poor sleepers to increase their time in bed, thinking as they do that by
“casting a wide net” they will catch as much sleep as possible. This literature also sheds light
on how insomnia can persist for years after it first appears when triggering events have long
since resolved. It should be noted these studies primarily examined the effects of increasing
TIB in noncomplaining individuals, as opposed to people with insomnia. In general, when
noncomplaining subjects are confined to bed for longer than usual periods of time, they do in
fact accumulate more sleep, and their daytime sleepiness is decreased. However, their sleep
becomes more fragmented or even biphasic; it begins to resemble in this respect the disturbed
sleep of insomnia.

Table 3 Rationale Offered to Patients for the Effectiveness of SRT

– The sleep loss entailed by SRT increases sleep drive, which in turn is manifest as

a. More rapid sleep onset,

b. Increased depth of sleep,
c. Fewer or briefer awakenings during the night,
d. Increased daytime sleepiness and fatigue. (Taken as evidence that the sleep drive has in fact
increased. As sleep improves over the first few weeks, TIB will be increased and fatigue reduced.)
– Reducing TIB addresses factors that perpetuate insomnia:
a. More predictable sleep (few very poor or very good nights) reduces anticipatory anxiety over what
each night will bring.
b. Less time spent tossing and turning in bed repairs the broken association between the bed and sleep.
c. More consistently timed sleep rebuilds an attenuated circadian sleep/wake cycle.
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INSOMNIA: SLEEP RESTRICTION THERAPY 283

One early study asked subjects to remain in bed for nearly 24 hours. Sleep broke into
fragments, but the duration of these stints of sleep summed up to more than 14 hours or about
60% of TIB (50). In another study of prolonged bed rest, this time to sixty hours, sleep expanded
to fill nearly 50% of TIB; once again sleep was frequently interrupted by awakenings (51).
Whether the greater percentage of time given over to sleep in these studies reflected the effects
of prior sleep restriction or merely the opportunity presented by extra time in bed is open to
interpretation.
Another study (51) looked at the effects of chronic rather than acute extension of bedtime.
Normal control subjects were exposed to a conventional photoperiod (16 hours, followed by
8 hours in bed) for one week and a short photoperiod (10 hours, followed by 14 hours in
bed) for four weeks. Sleep duration increased by about one hour a night under conditions of
prolonged bed rest. As seen in the studies of acute bedtime extension, sleep efficiency was
reduced and sleep fragmentation increased. However, a distinct pattern emerged with repeated
10:14 light/dark cycles: Sleep was split into two equal bouts, the first on the “evening” end of the
prolonged bed rest period, the second on the “morning” end, separated by one to three hours of
wakefulness. The author suggests that this biphasic sleep pattern may be more representative
of sleep in humans over hundreds of thousands of years until the recent past, when artificial
light became available to produce a fixed, prolonged photoperiod across the seasons, resulting
in the monophasic, highly efficient sleep we think of as “normal.”
Another protocol employed prolonged bed rest to investigate the presence of objective
sleepiness [a sleep latency less than or equal to six minutes on a multiple sleep latency test
(MSLT)] in individuals with no subjective sleepiness complaint (52). One group of subjects
spent 10 hours in bed and the other spent their habitual time in bed (averaging about 8 hours)
for 14 days. Nocturnal sleep recordings followed by daytime MSLTs occurred periodically across
the two weeks. Consistent with the studies cited above, the group following an extended TIB
schedule showed increased sleep time and reduced sleep efficiency at night, as well as reduced
objective sleepiness during the day, compared to those following a self-selected TIB schedule. It
is interesting to note with regard to the present discussion that a subgroup of individuals in this
study did not demonstrate reduced objective sleepiness after extending TIB. Sleep efficiency
plummeted immediately after TIB was increased for these subjects. This response is similar
to the experience of individuals with insomnia, who try to accumulate additional sleep by
spending more time in bed and wind up instead with more frequent or longer awakenings.
A second component of the rationale for SRT is that it focuses on practices perpetuating
insomnia that are more amenable to treatment. According to our conceptualization of insomnia
(known as the 3P Model, Figure 1 53,14) the factors that predisposed a particular patient to

PRECIPITATING/PERPETUATING FACTORS
CONTRIBUTING TO INSOMNIA OVER TIME
INSOMNIA SEVERITY

PERPETUATING
E.G., PRECIPITATING
Insomnia SLEEP EXTENSION PREDISPOSING

Threshold E.G.,
LIFE
STRESS

E.G.,
HYPERMETABOLIC
Time

Figure 1 The 3P model of insomnia depicting changing influences during the course of insomnia. Source: From
Ref. (53, Adapted from 14; modified by Max Hirschkowitz and Michael Perlis).
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284 SPIELMAN ET AL.

insomnia as well as those that precipitated the disturbance may be too remote or too entrenched
to serve as fruitful targets for short-term treatment. However, insomnia can still be effectively
treated by addressing factors, which perpetuate the sleep disturbance. Compensating for sleep
loss by spending an excessive amount of time in bed is, as discussed above, a frequently
encountered factor maintaining chronic insomnia—one that is directly targeted by SRT.
In some cases patients may readily concur that the factors that originally triggered their
sleep disturbance are not operative at present. For example, insomnia may have appeared in the
midst of a patient’s bitter divorce, yet his sleeplessness persists in the context of a successful new
relationship. Or it may have followed the arrival of a colicky newborn, who three years later, is
now sleeping through the night while her mother still struggles with frequent awakenings.
Even when the original trigger of insomnia still looms large as a source of distress, it
may be advantageous to target seemingly secondary perpetuating factors to achieve rapid
improvement. For example, a woman’s sleeplessness may be clearly related to the ongoing
stress of contending with a tyrannical boss who never appears satisfied with her performance.
A holistic approach to this problem may include advocating changes in behavior (such as
negotiating clearly defined benchmarks that will serve as the basis of regular reviews) as well
as attitude (such as challenging the idea that any shortfalls in meeting objectives necessarily
reflect incompetence). While these changes are being supported, it still may make clinical sense
to take steps that directly impact sleep. It may not be easy to adhere to an early alarm, but at least
this is an action that is fully under the patient’s control, and one that should yield predictable
results. It counters the loss of efficacy that can prove so corrosive to self confidence, regardless
of whether that sense of helplessness is encountered on the job or when trying to sleep.
The 3P Model also posits that patients may, over the course of a chronic insomnia, become
sensitized to potential sources of sleep disruption. Prior to the onset of the disturbance, sleep is
often seen as more resilient, and behaviors such as drinking caffeinated or alcoholic beverages
at dinner or oversleeping on weekends could apparently be engaged in with impunity. Seven
and a half hours in bed would hardly be deemed generous. We explain that “that was then”
and that now, at least for the time being, a patient in a sensitized or hyperaroused state may
not be capable of consistently sustaining seven or more hours of sleep. It is better under these
conditions to more closely match bedtime with expected total sleep time, even if that is currently
six hours. While we do not guarantee that seven and a half hours of sleep will eventually be
attained on a nightly basis, we do hold out the reasonable expectation that both bedtime and
sleep time will gradually increase over the course of treatment, and invite patients to partner
with us in determining what the optimal balance between sleep restriction and sleep quality is
for them.
A third major benefit of SRT is that it improves the experience of going to bed. Tossing
and turning for hours on end is not pleasant. The bed starts to be dreaded as a place of torment
rather than as a haven from waking concerns. A self-fulfilling prophecy is set in motion, one
in which the expectation of another miserable night and the prospects of having to muddle
through the next day increases anxiety and arousal, thereby leading to that very result. By
contrast, with SRT patients come to expect that bedtime will be short—and sweet, in the sense
that a greater proportion of it will be spent in blissful oblivion. They may actually look forward
to the designated time when they can “finally get into bed.”
A fourth reason why SRT benefits people with insomnia is that it strengthens the circadian
sleep–wake cycle. It replaces a welter of short stints of sleep occurring at various times around
the clock with a single nocturnal period that is more predictably filled with sleep. Patients are
more likely to be awoken by an alarm when under this treatment, leading to consistently timed
exposure to morning light and the various demands of waking life. These cues help keep sleep
synchronized with other biological rhythms, which in turn leads to the more reliable appearance
of sleep shortly after bedtime, and deeper sleep once it arrives.
Offering a considered and detailed rationale for the effectiveness of SRT satisfies patients’
‘need to know’ while acknowledging the counterintuitive nature of the treatment. Taking the
time to thoroughly prepare patients for this therapy will motivate them for the difficulties
ahead. Hopefully they will begin to think differently about their prospects for sleep, about
what it means to be awake and out of bed later into the night or earlier in the morning, and
more generally about their ability to shape their nocturnal experience over the long term. These
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INSOMNIA: SLEEP RESTRICTION THERAPY 285

cognitive changes are critical therapeutic components that work in concert with behavioral
change to foster improved sleep.
IMPLEMENTING SLEEP RESTRICTION THERAPY
SRT begins with a two-week sleep diary. The average subjective sleep time over the course of
this diary is calculated. This value is then prescribed, as the amount of time in bed (TIB) patients
should spend at the start of treatment. Changes in sleep efficiency (SE, calculated as subjective
sleep time/time in bed X 100%) more than a five day moving window trigger increases and
decreases in TIB (see Table 4) (1).
Setting specific times of retiring and rising to delimit an initial time in bed requires
thoughtful analysis. The patient’s sleep diary may offer clues as to what period would be most
likely to maximize sleep at the start of treatment. In the case of a patient who has no difficulty
falling asleep but who awakens too early in the morning, with difficulty falling back to sleep,
TIB should start at the habitual time of retiring at night. As a result the wake-up time will
be earlier than usual. In patients who typically get their best sleep in the middle of the night,
or whose sleep is quite broken with awakenings scattered haphazardly across the night, the
assigned sleep schedule should start later and end earlier than usual. Finally, if a patient’s
primary difficulty is one of falling asleep, the assigned retiring and rising times should be later
than usual, within the constraint of meeting starting time for work.
Some patients will have obligations such as variable work shifts or shared childcare
responsibilities that necessitate rising early on an intermittent basis. In the interests of entraining
a robust circadian sleep–wake cycle, the clinician may take the opportunity to set a fixed early
morning rising time as part of the initial SRT instructions. The choice of retiring and rising times
should also take various practical concerns into account such as possible disturbance of bed
partners or nighttime needs of pets.
It should be stressed that although SRT can be summarized with a few quantitatively
based prescriptions, this does not relieve the clinician of the need to exercise judgment. Patients’
forbearance for the challenges posed by the treatment is typically limited to one good effort, and
this chance for improvement may be squandered if the clinician’s approach is too rigid. Some
individuals become so concerned at the prospect of a limited bedtime (“. . .but I always sleep so
much worse when I know I have to get up early”) that clinical judgment trumps strict adherence
to the SRT method. Negotiation with such patients is required to come up with an acceptable
level of sleep restriction. In anticipation of their difficulties adhering to even modified SRT
schedules, it is recommended that the clinician ‘go on record’ as follows: “OK, we will permit a
bit more time in bed for you, but it may take longer for your sleep to improve. Therefore, for this
to work it is imperative that you limit your time in bed to the specific hours we have agreed on.”
A number of variations on the original SRT procedure have emerged in the two decades
since the therapy was introduced. Some investigators and clinicians set the initial TIB equal to
the average sleep obtained from the sleep diary plus half-hour, since even good sleepers do not
have 100% sleep efficiency. The extra bedtime therefore allows a more realistic possibility of
garnering the targeted amount of sleep. Another method called sleep compression (54) restricts
TIB minimally at first. As treatment proceeds time in bed is further reduced. This approach is
easier for patients to adhere to at the start of treatment. We have employed an SRT variation
that runs in the opposite direction, with initial TIB initially quite restricted as in standard SRT,
followed by weekly extension of TIB in 15 or 30 minute increments, continued so long as TIB
contains less than 45 minutes of wakefulness (15). This method avoids the dispiriting effect of
having to reduce TIB repeatedly—the patient knows that “the worst is over” in terms of bedtime
restriction after the first week or so.

Table 4 Sleep Restriction Therapy Method (1)

r Determine average time asleep from sleep diary
r Set time in bed = time asleep
r Set a consistent wake-up time
r No daytime naps
r If 5 day average sleep efficiency ≥ 90% (≥ 85% in > 65 yr olds) then increase time in bed (15–30 min)
r If 5 day average sleep efficiency < 85% (< 80% in > 65 yr olds) then decrease time in bed (15–30 min)
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286 SPIELMAN ET AL.

Patient characteristics should be taken into account before prescribing SRT. There is little
reason, for example, to recommend SRT to individuals whose sleep is already compact. (These
individuals may still present with insomnia, typically complaining of insufficient sleep due to
early morning awakenings.) Consider the patient who can fall asleep soon after getting into
bed at 11 PM and obtain a solid five hours of sleep, but who then awakens around 4 AM and
ruminates on the day ahead for two hours before getting out of bed. Her sleep efficiency is
low at 71% and she is complaining of daytime fatigue. Restricting bedtime to about five hours
via SRT is not likely to significantly heighten her sleep drive, because it will not appreciably
reduce total sleep time. She is likely to continue to have a compact but short sleep period of
five hours on SRT. Employing stimulus control instructions may present the better option here,
with the aim of weakening the association between this patient’s early morning awakenings
and the opportunity they present to obsess in bed. It would allow the possibility of “resetting”
her frame of mind through a period of distracting activity such as reading and then returning
to bed and to sleep. If, on the other hand, you deduce that a patient is in fact flitting in and
out of sleep for the last two hours in bed, perhaps understandably not counting this as “really
sleeping,” SRT offers an appropriate treatment choice.
When conducting SRT in patients with Paradoxical Insomnia (previously called Sleep
State Misperception) the original rules for increasing time in bed do not work well. It is true
that sleep efficiency can be marginally increased when the assigned time in bed of patients
who report, say, one hour of sleep is decreased well below the minimum duration of about five
hours we typically employ. However, their sleep efficiency will rarely approach even a relaxed
criterion for increasing time in bed, as these patients typically do not perceive and report any
increases in sleep time (unpublished data). In these patients, weekly increases in time in bed
following a severe initial reduction, one of the SRT variants discussed above, may improve
daytime functioning although nighttime complaints will likely persist.

A COST/BENEFIT MODEL OF SLEEP RESTRICTION THERAPY UTILIZING SLEEP

EFFICIENCY AND DAYTIME FUNCTIONING AS MARKERS OF SLEEP NEED
SRT is predicated on the use of sleep efficiency as a means to constrain TIB. Sleep efficiency is
a particularly useful index on which to base adjustments to TIB because it is a single ratio that
is derived from measures of both sleep and wakefulness. It can be conceived of as a measure
of the density of sleep, and is affected by both voluntary choices regarding times of retiring
and rising, as well as involuntary experiences such as difficulties encountered in falling and/or
staying asleep. While it cannot serve as a surrogate for sleep sufficiency—a two-hour bedtime
will likely be both highly efficient and grossly insufficient—it does neatly convey a sense of the
quality of the sleep that has been obtained.
Sleep efficiency, when combined with an evaluation of daytime functioning, may serve as
a marker within the ill-defined territory of sleep need. Changes in sleep efficiency and daytime
functioning over the course of SRT can be construed as reflecting the degree to which sleep
need is being satisfied by a given sleep/wake pattern, and at what cost. We have modeled the
changing ratio of benefits and costs as tracked by sleep efficiency and daytime functioning in
Figure 2. Benefits in this model are nocturnal sleep duration and daytime functional capacity
while costs are time spent in bed and vulnerability to insomnia.
Prior to the start of SRT treatment costs are high. Much time is “spent” in bed and there is
high vulnerability to sleep disturbance. Benefits are relatively low in this pretreatment phase.
Sleep time is reduced or variable, while fatigue, poor concentration, irritability and/or other
daytime impairments are present. The daytime deficits suggest that sleep need is nowhere near
being satisfied despite sleep efficiency being low—that is, despite the potential for extra sleep
afforded at least in theory by the extended bedtime.
At the start of SRT costs are dramatically reduced. Not much time is “spent” in bed and
there is little vulnerability to sleep disturbance, given the substantial increase in sleep propensity
that occurs as a result of accruing sleep loss. However, benefits are also further reduced as a
result of the severe curtailment of TIB dictated at the start of treatment. Less sleep is accumulated
than had been present at baseline, and functional capacity is even further diminished. While
sleep efficiency has now risen markedly, the exacerbation of daytime functional deficits testifies
to continuing unsatisfied sleep need.
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INSOMNIA: SLEEP RESTRICTION THERAPY 287

High

Benefits

Costs

Low

Baseline High Restriction Optimal Restriction Low Restriction

Figure 2 A cost/benefit model of sleep restriction therapy utilizing sleep efficiency and daytime functioning as
markers of sleep need. Costs are indexed by time spent in bed and vulnerability to insomnia while benefits are
reflected by duration of sleep time and daytime function.

As treatment proceeds levels of TIB are gradually increased while maintaining sleep
efficiency near an optimal level. Both costs and benefits rise, but initially the rate of beneficial
change greatly outpaces the rise in costs. Consistent accumulation of well-consolidated sleep,
even if of modest duration, yields better daytime performance than had short stints of sleep
scattered haphazardly across the clock. Relatively few hours are being spent in bed, while
residual sleep loss guards against the resurgence of insomnia. Through a process of bedtime
titration, a point is reached where both sleep efficiency and daytime functioning are at relatively
high levels, where sleep need has been satisfied, but not sated to the point of inviting the
reappearance of insomnia. The benefit/cost ratio will be highest on this bedtime schedule. It
should be maintained going forward at least until such time that other salient factors which
had predisposed, precipitated and/or perpetuated insomnia have changed. For example, once
anticipatory anxiety over what each night will bring has subsided, a slightly longer TIB may be
indulged in without courting harm to sleep.
As TIB approaches baseline levels, the slope of the curve representing incurred costs
accelerates. A relatively large amount of time is again being spent in bed. More critically, the
potential for sleep disturbance rises disproportionately at higher levels of TIB. There is little
residual sleep loss at this point that may be counted upon to quickly induce and sustain sleep.
Meanwhile, benefits plateau when TIB is minimally restricted. Neither sleep time nor functional
capacity can be expected to continue to rise much, if at all, as sleep efficiency begins to ebb.
Thus sleep need may still be partially unmet after successful treatment. Optimally balancing
sleep efficiency and daytime functioning does not mean that either nocturnal sleep or daytime
capacity alone will be maximized. There are many intransigent aspects of insomnia (typically
categorized in the 3P Model as predisposing factors, such as hyperarousal) that may require
concessions of benefits received from sleep, both by night and day, in the interest of maximizing
the overall sleep/wake experience.

CONCLUSION
In the 21 years since SRT was first introduced, awareness of the health, economic and public
safety issues raised by sleep disturbance has crystallized. Insomnia is no longer exclusively
confined to the role of symptom or side effect, but rather recognized as at times a primary
complaint, with its own course and indications for treatment (55). A new generation of hypnotic
medication has been developed to remedy sleep initiation and maintenance difficulties, and a
new paradigm of long-term reliance on such medication has gained adherents. In this context,
the role played by psychological factors such as anticipatory anxiety and drug dependence in
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288 SPIELMAN ET AL.

perpetuating insomnia looms large. CBT-I, with SRT now firmly ensconced among its corner-
stones, is uniquely positioned to address the psychophysiological, behavioral and cognitive
challenges posed by chronic insomnia. A multitude of patients stand to benefit as their physi-
cians and clinicians gain a stronger appreciation of these demonstrably effective treatments.

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26 Other Nonpharmacological Treatments

of Insomnia
Daniel J. Taylor, Emily A. Grieser, and JoLyn I. Tatum
Department of Psychology, University of North Texas, Denton, Texas, U.S.A.

There are a wide variety of nonpharmacological treatments for insomnia including stimulus
control, sleep restriction, and cognitive therapy (1,2), which are all covered extensively elsewhere
in this volume. There are also “other” types of nonpharmacological treatments sometimes used
to treat insomnia discussed within this chapter. Some of these methods, such as progressive
muscle relaxation and paradoxical intention, are commonly used, have significant empirical
backing, and have been listed as “effective and recommended therapies” by the Standards of
Practice Committee of the American Academy of Sleep Medicine (3). Others (e.g., exercise,
acupuncture, aromatherapy) have less rigorous empirical backing, often consisting of case
studies or case-series designs without control conditions, but were deemed worthy of review
because they are used by some practitioners and have not received adequate review elsewhere.
The current chapter addresses these “other” nonpharmacological treatments of insomnia with
a description of efficacy/effectiveness studies. In terms of description of efficacy/effectiveness
studies, more focus was given to those treatments which have received less systematic review
in the current literature.

RELAXATION TECHNIQUES
Relaxation techniques are some of the most frequently used treatments of insomnia (2,4,5). The
rationale and proposed mechanisms of action underlying the use of relaxation methods in the
treatment of insomnia stem from the hypothesis that people with insomnia suffer from increased
somatic and cognitive arousal. Relaxation methods serve to reduce somatic arousal and/or
cognitive arousal, thereby increasing the likelihood that patients will fall asleep. Although a
variety (e.g., breathing retraining, imagery, meditation, biofeedback) of relaxation interventions
have been tested as treatments for insomnia, progressive muscle relaxation (PMR) (6,7) has the
most evidence as a treatment for insomnia (3).

Progressive Muscle Relaxation (PMR)

The Standards of Practice Committee of the American Academy of Sleep Medicine identified
PMR as an “empirically supported treatment” because four studies demonstrated that relax-
ation was better at treating insomnia than a placebo control (highest level of evidence) (3).
Progressive muscle relaxation involves alternately tensing and relaxing different muscle groups
throughout the body (8). Homework involves practicing the relaxation at home during the day,
just prior to bedtime, and sometimes during nighttime awakenings. Patients are trained to focus
and compare feelings of relaxation with the tension that was present before the relaxation pro-
cedure. This technique typically takes 10 to 30 minutes. Multiple scripts for progressive muscle
relaxation are available both online and within treatment texts (e.g., 9–11). A copy of the script
used in our laboratory, developed from the text of Lichstein (9), is reproduced in Appendix A.

Other Relaxation Methods

As mentioned, many other relaxation techniques exist, but to date only meditation, imagery, and
autogenic training have been assessed for the treatment of insomnia. Although these treatments
have shown effectiveness in at least one clinical trial, other studies found no benefit, and the
overall evidence did not support a recommendation of these techniques as single treatments
(1). Other relaxation methods such as diaphragmatic breathing, hypnosis, and transcendental
meditation, may be used clinically, but they have no empirical backing as treatments of insomnia.
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Few studies have compared relaxation procedures, so the fact that PMR has the greatest
evidence may be due to a greater interest in this procedure during the early days of insomnia
treatment research, with little subsequent research focusing on single methods of treatment. It
is possible that other relaxation treatments are equally efficacious, but have not been rigorously
evaluated. In practice, many if not most clinicians actually combine multiple forms of relaxation
treatment (e.g., progressive relaxation, breathing retraining, and autogenics). Detail about the
actual techniques of the various relaxation treatments available and the myriad of issues (e.g.,
variants, therapist issues, common factors) involved in each are covered in much greater depth
in numerous texts (e.g., 9–11).

Biofeedback
Because only one placebo-controlled trial has been performed to date, the Standards of Practice
Committee of the American Academy of Sleep Medicine did not identify this treatment as
“empirically supported,” instead listing it as “probably efficacious” because two studies have
shown it was better than wait-list control and one study showed it was better than no treatment.
Biofeedback is a specific form of relaxation treatment that differs from those mentioned
above in that it actually provides sensory feedback (usually visual or auditory), either mechan-
ically (i.e., thermometers) or more frequently with computers and amplifiers, to help patients
learn how to control physiological parameters such as finger temperature or muscle tension, in
order to reduce somatic arousal (3). For instance, frontalis electromyography (EMG) biofeed-
back, the most commonly studied, teaches subjects to reduce muscle tension in the muscles of
the forehead and face. Biofeedback seems to help patients attain states of mental and physical
relaxation and become more aware of their own bodily sensations and responses to stressors.
Biofeedback actively involves the patient in the therapeutic process and provides immediate
measures of progress. One difficulty with evaluating the effectiveness of biofeedback is that it is
often paired with some form of relaxation exercise, making it difficult to parse out the indepen-
dent effects of each. In addition, improvements appear to be comparable to PMR, which takes
less time for the patient to learn and requires no expensive equipment. Therefore, this method
is not recommended over stimulus control, sleep restriction, or PMR, unless the patient fails to
benefit from those other methods.

Other Biofeedback Methods

Neurofeedback (EEG biofeedback) may offer an alternative treatment for insomnia (12). Thus
far, one case study and two case-series studies have shown that some form of neurofeedback
was effective in improving self-report insomnia measures (13,14). The results were somewhat
mixed for the one study that evaluated objective sleep with overnight polysomnography (14).

Yoga
Kundalini Yoga was popularized by Yogi Bhajan in the late 1960s as a means of general life
enhancement and to explore altered states of consciousness without the use of drugs. Yoga
involves the awareness of breath (pranayama) and thought processes in addition to a series of
postures (asanas) designed to stretch and strengthen the body. Yoga as traditionally practiced is
often combined with aspects of PMR (especially in “corpse pose”) and meditation. As one can
see, many of these elements overlap with the relaxation techniques already discussed.
There is growing evidence supporting yoga as an alternative treatment for insomnia, and
yoga research has recently received funding from the National Institute of Complementary and
Alternative Medicine at the National Institutes of Health (15). So far, many trials investigating
the use of yoga for the purpose of improving sleep have been limited by small sample size and
lack of replication (16). One randomized controlled trial found that yoga was more effective than
wait-list control in reducing self-reported sleep disturbance in elderly residents in a care facility.
To date, the majority of the data concerning the efficacy of yoga consists of case series designs
using mainly self-report measures of improvement (17,18). This is less than optimal because
these forms of assessment are more susceptible to social desirability and placebo effects. It is
also unknown how much of the benefit gleaned from Yoga in these previous studies would
have been found by just using traditional relaxation procedures, due to the lack of comparison
groups.
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292 TAYLOR ET AL.

PARADOXICAL INTENTION
Paradoxical intention aims to reduce the patient’s performance anxiety about falling asleep
through instructions to get in bed and passively remain awake rather than try to fall asleep. This
persuasion to engage in a feared behavior (staying awake) is thought to alleviate performance
anxiety, thereby allowing sleep to come more easily (2).
All research on this technique has focused on patients with sleep-onset insomnia, with
two studies showing it to be more effective than placebo control, and one study showing it to be
better than wait-list control. Because the effects of this intervention are generally smaller than
the single treatments of stimulus control, sleep restriction, and PMR, it is rarely recommended
over those interventions, but may be useful to those who do not benefit from other methods
(2,4,5).

BRIGHT LIGHT THERAPY

Many companies sell phototherapy devices to the public, usually made of full-spectrum or cool
white fluorescent light bulbs emitting on average 2500 lux (19). These devices simulate bright
sunlight via indirect exposure to the eyes, and use is recommended while reading, eating meals,
or during similar activities.
Studies show bright light therapy can be used to realign the circadian rhythms through
effects on the Suprachiasmatic Nucleus (SCN) (20). The proposed mechanism of action for the
treatment of insomnia is that some insomnias may be due in part to a circadian misalignment,
such as advanced sleep phase syndrome (early bedtime and early awakening) and delayed
sleep phase syndrome (late bedtime and late awakening) (19). Past studies have shown that
bright light therapy was useful in treating these two circadian rhythm disorders (20). The use
of bright light in the treatment of specific sleep–wake schedule disorders is discussed in detail
elsewhere in this text. In milder forms, phase shifts could present as terminal or onset insomnia.
Therefore, it stands to reason that in those cases of insomnia where a circadian component is
at work, bright light therapy (BLT) might be a useful treatment. In addition, it could be that
BLT works even in those without a strong circadian component, simply by increasing sleep
propensity during the nighttime hours.
Three placebo controlled studies have now been performed examining the effect of varying
intensities (i.e., lux and duration) of BLT, on the sleep of different types of insomnia, with mixed
results. One trial of half-hour exposure to 2000 to 2500 lux in the morning for five days in
patients with “winter” insomnia (occurring during the “dark period” above Arctic Circle),
resulted in shorter sleep latency and increased drowsiness compared to a wait-list control (21).
In a randomized placebo-controlled trial of older adults (age 62–81) with sleep-maintenance
insomnia, 12 days of BLT (4000 lux) improved both maintenance insomnia and sleep quality
over the dim red light control (50 lux) (22). These results were not replicated in a more recent case-
series design by these same researchers (23). The most rigorous of these trials was a more recent
single-blind, placebo-controlled, 12-week, parallel-group randomized design comparing four
treatment groups representing a factorial combination of two lighting conditions (∼ 4000 lux vs.
∼65 lux) for 45 minutes with two different times of light administration (morning vs. evening),
in a mixed sample of insomnia types (i.e., onset, maintenance, terminal, nonrestorative) (24).
These authors found “Scheduled light exposure was able to shift the circadian phase predictably
but was unrelated to changes in objective or subjective sleep measures.”
Clearly, before specific recommendations can be made about the use of BLT to treat specific
types of insomnia, more efficacy research is needed. This research might focus on other specific
types of insomnia (i.e., onset and terminal insomnia) and be more strategic in administration (i.e.,
morning administration for onset insomnia and evening administration for terminal insomnia).
It is important to note that side effects of bright light therapy can include jumpiness or jitteriness,
headache, and nausea (25).

EXERCISE
Exercise and physical activity have known benefits on health (e.g., improved cardiovascular
fitness, weight loss, increased maximal oxygen uptake) (26). There is also a known relationship
between physical activity and sleep, although the exact nature of that relationship is unknown.
The strongest theoretical basis for this relationship comes from the thermodynamic hypothesis of
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sleep. This theory is founded on the drop in body temperature that accompanies the onset of
sleep, and which may serve as a signal to the body that it is time for sleep. If the rapid decrease
in temperature that precedes sleep serves as a signal for sleep onset, it is possible that by raising
the body temperature (e.g., via exercise), the internal signal will either be enhanced (i.e., if
exercise occurs at the right time to have the resultant cooling of the body coincide with sleep
onset), or delayed (i.e., if exercise occurs too close to sleep) (27,28).
Generally, research shows that moderate to high intensity exercise sessions four to eight
hours before bedtime results in improved sleep quality in a normal population (29–31). There
is also evidence that discrete episodes of physical activity either less than four or more than
eight hours before bed time can actually be detrimental to sleep (29). Unfortunately, there is
little information regarding the effects of physical activity on insomnia. Most of the research
that has examined these two variables has been epidemiological in nature. For example, a
longitudinal study in older adults found lower levels of physical activity consistently predicted
insomnia status, along with depressed mood and lower physical health, over an eight-year
period (32). Another epidemiological study found that regular exercise was associated with a
lower prevalence of insomnia (33).
One intervention study, in older adults with moderate sleep complaints, showed that a
16-week moderate intensity exercise program was better than a wait-list control at improving
global Pittsburg Sleep Quality Index (PSQI) (34) scores as well as sleep onset latency, sleep
duration, and rated sleep quality, as assessed by the PSQI and sleep diaries (31). Another study
that did not specifically target insomnia, but whose sample met the research diagnostic criteria
for insomnia at baseline, also found positive results following a four-week moderate intensity
exercise intervention (35). However, this was a very small study that also included an afternoon
nap as part of the intervention; thus, the results are not as easily interpreted.
While epidemiologic research provides some information regarding the relationship
between insomnia and physical activity, there is a definite need for additional randomized
controlled trials examining the effects of a physical activity intervention in a population with
insomnia and on the specific sleep parameters that make up insomnia.

ACUPUNCTURE
Based in Traditional Chinese Medicine, acupuncture involves the insertion of very fine needles
into the skin at specific points to influence the body’s functioning. These points are considered
to rest on ‘meridians’, or channels of a network of energy called ‘chi’ that flows throughout
the body. Each meridian is thought to be related to specific internal functions and imbalances
in the flow of chi are thought to lead to disease processes in whichever internal function
the imbalanced meridian governs. Acupuncture is thought to correct this imbalance, thereby
alleviating the disease process. The neurological mechanisms of acupuncture are beyond the
scope of this chapter, and are more thoroughly covered in other texts (e.g., 36,37).
One open clinical trial of 18 anxious adult subjects found that acupuncture significantly
increased nighttime endogenous melatonin secretion, as well as improving PSG measures of
SOL, TST, and SE (38). Although this was not a group of people with insomnia, we do know
that insomnia and anxiety are closely related (39,40), and it is reasonable to assume that if
acupuncture can improve sleep in those without a diagnosed insomnia disorder, then it may
produce similar or greater changes in those with insomnia. To date, very little efficacy data
exists on the effects of acupuncture on insomnia. Almost all of the data come from case-series
studies showing improvement of sleep in individuals with disorders other than insomnia (e.g.,
HIV, stress) (41,42). In addition, many have publication or location biases (43).

Alternate Forms
Acupuncture is sometimes used in combination with other forms of traditional Eastern
medicine, such as moxibustion. Moxibustion is the combustion of mugwort herb that has
been ground into a powder; it is either applied directly to the skin or held over acupuncture
points and is thought to warm and stimulate the circulation and chi. Electroacupuncture is the
application of a pulsating electrical current to acupuncture needles. This is thought to provide
stronger and more prolonged stimulation to the acupuncture point than could be attained
via finger stimulation alone. Acupressure involves the application of finger pressure, not
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294 TAYLOR ET AL.

needles, to acupuncture sites. Auriculotherapy involves stimulation of specific acupoints on

the auricle of the ear in order to treat various disorders of the body. To date, none of these
alternate forms of acupuncture have been adequately assessed in patients with insomnia.

MASSAGE
Massage is manipulation of the body’s soft tissues (muscles, connective tissue, lymphatic vessels,
etc.) either manually or with aids such as rollers or rocks. Various types of massage exist, from
Swedish “relaxation” massage to deep tissue “shiatsu” massage. Each can be applied to various
parts of the body, including feet, back, shoulders, and face. Among the many goals of massage
(physical, therapeutic, psychological) it has the potential to improve sleep by reducing somatic
arousal and/or cognitive arousal, similar to the previously reviewed relaxation methods (44).
To date, no studies have specifically examined the effects of massage on insomnia. Several
case-series studies have been performed which examine the effect of various types of massage
on sleep in populations without insomnia. For instance, a back massage technique similar to
Effleurage (i.e., skim or lightly touch the skin) has been shown to improve sleep in elderly
hospital patients. One technique of massage combined with sesame oil, increased post-massage
sleep time versus no-treatment control in healthy infants versus control group (45).

AROMATHERAPY
Aromatherapy is a rapidly growing subfield of Complementary and Alternative Medicine (46),
but little evidence exists for the efficacy of aroma alone. Aromatic essential oils reported to have
calming, relaxing or sedating effects include: Bergamot (Citrus bergamia), Roman Chamomile
(Chamomelium nobilis), Jasmine (Jasminum grandiflorum), Lavender (Lavandula angustifolia), Man-
darin (Citrus deliciosa), Marjoram (Origanum majorana), Melissa (Melissa officinalis), Neroli (Neroli
bigarade), Patchouli (Pogostemon cabin), Egypt Rose (Rosa damascene), Ylang-ylang (Cananga
odourata), and Vetiver (Vetivera zizanoides) (47). Aromatherapy is dispersed via mists or a special-
ized misting machine, sprayed on pillows, placed in sachets, potpourri, or scented oil warmers,
or combined with massage. As with herbal therapies, the exact “mechanisms of action are
speculative and unclear ”(48).

Lavender
One small (N = 10) randomized controlled trial using a cross-cover design showed a trend (p =
0.07) for Lavender oil (Lavandula angustifolia) to improve scores on the PSQI (48). Another small
(N = 12) study of children aged 12 to 15 with autism and learning difficulties showed no benefit
on sleep patterns of aromatherapy massage with lavender oil (49). In a single-blind repeated
measures study of 42 female college students, diluted lavender fragrance had a beneficial effect
on several sleep parameters—sleep latency, insomnia severity, and sleep quality (50). Other
studies have shown some improvements in sleep of “healthy” sleepers, but these have not been
translated to insomnia patients (51). Effective proportions of lavender oil/carrier oil have yet to
be confirmed through further studies.

Sandalwood
A study using inhaled diluted sandalwood oil in sleep-disturbed rats showed significant
decreases in total wake time and an increase in total nonrapid eye movement sleep (52). This
method of aromatherapy may be useful in individuals with difficulty maintaining sleep, but
human replication of this study is lacking.
Aromatherapy is not recommended in critically ill patients due to the unclear research on
safety and efficacy in this population (53). Contraindications to the use of aromatherapy include
pregnancy, recent surgery, thrombosis, fractures/wounds, and some medications (54).

SUMMARY
There are a wide variety of “other” types of nonpharmacological treatments used to treat
insomnia, not including stimulus control, sleep restriction, and cognitive therapy (1,2), which
are covered elsewhere in this volume. Progressive muscle relaxation and paradoxical intention
both have significant empirical backing, and have been listed as “efficacious” by the Standards
of Practice Committee of the American Academy of Sleep Medicine, while biofeedback has
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good empirical backing and is listed as “probably efficacious” (3). Other forms of relaxation
therapy, yoga, bright light therapy, exercise, acupuncture, massage, and aromatherapy, all show
some promise as treatments for insomnia, but do not have sufficient empirical support to
be recommended as treatments. Future studies are needed to more effectively evaluate these
alternate treatments of insomnia.

APPENDIX A
RELAXATION PROCEDURE
Please close your eyes and get as comfortable as possible. Keep your eyes closed throughout the
procedure and listen to my instructions. (If legs or arms are crossed ask them to uncross them.)
I am going to help you achieve a deeper level of relaxation with the following procedures. Most
people find this is an enjoyable experience. It is not hypnosis. You will not lose consciousness
and will not lose control.
I am going to ask you to tense different muscles of your body. When I do, I want you to
focus all your attention on those muscles until I say, “relax”. As soon as I say, “relax” I want you
to relax muscles immediately. Throughout the tensing and relaxing phases it is very important
for you to focus all of your attention on the sensation coming from your muscles. It is also
important to only tense the one muscle group at a time while leaving the others as relaxed as
possible. Even if this means you cannot fully tense the target muscle group.

FOREHEAD
This time when I say “now”, I want you to tense the muscles of your forehead by raising your
eyebrows as high as they will go and wrinkling your forehead. “NOW” Keep your muscles
tight. . . I want you to feel the strain and tension. . . “RELAX” Relax immediately. . . Just give
up control of the muscles. . . Smooth out the muscles on your forehead letting all tension slip
away. . . Feel the muscles relax and become loose and limp. . . The more carefully you focus your
attention on calmness and tranquility, the greater the relaxation effect you will enjoy. . .
(Relax phase should take 45 seconds).

EYES AND NOSE

This time when I say “now”, tense the muscle in the middle part of your face by closing your
eyes tightly and wrinkling your nose. “NOW” Keep your muscles tight. . . feel the strain and
tension as your muscles work. “RELAX.” Relax immediately. . . Just let those muscles go loose
and limp. . . soft and calm. . . Compare in your mind the feeling of tension you were feeling just
a few seconds ago in your eye and nose muscles to the restful feeling that is now gradually
emerging. . .
(Relax phase should take 45 seconds).

MOUTH
This time when I say “now”, I want you to tense the lower part of your face by pursing your lips,
pressing your teeth together and pressing your tongue against the roof of your mouth. “NOW”
Keep the muscles tight. . . The muscles are working very hard. “RELAX.” Relax immediately
and completely. . . Let your teeth part, and let all the muscles in your jaw and around your
mouth relax. . . Let the tension in those muscles melt away. . . Let your muscles go loose and
limp. . . Soft and calm. . .
(Relax phase should take 45 seconds).

SHOULDERS AND MIDDLE BACK

This time when I say “now” I want you to tense the large muscle groups in your shoulders and
the middle of your back by pulling your shoulders up and back as though you were trying to
touch your shoulder blades behind your ears. Do this “NOW”. Tense your muscles. . . Feel the
burning. “RELAX” Relax completely. . . Feel the tightness in your muscles going away. . . Feel
the stillness and peacefulness. . . Just give up control of the muscles and then let them lie there
quietly. This is an area where a lot of people hold tension during the day. Just let these muscles
go loose and limp. . . Soft and calm. . .
(Relax phase should take 45 seconds).
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296 TAYLOR ET AL.

RIGHT BICEP
This time when I say “NOW,” go ahead and tense the bicep of your right arm, by bending your
arm at the elbow and flexing. Remember, I want you to try to keep your hand and forearm
relaxed, as well as your shoulder. Make sure not to make a fist with your hand. “NOW”. Keep
it tight. . . feel the strain. . . feel the tension. (wait 7 seconds) “RELAX.” Relax completely and
immediately. . .
Think about how relaxed your muscles feel. . . Imagine the tightness and pain flowing out
of your bicep. . . Let your muscles go loose and limp. . . Soft and calm. . .
(relax phase should take 45 seconds).

RIGHT HAND AND FOREARM

When I say “now” I want you to go ahead and tense the muscles of your right hand and forearm
by clenching your fists. Remember to only tense this muscle group while leaving the others
as relaxed as possible. “NOW” Keep it tight. . . feel the strain. . . feel the tension. (7 seconds)
“RELAX.” Relax completely and immediately.
Just give up control of the muscles and then let them lie there quietly. . . Compare in your
mind the feeling of tension you were feeling just a few seconds ago in your right hand and
forearm to the restful feeling that is now gradually emerging. . .
(Relax phase should take 45 seconds).

LEFT BICEP (See RIGHT BICEP above)

LEFT HAND AND FOREARM (see RIGHT HAND AND FOREARM above)

RIGHT UPPER LEG

When I say “now”, tense the muscles in your upper right leg. The thigh has many muscles that
work in opposition to each other. You can tense all of these at the same time by raising your
leg about an inch and making your thigh hard. “NOW” Feel the strain and tension in your
muscles. . . Keep the muscles tight. . . “RELAX” Relax completely. . . Feel the peacefulness. . .
Focus on this peacefulness. . . Give up the control of your muscles and focus on the feelings
of peace and tranquility. . . Feel the muscles relax and become loose and limp, tension flowing
away like water out of a faucet. . . Focus on and notice the difference between the tension and
the relaxation. (Relax phase should take 45 seconds)

RIGHT CALF
When I say “now”, tense your right calf by pointing your foot and toes forward. Don’t strain
too hard, this muscle has a tendency to cramp. “NOW” Tighten the muscle. . . (only 3 seconds
here). “RELAX” Relax completely. . . Focus on the stillness. . . Just give up control of the muscles
and then let them lie there quietly. . . Compare in your mind the feeling of tension you were
feeling just a few minutes ago to the restful feeling that is now gradually emerging. . . Let
the comfortable feelings of tranquility grow deeper and deeper. . .deeper and deeper. Feel the
peaceful. . . calm sensations. (Relax phase should take 45 seconds).

LEFT UPPER LEG (see RIGHT UPPER LEG above)

LEFT CALF (see RIGHT CALF above) (tense for only 3 seconds)

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A survey of the opinions of 223 professional organizations. Complement Ther Med 2001; 9(3):178–185.
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27 Cognitive Therapy for Insomnia

Colin A. Espie
University of Glasgow Sleep Centre, Sackler Institute of Psychobiological Research, Southern General
Hospital, Glasgow, Scotland, U.K.

Jason Ellis
Northumbria Centre for Sleep Research, School of Psychology and Sports Science, Northumbria University,
Newcastle upon Tyne, U.K.

INTRODUCTION
Cognitive therapy is a generic term, referring to a broad set of therapeutic techniques designed
to address the maladaptive thought processes associated with a specific disease or disorder.
As the term cognition encompasses all aspects of thinking (i.e., perception, attention, memory,
problem solving, attitudes, beliefs, attributions, and expectations), the breadth and range of
cognitive therapies is extensive, and most certainly has not yet been exhausted. It should
also be acknowledged that even predominantly behavioral interventions (Chapter 24) should
be considered within a cognitive context, in that, behavior is often determined, and as such
challenged and changed, through cognitive processes. However, the aim of this chapter is to
examine the contribution of cognitive therapies to the management of insomnia, and therefore
the focus will be on interventions that are predominantly cognitively orientated.

COGNITIVE-ATTENTIONAL PROCESSES IN INSOMNIA

Before describing and evaluating these cognitive interventions in turn, two issues merit con-
sideration. First, it remains rather unclear what terminology is best applied to these cognitive
‘treatments’. Does each constitute a distinct cognitive therapy? Are they better regarded as
cognitive techniques or as cognitive strategies? Certainly at this point we would advocate cau-
tion in any claim that there is a well-tested cognitive therapy for insomnia, in the traditional
sense. With this caveat in mind, we will inevitably use terms somewhat interchangeably in this
chapter, but we will always be referring to intervention upon some aspect of the cognitive-
attentional system. Second, however, and perhaps in contrast to the above, we do actually have
several well-argued cognitive theoretical frameworks for understanding insomnia. It is beyond
the scope of this chapter to review these in detail, but three well articulated and empirically
supported models converge in recognizing the importance of cognitive-attentional systems in
the aetiology and maintenance of insomnia. These are Perlis’ neurocognitive model (1), Har-
vey’s cognitive model (2), and Espie’s psychobiological inhibition model which incorporates
the attention-intention-effort pathway (3,4) [for a comprehensive review, see Perlis et al, 5].

COGNITIVE THERAPEUTIC APPROACHES FOR INSOMNIA

Each of the cognitive interventions outlined in this chapter aim to address one or more of seven
potential cognitive-attentional mechanisms that either fuel or are a causal pathway to insomnia.
In Table 1 these have been brought together under three cognitive domains each having two or
three associated therapeutic mechanisms. The types of thoughts that, in our opinion, are most
likely to respond to each cognitive intervention have also been outlined.
Probably the best known approaches are those that can be termed active rational. Sleep
education is seldom a stand-alone therapy, but can provide, along with data gathered from per-
sonal sleep diaries, observations and experiments, the raw material upon which formal cognitive
restructuring can operate. Thus these corrective and appraisal actions may ameliorate the cogni-
tive component of insomnia. Consequently, these will be considered together in the same section.
We suggest that there is also a protective-preventative domain of cognitive action. Three
cognitive therapies are linked here because they have in common a focus upon avoiding or
curtailing sleep-interfering mental processes. Cognitive control is viewed as a preemptive strike
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300 ESPIE AND ELLIS

Table 1 Cognitive Therapies for Insomnia and their Proposed Action Upon Cognitive Attentional Mechanisms
(After 6)

Specific action upon

cognitive attentional Thought content most Specific cognitive
Cognitive domain mechanisms likely to respond therapy
Active-rational
Corrective Misunderstanding of sleep Sleep education
processes and needs
Appraisal Intrusive, irrational but Cognitive restructuring
compelling negative
thinking
Protective-preventative
Preemptive Rehearsal, planning, Cognitive control
self-evaluative
reflections
Blocking Repetitive but nonaffect Articulatory suppression
laden thoughts
Distraction Agitated, unfocused, flitting Imagery training
thoughts, mental tension
Passive-paradoxical
Acceptance Persistent worry about lack Mindfulness meditation
of control over sleep
Disengagement Rumination about Paradoxical intention
sleeplessness and its
consequences, sleep
effort

against thought content that would otherwise occupy quiet wakefulness; and imagery training
and the lesser known articulatory suppression technique distract or block unwanted intrusive
thinking.
Finally, we suggest that there are useful passive-paradoxical techniques. Unlike the cognitive
therapies, which at some level emphasize control or at least active management of thoughts and
behaviors, paradoxical intention is a disengagement method and mindfulness an acceptance-
based approach. Indeed paradox might even be regarded as the extreme/ultimate end of the
acceptance dimension.

COGNITIVE RESTRUCTURING AND SLEEP EDUCATION

Cognitive restructuring was developed as part of Beck’s (7,8) Cognitive Behavioral Therapy and
Ellis’ (9) Rational Emotive Therapy. The rationale behind cognitive restructuring suggests that
negative thoughts have the potential to create a negative schema, through an interpretative bias.
In other words, a particular problem or issue (e.g. perception of poor sleep) will stimulate the
activation and refinement of distal attitudes, beliefs, and expectations about that problem and
these will be evaluated against any thoughts, feelings, or behaviors believed to be a result of the
problem (irrespective of whether they are or not), further maintaining a catastrophic schema.
As such, cognitive restructuring involves eliciting and discussing the responses to six main
questions (Table 2) in order to identify, appraise and correct any and all forms of dysfunctional
thought.

Table 2 The Process of Cognitive Restructuring

1. Are these attitudes and beliefs about the problem accurate?

2. What evidence is there to support these attitudes and beliefs?
3. Are there alternative explanations for these attitudes and beliefs?
4. Do I underestimate my ability to cope with the current problem?
5. What is the worst that can happen if these attitudes and beliefs are true?
6. What can I do to address the problem?
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COGNITIVE THERAPY FOR INSOMNIA 301

Dysfunctional sleep-related attitudes and beliefs are generally accepted to be a central fea-
ture of insomnia. For example, Morin, Stone, Trinkle et al (10) found that people with insomnia
endorsed more dysfunctional beliefs about sleep compared to controls. However, the extent to
which they mediate the relationship between perceptions of sleep, catastrophic interpretations
about the consequences of poor sleep, and attributions for insomnia is still unclear, but thought
to be significant (11). In addition, it has been shown that the endocrine system reacts negatively
when there is a discrepancy between what is expected and what really exists (12). Although
Eriksen et al’s (12) study related to stress, it has been shown that subjective sleep quantity and
quality are better indicators of insomnia reporting than objective sleep measures (13). Addi-
tionally, researchers have found that irrespective of the actual sleep obtained, those who scored
highly on the Dysfunctional Beliefs and Attitudes to Sleep Scale (DBAS) were also those who
were more likely to complain of disrupted sleep (14,15).
The primary mechanism by which dysfunctional beliefs affect sleep is thought to be
through the relationship between attitudes and sleep-incompatible behaviors. An individual
who believes that they need eight hours of sleep is more likely to reduce their sleep efficiency
by attempting to obtain sleep during the day, lying in bed when not asleep, or going to bed
earlier, all of which are sleep incompatible behaviors and are likely to exacerbate the problem.
Dysfunctional beliefs may be particularly pertinent for older adults, whose sleep patterns
can change as a function of normal ageing. Changes in the timing of the circadian rhythm,
as well as structural changes in sleep architecture, can render the belief that eight hours of
consolidated sleep is essential for normal functioning as even more unrealistic (16) and the
dissonance between this expectation and perceived reality becomes greater and more anxiety
provoking.
The notion of general sleep education falls within the remit of cognitive restructuring in
so far as its intention is to provide information about a) what constitutes ‘normal’, or more
likely, ‘typical’ sleep over the life span and the intra-individual differences therein, b) what
sleep disruption is, c) an exploration of the factors which exacerbate or increase the likelihood of
sleep disruption, and d) an exploration of the factors which increase the likelihood of good sleep
occurring. In this instance, exploring the individuals’ constructs of ‘sleep’ and ‘sleep disorder’
can offer a platform for identifying sleep-related dissonance and provide the beginnings of an
intervention aimed at reducing this dissonance.

The Efficacy of Cognitive Restructuring in the Management of Insomnia

Unfortunately, cognitive restructuring has not been evaluated as a stand-alone therapy, however,
Edinger, Wohlgemuth, Radtke, Marsh & Quillian (17) found that Cognitive Behavior Therapy
for Insomnia (CBT-I), which specifically targeted sleep-related dysfunctional beliefs, resulted in
both improvements to objectively measured sleep parameters and subjective sleep satisfaction.
Likewise, Espie et al (18) reported that many item scores on the DBAS reduced, following CBT.
Indeed, interventions that have incorporated cognitive restructuring tend to routinely use this
measure as a secondary index of treatment efficacy (19). In these respects, the evidence for
incorporating cognitive restructuring within CBT-I is good. However, one of the main issues
with cognitive restructuring is that it is difficult to deliver in a self-help or remote format (e.g.
manualized CBT-I), because a therapist is usually needed to help people identify and challenge
current negative schemas and develop new positive ones.

COGNITIVE CONTROL
It is well documented that intrusive, unwanted thoughts and images are a prominent feature of
most psychological disorders (20) and that attempts to suppress intrusive thoughts usually result
in a rebound effect. Clark and Rhyno (21) define intrusive thoughts as ‘any distinct, identifiable
cognitive event that is unwanted, unintended, and recurrent. It interrupts the flow of thoughts, interferes
in task performance, is associated with negative affect, and is difficult to control.’ (p. 4)
The role of intrusive thoughts, and the subsequent use of thought control strategies to
deal with them in insomnia, is well documented (22–24). In addition, when the suppression of
presleep cognitive activity has been experimentally manipulated, those told to suppress had
longer sleep-onset latencies than nonsupressors (25).
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302 ESPIE AND ELLIS

Table 3 Cognitive Control (“putting the day to rest”) instructions

You may find this technique particularly useful for thoughts that have to do with the past day and planning for
the following day. The aim is to put the day to bed, along with your plans for the next day . . . so that you can
get to sleep!. If you can manage to stop the thinking you usually do in bed, before it happens, then you should
sleep better.
To put the day to rest :-
1. Set aside 20 minutes in the early evening (say around 7 pm.) and sit down with a pen and a notebook
2. Think of what has happened during the day, how it has gone, and how you feel about it – evaluate things
3. Write down anything you need to do on a ‘to do’ list, and any steps that you can take to complete any
loose ends
4. Try to use your 20 minutes to leave you feeling more organized and in control and close the notebook
when you are done
5. When it comes to bedtime remind yourself that you have already dealt with things when they come to your
mind
6. If new thoughts come up note them down on a piece of paper at your bedside, to be dealt with the next
day
Source: From Ref. 33, pp. 97–98.

Harvey (26) examined the individual contributions of the different forms of thought
control in insomnia; namely distraction (focusing away from the thought), punishment (self-
chastisement for the thought), reappraisal (logical interpretation of the thought), worry (wor-
rying about the thought), and social control (seeking support about the thought’s validity). She
found that poor sleepers were more likely to use distraction, reappraisal, and worry, as opposed
to punishment and social control. However, to explain paradoxical effects, Harvey makes a
distinction between suppression and replacement when distraction is used as a thought control
strategy, believing suppression to be a negatively toned thought control strategy and replace-
ment to be a positive one.
Perhaps surprisingly, Ellis and Cropley (27) found that distraction (not separated into
suppression and replacement) was related to not developing chronic insomnia, and that the main
strategies used by people with chronic insomnia were worry and punishment, with punishment
being associated with a longer reported duration of insomnia. This pattern of thought control
use conforms to findings from research on other anxiety related disorders (28). Further support
for the role of thought control in the maintenance of insomnia comes from Watts, Coyle and
East (29). They found the presleep cognitions of nonworrying people with insomnia focused on
not sleeping, whereas worrying insomniacs focused on a diversity of topics. In a more recent
study, intrusive thoughts and avoidance behaviors were not strongly related to subjective sleep
quality, only objective sleep latency (30) suggesting that the outcome measures used may be an
important factor in determining the importance of cognitive intrusions. Similarly, Bonnet and
Arand (31) found no increases in subjective anxiety after a period of poor sleep in 10 patients
with insomnia. These findings together suggest that thought control does play a role in insomnia
but may not lead to, or exacerbate further, cognitive activity directly.
The only specific cognitive control procedure used in the treatment of insomnia was
initially outlined in a case study first described some 20 years ago (32). It is really an extension
of the idea of stimulus control (Chapter 24), but recognizes that it may be primarily thoughts
and worries that seem to be incompatible with successful sleep. The great majority of people
with insomnia report excessive mental arousal in bed. They complain of difficulty in emptying
their minds and of racing thoughts. Cognitive control comprises a simple set of procedures
to remove mental activity from the bed and bedroom environment, or at least to reduce the
influence of cognitive activity upon sleep. The instructional set is provided in Table 3.

The Efficacy of Cognitive Control in the Management of Insomnia

Although there are no interventions solely related to cognitive control within insomnia popu-
lations cognitive control does fall within the broader premise of sleep stimulus control, which
is highly efficacious for insomnia (34–36), and cognitive control procedures are routinely used
within multicomponent CBT (33).
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COGNITIVE THERAPY FOR INSOMNIA 303

Table 4 Instructions for Using Articulatory Suppression

1. While lying in bed with your eyes closed

2. Repeat the word ‘the’ once or twice every second in your head
3. Don’t say it out loud, but it may help if you ‘mouth it’
4. Keep up these repetitions for about 5 minutes or until sleep ensues

ARTICULATORY SUPPRESSION
As the review of cognitive factors in the previous section might suggest ‘thought-blocking’
techniques have obvious intuitive appeal in insomnia. Although, there is some evidence that
thought suppression may be a counterproductive strategy employed by poor sleepers (37),
Morin & Espie (33) report that there is one form of thought-blocking that might be recommended.
Articulatory suppression is a technique widely used in studies of working memory. The
phonological component of the central executive is referred to as the articulatory loop, which
serves to hold in store the verbal elements required in any cognitive task. Levey et al. (38) applied
articulatory suppression techniques to the treatment of insomnia. They thought that by blocking
up this short-term store with semantically meaningless phonemes no other mental information
would be processed. They presented an interesting case series supporting this contention,
particularly for sleep maintenance insomnia (i.e. using the technique at any wakening from
sleep). The instructions for articulatory suppression are summarized in Table 4.

The Efficacy of Articulatory Suppression in the Management of Insomnia

As for cognitive control, there is only case study material supporting the efficacy of articulatory
suppression (and other thought blocking techniques) as single component therapy.

IMAGERY TRAINING
Harvey (39) suggests that unwanted cognitive activity can be visual as well as verbal, and
controlling or replacing these images, using distraction techniques, has been shown to result
in reduced arousal in several anxiety-related disorders (40–42). It has been demonstrated that
poor sleepers report more negative images than normal sleepers and the imagery of poor
sleepers tends to be catastrophic (envisioning the worst possible outcome), in that it is usually
distressing and related to physical sensation (43). They also showed that levels of visual imagery
in poor sleepers related to an increased subjective Sleep Onset Latency (43). Using replacement
distraction visual imagery when faced with a visually catastrophic stimulus has been shown to
be effective in samples of poor sleepers (44,45).
The aim of imagery training is to block or distract the individual from intrusive and
preoccupying sleep-related thoughts, using visualization techniques. Imagery techniques are
useful for some but not all patients, probably because there are individual differences in the
ability to visualize. First, there is need to establish the patient’s ability to visualize, and their
degree of comfort with the process. This can be achieved by asking them to close their eyes and
try to picture some objects (a boat under sail in a gentle breeze, a clock face with a ticking second
hand). Second, it is better to get patients to decide upon an imaginable scene for them to use
rather than to leave it literally to their imagination at the time. For example, if it is something
like walking through a favorite piece of parkland and gardens, they should prepare the scene
and the sequence in advance, so it is like ‘rolling the tape’ when it comes to using the imagery.
Finally, practice is crucial to train the imagery if it is going to be useful (33).

The Efficacy of Imagery Training in Managing Insomnia

Studies examining the efficacy of imagery training as a sole intervention are rare and this is
reflected in AASM being unable to recommend it is a discrete management strategy. Morin &
Azrin (46,47) found that stimulus control was more efficacious than imagery training but that
the imagery training component was associated with shorter awakening durations. What is
worth noting is that both of Morin and Azrin’s studies showed an increase in efficacy at follow-
up, suggesting that with increased use, the intervention may become more powerful. Whether
this finding relates to increased sophistication and skill in the use of images to block unwanted
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304 ESPIE AND ELLIS

thoughts over time or whether this is artefact remains to be seen. Commonly imagery is used
alongside (other) relaxation techniques in clinical practice, and is used in some multicomponent
CBT-I interventions.

MINDFULNESS & ACCEPTANCE-BASED THERAPIES

Although ‘mindfulness’ techniques have been around for a long time, (Buddhism is believed to
originate in 6th Century BC), in one form of another, their incorporation into clinical research is
recent. Mindfulness-Based Stress Reduction (MBSR) was developed in 48 by Kabatzin with the
aim of reducing both cognitive and somatic arousal. This program consists of teaching the indi-
vidual mindfulness principles, namely; nonjudging, patience, beginner’s mind, trust, nonstriv-
ing, acceptance, and letting go. The premise behind mindfulness suggests that there are three
stages which result in negative action towards a given event or object; a latency stage containing
a deeper understanding of the self and its capabilities, a conscious stage whereby both internal
and external stimuli are processed affectively in response to a threat to this latent self, and a reac-
tive stage whereby actions ‘spill out’ as a result of this processing, creating emotional arousal.
Mindfulness teaches the individual to attend to and manage both latency thoughts and con-
scious thoughts, thus avoiding negative actions, through practiced meditation and acceptance.
In insomnia, instead of attempting to suppress or control intrusive thoughts, a common
occurrence presented by people with insomnia (49), which generally results in rumination or
thought rebound, this intervention teaches the patient to acknowledge the thought, feeling or
sensation, but not to dwell on it (i.e. to create cognitive deactivation) (50).

The Efficacy of Mindfulness in the Management of Insomnia

Although a relatively new area of investigation with regard to insomnia, the results from
uncontrolled studies to date are promising. Lundh and Hindmarsh (51) asked 40 people with
insomnia to monitor their presleep-onset thoughts, feelings, and bodily sensations, without any
attempt to change them, over the period of one week, and compared sleep diaries before and
afterward. The results showed reductions in sleep latency and increased sleep time. However,
because there was no control group and no measure of treatment adherence, these results
should be viewed cautiously. In another study, Ong, Shapiro & Manber (52) combined CBT
with MBSR and found a relationship between meditation practice and reduced trait arousal.
However, meditation adherence was only 57%, suggesting a problem with uptake. Finally, Yook
and colleagues (53) showed significant improvements in sleep after eight weeks of mindfulness-
based cognitive therapy for sleep problems in a sample of patients with anxiety disorders.
A better understanding of mindfulness is clearly warranted but whether it remains an
adjunct to other therapies or can be utilized as a strategy in its own right remains to be seen.

PARADOXICAL INTENTION
Although it could be argued that paradoxical intention is not exclusively a cognitive therapy,
in that it was not developed within a cognitive framework being more grounded in learning
theory, throughout its refinement it has applied cognition to its existing elements.
The term paradox was termed long before the intention part was introduced by Frankl
(54,55). Dubois (56), for example, suggested humor ‘paradoxically’ should be advocated for
patients to help them in dealing with their symptoms. Furthermore, Dunlap (57,58) suggested
one method that could be utilized to break a bad habit was to repetitively perform that particular
habit. Frankl (59), who was also a proponent of humor in the therapeutic encounter, refined these
early ideas, suggesting that in order to break vicious cycles of anticipatory anxiety surrounding
a thought or behavior, individuals must focus in on that particular problem or perform that
particular behavior repeatedly. Alongside paradoxical intention Frankl also outlined another
therapeutic technique; dereflection. Because Frankl believed the roots of most psychological
problems were caused by an overemphasis on the self, shifting attention away from the self
might also be used to alleviate the problem (an early version of thought blocking/distraction).
The main advocate of paradoxical intention, since its inception, has been Ascher, who
with various colleagues demonstrated its effectiveness in areas as diverse as urinary retention
and agoraphobia (60,61). In each case, the use of paradoxical intention has lead to a reduction
in symptom reporting, and in some cases, increases in self-efficacy.
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COGNITIVE THERAPY FOR INSOMNIA 305

Table 5 Suggested Rationale and Instructions for Using Paradoxical Intention Therapy in Insomnia

If you can’t get to sleep it might seem reasonable to ask someone who is a good sleeper how he/ she
manages it. What do you think they would say? Something like
I just fall asleep . . . it just happens . . . I don’t
do anything really?
You might think this is not very helpful, but the secret is right there – they do precisely
nothing!

Sleep is a natural process which happens involuntarily. The good sleeper doesn’t make it happen, or have
some kind of method that you don’t know about it. You are the one with all the methods and tactics, and none
of them works! To become a good sleeper you need to learn to abandon all your efforts to sleep because they
simply get in the way of the natural process. They make you too self-conscious about your sleep and about
your sleep failures. You know how sometimes you lie awake for ages or toss and turn until it’s getting close to
morning time? And you feel some relief as you think that soon you can get up? Why do you sometimes fall
asleep at that point? That’s because you give up trying then and you give up being concerned. How about
having that as a general approach. Try this:-
1. When you are in bed lie in a comfortable position and put the light out
2. In the darkened room, keep your eyes open, and try to keep them open ‘just for just a little while longer’.
That’s your catch phrase
3. As time goes by congratulate yourself on staying awake but relaxed
4. Remind yourself not to try to sleep but to let sleep overtake you, as you gently try to resist it
5. Keep this mind set going as long as you can, and if you get worried at staying awake remind yourself
that that is the general idea, so you are succeeding
6. Don’t actively prevent sleep by trying to rouse yourself. Be like the good sleeper, let sleep come to you
Source: From Ref. 33.

Within the framework of insomnia, paradoxical intention aims to reduce the anxiety and
frustration often experienced by people with insomnia at sleep-onset by recommending that
the individual do the opposite of their normal behavior (Table 5). In this case, to lie down
with their eyes open and attempt to stay awake for as long as possible. This strategy operates
on the premise that, in insomnia, sleep onset is prevented because the patient is attempting
to place sleep under voluntary control, resulting in arousal of the autonomic nervous system.
In other words, the more effortful monitoring that is employed to sleep, the more likely it is
to keep the individual awake, creating performance anxiety which then leads to catastrophic
interpretations about daytime functioning, fuelling a vicious cycle of performance anxiety.
Evidence for this comes from the use of measures such as the Glasgow Sleep Effort Scale,
Sleep Associated Monitoring Index and Sleep Preoccupation Scale which, independently, have
identified people with insomnia as being more effortful in their attempts to sleep, spending
more time self-monitoring, and becoming increasingly anxious and sleep preoccupied when
these efforts fail (62–64). As such, sleep may be facilitated by breaking the pathway between
attention to sleep-related cues – increased intention to sleep – and increased effort to sleep (4).

The Efficacy of Paradoxical Intention in the Management of Insomnia

One of the first reports on the efficacy of paradoxical intention for insomnia came from Ascher
and Efran (65) who demonstrated a significant reduction in SOL (from 40 minutes to 10 min-
utes). Although this was a very small sample, subsequent uncontrolled studies (66–69) and
randomized controlled trials (70,71) suggested this to be a robust effect. On the other hand,
three other studies have questioned the use of paradoxical intention, finding that it did not
result in decreased sleep-onset latencies (72,73,74).
Overall, paradoxical intention appears to be effective and retains a ‘guideline’ rating
according to the American Academy of Sleep Medicine (34). Recently, Broomfield & Espie (75)
found that those who used paradoxical intention had lower levels of sleep performance anxiety
and reduced their sleep effort compared to controls.

COGNITIVE THERAPY WITHIN COGNITIVE-BEHAVIORAL-THERAPY

FOR INSOMNIA (CBT-I)
As is discussed in chapter 29, the main framework under which cognitive therapies are delivered
and have been evaluated is within studies of multicomponent CBT-I. Cognitive therapies have
taken various forms ranging from sleep education and low-level cognitive interventions, to
in depth cognitive restructuring and paradoxical intention. Although this creates a difficulty
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306 ESPIE AND ELLIS

when attempting to determine the relative value of cognitive therapy within CBT-I, there is
undoubtedly very strong evidence that CBT-I as a “package” is an effective treatment for
persistent insomnia. Cognitive components are perhaps integral to this success.
To date, there has been only one study that has formally examined cognitive therapy as a
stand-alone treatment (76). Based on Harvey’s (2) cognitive model, and using a mainly Socratic
questioning approach, this therapy involved three phases (case formulation, personalized exper-
iments with guided discovery, and planning for continued success whilst preventing against
relapse). The therapeutic aim was to reverse the five main cognitive processes thought to main-
tain insomnia; namely, worry and rumination, attentional bias and monitoring for sleep-related
threat, unhelpful beliefs about sleep, the use of safety behaviors that maintain unhelpful beliefs,
and misperception of sleep and daytime deficits, (77). In terms of efficacy, significant improve-
ments in sleep diary measures as well as significant reductions in anxiety and depression scores
were obtained and maintained at 12 months follow up.
Although the lack of a control group or comparable intervention and the small sample size
limit the reliability and generalizability of the Harvey et al. (76) study, it represents emerging
evidence that cognitive therapy may prove to be effective for persistent insomnia. Whether it
would outperform CBT-I as a standard therapy, however, remains questionable.
Another welcome development in the literature has been the examination of cognitive
processes in insomnia beyond the actual intervention itself. Recently, interpersonal aspects
surrounding the patient/therapist interaction have come under scrutiny. For example, one
study has suggested that increased levels of perceived therapeutic alliance may provide additive
efficacy to CBT-I (52). As such it may not be just the intervention itself, but the mode of delivery
that can increase the chances of treatment success.

SUMMARY AND FUTURE DIRECTIONS

Clearly, cognitive therapies warrant further attention both as a stand-alone treatment and within
the broader framework of CBT-I. What is clear is that there is a range of cognitive interventions to
choose from. However, the evidence base is rather limited, relative to other CBT strategies (78).
With increasing interest in addressing daytime cognitions of patients with chronic insomnia as
well as their night-time symptoms, coupled with a broadening of cognitive models and therapies
to include all aspects of cognition (both proximal and distal), an improved understanding of
the impact cognitive therapies may not be far away. Another area, yet to be addressed, where
cognitive therapies may prove beneficial, is in the domain of adjustment or acute insomnia (27).
The two main factors that may differentiate acute insomnia from its chronic presentation are the
absence of a conditioned response to the bedroom or pre-sleep routine and the presence of an
identifiable stressor. Cognitive approaches may be appropriate to circumvent the establishment
of poor sleep as a conditioned response, thus a therapeutic focus upon the perception of stress
(rather than the actual stressor) may also be beneficial.

REFERENCES
1. Perlis ML, Giles DE, Mendelson WB, et al Psychophysiological insomnia: The behavioural model and
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28 Short-Term and Group Treatment Approaches

Christina S. McCrae
Department of Clinical and Health Psychology, University of Florida, Gainesville, Florida, U.S.A.

Natalie D. Dautovich
Department of Psychology, University of Florida, Gainesville, Florida, U.S.A.

Joseph M. Dzierzewski
Department of Clinical and Health Psychology, University of Florida, Gainesville, Florida, U.S.A.

INTRODUCTION
The efficacy of cognitive behavioral treatments of insomnia has been well-documented in adults
of all ages (1). A major challenge facing behavioral sleep medicine experts is how to best
disseminate cognitive behavioral treatments to patients in primary care settings. A major barrier
to the routine provision of such interventions in primary care settings is the length of the time
required for treatment. Cognitive behavioral interventions have traditionally been administered
over the course of 6 to 10 sessions lasting 50 to 90 minutes each (1). Another barrier is the common
approach of providing treatment on a one-to-one basis. It is not difficult to see how lengthy
intervention periods and individually administered treatment combine to consume a great deal
of clinician time-–a valuable and often limited resource in primary care settings. As a result,
access to cognitive behavioral treatments for insomnia is frequently limited outside of a few
select academic medical settings and specialized sleep treatment centers. Both of the intervention
approaches presented in this chapter represent methods of treatment administration that offer
potential solutions to these barriers. For example, shortened protocols and group treatment
(treating more than one patient at a time) can make the best use of available healthcare provider
resources by reducing demands on clinician time. Importantly, evidence suggests that these
alternative approaches to administering cognitive behavioral treatment of insomnia can be
adopted without compromising treatment quality. As will be presented in this chapter, research
indicates that both brief and group approaches can be as efficacious in the treatment of insomnia
as traditional cognitive behavioral protocols. Additionally, although the majority of research on
these approaches has examined their efficacy, a smaller body of evidence provides promising
preliminary support for their effectiveness as well. The first half of this chapter provides an
overview of brief interventions, while the second half focuses on group therapy.

BRIEF INTERVENTIONS
A growing number of researchers have examined briefer approaches to insomnia treatment
using cognitive behavioral therapy. The majority of studies have contrasted multicompo-
nent cognitive behavioral approaches to ‘usual care’ treatment (typically consisting of sleep
hygiene/sleep education). The number of sessions examined has ranged from one to five ses-
sions. In a review of psychological and behavioral treatments for insomnia, Morin and colleagues
(2006) described the average number of treatment sessions as 5.7 meetings (1). Consequently,
for the purpose of this chapter, therapies not exceeding five treatment sessions will be reviewed
and designated as ‘brief approaches’.

Brief Interventions (4–5 Sessions)

Brief behavioral interventions of a longer length (i.e., 4–5 sessions) will be examined first. The
effectiveness of brief behavioral treatments was examined within a rural elderly sample (2).
Sleep treatments were administered to rural elderly within the framework of an existing service
delivery system. Two brief approaches were compared: multicomponent behavioral treatment
(MBT; stimulus control, sleep restriction, and passive relaxation) and sleep hygiene education
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SHORT-TERM AND GROUP TREATMENT APPROACHES 311

(SHE). Treatment was primarily administered in two in-person sessions and two telephone ses-
sions. Results indicated that the MBT approach resulted in greater improvements as measured
by sleep diary for sleep-onset latency and sleep efficiency compared to SHE (Table 1). Addition-
ally, the results for MBT had greater clinical significance with 10 participants no longer meeting
the criteria for insomnia after receiving the MBT versus three for the SHE treatment.
The efficacy of four treatment sessions for alleviating sleep complaints was examined in a
sample of older adults with secondary insomnia (10). The treatment package consisted of sleep
hygiene, stimulus control, and relaxation exercises. Compared to the delayed treatment condi-
tion, participants receiving the treatment showed significant improvement at posttreatment for
the sleep diary measures of wake time after sleep onset, sleep efficiency, and sleep quality. The
results appeared durable at three months with improvements maintained for wake time after
sleep onset, sleep efficiency, and sleep quality.
Another study also examined the efficacy of four treatment sessions for treating insomnia
in older adults but compared various components of behavioral treatments (12). One treat-
ment group received a combination of sleep hygiene and relaxation exercises while another
treatment involved sleep hygiene and stimulus control components. There were significant
differences in pre/post scores for the treatment groups compared to the waitlist controls. The
sleep hygiene/relaxation group and the sleep hygiene/stimulus control group significantly
improved on the sleep diary measures of sleep-onset latency, total sleep time, and sleep effi-
ciency compared to the control group. The significant improvement for the two treatment groups
was maintained at follow-up. There were no significant differences between the two treatment
groups suggesting that both approaches were efficacious.
The efficacy of a four session brief treatment approach was assessed in an older adult sam-
ple using one of three treatment conditions (sleep hygiene education, sleep restriction and sleep
hygiene, and a nap restriction condition) (7). The nap restriction condition encouraged partici-
pants to partake in a daily 30 minute nap between 1 PM and 3 PM. Results indicated significant
improvement at posttreatment for the sleep and nap restriction conditions for actigraphically
measured total sleep time and for sleep diary sleep efficiency and time in bed.
Finally, two studies by Perlis and colleagues (38,39) examined the behavioral treatment
for insomnia using a case based approach in which the number of sessions ranged from three to
nine. Due to the variability in the number of sessions, these studies are not reviewed in depth
here.

Brief Interventions (∼2 Sessions)

Two to three session brief behavioral treatments were investigated by a number of authors
(3,4,6,8,9,11,14). These approaches either delivered treatment across two sessions or delivered
treatment primarily in one session while using the second session to follow-up with participants.
A brief behavioral treatment of insomnia (BBTI) was compared to an information-only control
(IC) in a sample of older adults who had normal psychiatric and medical comorbidities associ-
ated with aging (8). Both treatments consisted of two sessions. The BBTI treatment consisted of
sleep education, sleep hygiene, stimulus control, and sleep restriction. The results indicated that
in terms of sleep diary outcomes, the BBTI treatment resulted in significantly greater pre/post
improvements in overall sleep quality, sleep latency, and wake time after sleep onset compared to
the IC group. Additionally, there were moderate improvements in depression for the BBTI group.
A one-session CBT approach to treating insomnia showed significant improvements in
sleep (4). A unique aspect to this approach included a cognitive restructuring component in
the CBT regimen. The authors assessed sleep using the Sleep Questionnaire and Assessment of
Wakefulness (37) and did a pre/post comparison with the postassessment occurring approxi-
mately 222 days after treatment. The results suggest that the brief CBT approach significantly
decreased sleep-onset latency, wake time after sleep onset, and increased total sleep time.
Although some of the participants received one to two follow-up sessions after the initial ther-
apy, treatment was primarily delivered in one session, and there were not significant differences
in treatment outcomes across the treatment lengths.
A two session, abbreviated cognitive-behavioral intervention (ACBT) produced signifi-
cantly better improvement over baseline as measured by sleep diaries compared to a usual care
(text continues on page 324.)
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312
Table 1 Summary of Research Employing Brief Treatment Approaches for Insomnia
#, Format of
sessions, &

March 28, 2010

length of
intersession Content of Therapist Exclusionary Durability of
Study interval sessions qualifications Population criteria Measures Results Effects Effect Size∗
Carter (3) 2 in-person (Caregiver Sleep – Master’s level – 19 women, 11 – major PSQI (sleep diary) (PSQI) overall large effect
sessions Intervention – CASI) nurses men depressive actigraphy – significantly – significantly sizes (sleep diary)
intersession – 1st session: stimulus – trained during – age (m = 53, disorder sleep diary greater lower PSQI for – SOL d = 0.84 for
interval of 2 control, relaxation 1 CES-D decrease in CASI vs. CASI vs. control
/2 day range 21–85) – sleep disorder

9:44
wks therapies, cognitive intensive other than CQOLC SOL for CASI control at week 5
therapy, sleep training session insomnia vs. control (14 (decrease of – (PSQI) - PSQI
hygiene (60 min) min) at wk 5 4.5) after 4mo for CASI vs.
– 2nd session: review (one wk after (actigraphy) control,

Char Count=
and rates goal second – significantly d = 1.03 after
attainment (60 min) session) lower SOL 4mths
(decrease of (actigraphy)
No significant 5.4 min) after 2 – SOL d = 0.79
differences mo and higher after 2mths and
between TST (increase TST d = 1.15
intervention and of 1.1hr) after after 4mths for
control for CES-D 4mo for CASI CASI
or CQOLC vs. control vs. control
Chambers & 1–3 in-person – included stimulus – clinical – 69 women, 34 – organic sleep SQAW SOL ↓30 min, postassessment overall small/
Alexander (4) sessions control, sleep psychologist men disorders TST ↑68 min, was conducted at medium to large
Unable to restriction, sleep – age (m = 39.9, – poor physical WASO ↓23 min follow-up (on effect sizes SOL
ascertain hygiene, & cognitive range 19–75) health Secondary average 222 days d = 0.42 TST
intersession restructuring – acute outcomes: later; see results d = 0.75 WASO
interval (typically delivered in psychiatric Significant section for d = 0.57
one 2—3 hr session) conditions improvement in post-assessment
– follow-up sessions – required daytime findings)
(1–2) were used for prescription of sleepiness,
some to monitor anxiolytics, daytime fatigue,
progress and antidepressant alertness during
encourage or neuroleptic

McCRAE ET AL.
the day, & general
compliance med well-being
– no differences in following
treatment outcome treatment
for number of
sessions
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Edinger, et al. 1, 2, 4, & 8 1st session: sleep – 2 Clinical – 43 women, 43 – pregnancy sleep diaries – 1 and 4 6 month follow-up Overall medium to

SHORT-TERM AND GROUP TREATMENT APPROACHES

(5) sessions education, stimulus Psychologists men – med condition actigraphy sessions: 1,2, 4 sessions: large effect sizes
Sessions control, & sleep – 5–17 yr – age (m = 55.4 affecting sleep ISQ – ↑12% and – ↑9.3%, 6.9%, Posttreatment:
were restriction (45—60 experience ± 9.7) – major BDI 10% for sleep and 11.9% for – 1 and 4 sessions:
conducted min) working with psychiatric STAI diary SE sleep diary SE – d = 1.13 and d =

March 28, 2010

in-person with Follow-up session: sleep- disorder POMS – WASO min – TST min ↑34.7, 1.16 for sleep
a taped troubleshoot & modify disordered – <27 MMSE SES ↓53.6 and 52.4 44, and 40.6 for diary SE
recording of TIB prescription as patients – substance for sleep diary sleep diary – WASO d = 1.07
sleep needed (15—30 min) abuse / sleep – TWT min ↓64.3 – TWT min and d = 1.28 for
education and medication and 58.5 for ↓46.5, 28.9 sleep diary
a pamphlete – anxiolytics / sleep diary and 60.1 for – TWT d = 1.24
describing antidepres- – TWT min ↓21.3 sleep diary and d = 1.24 for
stimulus sants and 29.9 for sleep diary

9:44
control & – PLM 4 sessions: – TWT min
actigraphy
sleep – primary sleep – ↓52.7 min for d = 0.41 and
restriction disorder other 4 sessions: sleep diary d = 0.80 for
– ↑4.7% for WASO

Char Count=
provided than PI - PSG actigraphy
Intersession sleep time ≥ 2 actigraphy SE – ↑6.1% for
intervals: x higher than actigraphy SE 4 sessions:
ISQ scores – TWT min ↓30.1 – d = 0.60 for
– 2 sessions sleep diary
improved from for actigraphy actigraphy SE
(3 wk) sleep time
baseline to
– 4 sessions posttreatment for Follow-up:
(2 wks) 1,4, & 8 sessions – 1,2, 4 sessions:
– 8 sessions and from baseline – d = 0.92,
(no interval to follow-up for 1 d = 1.00, and
between & 4 sessions d = 1.52 for
sessions) sleep diary SE
– TST d = 0.70,
d = 1.11 and
d = 0.87 for
sleep diary
– TWT d = 0.86,
d = 0.78 and
d = 1.24 for
sleep diary
4 sessions:
– d = 1.39 for
sleep diary
WASO
– d = 0.59 for
actigraphy SE
– TWT d = 0.60
for actigraphy

313
(Continued)
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314

March 28, 2010

Table 1 Summary of Research Employing Brief Treatment Approaches for Insomnia (Continued )
#, Format of
sessions, &

9:44
length of Therapist
intersession Content of qualifica- Exclusionary Durability of
Study interval sessions tions Population criteria Measures Results Effects Effect Size∗

Char Count=
Edinger & 2 in-person (ACBT) – beginning- 2 women, 18 men – sleep- sleep diary Sleep diaries: 3mo after Insufficient
Sampson (6) sessions – 1st session: level clinical – age (m = 51.0 disruptive med ISQ – ACBT: WASO treatment information to
pamphlet with review of sleep psycholo- ± 13.7) condition SES ↓43 min, SE Sleep diaries: calculate effect
behavioral logs, sleep gist – terminal illness DBAS ↑9%, SQ ↑.3/5 – ACBT: sizes
recommenda- education, – received – other primary – SHC: WASO WASO ↓51
tions & audio stimulus control, training and sleep disorder ↑1min, SE min, SE
cassette with sleep restriction monthly – Axis I disorder ↑1%, SQ no ↑12%, SQ
treatment – 2nd session: supervision – use of change ↑.2/5
guidelines review from 1st hypnotics / – SHC:
provided instructions, Secondary WASO
author alcohol as
2 wk trouble shoot outcome ↑8min, SE
sleep aid
intersession – sessions ∼ 25 measures: ↑3%,
interval min ACBT group SQ.1/5
showed
(SHC) significant Secondary
– 1st session: improvement outcome
review of sleep compared to SCH measures:
logs (no problem group on ISQ, ACBT group
solving), sleep DBAS showed
education, sleep significant
hygiene improvement
– 2nd session: compared to

McCRAE ET AL.
review SCH group on
instructions, ISQ,
trouble shoot sleep-related
– sessions ∼ self-efficacy,
25min DBAS
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Friedman 4 in-person Control condition Not able to 24 women, 11 – sleep apnea actigraphy Actigraphy 3mths after overall medium to

SHORT-TERM AND GROUP TREATMENT APPROACHES

et al. (7) treatment (CC): ascertain men – periodic limb sleep logs – Significant treatment large effect sizes
sessions Sleep hygiene – age (m = 64.2 movements polysomnography improvement at Unable to Posttreatment:
1 wrap-up education provided ± 7.4) – acute, unstable MSLT posttreatment ascertain Actigraphy
session at end except for Participants met
medical or SSS for NR and SR – Significant

March 28, 2010

of treatment information on psychiatric Urine toxicology condition for improvement at
napping or regular criteria for TST ↑24 min & posttreatment
illness
Brief meeting bed/wake times. insomnia 26 min for NR and SR
– chronic illness
at 3mth condition for
Sleep Restriction associated with
follow-up Sleep diary: TST d = 0.47 &
(SR): insomnia
No – use of – significant d = 0.77
In addition to improvement at
intersession education received stimulating or
intervals posttreatment Sleep diary:
by CC, sleep sedating

9:44
between 4 medications for NR and SR – significant
restriction therapy condition for improvement at
in-person as described in – not free of
sessions sleeping posttreatment
Friedman et al. SE ↑8.6% & for NR and SR

Char Count=
(1991) was medications for 15.2%, ↓TIB
3 wk condition for SE
provided 55min & 95min d = 0.80 & d =
– MMSE
Nap Restriction 1.07, ↓TIB d =
(NR): 0.92 & d = 2.04
Identical protocol to
SR group except
were encouraged
to take a 30 min
daily nap between
1–3 pm
(Continued)

315
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316

March 28, 2010

Table 1 Summary of Research Employing Brief Treatment Approaches for Insomnia (Continued )
#, Format of

9:44
sessions, &
length of
intersession Content of Therapist Exclusionary Durability of
Effect Size∗

Char Count=
Study interval sessions qualifications Population criteria Measures Results Effects
Germain 2 sessions (BBTI) – Masters-level (BBTI) PSQI Significant n/a overall
et al. (8) with 2 wk – 1st session: adult – 12 women, 5 sleep diary differences medium to
intersession sleep education, psychiatric men HRSD between the two large effect
interval sleep hygiene, and primary – age (m = 70.9 HRSA groups were sizes
(BBTI) stimulus control, care nurse ± 5.3) reported for the (sleep diaries)
– in-person sleep restriction practitioner following: SOL d = 0.80
– wkbook (45min) (IC) (sleep diaries) WASO d =
– trained in
– 2nd session: BBTI – 13 women, 5 – BBTI: SOL ↓22 0.67
(IC) review sleep men min, WASO ↓33 (PSQI)
intervention
– in-person education, – age (m = 69.6 min d = 1.37
– telephone treatment ± 7.3) – IC: SOL ↓3 min,
follow-up adherence, – 33 participants WASO ↓12 min
– pamphlets modify sleep were
schedule as Caucasian (PSQI)
needed (30 min) – 14 participants – BBTI: ↓ 3.94
were using – IC ↑.06
(IC) hypnotics
– 1st session: (clinical
given 3 AASM significance)
brochures 53% BBTI, 17% IC
met criteria for

McCRAE ET AL.
remission
Moderate
improvement in
depression
(HRSD) for BBTI
group
 c28
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SHORT-TERM AND GROUP TREATMENT APPROACHES
Germain, 1 in-person – session – delivered by – participants – substance PSQI – small post- overall medium
et al. (9) session & consisted of a doctoral-level met diagnostic abuse PSQI-A improvements assessment effect size
follow-up combination of practitioner criteria for – psychotic Pittsburgh Sleep for PSQI was PSQI d = 0.66
telephone call imagery PTSD /bipolar Diary (p<0.10) conducted
(3 wk later) rehearsal – 4 women, 3 disorder, major – marked 6–8 wk post-

March 28, 2010

Materials therapy (IRT) a men depression improvements intervention
provided: CBT to reduce – sleep apnea in PTSD (see results
wkbook with post-traumatic age ( m = 33.93 ± section)
diagnosis symptoms
educational nightmares and 5.67)
materials CBT for
insomnia
– session included
education about

9:44
sleep &
nightmares,
rationale &

Char Count=
practice of
imagery
rescripting &
rehearsal,
stimulus control,
sleep restriction
– 90 min session
– follow-up phone
call was
scheduled 3wks
later to asses
time in bed
prescription

(Continued)

317
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Table 1 Summary of Research Employing Brief Treatment Approaches for Insomnia (Continued )

318
#, Format of
sessions, &
length of
intersession Content of Therapist Exclusionary Durability of
Study interval sessions qualifications Population criteria Measures Results Effects Effect Size∗

March 28, 2010

Lichstein, 4 in-person Treatment package 4 graduate – 21 women, 23 – medication sleep diary Sleep Diary: Follow-up was overall small
et al. (10) sessions (1 h) was composed of students in men age taken IIS Treatment group conducted at to large effect
No intersession sleep hygiene clinical (treatment specifically for GDS showed 3mos sizes
interval (sessions instructions, psychology group m = 67.1 sleep STAI significant Sleep Diary: Sleep Diary:
occurred on a stimulus control, Training ± 6.1; control – presence of adherence logs improvement at Treatment group Treatment
weekly basis) and relaxation included group m = 70.1 other sleep posttreatment for showed group at
studying a ± 6.8) disorders (e.g., WASO↓26min, significant posttreatment

9:44
Participants were SE ↑11%, improvement at
detailed sleep apnea, for WASO d =
assigned to either SQ↑0.5 follow-up relative
treatment periodic limb 0.42, SE d =
a treatment group to baseline for
manual, mock movement, No significant 0.69, SQ d =
or delayed

Char Count=
therapy narcolepsy) differences were WASO↓31min, 0.71
treatment SE ↑11%,
sessions, – irregular sleep observed for
condition SQ↑0.5 Sleep Diary:
observation, schedule due secondary
No significant Treatment
discussion, to shift work measures
differences were group at
and weekly follow-up for
supervision observed for
secondary WASO d =
provided by 1st 0.59, SE d =
author measures
0.77, SQ d =
0.77
Means, et al. 3 in-person Treatment 3 graduate – 85 women, 33 – medication sleep diary Sleep Diary: No follow-up overall
(11) sessions consisted of a 16 students men age (m = taken IIS Treatment group assessment medium to
Intersession muscle group Students 21.2 ± 5.2) specifically for DBAS had significantly large effect
interval (sessions relaxation received sleep ESS better WASO sizes
occurred 3–7 performed at – presence of FSS ↓9min, SE Sleep Diary:
days apart) least 3 practice other sleep PSWQ ↑3.6%, and SQ Treatment
Treatment group sessions, had disorders (e.g., ↑0.3 than control group WASO
was compared to competence sleep apnea, group at d = 0.58, SE
a waitlist control assessed by periodic limb posttreatment d = 0.52, and
group 2nd author, movement, No group SQ d = 0.75
and therapy narcolepsy) differences were at
Authors also
was – irregular sleep observed for posttreatment
assessed sleep

McCRAE ET AL.
supervised by schedule due daytime
and daytime
2nd author to shift work measures
functioning of a
– chronic illness
subset of
– persistent
participants not
anxiety or
complaining of
depression
insomnia
 c28
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SHORT-TERM AND GROUP TREATMENT APPROACHES
McCrae, 2 in-person – MBT 1st session: – mental – 13 women, 7 – significant med sleep diary (Sleep diaries) n/a overall large
et al. (2) sessions stimulus control, health men condition – MBT: SOL ↓25 effect size for
2 telephone sleep restriction counselor – age (m = 77.2 affecting sleep min, SE ↑16% treatment
sessions (∼50mins) – social ± 8.0) – major psy- (significantly group
Materials – 2nd session: worker chopathology greater than (Sleep

March 28, 2010

provided: wk book passive – provisionally – other sleep SHE) diaries)
& audio tape of relaxation licensed disorders – SHE:
– MBT: SOL
passive relaxation – 2 telephone counselor – MMSE ≤ 23
SOL ↓0 mins, SE d = 1.12,
provided follow-ups: – training was
↑6% SE d =
progress provided by
No intersession (clinical 2.12
review & McCrae
interval (sessions significance) – SHE:
troubleshooting during 2-day
were conducted 10 MBT, 3 SHE
– SHE initial workshop SOL d = 0.02,

9:44
on weekly basis) no longer met
session: sleep
insomnia criteria SE d = 0.99
education &
sleep hygiene

Char Count=
– 2nd session:
sleep education
– 2 telephone
follow-ups:
progress
review &
troubleshooting

319
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320
Table 1 Summary of Research Employing Brief Treatment Approaches for Insomnia (Continued )
#, Format of
sessions, &

March 28, 2010

length of
intersession Content of Therapist Exclusionary Durability of
Study interval sessions qualifications Population criteria Measures Results Effects Effect Size∗
Pallesen et al. 4 in-person – Sleep hygiene Not able to – 46 women, 9 – MMSE<25 sleep diary Sleep Diary: Follow-up was overall small
(12) sessions (∼30 and relaxation ascertain men – primary goal to life satisfaction Significant conducted 6mths to large effect
min) tape (SH+R): – age (m = 69.8 stop taking (13) differences post-intervention size for
No intersession – advice based on ± 6.53) hypnotics intervention log between Significant immediate
immediate and

9:44
interval (sessions standard sleep – participants differences at treatment
were conducted treatment with affective delayed treatment posttreatment group
on a weekly – relaxation tape and anxiety groups (no were maintained Sleep Diary:
basis) involved oral disorders, difference

Char Count=
at follow-up pre to post
instructions with patients who between difference
Immediate treatment groups)
components used hypnotics,
Treatment SH+R:
consisting of and those with SH+R:
groups:
restless legs SOL d = 0.57
progressive SOL ↓20 mins,
– Sleep hygiene mins, TST d
relaxation, syndrome were TST ↑26mins,
and relaxation = 0.50, SE d
passive focal included to SE↑7%
tape = 0.79
attention, and increase
– Sleep hygiene SH+SC: SH+SC:
active expiration. external validity
and stimulus SOL ↓31 mins, SOL d = 0.49
control Sleep hygiene and TST ↑30mins, mins, TST d
stimulus control SE↑12% = 0.39, SE d
Waitlist control (SH+SC): There were no = 0.89
– consisted of significant Sleep Diary:
sleep hygiene differences pre to
advice described between the follow-up
above immediate and difference
– stimulus control delayed treatment
consisted of 6 groups for SH+R:
standard daytime SOL d = 0.53
stimulus control measures mins, TST d
instructions = 0.69, SE d
= 1.00

McCRAE ET AL.
SH+SC:
SOL d = 0.52
mins, TST d
= 0.42, SE d
= 0.94
 c28
IHBK059-Sateia
SHORT-TERM AND GROUP TREATMENT APPROACHES
Riedel et al. 4 groups: Stimulus control – graduate – 11 women, 10 – current sleep diaries No significant Follow-up was overall small
(14) – stimulus control sessions: psychology men nonpharmaco- use of hypnotic improvement for conducted 8wks to large effect
with medication – consisted of students – age (m = 56.6 logical medication stimulus control after size for
withdrawal standard recom- – therapists ± 13.8) treatment for ESS participants from posttreatment stimulus
– stimulus control mendations were trained – individuals insomnia BDI pre to post Significant control

March 28, 2010

alone by first were included – alcohol use STAI-T Significantly less improvement for treatment
– medication Sleep medication close to stimulus control
author and a in the study daytime stimulus control Stimulus
withdrawal withdrawal bedtime compliance
supervising who had sleepiness for participants from control
alone program: – self-report of
faculty hypnotic- stimulus control pre to follow-up participants
– waitlist control – education on member dependent medical
short and participants at for TST, SE, and from pre to
– supervision insomnia and conditions posttreatment SQ follow-up
Those receiving long-term effects affecting sleep
was primary
stimulus control of sleep – other sleep Medicated Medicated
provided insomnia

9:44
met with therapist medication on disorders (e.g., stimulus control stimulus
through
for 2 one-hour sleep and side sleep apnea or participants: control
weekly
in-person effects meetings periodic limb – TST ↑33 mins, participants:
SE ↑6%, SQ – TST d =

Char Count=
sessions for – provided movement)
stimulus control instructions for ↑0.3 0.39, SE d
treatment gradual = 0.47, SQ
withdrawal from Nonmedicated d = 0.59
There was no stimulus control
intersession sleep medication
participants: Nonmedicated
interval (sessions – TST ↑60 mins, stimulus
were held on SE ↑14.5%, control
consecutive SQ ↑0.6 participants:
weeks)
The two groups Significantly less – TST d =
undergoing daytime 0.75, SE ↑
medication sleepiness for d = 1.23,
withdrawal stimulus control SQ d =
participated in a participants at 0.57
sleep medication follow-up
withdrawal
program (1
session)
(Continued)

321
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322
Table 1 Summary of Research Employing Brief Treatment Approaches for Insomnia (Continued )

March 28, 2010

#, Format of
sessions, &
length of
intersession Content of Therapist Exclusionary Durability of
Study interval sessions qualifications Population criteria Measures Results Effects Effect Size∗
Strom et al. Treatment Treatment 2 clinical – 71 women, 38 – young (<18yrs) sleep diary Sleep Diary: Treatment group Sleep Diary:
(15) duration consisted of sleep psychologists men – sleep apnea or HADS – greater (follow-up – pre/post

9:44
consisted of 5 restriction, stimulus – age (m = 44.1 related medication index pre/post conducted after improve-
consecutive wks control, information ± 12.0) self-reported DBAS improvement in 9mths) saw ment in
No intersession about sleep respiratory treatment TWT (↓55 improvements TWT d =

Char Count=
treatment hygiene, cognitive problems credibility mins), TST maintained over 0.79, TST d
intervals restructuring, – restless legs (↑34mins), and pretreatment for = 0.46, and
Two groups: information about syndrome SE (↑10%) for Sleep Diary: SE d =
Treatment group medication – depression or treatment – SE (↑10%), 0.71 for
(sleep withdrawal, and anxiety group TST (↑51min), treatment
management applied relaxation – sleep compared to TWT (↓47 min), group
program) and difficulties control group SQ (↑0.54)
– improvements Treatment
waitlist control explained by
in SOL, NWAK, Waitlist control group
physical
All information WASO, early group (follow-up (follow-up)
symptoms
was presented morning conducted 6mths improvements
– night-shift work
via the internet. awakening, after completing over
or regular
TIB, and SQ treatment): pretreatment
daytime sleep
were noted for for:
– previous or – SE improved
ongoing CBT both treatment – SE d =
compared to
for insomnia and control 0.86, TST d
pretreatment
– insomnia being group = 0.87,
(↑7%) and
a minor – control group TWT d =
problem also saw 0.82, SQ d
improvements = 1.39
Waitlist
control group

McCRAE ET AL.
for follow-up:
– SE
improved
compared
to
 c28
IHBK059-Sateia
SHORT-TERM AND GROUP TREATMENT APPROACHES
Strom et al. Questions, on TWT, TST, and posttreatment pretreatment
(15) questionnaires, SE (↑3%), TST d = 0.72 and
and diaries were – greater improved posttreatment
submitted through reduction of compared to d = 0.35 ,
the internet DBAS and pretreatment TST improved

March 28, 2010

Psychologists medication use (↑30min) and compared to
would prompt for treatment posttreatment pretreatment
participants to compared to (↑23min), TWT d = 0.57 and
complete their control group improved posttreatment
sleep diaries if compared to d = 0.46,
they were late to pretreatment (↓39 TWT
do so and also min) and improved
posttreatment compared to

9:44
responded to
questions (↓23 min), SOL pretreatment
improved d = 0.73 and
compared to posttreatment

Char Count=
pretreatment d = 0.51,
(↓12min), SQ SOL improved
improved compared to
compared to pretreatment
pretreatment d = 0.41, SQ
(↑0.64) improved
compared to
pretreatment
d = 1.77
Notes: ∗Effect Size Estimates represent Cohen’s d.
Abbreviations: BDI, Beck Depression Inventory (16); CES-D, Center for Epidemiological Studies Depression Scale (17); CQOLC, Caregiver Quality of Life Index-Cancer (18); DBAS, Dysfunctional
Beliefs and Attitudes about Sleep Scale (19); ESS, Epworth Sleepiness Scale (20); FSS, Fatigue Severity Scale (21); GDS, Geriatric Depression Scale (22); HADS, Hospital Anxiety and Depression
Scale (23); HRSA, Hamilton Rating Scale for Anxiety (24); HRSD, Hamilton Rating Scale for Depression (25); IIS, Insomnia Impact Scale (26); ISQ, Insomnia Symptom Questionnaire (27); MSLT,
Multiple Sleep Latency Test (28); POMS, Profile of Mood States (29); PSWQ, Penn State Worry Questionnaire (30); PSQI, Pittsburgh Sleep Quality Index (31); PSQI-A, PSQI addendum for PTSD
(32); SES, sleep related Self-Efficacy Scale (33); SII, Sleep Impairment Index (34); SSS, Stanford Sleepiness Scale (35); STAI, State-Trait Anxiety Inventory (36); SQAW, Sleep Questionnaire and
Assessment of Wakefulness (37);

323
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324 McCRAE ET AL.

sleep hygiene/education treatment (6). Participants in the ACBT group experienced decreased
wake time after sleep onset, improved sleep efficiency, and higher sleep quality ratings. The
authors also compared the two groups at a three-month follow-up period. The results indicate
the durability of ACBT intervention with the significant gains of the ACBT group maintained
over time.
Significant improvements in sleep were seen for college students diagnosed with insom-
nia using a three-session treatment approach (11). Treatment consisted of a 16-muscle group
progressive relaxation exercise. The group receiving the relaxation treatment showed signifi-
cantly better improvement at posttreatment compared to the waitlist control for the sleep diary
variables of wake time after sleep onset, sleep efficiency, and sleep quality.
A brief approach of two to four sessions was used to reduce sleep medication use and
improve insomnia among individuals with hypnotic dependent insomnia and primary insom-
nia (14). Three treatment groups (stimulus control with medication withdrawal, stimulus control
alone, medication withdrawal alone) were compared to a waitlist control. The results suggested
that while there was no significant improvement for the groups at posttreatment, follow-up
testing conducted eight weeks after treatment indicated significant improvement for both stim-
ulus control groups in terms of the sleep diary variables. The stimulus control with medication
withdrawal group experienced an increase in total sleep time, an increase of sleep efficiency, and
an increase in sleep quality. The nonmedicated stimulus control group experienced an increase
in total sleep time, an increase in sleep efficiency, and an increase in sleep quality. Additionally,
in terms of secondary outcome measures, the groups receiving stimulus control experienced
significantly less daytime sleepiness at posttreatment and follow-up.

Brief Approaches with post-traumatic stress disorder (PTSD) Patients and Caregivers
The applicability of brief cognitive behavioral intervention for insomnia to different populations
was demonstrated in two studies. A brief, one session, cognitive behavioral intervention was
developed to treat individuals diagnosed with post-traumatic stress disorder (PTSD) and poor
sleep (9). The cognitive behavioral intervention included a combination of imagery rehearsal
therapy (IRT), CBT to reduce posttraumatic nightmares, and CBT for insomnia. The results sug-
gested small (p<0.10) improvements in self-reported sleep quality as measured by the Pittsburgh
sleep quality index (PSQI) (31) and marked improvements in PTSD symptoms (9).
Second, the effectiveness of a brief CBT intervention for caregivers was demonstrated
in a study (3) which examined the effectiveness of a two-session caregiver sleep intervention
(CASI) (3). The results indicated that compared to controls, the participants who received the
CASI treatment showed significantly greater improvements in sleep-onset latency as measured
by sleep diaries compared to the baseline period. Additionally, follow-up testing revealed
significantly lower sleep-onset latency and higher total sleep time as measured by actigraphy
for those receiving the CASI treatment.

Brief Approaches Delivered Using Alternate Formats

The utility of an internet-based brief approach for the treatment of insomnia was evaluated
during a five-week period of online treatment that consisted of sleep restriction, stimulus control,
sleep hygiene, cognitive restructuring, information about medication withdrawal, and applied
relaxation (15). All information was presented via the internet, and two clinical psychologists
monitored completion of sleep diaries and responded to participant questions. At posttreatment,
the treatment group saw greater improvements in sleep diary variables of total wake time, total
sleep time, and sleep efficiency. Additionally, the treatment group had greater improvement of
their dysfunctional beliefs about sleep and their medication use compared to the control group.
The sleep diary improvements were maintained over the nine-month follow-up period.

Dose-Response Effects of Brief Approaches

A unique approach has been employed to examine the differential effects of increasing the
number of treatment sessions using a ‘dose-response’ study (5). The benefit of this approach
is the ability to isolate the effect of treatment length and control for extraneous factors (e.g.,
therapist qualifications, content of treatment, setting). Treatments consisting of one, two, four,
and eight sessions were compared in terms of short and long-term outcomes. All treatment
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SHORT-TERM AND GROUP TREATMENT APPROACHES 325

patients received one in-person CBT session lasting 45 to 60 minutes. The session consisted
of sleep education, stimulus control, and sleep restriction. Additional treatment for patients
receiving more than one session consisted of in-person 15 to 30 minute sessions designed to
troubleshoot and modify the time-in-bed prescription as needed. Results indicated that the
one and four-session CBT dose resulted in significant pre- to post-treatment improvement in
actigraphy total wake time as well as several sleep diary variables, including sleep efficiency,
wake time after sleep onset, and total wake time. Additionally, the four-session CBT dose
resulted in significant improvement in actigraphy sleep efficiency.
In terms of the durability of outcomes at a six month follow-up period, the participants
receiving the one, two, and four session dose of CBT showed significant improvements com-
pared to baseline measures for sleep diary sleep efficiency, total sleep time, and total wake time.
Additionally, the four-session CBT dose saw continued improvement in actigraphy sleep effi-
ciency and total wake time. As mentioned above, the sessions subsequent to the first treatment
session were primarily ‘follow-up’ sessions designed to troubleshoot any treatment difficulties.
In summary, while improvements were seen posttreatment with the one and four dose
treatments and at follow-up with the one, two, and four dose treatments, it appears that the
four dose treatment demonstrated the greatest improvements on both sleep diary and actig-
raphy measures of sleep. Importantly, the four-session dose consisted of bi-weekly delivery of
treatments (compared to a three week intersession interval for the group receiving two sessions
and no intersession interval for the group receiving eight sessions). The authors hypothesize
that scheduling session bi-weekly may provide sufficient time for the patients to independently
develop behavioral changes while still receiving support.

Brief Approaches–Integration of Findings

Overall, the brief treatment approaches reviewed herein exhibited effect sizes ranging primarily
from medium to large effects (Table 1). The effect sizes of brief treatments are comparable
to the effect sizes for behavioral treatments for insomnia that are of a longer length (40,41)
suggesting that treatments of a shorter length can be as effective as traditional behavioral
approaches for treating insomnia. Considering that a benefit of briefer approaches is to increase
the availability of treatment, it is of interest whether briefer approaches can be effectively
delivered by nondoctoral level practitioners. Brief treatments were provided by both doctoral
level (4–6,9,15,42) and non-doctoral level practitioners (2,3,8,10,11,14). For the studies utilizing
non-doctoral level practitioners, training and supervision was typically provided by doctoral
level practitioners.
In terms of treatment length, treatments varying from one to five sessions were found
to be efficacious. The one study (5) that compared varying session lengths within the same
experiment found that a four-session treatment produced the best outcomes. In the studies that
examined one length of treatment (e.g., two sessions) it is possible that although significant
improvements were noted for the treatment length, more or fewer sessions may also have
resulted in comparable or even greater improvements. Interestingly, Edinger and colleagues
(2007) commented that it is not only the frequency of treatments that may impact sleep outcomes
but also the duration of intervals between sessions that may play a role in treatment effectiveness.
Overall, the majority of brief approaches were conducted on a weekly or bi-weekly basis.
The mean ages of participants examined in the brief behavioral treatment studies ranged
from 21 to 77 years suggesting that brief treatments are applicable to both adults and older adults.
A variety of exclusionary criteria were employed in the studies. Stringent criteria resulted in
the inclusion of primarily physically and mentally healthy individuals who were not suffering
from a sleep disorder other than insomnia in the majority of studies while a minority of studies
included participants with physical and psychiatric complaints. It appears that specialized brief
behavioral approaches can be helpful for treating insomnia in specific populations (e.g., those
diagnosed with PTSD and caregivers). It is not yet clear how effective brief approaches are with
the typical primary care patient diagnosed with medical and psychiatric comorbidities.
Interestingly, the majority of brief approaches were uniform in the content of their CBT
sessions. The sessions were multicomponent and typically consisted of sleep education, sleep
hygiene, stimulus control, and sleep restriction. Two studies (5,43) also included cognitive
restructuring in the treatment regimen.
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326 McCRAE ET AL.

Brief Approaches – Future Directions

Despite the existence of a body of research examining brief CBT approaches, there are a number
of areas that could benefit from future research. First, the majority of studies saw improvement
on self-report measures. Few studies employed both objective and subjective measures. It would
be interesting to see if the effects of brief behavioral treatments hold over both subjective
and objective measures. Second, it would be worthwhile to vary the inter-session time period
in future studies in order to examine the impact of duration between sessions in addition to
examining simply the total number of sessions used. Third, it would be interesting to examine
the benefits of additional cognitive approaches (e.g., cognitive restructuring) within a brief
model. Fourth, the participants enrolled into the studies were primarily homogenous. It would
be helpful to be able to generalize findings regarding brief approaches to individuals with
more diverse cultural backgrounds and physical/mental diagnoses. Finally, sessions ranging
in number from one to five were found to create significant improvements in sleep. In order to
conclusively determine the optimum number of sessions, it would be helpful for more studies
to employ a dose-response methodology in order to examine the differential effects of varying
numbers of sessions on sleep and sleep-related outcomes.

Conclusions
Examination of the literature investigating brief behavioral approaches to treating insomnia
suggests that treatment sessions ranging from one to five can be effective for the treatment
of insomnia. While the majority of studies relied on subjective measures of sleep, significant
improvements were seen with both subjective and objective measures of sleep (3,5,7,42). In
addition to significant posttreatment improvements in sleep, brief behavioral approaches appear
to exhibit durability up to six to eight weeks (9,14), three (6,7,10), four (3), six (5,12,42), seven
(43), and nine (15) months after treatment. Consequently, it appears that brief approaches are
efficacious in the short and longer term (up to nine months) for individuals ranging in age from
21 to 77 years of age.

GROUP INTERVENTION
The ability to simultaneously treat the insomnia symptoms of multiple individuals is an intrigu-
ing concept. A growing number of research studies have employed group treatment approaches.
Although the majority of these studies appear to have used a group approach due to the cost
effectiveness of treating multiple patients at the same time, a few studies have explicitly exam-
ined the impact of different aspects of the ‘group process’ in the treatment of insomnia.

General Overview of the Elements of Group Treatment

One of the most substantial and in-depth accounts of group treatment is found in the classic
work by Yalom (1995), The Theory and Practice of Group Psychotherapy. He described eleven
therapeutic factors of group therapy that are associated with change in behavior (Table 2).

Table 2 Therapeutic Factors of Group Psychotherapy

1. Installation of hopea
2. Universalitya
3. Imparting informationa
4. Altruism
5. The corrective recapitulation of the primary family group
6. The development of socializing techniques
7. Imitative behaviora
8. Interpersonal learninga
9. Cohesiveness
10. Catharsisa
11. Existential factors

a
Factors that could be employed in the group treatment of insomnia.
Source: From Ref. 44.
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SHORT-TERM AND GROUP TREATMENT APPROACHES 327

Table 3 Factors Associated with Group Satisfaction

1. The group meets goals in therapy

2. Satisfaction gained from relationships with other group members
3. Satisfaction gained from participation in the group
4. Satisfaction gained from the group by means of the outside world

Source: Adapted from Ref. 44.

In conjunction with these factors, Yalom (1995) also states that group treatment approaches must
be inherently distinct from individual approaches to change. These groups should encompass
more than a simple increase in the number of patients present. Group treatment should be
based on the group, not on the individualized treatment approach. According to Yalom, in
group treatment approaches “it is the group that is the agent of change” ((44), p. 109).
In this vein of reasoning, Yalom (1995) has proposed four main factors considered to be
essential to patient satisfaction with group treatment (Table 3). These factors generally include
the group meeting the patient’s needs in alleviating symptoms and the patient’s interaction
in the group and with group members. While traditional cognitive behavioral treatments of
insomnia have proven very efficacious in symptom reduction, the group implementation of such
cognitive behavioral treatments seems to be lacking a focus on the group interaction factors.
Only a handful of studies employing a group treatment approach have examined aspects of the
group interaction.

Group Treatment with a Focus on Group Interaction Factors

Kupych-Woloshyn and colleagues (1993) were the first to describe a group approach to the treat-
ment of insomnia (45). Their approach was based on interpersonal and cognitive-behavioral
approaches and integrated group interaction as a mean of therapeutic change with didactic and
cognitive-behavioral techniques. Unfortunately, the authors did not present data on the efficacy
of their approach. Nonetheless, the theoretical blend of interpersonal and cognitive-behavioral
processes makes their model truly unique. They presented seven primary principles that under-
lie the group treatment of insomnia. These principles are presented in Table 4. However, as
described later, the majority of research has opted to focus specifically on the implementation
of symptom specific cognitive behavioral techniques.
Only one study was found that examined group therapy process variables in cogni-
tive behavioral treatment for insomnia (46). This intervention, based on interpersonal theory,
assessed the impact of patient expectations and perceived therapeutic alliance on sleep out-
comes. They found that both early patient expectations and the perceived therapeutic alliance
were predictive of sleep outcomes and also differentiated between patients who dropped out
of the treatment and those that remained. Patients who had low pretreatment expectations and
perceived their therapists as more affiliative had less nightly total wake time; patients who per-
ceived their therapist as more confrontative were less satisfied with treatment and were more
likely to drop out of treatment (46). The results suggest the importance of the installation of
hope in early sessions and the need for therapists to be nonjudgmental and to strive to form a
positive alliance with group members.

Table 4 Principles Proposed Essential to the Group Treatment of Insomnia

1. Normalizing insomnia
2. Flexibility to meet the individual needs and expectation of members
3. Individual differences are recognized and discussed
4. Change is possible following education, and identification and insight within a supportive environment
5. Group validation and acceptance allows individuals to move beyond suffering
6. Individual presentation allows for multiple hypotheses and explanations for sleep disturbances
7. Secure, structured group environments facilitate self-disclosure

Source: Adapted from Ref. 45.

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328 McCRAE ET AL.

Patient perceived mechanisms of change in the group treatment of insomnia is a difficult

variable to assess. However, in comparing the effectiveness of group and individual treatment
approaches, it was found that individuals treated in the group format rated their interactions
with fellow patients with insomnia as the third most helpful aspect of treatment (47). Only
behavioral techniques (sleep restriction and stimulus control) and cognitive restructuring were
rated as more helpful. This patient interaction was rated higher than relaxation training. This
finding provides support for the stance that the group treatment of insomnia is uniquely different
from individualized treatments. However, how to best capitalize on these differences has yet to
be answered.

Group Treatment Focusing on Insomnia Symptoms

Community Recruited Volunteers

Traditional individual cognitive behavioral treatment of insomnia has been compared to group
cognitive behavioral treatment and telephone consultation (48). In this investigation, all indi-
viduals received cognitive behavioral treatment of insomnia that included stimulus control,
sleep restriction, cognitive therapy, and sleep hygiene. Treatment arms only differed in the
modality of treatment delivery and not in treatment content. Results indicated that from pre-
to post-treatment all groups significantly improved their total wake time, sleep efficiency, wake
time after sleep onset, sleep efficiency, and sleep quality rating. Total sleep time continued to
improve from posttreatment to three-month follow-up. However, no improvements were seen
from three-month follow-up to six-month follow-up. Promisingly, 9 out of the 16 group patients
(82%) had sleep efficiencies above 80% at six-month follow-up. Importantly, the three treatment
groups did not differ significantly in their sleep at any time point, suggesting the comparable
nature of the treatment conditions (48).
In patients representing mild cases of insomnia, the effectiveness of relaxation, single-
item desensitization, and the combination of relaxation and desensitization, performed in small
groups, produced relatively equivocal gains in sleep (49). Pre- to post-treatment improvements
in sleep-onset latency and rated difficulty in falling asleep and number of awakenings per
night were observed across all groups. A case-by-case examination of the data suggested that
the combination therapy may be the most useful group treatment for more severe cases of
insomnia (49).
The usefulness of group cognitive behavioral treatment of insomnia as an early inter-
vention for insomnia was examined in subjects who had experienced the onset of insomnia
within the previous 3 to 12 months (50). Groups of 6 to 10 patients underwent six weekly
sessions of group treatment that included problem solving, relaxation, worry time, distraction,
paradoxical intention, observation exercise, sleep hygiene, stimulus control, sleep restriction,
cognitive therapy, stress management, sleep beliefs, sleep medications education, coping, and
sleep management. Compared to a control group, the group condition demonstrated signif-
icant improvements in many self-report sleep variables from baseline to one-year follow-up
(i.e., sleep-onset latency, wake time after sleep onset, total sleep time, sleep quality, and sleep
efficiency). In addition, the group condition produced more clinically significant gains than the
control group at one-year follow-up.
The relationship between group adherence and posttreatment sleep outcomes has been
examined in insomnia outpatients (51). Groups of five to six patients underwent seven weekly
sessions of cognitive behavioral treatment of insomnia that included sleep hygiene, stimulus
control, medication withdrawal, relaxation, sleep restriction, cognitive therapy, stress man-
agement, and problem solving. Significant pre- to post-treatment improvements were seen
across numerous sleep variables. Interestingly, therapist-rated adherence was the only signifi-
cant adherence predictor of outcome variables in the group treatment of insomnia. No follow-up
data were presented.

Physician/Clinically Referred Patients

Durability of individual CBT-I has been well-established. Similarly, the long-term effectiveness
of short-term group cognitive behavioral treatment of insomnia has begun to receive empir-
ical support. For example, 20 physician-referred insomnia patients treated with six weekly
c28 IHBK059-Sateia March 28, 2010 9:44 Char Count=

SHORT-TERM AND GROUP TREATMENT APPROACHES 329

sessions of multicomponent group treatment demonstrated significant pre- to post-treatment

improvements in total sleep time and sleep efficiency These treatment-induced gains were well
maintained at three-year follow-up (52). The immediate and long-term effectiveness of nurse-
led group cognitive behavioral treatment of insomnia in general practice patients, as compared
to treatment as usual, has also been examined (53). Groups consisted of four to six patients,
met for five weekly sessions, and employed stimulus control, sleep restriction, and cognitive
therapy. Significant pre- to post-treatment improvements in self-reported sleep for the group
condition were observed for sleep onset latency and sleep efficiency. The significant group dif-
ferences were not maintained at six-month follow-up. However, PSQI measured global sleep
disturbance was significantly reduced for the group condition compared to the treatment as
usual condition at post-treatment and six-month follow-up (53).
The utility of group cognitive behavioral treatment of insomnia in routine clinical settings
has also began to receive empirical support (54). It has been reported that groups of four to eight
patients who underwent 11 weekly multicomponent sessions of CBT-I displayed significant
improvements in overall sleep quality. Self-reported improvements in sleep at post-treatment
included: total sleep time, sleep efficiency, and number of awakenings. No improvements were
seen on PSG measures of sleep. Gains in self-reported sleep were maintained at 3- and 12-month
follow-up.
Existing data suggest that group and individualized cognitive behavioral treatment
of insomnia may produce comparable outcomes. A comparison of group and individual
CBT-I found significant improvement in measures of sleep onset, maintenance and efficiency
at post-treatment and nine-month follow-up (47). No statistically significant differences were
seen as a function of treatment modality. However, when the clinical significance of improve-
ments in sleep was assessed, only 16% of patients receiving group treatment compared to 34%
of individually treated patients produced clinically significant gains in sleep, suggesting that
individualized CBT-I may produce greater overall gains. It appears the equivalence of treatment
modalities in terms of clinical significance needs further investigation.
The above referenced research all suggest the long-term effectiveness of multicomponent
CBT-I. However, predictors of patient-perceived improvements following group treatment of
insomnia are less well known. To examine potential predictors of patient-perceived improve-
ments following group cognitive behavioral treatment of insomnia, groups of five to six patients
met weekly for six sessions and received a multicomponent group CBT-I. Perceived improve-
ment was assessed with the clinical global improvement scale (CGI). Significant improvements
from pre- to post-treatment were found for sleep quality, sleep efficiency, sleep duration, and
sleep-onset latency. At post-treatment, 41.4% of patients met the criteria for clinically significant
improvements. Results indicated that sleep quality and sleep duration were the best predictors
of perceived improvements resulting from group treatment of insomnia (55).

Special Populations
The effectiveness of group CBT-I has been assessed in numerous special populations. For exam-
ple, the utility of group cognitive behavioral treatment of insomnia for improving sleep and
preventing recidivism in adolescents with substance abuse problems has been studied (56).
Adolescents (between the age of 13 and 19) underwent a multicomponent group treatment and
stress reduction administration. Importantly, only 42% of the sample attended at least four treat-
ment sessions. Sleep improvements in individuals that attended at least four treatment sessions
were found for sleep efficiency, sleep-onset latency, number of awakenings, total sleep time,
and sleep quality. These individuals also strongly endorsed the program at post-treatment. All
adolescents increased their substance use during the course of treatment. The authors suggest
that the effects of improved sleep on substance abuse in adolescents may manifest over a longer
period of time, but group cognitive behavioral treatment of insomnia did produce improved
sleep for the adolescents who completed treatment.
The effectiveness of group intervention to treat insomnia secondary to chronic pain has
been examined via seven weekly sessions of multicomponent CBT-I. Results indicated sig-
nificant improvements in sleep (by diary and actigraphy) from pre- to post-treatment for the
treated patients compared to controls for sleep onset latency, sleep efficiency, wake time after
c28 IHBK059-Sateia March 28, 2010 9:44 Char Count=

330 McCRAE ET AL.

sleep onset, and PSQI Quality. These reductions were maintained at three-month follow-up. No
significant improvements in pain, depression, or medications usage were noted (57).
Cancer patients with insomnia were treated with stimulus control, relaxation, sleep edu-
cation, worry time, and cognitive restructuring in groups for seven weeks and found to have
significant improvements two weeks following treatment for: number of awakenings, wake time
after sleep onset, total sleep time, sleep efficiency, sleep quality, and SII (58). Importantly, no
participants continued to meet the diagnostic criteria for insomnia at two weeks post-treatment.
Likewise, the effectiveness of group cognitive behavioral treatment of insomnia for indi-
viduals with a “serious mental illness” has been investigated. Multicomponent CBT-I was
delivered over 10 weekly sessions. From pre- to post-treatment, patients rated their sleep as
significantly better (via the SII.). However, no changes in self-reported sleep parameters were
noted. This is suspected to be largely due to the small (n = 10) sample size (59).
Short-term, group cognitive behavioral treatment of insomnia for “severely mentally ill
patients” has been examined (60). Treatment was delivered over two weekly sessions and
components used include: sleep education, stimulus control, sleep restriction, and sleep hygiene.
From pre- to post-treatment, patients rated their sleep as significantly improved in terms of sleep
onset latency and wake time after sleep onset. These improvements were maintained at three-
month follow-up.

Group Treatment–Integration of Findings

The growing numbers of empirical research studies that have employed a group-based approach
for the treatment of insomnia have varied widely in their approach to the group treatment of
insomnia (Table 5 for specific details of each empirical investigation reviewed). In general, the
group treatment of insomnia has been successfully employed, based on subjective reports of
improved sleep, with a variety of populations, including community recruited volunteers (48–
51,61), physician/clinically referred (46,47,52–54), adolescents with substance abuse problems
(56), patients with chronic pain (57), patients with cancer (58), and patients with a comorbid
mental illness (59,60).
Group sizes have ranged from two (56) to as many as fifteen patients (46). Similarly,
treatment length has varied from a minimum of three weekly sessions (49) to a maximum of
eleven, 90 minute weekly sessions (54). Patients as young as 13 years (56) and as old as 85 years
(46) have been treated in a group format. Typically, group treatment has been conducted by
doctoral students in clinical psychology graduate programs (49,56–58). However, treatment has
also been successfully implemented by staff psychologists (46,59) and primary care nurses (53).
In situations where the individual delivering treatment was not a doctoral-level practitioner,
training and supervision was provided by a doctoral-level psychologist.
Although the specific content of the various group treatments have also varied, all the
group treatments reported herein have contained one or more components of traditional cog-
nitive behavioral treatment of insomnia as typically employed in individual treatment contexts
(i.e., relaxation, sleep hygiene, stimulus control, sleep restriction, cognitive restructuring). Once
again, for a complete list of group treatment approaches, please refer to Table 5.
Overall, these group approaches to the implementation of individualized cognitive behav-
ioral treatment of insomnia have shown to be both effective (52–54) and efficacous (48–51,55–
61) in improving sleep. All of the studies depicted in Table 5 demonstrated an improvement
in subjective sleep characteristics following treatment. The effect sizes of the group treatment
approaches reviewed herein ranged from small to large (Table 5) and are comparable to the
effect sizes for behavioral treatments for insomnia that are individually administered (40,41).
Importantly, many have shown a lasting effect of the treatment many months post-treatment.
This has previously been shown in meta-analytic studies of treatment effects on insomnia symp-
toms. Murtagh and Greenwood (1995) performed a meta-analysis of the effects of psychological
treatment on insomnia. They also examined the potential effects of several moderator variables
on the treatment effect sizes. These authors found that all psychological treatment approaches
produce substantial effect sizes and that the specific type of treatment approach (group vs.
individual) did not result in different effect sizes (41). The equality of effects across various
modalities of treatment were further demonstrated in direct comparisons of studies (47,48).
Overall, the results of these meta-analytic studies as well as the studies reviewed herein suggest
(text continues on page 338.)
 c28
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SHORT-TERM AND GROUP TREATMENT APPROACHES
Table 5 Summary of Research Employing Group Treatment for Insomnia

March 28, 2010

Patient Exclusionary Treatment Treatment
Source sample critieria Group size length Therapist components Measures Results Durability Effect Sizea
Backhaus, 20 Physician Co-morbid 6–8 patients 6 weekly Experienced Progressive PSQI, BDI, Significant pre 3-yr follow-up Overall
et al. (52). referred, psychiatric sessions/ psychologist muscle and STAI to post for TST (+83 small/medium/large
maen age = condition, 90 min each relaxation, improvements min) and SE effect sizes PSQI:
43 yr (SD = sleep-relevant session cognitive for SOL (-36.3 (+20) Pre/post SOL d = 0.592,
12.2 yr) somatic relaxation, min), TST TST d = 0.620, SE d =

9:44
disorder stimulus (+53 min), SE 1.051 3-mo follow-up
control (+18%), and SOL d = 0.673, TST d =
(modified), BDI (-2.5 0.837 , SE d = 1.222
1-yr follow-up SOL d =

Char Count=
thought points)
stopping, and 0.529, TST d = 0.932,
cognitive SE d = 1.134 3-yr
restructuring followp-up SOL d =
0.366, TST d = 0.826,
SE d = 0.957

Bastien, et 45 Presence of a 4–6 patients 8 weekly Certified Stimulus SD, ISI, Significant pre 82% had SE Overall medium/large
al. (48). Community- sleep disorder sessions/ clinical control, sleep DBAS, BDI, to post above 80% at effect sizes
recruited other than 90 min each psychologists restriction, and BAI improvements 6 mo follow-up Group condition
volunteers, insomnia, session and doctoral cognitive for TWT (+64 Sleep diary:
mean age = presence of students in therapy, and min), SE Pre/post TWT d = 1.346,
41.8 yr (SD = an Axis I psychology sleep hygiene (+11%), SE d = 1.193, WASO d
9.9 yr) disorder, WASO (-31 = .764, SQR d = .965
sleep min), SQR 3-moh follow-up TWT
disturbance (+6 points), d = 1.088, SE d =
due to ISI (-11 0.942, WASO d = 0.605,
substance points), DBAS SQR d = 1.206 6-mo
use, use of (-26 points), follow-up TWT d =
hypnotics, BDI (-8 0.890, SE d = 0.477,
current points), and WASO d = 0.662, SQR
involvement in BAI (-6 points) d = 1.033
psychological
treatment
(Continued)

331
 c28
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Table 5 Summary of Research Employing Group Treatment for Insomnia (Continued )

332
Patient Exclusionary Treatment Treatment
Source sample critieria Group size length Therapist components Measures Results Durability Effect Sizea
Biancosino, et 36 Insomnia No sleep Not reported 2 weekly Not reported Sleep SD, SWAI Significant pre Improvements Overall small effect sizes
al. (60) patients with problem, sessions/ 60 educations, to post maintained at Sleep diary: Pre/post
co-morbid mental min each stimulus improvements 3 mo SOL d = 0.271, WASO d

March 28, 2010

mental illness, retardation session control, sleep for SOL (-10.3 = 0.122 3-mo follow-up
mean age = hygiene, and min) and SOL d = 0.217, WASO d
47.4 yr (SD = sleep WASO (-4.5 = .094
12.6 yr, range restriction min)
= 21–69 yr)
Bootzin & 55 No complaint 2–6 patients 6 weekly Two advanced Stimulus SD, SD: SE Decreased Overall large effect sizes
Stevens (56). Adolescents of sleep sessions with graduate control, bright actigraphy, (+8%), SOL drug use at Sleep diary: Pre/post SE

9:44
completed disturbance or a week break students light, sleep PSWQ, ESS, (-19 min), 12-mo d = 1.593, SOL d =
drug abuse daytime between hygiene, GMHI, and NWAK (-.88 follow-up 1.173, NWAK d = 1.596,
counseling, impairment, session 5 and cognitive drug use awakenings), TST d = .944, SQR d =

Char Count=
mean age = not 6/ 90 min therapy, and TST (+61 1.628
16.13 yr (SD completing or each session Mindfulness- min), and
= 1.215 yr, recently Based Stress SQR (+.76
range = completed Reduction points). No
13–19 yr) substance actigraphy
abuse improvements
treatment
Borkovec, et 24 Less than 30 4 patients 3 weekly Clinical Relaxation Daily ques- Posttreatment No follow-up Not enough information
al. (49). Community- min SOL, use sessions graduate alone, desen- tionnaires improvements provided.
recruited of drugs, students sitization with in SOL (-16
volunteers, no current relaxation, min) and rated
age treatment desensitiza- difficulty in
information tion without falling asleep
reported relaxation and NWAK
Currie, et al. 60 Patients Have 5–7 patients 7 weekly Doctoral Education, SD and SD: SOL (-27 Maintained at Overall medium/large
(57). with fibromyalgia, sessions/ 2 students or sleep actigraphy, min), SE 3-mo effect sizes
co-morbid no sleep hours each interns in restriction, pain, (+13%), follow-up Group vs wait list
insomnia and complaint, session clinical stimulus emotional WASO (-50 Sleep diary:
chronic pain, over the age psychology control, distress, and min), and Posttreatment SOL d =
mean age = of 60, have relaxation medication PSQI Quality .735, SE d = 1.006,
45 yr (SD = 8 major medical training, usage (-5 points) WASO d = .925 PSQI:

McCRAE ET AL.
yr, range = and cognitive SQR d = 1.130 3-mo
29–59 yr) psychiatric restructuring, follow-up
conditions, and sleep Sleep diary: SOL d =
not willing to hygiene 0.646, SE d = 0.962,
undergo WASO d = 0.830 PSQI:
randomization SQR d = 1.534
 c28
IHBK059-Sateia
↓ TWT, ↓

SHORT-TERM AND GROUP TREATMENT APPROACHES

Constantino, 86 Physician None 10–15 7 weekly Licensed Sleep SD, ISI, No follow-up Overall large effect sizes
et al. (46). referred, provided patients sessions with clinical education, Treatment Daytime Pre/post Sleep diary:
mean age = the final 2 psychologists relaxation, Satisfaction, interference, TWT d = .718
48.95 yr (SD sessions sleep Patient patient
= 15.19 yr, occurring restriction, Expectations, expectations

March 28, 2010

range = biweekly/ stimulus Group and
19–85 yr) 90 min per control, Therapy therapeutic
session cognitive Session alliance are
restructuring Report important
predictors of
dropout and
satisfaction

9:44
Davidson, et 12 Cancer Currently 4–6 patients 7 weekly Doctoral Stimulus SD, SII, and NWAK (-.72 No follow-up Overall large effect sizes
al. (58). patients with receiving sessions with students in control, HADS awakenings), Pre/post Sleep diary:
insomnia, cancer four weeks clinical relaxation WASO (-31 NWAK d = 1.041,
mean age = treatment (or between psychology training, sleep min), TST WASO d = 1.557, TST

Char Count=
54.7 yr (SD = within 1 mo to session 5 and education, (+35 min), SE d = .559, SE d = 1.899,
10.4 yr) baseline), 6/ 60 – 90 min ‘worry time’, (+16%), SQR SQR d = 1.48
suspicion of a each session and cognitive (+.9 points),
sleep disorder restructuring and SII (-11
other than points)
insomnia,
medical or
psychiatric
disorder
effecting
sleep, and
medication
(hypnotics,
prednisone,
dexametha-
sone,
opioids)
(Continued)

333
 c28
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334

March 28, 2010

Table 5 Summary of Research Employing Group Treatment for Insomnia (Continued )
Patient Exclusionary Treatment Treatment
Source sample critieria Group size length Therapist components Measures Results Durability Effect Sizea

9:44
Dopke, et 11 Insomnia None Unknown 10 weekly Staff clinical Sleep SD and SII Increased No follow-up Overall small effect sizes
al. (59). patients with sessions/ 50 psychologist education, sleep quality Pre/post
comorbid min each and doctoral effects of via SII. No Sleep diary:

Char Count=
mental illness, session student substances, changes in SOL d = .320, WASO
mean age = medical SD. d = .170
45.6 yr (SD = conditions,
9.85 yr) psychiatric
conditions, life
circum-
stances, and
sleep habits
on sleep,
stimulus
control and
sleep
restriction,
and physical,
cognitive, and
behavioral
relaxation
Espie, et 201 General Deteriorating 4–6 patients 5 weekly Community Stimulus SD, SOL (-23.3 SD not Overall medium effect
al. (53). practice health or sessions/ 60 nurses based control, sleep actigraphy, min) and SE maintained at sizes Group condition
patients with dementia, min per in primary restriction, and PSQI (+9%) and 6-mo Sleep diary: Pre/post
insomnia, incapacitating session care teams and cognitive improved follow-up, SOL d = .497, SE d =
mean age =

McCRAE ET AL.
pain or illness, therapy PSQI PSQI .522 6-mo follow-up SOL
54.2 yr (SD = untreated maintained d = 0.391, SE d = 0.417
14.9 yr) mental health
problems,
other sleep
disorders
 c28
IHBK059-Sateia
Jansson & 136 Not fulfill the 6–10 patients 6 weekly Certified Problems

SHORT-TERM AND GROUP TREATMENT APPROACHES

SD, DBAS, SOL (-24 Maintained at Overall small/medium
Linton Community- diagnostic sessions with cognitive- solving, and HADS min), WASO 1-yr effect sizes
(50). recruited requirements a booster behavioral relaxation, (-66 min), TST Group vs. control
volunteers, for insomnia, session two therapists worry time, (+60 min), Sleep diary: 1-yr
mean age = not of working mo following distraction, SQR (-1.3 follow-up SOL d = .610,

March 28, 2010

49.5 yr (SD = age (16 – 65 session 6/ 2 paradoxical points), and WASO d = .386, TST
11 yr) yr old) hours each intention, SE (+13%). d = .272, SQR d = .543,
session observation Improved SE d = .427
exercise, anxiety HADS
sleep hygiene,
stimulus
control, sleep
restriction,

9:44
cognitive
therapy, stress
management,

Char Count=
sleep beliefs,
sleep
medications,
coping, and
sleep
management
Schramm, 28 Physician Insomnia 4–8 patients 11 weekly Cognitive- Behavior SD, PSQI, Significant PSQI Overall small/medium
et al. (54). referred, “secondary” sessions/ behavioral analysis, and PSG improvements maintained at effect sizes
mean age = to psychiatric 90 min each therapist and relaxation, in overall 3- and 12-mo Sleep diary:
47.5 yr (SD = or medical session graduate sleep sleep quality follow-up. Pre/post TST d = .305,
13.5 yr) conditions, student in education, (PSQI). TST SE d = .620, NWAK
sleep disorder clinical sleep (+28 min), SE d = .282
other than psychology restriction, (+10%), and
insomnia stimulus NWAK (-.28
control, awakenings).
cognitive No PSG
restructuring, improvement.
stress-
management,
problem
solving, and
increasing
daytime
activities
(Continued)

335
 c28
IHBK059-Sateia
336

March 28, 2010

9:44
Table 5 Summary of Research Employing Group Treatment for Insomnia (Continued )

Char Count=
Patient Exclusionary Treatment Treatment
Source sample critieria Group size length Therapist components Measures Results Durability Effect Sizea
Verbeek, 40 Clinically Psychopathology 5–7 patients 6 weekly Unknown Psychoeducation, SD, DBAS, Improvements Maintained at Overall
et al. (47). referred (depression or sessions/ 2 stimulus control, and SII at post- 9-mo follow up small/medium/large
patients with anxiety, refusal of hor and 30 sleep hygiene, treatment effect sizes Sleep
chronic group treatment, min each sleep restriction, were seen for diary: Pre/post
insomnia, regular hypnotic session cognitive SOL, WASO, SOL d = .610,
mean age = use restructuring, and TST, and SE TST d = .310, SE
43.68 yr (SD relaxation d = 1.136, WAS0
= 10.10 yr) d = .513 9-mo
follow-up SOL
d = 0.567, TST
d = 0.467, SE
d = 0.941, WAS0
d = 360
Vincent & 50 Shift work, sleep 5–6 patients 7 weekly Staff Sleep hygiene, SD, PSQI, SOL (-20 No follow-up Overall large
Hameed Community- disorder other sessions/ psychologist stimulus control, DBAS, and ISI min), TST effect sizes
(51). recruited than insomnia, 90 min each medication (+54 min), SE Sleep diary:
volunteers brain injury, session withdrawal, (+6%), DBAS Pre/post TST
and bipolar disorder, relaxation, sleep (-19 points), d = .833

McCRAE ET AL.
respirologist schizophrenia, restriction, PSQI (-4.48
referred serious medical cognitive therapy, points), and
patients, condition stress ISI (-6.6
mean age = management, points).
51.4 yr (SD = and problem
11.4 yr) solving
 c28
IHBK059-Sateia
SHORT-TERM AND GROUP TREATMENT APPROACHES
Vincent & 43 Shift work, sleep 5–7 patients 6 weekly Psychologist Sleep hygiene, SD and SII No sleep data No follow-up Not applicable
Lionberg Community- disorder other sessions and doctoral stimulus control, reported
(61). recruited than insomnia, student medication
volunteers, brain injury, withdrawal,
mean age = bipolar disorder, relaxation, sleep

March 28, 2010

51.33 yr (SD schizophrenia, restriction, and
= 12.37 yr) serious medical cognitive therapy
condition,
concurrent or
prior CBTi
Vincent, et 70 Clinically No exclusion 5–6 patients 6 weekly Clinical Sleep education, SD, PSQI, Improved No follow-up Overall
al. (55). referred criteria sessions/ psychologist sleep hygiene, DBAS, and SQR, SE, medium/large

9:44
patients, 90 min each relaxation, ISI. BDI, Sleep effect sizes
mean age = session stimulus control, PSWQ, and Duration, and Sleep diary:
49.7 yr (SD = sleep restriction, CGI SOL as Pre/post SE
d = .815, TST

Char Count=
12.0 yr) medication measured by
withdrawal, and the PSQI. SD: d = .655, SOL
cognitive therapy SE (+9%), d = .453
TST (+42
min), and SOL
(-12 min).
Improvements
for the DBAS,
ISI, PSWQ,
and BDI
a
Effect Size Estimates represent Cohen’s d and were calculated for pre to post treatment changes for the group condition alone (when no control condition was employed) or represent differences (if
adequate control group was used), when sufficient information was available, in subjectively recorded sleep only.
Abbreviations: SD, sleep diary; PSQI, Pittsburg Sleep Quality Index (31); BDI, Beck Depression Inventory (16); BAI, Beck Anxiety Inventory (62); PSG, polysomnography; SOL, sleep-onset latency;
WASO, wake time after sleep onset; TWT, total wake time; TST, total sleep time; SE, sleep efficiency; SQR, sleep quality rating; DBAS, Dysfunctional Beliefs and Attitudes About Sleep (19); ISI, Insomnia
Severity Index (34); PSWQ, Penn State Worry Questionnaire (63); HADS, Hospital Anxiety and Depression Scale (23); STAI, State-Trait Anxiety Inventory (36); CGI, Clinical Global Improvement Scale;
SII, Sleep Impairment Index (34); GMHI, General Mental Health Distress Index (64); SWAI, Sleep-Wake Activity Inventory (65); and ESS, Epworth Sleepiness Scale (20).

337
c28 IHBK059-Sateia March 28, 2010 9:44 Char Count=

338 McCRAE ET AL.

that group treatment can be as efficacious and effective as traditional behavioral approaches for
treating insomnia.

Future Directions
The research that has previously been conducted on the group treatment of insomnia provides
great hope for this modality of implementation. However, many questions are left unanswered.
What is the optimal number of patients per group? Are there patients who are better or worse
suited for group treatment approaches? What potential patient characteristics might distin-
guish patients who might most benefit from group treatment? How are these potential patient
characteristics best assessed? Are there personal characteristics of group leaders that may lead
to improved efficacy of group treatments? Is a purely interpersonal approach to the group
treatment of insomnia practical? What is the best way to integrate group processes into the
group treatment of insomnia? Which traditional cognitive behavioral treatments of insomnia
techniques are best suited for implementation in group contexts?
All of these questions are intriguing. In the age of Health Maintenance Organizations
(HMOs), it is critically important to provide empirical evidence of the effectiveness of treatment
approaches. The cost-effectiveness of treating multiple patients simultaneously may potentially
lead to group-based cognitive behavioral treatment of insomnia as the treatment of choice. While
the extant literature suggests that a group approach is an effective treatment for insomnia in
many different sub-populations of individuals with insomnia, much work is still needed. Given
the high prevalence of insomnia and the preliminary results of group treatment approaches,
this line of research warrants continuation and expansion. Furthermore, as presented in Table
5, many of the studies that have employed a group-based treatment approach have included
patients with several comorbid conditions. Traditional logic suggests that patients with comor-
bid conditions are the hardest to successfully treat. Thus far, insomnia comorbid with drug
abuse (56), chronic pain (57), cancer (58), and mental illnesses (59) have all been successfully
treated within a group approach.

Conclusions
The group treatment of insomnia is a natural extension of individually administered cognitive
behavioral treatment of insomnia. While preliminary work suggests these group approaches to
be highly efficacious, the majority have apparently not capitalized on the unique therapeutic
aspects that group therapy engenders. As Yalom (1995) stated, “groups resting solely on other
assumptions, such as psycho-educational or cognitive-behavioral principles, fail to reap the full
therapeutic harvest of group therapy. Each of these forms of therapy can. . . be made even more
effective by incorporating a focus on interpersonal process” (Yalom, 1995, p. xiv).
Results from the small number of research studies that have employed a group treatment
approach are very promising. Given its cost effectiveness, group treatment may prove to be a
viable early intervention for insomnia (50) and appears to be suitable for delivery by trained
nurses (53). Furthermore, its application to a wide range of clinical populations attests to the
durability of this treatment modality. Lastly, patient perceptions of interactions with other
individuals with insomnia as therapeutic provide some evidence of the added benefit of group
treatment (47).

BRIEF AND GROUP INTERVENTIONS – SUMMARY AND CONCLUSIONS

The traditional approach of individually administering cognitive behavioral treatment of insom-
nia over the course of 6 to 10 sessions places heavy demands on clinician time and therefore,
is not practical for use in ‘real world’ primary care settings. Briefer intervention protocols and
the group administration of cognitive behavioral treatment of insomnia represent attractive
alternatives, because they place fewer demands on clinician time. Effect sizes for both brief and
group approaches are comparable to cognitive behavioral treatment of insomnia that is longer
in duration and individually administered, suggesting that these alternate modes of administra-
tion appear to be as efficacious as traditional protocols. Studies of brief and group treatment of
insomnia have demonstrated the utility of these approaches across a variety of ages and patient
populations. Because the bulk of the research in this area has focused on efficacy trials (with
a few notable exceptions) conducted with middle-class participants and delivered in “ideal”
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SHORT-TERM AND GROUP TREATMENT APPROACHES 339

settings (academic research), more research on the effectiveness of such approaches is needed
in order to fully understand how well such interventions translate to ‘real world’ primary care
settings. To date, the few studies of effectiveness in this area have produced promising results
(15,19–21,31,53). More research on the effectiveness of these approaches is needed, because
several important questions remain regarding the best approach(es) to administering brief
and/or group interventions in applied settings (e.g., Who is best suited to administer such
treatment?; What is the ideal length of treatment?; What is the optimal group size for group
treatment?).

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29 Multimodal Cognitive Behavior Therapy

Colleen E. Carney
Department of Psychology, Ryerson University, Toronto, Ontario, Canada

Jack D. Edinger
Psychology Service, VA Medical Center, Department of Psychiatry and Behavioral Sciences, Duke University
Medical Center, Durham, North Carolina, U.S.A.

HISTORY AND RATIONALE FOR MULTIMODAL CBT

As described in previous chapters, insomnia is a highly prevalent and often serious health
condition that may be precipitated by stress, environmental factors, changes in the sleep–wake
cycle, medical or psychiatric illnesses, and/or use of sleep-disrupting substances. Regardless
of its initial cause(s), insomnia may assume a chronic course perpetuated by cognitive, emo-
tional, and behavioral factors that persist over time and cause continual sleep disruption (43).
Included among the cognitive factors are unhelpful beliefs and attitudes that may contribute to
sleep-related performance anxiety and lead to sleep-disruptive bedtime arousal (1). In addition,
misconceptions about how one should respond to a poor night’s sleep might give way to a vari-
ety of compensatory strategies that only further disrupt sleep. For example, daytime napping or
spending extra time in bed in pursuit of elusive, unpredictable sleep may interfere with normal
homeostatic mechanisms designed to correct for accumulated sleep debt. Alternately, the habit
of “sleeping in” beyond the normal rising time following a poor night’s sleep may disrupt
circadian mechanisms that regulate the normal sleep–wake rhythm. Additionally, engaging in
mentally demanding work late into the evening without allotting sufficient wind down time
before bed may result in excessive mental arousal that interferes with sleep onset. Over time,
these cognitive and behavioral factors may result in the repeated association of the bed and
bedroom with unsuccessful sleep attempts and lead to the development of a sleep-disruptive
conditioned arousal in response to the home sleeping environment.
Although it seems intuitively obvious that relaxation before bed and practicing good
sleep habits (i.e., following a routine sleep–wake schedule; avoiding daytime napping, etc.)
facilitates sleep quality, recognition of the effectiveness of these behavioral insomnia remedies
did not emerge until the past half century. Between the late 1950s and mid 1980s a number
of first generation therapies emerged as viable insomnia treatments. Included among these
are such treatments as relaxation training, stimulus control, sleep restriction, and sleep hygiene
education, which have been described in detail in the preceding chapters. As outlined in Table 1,
each of these therapies is designed to target a fairly-specific subset of the above-mentioned array
of cognitive and behavioral factors that can perpetuate insomnia. Consequently, each of these
treatments ignores selected cognitive or behavioral that may be more or less important as
perpetuating mechanisms across insomnia patients. Therefore, none of these first generation
therapies represents a panacea that would be expected to be consistently effective from one
insomnia sufferer to the next.
Given this realization, interest in more omnibus, multicomponent behavioral insomnia
therapies emerged in the late 1980s and early 1990s. It was during this time-period that the
initial trials of what constitutes current-day multimodal cognitive-behavioral insomnia therapy
(CBT) were first reported (2–4). These early trials first demonstrated the promise of an insomnia
therapy that combines several effective cognitive and behavioral strategies into a comprehensive
treatment package. Since that time, various multimodal CBT protocols have been proposed.
However, most of these have minimally included stimulus control, sleep restriction, and a
cognitively oriented strategy so as to form an insomnia therapy that can be expected to be more
broadly and consistently effective across insomnia patients.
Multimodal CBT is appealing for its presumed ability to address the range of insomnia
complaints and etiologic factors that can occur in insomnia. For example, it seems unreasonable
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MULTIMODAL COGNITIVE BEHAVIOR THERAPY 343

Table 1 First Generation Treatment Descriptions and Their Respective Primary Treatment Targets

Type of Primary treatment

treatment Treatment description target(s)
Relaxation r A structured series of mental or muscle-focused Sleep-disruptive
training exercises designed reduce or eliminate physiological and/or
sleep-disruptive physiological (e.g., muscle tension) mental arousal occurring
and/or cognitive (e.g., racing thoughts) arousal. at bedtime or in bed
r Examples include progressive muscle relaxation,
passive relaxation, autogenic training, biofeedback,
imagery training, meditation, and hypnosis.

Stimulus control r A structured behavioral regimen that instructs the Conditioned arousal
patient to (1) establish a standard rising time; (2) go associated with the
to bed only when sleepy; (3) get out of bed whenever bed/bedroom and
awake for long periods; (4) avoid reading, watching attempts to sleep
TV, eating, worrying and other sleep-incompatible Improper sleep–wake
behaviors in the bed/bedroom; and (5) refrain from scheduling that
daytime napping. interferes with circadian
r The goal of this treatment is that of reassociating the control over sleep
bed and bedroom with successful sleep attempts. Daytime napping that
reduces homeostatic
sleep drive

Sleep restriction r Sleep restriction therapy reduces nocturnal sleep Excessive time spent in
disturbance primarily by restricting the time allotted for bed that reduces
sleep each night so that the time spent in bed closely homeostatic sleep drive.
matches the individual’s presumed sleep requirement.

Sleep hygiene r Patients are educated about normative sleep Patients’ misconceptions
education requirements, healthy sleep behaviors and about sleep.
sleep-conducive environmental conditions. Use of sleep-disruptive
r Typically they are encouraged to exercise daily, substances
eliminate the use of caffeine, alcohol, and nicotine, Lifestyle &
eat a light snack at bedtime, and ensure that the environmental factors
sleeping environment is quiet, dark, and comfortable. that disrupt sleep

to expect that a person, who presents with a significant worry component and good sleep
habits, should receive the same single component therapy as a patient who presents primarily
with an irregular sleep–wake schedule. Since multimodal CBT includes several stand-alone
interventions, it presumably casts a wider treatment net, thus providing a more broadly effective
therapy across a range of insomnia subtypes (i.e., those with sleep onset insomnia, those with
sleep maintenance insomnia, those complaining predominantly of cognitive arousal, etc.).
Given its inclusion of several of the first-generation behavioral treatment strategies, Mul-
timodal CBT is a more complex therapy than are its predecessors. Yet multimodal CBT does
not require more time in therapy than do the single component treatments. In fact, CBT is typ-
ically administered in one to eight sessions. Given the accumulation of supportive data, CBT
arguably has become the nonpharmacologic treatment of choice for insomnia, and most recent
RCTs involving psychological interventions for insomnia have focused on various forms of this
multicomponent approach.

Multimodal CBT Components

As suggested above, multimodal CBT consists of a number of effective and well-established
first generation behavioral insomnia therapies used in combination to form an omnibus and
broadly effective insomnia treatment. As its name would imply, this form of therapy includes
a number of specific strategies to address both the cognitive factors and sleep disruptive habits
that sustain insomnia over time. However, since the time of the earliest descriptions (2–4) of this
treatment were published, various versions of multimodal CBT have been proposed. As a result,
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344 CARNEY AND EDINGER

multimodal CBT currently cannot be characterized as a fixed brand of psychological treatment.

In fact, the pertinent empirical and descriptive literature shows that the specific number and
nature of treatment components included treatment packages labeled multimodal CBT has
varied considerably over the years. Presumably such variability is largely attributable to provide
preferences since what constitutes the optimally effect CBT package has yet to be determined.
Therefore, a thorough description of CBT treatment components requires discussion of a number
of core strategies that are found in most published CBT descriptions as well as a number of
add-on strategies, which are commonly included to compliment the core strategies.
Cognitive-behavior therapy, by definition, must include some form of cognitive-focused
intervention to merit this descriptive label. In the case of insomnia, a variety of cognitive
treatment “targets” may emerge and warrant specific treatment attention. However, the exact
nature of the cognitive factors contributing to insomnia may vary considerably across patients
so it is often necessary to include an array of specific cognitive therapy techniques in multimodal
CBT to meet patients’ needs.
Among the common cognitive factors that perpetuate insomnia are a variety of unhelpful
beliefs and attitudes about sleep that may heighten sleep-related anxiety and/or promote sleep-
interfering habits (5). For example, beliefs that sleep is beyond one’s control or that insomnia
may have serious negative effects of one’s functioning or health can increase anxiety about sleep
and, in turn, disrupt the sleep process. Further, insufficient knowledge about how one should
respond to a night of poor sleep may promote sleep-disruptive habits (e.g., daytime napping
or “sleeping in”) that interfere with the next night’s sleep. As a result, multimodal CBT typ-
ically includes therapeutic strategies designed to alter these unhelpful beliefs. One technique
proposed for addressing such beliefs involves providing patients a standardized psychoeduca-
tional intervention designed to correct common misconceptions insomnia patients have about
their sleep difficulties. Alternately, these unhelpful beliefs may be addressed via formal cognitive
restructuring methods. In the latter case, the therapy process may be assisted by use of special
questionnaires (4) designed to identify each patient’s most problematic sleep-related beliefs or
by employing insomnia-focused thought records that modify unhelpful sleep-related beliefs.
For many insomnia patients, cognitive arousal arising from sleep-disruptive practices
such as engagement in mentally stimulating activities immediately prior to bedtime or the habit
of taking one’s worries to bed may confound the sleep process. Encouraging such patients to
avoid mentally stimulating activities in the hour or so before bedtime and to schedule an early
evening structured problem-solving time to address daily worries (6) are additional cognitive
therapy approaches that may be employed to reduce mental arousal during the sleep period.
Some CBT packages offer patients systematic instructions for engaging in constructive worry as
well as constructive worry worksheets to aid patients in their home application of this technique.
Along with one or more of the mentioned cognitive-focused interventions, multimodal
CBT typically includes both stimulus control and sleep restriction instructions as core treatment
strategies. As noted earlier, these two interventions are used in combination in most multimodal
CBT protocols so as to re-establish normal homeostatic and circadian control over the sleep
process and to eliminate conditioned arousal resulting from repeated association of the bed and
bedroom with unsuccessful sleep attempts. In some published treatment guides (7), stimulus
control and sleep restriction instructions are presented in separate sessions as independent
treatment components. However, given the overlapping treatment instructions included in
each of these strategies, it is also easy to combine stimulus control and sleep restriction into a
single set of instructions that can be presented in a single session. For example, we (2) have
employed an instructional set that directs each patient to (1) adhere to a standard rising time; (2)
get out of bed whenever awake for > 15 to 20 minutes; (3) avoid reading, watching TV, eating,
worrying and other sleep-incompatible behaviors in the bed and bedroom; and (4) refrain from
daytime napping; and (5) go to bed when sleepy but not before an individually prescribed
bedtime. Consistent with the sleep restriction approach, an average total sleep time (ATST)
is determined for each patient using pretherapy sleep logs/diaries and this ATST is used to
ascertain a prescribed time in bed (PTIB) for each patient. Once the standard rising time is
selected, the PTIB is used to determine the earliest allowable bedtime for each patient and is,
thus, incorporated into the modified stimulus control/sleep restriction instructions shown (See
Ref. 8 for more details).
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MULTIMODAL COGNITIVE BEHAVIOR THERAPY 345

As there has been considerable attention devoted to “hyperarousal” as an etiologic fac-

tor in insomnia (9), relaxation therapy is often included as a component of multimodal CBT.
Relaxation therapy (RT) techniques include strategies such as progressive muscle relaxation,
passive relaxation, autogenic training, and imagery (10). Regardless of the specific RT strategy
used, treatment entails teaching the insomnia patient formal exercises designed to reduce anx-
iety and arousal at bedtime so that sleep is facilitated. Most forms of therapy require multiple
treatment sessions with additional intersession home practice to achieve optimal results. With
this training, the patients are expected to achieve sufficient relaxation skills so as to reduce or
eliminate sleep-related performance anxiety and bedtime arousal presumed to perpetuate their
insomnia. In addition, RT may have the added, and perhaps unintended, benefit of distracting
patients from their usual bedtime worries and intrusive thoughts that interfere with the sleep
process (11). As discussed in more detail below, CBT protocols that do not include relaxation
have proven highly effective for insomnia management so the value-added of RT as a CBT
component remains an open question. Hence, RT may be best classified as a popular add-on
rather than a core component of the multimodal CBT package for insomnia.
Inasmuch as one’s lifestyle, patterns of consumption, and usual sleeping environment
may play a role in sleep difficulties, sleep experts have long recognized the value of address-
ing these factors in managing insomnia complaints. As such, multimodal CBT protocols often
include a set of so-called sleep hygiene (12) education to address such factors. The specifics of
sleep hygiene may vary across CBT protocols but typically it includes education about healthy
sleep behaviors and sleep-conducive environmental conditions. For example, patients may be
encouraged to exercise, reduce caffeine, alcohol, and nicotine use, eat a bedtime snack that
includes food items (e.g., milk products, peanut butter) rich in the sleep-promoting amino
acid, L-tryptophan, and ensure that the bedroom is quiet, dark, and comfortable. Although
sleep hygiene recommendations alone are insufficient for insomnia management, they are often
add-on components of CBT protocols to address lifestyle and environmental factors that other-
wise may dampen response to the core elements of this therapy.

GENERAL EFFICACY AND EFFECTIVENESS OF CBT

There is substantial evidence supporting the usefulness of multimodal CBT for management of
primary insomnia. Both single-case and randomized controlled trials have shown that CBT pro-
duces significantly greater sleep improvements for primary insomnia patients than do either no
treatment (wait list) control conditions (4,13,14) or such stand-alone therapies as relaxation train-
ing (3), sleep hygiene education (15,16) and a credible sham (placebo) psychological treatment.
In addition, several randomized trials (17,18) collectively have shown that CBT and pharma-
cotherapy with common prescription hypnotics (e.g., zolpidem, zolpiclone, temazepam) yield
similar sleep improvements during active treatment, but only CBT produces improvements that
endure long after active therapy is discontinued. Furthermore, two large clinical effectiveness
studies (19,20) have shown multimodal CBT is superior to treatment as usual (most typically
pharmacotherapy) for the management of primary insomnia patients who present to medical
clinics for care.
Along with these findings, there is growing evidence that multimodal CBT may provide
benefits for patients with more complex forms of insomnia. To date, a number of small to
moderately sized single-site, randomized clinical trials have suggested that CBT is efficacious
for ameliorating sleep problems among patients with chronic peripheral pain syndromes (21),
breast cancer survivors, fibromyalgia sufferers (22), older mixed medical patients (14), and those
with chronic alcohol abuse. In addition, several case series or clinic-based studies support the
efficacy of CBT among patients with mixed mental and medical conditions (23). Moreover,
some of these reports have suggested that CBT may also result in improvements in mood
status or other disease-specific symptoms. Given these findings along with those derived from
studies of primary insomnia patients, multimodal CBT can be regarded as a well-established
or frontline therapy for ameliorating sleep disturbance in both simple and complex forms of
chronic insomnia.
In addition to improving sleep, one would expect that the multiple components of CBT
should address the hypothesized cognitive and behavioral factors that purportedly perpet-
uate or maintain insomnias. Since multimodal CBT typically has a cognitive component,
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346 CARNEY AND EDINGER

troublesome thoughts or cognitive arousal should be improved in this modality. Indeed, studies
suggest that CBT improves several cognitive factors such as sleep-interfering beliefs (44), sleep-
related self-efficacy (e.g., confidence in one’s ability to produce sleep) (21), and cognitive arousal
(24–26). Likewise, CBT appears to address sleep-interfering behavioral factors such as spending
excessive time in bed (27), or varying bedtime and rise times (4,15,17,28). Moreover, although
limited in number, the studies that have examined CBT mechanisms have shown that changes
in selected, CBT-targeted cognitive and behavioral perpetuating mechanisms appear to mediate
improvements in sleep and global insomnia symptoms. Thus, the outcomes achieved with CBT
apparently result, at least in part, from the fact that this therapy effectively targets cognitive and
behavioral mechanisms critical to sustaining insomnia problems.

MODES OF DELIVERY
Despite the efficacy of multimodal CBT for managing insomnia, access to this treatment can
be limited due to the scarcity of providers with CBT expertise. Indeed the number of patients
who might benefit from such an intervention currently exceeds the capacity of the number of
trained providers of this treatment. This state of affairs has created significant impetus for the
development of innovative methods of CBT delivery so as to allow for more facile dissemination
of this treatment. Whereas efforts to enhance CBT dissemination is a fairly new effort, there have
been a number of innovative CBT delivery methods proposed that might lead to greater public
accessibility of this treatment.
Like many other psychological treatments, multimodal CBT is easily adapted to a group
therapy format. The obvious advantage of this format is that it allows one trained provider to
administer treatment to multiple patients simultaneously. Moreover, a group therapy format
can have the added benefit of providing patients peer support as they proceed through the
treatment process. Although a previous metaanalytic review (29) suggested a slight superiority
of individually administered treatments over group therapy, several controlled evaluations have
shown that group CBT models involving six to eight sessions produce notable improvements
in subjective/objective sleep patterns, general mood status and unhelpful beliefs about sleep
(4,17,19,30). Studies comparing the relative efficacy of individual versus group CBT have been
limited, but one recent study did show comparable outcomes for insomnia patients assigned to
either group or individualized CBT therapy. Nonetheless, more studies are needed to further
explore this issue.
Because most insomnia patients who seek care do so in primary care clinics (31), there
has been some interest in developing multimodal CBT protocols suitable for such medication
settings. Espie and colleagues (19,20) tested a group CBT protocol administered by office nurses
working in outpatient medical clinics and found this approach to be more effective than usual
care for managing insomnia patients seen in such settings. However, the treatment effect sizes for
this form of intervention appeared to be somewhat smaller than those reported for trials wherein
treatment was administered by doctoral-level providers and/or sleep specialists (20,32). As an
alternative to this approach, some investigators (15) have proposed abbreviated two-session CBT
protocols suitable for delivery by primary care providers. Whereas results from pilot tests of
these interventions have been promising, it is yet to be demonstrated that MD-level providers
are willing and able to effectively administer such protocols in their busy medical practices.
Thus, continued consideration of CBT models suitable for primary care would seem beneficial.
Of course many insomnia sufferers do not seek care from professionals but rather attempt
to manage their sleep problems on their own by using over-the-counter sleep aids or other less
than optimal “home remedies” such as alcohol (33). With these sorts of individuals in mind,
Mimeault and Morin (13) tested a self-help, CBT bibliotherapy with and without supportive
phone consultations against a wait list control group. Compared to the control condition, those
treated with the bibliotherapy showed substantially greater sleep improvements than control
patients, and these improvements were maintained at a three-month follow up. The addition
of phone consultations with a therapist conferred some advantage over bibliotherapy alone at
posttreatment, but these benefits disappeared by follow up. Oosterhuis and Klip (34) reported
promising results from a novel study wherein a multimodal behavioral insomnia therapy was
provided via a series of eight, 15-minute educational programs broadcast on radio and television.
More than 23,000 people ordered the accompanying course material, and data from a random
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MULTIMODAL COGNITIVE BEHAVIOR THERAPY 347

subset of these showed sleep improvements and reductions in hypnotic use, medical visits, and
physical complaints were achieved among those who took part in this educational program.
More recently, Strom and colleagues (35) tested a five-week self-help interactive CBT program
delivered to insomnia patients via the Internet. Although the treated group did show greater
reductions in unhelpful attitudes toward sleep than did untreated patients, the treatment and
control groups did not differ on their self-reported sleep improvements. These findings provide
a mixed view of self-help protocols but do imply that some guidance from trained therapists
(via phone consultation or mass media) may enhance outcomes for these self-help interventions.
Hence, the question of how best to optimize the efficacy of these self-help CBT interventions
merits research attention.

APPLICATIONS WITH HYPNOTIC USERS

Despite the growing recognition that multimodal CBT is a safe and effective treatment, phar-
macotherapy remains the most used first-line intervention provided to those insomnia patients
who seek treatment (31,36). Moreover, clinical experience indicates that a sizable proportion
of insomnia patients who eventually present seeking nonpharmacological therapy do so while
continuing hypnotic medications prescribed for their sleep difficulties. This state of affairs, in
turn, leads to a number of important questions in regard to the use of multimodal CBT with
such individuals. First, it seems useful to consider whether these patients derive similar benefits
from CBT, as do unmedicated patients. Secondly, it seems useful to question if there is an opti-
mal protocol to follow for those patients who wish to combine CBT with pharmacotherapy for
insomnia. Finally, it is also useful to determine if CBT and other nonpharmacological approaches
might prove useful to hypnotic-dependent patients who ultimately wish to discontinue their
sleep medication use.
To date, there have been no studies specifically conducted to compare the CBT responses
of patients who do and do not use sleep medications. However, post hoc analyses conducted
in a number of published studies suggest a history of hypnotic use does not dampen patients’
responses to multimodal CBT interventions. In a large trial (n = 161 CBT-treated patients)
that tested a nurse-administered CBT, Espie (19) found that patients who had used hypnotic
medications achieved sleep improvements similar to those shown by medication-free patients.
Similarly Verbeek et al. (37) conducted a large (n = 127 CBT treated patients) case replica-
tion series study and found no differences between the CBT responses of hypnotic users and
nonusers. Whereas one single group study (30) showed that unmedicated patients responded
better to CBT than did medicated patients, the small sample size (n = 21) of this investigation
raises questions about the stability of its results. Thus, the current evidence would suggest that
a history of hypnotic medication use should not be considered as a contraindication or limiting
factor when screening patients for insomnia treatment with multimodal CBT.
In contrast, the research pertaining to CBT/hypnotic combination therapy has provided
somewhat mixed results. Three previous studies (17,18,38) with similar research designs com-
pared treatments consisting of CBT alone, hypnotic medication alone, a CBT + hypnotic treat-
ment combination, and a medication placebo. In each of these studies, patients received treat-
ment for a fix period of time (6–8 weeks) and then entered an extended follow-up period during
which they received no addition CBT instruction or medication. In all three of these studies,
patients who received CBT alone showed better long-term outcome than did those who received
the combined CBT/medication therapy or the other two treatments. One implication of these
results is that the presence of medication somehow dampens patients’ responses to CBT. How-
ever, more recent studies have shown that a sequential treatment protocol in which patients
initially receive hypnotic medication with CBT and then are withdrawn from medication and
continue with further CBT alone, achieve better short- and long-term outcomes than do patients
who receive only CBT intervention. Although more research of this nature is needed, these find-
ings suggest that a time-limited course of hypnotic medication at the outset of CBT therapy may
potentiate the treatment effects of this multimodal behavioral intervention.
Of course not all patients are accepting of medications, and some who use hypnotic
medications chronically wish to discontinue them and learn to sleep well without sleep aids.
For such individuals there is ample evidence that CBT may help some patients achieve this goal.
Several studies (13,19,30,37) for example, have shown that a notable proportion of patients who
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348 CARNEY AND EDINGER

100
85
80

60 54
% 48

40

20

0
CBT Medication CBT + Taper
Taper

Figure 1 Proportion of patients who were able to stop hypnotic use with treatment

undergo CBT are able to reduce or stop their hypnotic use during the course of this treatment.
Perhaps as a result of such observations, some investigators have tested the usefulness of
combining multimodal CBT for insomnia with structured medication tapering protocols to aid
hypnotic-dependent patients who wish to discontinue sleep medication use. In one such study,
Morgan et al. (39) compared a treatment consisting of CBT + medication tapering against a
waitlist condition and found the former treatment was superior to the control condition for
both improving sleep and producing at least a 50% reduction in sleep medication use by a six-
month follow-up. In a subsequent study, Morin compared the relative efficacy of CBT, a guided
medication tapering protocol, and a combined CBT + guided taper protocol (40). As shown by
Figure 1, the proportion of patients who were able to stop their hypnotic use was substantially
higher in the combined treatment condition than in the other two unitary treatment approaches.
Patients who received CBT reported greater sleep improvements than those who received only
the guided medication tapering protocol. Furthermore, overall hypnotic abstinence rates at a
long-term follow-up favored the combined CBT + guided tapering condition over the other
two treatments. Given these findings, multimodal CBT appears to be a very useful therapy for
helping patients reduces or discontinue their use of hypnotic medications.

SUMMARY AND FUTURE DIRECTIONS

Multimodal CBT is a combination treatment that utilizes effective single-component cognitive
and behavioral therapies in a single, easy-to-administer standardized delivery package. This
form of therapy has intuitive appeal because it is designed to be a comprehensive intervention
strategy suitable for most insomnia subtypes. It also has theoretical appeal as the components of
this therapy purportedly address major cognitive and behavioral etiologic factors in insomnia.
The inclusion of this therapy in the most recent RCTs suggests it is one of the most commonly
used psychological therapies in insomnia treatment. These RCTs have demonstrated that CBT
is very effective not only for uncomplicated forms of insomnia but also can be effective for
more complicated insomnia sufferers including those with comorbid disorders. Moreover, these
studies have shown that CBT is effective for improving sleep and reducing/eliminating sleep
medication use even among patients with long-standing histories of hypnotic dependence.
Future research areas for this treatment will likely include dismantling and treatment-
matching studies. As noted previously, various versions of multimodal CBT have been pro-
posed. The more streamlined versions tend to include stimulus control, sleep restriction and
some form of cognitive therapy. The most complex models include these core components plus
additional sleep hygiene education and some form of relaxation therapy. The value-added of
the relaxation component is questionable since both CBT with relaxation and CBT without
relaxation are currently regarded as well-established insomnia therapies. Head-to-head trial of
various CBT models have not yet been conducted so what constitutes the optimal and most
cost-effective CBT model remains an open question. Studies to address this question would
seem warranted.
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MULTIMODAL COGNITIVE BEHAVIOR THERAPY 349

Treatment matching relies on a case formulation approach. For example, Patient X and
Y complain primarily of cognitive arousal, thus we expect a cognitive approach would be
superior to a less cognitively oriented therapy. Patient X is randomly assigned to a cognitively
oriented therapy and Patient Y to a predominantly behavioral therapy, and we test whether
matching Patient X to a cognitive intervention produces superior treatment outcome to the more
behavioral approach. It would be useful to test a matching approach with contemporary treat-
ment approaches and comprehensive outcome measures to determine if tailored approaches
are superior to “packaged” treatment approaches.
In this regard, there is also need for research to determine if tailored or augmented CBT
protocols need to be developed for complex forms of insomnia. As discussed previously, studies
have supported the efficacy of CBT for treating primary insomnia and insomnia with comorbid
medical and psychiatric conditions. Nonetheless, to date, no studies have been conducted to
evaluate the relative efficacy of CBT delivered in a fixed dose and format to primary and
comorbid insomnia patients. Those with comorbid disorders often have symptoms (e.g., pain,
lethargy, anxiety, etc.) that can confound sleep and treatment acceptance/adherence. Thus, it is
possible that those with comorbid insomnia may respond less well to the CBT dose and format
that is optimal for primary insomnia patients. Of course, a corollary of this speculation is that
cognitive/behavioral insomnia treatments may benefit from special tailoring or augmentation
(41) to better fit the needs of those with various forms of comorbid insomnia. Hopefully, future
research will address these questions and speculations.
Lastly, dissemination remains a challenge to this very effective treatment. Given its supe-
rior durability to pharmacologic approaches and absence of potentially dangerous side effects,
CBT should be a more common first-line approach in primary care and mental health settings
(42). This, however, is not the case, so dissemination of the effectiveness of the treatment as well
as dissemination of available treatment providers in the community is needed. CBT training
facilities are growing but we need more treatment providers to match the prevalence of this dis-
order. Perhaps a growing number of the recently reported (e.g., self-help, internet, CBT tailored
for primary care) (13,15) and yet to be developed alternative delivery modes will increase the
treatment accessibility for this very effective intervention.

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30 Cognitive-Behavior Therapy for Comorbid and

Late-Life Insomnia
Kenneth L. Lichstein
Department of Psychology, The University of Alabama, Tuscaloosa, Alabama, U.S.A.

Bruce Rybarczyk
Department of Psychology, Virginia Commonwealth University, Richmond, Virginia, U.S.A.

Haley R. Dillon
Department of Psychology, The University of Alabama, Tuscaloosa, Alabama, U.S.A.

INTRODUCTION
By the mid 1980s, cognitive-behavior therapy for insomnia (CBTi) was a mature science in many
respects (1). A substantial literature had accumulated that boasted strong, durable treatment
effects with rigorous methodology.
However, the bulk of the research to that point had focused on primary insomnia in
young and middle-aged adults. Anticipating possible diminished efficacy and potential safety
concerns, individuals with hypnotic-dependent insomnia, individuals with sleep active comor-
bid conditions, and older adults with insomnia were systematically screened from nearly all
of these studies. It was difficult to justify allocating scarce healthcare/scientific resources when
confronted by gloomy outcome expectations.
It is now clear that young adult and middle-aged, primary insomnia accounts for a
narrow sliver of the insomnia population (see chapter 1 in this volume). Neglecting more
complex, severe insomnia also ignores the most needy patients. The literature that has emerged
on comorbid and late-life insomnia is now about two decades old and has soundly refuted the
apprehensions that denied CBTi treatment to so many in the past.
The present chapter will review the literature in the domains of CBTi for comorbid and
late-life insomnia with the intent of estimating clinical efficacy. We will also assess the method-
ological rigor of these studies to gauge the confidence of their findings. To identify the relevant
literature, we searched PsycINFO and MEDLINE for the years 1965 through 2007. We also
examined the citations from retrieved studies to identify additional articles.

COMORBID INSOMNIA

General Characteristics
Until recent years chronic insomnia has been classified into two broad categories: as either
a ‘primary’ disorder or one that is ‘secondary’ to a primary medical or psychiatric disorder
(2). The different diagnostic systems for sleep disorders and treatment recommendations for
insomnia reflected this basic dichotomy. When a primary medical or psychiatric disorder was
present, the standard approach was for treatment to be aimed at the primary disorder, with the
expectation that insomnia will improve once the primary disorder remits. A study of specific
treatment recommendations made by sleep specialists for patients with insomnia confirmed
that this approach was present in actual practice (3).
However, a rapid shift in this clinical logic coincided with the beginning of the 21st cen-
tury. In a 2000 book chapter, Lichstein (4) outlined the difficulty of determining whether various
coexisting medical and psychiatric conditions predate and/or exacerbate the insomnia. Further-
more, beginning in that same year with Lichstein, Wilson and Johnson’s (5) study, randomized
controlled trials with state-of-the-art behavioral treatments were expanded to populations that
were previously overlooked on the grounds that they had secondary insomnia. In the majority
of these studies the issue of whether the medical or psychiatric condition predated the insomnia
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COGNITIVE-BEHAVIOR THERAPY FOR COMORBID AND LATE-LIFE INSOMNIA 353

was not addressed in the inclusion criteria (2). Finally, a 2005 State-of-the-Science Conference (6)
recommended that secondary insomnia be removed from the clinical taxonomy and be replaced
with the more descriptive diagnostic term, comorbid insomnia. Similarly, treatment guidelines
have also shifted such that behavioral methods are recommended as a first-line of treatment
for all chronic insomnias, regardless of the presence of a comorbid medical and/or psychiatric
condition. The behavioral treatment literature in support of this paradigm shift will be outlined
and summarized in the next sections.

Literature Search
We identified 21 published behavioral intervention studies between the years 1989 and 2007.
Three additional case studies were published between 1980 and 1990 and four case series
studies have been published since 1994. These seven papers were not included in the count of
21 because they were not designed as a priori studies. Another paper that focused on caffeine
reduction among HIV patients (7) was not included in the count because it employed a single
sleep hygiene treatment strategy. Among the 21 studies, 11 were classified as randomized
clinical trials (RCT, Table 1), with the remainder being quasi-experimental designs, multiple
case studies, or multiple baseline case studies.
Unlike the gradual integration of older adults into the CBTi literature (see below), 15 of the
21 studies have occurred since the year 2000. Consequently, it may not be an exaggeration to say
that the comorbid insomnia subset, largely ignored until the 21st century, is now receiving the
majority of attention in CBTi research. We will likely to see a wide range of RCT studies applied
to different comorbid conditions in the near future and this will be a welcome contribution to
the empirical evidence and will hopefully translate into higher levels of behavioral treatment
in the clinical setting.

Methodology
Studies of CBTi for comorbid insomnia have employed the full spectrum of methods, including
single case studies (e.g., 8–10), multiple case designs (11–15), a large uncontrolled trial (16), a
large trial with a convenience sample as a control group (17), RCTs with no-treatment control
groups (Table 1), and RCTs with a placebo treatment or other treatment comparisons (Table 1).
There have been four additional case-series reports of treatment cases at sleep clinics with a
range of comorbidities, usually of a psychiatric nature (18–21).
A variety of types of comorbid conditions have been targeted in the RCTs. In the domain
of medical comorbidity, these studies have included mixed chronic illnesses (5,22,23), chronic
pain (24), cancer (17,25,26), coronary artery disease (27), osteoarthritis (27), fibromyalgia (28),
Alzheimer’s disease (29) and pulmonary disease (27). In the domain of psychiatric comorbidity,
only two RCT studies have been published and both of those included individuals with or
recovering from alcoholism (30,32). Additional, uncontrolled studies included crime victims
with posttraumatic stress disorder (16) and individuals with depression and insomnia (15).
Accordingly, there is a critical need in CBTi research with comorbid insomnia to address the
treatment efficacy of psychiatric comorbidities, including but not limited to anxiety disorders,
bipolar disorder, eating disorders and substance abuse disorders.
Most of the RCT studies have been conducted since multicomponent CBTi was established
as the “gold standard” for intervention, so all but the two oldest RCTs used this omnibus treat-
ment approach. The specific components within this omnibus approach were fairly uniform,
using a combination of stimulus control, sleep restriction, sleep hygiene recommendations,
guidelines for discontinuing or reducing hypnotics, and cognitive methods (31). The one excep-
tion was relaxation training, which was not included in three of nine multicomponent RCTs
(24,25,28). The two earliest RCT studies both employed single modality relaxation training inter-
ventions (32,33). The RCT with Alzheimer’s patients (29) also employed a necessarily different
treatment model, which included caregiver administered changes in activities, sleep windows
and light exposure (using a light box). Among the nonRCT studies, multicomponent CBTi
was also the norm, but one older study employed only stimulus control and sleep restriction
(13). Three studies tested home treatments as comparison groups for in-person multicompo-
nent treatments. These included relaxation training with audiotapes (22), multicomponent CBT
delivered via videotape and book instruction (23), and CBT book instruction alone (30).
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354 LICHSTEIN ET AL.

Table 1 Randomized Clinical Trials of CBT for Comorbid Insomnia

Sleep Posttreatment Follow-up

Study Conditions measure outcome outcome
Placebo/Treatment comparison control group
Rybarczyk et al. (27), 1 MT (SH, SC, SD SD: 1 > 2 (SE, SL, SD, TGO, sig. for: SE,
osteoarthritis, coronary SR, CT, RE) SII WASO, TTIB) SL, WASO, TTIB,
artery disease, and lung 2 SMW / PL PSQI ISI: 1 > 2 ISI & PSQI
disease PSQI: 1 > 2
Rybarczyk (67) report on
one yr. f/u data
Rybarczyk et al., (22), 1 MT (SH, SC, SD SD: 1 > 3 (SE, SD: 1 = 2 > 3 (SE,
mixed medical illness in SR, CT, RE) PSQI WASO, TTIB) WASO)
older adults 2 HART ACT 1 = 2 (SE, WASO, 1 > 3 (TTIB)
3 WLC TTIB) 1 = 2 (TTIB)
2 = 3 (SE, WASO, 2 = 3 (TTIB)
TTIB) PSQI: 1 = 2 > 3
2 > 1 = 3 (TST) ACT: ns
PSQI: 1 = 2 > 3
ACT: ns
Edinger et al. (28), 1 MT (SH, SC, SD SD: 1 > 3 (SE, SD: 1 > 3 (SE,
fibromyalgia SR, CT) ACT WASO, SL) WASO, SL)
2 SH ACT: 1 > 3 (SL) ACT: 1 > 3 (SL)
3 UC
Currie et al. (30), 1 MT (SH, SC, SD SD: 1 = 2 > 3 (SE, SD: 1 = 2 > 3 (SE,
recovering alcoholics SR, CT, RE) PSQI SL,WASO, SQ) SL,WASO, SQ)
2 SHMT ACT PSQI: 1 = 2 > 3 PSQI: 1 = 2 > 3
3 WLC ACT: ns ACT: ns
Epstein & Dirksen (25), 1 MT (SH, SC, SD SD: 1 > 2 (TIB) N/A
breast cancer patients SR, CT) TER TER: 1 > 2
2 SH ACT
McCurry et al. (29), 1 MT (ISH, LBE, ACT ACT: 1 > 2 (TWT, ACT: 1 > 2 (TWT,
Alzheimer’s Disease AI) NWAK) NWAK)
2 SH

No Treatment Control Group

Cannici et al. (33), cancer 1 RE SD SD:1 > 2 (SL) SD:1 > 2 (SL)
2 UC
Greeff & Conradie (32), 1 RE SQ SQ: 1 > 2 N/A
alcohol dependency 2 WLC
Currie et al. (24), chronic 1 MT (SH, SC, SD SD: 1 > 2 (SE, SL, SD: 1 > 2 (SE, SL,
pain SR, CT, RE) PSQI WASO) WASO)
2 WLC ACT PSQI: 1 > 2 PSQI: 1 > 2
ACT: 1 > 2 ACT: 1 > 2
Lichstein et al. (5), 1 MT (SH, SC, SD SD: 1 > 2 (SE, SD: 1 > 2 (SE,
psychiatric and medical RE) WASO, SQ) WASO, SQ)
illnesses 2 Control
Savard et al. (26), breast 1 MT (SH, SC, SD SD: 1 > 2 (SE, SL, SD: 1 > 2 (SE, SL,
cancer SR, CT, FM) ISI WASO, TWT) WASO, TWT)
2 WLC PSG ISI: 1 > 2 ISI: 1 > 2
PSG: n.s. PSG: n.s.
Note: Posttreatment and follow-up outcomes reflect treatment condition relationships based on the primary or majority of the sleep
measures if individual sleep measures are not specified. In reporting outcome, = indicates no statistically significant difference
and > indicates a significantly better outcome (p < 0.05). This table reports between group comparisons at posttreatment and
follow-up, not within group comparisons over time, with the exception of one study’s findings at one-year follow up.
Treatment conditions: multicomponent treatment (MT), placebo (PL), stress management and wellness placebo (SMW), home
audiotape relaxation treatment (HART), self-help multicomponent treatment (SHMT), relaxation (RE), sleep compression (SCO),
sleep hygiene (SH), sleep restriction (SR), stimulus control (SC), cognitive therapy (CT), fatigue management (FM), wait-list
control (WLC), usual care (UC), light box exposure (LBE), activity increase (AI), individualized sleep hygiene (ISH), within group
analysis for treatment group only (TGO).
Sleep measures: actigraphy (ACT), polysomnography (PSG), sleep diaries (SD), sleep latency (SL), total sleep time (TST), total
wake time (TWT), total time in bed (TTIB), number of awakenings (NWAK), sleep efficiency (SE), wake after sleep onset (WASO),
Pittsburgh Sleep Quality Inventory (PSQI), sleep questionnaire (SQ), Insomnia Severity Index (ISI), Treatment Effectiveness
Rating (TER)
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COGNITIVE-BEHAVIOR THERAPY FOR COMORBID AND LATE-LIFE INSOMNIA 355

The nine RCT intervention studies employing multicomponent treatment were split rela-
tively evenly between group and individual treatment sessions, with the quantity of treatment
ranging between four one-hour individual sessions (5) to as many as eight two-hour group
sessions (27). Group treatments are necessarily longer due to the support and interactive con-
tent of the classes.
Therapists in the RCTs have ranged from behavioral sleep medicine clinicians (16), psy-
chologists (22,27), masters level mental health professionals (14,25,26) and psychology graduate
students (5). All of the group interventions have been led by two clinicians, either two psycholo-
gists (22,27) or a psychologist and a graduate student (16). All of the studies delivered treatment
in conventional health care settings, with the exception of the self-help interventions (22,23,30)
and the innovative caregiver-administered intervention for Alzheimer’s patients (29). This inter-
vention included six one-hour in-home sessions delivered by geropsychologists experienced in
behavioral interventions for dementia patients and their caregivers.
Outcomes and Meta-Analyses (MA)
As above, the review of outcomes will focus mainly on the RCT findings for multicomponent
interventions. Uncontrolled studies are reviewed in a limited way and case studies are not
addressed. We were only able to locate a quasi MA for CBTi for comorbid insomnia, published
in 2005 (34). Effect sizes were calculated and presented in a table of the literature, along with
a systematic review of current and recommended research in this area. Overall, the effect sizes
for the RCT studies for self-report variables are in the “moderate” to “strong” range, based
on Cohen’s (35) criteria, and are generally consistent with those reported in MA for CBTi
for primary insomnia (e.g., 36). Thus far, no studies with null findings for most or all sleep
variables have been reported in the small body of CBTi literature with comorbid insomnia. One
cautionary note is that not all studies employed intent-to-treat analyses, so the effect sizes may
be somewhat inflated.
As has been shown with larger MA examining the efficacy of CBTi for primary insomnia
(e.g., 36) these effect sizes were strongest with sleep efficiency, wake after sleep onset and sleep
quality ratings and absent or smaller for increases in total sleep time. Additionally, as has been
the case with primary insomnia (36), these effect sizes were largely maintained at long-term
follow-up assessments, ranging from three months to one year in duration. Taken together,
these findings suggest that CBTi treatment for comorbid insomnia is both highly effective and
robust in its long-term effects on subjective evaluations of sleep.
The findings are much more sparse and inconclusive when it comes to objective measures
of sleep. Among the six RCT studies that employed objective outcome measures (i.e., either
actigraphy or polysomnography) three found weaker effects compared to self-report (24,28,29)
and three found no effects (22,26,30). Only one of the RCT studies employed polysomnography
and that study found no significant effects (26). In contrast, two uncontrolled studies (13,14)
employed polysomnography measures and both found significant changes on sleep parameters.
One of the studies (14) had effect sizes that were 50% smaller compared to sleep diary (though
still in the “strong” range) and the other had effect sizes that were comparable to those obtained
for self-report for three chronic pain subjects in the study (13). The fact that a number of
RCT studies have failed to obtain actigraphy outcomes may be partially due to the limitations
of the scoring algorithms for particular populations, as some evidence suggests that it may be
suboptimal as a measurement of insomnia in older adults (37) and other specialized populations.
In the comorbid CBTi literature, systematic comparisons of different intervention types
are not possible because 9 of 11 of the RCTs employed similar, multicomponent interventions.
The two studies employing relaxation interventions (32,33) did obtain strong effects, though
outcomes were only measured and analyzed for limited variables. In the three studies which
included a self-administered CBTi treatment group, all three found significant effects for self-
help treatment, with some additional benefits for professional-led treatment compared to self-
help. In the Rybarczyk et al. (22) and Rybarczyk et al. (23) studies, the rate of clinically significant
improvement was approximately 50% greater for the in-person treatment compared to self-
help treatment. In the Currie et al. (30) study with recovering alcoholics, the outcomes were
comparable at posttreatment but professional-led treatment was superior at the six-month
follow-up on a measure of clinical significance.
Based on a review of the effect sized calculated in the Smith et al. MA (34), it is apparent
that the three case series studies show smaller effect sizes than most of the RCTs. This is most
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356 LICHSTEIN ET AL.

likely due to the fact that relative to carefully screened and incentivized research subjects,
“real world” clients often have complicating factors (e.g., lower motivation, lack of treatment
adherence) that attenuate treatment efficacy. Also important to note is that in most studies
individuals who were using hypnotics were not excluded and this variable was shown to have
no impact on the efficacy of the intervention. In fact, several studies determined that hypnotic
usage was reduced as a result of the intervention (26,30).
It has been hypothesized that the bi-directional relationship between insomnia and day-
time functioning is heightened in comorbid insomnia, for both medical and psychiatric con-
ditions (2). For example, it has been shown that in addition to insomnia being aggravated by
increased pain, pain is also increased following nights of insomnia (38). Accordingly, most of the
11 RCT studies hypothesized that secondary daytime medical, mental health and quality of life
benefits would follow from improved sleep. In general, secondary findings have been limited to
the RCTs addressing insomnia in cancer and Alzheimer’s patients. The Quesnel et al. (14) study
demonstrated that cancer patients receiving CBTi showed improvements in mood, general and
physical fatigue, and global and cognitive dimensions of quality of life. The Savard et al. (26)
study showed that cancer patients in the treatment group had lower depression and anxiety
as well as greater global quality of life compared to controls. The one study with Alzheimer’s
patients (29) showed that treatment group participants had reduced symptoms of depression
and greater levels of activity compared to controls.
In contrast, in the two studies by Rybarczyk and colleagues (22,27), assessing an array of
secondary outcome measures that were relevant to chronic illness, only a single global rating
of daytime effects of insomnia produced significant effects in one of the two studies (27).
Currie et al. (24) found no secondary benefits among chronic pain patients and Edinger et al.
(28) only found pain benefits in his fibromyalgia sample for the sleep hygiene only treatment
condition compared to controls. Although the RCTs produced inconsistent findings, all of the
seven uncontrolled studies that included daytime functioning measures reported significant
findings. However, given the uncontrolled nature of these studies, it is likely that regression to
the mean and other threats to internal validity are responsible for a portion of the variance in
these findings.

LATE-LIFE INSOMNIA

General Characteristics

Definition
Insomnia is more prevalent, more severe, more chronic, and more impairing in older adults
than in any other age group (39–42). Late-life insomnia is simply defined as insomnia occurring
in older adults. There is no standard age cut-off for qualifying, but 60 years is commonly used.
It may also be salient to acknowledge that no CBTi study has distinguished between late-
life insomnia that initiates in late-life versus chronic middle-aged insomnia that persists into
later life. The clinical implications of this distinction are unknown (43).

Literature Search
We identified 41 articles between the years 1974 and 2007 and a frequency distribution of their
publication dates are given in Figure 1. The level of interest in CBTi for late-life insomnia is
somewhat misleading from this figure. The first six publications either included sleep as a sec-
ondary outcome or did not focus on insomnia in older adults, they just did not exclude them and
typically included correlations between age and outcome to assess age as a moderating variable.
The first study to exclusively focus on CBTi in older adults was published in 1983 (44). The first
RCT with an active control group was published in 1999 (45). During the 1990s, interest leveled
off to about one article a year and that rate about doubled in the first five years of the 21st century.
The prorated rate of publication during the years 2005 to 2007 is greater than two per year.
Five of the 41 studies were on comorbid insomnia in older adults (5,22,23,27,29). These
fit equally well in the comorbid section and the late-life section. We arbitrarily chose to include
them in the comorbid section above and have omitted them from the reporting of outcomes
below to avoid redundant discussion.
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COGNITIVE-BEHAVIOR THERAPY FOR COMORBID AND LATE-LIFE INSOMNIA 357

# publications of cognitive-behavior therapy

for insomnia in older adults
10

8
# publications

0
∗
70-74 75-79 80-84 85-89 90-94 95-99 00-04 05-07
5 year period
Figure 1 Publication count of the 41 CBT for insomnia studies in five-year periods. ∗ Signifies that the last period,
05–07, is only three years.

Methodology
A variety of methodologies have been used to study late-life insomnia including case studies
(e.g., 46,47), single subject experimental designs (e.g., 48,49), RCTs with wait-list control groups
(Table 2), and RCTs with placebo or other treatment comparisons (Table 2).
A variety of types of late-life insomnia have been targeted including primary insomnia
(e.g., 50,51), comorbid insomnia (e.g., discussed in the above section), hypnotic-dependent
insomnia (e.g., 52,53), and insomnia in caregivers (e.g., 54,55).
Therapists have mostly been experienced behavioral sleep medicine clinicians (e.g., 48,50)
or psychology graduate students (e.g., 5,56). One study trained nondoctoral counselors and a
social worker to present CBTi (57).
Most of the studies delivered treatment in conventional health care settings, but two
studies were distinctive. One presented CBTi in primary care (58) and the other in a rural
clinic (57).

Outcome Studies
For purposes of efficiency, this discussion will not consider case studies or single-subject design.
Excluding the several comorbid insomnia studies reported above, we found six studies that
included placebo or treatment comparison controls and 10 studies with a wait list control.
A summary of these studies is given in Table 2. This discussion will emphasize the most
methodologically rigorous of these studies, those with the placebo or treatment comparison
control.
To get a sense of which treatments have received the most attention, we did a frequency dis-
tribution among these 16 studies. Stimulus control was the most common (12 studies included
a form of this treatment), sleep hygiene, which was usually included as a secondary treat-
ment component, was next (11 studies), and other treatments in decreasing order were sleep
restriction/compression (8 studies), relaxation (8 studies), and cognitive therapy (5 studies).
Thorough descriptions of these clinical procedures are available elsewhere (59). Every study
used sleep diaries as a dependent measure. Actigraphy was also included in one study and
polysomnography in six studies.
Of the six placebo/treatment comparison studies, the study by Freidman et al. (60) had the
weakest results. The two active treatment groups, sleep restriction fortified with sleep hygiene
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358 LICHSTEIN ET AL.

Table 2 Randomized Clinical Trials of CBT for Late-Life Insomnia

Sleep Post-treatment Follow-up

Study Conditions Measure Outcome Outcome
Placebo/Treatment Comparison Control Group
Friedman et al. (60) 1 SR/SH ACT ACT: ns ACT: ns
2 SR/SH/nap SD SD: 1 = 2 > 3 SD: ns
3 SH
Lichstein et al. (62) 1 RE SD SD: 1 = 3 > 2 (TST) SD: ns
2 SCO PSG 2 > 3 (NWAK) PSG: ns
3 PL CS CS: 1 = 2 > 3 CS: 2 > 1 = 3
No PSG data at
post-treatment
McCrae et al. (57) 1 SH SD SD: 2 > 1 No follow-up data
2 MT (SC, SR, RE) CS CS: 2 > 1

Morin et al. (45) 1 MT (SH, SC, SR, SD SD: 1 = 2 = 3 > 4 No between group
CT) PSG PSG: 1 = 2 = 3 comparisons at
2 PCT SII 1=2=4 follow-up
3 MT/PCT CS 3>4
4 PL SII: 1 = 3 > 2 = 4
CS: 1 = 3 > 4 (SE)
1 = 2 = 3 (SE)
2 = 4 (SE)
1 = 2 = 3 > 4 (SII)
Morin et al. (63) 1 MW SD SD: 2 = 3 > 1 SD: ns
2 MT (SH, SC, SR, PSG PSG: ns PSG: ns
CT) MED MED: 3 > 1 = 2 MED: ns
3 MW/MT
Sivertsen et al. (64) 1 MT (SH, SC, SR, SD SD: ns SD: 1 > 2 (TWT)
CT, RE) PSG PSG: 1 > 2 = 3 (TWT, PSG: 1 > 2 (TWT,
2 PCT CS SWS) SWS, SE)
3 PL 1 > 3 (SE) CS: 1 > 2
1 = 2 (SE) No follow-up data for
2 = 3 (SE) group 3
CS: 1 > 2

Wait-List control (WLC) group

Creti et al. (68) 1 CR SD SD: ns SQ: ns
2 RE SQ SQ: ns No analyses with SD
3 WLC data
Davies et al. (69) 1 CC SD SD: 1 > 2 No follow-up data for
2 WLC group 2
Engle-Friedman et al. 1 SH/SU SD SD: 3 > 4 (FR) SD: 3 > 1 = 2
(70) 2 SH/SU/RE PSG PSG: ns 2 > 1 = 3 (FR)
3 SH/SU/SC No follow-up data for
4 WLC group 4
No PSG data at
follow-up
McCurry et al. (55) 1 MT (SH, SC, SD PSQI: 1 > 2 PSQI: 1 > 2
SCO, RE) PSQI CS: 1 > 2 No SD data for group 2
2 WLC CS No SD data for group 2
Morgan et al. (58) 1 MT (SH, SC, RE, PSQI PSQI: 1 > 2 PSQI: 1 > 2
CT) MED MED: 1 > 2 MED: 1 > 2
2 Control
Morin & Azrin (56) 1 SC SD SD: 1 > 3 (WASO) SD: ns
2 IT 1 = 2 (WASO) No follow-up data for
3 WLC 2 = 3 (WASO) group 3
1 > 2 = 3 (TST)
(Continued)
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COGNITIVE-BEHAVIOR THERAPY FOR COMORBID AND LATE-LIFE INSOMNIA 359

Table 2 Randomized Clinical Trials of CBT for Late-Life Insomnia (Continued)

Sleep Post-treatment Follow-up

Study Conditions Measure Outcome Outcome
Morin et al. (71) 1 MT (SH, SC, SR, SD SD: 1 > 2 SD: ns
CT) PSG PSG: 1 > 2 (TWT) No PSG data at
2 WLC CS CS: 1 > 2 follow-up

Pallesen et al. (72) 1 SH/SC SD SD: 1 = 2 > 3 SD: 1 = 2

2 SH/RE No follow-up data for
3 WLC group 3
Puder et al. (44) 1 SC SD SD: 1 > 2 No follow-up data for
2 WLC CS CS: 1 > 2 group 2
Riedel et al. (73) 1 SCO/SH (video SD SD: 2 > 1 (TST) SD: 2 > 3 (TST)
plus guidance) SS SS: 1 > 3 SS: 1 > 3
2 SCO/SH (video 1=2 1=2
only) 2=3 2=3
3 WLC
Note: (1) This table excludes several studies on comorbid late-life insomnia reported in the comorbid insomnia section above.
(2) Posttreatment and follow-up outcomes reflect treatment condition relationships based on the primary or majority of the sleep
measures if individual sleep measures are not specified. (3) In reporting outcome, = indicates no statistically significant difference
and > indicates a significantly better outcome (p < 0.05). This table reports between group comparisons at post-treatment and
follow-up, not within group comparisons over time.
Abbreviations: Treatment conditions: placebo (PL), relaxation (RE), sleep compression (SCO), sleep hygiene (SH), sleep restric-
tion (SR), multicomponent treatment (MT), stimulus control (SC), cognitive therapy (CT), pharmacotherapy (PCT), medication
withdrawal/taper (MW), countercontrol (CC), support (SU), imagery training (IT), wait-list control (WLC), cognitive refocusing
(CR).
Sleep measures: actigraphy (ACT), polysomnography (PSG), sleep diaries (SD), clinical significance (CS), total sleep time
(TST), total wake time (TWT), number of awakenings (NWAK), sleep efficiency (SE), slow-wave sleep (SWS), wake after sleep
onset (WASO), feeling refreshed upon awakening (FR), Pittsburgh Sleep Quality Inventory (PSQI), sleep questionnaire (SQ),
medication use/reduction (MED), Sleep Impairment Index (SII), sleep satisfaction (SS).

and sleep restriction fortified with sleep hygiene and a daytime nap, demonstrated a stronger
effect than sleep hygiene alone at posttreatment and only on self-reported sleep efficiency. All
other diary and actigraphy results at posttreatment and follow-up were nonsignificant. Indeed,
had a Bonferroni correction been applied to control for testing multiple measures, this one
significant effect would have been nullified. These results are particularly discouraging because
sleep hygiene is a weak unitary treatment (61).
Lichstein et al. (62) observed modest self-reported sleep gains at posttreatment and follow-
up associated with their two active treatments, sleep compression (a method similar to sleep
restriction) and relaxation, compared to placebo treatment. No significant PSG effects were
demonstrated at follow-up and PSG data were not collected at posttreatment. Clinical signifi-
cance markers favored sleep compression. As was predicted, differential treatment effects were
associated with presence or absence of daytime impairment. Subjects with high daytime fatigue
(implying they needed more sleep) responded better to relaxation and patients with low daytime
fatigue (implying they did not need more sleep) responded better to sleep compression.
In a recent effectiveness study, McCrae et al. (57) utilized existing providers in rural health
clinics to deliver brief multicomponent behavior therapy (stimulus control, sleep restriction,
and relaxation) or sleep hygiene education. The group receiving multicomponent therapy fared
better at posttreatment on subjective sleep reports (sleep latency and sleep efficiency) and clinical
significance markers than participants receiving sleep hygiene education alone. Although no
follow-up data were reported, these initial results support the feasibility and value of providing
brief behavioral interventions for insomnia in primary care settings.
When compared to a placebo group at posttreatment, Morin et al. (45) observed signif-
icant improvements in self-reported sleep for all three active treatment groups, CBT alone,
pharmacotherapy alone, and a combination of the two. Only the combined treatment group
performed better than the placebo on posttreatment PSGs. While there were no significant
differences among the three active treatment conditions, a trend was noted for the combined
treatment to result in slightly greater improvements on sleep diary and PSG data than either
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360 LICHSTEIN ET AL.

treatment component alone. However, despite these initial gains, long-term outcomes were
highly variable in the combined treatment group and some participants reported significantly
worse sleep patterns at follow-up. Participants in the pharmacotherapy only group gradually
lost sleep gains over time, while those in the CBT only group maintained improvements in
sleep up to 24-months later. Also of note, participants in the combined treatment and CBT
only conditions rated themselves as significantly more improved at posttreatment, more satis-
fied, and having less interference with daytime functioning than participants in the other two
conditions.
Another study conducted by Morin et al. (63) tested the efficacy of three interventions for
benzodiazepine discontinuation; supervised medication taper alone, CBT alone, and a combi-
nation of medication tapering and CBT. In regards to benzodiazepine reduction, the combined
treatment group had significantly more medication-free patients at posttreatment than either
CBT alone or medication taper alone conditions. The combined treatment group also had
more medication-free patients at 3- and 12-month follow-ups, although group differences were
no longer statistically significant. PSG data demonstrated sleep gains at posttreatment for all
three groups, with no differences between treatment conditions. However, participants receiv-
ing insomnia-specific treatments (either CBT alone or CBT combined with medication taper)
reported greater improvements in self-reported sleep than the medication taper only condition.
Interestingly, all three conditions showed additional gains in self-reported sleep from posttreat-
ment to follow-up, though no significant differences were observed between groups. These
results suggest that improvements in sleep may not be noticeable until several months after
discontinuing or reducing medication use.
Sivertsen et al. (64) compared CBT with pharmacotherapy and placebo treatment. At
six-weeks posttreatment, there were no differences between the three groups on self-reported
sleep, although PSG data favored the CBT condition on most sleep variables. The CBT group
demonstrated greater increases in PSG-recorded slow wave sleep compared to pharmacother-
apy or placebo conditions, while the pharmacotherapy condition actually showed decreases
in slow wave sleep at posttreatment. Six-month follow-up data for the two active treatments
indicated that the pharmacotherapy group maintained sleep gains, but the CBT group pro-
duced significantly better results on all self-reported and PSG outcome variables except for
total sleep time. Clinical significance markers also favored CBT at both posttreatment and
follow-up.
Daytime functioning is plausibly expected to profit from sleep improvement but it is
not always measured before and after treatment. Only three of the active controlled studies
assessed changes in daytime functioning. One study reported substantial daytime functioning
gains accruing to CBTi (45) and two others did not (60,62).
Most of the studies reviewed above included a multicomponent treatment condition that
consisted of several behavioral and cognitive techniques for addressing insomnia. Of the stud-
ies comparing specific interventions, two trials found that behavioral treatments were more
effective than sleep hygiene alone, although neither study included a placebo or additional
control group for comparison (57,60). Lichstein et al. (62) also reported sleep gains for two
different behavioral treatments, with stronger effects for sleep compression. The two trials that
compared psychological treatments with pharmacotherapy found conflicting results for phar-
macotherapy conditions, but both found positive treatment effects for CBT (45,65). In particular,
the study by Morin et al. (45) raises question as to the lasting benefits of combining CBT with
pharmacotherapy and whether the addition of pharmacotherapy might undermine the long-
term effectiveness of CBT. A trial focused on chronic users of benzodiazepine medication found
that supervised medication tapering is safe and effective with older adults and suggested that
combining CBT with a medication taper may facilitate benzodiazepine discontinuation by tar-
geting insomnia and withdrawal symptoms (63). Taken together, the most consistent finding
across these controlled studies is that including components of CBTi when treating late-life
insomnia generally produces statistically and clinically significant improvements in subjective
sleep that are well maintained over time. More research is needed to determine the individual
components of CBTi that are responsible for these treatment effects and to clarify the risks and
benefits of using pharmacotherapy by itself or in conjunction with other treatments for late-life
insomnia.
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COGNITIVE-BEHAVIOR THERAPY FOR COMORBID AND LATE-LIFE INSOMNIA 361

Meta-Analyses
Meta-Analyses (MA) have the ability to digest large numbers of articles efficiently and provide
a broad perspective of the field from a quantitative perspective. The three MA presented below
are all based on self-reported sleep data.
One of the first MA on CBT for insomnia found that treatment effects did not significantly
vary with age (36). Two MA focused on CBT for older adults with insomnia. The first reported
results for 13 studies (65). Effect sizes based on therapeutic increment above control group
changes found the largest effect for WASO, d = 0.61, the smallest effect for TST, d = 0.15,
with NWAK and SOL intermediate. More recently, a MA compared CBT effects on insomnia in
middle-aged and older individuals (66). There was no significant difference in treatment effects
in these two age groups for sleep quality ratings, SOL, or WASO. The younger group exhibited
stronger treatment effects for TST and SE.
To summarize the MA findings, CBTi for late-life insomnia is often as effective as with
younger adults. Differential effectiveness has been observed indicating greater treatment effects
are sometimes obtained in younger adults. Interestingly, sleep maintenance insomnia (charac-
terized by WASO), which may be the most common form of insomnia in older adults, does not
exhibit diminished responsiveness in older samples.

CONCLUSIONS
CBTi for comorbid and late-life insomnia is effective, and the pattern of characteristics in these
two literatures is very similar. The following conclusions apply equally well to both domains.
r Strong insomnia efficacy is consistently demonstrated.
r There exists good methodological rigor in many of these studies including well- controlled
RCTs.
r There is good long-term maintenance of sleep effects.
r Self-reported sleep improvement is often stronger than objective findings. This may be
disquieting to researchers but is good news for patients.
r There is inconsistent improvement in daytime functioning associated with sleep improve-
ment.
Overall, we strongly conclude that earlier reluctance to apply CBT to comorbid and late-
life insomnia was not justified and deprived patients of effective treatment.

ACKNOWLEDGEMENT
Preparation of this chapter was supported in part by National Institute on Drug Abuse grant
DA13574 awarded to the first author and National Institute of Aging grant AG017491 awarded
to the second author.

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31 Pharmacology of the GABAA Receptor Complex

Alan N. Bateson
Institute for Membrane and Systems Biology, Faculty of Biological Sciences, University of Leeds, Leeds, U.K.

INTRODUCTION
Gamma-aminobutyric acid (GABA) is an amino acid neurotransmitter, first discovered more
than 50 years ago (1). Approximately 30% of synapses in the vertebrate central nervous system
have been show to contain GABA, making it the most abundant inhibitory neurotransmitter.
Consequently it is not surprising that GABAergic neurotransmission plays a key role in the
normal physiological function of the brain, including sleep regulation (2–5), as well as various
pathophysiological sequelae (6). GABA receptors have traditionally been classified according
to pharmacological criteria into three groups, GABAA , GABAB and GABAC receptors. GABAA
and GABAC receptors are ligand-gated ion channels whereas GABAB receptors are G protein-
coupled receptors (7). Molecular cloning studies have revealed the structural basis for this
classification, a heterogeneity hitherto unrealized (particularly in the case of GABAA receptors)
and that GABAC receptors should be considered part of the GABAA receptor family (7,8).
GABAA receptors posses a rich pharmacology with a number of distinct binding sites for
a variety of molecular entities that are separate to that of the agonist GABA. These binding sites
are often, though not exclusively, modulatory such that their occupation leads to an allosteric
modulation of the action of GABA or other agonists. Benzodiazepines, barbiturates, alcohol
and certain anesthetics all bind to GABAA receptors and modulate their activity. From the
perspective of sleep medicine it is clearly the benzodiazepine binding site that has attracted the
most interest. Elucidation of the molecular composition of GABAA receptors has revealed that
compounds that interact with the benzodiazepine site can modulate GABA-induced receptor
activity in a positive or negative fashion.
Members of the GABAA receptor family are the targets for both the traditional benzodi-
azepine hypnotics and as well as the newer non-benzodiazepine “Z” drugs (zaleplon, zolpidem,
zopiclone and eszopiclone) (9). The realization from basic science studies that the GABAA recep-
tor is not a single entity but a family of related receptors has opened the door to the possible
targeting of specific GABAA receptor subtypes in the pursuit of novel therapeutic interven-
tions for sleep and other disorders. This chapter provides an overview of GABAA receptor
pharmacology, with particular reference to classic and newer hypnotics. It also discusses the
ongoing elucidation of GABAA receptor heterogeneity and how this might be relevant to the
understanding of the physiology sleep, its disorders and their treatment. The rich pharmacol-
ogy of this receptor family and the specific distribution patterns and physiological functions
of its members means that there is significant potential for the further development of novel
hypnotics that act at members of this important receptor family.

GABAA RECEPTOR HETEROGENEITY

GABAA receptors are members of the cys-cys loop ligand-gated ion channel superfamily (7)
that includes the nicotinic acetylcholine, glycine and serotonin type 3 (5HT3 ) receptors. That
is to say, all these receptor families share a degree of primary amino acid sequence identity to
such an extent that they display three-dimensional structural similarities. Indeed, the nicotinic
acetylcholine receptor is considered the archetypal member of the cys-cys loop receptor super-
family and has provided the lead in studies examining receptor structure (10). All receptors in
this family are pseudosymmetric pentamers with an integral ion channel pore (11,12). Evolu-
tionary studies indicate that members of this superfamily are highly conserved even down to
invertebrates (13). Within a single receptor family there is a greater degree of sequence identity
than between families (14).
The GABAA receptor family comprises of at least 19 genes each encoding a single subunit.
Comparisons of sequence identity between individual GABAA receptor subunits have led to
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366 BATESON

their classification into seven isoform groups (␣, ␤, ␥ , ␦, ε, ␪, ␲, ␳ ; 1,7,9,16). In mammals there are
six ␣, three ␤, three ␦, one each of ε, ␪ and ␲, and three ␳ subunit genes, the latter being previously
classified as GABAC receptors (7,8). Alternate splice forms have been described for a number
of GABAA receptor gene transcripts, thereby potentially increasing diversity. Combinatorial
association of these subunits into pentameric receptors results in the production of a large
number of GABAA receptor subtypes. The actual number of GABAA receptor subtypes in
mammalian brain is not currently known, but although the theoretical number of combinations
is immense, evidence exists for a few dozen rather than thousands of different GABAA receptor
subtypes (8,15). ␣ and ␤ subunits commonly occur together with ␥ subunits, although ␦ subunits
do occur in place of a ␥ subunit. The most abundant receptor subtype comprises of two ␣1, two
␤2 and one ␥ 2 subunit (7,9,16).

GABAA RECEPTOR DISTRIBUTION

Prior to the molecular cloning of GABAA receptor subunit genes, pharmacological analysis of
GABAA receptor subtypes suggested at least two subtypes (BZ1 and BZ2) existed that could
be differentiated by their affinity for CL218872, a nonbenzodiazepine triazolopyridazine ligand
that binds to the benzodiazepine site. BZ1 binding sites showed high affinity for CL218872 and
distribution primarily in the cerebellum, whereas BZ2 binding sites exhibited lower affinity for
CL218872 and were found in hippocampal and cortical structures (17,18). It is now clear that
each GABAA receptor subunit gene exhibits a specific spatial (and temporal) expression pattern,
with the distribution of some subunits being wide and others more limited (18).
That specific neuronal populations express a subset of GABAA receptor genes has been
known for some time (19,20). What has become apparent in recent years is that the subcellular
localization of GABAA receptor subtypes is also subject to control. The mechanisms govern-
ing the distribution of specific GABAA receptor subtypes are beginning to be understood. For
example, analysis of intracellular proteins that interact with certain GABAA receptor subunits
has revealed that one of these, gephyrin, is necessary, along with the ␥ 2 subunit, for the correct
postsynaptic clustering of GABAA receptors (21–23). Further, immunohistochemical studies
have revealed that certain GABA receptor subtypes are concentrated in specific regions of hip-
pocampal pyramidal neurons, with ␣1 subunit-containing receptors being detected on the cell
soma while ␣2 subunit-containing receptors localize to the axon initial segment. These post-
synaptic localizations correspond to neuron-specific innervation. Thus parvalbumin-positive
basket cells form GABAergic terminals on the cell soma of hippocampal pyramidal neurons
and parvalbumin-positive chandelier cells innervate axon initial segment (21).
Finally, perhaps the most exciting development in recent years in this area has been the
realization that GABAA receptors are present outside of the traditional synaptic structure as
extrasynaptic receptors (16,24). These have been shown to be present on a number of different
neuronal types, each possessing a specific extrasynaptic GABAA receptor subtype (16,21,25,26).

POSTSYNAPTIC AND EXTRASYNAPTIC GABAA RECEPTORS MEDIATE PHASIC

AND TONIC INHIBITION
Postsynaptic GABAA receptors are responsible for phasic inhibition. In response to an action
potential, GABA is released from the presynaptic membrane and diffuses into the synaptic
cleft at a high concentration. It binds to and activates the postsynaptic receptors causing the
postsynaptic membrane to hyperpolarise by opening the integral chloride ion channel of the
GABAA receptor. Two processes terminate the action of this phasic release of GABA. One
is a general mechanism involving the rapid removal of the neurotransmitter GABA from
the synaptic cleft by GABA transporters (16,27). A second, GABAA receptor subtype-specific
mechanism, leads to the termination of GABA activation and is governed by the specific kinetic
properties of the receptor. GABAA receptor subtypes exhibit varying rates of desensitization
with many of the synaptic subtypes showing quite rapid rates. Before released GABA can be
removed from the synaptic cleft, GABAA receptors that have been activated can move into a
desensitized closed configuration. Thus phasic GABAergic neurotransmission is determined
by a combination of the structure of the synaptic cleft, the uptake mechanisms for removal of
neurotransmitter from the synaptic cleft, and the kinetic properties of the postsynaptic GABAA
receptor subtypes (16).
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PHARMACOLOGY OF THE GABAA RECEPTOR COMPLEX 367

Many postsynaptic GABAA receptors contain ␥ 2 subunits, which given the linked role
of these subunits with that of gephyrin in postsynaptic localization is perhaps not surprising
(21). This is not a simple one-to-one correlation, however, as ␥ 2 subunit-containing GABAA
receptors have been shown to be located beyond the immediate postsynaptic area (18) and
different neuronal types exhibit differing GABAA receptor subtypes at postsynaptic sites (15).
In contrast to postsynaptic GABAA receptors, some of the best characterized extrasynaptic
GABAA receptor subtypes possess kinetic properties that allow them to function effectively in
the absence of the high concentrations of GABA seen in the synaptic cleft immediately following
phasic release. Low millimolar concentrations of “ambient” GABA are found extrasynaptically
which arise from spillover or leakage from GABAergic synapses and are not likely to exhibit
the rapid changes in concentration seen within a GABAergic synaptic cleft (16,22). Thus, the
combination of ␣6, ␤2 or ␤3, and ␦ subunits, which is found in cerebellar granule cells, and
the ␣4␤2/3␦ combination, which is found in dentate gyrus granule neurones and thalamocor-
tical neurons of the ventro-basal complex, are located extrasynaptically (16,15,24,26,28). These
subunit combinations result in receptors with high affinity for GABA and slow desensitiza-
tion properties. Their high affinity for GABA means that they bind the neurotransmitter even
when it is present at the low concentrations found outside of the synapse. Further, the slow
desensitization properties of some extrasynaptic GABAA receptors means that once they are
activated they produce a longer lasting (tonic) inhibition. These properties are particular to
those receptor subtypes that contain ␣4 or ␣6 subunits in combination with a ␦ subunit (16,22).
It has been estimated that under these particular conditions a greater charge transfer occurs
via such extrasynaptic GABAA receptor-mediated tonic inhibition than that which occurs via
phasic inhibition by postsynaptic GABAA receptors (29). Extrasynaptic GABAA receptors have
been identified that comprise of other subunit combinations, and which exhibit different kinetic
properties; the consequences of this are currently under investigation (18,28).

GABAA RECEPTOR SUBTYPES EXHIBIT SPECIFIC PHARMACOLOGICAL PROFILES

The functional consequences of the cell and subcellular localization of specific GABAA recep-
tor subtypes are not fully understood, but are clearly dependent upon the specific properties
of these different GABAA receptor subtypes. The cloning of GABAA receptor subunit cDNAs
in the late 1980s and early 1990s revealed the existence of the GABAA receptor gene family.
Determination of the contribution that individual subunits make to the physiological and phar-
macological properties of GABAA receptors became the goal of numerous research laboratories
in the following years and relating these to in vivo receptor properties is ongoing. What has
emerged is a picture in which related subunits confer specific physiological features to the
receptor, which include GABA affinity and kinetic properties such as desensitization rates, as
well as pharmacological characteristics such as benzodiazepine binding site affinity and effi-
cacy of benzodiazepine action. Thus, the combinatorial association of different GABAA receptor
subunits exquisitely determines the functional characteristics of GABAA receptor subtypes as
well playing a role in their localization (9,15).
The earliest indication that subunit heterogeneity determined the pharmacological profile
of GABA receptors came a year after publication of the first GABAA receptor cDNA clones
(30,31). Although the 1987 study had indicated that the full pharmacological profile of GABAA
receptors was recapitulated in heterologous expression systems using only the ␣ and ␤ subunits
(31), it became apparent that the benzodiazepine response was not robust and a third subunit
class, the ␥ subunits, needed to be co-expressed with an ␣ and a ␤ subunit in order to achieve
potentiation of GABAA receptor activity with classical benzodiazepines (30).
A molecular explanation of BZ1 and BZ2 binding profile soon followed with ␣1 subunits
conferring the BZ1 binding phenotype and ␣2, ␣3 and ␣5 the BZ2 binding phenotype (30,32,33).
Further, specific amino acids in the N-terminal domains of these ␣ subunits were identified as
being responsible for these different pharmacological profiles (34). In contrast, receptors incorpo-
rating ␣4 or ␣6 subunits with ␤ and ␥ subunits could not bind classical benzodiazepine agonists,
although they did bind antagonists and inverse agonists (see below) (35,36). Thus ␣ subunits
play a key role in the benzodiazepine recognition properties of GABA receptor subtypes.
What of the ␥ subunits? While it was known that they were necessary for benzodi-
azepine recognition (30), it soon became apparent that different ␥ subunit isoforms contribute to
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368 BATESON

benzodiazepine recognition and functional properties in combination with ␣ subunits (37). For
example, in contrast to those containing ␥ 2 or ␥ 3 subunits, ␥ 1-containing receptors show little
affinity for the antagonist flumazenil (Ro15–1788). Further, methyl ␤-carboline-3-carboxylate
(␤CCM), which binds to GABAA receptors at the benzodiazepine site, is a positive modulator at
some receptor subunit compositions and a negative modulator at others (37). Thus both ␣ and
␥ subunits determine the recognition and functional properties of the benzodiazepine binding
site of the GABAA receptor.
The ␦ subunit has a discrete expression profile and is found in combination with a variety
of ␣ and ␤ subunits in place of a ␥ subunit. ␦ subunit-containing receptor subtypes exhibit an
interesting pharmacology in that they do not bind classical benzodiazepine agonists but play
an important role in the mechanism of action of the natural modulators neurosteroids (25).
Recent studies combining DNA mutagenesis, transgenic technology and psychopharma-
cology have shed light on the role played by specific GABAA receptor subtypes in the phar-
macological profile of drugs that act at GABAA receptors (18,38,39). For example, the sedative
properties of the classical benzodiazepine diazepam are mediated via ␣1 subunit-containing
receptors while its anxiolytic properties are mediated by ␣2 subunit-containing receptors at low
receptor occupancy and both ␣2 and ␣3 subunit-containing receptors at high receptor occu-
pancy (28,38). Thus the principle of targeting a single GABAA receptor subtype (or a limited
number) in order to achieve a specific pharmacological outcome has been established.
It is clear therefore that the subunit combination, as well as the site(s) of expression, both
with respect to cell compartment and cell type, should be taken into account when considering
GABAA receptors as therapeutic targets.

THE BENZODIAZEPINE SITE AS TARGET FOR SLEEP MEDICINES

Classical benzodiazepine agonists have long been used as therapeutics for the treatment of
anxiety and sleep disorders but, as indicated above, it is only in recent years that the identities
of their molecular targets have become apparent. A salient lesson from these studies is that the
pharmacology of benzodiazepines, or other compounds that act at the benzodiazepine binding
site of the GABAA receptor, can only be defined when both the compound and the precise
GABAA receptor subtype is specified. While this is currently possible for a number of GABAA
receptor subtypes, particularly the most abundant (␣1,␤2,␥ 2), our lack of a full appreciation of
GABAA receptor heterogeneity in vivo means that this is still a goal rather than a reality.
Progress has been made, however, in defining the molecular site of interaction between
certain benzodiazepines and their binding site on the GABAA receptor protein. Specific amino
acids have been identified on both the ␣ and ␥ subunits that play roles in determining both
the affinity and the efficacy of benzodiazepine interactions. These studies have demonstrated
that the benzodiazepine-binding pocket lies at the interface of the ␣ and ␥ subunit, thereby
explaining why both ␣ and ␥ subunit isoforms play a role in determining benzodiazepine
pharmacological properties (40).
Compounds that act at the benzodiazepine site which are sedative-hypnotics can be
divided into two broad classes; classical benzodiazepine agonists and newer nonbenzodiazepine
agonists. Although chemically distinct, they all bind to the same site on the GABAA receptor
and are believed to produce their actions by similar molecular mechanisms that result in the
potentiation of the actions of GABA leading to an increase in GABAA receptor-meditated inhibi-
tion. The pharmacological differences between these therapeutic agents, both within a class and
between the classes, lie in their specificity of action with respect to GABAA receptor subtypes
and their pharmacokinetics. With respect to the latter, it is obvious that the pharmacokinetic
properties of an ideal hypnotic would include rapid onset of action (to promote sleep induction)
and an appropriate half-life (to limit drug-mediated daytime effects) of both the parent drug
and any active metabolites (2,41).

CLASSICAL BENZODIAZEPINE HYPNOTICS

The classical 1,4-benzodiazepines are hypnotics that also display sedative, anxiolytic, anticon-
vulsant, muscle relaxant and amnesic activities. Those indicated for treatment of insomnia
include estazolam (U.S.A.), flurazepam (U.S.A., U.K.), quazepam (U.S.A.), temazepam (U.S.A.,
U.K.) nitrazepam (U.K.), loprazolam (U.K.), lormetazepam (U.K.) and triazolam (USA) (42,43).
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PHARMACOLOGY OF THE GABAA RECEPTOR COMPLEX 369

Most classical benzodiazepine hypnotics appear not to differentiate between different GABAA
receptor subtypes, although there are a few studies, which indicate that quazepam and
lormetazepam show a 10- and 3-fold, respectively, selectivity for receptors containing ␣1
subunits (30,44).
Significant advances in our understanding of the mechanisms of action of classical benzo-
diazepines have occurred more than the past 10 years, largely due to use of transgenic animal
studies. Therefore we now have a much clearer, though by no means complete, understanding
of which GABAA receptor subtypes mediate specific aspects of the complex pharmacologi-
cal profile of classical benzodiazepine agonists. Unfortunately, these studies have largely used
diazepam as an exemplar and hence we can only draw conclusions based upon the very similar
pharmacodynamic profile that diazepam shares with the currently prescribed classical benzo-
diazepine hypnotics indicated above.
Two sorts of transgenic studies have shed light on this area: gene knock-out mice, where
the expression of a specific GABAA receptor subunit gene is ablated; and knock-in mice, where
a specific amino acid is altered in one subunit to alter its pharmacology (e.g., to change its
recognition properties from diazepam sensitive to diazepam insensitive) (39). These allow the
analysis of the sedative-hypnotic properties of benzodiazepine-site compounds when combined
with such behavioral tests as locomotor activity and loss of righting reflex (39). However, such
studies are not without problems, particularly in knock-out animals where compensation for
the loss of expression of one GABAA receptor gene has been seen in the form of up regulation
of the expression of other GABAA receptor genes (e.g., 45) making interpretation difficult. Thus
in ␣1-subunit knock-out mice diazepam’s hypnotic action was increased, which was opposite
to the effects of the ␣1 subunit-specific hypnotic zolpidem (39,45). In contrast, using ␣1-subunit
knock-in mice it was clearly demonstrated that the sedative effects of diazepam were mediated
via the ␣1 subunit (46,47). Changes in EEG patterns caused by diazepam during sleep are well
known but experiments with knock-in mice suggested that the ␣1 (48) and ␣3 (49) subunits
do not mediate these particular effects, but there is an involvement of ␣2 subunit-containing
receptors in the diazepam-mediated modulation of delta-wave activity (50).

NON-BENZODIAZEPINE HYPNOTICS
There are a number of nonbenzodiazepine compounds of various structural classes that bind
to the benzodiazepine site of the GABAA receptor and which are very effective hypnotics.
These include the so-called “z-drugs” zaleplon (pyrazolopyrimidine), zopiclone and eszopi-
clone (cyclopyrrolones), and zolpidem (imidazopyridine), as well as others such as indiplon
(pyrazolopyrimidine). Some of these are licensed in the USA (43) but, somewhat controversially,
while the “z-drugs” are licensed in the UK, they are not recommended by the National Institute
for Health and Clinical Excellence (42,51,52).
In general these hypnotics all show selectivity for ␣1-subunit containing GABAA receptors,
although to varying degrees. Data from published studies indicate a range of values for affinity
and potency at defined GABAA receptors subtypes, dependent to an extent on the methodology
used by different laboratories.
Zaleplon shows a ∼10 fold higher affinity for ␣1 subunit-containing receptors over those
containing ␣2 or ␣3 subunits, and a ∼30 fold higher affinity over those containing the ␣5 sub-
unit (53). The difference in zopiclone’s affinity for ␣1 versus ␣2, ␣3 or ␣5 subunit-containing
receptors is less (2–6 fold: 53,54,55). Zolpidem shows the greatest selective affinity for ␣1 subunit-
containing receptors compared to those containing ␣2 (5–24 fold), ␣3 (14–19 fold), or ␣5 (>1000
fold) subunits (32,54). One study reported similar values for zolpidem for ␣1 and ␣3 but not
␣2 subunit-containing receptors where they were unable to detect binding of zolpidem (53).
Although not tested on defined receptor subtypes, the S(+)-enantiomer of zopiclone (eszopi-
clone) displays approximately 50- and 25-fold higher affinities for GABAA receptor benzo-
diazepine binding sites in mouse brain than the racemate zolpidem or the R(+)-enantiomer,
respectively (56).
Studies on the relative potency of these drugs at different receptor subtypes further
demonstrates their selectivity for ␣1 subunit-containing receptors, although the actual val-
ues vary markedly from study to study. Overall, it is clear however, that zaleplon, zopi-
clone, eszopiclone, zolpidem and indiplon are more potent at ␣1 compared to ␣2 (2–9 fold)
c31 IHBK059-Sateia March 31, 2010 10:59 Char Count=

370 BATESON

and ␣3 (3–29 fold) subunit-containing receptors (2,57,58). At ␣5 subunit-containing receptors,

however, a different picture emerges which serves to differentiate these compounds further.
Zopiclone shows similar potency to that exhibited at ␣1 subunit-containing receptors (57),
zaleplon and indiplon demonstrate a 3 to 30 fold (study dependent) selective potency for recep-
tors with ␣1 subunits (2,57–59) and two studies report that zolpidem does not potentiate ␣5
subunit-containing receptors at all (57,58).
These findings using defined receptor subtypes concur with those produced using less
reductionist approaches such as isolated neurons, brain membranes or whole animals, which
indicate that all of these compounds act primarily through ␣1-subunit containing receptors (BZ1
type receptors) to produce their pharmacological effects (e.g., 60–63). Only zolpidem, however,
has been investigated using transgenic animals, demonstrating that its sedative effects are
produced exclusively via ␣1 subunit-containing receptors (64).
Another important aspect of the non-benzodiazepine hypnotics’ pharmacology is their
pharmacokinetic profile, in particular their half-lives. The very nature of the use of hypnotics
for the treatment of insomnia dictates that a short half-life is desirable to limit or obviate
day-time effects. The half-lives of these hypnotics are: zaleplon, 1 hour; zopiclone, 4.4 hour;
zolpidem 1.9 (52); and indiplon 1.5 to 2 hour (65). This fits the ideal better than the “short-
acting” benzodiazepines such as temazepam, for example, which has a half life of 9 h (52).
The pharmacodynamic and pharmacokinetic profiles of these nonbenzodiazepine hyp-
notics are markedly suited for the treatment of insomnia. Their selectivity for ␣1 subunit-
containing GABAA receptors predicts a more limited side-effect profile compared to classical
benzodiazepines. Studies using transgenic mice demonstrate that tolerance to the sedative
effects of diazepam require the presence of receptors containing the ␣5 subunit (66). Given
that zolpidem does not act at ␣5 subunit containing receptors, it might be expected that zolpi-
dem would exhibit reduced tolerance and while there is data to support this notion, not all
studies agree (see 67 for discussion). The abuse liability of benzodiazepines is widely rec-
ognized and a number of studies have indicated that nonbenzodiazepine hypnotics present
a lower, albeit non-zero, potential for abuse (52,68,69). Thus the selectivity of nonbenzo-
diazepine hypnotics coupled with their short half lives comprise advantages over classical
benzodiazepines.

THE GABA-AGONIST SITE AS TARGET FOR SLEEP MEDICINES

Given the utility of modulating GABAA receptor activity in order to induce or maintain sleep,
it is perhaps surprising that direct activation of GABAA receptors has not been utilized for
the same end more extensively. Indeed, although ∼60%of GABAA receptors comprise ␣1␤2␥ 2
and there a number of other ␥ subunit-containing receptor subtypes, there are also GABAA
receptors which do not comprise of the appropriate subunit complement for modulation by
benzodiazepines (28). Ligands that act at the GABA-agonist site therefore have the potential to
promote inhibition of neurons that are not modulated by benzodiazepines. Despite this, few
such ligands have been successfully developed as sleep medications. The most promising of
these in recent years was a rigid analogue of GABA, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-
3-ol (THIP) developed under the name gaboxadol, which although reaching phase 3 trials was
withdrawn from further development in 2007 by Lundbeck and Merck due to some safety and
efficacy concerns. Nevertheless, the proof-of-principle was established by the data from pre-
clinical experimentation and clinical trails that gaboxadol is an effective sleep medication that
works via GABAA receptors but by mechanisms distinct from that of the benzodiazepine-site
agonists (2,22,27,70).
Gaboxadol has an interesting pharmacological profile that suggests new possibilities for
targeting the GABAA receptor to promote sleep. It has high potency at ␣4␤3␦ GABAA receptors
with a greater maximum response than GABA, while at receptors containing ␥ subunit instead
of a ␦ subunit gaboxadol is a low potency partial agonist (71). This receptor subtype has been
shown to be present extrasynaptically in thalamocortical neurons of the ventrobasal complex
where they regulate oscillatory activity that is associated with sleep (25,26). Examination of other
GABA-site agonists, particularly with respect to their subtype specificity, has the potential to
develop new hypnotics that target this site (2,22,24).
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PHARMACOLOGY OF THE GABAA RECEPTOR COMPLEX 371

OTHER GABAA RECEPTOR SITES AS TARGET FOR SLEEP MEDICINES

GABAA receptors display a rich pharmacology with a multitude of distinct modulatory sites for
ligands from a variety of chemical classes. Our lack of a complete understanding of the mech-
anisms by which compounds that act at these various sites produce their modulatory activity
and whether (and how) they are receptor-subtype selective, indicates that there is even further
potential for targeting the GABAA receptor beyond that of the benzodiazepine and GABA-
agonist sites. The sleep-promoting effects of barbiturates and alcohol are well established, but
problems of abuse and overdose limit their usefulness.
The general anesthetics halothane and enflurane have been shown to produce a loss of
righting reflex in mice that is mediated in part by the ␤3 subunit of the GABAA receptor (28).
Further, GABAA receptors that contain the ε subunit appear to be less sensitive to the actions
of the general anesthetic propofol (72), demonstrating GABAA receptor subtype specificity. The
loss of consciousness produced by general anesthetics has EEG features that are similar to those
seen in various stages of sleep and it has been proposed that normal sleep and anesthetic-
induced loss of consciousness may share some neuronal pathways in common, particularly
those that involve the thalamus (3). Hence it is possible that a greater understanding of the
molecular and neurobiological mechanisms by which general anesthetics operate via GABAA
receptors may yield novel ways of modulating sleep.
One the most exciting, yet underdeveloped sites on the GABAA receptor, is the target of
a class of natural modulators of GABAA receptor function the neurosteroids (73). It has long
been known that neurosteroids can modulate sleep in both rats (74) and man (75). The recent
finding that activation and modulation of GABAA receptor activity occurs at separate sites on
the receptor (76) coupled with the observation of subunit-selectivity and brain region-specific
action of neurosteroids (73), further indicates that the capacity of the GABA receptor as a target
for novel hypnotics is only likely to increase in the future.

CONCLUSION
The benzodiazepine site of the GABAA receptor has proven to be a most effective site for the
pharmacological manipulation of sleep. Our growing understanding of this receptor family,
in particular: the pharmacological distinctiveness of GABAA receptor subtypes; the diverse
expression patterns of individual GABAA receptor subtypes; and the emerging physiological
roles of specific GABAA receptors subtypes; all indicate that this receptor family is likely to
provide a rich vein for the development of GABAA receptor-mediated hypnotics in the future.

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32 Benzodiazepine Receptor Agonists:

Indications, Efficacy, and Outcome
Andrew D. Krystal
Insomnia and Sleep Research Laboratory, Department of Psychiatry and Behavioral Sciences, Duke
University School of Medicine, Durham, North Carolina, U.S.A.

INTRODUCTION
Many different agents are prescribed to treat insomnia. These agents represent at least 12
different medication classes. Among these classes are agents which mediate their therapeutic
effect by binding to sites on the gamma-aminobutyric acid (GABA) type A receptor complex,
thereby enhancing the inhibition that occurs when GABA binds to this receptor (1,2). These
agents represent a set of chemically related compounds referred to as benzodiazepines and
include triazolam, temazepam, flurazepam, diazepam, alprazolam, lorazepam, and oxazepam
(2) (Table 1). The benzodiazepines can have a diverse set of effects via their modulation of
GABAA receptors. These effects include sedation, anxiolysis, myorelaxation, antiseizure effects,
and psychomotor impairment (2). There appears to be variation among the benzodiazepines
in their profile of relative potency for these effects; however, all of them have some degree of
sleep enhancement. However, only five of these agents are indicated for insomnia treatment by
the U.S. Food and Drug Administration (FDA): triazolam, temazepam, flurazepam, estazolam,
and quazepam (Table 1) (3).Agents that modulate GABAA receptors at the same binding sites as
the benzodiazepines but that are unrelated chemically to these medications have been referred
to as “nonbenzodiazepines” (3). Nonbenzodiazepines indicated for the treatment of insomnia
in the United States include zolpidem, zolpidem CR, zaleplon, and eszopiclone. Together the
benzodiazepines and nonbenzodiazepines have been referred to as “benzodiazepine receptor
agonists” (BzRAs). While these agents are actually allosteric modulators and not agonists,
because this is the most commonly used term for these medications, it will be adopted here as
well (1). The BzRAs have dominated the pharmacologic management of insomnia for the last
50 years. They represent nearly all of the medications that have been approved by the FDA for the
treatment of insomnia during this period. There is a substantial body of literature documenting
their therapeutic effects in the treatment of insomnia. This chapter reviews this literature with
the goal of providing an overview of their indications, the evidence for efficacy, and the data
related to treatment outcome.

INDICATIONS
The first step in determining whether a BzRA might be indicated in a given patient is deter-
mining whether there is an indication to implement treatment for insomnia. This decision
should involve weighing the risks/costs associated with not treating a patient for insomnia
(the adverse effects of the untreated insomnia) against the anticipated benefits and risks of
the available insomnia therapies (3). Factors that should be taken into account when assess-
ing risks include medical and psychiatric conditions the patient may have such as obstruc-
tive sleep apnea, chronic obstructive pulmonary disease, pregnancy, etc., which may alter the
risks of administering particular treatments. Treatment should be administered if at least one
insomnia therapy is expected to deliver improvements in quality of life and/or function that
outweigh the associated side effects and costs. The greater the impairment an individual expe-
riences because of insomnia, the greater is the cost of not implementing treatment and the
greater the possible benefit with treatment and therefore, the greater the motivation to institute
treatment (35).
Once a decision has been made to implement treatment for insomnia, it is then nec-
essary to decide which treatment to administer. In addition to the BzRAs, available options
primarily include nonpharmacologic therapies such as cognitive behavioral therapy (CBT)
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376 KRYSTAL

Table 1 Properties of BzRAs

Sleep-
FDA Sleep-onset maintenance
Agentc indication T max (hr) t1/ (hr) Metabolism efficacya efficacya
2

Flurazepamb Insomnia 0.5–1.5 40–250 CYP2C19 + +

CYP3A4
Quazepamb Insomnia 2 20–120 CYP3A4, + +
CYP2C19
Estazolamb Insomnia 1.5–2 10–24 CYP3A4 + +
Temazepamb Insomnia 1–3 8–20 Glucuronide + +
conjugation
Triazolamb Insomnia 1–3 2–5.5 CYP3A4 + +
Glucuronide
conjugation
Clonazepamb Seizures 1–2 35–40 CYP2B
Anxiety CYP3A4
Acetylation
Lorazepamb Anxiety 1–3 12–15 Glucuronide
conjugation
Alprazolamb Anxiety 1–3 12–14 CYP3A4/5
CYP2C19
Diazepamb Anxiety 0.5–2 20–50 CYP2B,
Muscle CYP2C19
Spasm CYP3A4
Seizures Glucuronide
conjugation
Chlordiazepoxideb Anxiety 0.5–4 5–100 CYP2B,
ETOH CYP2C19
Withdrawal CYP3A4
Glucuronide
conjugation
Zolpidem (CR)c Insomnia 1.7–2.5 2.0–5.5 CYP3A4 + + (CR only)
CYP1A2
CYP2C9
Zaleplonc Insomnia 1.1 0.9–1.1 Aldehyde +
Oxidase;
CYP3A4
Eszopiclonec Insomnia 1.3–1.6 6–7 CYP3A1 + +
CYP2E1
a
Efficacy in at least one double-blind, placebo-controlled trial employing either self-report or polysomnographic endpoints.
b
Benzodiazepine.
c
Nonbenzodiazepine; t1/2 includes the half-lives of the parent compound and major active metabolites.
Abbreviations: CYP, Cytochrome P450.
Information in the table is from Refs. 4–34.

for insomnia, antidepressants, antipsychotics, anticonvulsants, melatonin receptor agonists,

and antihistamines (3). In determining which therapy to recommend, the anticipated risks
and benefits of all of the treatment options should be weighed and discussed with the
patient in the context of their personal preferences. The treatment which has the over-
all most favorable risks-to-benefits ratio taking all of these factors into account should be
recommended (3).
In order for clinicians to effectively carry out this decision-making process, they must have
access to data from placebo-controlled trials delineating the therapeutic and adverse effects of
the insomnia treatment options in the population of the patient in question (same age range,
comorbid condition, etc.). The BzRAs and the melatonin agonist ramelteon are the medications
currently in common use that have by far the strongest empirical support and have an indication
for insomnia treatment from the FDA (3). CBT also has a strong empirical basis (36). It is
noteworthy that some of the most commonly administered insomnia medications, including
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BENZODIAZEPINE RECEPTOR AGONISTS: INDICATIONS, EFFICACY, AND OUTCOME 377

antidepressants, antipsychotics, and anticonvulsants, have yet to be studied in controlled trials

in insomnia patients and are prescribed “off label” (3,37). Without controlled trials of these
agents, it is not possible to determine on empirical grounds whether they might be indicated
for use over BzRAs in a given patient. However, there are some factors relevant to deciding
whether treatment with a BzRA is indicated that do not derive from placebo-controlled clinical
trials.
One such consideration is abuse potential. Some degree of abuse potential exists for all
BzRAs; therefore, another therapy should be considered when abuse is a concern (3). However,
it is important to note that the population of insomnia patients that is at risk for abuse of
BzRAs is actually relatively small (38). The available evidence suggests that insomnia patients,
by and large, take their medications for therapeutic purposes and do not abuse insomnia agents
(39). Abuse of BzRAs appears to be limited to a relatively small subgroup of polysubstance
abuse-prone individuals (38,39). As a result, when treating a patient known not to have a
history of substance abuse, the risk of abuse is extremely small and should not be a significant
factor in considering treatment options. However, in many cases, it remains uncertain whether
the patient in question may be abuse prone and in these circumstances some risk of abuse
should be assumed in making treatment decisions. It is important to note that abuse potential
is not related to duration of medication therapy. It is as likely on the first day of treatment as
the 1000th. Dependence [seeking medication because of loss of benefit over time (tolerance),
withdrawal, or drug inaccessibility], however, is a phenomenon that increases in likelihood the
longer the duration of treatment. The tendency for this to occur can only be determined from
placebo-controlled trials of treatment (discussed in the following section).
Another important consideration in deciding whether a particular BzRA might be indi-
cated in a patient is the route of metabolism. This factor becomes particularly important when
treating individuals with significant hepatic or renal disease. Those agents, which are primarily
metabolized via a hepatic cytochrome P450 pathway, will be relatively more affected by hep-
atic disease than those metabolized via glucuronide conjugation or other mechanisms (40). This
would suggest that, among the BzRAs, the use of temazepam and lorazepam would be relatively
preferred in this setting (Table 1) (41–44). In those with significant renal disease, agents elim-
inated by glucuronide conjugation are relatively contraindicated. Among BzRAs this includes
temazepam, lorazepam, chlordiazepoxide, diazepam, and triazolam (41–44).
A final treatment-related consideration related to the choice of BzRAs versus other thera-
pies is the relative availability, feasibility, and likelihood of efficacy of nonpharmacologic ther-
apy. CBT for insomnia is a highly effective form of treatment, which is primarily limited by the
lack of availability of trained practitioners in clinical settings (45). As a result, despite a substan-
tial literature supporting the use of this treatment, many practitioners turn to pharmacotherapy
such as BzRAs (45). In some individuals, medications are preferable due to unwillingness or
inability to undergo CBT or a lack of maladaptive behaviors/cognitions that are targeted by
CBT (46).
These considerations should complement the evidence base as a means to optimize ther-
apy rather than serve as a basis for making decisions that are not supported by the available
data. As we will review in the next section, a substantial body of data from placebo-controlled
trials has been collected on the effects of BzRAs in insomnia patients. The available studies far
outnumber those of any other insomnia medications and provide data on the efficacy and safety
of BzRAs that can be used as a basis for clinical decision making.

EFFICACY
This section reviews the available double-blind, placebo-controlled trials of the treatment of
insomnia with BzRAs. Efficacy has been assessed via continuous measures of self-reported or
polysomnographic sleep-onset latency or sleep maintenance (either wake time after sleep onset
or number of awakenings) as has long been the standard in insomnia research. The results are
organized for presentation into the following subsections: (1) efficacy in adults with primary
insomnia, (2) efficacy in older adults with primary insomnia, (3) efficacy in children, (4) efficacy
in comorbid insomnia, (5) efficacy as a function of treatment duration, (6) efficacy in intermittent
dosing, and (7) comparative efficacy studies.
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Table 2 BzRA Dosages with Efficacy in ≥1 Double-Blind, Placebo-Controlled Trials

Onset in Onset in Maintenance Maintenance

adults elderly in adults in elderly Efficacy in comorbid
Agent (mg) (mg) (mg) (mg) insomnia
Flurazepam 15 30 30
30
Quazepam 30 30
Estazolam 1 1
2 2
Triazolam 0.25 0.125 0.5 0.125 RA: 0.125–0.25 mg
0.5 0.25 0.25 COPD: 0.125–0.25 mg
0.4 0.4
0.5 0.8
0.8
Temazepam 30 30 7.5–30
Zolpidem 10 5 10 Menopause: 10 mg
COPD: 10 mg
Zolpidem CR 12.5 12.5 MDD: 12.5 mg;
GAD: 12.5 mg
Zaleplon 10 5
20 10
Eszopiclone 2 2 2 2 MDD: 3 mg; GAD: 3 mg;
3 3 RA: 3 mg; Menopause: 3 mg
Abbreviations: MDD, major depressive disorder; GAD, generalized anxiety disorder, RA, rheumatoid arthritis.
Information in the table is from Refs. 4–34 and 47–59.

Efficacy in Adults with Primary Insomnia

Up to this point in time, there have been 22 double-blind, placebo-controlled studies of the
treatment of primary insomnia patients with BzRAs in adults where a significant difference
compared with placebo was reported on at least one sleep-onset or sleep-maintenance measure
(Table 2) (5,7,9–12,14,17,18,20,22,24,25,27–31,34,75). One challenge in applying this body of lit-
erature to clinical practice is uncertainty about how to best account for the variation among
agents in the number of positive studies. The tendency, particularly in the past, not to publish
negative studies makes it difficult to assume efficacy when there has only been one positive
study, as is the case for several BzRAs.
The available studies provide evidence of sleep-onset efficacy in adults for triazolam (three
studies), flurazepam (two studies), estazolam (two studies), quazepam (one study), temazepam
(one study), zolpidem (five studies), zolpidem CR (two studies), zaleplon (three studies), and
eszopiclone (three studies). On this basis, triazolam, flurazepam, estazolam, zolpidem, zolpidem
CR, zaleplon, and eszopiclone could be considered for the treatment of sleep-onset problems in
adults with relative confidence. There is also evidence for sleep-maintenance efficacy in adults
for triazolam (one study), flurazepam (one study), estazolam (three studies), quazepam (one
study), temazepam (one study), zolpidem (one study), zolpidem CR (two studies), and eszopi-
clone (3 studies). The strongest support for sleep-maintenance efficacy exists for estazolam,
zolpidem CR, and eszopiclone. These same agents have the strongest base of support for use in
patients with both onset and maintenance problems.

Efficacy in Older Adults with Primary Insomnia

In the elderly, 11 double-blind, placebo-controlled trials of the treatment of primary insomnia
have been carried out (6,8,13,15,16,19,21,23,26,32,33). Sleep-onset efficacy has been reported for
triazolam (five studies), flurazepam (two studies), zolpidem (one study), zaleplon (two stud-
ies), and eszopiclone (two studies). Evidence for sleep-maintenance efficacy in this population
exists for triazolam (three studies), flurazepam (one study), temazepam (one study), and eszopi-
clone (two studies). The available data provide relative support for the efficacy of triazolam,
flurazepam, zaleplon, and eszopiclone in addressing sleep-onset problems in older adults, and
triazolam and eszopiclone for treating sleep-maintenance problems in this population.
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Efficacy in Children with Insomnia

The most glaring deficiency in the literature on the treatment of insomnia with BzRAs is the
absence of any placebo-controlled trials in children (3).
In fact, there has yet to be a placebo-controlled trial of any insomnia agent in this pop-
ulation. Given the fact that pharmacotherapy of insomnia in children is common in clinical
practice, such studies are greatly needed (60).

Efficacy in Comorbid Insomnia

Twelve studies of the treatment of insomnia comorbid with medical and psychiatric conditions
have been carried out with BzRAs (Table 2) (47–59). Agents with a significant effect versus
placebo on sleep in patients with comorbid major depressive disorder (MDD) are lormetazepam,
clonazepam, eszopiclone, and zolpidem CR (48–52). Each was the subject of one published
trial in this population. Eszopiclone and zolpidem CR have also been noted to have efficacy
in a study of the treatment of insomnia occurring with generalized anxiety disorder (GAD)
(53,59). In patients with insomnia occurring with rheumatoid arthritis, both eszopiclone and
triazolam were reported to improve sleep versus placebo in a single study (57,58). Triazolam has
been reported to have efficacy in the treatment of insomnia occurring with chronic obstructive
pulmonary disease in two studies, while the efficacy of zolpidem in this population has been
noted in one study (55,56). Lastly, single studies demonstrate the efficacy of zolpidem and
eszopiclone in the treatment of menopausal insomnia (47,54).

Efficacy as a Function of Treatment Duration

The duration of treatment for which efficacy has been demonstrated may also be relevant to
clinical decision making. Because it is not possible to predict how long any individual will
experience insomnia, it is not possible to plan in advance how long pharmacotherapy will be
needed (3). As a result, periodic trial discontinuations may be helpful to determine the ongoing
need for medication via carrying out risk–benefit analyses of continued therapy following each
trial tapering of medication (3). At the same time, it is important to know how long efficacy can
be expected with a given agent to plan such trial discontinuations.
Despite the high prevalence of long-lasting insomnia, large-scale pharmacologic trials of
treatment beyond four to five weeks have only recently been carried out (14,16,61,62). These
studies contradict the long-held view that the pharmacologic treatment of insomnia with BzRAs
for longer periods of time is inevitably associated with tolerance (loss of benefit over time)
and/or withdrawal symptoms (63). The available data do not rule out the possibility that such
dependence phenomena occur in some individuals (the risk depends on the agent and dosage
and may vary among individuals); however, it has now been established that dependence phe-
nomena are not characteristic of nightly treatment for up to one year with some agents. Among
the BzRAs, eszopiclone has been the subject of two placebo-controlled trials demonstrating
efficacy over six months of nightly treatment (14,62). In one of these studies, subjects were
switched to single-blind placebo therapy for an additional six months during which there was
evidence for continued efficacy out to one year (76). An open-label study of zaleplon employing
nightly treatment for up to one year provided evidence for minimal adverse effects occurring as
a function of treatment duration (61). For other agents commonly in use, the longest durations
of efficacy that have been demonstrated in controlled trials are eight weeks for temazepam (in
the elderly) and five weeks for zolpidem and zaleplon (9,16,25,30). All of the other BzRAs have
been studied for maximal periods of four weeks or less.

Efficacy in Intermittent Dosing

It is important to note that the studies discussed so far have employed nightly dosing of
medication. Intermittent dosing, prescribed to approximately 41% of insomnia patients, is a
potential means to lower costs and lessen exposure to medication’s side effects, particularly
over longer periods of treatment (3,64). Three placebo-controlled studies of the intermittent
dosing of BzRAs have been carried out in primary insomnia patients (18,28,34). Two of these
demonstrated the efficacy of zolpidem when dosed three to five nights per week for periods
of two and three months (18,28). One additional study reported the efficacy of zolpidem CR
when dosed three to seven nights per week over a six-month period (34). These studies, which
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380 KRYSTAL

set minimum and maximum requirements for pill-taking each week, provide the best available
indicators of the properties of “as needed” dosing of insomnia medication. Studies of true
“as needed” dosing will be needed to determine if the required pill-taking frequencies in these
studies affected the results. In terms of the clinical application of these findings, we currently lack
data to indicate which patients with insomnia are best treated with this regimen. From a practical
viewpoint, the effective implementation of intermittent dosing requires that an individual must
be able to predict prior to going to bed that they are likely to have sleep difficulty (3). While
there may be some individuals who can effectively implement dosing following unsuccessful
attempts to sleep, there is a concern that this practice might be problematic from a behavioral
viewpoint. Such a practice may increase the focus on sleep and contribute to the perpetuation
of conditioned insomnia through allowing patients to experience ongoing sleep difficulty (3).

Comparative Efficacy Studies

Eleven studies have been carried out, which compared the efficacy of BzRAs to the efficacy of
(1) other BzRAs or (2) other treatments (7,8,16,19,24,26,27,65,66,67). The following comparisons
of medication therapies have been carried out: estazolam 2 mg versus flurazepam 30 mg, zale-
plon 10 to 20 mg versus triazolam 0.25 mg, zolpidem 10 mg versus trazodone 50 mg, triazolam
0.25 mg versus flurazepam 15 mg, triazolam 0.4 to 0.8 mg versus flurazepam 15 to 30 mg, triazo-
lam 0.25 to 0.5 mg versus 250 to 500 mg chloral hydrate, and eszopiclone 3 mg versus zolpidem
10 mg (7,8,12,19,24,26,27,65,66). Generally, these studies were not powered to detect differences
between the active treatments. Their primary aim was focused on documenting differences
between the active treatments and placebo. It is not surprising, therefore, that significant differ-
ences in sleep effects between medication therapies were only reported for two studies. In one
of these studies, triazolam 0.5 mg led to shorter sleep-onset latency and fewer awakenings than
250 to 500 mg of chloral hydrate, while triazolam 0.25 mg was associated with longer total sleep
time than both dosages of chloral hydrate (66). The other study, carried out in elderly insomnia
patients, reported that triazolam 0.25 mg led to significantly longer total sleep time and higher
ratings of sleep quality and restedness in the morning compared with flurazepam 15 mg (19).
When interpreting these data, it is important to bear in mind that the results apply only to the
dosages assessed, which may not have been optimal in some cases.
Two studies have been carried out comparing BzRAs (zolpidem 10 mg and temazepam
7.5 to 30 mg) with CBT (16,67). A limitation of these studies is that they employed a control for
pill-taking but did not employ a control for the behavioral therapy administered. These studies
did not find significant differences between the treatments during acute therapy; however, in
follow-up assessment, advantages for CBT over temazepam 7.5 to 30 mg and zolpidem 10 mg
were observed (16,67). It is important to note that the follow-up assessments were carried out
following BzRA discontinuation. As a result, they speak more to the degree of insomnia present
after a period of BzRA therapy rather than to the acute therapeutic effects of these agents. The
findings suggest that greater persistence of benefit occurs after a course of CBT than occurs
following discontinuation of a period of treatment with temazepam or zolpidem in primary
insomnia patients.

OUTCOME
The studies of the efficacy of BzRAs reviewed in the prior section provide an important basis
for making treatment decisions. However, they reflect only one aspect of outcome. In clinical
practice it is necessary to take other considerations into account, such as treatment-emergent
adverse effects and the degree of improvement in function occurring with treatment. Here, we
have reviewed the available literature on the effects of BzRAs on nonsleep aspects of outcome
as well as global outcome measures. The following five types of outcomes are reviewed in
the subsequent sections: (1) syndromal insomnia measures, (2) patient and clinician global
impressions, (3) measures of daytime function, (4) the severity of comorbid conditions, and (5)
adverse effects of treatment.

Syndromal Insomnia Measures

Measures that assess the entire constellation of features that constitute the syndrome of insomnia
have only recently been employed as outcome measures in placebo-controlled trials of BzRAs. A
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syndromal insomnia measure that has been used in several BzRA trials is the Insomnia Severity
Index (ISI) (68). The ISI consists of seven items, each of which is a 5-point Likert scale rating
of a DSM-IV defined insomnia symptom. Several thresholds for defining levels of insomnia
severity have been established—ISI 0 to 7: not clinically significant; ISI 8 to 14: subthreshold
insomnia; ISI 15 to 21: moderate insomnia; ISI 22 to 28: severe insomnia (62,68,69). Significantly
greater improvement versus placebo in the ISI total score has been reported in a number of
recent controlled trials of eszopiclone in adults and elderly with primary insomnia, insomnia
comorbid with MDD, and in menopausal insomnia (15,49,54,58,62). In three of these studies,
active treatment led to a significantly greater percentage of the subjects meeting ISI criteria for
subthreshold and not clinically significant insomnia and a lower percentage meeting criteria
for moderate and severe insomnia compared with placebo (49,54,62). These studies provide
evidence that treatment leads to improvement in the overall severity of the insomnia syndrome
and significantly increases the percentage of individuals who are not substantively affected by
the disorder. These studies illustrate how a syndromal measure could have relevance to clinical
practice and speak to the need to adopt consensus response and remission criteria and employ
them in controlled trials of BzRA treatment.

Patient and Clinician Global Impressions

While not a specific measure of the insomnia syndrome, global impression data can also provide
valuable, highly clinically relevant outcome data. These data have also been used to generate
categorical response criteria analogous to the analyses carried out with ISI data discussed in
the previous section. Several recent studies have employed global impression assessments com-
pleted by patients (PGI) and/or clinicians (CGI) (18,34,53). In a three-month study in primary
insomnia patients, zolpidem 10 mg dosed three to five nights per week led to significantly
greater improvement in CGI score than placebo treatment (18). Zolpidem CR taken three to
seven nights per week for six months by primary insomnia patients led to a greater percentage
of responders (rating of much improved or very much improved with treatment) on both CGI
and PGI compared with placebo (34). In a study of the treatment of insomnia comorbid with
GAD, subjects treated with eszopiclone 3 mg and escitalopram had greater CGI improvement
ratings than subjects treated with placebo and escitalopram (53).

Measures of Daytime Function

Syndromal and global measures of insomnia take into account daytime function; however,
they do not provide a specific indicator of the degree of functional impairment. While impair-
ment in daytime function is required in order to make a diagnosis of insomnia according to the
established criteria, measures of daytime function have generally not been included in insomnia
outcome assessment and have never been among the primary outcome measures in an insomnia
treatment trial (35,70). No studies have been powered to detect effects on a measure of daytime
function and no studies have required that subjects have daytime impairment on any instrument
as a requirement for study entry (35). These factors decrease the likelihood of finding a significant
effect of treatment on daytime function. For this reason, we review the studies of BzRAs that had
a significant effect versus placebo on at least one measure of daytime function but do not cite the
studies where no effect was found. Seven studies of eszopiclone dosed at 3 mg in adults and 2
mg in older adults reported significant effects on at least one measure of daytime function which
included (1) Likert ratings of “daytime alertness,” “ability to concentrate or think clearly,” “abil-
ity to function,” or “sense of physical well-being” (14,49,53,54,58,62,71); (2) a decrease in napping
among those who napped (15,71); (3) morning sleepiness ratings (71); (4) the Epworth Sleepiness
Scale (62); (5) the Fatigue Severity Scale (62); (6) the Quality of Life Enjoyment and Satisfaction
Questionnaire (QLESQ) (71); (7) the Work Limitations Questionnaire (62); (8) either the “vital-
ity,” “physical functioning,” or “social functioning” subscales of the SF-36; (15,62) and (9) at least
one subscale of the Sheehan Disability Scale (54,62). Zolpidem 10 mg was reported to have a sig-
nificant effect versus placebo on the SF-36 “vitality” subscale in patients with MDD in remission
who had residual insomnia (72). In a study of intermittent dosing with zolpidem CR 12.5 mg
in primary insomnia patients, significant effects were observed on Likert ratings of “morning
sleepiness” and “ability to concentrate,” as well as the Epworth Sleepiness Scale (34). These
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382 KRYSTAL

findings indicate the potential for BzRAs to improve daytime function and suggest the need for
better integration of measures of daytime function into insomnia research and clinical practice.

Severity of Comorbid Conditions

The majority of chronic insomnia occurs in association with medical and psychiatric disorders
(73). For many years, chronic insomnia was viewed as a symptom of these medical and psy-
chiatric conditions (63). As such, guidelines recommended treating the causative underlying
condition and discouraged administering insomnia-specific treatment (63). However, recent
studies have provided convincing evidence that this view is incorrect and suggest that the rela-
tionship between insomnia and comorbid conditions is complex and, in some cases, the causality
may be bidirectional (3). This emerging view legitimizes the use of measures of the severity
of the comorbid medical and psychiatric conditions associated with insomnia in assessing the
outcome of insomnia treatment. Six studies have reported statistically significant improvement
in measures related to the severity of associated medical or psychiatric conditions with BzRA
therapy compared with placebo (49,51,53,54,57,58). One of these was a study of the treatment of
insomnia comorbid with MDD where greater improvement in the Hamilton Depression Rating
Scale (HAM-D) occurred with clonazepam compared with placebo (51). Greater improvement
in the HAM-D with and without the sleep items as well as a greater depression remission
and response rate were also noted with eszopiclone 3 mg compared with placebo (49). Eszopi-
clone 3 mg also improved the HAM-D as well as the Hamilton Anxiety Scale (HAM-A) to a
significantly greater extent than placebo in patients with insomnia comorbid with GAD (53).
Two studies have demonstrated improvement in pain in patients with insomnia occurring in
association with rheumatoid arthritis (57,58). In the first such study, triazolam 0.125 to 0.25 mg
significantly improved morning stiffness ratings compared with placebo (57). The second study
reported that eszopiclone 3 mg led to significantly lower Arthritis Efficacy Scale score, lower
pain severity ratings, and fewer tender joints than placebo (58). Lastly, in a study of the treatment
of menopausal insomnia, eszopiclone 3 mg led to significant improvement in the Menopause
Specific Quality of Life Scale, the Greene Climacteric Scale Score, and the Montgomery–Asberg
Depression Rating Scale score, and also decreased awakenings due to hot flashes compared
with placebo (54). These studies provide clear evidence that the treatment of insomnia with at
least some BzRAs can improve the severity of comorbid medical and psychiatric conditions.
Whether this is a byproduct of improving insomnia or is a specific effect of these agents remains
unresolved. However, recent studies of insomnia comorbid with GAD and MDD treated with
zolpidem CR 12.5 mg reported significant improvement in sleep compared with placebo but did
not note corresponding improvement in depression or anxiety severity (48,59). These findings
may suggest that some of the effects of BzRA treatment on the severity of comorbid condi-
tions may be medication specific, though other factors such as differences in study design may
confound interpretation.

Adverse Effects of Treatment

In making treatment decisions and assessing the outcome of therapies, the beneficial effects
of treatment must be weighed against the associated adverse effects. The available studies are
relatively limited in their capacity to detect between-treatment differences in adverse effects.
Studies have generally not been powered to detect differences from placebo in adverse effects.
Further, adverse effects data are derived from spontaneous symptoms reported and not from a
systematic or standardized assessment of symptoms. As a result, instead of including studies
where significant differences were found between BzRAs and placebo, we report the relative
rates of adverse effects in these groups. This overview is focused on data from studies in the
elderly as this population is relatively vulnerable to a number of potential BzRA adverse effects.
We, therefore, expect that studies in older adults provide a more sensitive indicator of potential
adverse effects than studies in younger adults. The results are broken down into two groups:
(1) daytime sedation and (2) other adverse effects.
Daytime sedation: One study reported a statistically significantly greater rate of incidence
of somnolence as an adverse event with flurazepam compared with placebo and temazepam
(74). Relative frequencies of somnolence in BzRA therapies and placebo that have been reported
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are zolpidem 5 mg 10% versus zaleplon 10 mg 4% versus placebo 2% (6) and eszopiclone 2 mg
6.6% versus placebo 5.5% (15).
Other adverse effects: Temazepam dosed at 7.5 to 30 mg was associated with an 8% overall
incidence of adverse effects compared with 11% for placebo treatment (16). Zolpidem 5 mg was
noted to have a rate of CNS adverse effects of 25% versus 14% with placebo and zaleplon 10 mg
(6). Eszopiclone 2 mg led to unpleasant taste in 12% compared with 0% in placebo, dizziness in
6% versus 2% in placebo, and dry mouth in 7% compared with 2% in the placebo group (15).
In summary, the available data would suggest a relatively low rate of adverse effects for
the BzRAs compared with placebo. However, adverse effects data were available for a limited
number of the BzRAs.

CONCLUSIONS
BzRAs consist of the benzodiazepines and a chemically unrelated set of medications (zolpidem,
zaleplon, eszopiclone), which affect sleep via a related mechanism. These agents have domi-
nated the pharmacologic treatment of insomnia for the last 50 years. Nine BzRAs are indicated
for insomnia treatment by the FDA. A risk–benefit analysis should be used to decide whether
to administer treatment for insomnia in an individual, whether to use a BzRA, and which BzRA
to use. This analysis should be based on the published placebo-controlled trials of insomnia
therapies. More studies have been carried out documenting the efficacy and adverse effects of
BzRAs than any other agents. A number of BzRAs have been documented to have efficacy in
the treatment of sleep onset and/or maintenance difficulties with relatively minimal risk of
adverse effects. The available literature has some significant limitations, most notably the
complete absence of any controlled trials of insomnia pharmacotherapy in children. Another
gap in the literature is limited availability of studies of some of the most commonly prescribed
insomnia agents in key comorbid conditions. In addition to data from placebo-controlled trials,
there are some other factors that should be considered when deciding whether a BzRA is indi-
cated for a given patient, including abuse potential, route of metabolism, and the availability
and feasibility of other treatments. There is also a small amount of evidence that BzRAs have
therapeutic effects on syndromal measures of insomnia, global outcome, and daytime function.
Further studies employing such outcomes are needed to better characterize the treatment effects
of BzRAs.

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33 Benzodiazepine Receptor Agonist Safety

Timothy Roehrs and Thomas Roth
Sleep Disorders and Research Center, Henry Ford Hospital, and Department of Psychiatry and Behavioral
Neuroscience, School of Medicine, Wayne State University, Detroit, Michigan, U.S.A.

INTRODUCTION
The major side effect and safety issues associated with benzodiazepine receptor agonist (BzRA)
hypnotic use include psychomotor and cognitive (i.e., anterograde amnesia) impairment,
parasomnia-like episodes, discontinuation effects, and dependence liability. Some of these side
effects are mediated by the primary pharmacodynamic activity, sedation, of BzRAs and directly
relate to the pharmacokinetic properties of specific BzRAs. Other side effects can be attributed
to both pharmacokinetics and receptor selectivity of the drug. Finally, drug dose, duration of
use, and concomitant medications, comorbid medical, or sleep disorders may determine side
effects.
The side effect–safety profile of the BzRAs has to be weighed against the various alterna-
tives to treating insomnia, including no treatment, self-treatment, and alternative nonhypnotic
medications (i.e., drugs used as hypnotics that have sedative effects but are indicated for another
disorder). Unfortunately, comparisons to alternative nonhypnotics are limited by the fact that
there is little systematic information regarding the safety of the various alternative medica-
tions being used as hypnotics. This includes an absence of data at the lower doses frequently
used for sleep and for the effects on sleep-related activity (e.g., rebound insomnia, effects on
sleep-related breathing disorders). Importantly, the risks associated with nontreatment and self-
treatment also have to be compared with those of the BzRAs. The risks of nontreatment and
self-treatment are known.
This chapter will review the evidence and discuss the determinants of the side effects of
BzRA hypnotics. It will compare these risks to the risks associated with alternative drugs used
as hypnotics and self-treatment, as well as those risks associated with no treatment. Finally,
we will discuss ways by which the clinician can minimize the various side effect–safety risks
associated with BzRAs.

Benzodiazepine Receptor Agonist Risks

Psychomotor Impairment
Psychomotor impairment with BzRAs has been shown on various measures (i.e., as slowed
reaction times, response errors, tracking errors, lapses of attention, and driving deviations) in
laboratory performance testing and on actual roadway driving assessments. At their peak
plasma concentrations BzRA-associated impairments relate directly to the level of plasma
concentration, which is a function of dose. To illustrate, a study compared the daytime admin-
istration effects of 0.125, 0.25, and 0.50 mg triazolam; 5, 10, and 20 mg zolpidem; and 15,
30, and 60 mg temazepam (1). These BzRAs were compared on the basis of their differing
pharmacokinetics and receptor selectivity. Temazepam is known to be longer acting than zolpi-
dem and triazolam, and zolpidem is considered to be more receptor selective than triazo-
lam and temazepam. Each drug—zolpidem, triazolam, and temazepam—produced orderly
dose-related impairment in learning and recall and psychomotor performance at their peak
concentrations (1).
The duration of the impairment relates to the duration of action mediated by both the
half-life and dose of a specific BzRA. In the study cited earlier, the functions relating impairment
to time since ingestion for the three drugs revealed a six-hour duration impairment relative to
placebo with 60 mg temazepam and a three-hour duration impairment with 20 mg zolpidem,
although these two drugs and doses had comparable impairing effects at their peak (1). Although
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388 ROEHRS AND ROTH

zolpidem is considered more GABAA ␣1 -receptor selective than triazolam and temazepam, it
did not produce a differential pattern of impairment.
When the BzRA impairment extends to the morning following a nighttime administration,
this impairment is referred to as “residual effects.” Residual effects are merely the prolongation
of the therapeutic effect of the drug into next-day wakefulness. BzRAs with longer durations of
action, as determined by the half-life of the drug and secondarily by the dose of the drug (e.g.,
higher doses and longer half-lives extend duration of action), are more likely to produce residual
effects. Using performance and driving assessments and the Multiple Sleep Latency Test (MSLT),
studies have found differences in residual effects between short- and long-acting drugs and
between doses of the same drug. For example, an early study in healthy elderly compared the
daytime residual effects of triazolam 0.25 mg and flurazepam 15 mg administered before sleep
(2). Both drugs produced a comparable one hour increase in total sleep time, but flurazepam, a
long-acting drug, produced increased daytime sleepiness on the MSLT the following day, while
triazolam, a short-acting drug, reduced sleepiness on the MSLT. In the same study, next-day
vigilance performance was impaired with flurazepam, but not with triazolam.
Given a desired sleep period of eight hours, middle-of-the-night administration of a short
half-life drug (i.e., three to five hours) is likely to produce residual effects. In other words, the
likelihood of residual effects is determined by the time of administration relative to the desired
time of arising and the pharmacokinetics of the given drug. A study comparing the residual
effects of the short half-life drug (2.5–4.5 hours), zolpidem (10 mg), with the ultra short half-life
drug (1 hour), zaleplon (10 mg), illustrates this point (3). The drugs were administered in the
middle of the night at either 3, 4, 5, or 6 AM before a desired 8 AM awakening, translating to an
awakening that occurred—two to five hours postadministration. Zolpidem produced residual
effects on digit symbol substitution and immediate and delayed memory recall after all middle-
of-the-night administrations, but zaleplon administration had no effects at 8 AM, even after the
6 AM (two hours postadministration). The FDA label for recently approved hypnotics, given
their distinct pharmacokinetics, now includes the caution that “x” hours be devoted to sleep
when using the medication. For example, the zaleplon label cautions four or more hours, while
the zolpidem-CR formulation cautions eight hours.
Falls in the elderly are often cited as a special case of psychomotor impairment associated
with BzRAs, either due to elevated peak plasma concentrations or residual effects. Several ques-
tions arise, including whether the reported association is unique to BzRAs, whether that risk is
greater than the untreated condition, and if truly associated, how it can be minimized, which
will be discussed later. Falls in the elderly are not unique to BzRAs, which are not independent
predictors of falls when controlling for comorbid diseases. A case–control study of community-
living persons aged 66 years and older who visited emergency departments for injurious falls
during one year in a Canadian health district identified seven medication classes, including
sedatives, that were associated with falls (4). After controlling for comorbid conditions, nar-
cotics, anticonvulsants, and antidepressants were independent predictors, but not hypnotics.
In a prospective study of elderly women and fractures, narcotics and antidepressants were
associated with increased risk for fractures, while benzodiazepines and anticonvulsants were
not independent predictors (5).
There are data to suggest that sleep problems and daytime sleepiness in elderly are
independent factors increasing risk of accidental injury and falls. A representative sample
of elderly adults from northern California was surveyed by telephone (6). Nighttime sleep
problems were a risk for fractures and remained so after controlling for demographic variables
and concurrent medical diseases. A more recent study assessing the risk of BzRA-associated falls
in elderly controlled for insomnia (7). This large study of nursing home residents in Southeastern
Michigan found that insomnia represents a significant risk for falls but BzRAs do not. Thus, the
risk of falls associated with BzRAs was actually less than untreated insomnia.

Cognitive Impairment
Another major side effect of BzRAs is cognitive impairment, most typically anterograde amne-
sia. Anterograde, in contrast to retrograde, amnesia is failure to recall information presented
after consumption of the drug. The degree of amnesia is determined by the level of plasma
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BENZODIAZEPINE RECEPTOR AGONIST SAFETY 389

concentration at the time of information input. It can be because of attentional and/or consolida-
tion failures in the memory process. At peak plasma concentration, very orderly dose-dependent
amnesic effects have been demonstrated for BzRAs (1). The amnesia is, in part, related to the
sedative effects of the BzRAs, as the degree of the amnesia parallels the sedative effects of the
drug as measured by the MSLT (8). Failure to consolidate the newly acquired material is one
cause of the amnesia. This explanation is supported by a study in which the drug-induced rapid
return to sleep was delayed for 15 minutes (i.e., wakefulness was maintained for 15 minutes)
and memory was preserved (9). The extent to which the sedative effects mediate the amnesic
effects has been debated extensively. Several studies have attempted to dissociate these two
effects. The amnestic effects of drugs with differing sedative effects were compared, or the
antagonist, flumazenil, was used to dissociate sedative and amnestic effects, but the studies
had equivocal results (10,11). The problem in these studies was that sedation was self-reported
rather than objectively assessed. Another important complication is that sleep, even brief sleep
periods, produce retrograde amnesia.
Amnesia is associated with the receptor selectivity of the BzRAs. These act as allosteric
modulators of GABAA receptors and gene knockin studies have identified and characterized
various GABAA receptor subunits for their pharmacological profiles (12). The animal data
indicate that the ␣1 -receptor subtype mediates both the sleep and amnesic effects of the BzRAs
(12). When zolpidem, a nonbenzodiazepine hypnotic, was introduced, it was hypothesized that
because of the receptor selectivity of zolpidem, amnesia could be avoided. But, as noted above,
the ␣1 -receptor–selective agent zolpidem did not differ from nonselective benzodiazepines in
its amnesic effects (1). Zopiclone and its S-isomer, eszopiclone, are less selective for ␣1 -receptors
than zopidem and more selective for ␣3 -receptors, but we are unaware of studies that have
compared their amnestic effects, although adverse events characterized as amnesia have been
reported. It must be concluded that all BzRAs that act extensively at the ␣1 -receptor produce
dose-dependent anterograde amnesia with as yet no studies demonstrating differences between
the various drugs when sedative potency is controlled.
Finally, long-term BzRA use is purportedly associated with cognitive impairment, partic-
ularly in elderly. One has to distinguish time-limited impairment (i.e., the time over which drug
is present in plasma) in acute use from long-term impairment in chronic use. There have been
reports of “global amnesia” associated with BzRAs (13). The reported total amnesia lasted for
several hours after consuming triazolam, 0.5 mg, but the triazolam use was also accompanied
by variable amounts of reported alcohol consumption.
These reports of acute global amnesia contrast with the suggestion that chronic BzRA use
is associated with cognitive impairment. The results of studies assessing cognitive function in
elderly chronic BzRA users are equivocal, with some studies reporting impairment and others
finding minimal or no impairment (14–16). It is difficult to reach definitive conclusions because
these reports are cross-sectional and retrospective in nature with a number of confounds. Further,
determining the appropriate controls for these studies is problematic. Most of the information
on BzRA cognitive impairment is from patients with anxiety disorders, who are using long-
acting benzodiazepines. The relevance of these data to current best clinical practice for insomnia
pharmacotherapy (i.e., use of short-acting nonbenzodiazepine hypnotics) is questionable.

Discontinuation Effects
The most frequently reported discontinuation effect of the BzRAs in clinical use is rebound
insomnia (17). Rebound insomnia is defined as worsened sleep for one or two nights relative
to baseline. It can occur after even one to two nights of previous BzRA use (17). The rebound
insomnia does not appear to increase in severity with the duration of nightly use, at least in the
short term. Rebound insomnia was reported with the 0.5-mg dose, but not the 0.25-mg dose, of
the short-acting drug, triazolam (17). Proper multiple-dose studies that explore the threshold
dose for rebound with other BzRA hypnotics have not been done. Many studies report an
absence of rebound, but do not include a positive control that demonstrates that the study
design is robust enough to detect rebound. Rebound is likely to occur after high doses (i.e.,
beyond minimally effective doses) of all short- and intermediate-acting BzRAs. This prediction
is made based on the multiple-dose studies of daytime performance impairment that have
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390 ROEHRS AND ROTH

compared various BzRAs to triazolam and find comparable impairment at triazolam doses
that produce rebound (1). Rebound is unlikely to occur with a long-acting drug because of the
gradual decline in plasma concentrations inherent to its pharmacology.
Rebound insomnia is an exacerbation of the original symptom (i.e., difficulty falling and or
staying asleep), and thus, differs from recrudescence, which is the return of the original symptom
at its original severity. It is not a withdrawal syndrome (i.e., expression of new symptoms), at
least in the available short-term studies (i.e., two weeks and less), which induced rebound but
no other new symptoms (17). Its time course differs from that of a withdrawal syndrome, lasting
for one or two nights only. Finally, there is no evidence to suggest that the benzodiazepine and
nonbenzodiazepine BzRAs differ in the likelihood of producing rebound (17,18).
The extent to which duration of use and dose might combine to increase the likelihood of
rebound, even at clinical doses, when used in the long-term is unknown. A recent study assessed
rebound after six months of the nightly use of eszopiclone 3 mg, its clinical dose (19). Over the
14 days studied after discontinuation of eszopiclone, no increase in self-reported sleep latency
or wake after sleep onset relative to baseline was observed. These data need to be considered
cautiously as no positive control was used in this study. It also has been suggested that the
experience of rebound insomnia leads to continued chronic use of the hypnotic. Importantly, a
study, which directly tested that notion, showed that the experience of rebound insomnia does
not alter the subsequent likelihood of self-administering triazolam 0.25 mg (20). In summary,
while rebound insomnia is a reliable effect associated with BzRAs, its clinical significance, if
any, is yet to be identified.

Abuse Liability
There has long been concern that behavioral or physical dependence develops with chronic
use of BzRAs. The concern is based on reports of physical and behavioral dependence with
long-term daytime anxiolytic use of therapeutic doses of BzRAs (21). Systematic information
regarding the dependence liability of long-term therapeutic use of BzRA hypnotics at clinical
doses is very limited. Majority of persons in population-based studies report using hypnotics
for two weeks or less (22,23). Two recent placebo-controlled, double-blind studies of eszopiclone
3 mg reported no evidence of physical or behavioral dependence after six months of nightly
use (19,24). But, neither of these studies directly tested for physical and behavioral dependence
liability.
Short-term studies directly testing the behavioral dependence liability of BzRA hyp-
notics suggest that they have a low behavioral dependence liability (25). Behavioral depen-
dence liability can be directly tested by assessing the self-administration of active drug versus
placebo administered as color-coded capsules. After sampling each color-coded capsule over 7
to 14 subsequent nights, patients choose the desired capsule based on its color. Hypnotic self-
administration by insomniacs is not associated with dose escalation with repeated use when
provided opportunity to self-administer multiple capsules (26), does not increase with rebound
insomnia (20), does not generalize to daytime use (27), and varies as a function of the nature and
severity of the patients’ sleep disturbance (25). These short-term studies lead to the conclusion
that insomnia patients’ hypnotic self-administration is a therapy-seeking behavior and not drug
seeking or abuse. It should be noted that these conclusions are true for insomniacs and normal
controls, but not for individuals with a drug abuse history.
One important question is the extent to which receptor subtype selectivity may influence
the abuse liability of the BzRAs. One assessment of the relative abuse liability of hypnotic
drugs failed to find differential receptor subtype selectivity in abuse liability among drugs used
as hypnotics (28). For example, the ␣1 selective drug, zolpidem, did not differ from various
nonselective BzRAs. However, there are very few studies comparing multiple doses of multiple
drugs and thus the rating had to be made across a variety of methodologies and data sources.
In addition, the rating also included drug toxicities and thus was not specific to what is more
narrowly defined as drug abuse liability.

Amnestic Parasomnia Episodes

Reports of parasomnia-like side effects associated with BzRA hypnotics have appeared in the
public print and video media. These reports of “global amnesia”, somnambulism, sleep driving,
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BENZODIAZEPINE RECEPTOR AGONIST SAFETY 391

and sleep-related eating disorder are problematic; they are not peer-reviewed, generally not
independently documented, are subject to confirmation bias, and likely overrepresent the real
risk. Further, they do not provide information that can lead to a scientific medical understanding
of the phenomena, and they raise unnecessary concern among patients and their physicians.
In the scientific medical literature peer-reviewed case reports of parasomnia-like BzRA-
associated side effects have also appeared. But, again one must be cautious. Case reports do
provide some information about contributing factors, but it is not placebo-controlled informa-
tion. Most importantly, the real risk of BzRA-associated parasomnia is unknown because the
rate of exposure is not known. The number of prescriptions written and doses consumed at the
time of the event is unknown and consequently, the incidence of the events cannot be deter-
mined. Finally, there have been several publications that suggest that the appearance of media
reports and medical articles distort the true prevalence of adverse events.
As noted earlier, transient global amnesia has been reported in association with the use of
triazolam by otherwise healthy individuals experiencing sleep disturbance (13,29). The memory
loss was for all autobiographical events transpiring over an 8- to 12-hour period. In some of these
cases in which clinical doses were used, prior stress, sleep deprivation, and a virus may have
contributed to produce the amnesia. In other cases, supraclinical doses and alcohol ingestion are
likely contributory factors. It is unlikely that this phenomenon is unique to triazolam as similar
kinds of amnesia are produced by the intravenous administration of other benzodiazepines.
Somnambulism has been reported with zolpidem and zaleplon (30,31). These episodes
of somnambulism have occurred with two to three times the clinical doses of the drug, in
individuals with a prior history of somnambulism and in individuals with prior traumatic
head injury. Zolpidem-associated somnambulism also has been reported in combination with
antidepressant treatment (32). Somnambulism is believed to be associated with partial arousals
from sleep, which alcohol and sleep deprivation also exacerbate. Not surprisingly, both alcohol
and sleep deprivation also exacerbate somnambulism.
Finally, there are case reports of sleep-related eating disorder associated with psychotropic
medications, including BzRAs (33–35). There is a dispute as to whether sleep-related eating
disorder is a disorder of partial arousal from sleep with altered levels of consciousness or is the
psychiatric disorder of nocturnal eating with awareness and recall (36,37). Sleep-related eating
disorder is hypothesized to share a common pathophysiology with somnambulism. Zolpidem
was reported to exacerbate sleep-related eating disorder and in several cases induce it de novo
(37). In some of these cases greater than 10 mg of zolpidem doses were being used and in other
cases there was use of sedating antidepressants. Sleep-related eating disorder has also been
reported with triazolam (38,39).
These case reports have a common thread running through them—excessive hypnotic
activity or sleep drive. The excessive hypnotic activity is produced by high doses, clinical doses
in vulnerable individuals (i.e., those with a past history of sleep disorders or brain injury), the
combination of clinical or high doses with prior sleep deprivation due to stress or illness, or
the combination of clinical or high doses with the prior consumption of alcohol or other CNS
drugs. The types of behaviors described in these case reports also share a commonality. They all
are symptoms of excessive hypnotic activity or excessive sleepiness. Amnesia and memory dif-
ficulties are reported by patients with excessive daytime sleepiness. Sleep deprivation produces
intense slow wave sleep and abrupt arousals from slow wave sleep after prior sleep deprivation
is known to be associated with sleep inertia–behaving individuals with little consciousness and
memory. Patients with excessive sleepiness are known to engage in automatic behavior, and
sleep deprivation is known to induce somnambulism in individuals with a previous history
of somnambulism. Taken together the data suggest that parasomnia reports associated with
BzRAs are the result of excessive hypnotic/sedative activity in vulnerable individuals.

Risks Associated with Alternatives

Good clinical practice requires that the risk of BzRA insomnia treatment be weighed against the
risks associated with the alternatives. The common alternatives include no treatment, self-
treatment, and treatment with nonhypnotic medications, most typically low-dose sedative
antidepressants and antipsychotics. Epidemiological data indicate that a very small percentage
of people reporting insomnia are treated medically for their insomnia (40). In the population,
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392 ROEHRS AND ROTH

approximately one-third of those reporting insomnia self-medicate with either over-the-counter

(OTC) medications or alcohol (23). Finally, most patients receiving medical treatment for insom-
nia are prescribed off-label medications (41).

Nontreatment
Untreated insomnia has well-documented morbidity. Insomniacs report reduced quality of life
on the Short-Form-16 Quality of Life Questionnaire across all of its domains, and they rate their
quality-of-life akin to that of patients with other chronic disorders such as congestive heart
failure and clinical depression (42,43). Compared to individuals without insomnia, insomniacs
self-report increased days of restricted activity due to illness and increased days spent in bed as a
result of illness (44). Higher rates of absenteeism are reported by those with insomnia compared
with controls, and rates of work-related accidents and traffic accidents are higher (42,45). Among
nursing home residents, the risk of falls and fractures was higher in the untreated insomniacs
than those treated with hypnotics (7). This finding contradicts the general perception based on
earlier studies that hypnotic treatment in elderly is associated with greater risk of falls and the
risk reversal likely relates to a wider current use of short-acting rather than long-acting hypnotics
as in the earlier studies. Importantly, those earlier studies did not control for insomnia, which
itself is a risk factor for falls.
Untreated insomnia is associated with increased risk of incident cases and relapse of psy-
chiatric disorders and with an exacerbation of medical diseases. A number of studies have now
demonstrated a heightened risk of future depression in persons reporting insomnia without a
current or previous history of depression, and a study has shown insomnia precedes incident
depression as well as relapse (46–48). In addition, there is an increased risk of anxiety disorders
and drug and alcohol abuse associated with insomnia (46). Whether treating insomnia would
reduce these risks is yet to be determined. However, one recent study did find that adjunctive
pharmacological treatment of insomnia coexisting with primary depression not only improved
the insomnia, but also improved depressive symptoms beyond that found with standard antide-
pressant monotherapy (49).
Insomnia is comorbid with various medical diseases and evidence indicates that disturbed
sleep exacerbates medical disease, specifically diseases with pain as a prominent symptom.
In a prospective study, self-ratings of sleep and pain in patients with fibromyalgia showed
that nights with poor sleep were followed by days with greater pain (50). Also, patients with
rheumatological disorders frequently report insomnia and disturbed sleep. In two small studies,
treatment of insomnia associated with rheumatoid arthritis with either triazolam or zopiclone
failed to show concurrent improvement in both sleep and pain (51,52). However, in a recent
large study of patients with rheumatoid arthritis and coexisting insomnia, eszopiclone 3 mg
improved both nighttime sleep and daytime joint pain (53). Studies in healthy normals have
suggested that poor sleep may exacerbate pain. Studies have found that total sleep deprivation
is hyperalgesic and a recent study in healthy normals has shown that only a four-hour reduction
of sleep time for a single night is hyperalgesic to a radiant heat stimulus (54).

Self-Medication
The pursuit of ineffective and potentially dangerous self-treatments is not fully appreciated as
a risk of not treating the patient with insomnia. In a population-based study in Southeastern
Michigan, respondents with insomnia reported poorer sleep hygiene practices than noninsom-
niacs (55). Among the compensatory self-help behaviors reported by insomniacs is napping and
sleeping on weekends, behaviors that can potentially exacerbate and perpetuate the insomnia.
Insomniacs use nonprescription substances to self-treat their insomnia, including OTC
medications, herbals, and alcohol (23). The active component of all OTC sleep aids is H1 antihis-
tamine, typically diphenhydramine 25 to 50 mg. Beyond there being no clear placebo-controlled
studies that show diphenhydramine has hypnotic efficacy, rapid tolerance development to its
sedative effects has been shown (56). Low-dose alcohol as a sleep aid is potentially dangerous for
two reasons. Low-dose alcohol initially improves the sleep of insomniacs, which is why they
self-administer it as a sleep aid (57). However, within six nights tolerance develops, sleep is
worsened beyond that of baseline, and larger alcohol doses are self-administered to achieve the
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BENZODIAZEPINE RECEPTOR AGONIST SAFETY 393

sleep effect (57–59). Insomniacs who reported using alcohol as a sleep aid also reported greater
levels of daytime sleepiness than those who used prescription or OTC drugs for sleep (23).

Nonhypnotic Medications
The most commonly used drugs to treat insomnia according to the Physician Drug and Diagnosis
Audit (PDDA) database in 2002 (the most recently available published data) were sedating
antidepressants (60). They were 1.53 times more likely to be prescribed for insomnia than BzRAs
and the three most common were trazodone, amitriptyline, and mirtazapine. These prescribing
data may not represent current practice given the very recent introduction of a number of new
FDA-approved BzRA hypnotics. Nevertheless, the safety of sedating antidepressants used to
promote sleep, as opposed to treating depression, merits discussion.
Information on antidepressant safety is primarily derived from use in depressed patients
and the data are for higher doses (e.g., antidepressant doses) than typically used for insomnia.
As an example, the doses reported in the PDDA for trazodone were 50 mg in 53% of those men-
tioned, 100 mg in 31% and 150 mg in 14% (60). The 150-mg dose is the usual daily antidepressant
dose. However, on the basis of recent studies of low-dose doxepin as a hypnotic, antidepressants
at low doses are likely safer than the higher antidepressant doses (61).
Trazodone: Sedation is a widely reported side effect with trazodone use, which possibly
relates to its approximate 12-hour half-life in elderly patients, although in younger patients
the half-life is 6 hours (62). On an average across studies, 29% of depressed patients reported
daytime drowsiness at antidepressant doses. Even at the lower 50-mg dose, the only placebo-
controlled trial of its use as treatment for primary insomnia reported 23% of patients over the
two-week treatment had problems with daytime somnolence compared to 8% with placebo and
16% with zolpidem (63). Trazodone has significant cardiovascular risks including hypotension,
orthostatic hypotension, ventricular arrhythmias, conduction disturbances, and exacerbation of
ischemic attacks. Finally, trazodone is associated with priapism in many case reports and an
analysis found that most cases occurred with 50 to 150 mg daily doses, which are the doses
more typically used for insomnia (64). However, this case report information on priapism may
suggest a higher incidence than the estimated incidence of 1/5000.
Amitriptyline: It is known for its anticholinergic side effects, including blurred vision, dry
mouth, urinary retention, orthostatic hypotension, flushing, tachycardia, and confusion (65).
Cardiac toxicity in overdoses has been reported, and at clinical doses in patients with known
cardiovascular disease, there are increased cardiac risks. But it should be emphasized that this
information may not be relevant to the lower doses often used to treat insomnia.
Mirtazapine: The major side effects associated with mirtazapine are weight gain and
increased appetite. Increased daytime sleepiness and dizziness have also been reported (65).
Quetiapine and olanzapine: In the PDDA data for 2002, the antipsychotics quetiapine and
olanzapine and the antihistamines hydroxyzine and diphenhydramine were also frequently
used as hypnotics. As is true of the sedating antidepressants, there is no safety information for
these drugs at the doses used for hypnotic effects. These drugs are chosen for their reported
sedating effects, generally produced by their H1 antagonism. To the extent that a given drug has
a long half-life (i.e., olanzapine’s half-life is 20–50 hours), its duration of action will be extended
to the following day, producing residual impairment of function. But they also affect other
neurotransmitter systems, which produce other side effects such as dizziness and hypotension.

Minimizing the BzRA Risks

The risk of next-day psychomotor impairment can be minimized by choosing drugs that have a
duration of action that is limited to the desired sleep period. Drugs with half-lives greater than
5 hours will likely result in residual sedation. The lowest effective dose should be utilized. Low
doses also will reduce the likelihood of impairment during nighttime bathroom visits and as
discussed earlier, will reduce the likelihood of amnestic parasomnia episodes and decrease the
chances of experiencing rebound insomnia.
With regard to amnestic parasomnia episodes, two points should be emphasized. Firstly,
excessive sleep drive and hypnotic activity produced by high doses above the approved clinical
doses, a combination of sedating drugs, or a combination of prior sleep deprivation and a
sedating drug in vulnerable individuals should be avoided. Thus, dose, concurrent use of other
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394 ROEHRS AND ROTH

sedating drugs, and time-in-bed after drug ingestion should be carefully monitored. Secondly,
by most indications these are very rare side effects when the medications are used appropriately.
As with psychomotor impairment, the risk of cognitive impairment is reduced by
attention to duration of action and dose. Special caution should be taken for patients who are
elderly. Both duration of action and peak plasma concentration can be enhanced in elderly
with the result being a greater likelihood of psychomotor and cognitive impairment. The same
is true for patients with renal or hepatic problems. In addition, elderly patients are more likely
to be using multiple drugs, many of which have sedating effects, further enhancing risks of
cognitive impairment.
Rebound insomnia can be minimized with short- and intermediate-acting drugs by grad-
ually tapering the dose over several nights. Its impact can be reduced with patient instructions
that include the caution that rebound can occur, but that rebound endures for one to two nights,
when it does occur.
Finally, identifying patients with an enhanced liability of dependence development,
whether physical or behavioral, is quite difficult. The most reliable predictor is a previous
history of drug or alcohol abuse. While treating patients, possible dose escalation should be
closely monitored and the use of the medication outside of the therapeutic context noted. Thus,
any daytime use of a hypnotic, except for night workers who are day sleepers, should be
discouraged and when observed should be a sign of concern.

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34 Off-label Use of Prescription Medications for

Insomnia: Sedating Antidepressants,
Antipsychotics, Anxiolytics, and
Anticonvulsants
W. Vaughn McCall
Department of Psychiatry and Behavioral Medicine, Wake Forest University School of Medicine,
Winston-Salem, North Carolina, U.S.A.

The inclusion of a separate chapter regarding the off-label use of prescription medications
for insomnia in this book is a reflection of the peculiarities of the treatment of insomnia in
the United States. The idiosyncratic nature of off-label prescribing in the field of insomnia
is underlined by the absence of similar chapters devoted to off-label prescribing in standard
textbooks on cardiac pharmacology, pulmonary pharmacology, etc. The need for such a chapter
in a textbook on insomnia treatment is derived from statistics on physician prescribing that, until
recently, revealed that off-label medications were prescribed preferentially for insomnia, in lieu
of medications that are FDA approved for insomnia. As recently as 2002, the most-prescribed
medication for insomnia in the United States was trazodone, which is approved by the FDA
as an antidepressant, not as a hypnotic (1) (Table 1). It had not always been this way, as in
1986 the FDA-approved hypnotics triazolam, flurazepam, and temazepam were the leading
choices among physicians (2). Somehow during the late 1980s and early 1990s, FDA-approved
hypnotics were surpassed by trazodone. It is not entirely clear how and why this happened,
but we can hypothesize the action of several factors including

r a belief among prescribers that trazodone, other antidepressants, and later, some antipsy-
chotics were reliably effective for treating insomnia;
r a belief among prescribers that trazodone, other antidepressants, and later, some antipsy-
chotics may be safer for patients than FDA-approved hypnotics;
r a belief among prescribers that FDA-approved hypnotics would be needed or asked for by
patients for a duration of time that outstripped their FDA-approved indication of use, thus
exposing the prescriber to potential liability if there was an untoward event.
The beliefs contained in the three hypotheses are for the most part unsubstantiated, as
there are few placebo-controlled trials to show that any non-FDA approved sleep aid is effective
in insomnia, or has fewer side effects than approved medications. However, it is true that until
recently, the use of FDA-approved hypnotics in the United States appeared to be constrained
by package labeling that recommended that schedule IV hypnotics not be given for more
than two consecutive weeks, unless the patient was reevaluated. FDA-approved treatments for
insomnia generally require (1) two randomized, placebo-controlled clinical trials in insomnia
patients showing a superior induction/maintenance of sleep for the investigational medication
as compared with placebo and (2) evidence of superiority in both patient report and an objective
measurement of sleep [i.e., polysomnography (PSG)]. The data supporting trazodone and other
non–FDA-approved medicines prescribed for sleep generally lack one or more of these elements.
The importance of each of these elements is defined below:

1. The importance of a placebo comparison

Many investigations of the sleep properties of non-FDA sleep aids have omitted a placebo
comparator and instead, have looked at improvement in insomnia symptoms over
time that came with administration of the investigational drug, as compared with
a pretreatment baseline. This flaw in this approach is revealed in the studies that
show a strong placebo effect in insomnia clinical trials. Reductions in sleep latency
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Table 1 Drug “Occurrences” for Insomnia 2002:

The Verispan Data Base (In Millions)

Antidepressants
Amitriptyline 0.8
Doxepin 0.2
Mirtazapine 0.7
Trazodone 2.7
FDA-approved hypnotics
Flurazepam 0.2
Temazepam 0.6
Zaleplon 0.4
Zolpidem 2.0
Sedatives
Alprazolam 0.3
Clonazepam 0.4
Lorazepam 0.3
Antipsychotics
Olanzapine 0.2
Quetiapine 0.5
Antihistamines/sedative
Hydoxyzine 0.3

(SL) and increases in total sleep time (TST) are routinely seen with administration of
placebo alone, making it impossible to assume improvement in insomnia seen with
an investigational drug and is attributable to the drug and not the placebo effect, in
the absence of a placebo comparator (3,4).
2. The importance of testing in insomnia patients
Needless to say, medications may have different effects in persons who are ill than in persons
who are well. A classic example in insomnia research is the contrast of the effect of the
beta-blocker propranolol in good sleepers versus anxious sleepers. Placebo-controlled
comparisons of propranolol in good sleepers have shown a deterioration of sleep
(5,6), while a study in sleepers who were anticipating surgery the next day showed
better sleep with propranolol than with placebo (7). The take-home message is “in the
absence of testing done directly in the population of interest, it is hazardous to predict
how a medication might work in an ill-population”
3. The importance of measuring both patient-report as well as objective testing
Many non-FDA approaches to insomnia treatment have relied upon patient-report of improve-
ment without confirmation with an independent objective method (i.e., PSG), or occa-
sionally have relied upon PSG improvement, absent patient-reported improvement. The
hazards of both approaches are illustrated in the following two studies. The first study
examined the serotonin reuptake inhibitor (SSRI) fluoxetine in depressed insomniacs,
showing a perception of benefit, but concurrent PSG testing showed some worsening
of EEG-defined sleep in the same patients (8). In the second study, the anticonvulsant
tiagabine was found to enhance slow wave sleep (SWS), which is generally believed to
connote a benefit, but the same insomniac patients did not appreciate a meaningful subjec-
tive improvement in their sleep (9). These two studies show that patient’s impressions and
PSG data may dissociate in the direction of their effect. At the present time, it is impossible
to discern the meaning of patient benefit in the absence of PSG-benefit, or PSG-benefit in
the absence of patient-reported benefit. So, the present standard for showing anti-insomnia
efficacy is the demonstration of both patient-reported and PSG benefit.
The preferential use of non-FDA-approved approaches for insomnia entails its own unique
set of problems, over and above the risks inherent in the particular off-label medication pre-
scribed. In general, the FDA does not prohibit the use of approved medications for off-label
indications, as the FDA recognizes the judgment of the prescriber to best understand the needs
of the patient (10). However, the preferential avoidance of approved approaches and embrace
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Table 2 Drug “Occurrences” for Insomnia 2007:

The Verispan Data Base

Antidepressants
Amitriptyline 0.5
Mirtazapine 0.7
Trazodone 2.1
FDA-approved hypnotics
Eszopiclone 1.4
Ramelteon 0.9
Temazepam 0.6
Zaleplon 0.2
Zolpidem 3.6
Sedatives
Alprazolam 0.3
Clonazepam 0.5
Lorazepam 0.5
Antipsychotics
Quetiapine 0.9
Others
Clonidine 0.2
Cyclobenzaprine 0.2
Tizanidine 0.2

of nonapproved approaches require, at a minimum, some discussion between the prescriber

and the patient on how the prescriber arrived at the choice of treatment. Further, this discussion
should be documented in the patient’s medical record (11).
Recently, there is evidence that the tide is turning back in favor of FDA-approved hypnotics
as the preferred treatment for insomnia (James Walsh, personal communication, 2009) (Table
2). Zolpidem has bested trazodone for first place in the list of approaches to insomnia, with
trazodone falling to second place. This dynamic may be explained by (1) the availability of
generic, less-expensive zolpidem in 2007; (2) the more liberal package labeling of newer anti-
insomnia agents, which have no specific comments against prescription for longer than two
weeks; (3) vigorous direct-to-consumer advertising that has raised consumer awareness of
FDA-approved hypnotics. Still, despite the relative decline in trazodone usage within the last
five years, antidepressants, antipsychotics, and other medications not approved for insomnia
continue to play a large role in insomnia treatment. We have reviewed the literature regarding the
sleep effects of some of the most commonly used off-label prescribed medications for insomnia,
focusing on the best evidence available for each medication.

ANTIDEPRESSANTS

Trazodone

Pharmacology
Trazodone is a triazolopyridine antidepressant that was introduced in the United States in
1982 under the brand name Desyrel. It has relatively weak SSRI properties, and is a blocker
of postsynaptic serotonin receptors 5-HT1A , 5-HT1C , and 5-HT2 , as well as postsynaptic ␣1 -
adrenergic receptors. It has an elimination half-life of about five to nine hours. When prescribed
as an antidepressant, the usual doses of trazodone are ≥ 150 mg daily.

Sleep Efficacy
Although the sleep effects of trazodone have been poorly documented in persons who do not
have psychiatric disorders, it is widely believed to have beneficial effects on sleep, as reflected
in its favored status in the rank order of prescribing rates (Tables 1 and 3). Furthermore, a
recent survey revealed that trazodone was the first-line choice of 78% of psychiatrists when
prescribing for SSRI-related insomnia (12). This favoritism is baffling given the sparse evidence
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Table 3 Trends in Pharmacological Treatment of

Insomnia 1987–1996 (Number of Drugs Mentioned
in Thousands) (1)

1987 1996
Antidepressants
Amitriptyline 421 748
Doxepin 263 269
Trazodone 222 1328
FDA-approved hypnotics
Flurazepam 1677 373
Temazepam 1201 904
Triazolam 3199 209
Zolpidem — 1218
Sedatives
Alprazolam 397 250
Clonazepam 28 330
Lorazepam 346 398

of sleep effect in psychiatric patients. In 17 patients with insomnia associated with fluoxetine
or bupropion, the Pittsburgh Sleep Quality Index improved after one week of trazodone 50 mg,
compared with placebo (13). In seven patients with insomnia associated with the monoamine
oxidase inhibitor brofaromine, SWS increased and the number of polysomnographic awaken-
ings decreased after one week of trazodone 50 mg administration, compared with placebo (14).
The best evidence for a beneficial sleep effect comes from a single, large study in primary
insomniacs, albeit the period of study was for only two weeks. Walsh et al. conducted a three-
armed randomized comparison of bedtime doses of trazodone 50 mg, versus zolpidem 10 mg
and versus placebo in 278 primary insomniacs. Trazodone and zolpidem were both superior
to placebo in patient-reported reduction in SL for week 1, but trazodone did not separate from
placebo by week 2, while zolpidem maintained its efficacy in week 2. TST effects were mixed,
with both trazodone and zolpidem showing an advantage over placebo at week 1, but not week
2 (15).
In normal sleepers, trazodone 50 to 200 mg increases SWS over short periods of time (≤2
weeks) compared to placebo in 9, 8, and 6 subjects, respectively (16–18). As stated above, the
clinical significance of an increase in SWS is not always clear, although it is usually inferred to
be a sign of potential benefit.

Side Effects
The most common side effects of small bedtime doses of trazodone may be residual morning
sedation. Daytime doses of trazodone (TRZ) 100 mg impairs critical flicker fusion and choice
reaction time one to four hours later (19,20). Bedtime doses of TRZ 100 mg lowers BP and
impairs critical flicker fusion the next morning (21). Less common side effects include orthostatic
hypotension (from peripheral adrenergic blockade) and priapism (22). Priapism has an incidence
of about 1/6000 persons and can occur at low doses, early in treatment.

Amitriptyline

Pharmacology
Prior to the introduction of fluoxetine in the United States in 1987, tricyclic antidepressants
(TCAs) were first-line somatic treatment of major depressive episode (MDE), and TCA therapy
could be counted upon to produce reliable, early improvement in the sleep of persons with
insomnia and MDE, as compared to the relative lack of effect of psychotherapy on insomnia
(23). Amitriptyline is a TCA with a half-life of 20 to 30 hours. Its synaptic effects include reup-
take blockade of 5-HT, as well as anticholinergic, antihistaminergic, and ␣1 -blockade. Typical
antidepressant dosages are ≥ 75 mg.
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Sleep Efficacy
There are no data on the effect of amitriptyline on sleep in primary insomnia. However, in
depressed inpatients (many of whom are presumed to have had insomnia) a four-week course
of amitriptyline, escalated from 50 mg at bedtime (qhs) to 50 mg four times per day (qid),
was associated with an increase in PSG-determined TST, and a reduction in SL, early morning
awakening, and a general suppression of Rapid Eye Movement Sleep (REM) as compared to
baseline (24). This study did not have a placebo comparison and did not provide patient-reports.

Doxepin

Pharmacology
Doxepin is a TCA with a half-life of 10 to 25 hours. Like amitriptyline, at standard antidepressant
doses, doxepin has 5-HT and noradrenergic (NE) reuptake blockade properties, as well as
blockade of cholinergic, histaminergic, and ␣-adrenergic activity. Typical antidepressant doses
of doxepin are ≥ 75 mg daily. Smaller doses have been tested for hypnotic potential in primary
insomniacs. It is likely that at very low doses (<10 mg) doxepin’s meaningful pharmacologic
activity is almost exclusively antihistaminergic, with little or no significant effect in serotonergic
or adrenergic systems. Theoretically, this low-dose profile would facilitate sleep without other
side effects.

Sleep Efficacy
Doxepin 25 to 50 mg was superior over 4 weeks in 47 primary insomniacs in improving PSG
total sleep time, sleep efficiency and sleep quality, and daytime ability to work (25). These
effects were confirmed in a study of 67 young adults with primary insomnia who underwent
a four-period crossover design comparison of placebo versus doxepin 1, 3, and 6 mg (26). Each
treatment period lasted for two days. All three doses of doxepin in increased PSG-defined
TST and reduced Wake Time after Sleep Onset (WASO), while only the 6-mg dose reduced SL
compared with placebo. REM% decreased with the 3- and 6-mg dose with no change in SWS.
Patient-report showed superiority for doxepin in reducing SL and increasing TST only for the
6-mg dose.

Side Effects
The side effects of low-dose doxepin in primary insomniacs were infrequent and numerically
similar to placebo with the two-day exposure, four-way crossover design (26).

Nortriptyline

Pharmacology
Nortriptyline is a TCA with a half-life of 22 to 39 hours, potent reuptake blockade of NE, and
weaker reuptake of 5-HT. It also has anticholinergic effects as well as weak ␣1 -adrenergic and
histaminergic blockade.

Sleep Efficacy
There is no data regarding the efficacy of nortriptyline in primary insomnia, but in a sample
of 20 depressed insomniacs, acute exposure to nortriptyline reduced PSG-determined SL and
suppressed most measures of REM sleep. Patient-report was not described in this study (27).
In a somewhat different design, a comparison was made in the sleep profiles of previously
depressed, now-remitted elderly patients who had received one year of maintenance treatment
for depression with either nortriptyline versus placebo. Interestingly, the nortriptyline patients
had longer PSG-determined SL and no advantages in sleep maintenance, but the nortriptyline
patients did exhibit more intense SWS (28).

Side Effects
The most frequent side effect is dry mouth (29).
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Mirtazapine

Pharmacology
Mirtazapine is a tetracyclic piperazinoazepine with a half-life of 22 to 40 hours. It has minimal
effect on monoamine uptake, but is a potent inhibitor of 5-HT2 and 5-HT3 receptors, as well as
central ␣2 -adrenergic receptors (30). Typical antidepressant doses are ≥15 mg daily.

Sleep Efficacy
There are no placebo-RCT in primary insomniacs. However, mirtazapine 30 mg reduced PSG
sleep latency and increased SWS in six good sleepers on the first night in the sleep lab compare
to placebo in a crossover design (31). Mirtazapine 30 mg increased PSG sleep efficiency and
SWS compared to placebo on the third night in the laboratory in 20 good sleepers in parallel-
arm clinical trial (32). In 22 depressed insomniacs randomized to either mirtazapine 45 mg
or fluoxetine 40 mg, the conclusion of 8 weeks of treatment saw greater reductions in PSG-
determined SL and increases in TST for mirtazapine as compared with fluoxetine. Patient-report
was not described (33).

Side Effects
Bedtime doses of Mirtazapine were associated with prolonged motor reaction times the next
day (34) and impaired actual driving performance at 30 mg, compared with placebo with acute,
but not chronic dosing (30).

ANTIPSYCHOTICS

Quetiapine

Pharmacology
Quetiapine is an atypical antipsychotic with a half-life of two to three hours. It has high affinity
for 5-HT2A receptors and weak affinity for dopamine, muscarinic, and adrenergic receptors.
Typical antipsychotic doses are 150 to 800 mg daily.

Sleep Efficacy
There are no randomized controlled trials in primary insomnia. Quetiapine 25 or 100 mg at
bedtime was superior to placebo for one night in increasing PSG total sleep time and subjective
sleep quality in 14 good sleepers under noisy conditions. The authors speculate that the benefi-
cial sleep effect was mediated through blockade of histaminergic, dopaminergic, and adrenergic
receptors. Of note, the 100-mg dose induced periodic limb movements (PLMs) (35). Quetiapine
has been tested in an open study of doses of 25 to 75 mg at bedtime for 6 weeks in 18 patients
with primary insomnia, finding there were PSG-determined and patient-report improvements
in TST, but not SL, compared to baseline (36). Quetiapine has been tested against placebo in
demented patients with associated sleep disturbance. Doses of quetiapine started at 25 mg and
could be increased to 125 mg by the fifth week. Quetiapine was associated with increases in
actigraphically determined TST as early as the first week, and this advantage was still seen at
the end of the fifth week (37).

Side Effects
Quetiapine is associated with weight gain, with the potential for glucose intolerance. Similar to
other atypical antipsychotics, the FDA has required a black box warning for quetiapine noting
increased risk of cerebrovascular accident in elderly patients.

Olanzapine

Pharmacology
Olanzapine is an atypical antipsychotic and a derivative of thienobenzodiazepines. It has potent
antagonist properties for 5-HT2A and 5-HT2C receptors, with weak affinity for dopamine recep-
tors. Olanzapine also is active at muscarinic, ␣1 -adrenergic, and histaminergic receptors (38).
Olanzapine has a half-life of 36 hours. Typical antipsychotic dosages are ≥5 mg daily.
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Sleep Efficacy
There are no studies of Olanzapine in primary insomnia. The only placebo-controlled study of
Olanzapine was conducted in nine good sleepers, using a three-way crossover comparison of
three-nights exposure to placebo versus Olanzapine 5 or 10 mg. Both doses of Olanzapine were
associated with PSG-determined reductions in SL and WASO, increases in TST and SWS, and
suppression of REM. These volunteers also reported better sleep quality with olanzapine than
placebo (38). The same authors later examined the addition of a three-week course of olanzapine
2.5 to 10 mg to ongoing SSRI therapy in 12 depressed patients with an inadequate response
to SSRI monotherapy. There was no placebo control. The findings were similar to the earlier
study, with reductions in SL and WASO, and gains in TST and SWS. Unexpectedly, patients
reported difficulty getting up in the morning, with an approximate one-hour increase in time
in bed at home (39). Similar small, uncontrolled studies of olanzapine have been undertaken in
persons with schizophrenia, using doses up to 20 mg for up to four weeks, and again reported
PSG-determined increases in TST and SWS, and reductions in WASO (40,41).

Side Effects
Olanzapine is associated with weight gain, with the potential for glucose intolerance. Similar to
other atypical antipsychotics, the FDA has required a black box warning for olanzapine noting
increased risk of cerebrovascular accident in elderly patients.

Other Antipsychotics
Although the atypical antipsychotics risperidone and ziprasidone and the conventional antipsy-
chotics haloperidol and thiothixene are not among the most common medications prescribed
for insomnia (Tables 1–3), it is noteworthy that in general their sleep effects mirror to a greater
or lesser degree what is reported for quetiapine and olanzapine, namely increases in TST and
SWS (42–44).

Anxiolytics

Pharmacology
Lorazepam, clonazepam and alprazolam are all classic benzodiazepines with rapid absorption
and respective half-lives of 10 to 20, 24 to 56, and 10 to 15 hours. All three are indicated
for treatment of anxiety states, and clonazepam is also indicated for epilepsy. There are no
fundamental differences between those benzodiazepine approved for insomnia and those not
approved for insomnia, other than pharmacokinetics and route of administration.

Lorazepam

Sleep Efficacy
Lorazepam 2.5 mg was compared in a parallel design against midazolam 15 mg and placebo in
60 adults who were dosed the night before surgery. Outcomes were recorded by direct nursing
observation and found that while midazolam was superior for sleep induction, lorazepam was
significantly superior to placebo for sleep maintenance and patient-reported quality of sleep
(45). A similar study of sleep on the night before surgery was conducted in 60 adults allocated in
a randomized, balanced, parallel design to either lorazepam 2 mg, lorazepam 4 mg, nitrazepam
10 mg, lormetazepam 1 mg, lormetazepam 2 mg, or placebo. Both doses of lorazepam were
associated with longer sleep on the preoperative night as compared to placebo (46). A crossover
study of six good sleepers compared on night dosing of lorazepam 1 mg versus zolpidem 10 mg,
zopiclone 7.5 mg, triazolam 0.25 mg, and placebo under noisy conditions found that lorazepam
reduced SL and increased TST (47).
Lorazepam 0.5 mg tid and then 1.5 mg at bedtime were examined in a two-stage crossover
comparison with placebo in 12 adults with primary insomnia. Each treatment phase lasted for
four days. Both dosing strategies of lorazepam were superior to placebo in both subjective and
PSG sleep (48). A single-blind examination of lorazepam 3 mg was conducted for 7 nights in
6 adults with primary insomnia without the benefit of a placebo comparison. By both patient-
report and PSG, lorazepam was associated with decreased SL and increased TST (49).
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Lorazepam 2 mg showed improvement compared to baseline in 30 patients over 4 nights

in subjective sleep, with no placebo comparator (50).

Side Effects
In six adults with primary insomniacs, lorazepam 3 mg was associated with poorer perfor-
mance on the digit symbol substitution task (DSST) and timed card-sorting task as compared
with performance at baseline (49). In 30 adults with primary insomnia, lorazepam 2 mg was
associated with greater reported problems with dizziness, drowsiness, and poor coordination
than placebo (50). A single dose of lorazepam 4 mg at bedtime was associated with more com-
plaints of sleepiness, confusion, slurred speech, clumsiness, and blurred vision than placebo
presurgical patients (46). Morning alertness was reduced in a different study of presurgical
patients after a single bedtime dose of lorazepam 2.5 mg. A one-week exposure to lorazepam
1 mg at bedtime was compared against bedtime doses of alprazolam 0.25 mg and placebo in six
good sleepers using a blinded, randomized crossover design. Lorazepam, but not alprazolam,
was associated with slower reaction time the morning following the final dose in each treatment
phase (51). Lorazepam has also been associated with drug-withdrawal insomnia after as little
as seven nights of continuous use of either 2 mg (52) or 4 mg (53).

Clonazepam
There are no double-blind randomized placebo-controlled trials of clonazepam in primary
insomnia. However, a single-blind study found that clonazepam 0.5 mg reduced PSG-
determined total wake time over seven nights of dosing as compared with the pretreatment
baseline (54). However, clonazepam has been tested using double-blind randomized placebo-
controlled trials in patients with PLMs and depression associated with insomnia.
In 80 depressed patients receiving fluoxetine, the coadministration of clonazepam 0.5 to
1.0 at bedtime for 21 days was superior to placebo in improving scores on the Hamilton Rating
Scale for Depression (HRSD) sleep items over the entire three weeks (55). The success of this
study led the authors to repeat the study using a longer period of drug administration: 50
depressed patients received fluoxetine and the coadministration of clonazepam 0.5 to 1.0 versus
placebo at bedtime for 18 weeks. Again, clonazepam was superior to placebo in Hamilton Rating
Scale for Depression sleep items for the first three weeks, but clonazepam did not separate from
placebo after three weeks (56). Neither study reported an advantage for clonazepam for any
clinical parameter other than sleep.
In a mixed sample of 10 restless leg syndrome patients and 16 PLM patients, a single bed-
time dose of clonazepam 1 mg reduced PSG-determined SL and increased TST compared with
baseline, without impacting the rate of PLMs (57). In a sample of 20 PLM patients, including 8
with insomnia, one month of clonazepam 0.5–2.0 mg was superior to placebo in a parallel-design
comparison (58). In this study, clonazepam was associated with PSG-determined reductions in
SL, PLM frequency, PLM arousals, and increases in TST.

Alprazolam
There are no randomized, placebo-controlled trials of alprazolam for insomnia. Using a single-
blind design, alprazolam 1 mg was administered for one week at bedtime in six adults with
primary insomnia. Compared with baseline, alprazolam was associated with PSG-determined
reduction in SL and WASO, and increases in TST. However, a worsening compared with baseline
was seen during the first week of single-blind discontinuation of alprazolam (59).

ANTICONVULSANTS
Although no anticonvulsants appear on the list of most common medications prescribed for
sleep, several studies have shown potential clinical promise of anticonvulsants in selected
populations.

Gabapentin and Pregabalin

Many alcoholics experience persistent insomnia during abstinence from alcohol and those
that do experience insomnia are at a greater risk of relapse. Treatment of insomnia during
abstinence would seem to be a potential pathway to prevent relapse, but other than ramelteon,
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OFF-LABEL USE OF PRESCRIPTION MEDICATIONS FOR INSOMNIA 405

FDA-approved treatments for insomnia are controlled substances and convey some risk for
abuse in alcoholics. Gabapentin, 1-(aminomethyl) cyclohexane acetic acid, is a GABA analogue
excreted unchanged through the kidneys. Gabapentin is not a controlled substance, is not
thought to have potential for abuse, and can be used in alcoholics with reduced hepatic function.
It has also been shown to increase SWS in normals (60).
Gabapentin may also be helpful in treating insomnia during alcoholic abstinence. Fifty
alcohol-dependent outpatients with persisting insomnia were treated with either gabapentin
or trazodone for four to six weeks, according to the prescriber’s preference. Thirty-four were
treated with gabapentin (mean dose 888 mg) at bedtime and 16 were treated with trazodone
(105 mg) at bedtime. The gabapentin group improved significantly more than the trazodone
group in insomnia severity (61).
Finally, gabapentin has been shown to reduce alcohol use and cravings, as compared with
placebo (62).
Gabapentin has also been shown to reduce pain-related sleep disturbance in a variety
of pain syndromes, including fibromyalgia (63), peripheral neuropathy (64–66), and traumatic
nerve injury pain (67). Dosing of gabapentin for neuropathic pain is higher than what is used
for alcohol abstinence insomnia; doses of 2400 to 3600 mg/day would be common.
Pregabalin is closely related to gabapentin, and like gabapentin, it interferes with influx
of calcium into nerve terminals. Pregabalin’s half-life is five to six hours and it is exclusively
eliminated by the kidney. It is FDA approved for the treatment of fibromyalgia, neuropathic
pain, postherpetic neuralgia, and epilepsy. It has a robust literature showing that treatment
of these pain syndromes with pregabalin results in less patient-reported, pain-related sleep
disturbance at doses of 150 to 600 mg/day (68–71). Like gabapentin, pregabalin enhances SWS
in normal volunteers (72).

Valproic Acid
Sleep loss has been described as a risk factor for the precipitation or perpetuation of acute
mania. Therefore, it is likely that treatments for acute mania should have effects that sup-
port sleep induction or sleep maintenance. Valproic acid in the form of divalproex was
tested in 377 patients with acute mania, with patients randomly assigned in a 1:1 ratio to
21 days of double-blind treatment with divalproex ER (N = 192) or placebo (N = 185). Daily
dosage was increased to 500 mg daily by day 3. Treatment with divalproex was associated
with improvement on a mania rating scale, but specifically with reported improvement in
sleep (73).

Tiagabine
Tiagabine is a GABA uptake inhibitor with a half-life of seven to nine hours. Two hundred
and thirty-two men and women with primary insomnia were randomly assigned to receive
tiagabine 4, 6, 8, 10 mg or placebo in a randomized, double-blind, parallel-group study. Efficacy
was assessed using PSG and self-report measures. No significant differences were observed
between tiagabine and placebo in wake after sleep onset, latency to persistent sleep, or TST.
This study is important for testing the concept of whether induction of SWS is pathognomonic
for an effective insomnia agent, showing that SWS induction and anti-insomnia efficacy are
dissociable (9). Tiagabine is no longer under commercial development as a hypnotic.

CONCLUSIONS
Doxepin is the only medication with frequent off-label use for insomnia that is supported
by double-blind, placebo-controlled studies in primary insomnia, confirming superior activity
confirmed by both patient-report and PSG. Doxepin may receive FDA approval by the time this
chapter is published. Although none of the other medications described in this chapter meet
this same standard, there is still a suggestion of sleep efficacy for most of them. Intriguingly,
many of these medications enhance SWS, a feature not seen in the most recent FDA-approved
hypnotics (74–76). Although the lessons learned from tiagabine have shown that enhancement
of SWS can be divorced from the usual signs of sleep efficacy, enhancement of SWS seems to be
a near-universal feature of the off-label approaches to insomnia treatment.
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406 McCALL

If the use of off-label medications is driven in part by the belief that these medications
are in some way safer than FDA-approved hypnotics, then it is surprising how little safety
information is there about use of these off-label approaches in insomniacs. What data does exist
typically shows some degree of next-day impairment, bringing into question whether these
off-label approaches are really any safer than FDA-approved insomnia treatments.

RECOMMENDATIONS
None of the off-label approaches to treating insomnia can be recommended as first-line treatment
for primary insomnia, perhaps with the exception of low-dose doxepin. However, off-label
medications may be justified as monotherapy or as add-on therapy if FDA-approved treatments
fail, or if the patient has a strong preference for avoiding controlled substances. Also, off-label
approaches may be indicated in specific clinical circumstances, such as given in the following:
r Trazodone, tricyclic antidepressants, or mirtazapine for insomnia associated with depression
r Quetiapine or olanzapine for insomnia associated with psychosis
r Lorazepam, clonazepam, or alprazolam for insomnia associated with anxiety
r Clonazepam for insomnia associated with PLMs
r Valproic acid for insomnia associated with bipolar disorder
r Gabapentin or pregabalin for insomnia associated with alcohol abstinence or pain

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35 Melatonin in Sleep-Wake Regulation

Phyllis C. Zee and Kathryn J. Reid
Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, U.S.A.

INTRODUCTION
The circadian system plays an essential role in regulating the daily cycles of physiological and
behavioral functions, such as core body temperature, hormonal rhythms of cortisol and mela-
tonin secretion, and levels of sleepiness, alertness, and performance (1). Circadian rhythms are
endogenously generated cellular, physiologic or behavioral cycles with a genetically encoded
period of approximately 24 hours. In mammals, circadian rhythms are regulated by a central
circadian clock located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus
(2–4). The endogenous circadian period in humans has been shown to be approximately
24.2 hours (5). Because under normal conditions, the circadian system is synchronized or
entrained to the 24-hour rotation of the earth, individuals with an endogenous period longer
or shorter than 24 hours require a daily net advance or delay of the SCN-driven rhythm (6).
Light, melatonin, and high-intensity physical activity have been shown to act as synchronizing
agents for the circadian clock. However, light is the primary circadian synchronizing agent in
humans (7).
In humans, the most apparent function of the circadian system is the regulation of the
sleep–wake cycle (8). Circadian propensity for sleep and wakefulness is regulated by multisy-
naptic pathways from the SCN to wake and sleep promoting areas of the brain (9–12). Circadian
synchronizing agents such as light and melatonin not only reset the timing of circadian rhythms
but also can influence the firing rate of SCN neurons and thus modulate levels of alertness
and sleepiness. Thus, both light and melatonin have been studied for the treatment of sleep
disorders, including insomnia. In this chapter, we will discuss the evidence for a role of endoge-
nous melatonin in sleep regulation and the use of exogenous melatonin and melatonin receptor
agonists as treatments for insomnia.

ROLE OF MELATONIN IN SLEEP–WAKE REGULATION

Melatonin, an indoleamine hormone secreted by the pineal gland, was originally described in
1958 (13). Since its initial description, researchers have made significant gains in further under-
standing this hormone’s role in the organization of circadian rhythms and sleep. The circadian
rhythm of melatonin production is regulated by a multisynaptic pathway that originates from
the SCN via the paraventricular nucleus (PVN) to the sympathetic preganglionic thoracic spinal
cord neurons, which in turn project to the superior cervical ganglia (SCG) (Fig. 1). The superior
cervical ganglia releases norepinephrine to stimulate the ␤-adrenergic receptors of the pineal
gland to produce melatonin (14). This multistep process of melatonin production occurs at
night, when the firing rate of SCN neurons slow (15).
There is a distinct circadian rhythm of melatonin production, with high levels at night and
low levels in the daytime. In humans, the high nocturnal levels of melatonin reflect the biological
night, a time when sleep occurs. In an entrained individual with a conventional sleep–wake
time between 11 PM and 7 AM, the onset of melatonin secretion begins at about 9 PM or about
2 hours before typical sleep onset (16). Melatonin secretion reaches its peak between 2 and
4 AM, and then declines to almost undetectable levels by about 9 AM (17).
The primary site of action of melatonin is on melatonin receptors (MT1 , MT2 , MT3 ) in
the SCN. Melatonin acts on its receptors to inhibit SCN neuronal firing, leading to further
melatonin production (14). In contrast, exposure to bright light in the evening or night (at a
time when melatonin is being produced) will increase the firing rate of SCN neurons (18) and
suppress melatonin production. Melatonin binding to MT1 receptors produces inhibition of
SCN neuron firing, which has been linked to the sleep promoting effects of melatonin (19,20).
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MELATONIN IN SLEEP-WAKE REGULATION 411

Melatonin
Pineal
SCN
MT2
MT1
VSPZ VLPO Sleep
PVN DMH

LHA Wakefulness
SCG

Figure 1 This is a schematic representation of the role of the circadian system and pineal melatonin in the
regulation of sleep and wakefulness. Light–dark information is received by the retina (retinal ganglion cells
that are most responsive to short wavelength (blue) light) and travels via the retinohypothalamic tract to the
SCN. Information travels from the SCN via the paraventricular nucleus (PVN) to the sympathetic preganglionic
thoracic spinal cord neurons, which in turn project to the superior cervical ganglia (SCG) to signal the pineal to
produce melatonin. Melatonin binding to the MT1 receptors primarily produces inhibition of SCN neuron firing, and
melatonin binding primarily to MT2 receptors phase shift neural firing rhythms in the SCN. The SCN influences
sleep and wakefulness via efferent projections to other brain sleep [ventrolateral preoptic nucleus (VLPO)] and
arousal [lateral hypothalamus (LHA)] centers. The SCN sends projections to the ventral subparaventricular zone
(vSPZ) which in turn sends projections to the dorsomedial nucleus of the hypothalamus (DMH) and finally to the
VLPO and LHA.

It is thought that exogenous melatonin promotes sleep by its ability to inhibit electrical activity
or wake promoting signal from the SCN. Activation of MT1 and MT2 SCN receptors (primarily
MT2) can also reset the timing of circadian rhythms (21–23). Although the function of the MT3
receptor is not well understood, it is not likely to play an important role in sleep regulation
(24). Under normally entrained conditions, the activity of the MT1 and MT2 receptors promotes
sleep and also synchronizes the regular timing of the sleep–wake cycle. These distinct roles
for the different melatonin receptors offer opportunities for receptor-specific drug therapies of
circadian-based sleep disorders and insomnia.

EXOGENOUS MELATONIN
Exogenous melatonin has been shown to be efficacious for the treatment of sleep disturbances
associated with circadian rhythm sleep disorders. Substantial evidence shows that when timed
appropriately, melatonin is able to realign and synchronize circadian rhythms. On the basis of
its phase–response curve, melatonin, when given in the late afternoon/evening (prior to the
nadir of the core body temperature rhythm), produces phase advances, whereas, in the late
night/early morning (after the nadir of the core body temperature rhythm), it produces phase
delays in physiological and behavioral rhythms, including that of the sleep–wake cycle (25,26).
Because melatonin possesses both chronobiotic as well as soporific effects, it has been studied
and indicated for the treatment of circadian rhythm sleep disorders, such as delayed sleep phase
disorder, free-running disorder in blind people, jet lag disorder, and shiftwork sleep disorder
(27–30). However, in this section, we will focus on the use of exogenous melatonin for the
treatment of insomnia.
When Dr. Aaron Lerner first identified the pineal hormone melatonin, he connected it to
previously described lightening effects of pineal extracts on amphibian skin. He gave melatonin
to patients with vitiligo, hoping to treat the skin condition, but instead noted that his patients
became sleepy (13,31). Since then, several other studies have shown that administration of
exogenous melatonin during the biological day (when endogenous melatonin levels are low)
can promote sleep (32,33). These findings, together with findings of an association between
decreased level of nocturnal melatonin and pineal calcification (34,35) with insomnia provide
further rationale for using melatonin to improve sleep quality in insomniacs. However, clinical
studies on the efficacy of melatonin for the treatment of insomnia have yielded inconsistent
results. Such inconsistencies may be due to differences in pharmacokinetic properties of the
melatonin preparation, purity of the formulations, doses, and timing of administration that
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412 ZEE AND REID

were used in the various studies (36). Furthermore, clinical studies have not used well-defined
inclusion and exclusion criteria, and outcome measures to evaluate melatonin’s efficacy have
been inconsistent across studies.
This latter point is highlighted in recent meta-analyses and systematic reviews that eval-
uated the efficacy and safety of exogenous melatonin in the treatment of primary and sec-
ondary sleep disorders (37,38). One meta-analysis of 14 randomized controlled trials concluded
that with short-term use, melatonin was ineffective in treating most primary sleep disorders,
including insomnia. Although the authors did note that melatonin may be useful for the treat-
ment of sleep-onset insomnia associated with delayed sleep phase disorder (38). However, a
meta-analysis of 17 studies that included mixed populations of healthy volunteers, insomnia
patients, and individuals with psychiatric conditions concluded that melatonin is both effective
in improving sleep efficiency and decreasing sleep-onset latency (37).
Some of the more positive effects of melatonin treatment for insomnia have come from
studies in older adults (39–43), in particular those with low melatonin levels (34,39,41,44). Of
the various formulations of melatonin used, the prolonged-release (PR) formulations appear
to produce more consistent improvements in sleep maintenance (41), latency to persistent
sleep (LPS) (42), and subjective sleep quality (43). The effects of three-week prolonged-release
melatonin 2 mg was evaluated in a multicenter, randomized placebo-controlled study in 170
patients, aged 55 years and older with primary insomnia (43). In this large study, prolonged-
release melatonin improved measures of subjective sleep quality and morning alertness. There
were no withdrawal or rebound symptoms upon discontinuation and the adverse effects were
generally mild and not significantly different from placebo. Yet, it is important to note that
there are also studies in which melatonin did not improve sleep quality in older adults with
insomnia (45,46).
Melatonin has also been studied for the treatment of sleep disturbances in older adults
with dementia. Similar to the studies in general adults, studies in patients with dementia
have yielded inconsistent results (47,48). The largest multicenter randomized placebo-controlled
study of patients with Alzheimer Disease failed to show significant improvements in actigraphy
derived sleep measures with melatonin 5 mg, but there was a trend for improvement in the
group that received 10 mg (47,48). A recent randomized controlled trial in older adults with
dementia showed that melatonin 2.5 mg taken in the evening shortened sleep-onset latency
and increased average sleep duration by 27 minutes (47,48). However, melatonin had negative
effects on affect and also increased withdrawn behavior. Interestingly, these adverse effects were
not seen if melatonin was given in combination with daytime bright light, suggesting that in
this patient population, although low-dose melatonin can improve sleep, it is more effective
when combined with bright light exposure during the day (49).
While melatonin has been shown to be effective in treating insomnia in some studies, the
lack of large-scale, double-blind, placebo-controlled clinical trials in the general adult population
with insomnia, the variety of available preparations, differences in doses used, and concerns
about long-term effects have led the NIH State-of-the Science Consensus Statement on Chronic
Insomnia panel to conclude that “While melatonin appears to be effective for the treatment
of circadian rhythm disorders, little evidence exists for efficacy in the treatment of insomnia
or its appropriate dosage. In short-term use, melatonin is thought to be safe, but there is no
information about the safety of long-term use” (50).

MELATONIN RECEPTOR AGONISTS

Ramelteon, a selective MT1 and MT2 receptor agonist is the first melatonin receptor agonist to
be approved by the FDA for the treatment of insomnia, characterized by sleep-onset difficulty
[for a review (51)]. In comparison with melatonin, ramelteon had longer half-life (1–2.6 hours),
greater affinity and selectivity for the MT1 and MT2 receptor binding sites, and low affinity for
the MT3 binding site (52). Ramelteon is metabolized via cytochrome P450 (CYP isoenzymes),
predominantly CYP1A2 to several metabolites. One of these metabolites, M-II, is a much less
potent MT1 and MT2 receptor agonist, with a half-life of 2 to 4 hours.
Randomized multicenter clinical trials have shown that ramelteon reduces sleep-onset
latency in those with transient (53,54) and chronic insomnia (55–59). In a model of transient
insomnia in healthy adults, administration of ramelteon significantly decreased the time to fall
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MELATONIN IN SLEEP-WAKE REGULATION 413

asleep when compared to placebo (53,54). In patients with chronic primary insomnia, ramelteon
8 mg taken 30 minutes before bedtime improved LPS in the first week and for the duration of
five-week (55,60) and six-month studies (61). Subjective sleep latency improved in some, but
not in all studies, and was not maintained at all time points throughout the six-month period.
Improvements in other objective and self-reported sleep parameters, including total sleep time
were inconsistent among various studies.
Ramelteon has also been studied in special populations, such as older adults. Older adults
are particularly interesting because melatonin levels may decline with aging (62,63). In a large
study of older adults, 65 to 93 years with chronic insomnia ramelteon administration over a
five-week period significantly decreased self-reported sleep latency (56,57,64). However, there
were no significant differences between ramelteon and placebo on sleep quality and number of
awakenings.
In the clinical studies, ramelteon was generally well tolerated and was not associated
with withdrawal, abuse or rebound insomnia (55,57,65). The most common adverse events
were headache, somnolence, dizziness, and fatigue (55,56). Furthermore, ramelteon had no
significant effect on cognitive or psychomotor function compared to placebo (58,65) and no
impact on balance in the middle-of-the-night testing (61,66). Studies of long-term use (six
months) on endocrine function showed increases in prolactin in women, without measurable
effects on reproductive function (67). Other safety studies have included patients with mild to
moderate (68) and severe (69) chronic obstructive pulmonary disease (COPD) or obstructive
sleep apnea (70) in which administration of 8 mg of ramelteon showed no significant reductions
in oxygen saturation (68,69).

Melatonin Receptor Agonists in Development

Since the introduction of ramelteon in 2005, there has been an interest to develop other melatonin
receptor agonist for the treatment of circadian rhythm sleep disorders and insomnia. Of these,
clinical data is available for agomelatine, tasimelteon, and TIK-301.
There is limited clinical trial data on the efficacy and tolerability of TIK-301 (␤-methyl-6-
chloromelatonin). This compound is a melatonin analogue with high affinity for the MT1 and
MT2 receptors. In a double-blind placebo-controlled phase II trial in patients with moderate
to severe primary insomnia, TIK-301 was shown to produce a dose dependent (5–100 mg)
reduction in sleep latency (71).
Agomelatine (S20098) is a high-affinity MT1 and MT2 receptor agonist (72) and a 5-HT2C
and 5-HT2B receptor antagonist (73). Agomelatine has been shown to have effects on both the
circadian system and in mood regulation. Its circadian effects include promotion of sleep via its
action on melatonin receptors in the SCN (74) and resetting of the timing of circadian rhythms
(56). Although agomelatine is being developed primarily for the treatment of anxiety (75) and
depression (76–78). [for a review (79)] It has also been shown to improve sleep quality in studies
of major depressive disorder (43) and generalized anxiety disorder (75).
Tasimelteon (VEC-162) is an MT1 and MT2 agonist that has been studied in phase II and
phase III trials in healthy adults in a model of transient insomnia induced by a 5-hour phase
advance of the sleep–wake cycle (80). In both the phase II and phase III trials, tasimelteon was
given 30 minutes prior to bedtime at doses of 10 mg, 20 mg, 50 mg, and 100 mg. In the phase II
trial, only tasimelteon 100 mg significantly advanced dim light melatonin onset compared to the
placebo group. In the phase III trial, tasimelteon increased sleep efficiency and total sleep time
and decreased LPS (80). The most consistent improvements in objective and subjective sleep
quality measures were seen with tasimelteon 50 mg. Tasimelteon was generally well tolerated.

SUMMARY
Endogenous melatonin produced by the pineal gland plays an important role in sleep–wake
regulation. While exogenous melatonin has been shown to possess sleep-promoting properties,
studies on its effectiveness in the treatment of adults with chronic insomnia have yielded
inconsistent results. Some of these inconsistencies may be related to the differences in the study
populations, type of formulation, dose, and outcome measures of efficacy between studies.
Within the area of insomnia, the most promising results for melatonin come from studies in
late-middle age and older adults. Although melatonin has been shown to be effective in some
c35 IHBK059-Sateia March 25, 2010 9:53 Char Count=

414 ZEE AND REID

short-term studies of insomnia and found to be generally safe in low doses of 1 to 5 mg, more
short-term and long-term multicenter randomized clinical trials are needed before evidence-
based clinical guidelines can be established for its use in the treatment of insomnia.
The development of melatonin receptor agonists with more specific and stronger affinities
for particular receptor subtypes within the SCN will likely lead to improved understanding of
the role of endogenous melatonin in sleep regulation and help develop more targeted therapies
for insomnia.

ACKNOWLEDGMENTS
Funding for this work was provided by a National Institutes of Health grant R01HL069988.

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36 Nonprescription Pharmacotherapies: Alcohol,

Over-the-Counter, and Complementary and
Alternative Medicines
David N. Neubauer
Department of Psychiatry, Johns Hopkins Bayview Medical Center, Johns Hopkins University School of
Medicine, Baltimore, Maryland, U.S.A.

Kelleen N. Flaherty
Department of Biomedical Writing, University of the Sciences in Philadelphia, Philadelphia,
Pennsylvania, U.S.A.

INTRODUCTION
A large percentage of individuals with insomnia self-medicate with alcohol, over-the-counter
(OTC) antihistamines, or complementary and alternative preparations (1,2). In the United
States, the formulation and manufacture of OTC products are regulated by the U.S. Food
and Drug Administration (FDA). Other products not requiring a prescription, such as dietary
supplements, are unregulated. The National Center for Complementary Health and Alternative
Medicine (NCCAM) at the National Institutes of Health (NIH) defines “complementary and
alternative medicine (CAM)” as “practices that are unproven by science and not presently con-
sidered an integral part of conventional medicine” (3). CAM encompasses a variety of dietary
supplements, herbal compounds, or formulations containing a mixture of these (4,5). Individ-
uals seeking relief from insomnia may also combine two or more of any agents for insomnia
(including prescription medications, OTC agents, alcohol, and CAM preparations) (6). Alcohol
is the substance most commonly used to self-medicate for insomnia. Some 1.6 million non-
institutionalized adults with insomnia are estimated to use CAM to treat their insomnia or
difficulties in sleeping (7); 20% of the population using herbals alone (8). The popularity of
CAM in general is increasing; a 2007 national survey of adults and children found that 38.3%
of U.S. adults using any CAM increased from 36% in 2002. Of those individuals using CAM in
2007, 1.4% of adults and 1.8% of children were doing so for insomnia. Nonvitamin, nonmineral
products accounted for most (17%) CAM use (9).
Despite the perceived efficacy of these agents by the individuals who use them, there
are several concerns associated with their use. There have been very few controlled studies
conducted on most of these substances, and the available evidence has demonstrated little or no
clinical efficacy. Safety data are similarly scant or lacking (10,11). Since CAM preparations are
not regulated by the FDA, the consistent potency and product purity are not assured (10,12–14).
Compounding this, many herbal products are mixtures of more than one type of herb. The FDA
may intervene to remove a product from the market or issue advisories or warnings only when
significant safety concerns are evident, as was the case with tryptophan in 1990 (10,13,15,16)
and kava kava in 2002 (17). Although generally regarded as benign, the use of CAM substances
may be associated with clinically important and sometimes lethal adverse effects, such as the
liver toxicity reported for kava kava, as well as the myriad problems associated with exces-
sive alcohol use (10,12,18). CAM tends to be used more by individuals experiencing insomnia
comorbid with other chronic conditions, particularly psychiatric illness (e.g., anxiety and mood
disorders), congestive heart failure, hypertension, and obesity (7,19). Apart from the fact that
comorbid conditions themselves may lower the risk threshold associated with use of certain
OTC and CAM products (such as CNS and GI effects with antihistamine use (20) or hepatotox-
icity with kava kava) (8,10,18), the potential for pharmacologic interactions is also significant
(10,13). St. John’s wort, for example, is an inducer of cytochrome P450 isoenzymes (8,10) and
has the potential to interfere with protease inhibitors, chemotherapeutic agents, and oral con-
traceptives (21). Kava kava, valerian, and St. John’s wort may interact with anesthetics (22),
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418 NEUBAUER AND FLAHERTY

and tryptophan may have toxic effects when used concomitantly with certain psychiatric med-
ications (11). Further complicating these issues, most of the OTC and CAM products are per-
ceived by patients to be safe, as they often are touted to be “natural” (8), or are not considered
dangerous since they do not require a prescription. Frequently patients do not report their use
of these agents to their physicians when listing their “real” medications and physicians are not
necessarily aware that they should inquire about them (12,19).

ALCOHOL
Large-scale studies have estimated that 13% to 28% of individuals with insomnia use alcohol
specifically to induce sleep (6,23). One Japanese study reported the use of alcohol as a sleep-
promoting agent in 48% of male survey respondents (24). A National Sleep Foundation (NSF)
survey conducted in 1991 found that some 30% of their respondents with chronic insomnia used
alcohol as a sleep aid, and that 67% of them found it to be effective in reducing sleep latency
(25). Alcohol is a CNS depressant; its hypnotic properties may be a consequence of multiple
pharmacologic effects, including its interaction with gamma-aminobutyric acid (GABA) and
glutamate (26,27). Its effects on sleep have been investigated for decades, often in controlled
trials, but frequently with conflicting results. Some studies have shown that alcohol does, in fact,
decrease sleep latency (28–31), while others have shown that it does not (23,32,33). The effects of
alcohol on sleep typically are dose dependent (10,23) and may also depend upon the chronicity
of the insomnia as compared with individuals without insomnia (23). While total sleep time
(TST) is not usually affected by alcohol intake, a dose-dependent redistribution of REM sleep
and NREM sleep stages is common, although this has not been demonstrated consistently. A
common finding is REM suppression during the first half of the night, followed by REM rebound
(or “mini withdrawal”) during the latter half of the night as the alcohol is metabolized and the
serum level decreases (23,26,30,31). An increase in NREM stages 3 and 4 sleep during the first
half of the night may be associated with alcohol ingestion (31), as may an increase in NREM
stage 1 and waking in the latter half of the night (30). Low doses of alcohol have been shown
to increase TST and therefore, may result in mildly beneficial effects (23,32). Development of
tolerance to alcohol develops quickly, often within three nights in healthy volunteers (31), and
is associated with a concomitant return to normal sleep architecture (26). Use of alcohol as
a sleep aid has also been shown to impair secretion of growth hormone (GH), independent
of slow wave sleep (SWS) alterations (26,34); exacerbate snoring and sleep apnea (23,35); and
worsen restless legs syndrome (RLS) (2). Nightly use of alcohol can cause or worsen insomnia
or exacerbate other psychiatric conditions such as depression or anxiety (36). Chronic use of
alcohol for insomnia may lead to the development of alcohol dependence (36,37). Finally, it has
been argued that an improved mood associated with the use of alcohol may be contributing to
beneficial effects on sleep (23). Given the potentially significant problems associated with the
regular use of alcohol as a sleep-inducing agent, its use should be discouraged.

ANTIHISTAMINES
First-generation antihistamines, such as diphenhydramine, doxylamine, chlorpheniramine (as
well as the prescription drugs hydroxyzine and doxepin), are pharmacodynamic antagonists
at central histamine H1 receptors. The first-generation antihistamines are liposoluble and read-
ily cross the blood-brain barrier, and may be associated with significant anticholinergic and
sedative effects, hence their popularity as OTC sleep aids (38–40). Diphenhydramine is by far
the most common antihistamine encountered in OTC sleep aids, either by itself (e.g., Nytol
R
,

R
Sominex ) or in combination with pain relievers in “nighttime” or “PM” formulations (e.g.,
Tylenol PM
R
). Diphenhydramine has a tmax of 1.7 (±1) hours, a t1/2 of 9.2 (±2.5) hours, and a
duration of action of approximately 12 hours (39). Subjective improvement of sleep onset and
sleep quality are common in subjects taking diphenhydramine (typically at a dose of 25–50 mg)
(2,10,41–45), but few randomized, placebo-controlled studies assessing the safety and efficacy
of diphenhydramine in the treatment of insomnia have been conducted. Efficacy in at least one
sleep parameter has been demonstrated in populations of adults (41), geriatric subjects (includ-
ing those in long-term care) (44,45), pediatric subjects (42), and psychiatric patients (43). A
1983 double-blind, placebo-controlled, crossover study evaluated the use of diphenhydramine
50 mg in adult subjects complaining of difficulty with sleep onset. On the basis of subjective
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NONPRESCRIPTION PHARMACOTHERAPIES 419

assessments (daily sleep logs), diphenhydramine was significantly more effective than placebo
at decreasing sleep latency, decreasing frequency of awakenings, decreasing wake time after
sleep onset (WASO), increasing sleep duration, and increasing quality of sleep. Subjective physi-
cian assessment of efficacy was similar (41).
While diphenhydramine has been shown to be associated with sedation and improvement
in sleep parameters such as sleep onset, duration, and quality, it also is associated with signif-
icant safety concerns regarding its relatively long half-life and its anticholinergic properties
resulting from postsynaptic muscarinic receptor antagonism. Complaints of residual sedation,
drowsiness, or grogginess during the morning or daytime following bedtime use are common
(11,38,41). The anticholinergic activity has the potential to cause other side effects, such as
diminished cognitive function and delirium, dry mouth, blurred vision, urinary retention, con-
stipation, and risk of increased intraocular pressure in individuals with narrow-angle glaucoma
(11). Undesired sedation, delirium, and anticholinergic effects are of particular concern in geri-
atric patients (11,46). Additionally, there are potential pharmacokinetic and pharmacodynamic
interactions with concomitant medications, CAM substances, and alcohol. Caution is advised
when patients are taking other medications with anticholinergic effects. Diphenhydramine also
exacerbates the adverse effects of ethanol upon oculomotor coordination, cognitive function,
and driving ability (40). An additional concern with the use of diphenhydramine as a sleep
aid is the possible development of tolerance to its sedating effects. In one study in healthy
volunteers, diphenhydramine was administered 50 mg twice daily and sleepiness was assessed
both objectively and subjectively throughout the day. Development of tolerance to the sedating
effects of diphenhydramine was observed after administration of the medication for four con-
secutive days (47). The development of tolerance results in reduced efficacy and may contribute
to the development of dependence or abuse. Tolerance to the antihistamine sedating effects
may lead to dose escalation and other possible reinforcing effects, such as euphoria. Antihis-
tamine abuse has been documented; case reports exist for doses of diphenhydramine as high
as 3000 mg per day (48). The position of the American Academy of Sleep Medicine (AASM) on
diphenhydramine is as follows: “Sufficient evidence does not exist to support over-the-counter
(OTC) sleep aids . . . OTC sleep aids that contain antihistamine may provide modest, short-term
benefits for adults with mild cases of insomnia. It is important to be aware, however, that the
use of antihistamines may produce a variety of side effects” (49).

MELATONIN
Melatonin is a pineal hormone involved in the regulation of circadian rhythms. Although it
has sleep-promoting effects on healthy volunteers and has been assessed in a small num-
ber of controlled clinical trials, its efficacy in the treatment of insomnia has not been well
established (50,51), and some controlled studies have shown it to be indistinguishable from
placebo (52). Melatonin generally is considered to be safe, but its safety in long-term use has not
been demonstrated (11,50). Melatonin is a very popular dietary supplement. The 2002 Alter-
native Health/Complementary and Alternative Medicine Supplement to the National Health
Interview Survey (NHIS) interviewed an age and socioeconomically representative population
of 31,044 individuals about use of 25 pharmacologic and nonpharmacologic CAM therapies,
including melatonin. The use of melatonin was reported by 5.2% of the respondents and of
those individuals, 27.5% identified insomnia as at least one reason for its use. Most melatonin
use occurred without physician consultation (52). A retrospective meta-analytic study was con-
ducted in 2005 by Buscemi and colleagues evaluating the safety and efficacy of melatonin in the
treatment of primary insomnia. Initially, 1884 melatonin studies were identified; however, only
14 met the randomized-controlled trial criteria for assessment of efficacy and only 10 met the
criteria for safety assessment (50). Mean improvement of sleep latency was 11.7 minutes. Two
studies in the insomnia meta-analysis also investigated the efficacy of melatonin in shortening
sleep onset in subjects with delayed sleep phase syndrome (DSPS). Subjects with DSPS taking
melatonin experienced an average improvement in sleep latency of 38.8 minutes, as compared
with 7.2 minutes in subjects with insomnia. The meta-analysis also assessed secondary out-
come measures such as sleep efficiency, sleep quality, wakefulness after sleep onset (WASO),
TST, and percentage of time spent in REM sleep. None of these secondary measures reached
statistical significance. Safety assessment (headache, nausea, dizziness, drowsiness) showed no
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420 NEUBAUER AND FLAHERTY

significant difference in adverse events between melatonin and placebo. The study group for
the meta-analysis concluded that there was little evidence supporting the use of melatonin
as an exogenous sleep aid, although it might be useful for treating DSPS. The researchers
also concluded that melatonin appears to be safe, at least for short-term use (up to three
months) (50).
A second meta-analysis by Brzezinski and colleagues evaluated the effects of exogenous
melatonin on sleep in 17 randomized, double-blind, placebo-controlled trials using objective
measures of sleep evaluation and including at least six adult subjects with no severe disabling
systemic disease (53). Crossover and parallel group designs were included, but case studies
were not. This meta-analysis was a review of the trials investigating the effects of melatonin
on sleep and not on insomnia per se. However, nine of the trials in this meta-analysis involved
participants with insomnia (five of the insomnia studies were also included in the Buscemi meta-
analysis). In a subanalysis of healthy subjects with no relevant medical condition other than
insomnia, subjects administered exogenous melatonin had shorter sleep onset by an average of
3.9 minutes, higher sleep efficiency by an average of 3.1%, and a longer TST by an average of 13.7
minutes. The authors concluded that there was statistically significant evidence demonstrating
that the use of exogenous melatonin improves sleep latency, sleep efficiency, and TST (53).
However, it remains unclear whether these modest changes represent clinically significant
improvements. The meta-analysis authors also concluded that melatonin generally is safe, at
least for short-term use in adults.
The role of melatonin in sleep-wake regulation and the use of exogenous melatonin and
melatonin agonists as sleep aids is discussed further in chapter 35.

L-TRYPTOPHAN
L-tryptophan is an essential amino acid and dietary precursor of serotonin. The role it plays in
the biochemistry of sleep and its impact on sleep architecture have not been fully elucidated,
although it has been regarded as a “natural” sleep aid. Its purported positive effects on sleep
onset and maintenance are based on very few and mostly uncontrolled clinical studies that often
included noninsomniac subjects (10,19,54–57). L-tryptophan may be most beneficial in subjects
with mild insomnia or in normal subjects with situational insomnia accompanied by longer-
than-average sleep onset (58,59). Tryptophan generally is considered to be safe and reportedly
is not associated with visuomotor, cognitive, or memory impairment. However, L-tryptophan
as a supplement was removed from the market in 1989 because of the development of an often
serious and sometimes fatal (37 attributed deaths) eosinophilia myalgia syndrome (EMS) in
some individuals who had taken one of several tryptophan-containing products. The cause
of the eosinophilia myalgia syndrome was ultimately traced to a contaminant from a single
manufacturer, and L-tryptophan is once again available (2,15,16). Nevertheless, the NIH chronic
insomnia State-of-the-Science summary report cautions against the use L-tryptophan due to
possible adverse effects, particularly if used in conjunction with psychiatric medications (11).
When concern about L-tryptophan developed and its availability became limited, 5-hydroxy-
L-tryptophan (5-HTP, the immediate precursor to serotonin, or 5-HT) grew in popularity as a
“natural hypnotic.” After the L-tryptophan recall, scrutiny of 5-HTP for serious adverse events
was high, but no definitive toxicity with use of the agent has been confirmed (15). 5-HTP is
commercially produced by extraction from the seeds of Griffonia simplicifolia, a woody African
shrub. Effects of 5-HTP on insomnia are inconclusive (10,19).

HERBAL PREPARATIONS AND DIETARY SUPPLMENTS

Herbal products used as CAM are prepared from roots, stems, flowers, buds, or leaves of plants.
These plant products can be used whole, dried, crushed, and steeped as tea; other preparations
contain extracts. While some herbal preparations have shown some efficacy in improving some
sleep parameters in a few studies, most studies are small and uncontrolled or anecdotal in
nature. As production of these compounds is not overseen by the FDA, purity and consistency
are not assured. Significant adverse events may be associated with the use of some of these
herbal products. Individuals perceive these agents to be safe because they’re “natural” and
frequently do not report use of these supplements to their physicians.
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NONPRESCRIPTION PHARMACOTHERAPIES 421

Valerian (Valerian Root, All Heal, Garden Heliotrope, Vandal Root)

Valeriana officinalis is a perennial herb used in a variety of herbal supplements either by itself or
in combination with other agents. Among its major ingredients are valerenic acid, valepotriates,
sesquiterpenes, and hydroxypinoresinol; aqueous extracts contain significant concentrations
of gamma aminobutyric acid (GABA). The sedative and anxiolytic effects of valerian have
been attributed to the valepotriates and sesquiterpenes in the volatile oils (19). Studies have
also shown that valerian extract and valerenic acid are partial agonists of the 5-HT5A recep-
tor (60). Valerian-containing preparations have been assessed in many studies, including some
randomized, placebo-controlled trials, subjective assessments, and polysomnographic studies.
However, given the multiple pharmacologically active components of the herb and the lack of
consistency in manufacturing, the elucidation of its effects is difficult (2,10). Significant improve-
ments in both objective and subjective measures of sleep onset, wakefulness after sleep onset,
and sleep quality have been reported, but many studies also have shown no statistical improve-
ment in these measures. Valerian has not been shown to affect sleep architecture. Response to
valerian is typically dose dependent (10,22). Although generally considered to be safe, some
concerns exist about its potential for interaction with alcohol (61), anesthetics (22), the CYP3A4
metabolic pathway, as well as for potential interactions with sedatives, such as benzodiazepines
or barbiturates (2,61). Hallucinations, hepatotoxicity, and withdrawal effects also have been
reported (2,19,62), but case reports are rare. In the Alternative Health/Complementary and
Alternative Medicine Supplement to the NHIS, 5.9% of individuals surveyed reported using
valerian, 29.9% of whom identified insomnia as at least one reason for doing so. As with mela-
tonin use in this study, less than half of the individuals using valerian did so without consultation
with a health care provider (52). The 2005 NIH chronic insomnia State-of-the-Science summary
report concluded that the limited evidence shows no benefit compared with placebo (11).

Kava Kava (Awa, Kawa, Intoxicating Pepper)

Kava kava, which is derived from a pepper plant, Piper methysticum, is reported to have seda-
tive and anxiolytic properties (22). Its CNS pharmacologic effects are thought to include block-
ade of voltage-gated sodium and calcium ion channels, enhanced ligand binding to GABAA
receptors (although there is also evidence for lack of binding to GABA or benzodiazepine
receptors), diminished excitatory neurotransmitter release, and reduced neuronal reuptake of
norepinephrine. Several of these pharmacodynamic actions may contribute to the purported
hypnotic properties (18,19). Sleep-promoting effects of kava kava have been reported, although
mostly in anecdotal or uncontrolled studies, and not necessarily in populations of insomnia sub-
jects (63). Most research on the safety and efficacy of kava kava has been with anxiety outcomes.
One internet-based, randomized, placebo-controlled trial showed no statistical difference in
improvement of sleep scores (Insomnia Severity Index, sleep latency, and frequency of noctur-
nal awakening) with the use of kava kava as compared with placebo (64). Another nonblinded
trial assessing the efficacy of treating stress-related insomnia did, however, show significant
improvement of symptoms with use of kava kava as compared with placebo (63). While there
are concerns about the interaction of kava kava with other medications such as CNS depressants
and dopamine antagonists (22,65), the major concern associated with its use is hepatotoxicity.
Seventy-eight cases of hepatotoxity (via diffuse hepatocellular necrosis, cholestatic hepatitis, or
isolated gamma-GTP increase) were recognized after 1998, including 11 cases requiring liver
transplantation (4 resulting in death). The supplement was banned in the European Union and
Canada, and the U.S. FDA issued a consumer advisory in 2002 (17,18). Its use should be strongly
discouraged for this reason, particularly in any individual with hepatic impairment.

St. John’s Wort (Amber Touch and Heal, Goat Weed, Hardhay, Hypericum, SJW,
Klamath Weed, Millepertuis, Rosin Rose, Tipton Weed)
Hypericum perforatum is a perennial herb indigenous to Europe, but found across the United
States. It has been used for medicinal purposes for millennia. The above-ground portion of the
plant is dried and a red liquid is extracted to create the dietary supplements. There are several
pharmacologically active compounds in St. John’s wort, but those most likely to be responsible
for sleep-promoting effects are hypericin and hyperforin. Hypericum may exert its effects through
impact on catecholamine neurotransmission, via inhibition of neurotransmitter metabolism,
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422 NEUBAUER AND FLAHERTY

modulation of neurotransmitter receptor density and sensitivity, and synaptic reuptake inhi-
bition (14). Although the exact mechanism of action of Hypericum remains unknown, hyper-
forin has been demonstrated to inhibit the reuptake of serotonin, norepinephrine, dopamine,
GABA, and L-glutamate (10). Almost all of the safety and efficacy studies of St. John’s wort
have been for its utility in managing depression; none have been conducted for insomnia.
However, the effects of St. John’s wort on sleep architecture have been assessed in healthy
volunteers with varying results, including inconsistent reports of increased latency to REM
sleep and increased percentage of slow wave sleep (10,14). Adverse events associated with
the use of St. John’s wort include fatigue, gastrointestinal upset, dizziness, anxiety, headache,
photosensitivity, and phototoxicity. The significant concern associated with the use of St. John’s
wort, however, is its potential interactions with other drugs. Of all the popular herbal sup-
plements, St. John’s wort is the most problematic as far as pharmacokinetic interactions are
concerned. St. John’s wort is an inducer of several CYP450 isoenzymes, including CYP3A4.
Studies have shown that St. John’s wort decreases cyclosporine levels; may be associated
with breakthrough bleeding in women on oral contraceptives; lowers concentration levels of
statins, midazolam, nifedepine, protease inhibitors, theophylline, and tricyclic antidepressants;
decreases the effects of warfarin; can have significant interactions with SSRI antidepressants,
anesthetics, digoxin, loperamide, chemotherapeutic agents, and thyroid medications; and may
contribute to the development of the serotonin syndrome (14,21). Individuals taking any med-
ications that are metabolized by the CYP450 system should be cautioned against using St.
John’s wort.

Miscellaneous Herbs Used as Sleep Aids

Passionflower (Passiflora incarnata), Skullcap (Scutellaria laterifolia), Jamaica dogwood (Piscidia
erythrina or Piscidia piscipula), chamomile (Anthemis nobilis), hops (Humulus lupulus), lavender
(Lavandula officinalis), wild lettuce (Lactuca virosa), California poppy (Escholtzschia californica),
lemon balm (Melissa officinalis) and other herbs (and combinations of herbs) are commonly
marketed as natural remedies for insomnia. Little or no safety and efficacy studies have been
performed on these botanicals. Apart from Jamaica dogwood, which can be toxic if used in large
amounts (it is used as a fish poison and is the source of rotenone), no reports of toxicities to any
of these plant products has been made.
The position of the AASM on herbal supplements as a remedy for insomnia is as follows:
“There is only limited scientific evidence to show that herbal supplements are effective sleep
aids. Because these products may be marketed and sold without FDA approval and may involve
dangerous side effects or adverse drug interactions, they should be taken only if approved by
a physician” (66).

Vitamin and Mineral Supplements

Minimal information (often case reports) is available on the use of vitamins to treat sleep
disturbances. There are no randomized controlled clinical trials, and conclusions from studies
that have been performed are preliminary and provide the caveat that more studies are needed.
Some vitamins and minerals are hypothesized to have an impact on sleep based on evidence
that subjects who have taken high doses of certain vitamins and minerals experience disturbed
sleep or grogginess as a side effect (vitamin A and calcium are examples) (10,67). Two small,
uncontrolled trials evaluating nicotinamide have reported improved sleep (increased REM sleep
in one, and increased sleep efficiency in another) (68). Magnesium has been reported to enhance
the secretion of melatonin and therefore, may help promote sleep, but no studies on its use with
insomnia have been published (69). Vitamin B12 has been shown to have a significant effect
on circadian rhythm disorder in some case reports, but also has not been investigated for the
treatment of insomnia (10). In one large study of 519 subjects assessing the relationship between
vitamin use and sleep, significantly impaired sleep was seen in subjects taking multivitamins
or multiple single vitamins as compared with those not taking vitamins. Concomitant use of
herbal medicines, however, was not taken into account for this study. The authors concluded
that these results may be explained by the possibility that vitamins cause poor sleep, poor
sleepers seek vitamins, or unidentified factors promote both poor sleep and vitamin use, and
that more controlled studies are needed (67).
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Table 1 Nonprescription Pharmacotherapeutic Agents used as Sleep Aids

Nonprescription Reported effects on sleep in ≥ 1

agent study Safety concerns
Alcohol
Alcohol Decreases sleep latency (28–31) Tolerance (31)
Does not decrease sleep latency ↓ Secretion GH (26,34)
(23,32,33) ↑ Snoring, sleep apnea (23,35)
↑ TST by low doses (23,32) Worsens RLS (2)
↓ REM first half of night Cause or worsen insomnia (36)
↑ REM latter half of night Exacerbate comorbid psychiatric conditions
↑ NREM 3/4 first half of night (36)
(23,26,30,31) Dependence (36,37)
↑ NREM 1, ↑ waking in second half of
night (30)
Antihistamines
Diphenhydramine Subjective (physician and subject) Anticholinergic effects, particularly in older
improvement of sleep onset and individuals (11,38–40,46)
quality, ↓ awakenings, ↑ TST (2,10, Residual sedation, grogginess; long half-life
41–45) (11,38,41)
Efficacy in at least one sleep Interaction with concomitant medications,
parameter seen in adults, geriatric CAM agents, alcohol
subjects, pediatric subjects, and Tolerance (47)
psychiatric patients (41–45) Abuse (48)
Dietary Supplements
Melatonin ↓ Onset in some studies (50) Essentially not different from placebo; safe in
Effective in DSPS (50) short-term (≤ 3 months) (53)
L-tryptophan Might be beneficial in mild or Removed from market in 1989 due to
situational insomnia (58,59) fatality-related impurities; has since been
restored with caveats (2,15,16)
Possible interactions if used with psychiatric
medicines (11)
Valerian Significant improvements in both Potential interaction with alcohol, (61)
objective and subjective measures anesthetics, (22) the CYP3A4 metabolic
of sleep onset, WASO, and sleep pathway, and sedatives (2, 61)
quality have been reported (10,22) Hallucinations, hepatotoxicity, and withdrawal
Not been shown to affect sleep effects have been reported (2,19,62)
architecture (10,22)
Kava kava Sleep-promoting effects have been Interaction with CNS depressants and
observed in anecdotal/uncontrolled dopamine antagonists (22,65)
studies (63) Significant hepatotoxicity that can lead to liver
Improvement in stress-related transplantation and death (17,18)
insomnia symptoms in 1 trial (63) Warning: do not take with hepatic impairment
St. John’s wort Inconsistent results of ↑ latency to Fatigue, GI upset, dizziness, anxiety,
REM sleep, ↑ % SWS (10,14) headache, photosensitivity, phototoxicity
(14,21)
Significant concern with drug interactions;
induces several CYP450 enzymes,
especially CYP3A4
Studies: may cause decreased
concentrations of or have significant
interactions with certain prescription
medications
Warning: do not take concomitantly with
medications that are metabolized by the
CYP 450 system
Nicotinamide ↑ REM sleep (68; small, uncontrolled
trial)
↑ Sleep efficiency (68; small,
uncontrolled trial)
Abbreviations: CAM, complementary and alternative medicine; DSPS, delayed sleep phase syndrome; GH, growth hormone; GI,
gastrointestinal; NREM, non rapid-eye movement (sleep); REM, rapid-eye movement (sleep); RLS, restless leg syndrome; SWS,
slow wave sleep; TST, total sleep time; WASO, wakefulness after sleep onset.
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424 NEUBAUER AND FLAHERTY

SUMMARY
A variety of nonprescription pharmacologic agents are widely used as sleep aids (Table 1).
Although the most frequently used substance to induce sleep, alcohol has not been determined
to be safe or efficacious as a sleep aid or in the treatment of insomnia. OTC antihistamine sleep
aids may be popular because they are readily accessible, do not require a prescription, and are
perceived to be safe. Herbal and dietary supplements, such as melatonin and valerian, may be
appealing to consumers because they are viewed as “natural” products. Accordingly, it are not
surprising that the use of OTC and CAM compounds is widespread. However, data are scant or
lacking on the safety and efficacy of most of these agents, some can have serious side effects or
cause significant drug interactions, and consistent purity and concentration of the unregulated
marketed agents are not assured. Increased awareness of the potential safety issues associated
with OTC and CAM agents is required by both consumers and health care professionals alike.

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37 Current Advances in the Pharmacotherapy

of Insomnia: Pipeline Agents
Michael J. Sateia
Department of Psychiatry, Dartmouth Medical School, Lebanon, New Hampshire, U.S.A.

Medications used for the treatment of insomnia during the past century have largely employed
two basic mechanisms for sleep promotion. Prescription sleeping pills such as barbiturates, ben-
zodiazepines (BZDs), and other BZD receptor agonistic modulators (BzRAs) act at the GABAA
receptor complex to enhance GABA inhibitory activity and promote sleep. Over-the-counter
sleep medications have been and continue to be formulations of nonselective histamine antago-
nists such as diphenhydramine or doxylamine. Advances in the understanding of neurochem-
ical control of sleep–wake, coupled with identification of previously unknown transmitters,
such as hypocretin/orexin, have created new horizons in the pharmacotherapy of insomnia.
While some pipeline development continues to target activation of sleep-promoting GABAer-
gic mechanisms, many of the current pharmaceutical efforts are directed at the identification
of safe and efficacious medications that antagonize wake-active transmitter systems such as
orexin, 5-HT2A , and histamine. Other agents are targeted at the melatonin system, potentially
expanding the choice of such agents beyond ramelteon. Certain pipeline drugs offer multiple
potential mechanisms of sleep-promoting action.
The following chapter attempts to capture the cross section of compounds in development
as of 2009. However, a review of this literature underscores the unpredictability of pharmacolog-
ical research and development. Failures to replicate initially promising efficacy data, emergence
of unforeseen adverse reactions, shifts in the competitive environment, and numerous other
factors create an ever-changing field. In recent years, numerous promising drugs have been
derailed, sometimes in late stages of development. Therefore, in considering compounds dis-
cussed in this chapter, one should keep in mind that, in all likelihood, many, if not most, of
the drugs discussed will never achieve FDA approval. Despite that, the research engendered in
discovery and development of these agents often serves to advance our knowledge of not only
pharmacotherapy but also sleep–wake biology itself.

GABA AGONISTIC MODULATORS

GABA is the major inhibitory neurotransmitter in the brain, and GABAergic neurons of the
ventrolateral preoptic (VLPO) region of the hypothalamus demonstrate maximum firing rates
during sleep. For most of the past century, prescription agents for the treatment of insomnia
have exerted their primary mechanism of action on the GABA receptor complex. This is true
for the barbiturate compounds, widely used in the first half of the 20th century, as well as
the benzodiazepine agents, the dominant prescription medications since the late 1960s. The
BZDs and their more recently developed cousins (imidazopyridines, pyrazolopyrimidines, and
cyclopyrrolones), collectively referred to as benzodiazepine receptor agonists (BzRA), bind at
various subunits of the BZD receptor, located on the GABAA receptor complex, and exert a
modulating action that, in the presence of GABA, enhances chloride flux across the membrane
and hyperpolarizes the cell. BZDs themselves show little selectivity in receptor subtype binding,
while newer agents demonstrate greater selectivity primarily for the ␣1 -receptor subunit. The
pharmacology and clinical application of these agents is discussed extensively in preceding
chapters.
One newer BzRA agent, indiplon, has been in the pipeline for some time and undergone
full phase III trials (1–5). Indiplon, in both immediate and modified-release formulations, was
submitted for FDA approval that was denied in 2006. Particular concerns focused on the higher
dose, extended-release formulation, which was deemed not approvable. To date, the future of
this agent remains uncertain.
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428 SATEIA

EVT 201 (Evotec AG), a partial positive allosteric GABA receptor modulator in pre-clinical
studies, has undergone initial assessments for the treatment of primary insomnia. Sleep was
evaluated in 75 subjects who received placebo, EVT 201 (1.5 or 2.5 mg), in a cross-over design
(6). Two nights of polysomnography (PSG) and subjective sleep ratings indicated significantly
shorter latency to persistent sleep, greater total sleep time (TST), fewer awakenings, and reduced
wake after sleep onset. Sleep maintenance improvements were observed into the third and
fourth quarters of the night. Quality ratings were improved and no major adverse events were
reported, although mild effects on morning digit symbol substitution test were noted. A phase II,
randomized, placebo-controlled study (7) of EVT 201 in 149 elderly primary insomnia subjects
demonstrated increased TST, reduced latency to persistent sleep (LPS) and wakefulness after
sleep onset (WASO), and objective improvements in daytime alertness by multiple sleep latency
test (MSLT).
Adipiplon (NG2-73; Neurogen) has also been demonstrated to have partial GABA agonist
activity selective for the BZD ␣3 -subunit in pre-clinical studies. The unique selectivity profile
would theoretically promote both hypnotic and antianxiety effect. Phase I/II trials have been
conducted. These demonstrated significant reductions in sleep latency, reduction in WASO, and
improvements in TST and sleep efficiency (8,9). However, in a more recent phase II/III trial,
with an Ambien CR comparison, an unexpectedly high rate of adverse effects was reported (10).
As a result, Neurogen announced in 2008 that they had no further plans to advance adipiplon
at that time.
Further modifications to existing BzRA agents are also in various stages of development.
A longer-acting preparation (SKP-1041) of zaleplon, a short-acting agent with an elimination
half-life of only about one hour, is currently being evaluated. Somnus Therapeutics, Inc., has
allied with SkyePharma (SKP) to develop a longer-acting preparation using SKP’s GeoLock
controlled release technology. To date, only phase I assessment data of pharmacodynamics,
using varied formulations, have been published (11,12). Results show differing time courses
of sleep promotion using the MSLT as a primary evaluation tool, suggesting potential efficacy
for sleep-maintenance problems. Further clinical studies are currently underway. Intec Pharma
has also reported on development of a gastro-retentive formulation of zaleplon (zaleplon GR),
which provides a sustained duodenal infusion of the drug through the night.
An oral spray form of zolpidem (ZolpiMist
R
; NovaDel Pharma, Inc.) was approved in
late 2008 for short-term treatment of sleep-onset insomnia. At dosages of 5 and 10 mg, the
spray formulation produced therapeutic levels more rapidly than standard zolpidem tablets
(13). Commercialization efforts for the product are in progress.
A sublingual preparation of zolpidem (Edluar
R
, formerly Sublinox

R
) was approved for
short-term treatment of sleep initiation difficulty in March, 2009, and is now marketed in the U.S.
Recent studies (14) have demonstrated that sleep latency with this formulation is significantly
more rapid compared to standard, orally administered zolpidem. Another zolpidem sublingual
preparation (Intermezzo
R
; Transcept Pharmaceuticals, Inc.), in low-dose formulation (1.75 mg
and 3.5 mg) is being evaluated for treatment of middle-of-the-night (MOTN) awakening (15).
Eighty-two patients with primary sleep maintenance problems were administered sublingual
zolpidem (1.75 mg or 3.5 mg) or placebo following awakening. Latency to persistent sleep
after middle-of-the-night awakenings were significantly lower and TST increased compared
to placebo. Subjective ratings of sleep quality were improved at the higher dose. There was
no evidence of morning impairment by Digit Symbol Substitution or subjective assessment of
sleepiness. As of this writing, the FDA has requested additional safety data for MOTN dosing.
Other, novel agents targeted at the GABA receptor have also been explored. Gaboxadol,
a GABA analogue and select agonist, unlike BzRAs enhances slow wave activity and has been
shown to reduce sleep latency and improve efficiency in healthy subjects and insomniacs (16–
21). However, efforts to obtain FDA approval for gaboxadol for the treatment of insomnia have
been abandoned at the present time.

OREXIN ANTAGONISTS
The orexin (hypocretin) system was independently described by two groups in the late 1990s
(22,23). This system consists of a relatively small number of neurons located in the lat-
eral hypothalamus, with extensive projections to brain regions involved in the regulation of
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CURRENT ADVANCES IN THE PHARMACOTHERAPY OF INSOMNIA 429

sleep–wake, among others. Subsequent determinations that disruptions of this system play
a key role in the pathogenesis of narcolepsy with cataplexy fueled further interest in the
role of orexin neurons in sleep–wake regulation (24,25). It has since been demonstrated that
orexin neurons serve a controller function for other wake–active systems of the brain, including
other hypothalamic regions [histaminergic neurons of the tubero-mamillary nucleus (TMN)],
cholinergic basal forebrain and lateral dorsal / pedunculopontine nuclei, noradrenergic locus
coeruleus, and serotonergic dorsal raphe neurons (26). Orexin receptors are widely distributed
in the brain. Activation of orexin neurons and their downstream targets promotes wakefulness.
Orexins are neuropeptides derived from a larger neuropeptide, prepro-orexin. Orexin A
(hypocretin-1) and orexin B (hypocretin-2) act on two receptors, OX1 and OX2 (27). OX1 receptors
are most heavily distributed in locus coeruleus while OX2 receptors are expressed particularly
in histaminergic hypothalamic regions (TMN). Current evidence suggests that these receptors
play a critical role in induction/maintenance of wakefulness. Thus, it is not surprising that
there is significant ongoing investigation of orexin antagonists as potential sleep-promoting
medications.
Although there are a number of orexin antagonists in various stages of evaluation, the most
extensively studied to date is almorexant (Actelion-078573), a dual, selective and competitive
antagonist at both OX1 and OX2 receptors. Almorexant has an elimination half-life that varies
from 6 to 19 hours. Its effects on sleep have been evaluated in rats, dogs and humans. Brisbare-
Roch et al. (28). reported that almorexant, administered during the active period in rats, increased
indices of both NREM and REM sleep. Increases in NREM efficiency were comparable to those
observed with zolpidem and significantly greater than placebo. The increased proclivity to
sleep was accompanied by reduced locomotor activity as well. Similar effects were observed
with repeated dosing.
In humans, doses from 1 to 1000 mg were administered during morning hours. Brief (25
minutes) quantitative electroencephalographic (EEG) recordings were conducted 90 minutes
following administration and showed dose-dependent reduction in latency to persistent sleep.
Increases in theta and delta power were observed in the almorexant group but not in the
zolpidem group. Sedating effects resolved in dose-dependent fashion with effects no longer
evident for all but the maximal (1000 mg) dosage by 6.5 hours.
In these studies, the agent was apparently well tolerated; the most common adverse events
included somnolence, fatigue, reduced attention, dizziness, and diplopia. Of note, no evidence
of cataplectic-type events was observed in any species.
Initial proof-of-concept trials (29) in humans involved a randomized, placebo-controlled
crossover study of 161 primary insomnia subjects who underwent two nights polysomnography.
Dose-dependent improvement of sleep efficiency (by PSG) was observed at 50, 100, 200, and
400 mg. A dose-dependent trend to decrease in latency to persistent sleep and WASO was also
reported. A reduction in REM latency was noted but there was overall maintenance or increase
of REM%. No evidence of waking REM-intrusion symptoms was seen. Subjective ratings of
sleep were improved and the drug was apparently well tolerated with an absence of significant
daytime impairments.
Currently, almorexant is in phase III trials (RESTORA), which began in 2008 with expected
enrollment of 670 primary insomnia patients (30). Primary endpoints of the randomized,
placebo-controlled study will include measures of sleep onset and maintenance. A zolpidem
reference arm is also included.
GSK 649868 (GlaxoSmithKline Pharmaceuticals Ltd.) is a second orexin antagonist cur-
rently in phase II trials. Preliminary data (31) in healthy subjects and 52 patients with primary
insomnia show dose-dependent improvement versus placebo of sleep latency, wake after sleep
time, and TST at doses of 30 and 60 mg. REM sleep was also increased at the higher dose.
Other orexin antagonists are also being investigated but are in earlier phases of devel-
opment. The OX2 antagonist, JNJ-10397049, is highly selective, with little evidence of binding
at OX1 receptors (32). Comparison studies between almorexant and JNJ-10397049 have been
performed in rats. This preliminary work demonstrates that both agents reduce latency to per-
sistent NREM sleep, although the selective OX2 demonstrated this effect at dosages 10 times
lower than the dual antagonist (almorexant). MK-4305 (Merck & Co., Inc.) is also currently in
phase II development (33).
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430 SATEIA

5-HT2A ANTAGONISTS
Serotonergic neurons of the dorsal raphe play an important role in regulation of sleep and
wakefulness. An understanding of the function of serotonin (5-HT) in control of sleep–wake
has continued to evolve and is complicated by the heterogeneity of numerous receptor subtypes.
Serotonin activity of the dorsal raphe is at its highest firing rate during wake. Firing rate of these
neurons decreases with onset of NREM sleep and becomes negligible during REM sleep. A great
deal of research in this area has focused on the 5-HT2 family of receptors. It has been shown
that activation of 5-HT2A receptors is associated with tonic inhibition of NREM sleep (34).
Correspondingly, antagonism at the 5-HT2A receptor results in promotion of increased slow
wave activity in sleep (35).
These observations have led to significant interest in 5-HT2 antagonists as potential ther-
apies in the management of insomnia. Ritanserin, a potent 5-HT2 antagonist, has been studied
with respect to its effects on sleep in animals and humans. Early work demonstrated that admin-
istration of ritanserin to young, poor sleepers resulted in a doubling of slow wave activity, with
a corresponding decrease in N2 (stage 2 sleep) (36). Subsequent work has revealed compara-
ble increases in slow wave sleep in healthy volunteers (37), middle-aged poor sleepers (38),
and dysthymic patients (39). Some of these data have also suggested a reduction in frequency
of awakening (38) and improvement in subjective sleep quality (36). Ritanserin has also been
evaluated as a treatment for patients with schizophrenia (40). However, its patent has expired
without the drug ever becoming FDA-approved. In recent years, atypical antipsychotic medi-
cations with potent 5-HT2A and H1 antagonistic properties such as quetiapine and olanzapine
have been utilized off-label as sleep aids, particularly in psychiatric populations.
Eplivanserin (Ciltyri; Sanofi-aventis) is a 5-HT2A antagonist currently in phase III trials
for treatment of insomnia. A randomized, double-blind study (41) of 351 adults with chronic
insomnia treated to 4 weeks with either 1 mg or 5 mg of eplivanserin or placebo in the evening
found that the 5-mg dose resulted in a mean 39-minute reduction in the baseline 84-minute
wake time after sleep onset. This was significantly greater than the mean 26-minute reduction
with placebo. Eplivanserin 5 mg/day resulted in a 64% reduction in the number of nocturnal
awakenings, compared with a 36% decrease with placebo. More eplivanserin-treated patients
reported a significant improvement in the refreshing quality of sleep.
In two phase III, 12-week randomized controlled trial (RCTs) of eplivanserin (42,43) with
open-label extension, sleep maintenance insomnia subjects were treated with eplivanserin 5 mg
or placebo. Significantly greater reductions in WASO (least square means (LSM) difference =
11.5 min and 13.5 min, respectively) and number of awakenings was observed at 12 weeks with
eplivanserin with associated reported improvement in subjective sleep quality and morning
concentration. Other studies have demonstrated very significant increase in N3 sleep (44) and
delta frequency power on quantitative electroencephalographic analysis (45). In September,
2009, the FDA requested further information from Sanofi-aventis concerning risk–benefit ratio
for eplivanserin.
Sanofi-aventis has a second 5-HT2A antagonist, volinanserin, in development, although
this agent has not progressed as far in the pipeline as eplivanserin.
Pruvanserin (LY2422347; Eli Lilly and Company) was originally developed by Hypnion,
Inc., and obtained by Eli Lilly and Company in 2007. A phase II trial of this drug, which examined
its efficacy in the management of sleep-maintenance insomnia, was reportedly commenced in
2006. Published results for this trial were not identified. Eli Lilly and Company does not currently
(as of July 1, 2009) list pruvanserin among its pipeline agents (46) and appears to be focused
primarily on LY2624803, which has both 5-HT2A antagonist and antihistaminergic properties
(discussed in the following section).
Pimavanserin (ACP-103) is a selective 5-HT2A inverse agonist being developed by Aca-
dia Pharmaceuticals, Inc. Although the primary indication in development is for treatment of
Parkinson disease (PD) psychosis, a secondary evaluation of its effects on sleep maintenance
has also been pursued. In trials with older PD patients, pimavanserin improved psychosis and
also resulted in significant increase in slow wave sleep (47).
Another 5-HT2A inverse agonist, ADP-125 (Arena) showed promise in initial smaller trials
for treatment of insomnia. However, in late 2008 it was announced that the compound had failed
to meet primary or secondary endpoints in a larger phase II study. Indications at that time were
that the company no longer planned to pursue development.
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CURRENT ADVANCES IN THE PHARMACOTHERAPY OF INSOMNIA 431

In summary, these agents have theoretical promise as a treatment for sleep maintenance
insomnia and largely unexplored potential for improving sleep quality in other conditions
by virtue of their enhancement of slow wave sleep activity. However, development has been
fraught with setbacks and it appears that several of the drugs are no longer in the active
pipeline. Eplivanserin is closest to market and its future currently rests on its developer’s ability
to respond adequately to FDA concerns.

MELATONIN AGONISTS
Melatonin is an endogenous peptide that is synthesized and released by the pineal gland. It
represents the key “darkness” signal in mammalian CNS. Exogenously administered melatonin,
available as an over-the-counter nutritional supplement, has been used by millions in the treat-
ment of insomnia, particularly over the past two decades. Distinct from its usage as an effective
chronobiological agent, its efficacy for chronic insomnia is not especially well established. Meta-
analyses (48,49) show mixed results with pooled data suggesting very modest improvement in
sleep parameters of uncertain clinical significance. Against this background, the only currently
approved melatonin agonist, ramelteon, was launched in 2005. This agent produces modest
reductions of sleep latency in patients with chronic insomnia, but its very short half-life limits
its application primarily to sleep-onset difficulties.
Other melatonin agonists are presently in testing. Tasimelteon (VEC-162; Vanda Pharma-
ceuticals, Inc.), a potent MT1/MT2 receptor agonist has been studied in phase II and III trials.
The phase II trial (50) involved 39 healthy subjects who were studied at baseline for 3 nights,
for 3 treatment nights with tasimelteon (at dosages of 20 mg, 50 mg, or 100 mg) or placebo,
with a 5-hour phase advance of schedule, and for one night following treatment. Reductions of
PSG sleep latency and improved sleep efficiency were observed, along with a dose-dependent
advance in melatonin rhythm. In the phase III trial (50) of 411 healthy subjects using the same
5-hour phase advance model of transient insomnia, latency to persistent sleep was significantly
reduced and sleep efficiency increased. Wake after sleep onset was reduced at the two lower
(20 and 50 mg) dosages. The subjects appeared to tolerate the drug well and there were no
indications of adverse events in excess of those seen with placebo.
A subsequent phase III trial (51) of 322 subjects with chronic insomnia characterized by
sleep initiation difficulty showed significant reductions of latency to persistent sleep, which
persisted throughout the five-week study period. No significant improvements were observed
in standard measures for wake after sleep onset. Subjects did not show evidence of daytime
impairment following use of tasimelteon. Submission of a marketing application for tasimelteon
is expected by mid-2011.
Preliminary phase II results of another melatonin agonist, PD-6735, were announced in
2004 (52). Significant reductions in sleep latency were seen in 40 insomnia subjects. However,
further development data has not been released on this compound.

TRICYCLIC, COMBINED ACTION, AND OTHER COMPOUNDS

Since the advent of tricyclic medications, the sedative action of many of these drugs has been rec-
ognized. Agents such as amitriptyline have been and continue to be employed in low dosages as
sleep aids in a variety of conditions. In the past 20 years, the heterocyclic compound, trazodone,
has come to occupy an important role in the pharmacological management of insomnia, despite
a paucity of data supporting its efficacy. The mechanism of sedation of these medications varies.
Doxepin, developed as an antidepressant in 1968, is a tricyclic medication with proven antide-
pressant efficacy. Its sedative properties have long been recognized. In recent years, doxepin, in
dosages far lower than typical antidepressant dosages, has been developed as a sleep-inducing
agent. It appears likely that much of its sedative action is derived from potent antihistamin-
ergic properties, although other actions such as anticholinergic effect may also contribute to
sedation. One of the initial investigations of doxepin’s hypnotic action was conducted in 2001
(53). This RCT of primary insomnia patients demonstrated significant improvements in sleep
efficiency and TST on night 1 and night 28 on doxepin dosages of 25 to 50 mg, while WASO
was significantly reduced only on night 1. Sleep latencies were not altered since this population
was predominantly sleep-maintenance insomniacs with relatively normal baseline sleep laten-
cies. Subjective sleep and daytime performance ratings were likewise significantly improved.
Subsequently, smaller dosages (1, 3, and 6 mg, Silenor
R
; Somaxon Pharmaceuticals) have been
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432 SATEIA

evaluated in phase III trials involving adult (54) and elderly adult (55) primary insomnia sub-
jects. Each subject underwent two nights of PSG during each of five trials separated by 5 to 12
days in a multiple crossover design. An initial single-blind placebo assessment was followed by
randomized assignment to one of four sequences with every subject receiving all three doses of
doxepin plus placebo. The primary endpoint of wake during sleep showed significant reduc-
tions at the 3- and 6-mg dosage. TST, sleep efficiency, and WASO were improved at all three
doses. The 6-mg dose produced reduction of subjective time to fall asleep. The efficacy assess-
ment in elderly insomniacs was conducted with identical design and demonstrated comparable
results. All dosages were generally well tolerated without indication of significant anticholin-
ergic or other side effects. There did not appear to be significant daytime residual effects. In late
2009 Somaxon received an FDA response to its second submission for approval which indicated
continued efficacy concerns and denied approval of the drug in its current form.
Several current pipeline agents demonstrate dual or multiple mechanisms of action, which
may prove effective in management of insomnia. One of the most widely studied agents,
agomelatine (Servier; as Valdoxan in the European Union), is in development primarily as an
antidepressant drug and has already received approval in the European Union. It is in phase III
trials in the United States, licensed to Novartis International AG, which expects submission of
FDA application no sooner than 2012. The agent has a combined action of 5-HT2C antagonism,
coupled with potent melatonin agonistic properties. In addition to its proven antidepressant
properties, it demonstrates significant sedative properties.
Lemoine et al. (56) reported significantly greater subjective improvement in “getting to
sleep” and sleep quality in 332 patients with major depressive disorder treated with agomelatine
25 to 50 mg qd compared to venlafaxine. Other studies have demonstrated increased TST and
sleep efficiency and reduced WASO without significant change in REM% or latency in patients
with major depressive disorder (MDD) (57). Support for the contention that agomelatine sta-
bilized NREM sleep is derived from studies indicating that NREM cyclic alternating pattern
(CAP) is reduced by this agent (58). Additional reports (59) have found significant improvement
in subjective sleep latency in generalized anxiety disorder patients treated with agomelatine.
In addition to its direct effects on sleep continuity and architecture, agomelatine has also been
shown to have significant phase-shifting effects that may play a role in its therapeutic effects.
Older adults treated with early evening agomelatine experienced a phase-advance of approxi-
mately two hours (60). The drug has generally been well tolerated in trials with favorable side
effect profiles, including minimal sexual side effects.
LY2624803 (formerly HY10275; Eli Lilly and Company) is a dual acting H1 /5-HT2A antag-
onist originally developed by Hypnion, Inc., and sold to Eli Lilly and Company in 2007. Phase II
data released in 2007 (61) on HY10275/ LY2624803 describes 52 patients with primary insomnia
who were administered HY10275, 1 to 3 mg, or placebo in a randomized clinical trial. Signifi-
cant reductions were observed in wake after sleep onset, which decreased in a dose-dependent
manner by 62 minutes for 3 mg (p < 0.001) and 35 minutes for 1 mg (p < 0.002). Subjects with
moderate to severe transient insomnia responded as well as or better than subjects with mild to
moderate transient insomnia. The drug also met secondary efficacy endpoints including signifi-
cant reduction in latency to persistent sleep. No adverse events were reported during the course
of the trial and no evidence of next-day impairment or residual fatigue was noted. A phase II
RCT of LY2624803(SLUMBER) (62), with a zolpidem comparison arm, is currently underway.
Subjects include both primary and secondary insomniacs. Primary endpoint is TST.
Esmirtazapine (ORG 50081), a derivative of the widely used antidepressant, mirtazapine,
is currently under development for the management of insomnia and hot flashes. Esmirtazapine
is a potent 5-HT2A antagonist with H1 and ␣-adrenergic properties.
Initial proof-of-concept trials in primary insomnia at three dosages of the drug showed
significant improvement in TST and WASO (63). A long-term safety study of two doses (1.5
and 3.0 mg) in elderly primary insomniacs is currently underway. Merck acquired Organon as
part of its recent buyout of Schering-Plough and currently lists esmirtazapine in its Phase III
pipeline.
ITI-007 (Intra-Cellular Therapies, Inc.) is a dual action 5-HT2A /dopamine receptor phos-
phoprotein modulator (DPPM) agent developed for the treatment of schizophrenia. Phase
2 studies have also been conducted for sleep maintenance insomnia. ITI-007 has variable
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CURRENT ADVANCES IN THE PHARMACOTHERAPY OF INSOMNIA 433

dose-dependent activity, demonstrating predominantly 5-HT2A antagonism at lower dosages

(1–10 mg) with increasing dopamine receptor modulation at higher dosages (up to 30 mg).
Interim analysis (64) (N = 18), released in early 2009, of a placebo-controlled investigation of 1,
5, and 10 mg ITI-007 in sleep-maintenance insomniacs showed dose-dependent reductions of
WASO and increase of slow wave sleep.

CONCLUSIONS
Current investigations of novel compounds for the treatment of insomnia hold the promise of
introducing an array of new approaches to the management of this often chronic and highly
prevalent condition. Many of these agents would appear to have the potential to improve
sleep as defined by the conventional metrics of latency, WASO, TST, efficiency, and the like,
and by virtue of their unique mechanisms, offer additional advantages not seen with BzRAs,
such as enhancement of slow wave activity. Moreover, a number of these agents may offer dual
action in the management of insomnia comorbid with depression, attention deficit hyperactivity
disorder, hot flashes, or psychosis. However, as stated previously, the road to new drug appli-
cation is fraught with many obstacles and only time will tell which of these compounds reach
market.

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38 Clinical Trials and the Development

of New Therapeutics for Insomnia
Gary K. Zammit
Clinilabs, Inc., Sleep Disorders Institute, Columbia University College of Physicians and Surgeons,
New York, New York, U.S.A.

The development of new therapeutics for the treatment of insomnia involves the design and
execution of clinical trials. Clinical trials are research studies involving human subjects that
serve to characterize drugs under development; examine their safety, tolerability, and adverse
effects in healthy subjects; and document their efficacy and safety in patient populations. Clinical
trials are the most important and costly phase of the drug development process. According to
industry reports, the pharmaceutical industry spent $44.5 billion on research and development
(R&D) in 2007 (1) with clinical development costs representing approximately 60% of these
expenditures (2). The data derived from the conduct of clinical trials are critical to the delivery
of new therapeutics to the market. These data ultimately drive the drug development lifecycle
and provide the basis of all new drug applications (NDAs) in the United States and other
regulatory environments.

A BRIEF HISTORY OF CLINICAL TRIALS

The regulations governing the conduct of clinical trials in the United States have their origins in
the early 20th century. During this time, substantive legislative action was introduced to bring
drug products under governmental oversight. Among the first bills to receive approval was the
Federal Food and Drugs Act of 1906 (known as the Wiley Act). This Act primarily was designed
to control the manufacture, sale, or transportation of adulterated, misbranded, poisonous, or
deleterious foods, drugs, medicines, and liquors (3). Responsibility for the enforcement of the
provisions of the Wiley Act fell under the purview of the United States Bureau of Chemistry—
an early precursor of the modern-day U.S. Food and Drug Administration (FDA) (4). The
Act offered important safeguards to the public and was modified several times through 1934.
However, it did not require drug makers to conduct clinical trials to confirm the efficacy of drugs
marketed to treat medical conditions, and it imposed no restrictions on the claims that could
be made by drug sellers regarding their products. Consequently, a plethora of substances were
sold to treat medical conditions without any standardized assessment of their benefits or risks.
Not surprising were the many adverse events that resulted from the use of these treatments by
consumers. Serious injuries, disability, and death occurred due to the use of harmful or toxic
substances found in legally marketed “medications” of the day.
As the public continued to be exposed to risk related to the use of drug products, a terrible
and catastrophic incident occurred that ultimately strengthened the FDA’s ability to regulate
drug products (5). In 1937, the Massengill Company began marketing a raspberry-flavored
elixir of the antibacterial sulfa drug sulfanilamide, offering a new liquid formulation of a drug
that previously was sold in powder form. While the introduction of this formulation initially
was thought to be safe, hundreds of men, women, and children became seriously ill after using
this preparation. One hundred and seven people died as a result of ingesting this product.
Only later was it learned that the untested formulation was sulfanilamide diethylene glycol,
a chemical solvent known to be lethal when ingested by humans. Among the charges levied
against the Massengill Company under the Wiley Act was sale of a misbranded toxic substance
that was an acute poison. In response to public outrage over this event, President Franklin D.
Roosevelt signed the Food, Drug, and Cosmetic Act on June 25, 1938. This Act gave broad and
unquestionable authority to the FDA to require manufacturers to prove that their drugs were
safe before granting approval for marketing. It also gave the FDA the authority to require drug
labeling that provided directions for the safe use of these products (6).
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CLINICAL TRIALS AND THE DEVELOPMENT OF NEW THERAPEUTICS FOR INSOMNIA 437

While the Food, Drug, and Cosmetic Act compelled manufacturers to document the safety
of their drug products, it is remarkable that there still was no requirement that they document
efficacy. Claims could be made regarding a drug’s ability to treat or cure any kind of disease,
even when there was no evidentiary basis for such claims. To close this loophole, policy mak-
ers eventually introduced new legislation that expanded governmental control and regulatory
oversight of drug products, including requirements that certain products could be used only
under the supervision of a medical professional. In particular, the 1951 Durham–Humphrey
Amendment to the Food, Drug, and Cosmetic Act made certain medications available by pre-
scription only (6). This act limited access to drug products more than ever before, but the control
of drug products remained insufficient. Gaps in regulatory oversight continued to persist due
to controversy over how much power the FDA should wield over private industry and health
care practices. Therefore, the next truly significant milestone did not occur until 1958, after yet
another catastrophe brought inadequate regulatory policies into the spotlight once again. At
that time, the W.S. Merrill Company began marketing thalidomide in Germany as a treatment for
morning sickness. Shortly thereafter, an application was filed for the approval of this drug in
the United States. Some concerns regarding the safety of this drug led an astute medical officer
at the FDA, Frances Kelsey, to delay thalidomide’s marketing approval. Kelsey’s actions are
likely to have spared thousands of unborn children, as it was later learned that thalidomide
had serious teratogenic adverse effects. The West German pediatrician Widukind Linz reported
an association between thalidomide and the birth of nearly 4000 children exhibiting abnormal
limb growth. Relatively few cases of these birth defects were reported in the United States
because of Kelsey’s actions, and the drug was completely removed from the market in 1961 (7).
Interestingly, thalidomide later returned to the market under the brand name Thalomid, and
currently is indicated for the treatment of multiple myeloma and cutaneous manifestations of
moderate to severe erythema nodosum leprosum (ENL) provided that safety precautions are
taken (8).
It was in a climate of concern for consumer safety that Senator Estes Kefauver held
congressional hearings to address pharmaceutical industry practices regarding the development
of new drug products. These hearings led to the 1962 Kefauver–Harris Amendment to the Food,
Drug, and Cosmetic Act. This landmark legislation required drug manufacturers to demonstrate
“substantial evidence” of a drug’s efficacy for its marketed indication, in addition to requiring
demonstration of its safety. Further, the Kefauver–Harris Amendment expanded the FDA’s
authority to regulate advertising, inspect drug manufacturing facilities, and withdraw untested
drugs from the market (9,10).
Since the 1960s, many new forms of legislation and regulatory oversight have been intro-
duced to govern the drug development and approval process. One guidance document partic-
ularly important to the field of sleep medicine was produced by the FDA in 1977, specifically
relating to the development of hypnotics (11). This document provided guidelines regarding
acceptable approaches to the study of investigational hypnotics in human subjects. It also
offered specific recommendations regarding the types of clinical trials that should be con-
ducted as part of a hypnotic development program, as well as the endpoints that should be
considered. The durability of this document is remarkable, given that its content regarding
hypnotic development remains applicable to this day. In addition to guidance on the conduct
of clinical trials, the FDA recently has issued requirements for the labeling of hypnotics. In
December 2006, the FDA sent letters to manufacturers of products approved for the treat-
ment of sleep disorders indicating that they would be required to revise product labeling to
include warnings about certain potential adverse events (12). Although the likelihood of the
occurrence of these events was not stated in the FDA’s notice, these AEs were considered
significant enough to warrant a revision of the product labeling. The adverse events (AEs) of
concern were

r anaphylaxis (severe allergic reaction);

r angioedema (abrupt, severe swelling, especially facial), which can occur as early as the first
time the product is taken;
r complex sleep-related behaviors, which may include sleep-driving, making phone calls, and
preparing and eating food (while asleep).
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438 ZAMMIT

In conjunction with the labeling revisions required, the FDA required that each product
manufacturer send letters to health care providers highlighting these changes. Manufacturers
of sedative–hypnotic products also were requested to develop Patient Medication Guides for
sedative–hypnotic products to inform consumers of the potential risks associated with these
newly labeled adverse events.
As the FDA pursues its public health mission, it is clear that the regulatory oversight of
drug development continues to be based on requirements imposed by legislation. For example,
in 1981, the FDA and the Department of Health and Human Services (DHHS) revised regulations
for human subject protection based on the recommendations of the 1979 Belmont Report (13).
The most important revision undertaken at this time was the specification of the elements of
informed consent (14). Later, in 2002, the Best Pharmaceuticals for Children Act improved the
safety and efficacy of patented and off-patent medicines for children (14). These and other
current requirements for the development and testing of new drug products are now specified
in detail under several parts of the Code of Federal Regulations (CFR) title 21 (15). These
documents have relevance for the development of sleep therapeutics, and when combined with
specific guidance related to the development of hypnotics, provide science and industry with
sound foundations upon which to base the development of hypnotics.

PRECLINICAL STUDIES
An important step in the development of any new therapeutic is the submission of an investi-
gational new drug (IND) application to the FDA. This application contains information gained
from preclinical studies that are required prior to the initiation of testing in human subjects. Pre-
clinical studies fall into two categories—in vitro and in vivo. In vitro studies evaluate the effects
of a drug on human or animal tissue. In vivo studies are performed in live animals, usually rats,
dogs, and primates. Combined, these preclinical studies yield the pharmacology and toxicology
data that form the basic safety profile of a drug (16). These data are extremely important in that
they are used to select a safe starting dose for human studies, establish estimates of the toxic dose
in humans, and gain a fundamental understanding of the pharmacokinetic (PK) and pharmaco-
dynamic (PD) properties of a drug. The type of information that regulatory reviewers examine
in investigational new drugs includes data from carcinogenicity studies, genotoxicity studies,
toxicokinetics and pharmacokinetics, toxicity testing, reproductive toxicology, and pharmacol-
ogy studies (16,17). It is interesting to note that preclinical testing represents approximately 27%
of pharmaceutical R&D costs (2), and fewer than 10% of all new molecular entities (NMEs) will
find their way forward from preclinical evaluation to the submission of a NDA. This is because
drug manufacturers must study large numbers of drugs and apply rigid screening criteria to
determine which ones they will take further into development.
Specific to the development of hypnotics, the types of preclinical studies used to examine
products under consideration include tests of locomotion or myorelaxation, as these variables
provide information regarding a compound’s sedative properties. Examples include the rotarod
test (18,19), the loaded grid test (18,20), and tests of abuse liability (21). In the rotarod test,
rats are placed on a rotating surface (a rod) and faced with the challenge of remaining on
the surface as it rotates. Drug-free baseline performance is assessed to determine minimum
performance thresholds. Animals are then given active drug or placebo and tested to determine
the amount of time they are able to remain on the rotarod. Animals that remain on the rotarod
for shorter periods following drug administration may be showing evidence of myorelaxation.
In the loaded grid test, animals hold on to a weighted grid with their front paws and are
tested to determine the load required before they release. Again, this test is conducted so as
to yield results for the baseline, placebo and drug conditions. Preclinical tests also include
electroencephalographic (EEG) measures of sleep that provide indications of hypnotic activity
(19,22–29). Hypnotics such as zolpidem, zaleplon, and zopiclone all have been characterized by
these types of preclinical tests.

CLINICAL DEVELOPMENT PHASES

Clinical trials are conducted in three different phases prior to a drug’s approval (phases I–III,
Fig. 1). One additional phase (phase IV) includes studies conducted after marketing approval.
Trials performed during the first of these phases of clinical development provide important
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CLINICAL TRIALS AND THE DEVELOPMENT OF NEW THERAPEUTICS FOR INSOMNIA 439

Drug Preclinical Clinical Trials FDA

Discovery Review

1 FDA -

NDA Submitted
>5,000 250 5 Approved

IND Submitted
Prediscovery

Drug

Phase I Phase II Phase III

Number of Volunteers
20–100 100–500 1000–5000

1.5–2
3–6 Years 6–7 Years Yr

Adapted: PhRMA 2008 report

Figure 1 The R&D process—long, complex, and costly.

information that constitutes the manufacturer’s evidence for carrying a drug forward, and
forms the basis of the NDA that is submitted to the FDA. Although these phases are repre-
sented in consecutive order, these phases may overlap or even run concurrently. For exam-
ple, a phase II study of hypnotic efficacy may be in progress when an important phase I
drug–drug interaction study is initiated.
Clinical drug development is costly. An analysis conducted in 2007 estimated that the
total combined cost of the preclinical and clinical trials required to bring a drug to the point of
submission of an NDA is more than $1.2 billion (30). This expense includes the costs of drugs
that fail to progress through the clinical development pipeline (31). For every 250 drugs that
complete preclinical testing, 5 will successfully complete phase I, and only one will ultimately
achieve regulatory approval (1). The four phases of clinical development are described in more
detail in the following section.

Phase I Trials
In these studies, researchers test an investigational drug or device in a small group of people
(20–100), usually normal health, volunteers (32). These studies are designed to determine the
metabolic and pharmacologic actions of a drug in humans, the side effects associated with
the drug at various doses, and if possible, to gain early evidence regarding drug effects using
biomarkers or tests in small cohorts of clinical populations. Common studies conducted in this
phase of drug development are first-in-human (FIH), single ascending dose (SAD), multiple
ascending dose (MAD), and drug–drug interaction (DDI) studies. During phase I, sufficient
information about the drug’s pharmacokinetics and PD effects should be obtained to permit
the design of well-controlled, scientifically valid, phase II studies. Phase I studies also evaluate
drug metabolism, structure–activity relationships, and the mechanism of action in humans (33).
There is a growing trend to include cohorts of patients in phase I studies, as researchers attempt
to learn more about drug effects early in development.

Phase II Trials
During phase II, an investigational drug or device is given to a larger group of people (100–500)
(32) to evaluate the efficacy and safety of a drug for a particular indication or indications in
patients with the disease or condition under study (34). Phase II studies also aim to determine the
common short-term side effects and risks associated with the drug or device under evaluation.
In clinical trials of hypnotics, it is common for phase II studies to employ experimental models in
healthy human subjects in order to assess efficacy, identify primary outcomes that will be used
in pivotal phase III studies, and determine the types of AEs that people report. However, in this
phase of drug development it is much more common to study small groups of patients, especially
when no experimental models exist. Phase II offers drug manufacturers an opportunity to
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440 ZAMMIT

determine the doses that will be carried forward into phase III by weighing the trade-offs
between efficacy and the risk of adverse events at each dose level evaluated.

Phase III Trials

Phase III studies represent the drug manufacturer’s most important opportunity to document
the efficacy and safety of their drug products by testing them in large groups of people (1000–
5000) (32). Studies conducted during phase III are intended to gather critical information regard-
ing the overall benefit–risk relationship of a drug, as well as provide an adequate basis for
labeling (34). By the time a drug enters this phase of testing, characteristics of its absorption,
distribution, metabolism, and elimination (ADME)are known, its likely therapeutic effects have
been defined and reduced to testable hypotheses, and its safety profile has been reasonably
characterized. Manufacturers who initiate phase III trials generally are confident that their
product will be shown to be safe and effective, and ultimately will win regulatory approval.
Even though the odds of success are much higher for a drug product at this point than when
entering preclinical evaluations, only one out of every five drugs that enters phase II testing
will successfully complete phase III (32).

Phase IV Trials
After a drug’s NDA has been approved by the FDA, phase IV trials may be conducted to further
clarify its efficacy and safety. Pharmacovigilence, pharmacoeconomic, and comparative efficacy
studies are most likely to be performed during this phase of the drug development lifecycle.
New and specific patient populations are likely to be studied. Elderly, pediatric, or other patient
groups could become a focus of research, depending on the potential use in those patient groups.
As an example, studies of therapeutics for insomnia have been conducted in special populations
of patients with comorbid depression and anxiety disorders, providing invaluable information
to the prescribing community. There are occasions when phase IV trials provide information
that is used to revise the labeling of a drug product (e.g., the inclusion of additional adverse
event information), and some phase IV trials may support a manufacturer’s decision to pursue
a secondary NDA (sNDA) that seeks approval for a new therapeutic indication for a drug.

STUDY DESIGNS COMMONLY USED IN THE DEVELOPMENT OF HYPNOTICS

Phase I Studies: Pharmacokinetics, Pharmacodynamics, and Interaction Studies

PK studies form the fundamental basis of most phase I testing programs. These studies exam-
ine the kinetics of drug absorption, distribution, metabolism, and excretion (ADME). Perhaps
the most critical information obtained in PK studies is related to the rate of drug absorption
and delivery into systemic circulation, and the rate of elimination by metabolic or excretory
processes in human subjects (35). The information obtained is based on plasma concentrations
at multiple time points following dosing and is reflected in outcome variables that include
the maximum plasma concentration (Cmax ), time to maximum concentration (Tmax ), half-life,
and area-under-the-curve (AUC)—a representation of overall drug exposure. These variables
provide information that reflects the relationships between dose, time, and plasma drug levels.
When appropriate, phase I studies may reveal the influences of demographic characteristics
(e.g., age, gender, race, ethnicity), certain disease states, external factors, and drug binding to
biological constituents (35). If hepatic metabolism and/or excretion accounts for a substantial
portion (>20% of the absorbed drug) of the elimination of a parent drug or active metabolite,
it is recommended that PK studies be performed in subjects with impaired hepatic functioning
(36). Similarly, whenever a drug is likely to be used in patients with renal impairment, and this
impairment is likely to significantly alter the PK of a drug and/or its active/toxic metabolites, or
require dosage adjustment for safe and effective use, testing in patients with renal impairment is
recommended (37). Finally, there may be circumstances under which it is important to perform
PK studies in special populations, for example, pregnant women (38) or children (39).
PK assessments of sedative hypnotics have become increasingly important to understand-
ing drug effects, especially since the introduction of new and novel formulations that may have
specific effects on latency to sleep onset, sleep maintenance, or both. For example, the PK
profiles of the original formulation of zolpidem and zolpidem ER (a reformulation of
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CLINICAL TRIALS AND THE DEVELOPMENT OF NEW THERAPEUTICS FOR INSOMNIA 441

zolpidem that provides the immediate release of drug from an outer layer and a delayed
release of drug from an inner core) are different from one another (40,41). These products, in
turn, can be expected to be different from sublingual or other formulations of zolpidem that do
not require absorption in the intestinal tract (42,43).
PK studies often are combined with PD assessments, resulting in PK/PD modeling that
guides the early-phase development of a drug. In the study of sedative hypnotics, the most
elegant of these is the PK/PD model developed by Greenblatt and associates. In this model, the
drug being studied typically is administered to healthy adult subjects in the morning, following
a full night of sleep in a controlled setting. Blood samples for PK assessments are taken predose
and at several time points following dosing (e.g., before medication and at 0.5, 1, 1.5, 2, 2.5, 3, 4,
5, 6, 8, and 24 hours postdosing) (44). These PK samples may be coupled with other evaluations
of sedation [e.g., electroencephalographic assessments of beta (␤) activity and the Digit Symbol
Substitution Test (DSST)] and various word recall instruments. The use of word recall tests
is important because of the known effects of many hypnotics on memory. The timing and
frequency of PK and PD sampling is determined by the experimental hypothesis appropriate
to the drug or formulation. For example, when testing a hypnotic with an extended-release
formulation, it may be important to assess the duration of sedative effects. The information
gleaned from this evaluation may guide dose selection or formulation, or provide information
regarding the residual effects investigators may observe in later-phase studies (45).
Drug–drug and food interaction studies are additional important studies conducted in
phase I. Phase I drug–drug interaction trials may include evaluations of a hypnotic’s interaction
with cytochrome P450 (CYP) inducers (e.g., rifampin), CYP inhibitors (e.g., azoles, ritonavir, and
erythromycin), histamine H2 receptor antagonists (e.g., cimetidine and ranitidine), antidepres-
sants, antipsychotics, antagonists of benzodiazepines, and other drugs known to cause sedation
(46).Food interactions also may be studied to examine the effect of certain foods or fasting on
drug absorption or metabolism (47–49). For example, grapefruit juice is a well-known inhibitor
of CYP3A4 and may be expected to increase exposure to hypnotics that are metabolized through
this pathway (50).

Phase II Studies: Experimental Models of Insomnia and Patient Studies

Phase II studies often are used to determine the dose of medication that will be carried forward
into phase III pivotal trials, or to identify the ideal outcome measures that ultimately will be used
to determine the efficacy and safety of a therapeutic. Several experimental models of transient
insomnia have been well validated for use in phase II studies. These include models based on
the first-night laboratory adaptation effects, phase-advanced sleep, and exposure to noise.
An experimental model based on first-night adaptation effects in a sleep laboratory envi-
ronment has commonly been used to assess hypnotic efficacy. This model takes advantage of
the long latency to sleep onset and sleep disruption experienced by healthy subjects during
their first night in a sleep laboratory environment. One of the first studies to use this model
examined temazepam’s hypnotic and sleep stage effects in a parallel group study of 201 healthy,
normal subjects with no sleep complaints. Each subject was randomly assigned to receive either
placebo, or 7.5 to 30 mg of temazepam 30 minutes before bedtime on their first night in the
sleep laboratory. Subjects were given an eight-hour sleep opportunity while polysomnographic
(PSG) recordings were obtained. The PSG data revealed that total sleep time and sleep efficiency
increased in a linear fashion with increasing doses of temazepam relative to placebo, providing
support for the use of the “first-night” effect as a model of transient insomnia (51). This model
appears particularly useful in assessing drug effects on sleep latency. One of the key trials in
zolpidem’s clinical development program examined the effects of zolpidem in a double-blind,
parallel-group study of 462 normal volunteers. Zolpidem was tested at doses ranging from 5
to 20 mg. Statistical analysis of the 7.5-mg and 10-mg doses showed that zolpidem decreased
sleep latency, increased sleep duration, and reduced the number of awakenings relative to
placebo, without significant effect on next-day psychomotor performance (52). Since the orig-
inal temazepam study was conducted, the model has been employed to assess the hypnotic
efficacy of benzodiazepines, nonbenzodiazepines, and other drugs with novel mechanisms of
action like ramelteon (53–57).
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Phase-advance models have been used with success in assessing the efficacy of hypnotics
in treating transient insomnia. One of the advantages of these models is that they can be used in
either crossover or parallel group designs, whereas first-night models, by definition, are limited
to parallel group designs only. One of the earliest studies of the phase advance model used
a 180-degree shift of the sleep–wake cycle in 12 healthy subjects to determine the effects of
triazolam, flurazepam, and placebo in a parallel-group design. Subjects who received placebo
demonstrated significant sleep loss following the manipulation of their sleep, while the effect
was attenuated for those in the active medication groups (58). One of the interesting aspects of
the phase-advance model is that it may be used to assess sleep maintenance by demonstrating
separation between active drug and placebo in the later portions of the sleep period (59). While
the magnitude of the phase-shift has been thought to be of importance, several studies have
used short phase advances in order to detect meaningful effects. For example, one study has
shown that temazepam 7.5 mg and 15 mg administered to subjects in a 2-hour phase-advance
paradigm had similar effects on sleep architecture 60. Statistically significant effects on LPS,
TST, and other sleep variables relative to placebo have been found with other drugs, such as
indiplon and gaboxadol using this model (55,61,62), occasionally coupled with the first-night
model of transient insomnia (55).
There are a variety of noise models that have been used in phase II studies of insom-
nia. While the specific implementations may differ, these models offer a method of assessing
drug effects in the presence of experimental stimuli that perturb sleep, thereby demonstrating
sleep maintenance effects. One noise model involves the exposure of normal, healthy sub-
jects to continuous white noise during the sleep period at levels sufficient to disrupt sleep
[e.g., 45–75 decibels (db)] (63,64). This design may be able to detect differences between drug
conditions when cyclic alternating patterns (CAP) are used (65). Another common noise model
involves the use of traffic noise played during sleep, and has been shown to separate immediate-
release from modified-release formulations of hypnotics (66). Problematically however, the use
of the traffic noise model has not shown consistent results when separating active drug from
placebo (67).
Some phase II studies require the use of patient populations rather than healthy volunteers.
These studies might be used when it is desirable to test drug effects on a specific sleep outcome
variable that may not be reliably produced using an experimental model, when certain crossover
comparisons are of interest, or when repeated (e.g., nightly) dosing may be desired. Such
studies are also useful when the identification of well-defined patient groups may provide more
informative data than experimental models (68). Several double-blind, randomized, placebo-
controlled clinical trials of hypnotics have employed small samples of insomnia patients to
assess the efficacy and safety of hypnotics in PSG sleep laboratory studies (68–78).

Phase III Studies: PSG and Outpatient Studies

Phase III study designs are “pivotal trials” that determine the efficacy and safety of new thera-
peutics. Phase III studies of hypnotics commonly include large samples of people with insomnia
tested in parallel-group designs, and may or may not include the use of polysomnography.
(79–83). At present, PSG results appear to be required for approval of a new hypnotic by the
FDA.
In the past, volunteers were enlisted to participate in trials for a short period of time. A
1997 meta-analysis of 22 double-blind, placebo-controlled studies of hypnotics showed that the
longest period of treatment assessed was 35 nights, with an average period of treatment lasting
12 nights, and a median period of 7 nights (84). However, recent trends in clinical care and
regulatory guidance have prompted a shift towards longer-term trials. A few phase III studies
of newer hypnotics have examined their use over longer periods of time. Multiple studies have
lasted up to six months, some incorporating an additional six month open-label treatment period
that provides data for up to a year of usage (85–88). PSG continues to be used in some of these
more lengthy evaluations to provide periodic assessments of objectively defined outcomes (89).
As an example, PSG could be employed at baseline, midway through treatment, at the end of
treatment, and following acute discontinuation in order to evaluate sustained efficacy, as well
as tolerance or withdrawal effects that might be associated with a hypnotic (90). In contrast,
other studies have relied exclusively on patient reported outcomes (PRO) (85,88,91–94). These
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CLINICAL TRIALS AND THE DEVELOPMENT OF NEW THERAPEUTICS FOR INSOMNIA 443

data are important because they provide impressions regarding efficacy and safety from the
patient’s perspective and offer information regarding the patient’s experience at home in their
natural sleep setting as opposed to the artificial sleep environment of a sleep laboratory where
most PSG recordings are performed.
One of the more interesting recent developments in hypnotic trials has been the use of
novel study designs that have employed the “as needed,” non-nightly, or non-bedtime use of
hypnotics. (95–99). One study assessed the effects of non-nightly use of zolpidem 10 mg or
placebo in 199 patients with primary insomnia. Patients were randomized in a parallel group
design, and were instructed to take no fewer than three pills and no more than five pills per
week for a period of 12 weeks. The data revealed that patients receiving zolpidem exhibited
(vs. baseline) a 42% decrease in sleep latency, a 52% reduction in number of awakenings, a 55%
decrease in wake time after sleep onset, and a 27% increase in total sleep time, without increases
in the amount of medication used during the study interval (100).
Some studies have involved non-bedtime dosing of hypnotics. This type of evaluation
is especially relevant for medications that may not have immediate sedative effects (enabling
administration earlier in the day), or for medications that have rapid onset of action, metabolism,
and elimination (enabling administration during nighttime awakenings). Studies employing
experimentally induced awakenings in subjects with primary insomnia have examined the
effects of treatment with short-acting hypnotics like zaleplon (101–104). One crossover design
PSG study examined the administration of zaleplon 10 mg, zolpidem 10 mg, and placebo
in 37 subjects with primary insomnia characterized by sleep maintenance difficulty. During
each treatment period, subjects were seen for an eight-hour PSG recording, during which they
were awakened and later given study drug or placebo. The study revealed that both zaleplon
and zolpidem reduced sleep latency in the middle of the night and increased total sleep time
following dosing, suggesting that after-bedtime treatment may be efficacious in treating sleep
maintenance insomnia (104). This approach is not risk free however. It is notable that zolpidem
was associated with poorer next-day performance and greater sleepiness on the multiple sleep
latency test (MSLT) than placebo; an indicator that PK/PD relationships are important when
selecting hypnotics for after-bedtime dosing. Additional studies have examined the use of
middle-of-the-night dosing with other drugs using PROs, including studies of indiplon and
sublingual zolpidem administered in lower doses than the oral formulation (42,105,106).

STUDY DESIGN CONSIDERATIONS

Subject Selection
The matter of subject selection is critically important to the success of clinical trials of hypnotics.
When healthy subjects are being considered for inclusion in phase II studies of hypnotics,
it is important that they are of the appropriate age (adult or elderly) and that they have no
confounding concurrent illness, concomitant medication use, abnormal findings on physical
examination, or abnormal clinical laboratory findings. Since recent FDA guidance now requires
manufacturers to assess the cardiac safety of all new drugs that have systemic exposure (107),
electrocardiographic (ECG) assessments are important in selecting subjects appropriate for
study.
Among the unique aspects of subject selection for hypnotic studies are those related to
subjects’ sleep habits. When selecting healthy subjects for clinical trials, one must consider
subjects’ usual bedtimes, rise times, napping, recent travel across multiple time zones, use of
stimulants such as caffeine or nicotine, and the use of alcohol or other substances that might
affect sleep. Some studies that have used experimental models of insomnia have been careful to
exclude otherwise healthy subjects who may be sleep deprived. Assessments used to identify
sleep deprivation include the Epworth Sleepiness Scale (108,109), Stanford Sleepiness Scale, and
the MSLT (110,111).
When identifying patients with primary insomnia to participate in phase II or III trials,
the selection criteria are of utmost importance. First and foremost, it is important that the
characteristics of the patient population be clearly specified. Most trials of hypnotics performed
for registration purposes have studied patients with primary insomnia, most often defined by
Diagnostic and Statistical Manual of Mental Disorders, version IV (DSM-IV) criteria. There are
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444 ZAMMIT

relatively minor, but important, differences between DSM-IV criteria for primary insomnia and
other diagnostic nomenclatures also used to identify insomnia complaints. The International
Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) specifies
criteria for “nonorganic insomnia” that stipulate that symptoms must be present at least three
times per week for at least one month, while the DSM-IV criteria specify a duration of one
month or longer but do not require a minimum number of times per week. In contrast to both
the DSM-IV and ICD-10, the Research Diagnostic Criteria (RDC) for insomnia disorder do not
specify a duration criterion. Therefore, the fundamental diagnostic definition of insomnia used
in a trial must be thoughtfully considered. The use of centralized interviews may be one way to
minimize variability in diagnostic ratings of insomnia made by clinicians, similar to those used
in clinical trials in other therapeutic indications (112).
Once the insomnia diagnosis is specified, it is important to consider the types of symptoms
that patients must have in order to participate in the trial. For example, if a clinical trial is
intended to assess the effects of a drug on sleep latency, the study protocol should require
subjects to report difficulty falling asleep. Similarly, if the clinical trial is intended to assess the
effects of a drug on sleep maintenance, the study protocol is likely to require subjects to report
wakefulness during the sleep period. The frequency and severity of the sleep problems required
for inclusion depends on the specific objectives of the protocol. Some recent studies assessing
drug effect in patients with sleep maintenance insomnia have required both a sleep latency
and wakefulness after sleep onset (WASO) of ≥20 minutes as measured by polysomnography
during the screening process (68,113).
The clinical trial protocol typically provides an exhaustive list of specific inclusion and
exclusion criteria for study subjects. All of these criteria must be met in order to enroll subjects
into a study. The determination that these criteria are met usually is based on an office visit
(“screening visit”) during which a clinician obtains all pertinent history and a physical exam-
ination, clinical laboratory tests, ECG, and other assessments are performed. The first office
visit is when written informed consent is obtained from the subject, prior to performing any
study-related activity. Failure to meet all inclusion and exclusion criteria may result in a protocol
violation, which may result in the exclusion of a subject from analysis.
It has become a common practice to include PSG screening nights in PSG trials of
hypnotics. These screening nights serve to confirm that subjects meet certain PSG inclu-
sion/exclusion criteria prior to randomization to active drug or placebo, and improve the
likelihood that trial participants mirror the insomnia diagnosis that investigators wish to eval-
uate. Studies designed to assess the effect of a hypnotic on reducing sleep latency commonly
require a minimum LPS criterion on PSG screening nights. For example, a mean LPS of ≥20
minutes on two or three PSG screening nights, with no night less than 15 minutes might be
employed. Studies designed to assess the effect of a hypnotic on sleep maintenance often employ
a minimum criterion for WASO. For example, a mean WASO of ≥60 minutes on two or three
PSG screening nights, with no night less than 45 minutes might be required for trial participa-
tion. Note that these criteria are dependent on the scientific hypothesis being tested and are not
hard-and-fast standards imposed by industry. In addition to such PSG inclusion criteria, there
are PSG exclusion criteria. The most common PSG exclusion criteria involve the exclusion of
subjects who have an apnea/hypopnea index (AHI) >10 or a periodic limb movement with
arousal index (PLMAI) >10. Some upward adjustments to these thresholds may be warranted
when working with elderly samples.

Multicenter Trials
Phase I studies often are conducted at single sites. However, as drugs enter phase II development,
clinical trials usually are assigned to a small number of specialized investigator sites. Hypnotic
studies typically might include six to eight investigator sites, all likely to have experienced,
trained staff and PSG recording capability. The use of multiple sites for phase II studies provides
geographic reach, enhances the accrual of study subjects from diverse populations, and enables
the study to progress more rapidly than those conducted at a single center. Further along this
continuum, phase III studies often involve such large samples that it is necessary to enlist
the assistance of a much larger number of investigator sites. At this point in the development
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CLINICAL TRIALS AND THE DEVELOPMENT OF NEW THERAPEUTICS FOR INSOMNIA 445

process, dozens of sites representing a multinational assembly of investigators may be employed

to execute pivotal phase III studies of hypnotics.
One of the most important considerations when conducting multicenter trials relates to the
standardization of clinical trial methodology. It is desirable for all investigators in a multicenter
trial to collect data in a uniform manner. Standardization of data collection processes contributes
to data quality, minimizes confounds, and reduces variance. The ultimate goal is to have all
investigator sites operating as a unified group so that results from a patient enrolled at one site
are comparable to the results expected if the same patient was enrolled at any other study site.
The foundation of such synchrony lies in the study protocol that specifies study procedures.
In hypnotic drug trials, study protocols often include specific instructions for the collection of
PSG or other outcome data. Highly specialized PSG recording manuals commonly accompany
clinical study protocols for hypnotics. Training of investigators and site staff on these procedures
significantly contributes to the ability of investigators to standardize data collection at their sites.
In recent years, multicenter trials have increasingly relied on centralized services in order
to standardize data collection and processing methodologies. Such centralized services may
include centralized subject assessment and diagnosis (which may now be performed using Web-
based or live interview services), centralized randomization and drug allocation, centralized
subject assessments, and centralized clinical laboratory and electrocardiographic (ECG) services.
The use of such services has not only enforced standardization but has also proved helpful in
reducing errors, minimizing variance in datasets, and establishing a single location for data
management and auditing. One centralized service specific to studies of hypnotics relates to
the use of centralized PSG scoring services. Such centralized services often are used to confirm
that subjects meet PSG inclusion/exclusion criteria and ensure that PSG scoring is performed
in accordance with a uniform standard.

Outcome Variables
The goals of traditional hypnotic therapy primarily relate to reducing latency to sleep onset
or reducing wakefulness during the sleep period. The most commonly used primary outcome
variables in traditional PSG hypnotic studies have been latency to persistent sleep (LPS), total
sleep time (TST), sleep efficiency, and number of awakenings. These outcome variables have
been used in trials of benzodiazepines, nonbenzodiazepines (zolpidem, zaleplon, zopiclone),
and novel therapeutics such as ramelteon and doxepin. More recent focus on the prevalence and
impact of sleep-maintenance insomnia has led to the development of hypnotics that address this
type of sleep complaint. In PSG studies of drug effects on sleep maintenance, the most commonly
used outcome variable is WASO. WASO has been used as a primary outcome variable in pivotal
trials of both zolpidem ER and eszopiclone. Self-reported measures of sleep latency, total sleep
time, and sleep maintenance complement objective PSG outcome variables. These self-reported
measures may be used either in the context of PSG trials or, separately, in outpatient studies with
no PSG component. Traditionally, these variables have been collected using sleep diaries. More
recently it has become common to obtain patient-reported data using electronic or integrated
voice response system (IVRS) technology. Table 1 provides a summary of common primary and
secondary outcome variables used in PSG and outpatient studies of hypnotics.
Within recent years there has been increasing recognition that insomnia complaints regard-
ing sleep “quantity” (e.g., LPS, WASO) may include disruptions of sleep not detected by
traditional sleep stage scoring alone. These disruptions may be concurrent with, or independent
of, complaints of poor quality or nonrestorative sleep. Preliminary evidence of these disruptions
has sparked an interest in examining sleep microarchitecture. Such trials might involve careful
assessment of slow wave sleep activity measured during stages 3 and 4 sleep or throughout
the entire sleep period, or may focus on other measurable aspects of sleep through the use
of power spectral analysis (114) or scoring of cyclic alternating patterns (CAPs) (64,115–117).
At present, these newer outcome variables are not commonly used clinical trial endpoints,
but further exploration may lead to their consideration as outcomes for insomnia treatment
studies.
Other potential treatment outcomes for insomnia may include measures of daytime func-
tioning or health. Functional outcomes might assess next-day well-being, sleepiness, fatigue, or
performance on various psychomotor or memory assessments—all of which may be important
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446 ZAMMIT

to understand the clinical utility and proper labeling of hypnotics. For example, recent clinical
studies of hypnotics have begun to demonstrate that improvements following hypnotic treat-
ment may be associated with less napping and significantly higher ratings of daytime alertness,
sense of physical well-being, and quality-of-life (118). Finally, health outcomes might represent
an important new focus of hypnotic treatment. Recent data suggesting that sleep deprivation
is related to impairments in glucose metabolism (119–121), obesity and diabetes risk (122,123),
hypertension (124,125), cardiac arrythmias (126,127), and mortality (128) may increase the fre-
quency with which health outcomes are included in hypnotic trials.
While one primary objective of clinical trials is to assess efficacy, the other is to assess
safety. Safety outcomes in trials of hypnotics frequently include assessments of adverse events
and serious adverse events, and involve specific measures of sedation, cognitive functioning,
psychomotor functioning, and withdrawal. Adverse events are any untoward experience in a
clinical trial participant, whether or not the experience is believed to be related to the investi-
gational drug (129). Serious adverse events (SAEs) are adverse events that result in death or are
life-threatening, result in hospitalization or prolongation of an existing hospitalization, result
in significant disability or incapacity, or result in congenital abnormalities or birth defects (129).
These AEs and SAEs are reported by investigators and are carefully considered by regulatory
authorities when reviewing NDAs. In hypnotic trials, assessments of self-reported sedation
might be captured as AEs, especially if it occurs during the day. Objective measures of sedation
might further include the Digit Symbol Substitution Test (DSST), Symbol Copying Test (SCT), or
word recall tests. These tests often are performed at baseline, immediately after drug administra-
tion, and in the morning following awakening in order to assess next-day, residual impairment
(8.5 hours or more after dosing). Some studies have used the multiple sleep latency test to assess
residual sleepiness. Safety assessments also might be performed during the typical nighttime
sleep period in order to determine a drug’s effect on cognitive or psychomotor performance
during awakenings. As an example, some recent studies have used computerized dynamic pos-
turography to assess balance and postural control following middle-of-the-night awakenings
of healthy elderly and those with insomnia following bedtime dosing with hypnotic agents.

Specialty Populations
There are a number of health conditions that commonly are comorbid with insomnia. They
include obstructive sleep apnea (OSA) (130), chronic obstructive pulmonary disease (COPD)
(131), pain, menopause (132,133), and psychiatric illness such as depression (134) or anxiety
(135). Therefore, the assessment of hypnotic efficacy and safety in insomnia comorbid with
these other conditions is an important aspect of hypnotic life cycle management. Depression is
among the most commonly associated conditions comorbid with insomnia, giving rise to studies
of the combination use of antidepressants and hypnotics. The use of zolpidem was examined
in SSRI-treated patients with persistent comorbid insomnia (134). Patients who participated in
this study were diagnosed with depression, treated stably with the SSRIs fluoxetine, sertraline,
or paroxetine, and complained of sleep-onset difficulty or inadequate sleep time at least three
nights a week with daytime impairment. Over a four-week period, treatment with zolpidem
10 mg lengthened sleep time, improved sleep quality, reduced the number of awakenings, and
improved multiple measures of daytime functioning as compared to placebo.
A recent study evaluated the coadministration of eszopiclone 3 mg with the SSRI fluoxetine
in major depressive disorder (MDD) patients over an 8-week period (136). Compared to flu-
oxetine alone, the fluoxetine–eszopiclone group demonstrated statistically significant improve-
ments in all sleep parameters evaluated at all time points. Measures included sleep latency,
wake time after sleep onset, total sleep time, sleep quality, and depth of sleep. Importantly,
eszopiclone also resulted in a greater treatment response to fluoxetine as measured by improve-
ments on the Hamilton Depression Rating Scale (HAM-D-17) and two clinical global impression
scales (CGI-I and CGI-S). Furthermore, a significantly greater percentage of individuals in the
cotherapy group were classified as responders (59% vs. 48%) and remitters (42% vs. 33%) at the
end of the study.
There are a limited number of clinical trials of subjects with insomnia and comorbid
anxiety. One double-blind, randomized, placebo-controlled, parallel-group study examined
the efficacy of eszopiclone combined with escitalopram in adult patients with insomnia and
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CLINICAL TRIALS AND THE DEVELOPMENT OF NEW THERAPEUTICS FOR INSOMNIA 447

generalized anxiety disorder (GAD) (135). Patients received 10 mg of escitalopram oxolate for
10 weeks and were randomized to also receive either 3 mg of eszopiclone (n = 294) or placebo
(n = 301) nightly for the first 8 weeks. For the last two weeks, eszopiclone was replaced with a
single-blind placebo. Sleep, daytime functioning, psychiatric measures, and adverse events were
assessed throughout the 10-week period. The results showed that, compared with treatment
with placebo and escitalopram, coadministration of eszopiclone and escitalopram resulted in
significantly improved sleep and daytime functioning (P < 0.05), greater improvements in total
Hamilton Anxiety Scale (HAM-A) scores at each week (P < 0.05) and at weeks 4 through 10,
and greater improvements on the Clinical Global Impressions (CGI) of Improvement (P < 0.02).
Overall, the data obtained for the treatment of insomnia and comorbid psychiatrics conditions
suggest that study designs like these will become increasingly valuable during phases IIIb and
IV development, and may be used to document the efficacy and safety of hypnotics in insomnia
comorbid with other conditions. Such documentation adds to the clinical understanding of the
potential uses of hypnotics and also helps to differentiate hypnotics from each other.
In addition to the comorbidities presented here, the clinical trials of insomnia in special
populations may represent an important area of focus for future clinical trials. In the future,
subjects with histories of alcohol or drug problems, or those with Alzheimer’s disease or other
forms of dementia, may become routinely included in clinical trials. In addition, children with
insomnia might be considered a population of interest for clinical trials, given that no hypnotics
have been specifically indicated for the treatment of pediatric insomnia.

CONCLUSION
Clinical trials for hypnotics occur in a well-controlled regulatory environment. These trials
represent the method by which the efficacy and safety of new drug treatments for insomnia are
determined. The development of new hypnotics includes both preclinical (animal) and clinical
(human) studies, the latter being grouped into three phases that occur prior to the submission of
an NDA, and a fourth phase that occurs following the approval of a drug product. The successful
completion of a hypnotic development program involves the careful consideration of subject
and patient populations, study designs, methodology, and study endpoints. While regulatory
guidance and precedents exist, our expanding knowledge of insomnia, its morbidities, and its
pathophysiology will undoubtedly lead to new clinical development strategies for hypnotics
and the development of new therapeutics that treat insomnia and its morbidities.

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39 Practice Models
Michael J. Sateia
Department of Psychiatry, Dartmouth Medical School, Lebanon, New Hampshire, U.S.A.

INTRODUCTION
Acute and chronic insomnia are prevalent in a multitude of medical settings. The degree of
relevance of this disorder to the particular medical care being delivered will vary substantially
from one setting to another. Nevertheless, it is incumbent on health care providers of all types
to recognize the potential importance of this problem and the influence it may have on care
delivery and outcome, and to be familiar with at least the basics of assessment and management.
Chronic insomnia is associated with increased health care utilization, chronic illness, and high
rates of disability and functional impairment (1,2) (see also chapter 3). As outlined in previous
chapters, the condition may also predispose to psychiatric disorders (3,4), alter pain thresholds
(5), and perhaps, adversely affect cardiovascular function (6), to name but a few of the possible
consequences.
Recognizing the presence of an insomnia problem is a relatively straightforward process,
in that it requires only a complaint of sleep disturbance, despite adequate opportunity to sleep,
that is associated with daytime consequences (7). Despite the relative simplicity of the general
diagnosis, we know that most individuals with the problem are not identified. Health care
providers are constantly assailed with the need to do more and more in a health care environment
that allows them less and less time per patient. In this climate of competition for the attention
of providers (and patients), it is necessary to make the case for why this particular problem
warrants precious time. Ultimately, this requires demonstration that intervention enhances
outcome in one or more spheres. At present, the field of sleep medicine is still some distance
from making that case in a convincing manner. The same, of course, may be said for a host
of other common health care practices. Nevertheless, data on outcomes in current therapeutic
research, though spotty, suggest that identification and treatment improves health and function
(8–10).
The extent to which insomnia is identified and addressed can be expected to vary widely
from one medical discipline to another. Although the greatest management expertise presum-
ably resides within sleep medicine, there can be little doubt that the great majority of insomnia
is encountered in primary care and mental health practices. Therefore, it is necessary to consider
what levels of intervention can reasonably be expected in these varied settings. A simple goal
would be mere identification of a chronic sleep problem, but the extant data suggest that cur-
rent practice is far from achieving this goal. Neither physicians nor patients seem particularly
inclined to bring this issue to medical attention, despite the fact that some patients, when asked,
report insomnia as a very significant symptom (11).
What, then, are realistic expectations at a primary care level? Routine health screening
should include, at a minimum, an inquiry regarding the patient’s sleep. This brief query, coupled
with determination of daytime consequences and adequacy of opportunity to sleep (i.e., time
in bed under conducive circumstances), is sufficient to establish the presence of an insomnia
problem. Primary care providers can also be expected to ascertain the duration of the problem.
Management of an acute problem is likely to be quite different from that of one that has been
present for years or decades.

ACUTE INSOMNIA IN THE PRIMARY CARE SETTING

The vast majority of acute or transient insomnia does not come to medical attention. However,
when short-term sleep disturbance is a source of significant distress or daytime dysfunction,
physicians may be called on to respond. Current practice typically consists of reassurance
and, in some cases, pharmacological recommendations. Most recent data indicate that these
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454 SATEIA

recommendations are quite often for over-the-counter (OTC) products (antihistamine or mela-
tonin) or off-label use of sedating antidepressants (12). Patients may have initiated self-
medication with alcohol or OTC products, including herbal supplements.
Optimal management of short-term insomnia is reasonably straightforward. It is neces-
sary to consider what current stresses or conditions may have precipitated the sleep problem.
The presence of other common and readily treatable illness such as major depression must
be considered. If the insomnia is, indeed, an adjustment disturbance, several straightforward
approaches are indicated. First, consideration of whether the patient requires further assistance
in coping effectively with the current stress. Brief stress management counseling in the office
or referral for more specialized mental health counseling are options. On occasion, daytime
pharmacotherapy (antianxiety medication) may be indicated. Second, sleep education is likely
to reduce the likelihood of an acute disorder evolving into chronic insomnia. These principles
are discussed in detail in chapter 23. Preventing the development of factors that are likely to
perpetuate the insomnia by encouraging maintenance of a regular schedule and stimulus con-
trol measures is particularly important. Finally, consideration must be given to pharmacological
aid. As noted, patients may already be self-medicating. Although specific practice parameters
regarding pharmacological management of adjustment insomnia do not exist, most sources
suggest that self-medicating is generally not advisable. Alcohol, the most common form of self-
medication for insomnia, clearly is contraindicated (chapters 16 and 36) and efficacy of OTC
products is not well established (chapter 36). When patient and physician agree that the degree
of distress or dysfunction warrants use of a sleep aid, a benzodiazepine receptor agonist (BzRA)
or melatonin agonist hypnotic is indicated (13). The efficacy of these drugs is well established
and, when used and monitored properly, they carry limited clinical risk. The most critical aspect
of choosing a specific hypnotic medication is matching the duration of the clinical action of the
drug to the sleep complaint. This issue is discussed at greater length in preceding chapters. Per-
haps most importantly, follow-up in the primary care setting is critical. This should include (1)
review of the current status of the insomnia; (2) inquiry regarding precipitating conditions; (3)
continued sleep hygiene and stimulus control education; (4) determination of effectiveness and
side effects of medication; (5) tapering and discontinuation of hypnotic medication as exacerbat-
ing events and sleep disturbance resolve, with education regarding possible transient rebound
insomnia.

CHRONIC INSOMNIA IN PRIMARY CARE

Most insomnia complaints that come to medical attention are chronic in nature (14). While the
greatest expertise in assessment and treatment of chronic insomnia lies with sleep medicine
physicians and behavioral sleep medicine specialists, sheer numbers dictate that initial evalu-
ation and treatment for the great majority will occur in primary care offices. Identification of
a chronic insomnia problem in this setting should be followed by consideration of potential
etiologies. The general etiologic categories to be considered for chronic insomnia are (1) pri-
mary insomnia; (2) insomnia comorbid with medical, neurological, psychiatric, or substance
use/abuse conditions; (3) sleep–wake schedule disorders; (4) insomnia comorbid with other
sleep disorders (e.g., breathing, movement, environmental). Primary care providers can be
expected to identify comorbid factors such as chronic pain, major psychiatric disorders, sub-
stances, or other medical and neurological problems, which may contribute to the insomnia.
These factors are discussed extensively in preceding chapters. Screening for primary sleep disor-
ders, especially breathing and movement disorders, is required. In most cases, positive screens
should prompt referral to a sleep specialist.
Therapy for chronic insomnia can be complex. It could be argued that the optimal treat-
ment for these patients would be in a comprehensive sleep center with available expertise
in cognitive behavioral treatment of insomnia. As is the case with many common conditions
though, a majority of these patients are and will continue to be managed by their primary
provider. Therefore, a realistic set of guidelines is necessary. These, in effect, can be distilled into
three major areas: (1) managing comorbid conditions; (2) pharmacotherapies; and (3) psycho-
logical and behavioral therapies.
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Comorbidities
Certainly, primary care physicians should address those common comorbidities that are within
the realm of their expertise—conditions such as major depression, substance abuse, pain,
gastro-esophageal reflux disorder (GERD), nocturia, nocturnal respiratory distress (e.g.,
asthma), or endocrine disease. A review of medications with consideration of possible offend-
ing substances is likewise appropriate. When comorbidities such as this are identified and a
suspicion of causal linkage to the insomnia exists, primary care providers have traditionally
been inclined to focus primarily on treating the comorbidity, with the expectation that the sleep
problem, as a “secondary” symptom, would resolve. More recent evidence indicates the need
for a paradigm shift in this respect (15). Studies in several key areas, particularly depression
and pain, suggest that optimal outcome may be achieved by concurrent treatment of not only
the comorbid condition, but the insomnia as well (16,17). Treatment for the insomnia may be
psychological/behavioral, pharmacological, or both.

Cognitive Behavioral Therapy

Guidelines for the treatment of chronic insomnia indicate that all patients, whenever possi-
ble, receive cognitive behavioral treatment for insomnia (CBT-I). (13) An abundant research
demonstrates the early and long-term effectiveness of these modalities (18,19). Unfortunately,
a substantial gap exists between the academic and the real world application of CBT-I. Iden-
tification of a skilled CBT-I therapist has been difficult to impossible for most clinicians in
general practice. There are, perhaps, more viable options available, although none have seen
widespread implementation. Some well-meaning clinicians will attempt to address certain cog-
nitive or behavioral aspects of chronic insomnia with brief discussion and education concerning
sleep hygiene. While such education may be quite helpful in preventing an acute insomnia prob-
lem from becoming chronic, there is inadequate evidence to support education as an effective
strategy for chronic insomnia, alone or combined with medication (18). A number of specific
CBT approaches have proven efficacy and an attempt needs to be made to deliver this to as
many patients as possible.
One option for the primary health care provider is to attempt to deliver some form of
these therapies from their office practice. It seems quite unlikely that many physicians are
going to have the time or inclination to learn and deliver this care themselves. However, there
is some evidence, as discussed in previous chapters, that providers other than doctoral level
individuals can be educated to offer these treatments in an effective manner (8,20). Educational
programs for would-be therapists are available on a regular basis and manualized treatment
approaches can make delivery somewhat more straightforward (8,21). Brief (3–5 sessions) group
CBT-I, offered by a nurse or other qualified health care professional, on a quarterly basis, for
example, could offer relief to significant numbers of individuals with chronic insomnia. There
are also a number of self-help, internet-based CBT approaches, sometimes coupled with phone
intervention (18,22–27). Assessment of these programs suggests some promising results and
primary physicians and patients with limited access to alternatives may consider this approach.
Having said that, it is likely that patients with the most severe chronic insomnia problems will
require the skills of a highly experienced expert in this area. Many of these experts are specifically
certified as behavioral sleep medicine specialists by the American Academy of Sleep Medicine
(AASM), and most are attached to accredited comprehensive sleep centers. Establishment of
stronger alliances between these sleep centers and the primary or specialty care practices in their
communities could serve as a foundation for identifying or developing resources for provision
of effective CBT-I.

Prescribing Hypnotics
The decision regarding prescription of medication for chronic insomnia patients is a complex
one. Numerous factors influence this decision. These include (1) patient preference; (2) prior
experience with medication and results of this; (3) willingness to engage in CBT-I; (4) availabil-
ity of CBT clinicians; (5) contraindications to use of hypnotics or other sedating medications.
Many physicians are reluctant to prescribe medication for chronic insomnia, based on fears of
dependency and tolerance. The practice of recommending OTC medication (commonly anti-
histamine compounds) or sedating antidepressants, in all likelihood, reflects the belief that
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456 SATEIA

these agents are safer alternatives to approved BzRA medications. Unfortunately, the efficacy
of these alternatives is not well established in chronic insomnia, and it is not clear that they are
intrinsically “safer” than standard hypnotics (28). Therefore, current AASM guidelines recom-
mend that when medications are prescribed for chronic insomnia, the first-line choice should
be an appropriate shorter-acting BzRA (13). The more important issues, perhaps, for health
care providers with respect to prescribing these medications are (1) patient education regarding
goals, expectations, and side effects of medication; (2) use of minimal effective dosages of a
medication with a duration of action appropriate to the insomnia complaint; (3) implemen-
tation of effective psychological and behavioral therapies; (4) tapering and discontinuation of
medication in conjunction with (3); and (5) continued follow-up during and after medication
trials. Alternative pharmacotherapies are addressed briefly in the following section on mental
health models and more extensively elsewhere in this text.

Combined Treatment
Clinicians must recognize that when hypnotic medication is prescribed for chronic insomnia,
it should, whenever possible, be accompanied by CBT-I. The primary reason for this dictum is
that current data make clear that short-term trials of sleep medication, while effective during
the period of active administration, do not typically produce sustained improvement of the
sleep disturbance (18,29,30). Evidence is also clear that CBT-I does produce durable change.
Thus, in the absence of these nonpharmacological therapies, clinicians are frequently left in the
uncomfortable position of either discontinuing medication, with resulting recrudescence of the
problem, or maintaining chronic hypnotic use.
For some time, there has been debate over whether combining pharmacotherapy with
CBT-I is advantageous or, alternatively, counterproductive. Proponents of combined treatment
argue that medication may provide faster relief and enhance patient confidence in their ability to
sleep, thus reinforcing gains associated with CBT. Opponents suggest that patients may misat-
tribute gains to medication, rather than to CBT, be less motivated to implement skills effectively,
and thus, be more prone to relapse with discontinuation of the medication. The evidence on
this is mixed. The most widely cited study of combined treatment (18) found that combined
therapy was associated with a trend toward greater improvement immediately posttreatment
than either treatment alone, but the longer-term outcome with combined treatment was more
variable than with CBT alone. Another study found no advantage of combined treatment over
CBT alone (29).

Chronic Hypnotic Usage

Even under the best of circumstances, some patients who have received adequate assessment
and treatment, including skilled CBT-I, will continue to suffer from insomnia without the assis-
tance of medication. Some of these patients will be well controlled on medication without
significant side effects or complications. Recent randomized, placebo-controlled studies have
confirmed long-term efficacy of newer generation BzRAs without significant dosage escalation,
side effect, withdrawal, or rebound insomnia complications (31,32). Therefore, it seems reason-
able to consider long-term use of hypnotics in CBT treatment-refractory patients. When sleep
medications are to be used chronically, the clinician must follow several practices, all involving
ongoing follow-up, to ensure optimal outcome. These include (1) verifying that the medication
is still effective; (2) making certain that no significant side effects or complications have devel-
oped (this would include indication of dosage escalation); (3) reassessing for the emergence
of new comorbidities that may complicate the management; (4) encouraging the continued
employment of cognitive behavioral strategies; (5) periodically readdressing the possibility that
medications may be tapered or discontinued.

Chronic Hypnotic Discontinuation

Providers are frequently confronted with established chronic hypnotic usage in insomnia
patients who have never received treatment other than pharmacotherapy and who are often
not experiencing adequate relief of the sleep problem even with regular use of medication.
The general mind-set among many clinicians is that this chronic reliance on sleeping pills is an
undesirable practice; however, the provider is frequently trapped between a desire to minimize
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PRACTICE MODELS 457

long-term complications or dependency risks (i.e., discontinue the medication) and a patient
who is desperate for relief from insomnia. To further complicate this scenario, patients often
report that the current medication, and many prior ones, are ineffective, but will resist efforts
to discontinue them. In turn, this may prompt further and increasingly desperate efforts on
the part of the prescriber to find an effective medication or combination of medications. While
pharmacotherapy has a legitimate place in the treatment of chronic insomnia, as discussed, it is
seldom the case that rapid turnover polypharmacy, in its own right, is the solution for chronic
insomnia. Efforts to simplify and discontinue medications in this population may be the more
advantageous therapeutic strategy in many cases. Given the fact that the improvements seen
with short-term medication trials alone are not generally sustained in chronic insomnia patients,
it is hardly surprising that primary care providers would often meet resistance and be frustrated
in efforts to achieve medication tapering or discontinuation without providing the patient with
effective alternative therapies. A growing body of evidence clearly defines the effectiveness of
CBT-I in promoting successful tapering and discontinuation of chronic hypnotic medication (18).
One study (33) demonstrated a twofold higher rate of complete hypnotic discontinuation
in older chronic hypnotic users when CBT-I (small group format × 8 weeks) was utilized in
combination with medication tapering (77% discontinuation) versus tapering alone (38%). This
differential was even greater at 12-month follow-up (70% vs. 24%). These observations have
been extended in a separate study to assess the combination of self-help CBT with tapering
(34). These two conditions produced comparable rates of reduction in hypnotic usage, although
sleep efficiency increased and wake time decreased in the CBT group. However, the sleep-related
improvements in the CBT group may reflect primarily the effects of restricted time in bed. In a
similar investigation (35) of BZD discontinuation in patients with anxiety disorder or insomnia,
treatment as usual (tapering and physician counseling) was compared to tapering coupled with
either group support or group CBT). Both group support and CBT produced significantly higher
rates of discontinuation (85% and 83%, respectively) than treatment as usual (39%). Of note,
however, is the fact that rates for group support (in which any specific recommendations were
specifically prohibited) were equivalent to those for CBT. A more recent placebo-controlled
investigation (36) suggests that administration of melatonin in conjunction with tapering may
promote higher rates of hypnotic discontinuation in an elderly population than tapering alone.
In summary, while some patients may benefit from chronic use of sleep medications, many
others have not received adequate evaluation or nonpharmacological therapies. Ultimately, a
number of chronic insomnia sufferers will not respond adequately to the level of treatment
offered by primary care providers. In such cases, consideration should be given to referral to a
specialist in sleep medicine. This is discussed further in later sections.

CHRONIC INSOMNIA IN THE MENTAL HEALTH SETTING

Insomnia is considered an intrinsic component of many major psychiatric conditions. As dis-
cussed earlier, this gives rise to the view, still widely held by mental health professionals, that
the sleep-related symptoms will resolve with treatment of the primary mental illness alone.
While this is indeed true in many cases, especially acute, short-lived disorders such as a single
major depressive episode, many psychiatric conditions are recurrent or chronic in nature and
provide ample opportunity for development of factors that perpetuate chronic insomnia. As
discussed previously, recent evidence supports the notion that pharmacological or behavioral
treatment of insomnia, concurrent with treatment of the psychiatric disorder, may produce
improved outcome for both sleep and psychiatric parameters (16,17). Further fueling the need
for such concurrent intervention is the observation that residual sleep disturbance conveys an
increased risk for persistence or recurrence of mental illness (37–39). Finally, adequate sleep is
likely to bolster coping mechanisms, enhance compliance with mental health treatment, and
generally improve quality of life in patients with serious mental illness.
The principles of treatment for chronic insomnia comorbid with psychiatric disorders are
much the same as those outlined above in the primary care section. However, several additional
considerations are worthy of note. For many years, the efficacy of CBT-I was demonstrated in
sample populations of patients with primary insomnia alone. Significant doubt existed as to
whether or not these therapies would be successful in patient with the added complexities of
mental disorders. On the basis of a number of trials (27,40–42) (see also chapter 30), it now
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458 SATEIA

seems quite clear that insomnia comorbid with psychiatric conditions has outcomes that are
quite comparable to those observed in primary insomnia. Widespread application of group
CBT-I by psychologists or psychiatric nurses in community mental health settings, inpatient
or partial hospitalizations, or rehabilitation programs might provide significant benefit, but
initiation of such endeavors is in its infancy, at best.
Patients with chronic psychiatric disorders often exhibit many complicating factors that
must be addressed if sleep disturbance is to improve. Substance abuse may be foremost among
these. The characteristics and management of insomnia comorbid with alcohol and drug abuse
is discussed in detail in chapter 16. As a result of isolation and lack of social zeitgebers, patients
with chronic psychiatric illness are prone to circadian disorders such as delayed or irregu-
lar sleep–wake rhythms. Special consideration must be given to the impact of psychotropic
medications on sleep–wake function. The contribution of certain symptoms associated with
specific psychiatric disorders to insomnia may also need to be addressed. One of the most com-
mon examples of this is recurrent nightmares in patients with posttraumatic stress disorder.
In recent years, two therapies have shown particular promise in managing nightmares. The
␣1 -adrenergic antagonist, prazosin, has been shown to not only reduce nightmare frequency,
but also to improve sleep in post-traumatic stress disorder (PTSD) patients (43,44). Likewise, the
cognitive-behavioral therapy of imagery rehearsal and desensitization shows similar outcomes
(45,46). Other symptoms such as nocturnal panic attacks or hallucinations may also require
specific treatment focus.
Pharmacotherapy for insomnia in the setting of mental illness requires special consider-
ations. In many cases, the primary psychopharmacological treatment may be a sedating com-
pound, which can be administered at bedtime and may significantly aid sleep. Examples of this
would include sedating antidepressant medications such as mirtazapine, or antipsychotic med-
ications including many first-generation neuroleptics as well as second-generation drugs such
as quetiapine, olanzapine, or risperidone. Mood-stabilizing agents may also provide substantial
sedative effect, which may be used to good advantage at bedtime. Certainly, combined use of
these medications for psychiatric indications and sleep disturbance may be quite appropriate
and may simplify the medication regimen.
Beyond this combined indication, however, there are many patients who require the
addition of a sedating medication primarily for the indication of insomnia. Psychiatrists, like
many primary care physicians, often prescribe off-label use of sedating antidepressants such as
trazodone (47–50), or sedating antipsychotics, especially quetiapine (51–53). These agents and
others are discussed in detail in chapter 34. While these agents may have certain advantages in
this population, it is important for practitioners to recognize that there has been very limited
assessment of these drugs, often in uncontrolled studies, with regard to their efficacy in chronic
insomnia. For this reason, guidelines suggest that BzRAs or ramelteon are the treatments of
choice for chronic insomnia, including those cases comorbid with mental disorders. Having
said that, it must also be recognized that in patients with high potential for abuse, such drugs
may be contraindicated.

THE ROLE OF SLEEP MEDICINE

When patients with chronic insomnia cannot be effectively evaluated and/or treated in other
settings, they should be referred to a comprehensive sleep center for specialized care. The role
of the sleep specialist is threefold: (1) more detailed assessment of the problem; (2) employment
of polysomnography, when indicated; and (3) more specialized, expert therapy, which includes
follow-up to the point of problem resolution or maximum therapeutic benefit.
While it is within the expected purview of primary care or mental health providers to iden-
tify the most common and straightforward comorbidities of chronic insomnia and to obtain a
basic characterization of the complaint, sleep specialists are trained to identify and integrate
the numerous and often complex medical, psychiatric, and behavioral components of chronic
insomnia. The intricacies of this are described elsewhere in the “Evaluation” section (chapter 9)
of this volume. It is also the primary responsibility of the sleep specialist to effectively screen for
other primary sleep disorders, most notably breathing and movement abnormalities that may
contribute to insomnia. Suspicion of these disorders is the major indication for polysomnog-
raphy in patients with chronic insomnia (54). Interpretation of the significance of the results
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PRACTICE MODELS 459

of sleep studies and development of multicomponent, phased treatment approaches is a key

aspect of sleep medicine’s role in the overall management of chronic insomnia.
Most patients referred to sleep centers for chronic insomnia have received some form of
pharmacotherapy before they arrive. It is the responsibility of the sleep specialist to review these
therapies, to determine what has and has not been effective, to implement new pharmacological
approaches, and to discontinue those medications that are ineffective or contraindicated. Beyond
this, comprehensive sleep medicine programs must be able to provide the highest level of
cognitive behavioral therapy, integrated with other components of treatment. Ideally, centers
could provide individual treatment by a behavioral sleep medicine specialist for all referred
patients. Given the scarcity of this resource, though, even these programs must think in terms
of brief, group therapy as an entry-level treatment for at least some chronic insomnia patients.
Ongoing monitoring and follow-up, medication tapering accomplished in concert with CBT-
I, and management of other comorbid sleep disorders are also essential. Finally, if effective
diagnosis and management of chronic insomnia is to occur, specialized centers need to provide
outreach to primary care, psychiatric and other practices in their regions. These outreach efforts
should include raising awareness of the frequency and significance of this condition, providing
simplified evaluation and diagnostic approaches, and clarifying the role of pharmacological
and psychological/behavioral therapies in the management of chronic insomnia. In light of the
paucity of available CBT-I, sleep centers should also be prepared to work with nurses and other
health care workers to provide training in entry-level CBT-I and consultation when greater
expertise is required.

CONCLUSIONS
Modern medicine, despite its many advances, is not providing reliable detection or effective
treatment for the vast majority of people with chronic sleep disturbance. This probably reflects
some degree of indifference to the problem, stemming from lack of education and awareness, as
well as uncertainty regarding the appropriate assessment and management. The net result of this
is unnecessary suffering, increased health care utilization, and in all likelihood, increased risk
for significant medical and psychiatric disorders. Chronic insomnia is probably preventable
for many, although we lack the large-scale public health interventions necessary to test this
assertion. Likewise, the great majority of established chronic sleep disturbance does not come
to medical attention. The economic cost of this enormous gap in loss of productivity, accidents,
OTC and self-help therapies, and increased health care utilization numbers in the billions. Yet,
capturing the attention of those affected and their care providers remains a daunting task.
Unfortunately, while medicine struggles to manage numerous problems that have no
effective treatments, this readily treatable disorder is largely ignored. However, sleep medicine
must come to terms with the fact that, while we have made great strides in developing and
testing efficacious therapies that can produce long-term improvement, we lag far behind in
identifying or developing the resources necessary to effectively deliver these therapies to even
a small percentage of the affected population. It seems likely that health care providers would
be far more prepared to address the issue of chronic insomnia if a clear treatment pathway and
necessary resources were available to them. Absent this, we should expect little change in the
current dynamic.

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47. Schwartz T, Nihalani N, Virk S, et al. A comparison of the effectiveness of two hypnotic agents for the
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48. Kaynak H, Kaynak D, Gozukirmizi E, et al. The effects of trazodone on sleep in patients treated with
stimulant antidepressants. Sleep Med 2004; 5(1):15–20.
49. Saletu-Zyhlarz GM, Anderer P, Arnold O, et al. Confirmation of the neurophysiologically predicted
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50. Nierenberg AA, Adler LA, Peselow E, et al. Trazodone for antidepressant-associated insomnia. Am J
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51. Philip NS, Mello K, Carpenter LL, et al. Patterns of quetiapine use in psychiatric inpatients: An
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53. Endicott J, Rajagopalan K, Minkwitz M, et al. A randomized, double-blind, placebo-controlled study
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Appendix: Resources

WEBSITES
http://www.sleepeducation.com – the public education site of the American Academy of Sleep
Medicine (AASM) includes detailed information on the causes and treatments of insomnia and
other sleep disorders.
http://www.aasmnet.org – the American Academy of Sleep Medicine professional site includes
detailed information on accreditation of sleep centers, professional education programs and
resources, clinical standards and useful information for the health professional within and
outside the field.
http://www.sleepcenters.org – this AASM site provides a roster of accredited sleep centers
across the United States.
http://www.sleepresearchsociety.org/ – the Sleep Research Society is the major professional
organization of sleep researchers. The site includes educational opportunities and products
and additional resources for sleep researchers.
http://www.nhlbi.nih.gov/about/ncsdr/index.htm – the National Center on Sleep Disorders
Research (NCSDR) is a division within the National Heart, Lung and Blood Institute (NHLBI).
This site provides public and professional education and research information.
http://www.sleepfoundation.org – the National Sleep Foundation engages in public education
and information gathering through its annual national sleep survey.
http://www.americaninsomniaassociation.org – the American Insomnia Association is a
patient-based organization which is dedicated to advancing identification and treatment of
insomnia through public and professional education and research.
http://www.absm.org/BSM Specialists.htm – the American Board of Sleep Medicine (ABSM)
maintains a list of certified behavioral sleep medicine specialists nationwide.
http://www.absm.org/Diplomates/listing.htm – the ABSM also maintains a list of health pro-
fessionals certified by this board.∗
∗
Since 2007, the board certification examination in sleep medicine is offered by the American
Board of Internal Medicine, in conjunction with other primary specialty boards. Rosters of
physicians certified since 2007 by these respective boards can be found on the web sites of those
organizations.

SELF-HELP BOOKS AND MANUALIZED TREATMENT APPROACHES FOR

CHRONIC INSOMNIA
No More Sleepless Nights by Peter Hauri and Shirley Linde
Sleep Manual: Training Your Mind and Body to Achieve the Perfect Night’s Sleep by Wilfred R. Pigeon
Say Good Night to Insomnia by Gregg D. Jacobs
The Insomnia Answer: A Personalized Program for Identifying and Overcoming the Three Types of
Insomnia by Paul Glovinsky and Art Spielman
app IHBK059-Sateia March 31, 2010 22:17 Char Count=

464 Appendix: Resources

Cognitive Behavioral Treatment of Insomnia: A Session-by-Session Guide by Michael L. Perlis, Carla

Jungquist, Michael T. Smith, and Donn Posner
Overcoming Insomnia: A Cognitive-Behavioral Therapy Approach Workbook (Treatments That Work)
by Jack D. Edinger and Colleen E. Carney
The Insomnia Workbook: A Comprehensive Guide to Getting the Sleep You Need by Stephanie Silber-
man and Charles Morin
The Harvard Medical School Guide to a Good Night’s Sleep (Harvard Medical School Guides) by
Lawrence Epstein and Steven Mardon
ind IHBK059-Sateia March 28, 2010 14:3 Char Count=

Index

Note: Page numbers followed by f, n, and t indicate figures, notes, and tables, respectively.

Abbreviated cognitive-behavioral intervention, Amitriptyline, 393, 400–401

311, 314t Amnesia
Absenteeism, 21–22 anterograde, 389
ACBT. See Abbreviated cognitive-behavioral global, 391
intervention Amnestic parasomnia, 390–391
Accidents Amphetamines, 167t, 172
automobile, 22 Amygdale, 78
hypnotics, 23 Anecdotal, 36
lack of attention, 23 Anticonvulsants, 144
sleep deprivation, 23 carbamazepine, 174
work, 23 gabapentin, 174
ACTH. See Adrenocorticotropic hormone See also under Off-label prescribing in insomnia
Actigraphy, 93, 184, 357 Antidepressants, 133t, 134, 174, 251. See also under
Acupressure, 293 Off-label prescribing in insomnia
Acupuncture, 293 Antihistamines, 245, 418–419
Acute insomnia Antipsychotics, 133t, 134, 157, 174. See also under
ICSD-2 insomnia disorders, 104t Off-label prescribing in insomnia
in primary care, 435–454 Anxiety
AD. See Alzheimer’s disease and depression, 11
Adipiplon, 428 disorders, 35
Adjustment insomnia Anxiety sensitivity index, 131
ICSD-2 insomnia disorders, 104t Anxiolytics, 403
pediatric, 238t Apnea hypopnea index, 215, 229
Adolescents, sleep pattern of, 236 Aromatherapy, 294
Adrenocorticotropic hormone, 68, 69f Arousal
Adults with insomnia, 378, 378t basic systems, 77
Advanced sleep phase, 229 disorders, 240
Advanced sleep phase disorder. See under emotional, 118–119
Circadian rhythm sleep disorders sleep-interfering, 44
Affect Articulatory suppression, 302–303, 303t
measures of ASI. See Anxiety sensitivity index
Beck depression inventory, 47 ASP. See Advanced sleep phase
state-trait anxiety inventory, 47 ASPD. See Advanced sleep phase disorder
profile of mood states, 47 Athens insomnia scale, 91
role of, 46–47 Attention–intention–effort pathway, 45
Agomelatine, 413 Auriculotherapy, 294
Agoraphobia, 130 Avian influenza vaccine, 37
AHI. See Apnea hypopnea index
AIS. See Athens insomnia scale Balance in insomniacs, 14
Alcohol intake, 217, 219, 260–261, 392, 393, 418, 454 Basal forebrain, 77–78
Alcoholism, 36, 165–169, 166t, 168f Basic sleep patterns
Alertness, 14 bipolar disorders, 127t, 129
Allodynia, 143 depressive disorders, 127t, 128
Almorexant, 429 generalized anxiety disorder, 127t, 130
␣2 -adrenergic receptor agonists, 246 panic disorder, 127t, 131
Alprazolam, 404 posttraumatic stress disorder, 127t, 131
Alzheimer’s disease, 157 schizophrenia, 127t, 132
ind IHBK059-Sateia March 28, 2010 14:3 Char Count=

466 Index

BBTI. See Brief behavioral treatment of insomnia hypothalamus, 77–78

BDI. See Beck depression inventory limbic and paralimbic system, 78–79
Beck anxiety inventory, 95 cortical arousal, 79
Beck depression inventory, 11, 47, 95, 128, 129 hippocampus, 79
Behavioral insomnia of childhood, 104t, 105 magnetic resonance imaging, 79
extinction techniques, 243–244 mirror tracing task, 79
limit-setting type, 237, 239t pharmacotherapy, 79
night awakenings, 244 neocortex, 80
parental education, 244 paralimbic system, limbic and, 78–79
sleep onset association type, 237, 239t prefrontal cortex function, 80
treatment, 243t thalamocortical activity, 80
Benzodiazepine, 174, 202, 230, 250, 278, 360 Brain metabolic activity, 67
in Alzheimer’s disease, 157 Brainstem, 77–78
chronic obstructive pulmonary disease, 154 Brazilian insomniacs, 21
hypnotics, 368–369 Breathing disorder and insomnia. See Sleep-related
sedative hypnotics, 78, 79 breathing disorder
for sleep medicines, 368 Brief behavioral treatment of insomnia. See
Benzodiazepine receptor agonist, 144, 174, 375–377 Short-term treatment approach
dosages, 378t Brief panic disorder screen, 131
efficacy, 377 Bright light therapy, 292
in adults, 378 Brotizolam, 56
in children, 379 Bruxism, 204–205
in comorbid insomnia, 379 BZRAs. See Benzodiazepine receptor agonists
comparative studies, 380
of treatment duration, 379 Caffeine, 166t, 169–170, 261–262
in intermittent dosing, 379–380s CAM. See Complementary and alternative
in older adults, 378 medicine
hypnotics, 250 Cancer patients with insomnia, 330
indications Cannabidiol, 170
BzRA, 375–377 CAP. See Cyclic alternating pattern
CBT, 375, 376 Carbamazepine, 174
outcome Cardiovascular disease, 36
adverse effects of treatment, 382 Catecholamines, 70
clinician global impressions, 38 CBT. See Cognitive behavioral therapy
comorbid insomnia, severity of, 382 Central sensitivity syndromes, 143
daytime function measures, 381–382 Central sensitization, 215–216
patient global impressions, 381 Cerebrovascular disease, 159
properties of, 376t CFR. See Code of Federal Regulations
syndromal insomnia, 380–381 CGI. See Clinician global impressions
Benzodiazepine receptor agonist safety Childhood insomnia, 104t, 105. See also Pediatric
risk minimization, 393–394 insomnia
risks of BzRA Cholinergic nuclei, 77
abuse liability, 390 Chronic hypnotic discontinuation, 456–457
amnestic parasomnia, 390–391 Chronic hypnotic usage, 456
cognitive impairment, 388–389 Chronic insomnia, 5, 84
discontinuation effects, 389–390 Chronic insomnia, health practices for
nonhypnotic medications, 393 in mental health, 457–458
nontreatment, 392 in primary care, 454
psychomotor impairment, 387–388 chronic hypnotic discontinuation, 456–457
self-medication, 392–393 chronic hypnotic usage, 456
Beta frequency activity, 54, 55f cognitive behavioral therapy, 455
Beta power, 79 combined treatment, 456
Biofeedback, 291 comorbidities, 455
Bipolar disorders, 34, 127t, 129 prescribing hypnotics, 455–456
Bipolar EEG derivations, 57t Chronic kidney disease, 154
Bootzin’s theory, 42 Chronic obstructive pulmonary disease, 153
BPDS. See Brief panic disorder screen Chronic pain, 36
Brain imaging Chronic pain, insomnia in
basal forebrain, 77–78 autoimmune conditions, 142
brainstem, 77–78 clinical recommendations
functional neuroimaging, 80 cognitive processes and thought content, 147
ind IHBK059-Sateia March 28, 2010 14:3 Char Count=

Index 467

coping, 148 principles of treatment

mood states, 147 phase shifting, 184–185, 186–187
psychiatric distress, 147 prescribed sleep scheduling, 187
sleep disturbance, 147 symptomatic treatment, 187
social function, 147–148 shift work disorder, 190
cognitive-behavioral therapy combination treatment, 193
for insomnia in chronic pain, 145–146 pharmacologic symptom control, 192
for pain, 145 prescribed sleep scheduling, 192
costs, 139 timed light exposure, 191
definition, 139 timed melatonin administration, 191–192
experimental sleep disruption, 140–141 types of
idiopathic pain disorders, 142–143 advanced sleep phase disorder, 181
inflammatory conditions, 142 delayed sleep phase disorder, 181
neuropathic pain syndromes, 143–144 free-running disorder, 181
pain administration, 141 irregular sleep–wake disorder, 181
pharmacologic treatments jet lag disorder, 181
for pain, 144–145 shift work disorder, 181
for sleep disturbance, 144 CKD. See Chronic kidney disease
prevalence, 139 Clinical drug development costs, 439
sleep–pain relationship Clinical global impression scales, 447
improved, 146–147 Clinical trial protocol, 444
longitudinal, 141 Clinical trials for medication. See Insomnia
reciprocal, 140t treatment, clinical trials for
Chronotherapy, 189 Clinician global impressions, 381
Circadian contributions, 120 Clinician-administered scales, 90
Circadian rhythm, 116, 225–227 Clock genes, 184
Circadian rhythm sleep disorders, 133t, Clonazepam, 404
135–136 Clonidine, 245
advanced sleep phase disorder, 181 Cocaine, 167t, 171–172
combination treatment, 190 Code of Federal Regulations, 438
pharmacologic symptom control, 190 Cognitive arousal, 44, 47, 118–119
prescribed sleep schedule, 190 Cognitive behavioral therapy, 33, 120, 122, 123, 133,
timed light exposure, 190 175, 216
timed melatonin administration, 190 chronic insomnia, 455
circadian misalignment, 181–183 combination therapy, 347–348
diagnostic assessment, 183–184 for comorbid insomnia
diagnostic criteria, 181 characteristics, 352–353
delayed sleep phase syndrome, 181, 187 outcomes and meta-analyses, 355–356
combination treatment, 189 randomized clinical trials, 354t
pharmacologic symptom control, 189 insomnia treatment, 257, 305–306
prescribed sleep schedule, 189 intervention (SCT), 271
timed light exposure, 188 for elder patients, 230–231
timed melatonin administration, 188–189 for late-life insomnia
epidemiology, 181 characteristics, 356–357
free-running disorder – blind, 195 meta-analyses, 361
free-running disorder–sighted, 181 outcome studies, 357–360
combination treatment, 195 randomized clinical trials, 358t–359t
prescribed sleep scheduling, 195 multicomponent, 329, 330, 353
timed light exposure, 194 for pain, 145–146
timed melatonin administration, 194 in sleep-related breathing disorder
irregular sleep–wake disorder, 181 sleep compression, 230
pharmacologic symptom control, 196 sleep hygiene, 230
prescribed sleep scheduling, 195–196 sleep restriction, 230
timed light exposure, 195 stimulus control, 230
timed melatonin administration, 195 in stimulus control, 271, 272
jet lag disorder, 181 Cognitive control, 301–302, 302t
combination treatment, 194 Cognitive impairment, 388–389
melatonin administration, 193–194 Cognitive model, 45–46
pharmacologic symptom control, 194 Cognitive processes (and thought content),
prescribed sleep scheduling, 194 147
timed light exposure, 193 Cognitive restructuring, 300–301, 300t
ind IHBK059-Sateia March 28, 2010 14:3 Char Count=

468 Index

Cognitive therapy, 299 Depression, insomnia and

acceptance-based therapies, 304 longitudinal studies, 32–34
articulatory suppression, 302–303, 303t prevalence estimates, 32, 32t
cognitive attentional mechanisms, 299, 300t scale, 11
cognitive behavioral therapy, 305–306 treatment, 11
cognitive control, 301–302, 302t Depressive disorder, 127t, 128–129
cognitive restructuring, 300–301, 300t Descriminant validity, 109
cognitive therapeutic approaches, 299 Desyrel, 399
imagery training, 303 Diabetes mellitus, 154
mindfulness, 304 Diabetic peripheral neuropathy, 144, 154
paradoxical intention, 304–305, 305t Diagnostic and statistical manual of mental
sleep education, 300 disorders, 2, 106, 144
Cognitive-attentional processes, 299, 300t classification systems, 100
Combination treatment, 189, 190, 193, 194, 195 diagnostic classifications for sleep disorders,
Community recruited volunteers, 328 101t, 103t
Comorbid insomnia, 23, 27, 86, 86t, 379 reliability, 107t, 108
breathing disorder, 215 Diagnostic classification of sleep and arousal
severity of, 382 disorders, 100, 101t, 102, 103t
sleep in, 27 disorders of excessive sleepiness, 102
symptoms of, 86 disorders of initiation and maintenance of sleep,
See also Chronic pain, insomnia in; Cognitive 102
behavioral therapy; Psychiatric disorders, disorders of sleep/wake schedule, 102
insomnia in parasomnias, 102
Complementary and alternative medicine, 417, 420 Diathesis-stress theory, 42, 118
Complicated grief disorder, 34 Digit span, 13
Computational ability, 14 Digit symbol substitution test, 13, 441, 446
Computer-adapted testing, 95 Digital period analysis, 54
Construct validity, 109 DIMS. See Disorder of initiation and maintenance
Context, role of, 47–48 of sleep
Continuous positive airway pressure, 213, 228 Diphenhydramine, 418, 419
Convergent validity, 107t Diphenhydramine hydrochloride, 245
COPD. See Chronic obstructive pulmonary disease Direct costs of insomnia, 24
Coping, 140t, 148 Disorder of initiation and maintenance of sleep, 52,
Cortical arousal, 44, 79, 119–120, 141 102
Cortisol secretion, 69f, 70f Disorders of excessive sleepiness, 102
Cosinor analysis, 68, 71 Divalproex, 405
Costs of insomnia. See under Socioeconomic impact DLPFC. See Dorsolateral prefrontal cortex
CPAP. See Continuous positive airway pressure DOES. See Disorders of excessive sleepiness
CRSD. See Circadian rhythm sleep disorders Dorsolateral prefrontal cortex, 80
Cyclic alternating pattern, 55–56, 57t Doxepin, 401, 431, 432
Cyclical psychodynamics, 278 DPA. See Digital period analysis
Cytokines, 263 DPN. See Diabetic peripheral neuropathy
proinflammatory, 71–72 Drug effects on OSA
sleep-related, 36 alcohol, 217, 219
hypnotics, 219
Daytime functioning, 85, 286, 287f, 381 narcotics, 219
Daytime napping, 43 sedatives, 217
Daytime sedation, 382–383 Drug for pediatric insomnia, 239t
Daytime sleep testing, 72 Drug-free baseline performance, 438
Daytime symptoms (insomnia), 85, 117t Dry mouth, 401
DBAS. See Dysfunctional attitudes and beliefs DSM. See Diagnostic and statistical manual of
about sleep mental disorders
DCSAD. See Diagnostic classification of sleep and DSPD. See Delayed sleep phase disorder
arousal disorders DSPS. See Delayed sleep phase syndrome
Delayed melatonin rhythm, 114 DSST. See Digit symbol substitution test
Delayed sleep phase, 114, 135 Duloxetine, 144
Delayed sleep phase disorder. See under Circadian Dysfunctional attitudes and beliefs about sleep,
rhythm sleep disorders 92
Delayed sleep phase syndrome, 237, Dysphoria, 10, 12
419 Dyssomnias, 102, 106
Dementia, 228, 412 Dysthymic disorder, 128
ind IHBK059-Sateia March 28, 2010 14:3 Char Count=

Index 469

Eating disorder, sleep-related, 391 FSS. See Fatigue severity scale

Ecological validity, 109 Functional magnetic resonance imaging, 81
Ecstacy, 166t, 171 Functional neuroimaging, 80
EEG. See Electroencephalography
Electroacupuncture, 293 GABA. See Gamma-aminobutyric acid
Electroencephalography, 122 GABAA receptor complex. See
Electroencephalography sleep, 51–54 Gamma-aminobutyric acid receptor
Electromyogram, 57t complex
EMG. See Electromyogram Gabapentin, 174, 203, 206, 404–405
Emotional arousal, 118–119 Gaboxadol, 370
Eosinophilia–myalgia syndrome, 420 GAD. See Generalized anxiety disorder
Epinephrine, 70 Gamma-aminobutyric acid, 250, 260, 427–428
Episodic pain disorder, 143 Gamma-aminobutyric acid receptor complex
Eplivanserin, 430 benzodiazepine, classical
Epworth sleepiness scale, 10 for sleep medicines, 368
ERP. See Event-related potentials hypnotics, 368–369
Escitalopram oxalate, 447 transgenic studies, 369
Esmirtazapine, 432 cloning, 366, 367
Espie’s psychobiological inhibition model, 45 extrasynaptic GABAA receptors, 366
ESS. See Epworth sleepiness scale GABA-agonist site, 370–371
Eszopiclone, 78, 381, 383 heterogeneity, 365–366
depression, 34 nonbenzodiazepine hypnotics, 369–370
mood, 11 pharmacological profiles, 367–368
quality of life, 12, 27 postsynaptic GABAA receptors, 366
Event-related potentials sleep medicines, 368, 370–371
early NREM sleep, 57 subtypes, 366
at sleep onset, 57 GDS. See Geriatric depression scale
during wakefulness, 56–57 Generalized anxiety disorder, 35, 127t, 130
waveforms, 58t Geriatric depression scale, 129
Evotec AG, 428 Global amnesia, 391
Excessive sleepiness Good sleepers, 51, 52f, 56, 58t
circadian misalignment, 187 Graphic sleep diary, 94t
jet lag disorder, 194 Group treatment approaches
shift work disorder, 192 elements, 326
Exercise group interaction factors, 327–328
and physical activity, 292–293 group psychotherapy, 326t
on sleep, 262–263 group satisfaction, 327t
Exogenous melatonin, 411–412 insomnia symptoms
Experimental sleep disruption, 140–141 community recruited volunteers, 328
Extrasynaptic GABAA receptors, 366 physician/clinically referred patients,
328–329
Face validity, 109 special populations, 329–330
Fatal familial insomnia, 159 integration of findings, 330
Fatigue measurement principles, 327t
fatigue severity scale, 11 research, 331t–337t
profile of mood states, 11
tiredness symptoms scale, 11 HAM-A. See Hamilton anxiety scale
Fatigue severity scale, 11 HAM-D. See Hamilton depression rating scale
FDA. See Food and drug administration (US) Hamilton anxiety scale, 382
FFI. See Fatal familial insomnia Hamilton depression rating scale, 11, 382, 447
Fibromyalgia, 199 Hamilton rating scale for depression, 31, 95, 404
5-HT2A antagonists, 430–431 Hand/eye coordination, 4, 14
Flumazenil, 368 Hangover effect, 261
Fluoro-2-deoxy-D-glucose (FDG), 78 Harvey’s cognitive model, 45–46
Flurazepam, 382 HD-16. See Hotel Dieu-16
fMRI. See Functional magnetic resonance imaging Headache disorders, 143
Food and drug administration (US), 436 Health care use, 23
Food, Drug, and Cosmetic Act (1938), 436, 437 Healthy sleep practices
FRD. See Free-running disorder alcohol consumption
Free-running disorder. See under Circadian rhythm breathing complication, 261
sleep disorders gamma-aminobutyric acid, 260
ind IHBK059-Sateia March 28, 2010 14:3 Char Count=

470 Index

Healthy sleep practices (Continued) Hypothalamus, 77–78

hangover effect, 261 Hypoxemia, sleep-related, 153
sleep-promoting substance, 260
caffeine, 261–262 IASP. See International Association for Study of
for excessive sleepiness, 261 Pain
mild CNS stimulant, 261 ICSD. See International classification of sleep
sleep initiation, 262 disorders
substance abuse, 262 Idiopathic insomnia, 104t, 114, 238t
exercise, 262–263 Idiopathic pain disorders, 142–143
scheduling, 263–264 IDS-SR. See Inventory of depressive
Heart rate variability, 66 symptomatology self-report
Hippocampus, 79 Imagery training, 303
History-taking process in insomnia Immune function, 36–37
comorbid disorders, 86, 86t Immune system changes, 71–72
daytime behaviors, 85 Immunomodulating medications, 160
daytime symptoms, 85 Inadequate sleep hygiene
family history, 87 clinical assessment, 115
habits, 85, 86 pediatric, 239t
medications, 87 IND. See Investigational new drug
occupational history, 87 Indiplon, 12
past history Indirect costs of insomnia, 25
medical, 87 Infants, sleep habits of, 235
psychiatric, 87 Inflammatory conditions, 142
surgical, 87 Insomnia
primary complaint complaints, 213–214, 214t
circumstances, 84 definition, 2–3
nature of symptoms, 84 standardized criteria, 3t
onset and duration, 84 nonrestorative sleep, 3–4
temporal pattern, 84 diagnosis. See Insomnia classification
prior medical documents, 87 duration and course, 7
sleep patterns, 85 in elderly. See Older adults, insomnia in
sleep-related behaviors, 85–86 epidemiologic study, 5–7
social history, 87 pharamacotherapy, 257
substances, 87 sample selection, 4t
Homeostatic processes, 225 socioeconomic impact. See Socioeconomic
Hormonal replacement therapy, 73 impact of insomnia
Hotel Dieu-16 scale, 27–28 symptoms and diagnoses, 6t
HPA. See Hypothalamic–pituitary–adrenal axis Insomnia as risk factor
HRSD. See Hamilton rating scale for depression in medical illness
HRT. See Hormonal replacement therapy cardiovascular disease, 36
Human immunodeficiency virus, 155 chronic pain, insomnia and, 36
Human sleep neuroimaging. See Brain imaging hypertension, 36
Hybrid cognitive-behavioral model immune function, insomnia and,
Lundh and Broman, 44 36–37
Morin’s, 43–44 in psychiatric illness
11-Hydroxycorticosteroid excretion, 68 anxiety disorders, insomnia and,
17-Hydroxysteroid excretion, 68 35
Hydroxyzine, 245 bipolar disorders, 34
Hyperarousal, 56, 58t complicated grief disorder, 34
model, 65 depression, insomnia and, 31–32
in primary insomnia, 50 generalized anxiety disorder, 35
in wakefulness, 57 substance abuse disorders, 35–36
Hypericum perforatum, 421 suicide and suicidality, 34
Hypersomnias, 102 Insomnia evaluation studies
Hypertension, 36 measurement of insomnia
Hypnotic medications, 192 clinical research, 90
Hypnotic-dependent insomnia, 357 epidemiological studies, 90
Hypnotics, 174, 219, 455–456 needs and constraints, 89
Hypocretin system, 428 measures of insomnia
Hypopneas, 210, 211f actigraphy, 93
Hypothalamic–pituitary–adrenal axis, 68–70 clinician-administered scales, 90
ind IHBK059-Sateia March 28, 2010 14:3 Char Count=

Index 471

medical history reviews, 93 preclinical studies, 438

physical examination, 93 study design
psychiatric health evaluation, 95 multicenter trials, 445
self-report questionnaires, 90–93 outcome variables, 445–446
sleep diaries, 93, 94t specialty populations, 446–447
methodological issues, 95 subject selection, 443–445
Insomnia classification, 101t, 103t, 104t Insomnia treatment, overview of
classification systems behavioral treatments
DSM, 100, 101t, 103t, 106, 107t dose, 257
duration-based, 99–100 elements, 257
ICSD, 100, 101t, 103t, 104t–105t, 107t general treatment
multiple systems, 99 combination treatment, 257–258
nonrestorative sleep, 100 sequenced treatment, 257–258
sleep maintenance insomnia, 100 specific patients, 257
sleep onset insomnia, 100 measurement of insomnia
definitions self-report outcomes, 256
categorical model, 98 waking symptoms measurement, 257
diagnosis, 98 optimal management of patients, 258f
illness or disorder, 98 pharmacology
signs, 98 delivery system, 257
symptoms, 98 optimal duration, 257
key attributes, 99 targets, 257
reliability, 107–109 Insomniacs, 20, 21, 23
validity Integrated voice response system, 445
construct validity, 109 Intensive sleep retraining, 272, 273
descriminant validity, 109 Interleukin-6, 71, 72f
ecological validity, 109 Intermittent dosing, 379–380
face validity, 109 International Association for Study of Pain, 139
predictive validity, 109 International classification of sleep disorders, 2, 19
See also Diagnostic classification of sleep and classification systems, 100
arousal disorders diagnostic classifications for sleep disorders,
Insomnia severity index, 12, 90–91 101t, 103t
Insomnia treatment general insomnia criteria, 105t
brain imaging, 78 idiopathic insomnia, 114
in cancer, 156 inadequate sleep hygiene, 115
chronic kidney disease, 155 paradoxical insomnia, 114
chronic obstructive pulmonary disease, psychophysiological insomnia, 113
153 reliability, 107t, 108
chronic pain, 144–147 second edition classification (pediatric)
classical benzodiazepine hypnotics, adjustment insomnia, 238t
368–369 behavioral insomnia of childhood, 237, 239t
cyclic alternating pattern, 55–56 idiopathic insomnia, 238t
Diathesis-Stress model, 118 inadequate sleep hygiene, 239t
medications, history of, 87 insomnia by drug or substance, 239t
mood, 11 insomnia by mental disorder, 239t
quality of life, 12, 27 paradoxical insomnia, 238t
socioeconomic factors, 20–21 psychophysiologic insomnia, 238t
substance-induced insomnia, 173–175 second edition insomnia disorders, 104t–105t
Insomnia treatment, clinical trials for Internet-based brief approach, 324
clinical development phases, 438 Interrater reliability, 107t, 108
phase I trials, 439 Intoxication
phase II trials, 439 alcohol, 165–168, 166t
phase III trials, 440 amphetamines, 167t, 172
phase IV trials, 440 caffeine, 166t, 169–170
history of trials, 436–438 cocaine, 167t, 171–172
in hypnotics development ecstacy, 166t, 171
experimental models, 441–442 marijuana, 166t, 170
outpatient studies, 442–443 nicotine, 166t, 169
patient studies, 442 opioids, 166t, 170–171
pharmacokinetics, 440–441 Inventory of depressive symptomatology
polysomnographic studies, 442–443 self-report, 128, 129
ind IHBK059-Sateia March 28, 2010 14:3 Char Count=

472 Index

Investigational new drug (IND), 438 prescription, 20

Iron deficiency, 202 self, 392–393
Irregular sleep–wake disorder. See under Circadian tricyclic, 431
rhythm sleep disorders Melatonin, 174, 187, 226, 250
ISI. See Insomnia severity index agonists, 431
ISWD. See Irregular sleep–wake disorder as dietary supplement, 419–420
IVRS. See Integrated voice response system receptor agonists, 412–413
in sleep regulation
Jet lag disorder, 181 exogenous melatonin, 411–412
combination treatment, 194 melatonin receptor agonists, 412–413
melatonin administration, 193–194 sleep–wake regulation, role in, 410–411, 411t
pharmacologic symptom control, 194 Memory, 13–14
prescribed sleep scheduling, 194 Menopause, 72–73
timed light exposure, 193 Mental disorder, 239t
Jiggling of legs, 200 Mentalis electromyogram, 57t
JLD. See Jet lag disorder Metabolic function. See under Neurobiological
Job performance of insomnia patients, 13 disturbances
Methyl ␤-carboline-3-carboxylate (␤CCM), 368
Kava kava, 421 Middle-of-the-night awakening, 428
Mindfulness-based stress reduction, 273
Late-life insomnia. See under Cognitive behavioral Mindfulness-based therapy, 304
therapy Mineral supplements, 422
Lavender (aromatherapy), 294 Minnesota multiphasic personality inventory, 11,
Leg discomfort, 154 47
Levodopa, 202 Mirror tracing task, 79
Light therapy, 231 Mirtazapine, 393, 402
Light, role of, 226 Mismatch negativity waveform, 56
Limbic system, 78–79 MMN. See Mismatch negativity
Limit-setting sleep disorder, 105 MMPI. See Minnesota multiphasic personality
Logical reasoning, 14 inventory
Lorazepam, 403–404 Modafanil, 187
L -tryptophan, 420 Monopolar EEG derivation, 57t
Mood components
Magnetic resonance imaging, 79, 80 Epworth sleepiness scale, 10
Maintenance of wakefulness test, 14, 15, 192 fatigue, 10
Major depressive disorder, 31 insomnia treatment, 11
Marijuana, 166t, 170 sleepiness, 10
Massage, 294 tiredness symptoms scale, 11
MBSR. See Mindfulness-based stress reduction Mood disorders questionnaire, 129
MDD. See Major depressive disorder Morin’s hybrid cognitive-behavioral model, 43–44
MDMA (3, 4-methylenedioxymethamphetamine), MOTN. See Middle-of-the-night awakening
171 Motor vehicle accidents, 22–23
MDQ. See Mood disorders questionnaire Movement disorders
Mean preintervention sleep latency, 201 periodic limb movement disorder
Medial prefrontal cortex, 47 arousal phenomena, 204
Medical disorders, insomnia-related and insomnia, 203–204
chronic kidney disease, 154–155 leg cramps, 205–206
chronic obstructive pulmonary disease, rhythmic movement disorder, 205
153–154 of sleep, 203
diabetes mellitus, 154 sleep-related bruxism, 204
HIV infection, 155–156 restless legs syndrome
malignancy, 156 definition, 199
Medical outcomes study short form, diagnosis, 199–200
12 epidemiology, 200
Medications insomnia, 200–201
for childhood insomnia. See under Pediatric management, 202–203
insomnia pathogenesis, 200
history of, 87 sleep-related, 133t, 135
hypnotic, 192 Moxibustion, 293
immunomodulating, 160 MPFC. See Medial prefrontal cortex
nonprescription, 20 MS. See Multiple sclerosis
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MSA. See Multisystem atrophy Neuroticism scale, 47

MSLT. See Multiple sleep latency test Nicotine, 166t, 169
Mugwort herb, 293 Nocturnal leg cramps, 199
Multicenter trials, 445 Nocturnal symptom phenotypes, 120–121
Multicomponent cognitive behavior therapy, 329, Nonbenzodiazepine hypnotics, 369–370
330, 353 Nonhypnotic medications
Multimodal cognitive behavior therapy amitriptyline, 393
CBT components, 343 mirtazapine, 393
CBT/hypnotic combination therapy, 347–348 olanzapine, 393
first generation treatment, 343t quetiapine, 393
history, 342 trazodone, 393
modes of delivery, 346–347 Nonpharmacological treatmemnt, 121, 122
rationale, 342 acupuncture, 293
usefulness of CBT, 345–346 aromatherapy
Multiple sclerosis, 160 lavender, 294
Multiple sleep latency test, 11, 14, 72, 118, 388 sandalwood, 294
Multisystem atrophy, 159 bright light therapy, 292
Multivariate logistic regression analyses, 21 case studies
MVA. See Motor vehicle accidents eyes and nose, 295
MWT. See Maintenance of wakefulness test forehead, 295
left bicep, 296
Napping relaxation procedure, 295
daytime, 43 right bicep, 296
prescribed, 192 right calf, 296
prophylactic, 192 right hand and forearm, 296
recuperative, 192 right upper leg, 296
Narcotics, 219 shoulders and middle back, 295
National Sleep Foundation (US), 19 exercise and physical activity, 292–293
Nationwide insomnia screening and awareness massage, 294
study (Germany), 21 paradoxical intention, 292
Neocortex, 80 relaxation techniques
Neurobiology of insomnia biofeedback, 291
autonomic changes, 65–66 progressive muscle relaxation, 290–291
heart rate variability, 66 yoga, 291
hormonal changes, 72–73 Nonprescription medication, 20
hyperarousal model, 65 Nonprescription pharmacotherapy(ies)
immune system changes alcohol, 418, 423t
interleukin-6, 71, 72f alternative medicine, 417, 420
tumor necrosis factor ␣, 71–72, 72f antihistamines, 418–419, 423t
metabolic function complementary medicine, 417, 420
brain metabolic activity, 67 dietary supplements, 420
whole body metabolic rate, 66–67 kava kava, 421, 423t
neuroendocrine changes mineral supplements, 422
catecholamines, 70–71 St. John’s wort, 421–422, 423t
hypothalamic–pituitary–adrenal axis, 68–70 valerian, 421, 423t
in postmenopausal women, 72–73 vitamin, 422
Neuroendocrine changes. See under Neurobiology L -tryptophan, 420, 423t
of insomnia melatonin, 419–420, 423t
Neurofeedback, 291 Nonrapid eye movement sleep, 44, 67
Neuroimaging cyclic alternating pattern, 55–56
functional, 80 event-related potentials, 57–58
techniques, 67 human sleep neuroimaging, 77
Neurological disorders, insomnia-related quantitative EEG, 54
cerebrovascular disease, 159 thalamus and neocortex, 80–81
fatal familial insomnia, 159 Nonrestorative sleep, 3–4, 117, 121
multiple sclerosis, 160 Norepinephrine, 71
neurodegenerative diseases, 156 Normal sleep. See under Pediatric insomnia
synucleinopathies, 158–159 Nortriptyline, 401
tauopathies, 157–158 NREM sleep. See Nonrapid eye movement
traumatic brain injury, 160 sleep
Neuropathic pain syndromes, 143–144 NRS. See Nonrestorative sleep
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Number of awakenings, 50n, 332t, 335t OSA. See Obstructive sleep apnea
NWAK. See Number of awakenings Outcome variables, 445–446
Overall oxygen consumption, 66, 67f
Objective daytime consequences
balance, 14 Pain administration, 141
hand/eye coordination, 14 Pain, chronic, 36
logical reasoning, 14 Paired t-tests, 79
math, 14 Panic disorder, 130–131
memory, 13–14 Paradoxical insomnia, 66, 110, 114
sleepiness/alertness, 14 ICSD-2 insomnia disorders, 104t
vigilance, 14 pediatric, 238t
Obstructive sleep apnea, 93 sleep restriction therapy, 286
pediatric insomnia, 237 Paradoxical intention, 292, 304–305, 305t
psychiatric disorders, 133t, 135 Paralimbic system, 78–79
sleep-related breathing disorder, 210, 211 Parasomnias, 102, 106
symptoms, 86t Parkinson’s disease, 158
Off-label prescribing in insomnia Passive-paradoxical techniques, 299
anticonvulsants Patient global impressions, 381
gabapentin, 404–405 Patient history in pediatric insomnia, 241t
pregabalin, 405 Patient medication guides, 438
tiagabine, 405 Pediatric insomnia, 379
valproic acid, 405 classification, 237, 238t–240t
antidepressants definition, 235
amitriptyline, 400–401 differential diagnosis
doxepin, 401 delayed sleep phase syndrome, 237
mirtazapine, 402 disorders of arousal, 240
nortriptyline, 401 obstructive sleep apnea, 237
trazodone, 399–400 periodic limb movement disorders, 237
antipsychotics restless leg syndrome, 237
alprazolam, 404 disorders of arousal, 240
anxiolytics, 403 epidemiology
clonazepam, 404 family history, 236
lorazepam, 403–404 neurological and psychiatric disorders, 236
olanzapine, 402–403 evaluation, 240, 241t
quetiapine, 402 management, 240,
drug occurrences, 398t, 399t behavioral insomnia of childhood, 242–
patient-report evaluation, 398 244, 243t
pharmacological treatment, 400t pharmacologic interventions, 245–251
placebo comparison, 397 sleep hygiene for children, 242t
testing in insomnia patients, 398 medications
Olanzapine, 402–403 alpha2-adrenergic receptor agonists, 246
Older adults, insomnia in, 378, 378t antidepressants, 251
age-related sleep/wake pattern antihistamines, 245
circadian rhythms, 225–227 benzodiazepines, 250
homeostatic processes, 225 BzRA hypnotics, 250
sleep architecture, 224–225 melatonin, 250
cognitive behavioral therapy, 357f, 361 normal sleep, development of
correlates of insomnia adolescents (13–18 years), 236
dementia, 228 infants and toddlers (0–2 years), 235–236
medical factors, 227 school-aged children (7–12 years), 236
medications and substances, 229 young children (3–6 years), 236
psychiatric disorders, 227 pharmacotherapy, 246t–249t
sleep disorders, 228–229 Penn state worry questionnaire, 130
treatment Periodic limb movement disorder,.
cognitive-behavioral treatment, 230–231 pediatric insomnia, 237
light therapy, 231 psychiatric disorder, 134
pharmacologic, 229–230 See also under Movement disorders
Opioids, 166t, 170–171 Periodic limb movements, 135
Opponent process model, 182, 182f, 183f Periodic limb movements in sleep, 228
Orexin antagonists, 428–429 Personality, 46–47
Organic sleep disorders, 106 PET. See Positron emission tomography
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PGI. See Patient global impressions sleep diaries, 93

Pharmaceutical research and development, 438, sleep-related breathing disorder, 212
439f POMS. See Profile of mood states
Pharmacokinetics, 439, 440, 441 Poor sleepers, 56, 65–66, 85
Pharmacologic symptom control, 189, 190, 192, 194, Positron emission tomography, 77
196 Postsynaptic GABAA receptors, 366
Pharmacologic treatments Posttraumatic stress disorder, 35, 131, 324
for pain, 144–145 Power spectral analysis, 54
for sleep disturbance, 144 Practice models
Pharmacology acute insomnia in primary care, 435–454
alprazolam, 404 chronic insomnia. See Chronic insomnia, health
amitriptyline, 400 practices for
anxiolytics, 403 sleep medicine, role of, 458–459
clonazepam, 404 PRC. See Phase response curve
doxepin, 401 Predictive validity, 109
mirtazapine, 402 Prefrontal cortex function, 80, 81
nortriptyline, 401 Pregabalin, 405
olanzapine, 402 Prescribed napping, 192
quetiapine, 402 Prescribed sleep schedule, 187, 189, 190, 192, 194,
trazodone, 399–400 195, 195–196
Pharmacotherapy, 79, 122 Prescribed time-in-bed, 344
Phase response curve, 184, 186f Prescription medication, 20
Phase shifting Primary care physicians, 455
with appropriately timed light exposure, 184–185 Primary complaint of insomniacs. See under
with timed melatonin administration, 185–187 History-taking process in insomnia
Phase-advance models, 442 Primary insomnia, 11, 12, 378. See also
Phototherapy, 158 Electroencephalographic study of sleep
Pimavanserin, 430 Primary insomnia, clinical assessment of
Pineal melatonin, 411, 411t case conceptualization
Pipeline drugs circadian contributions, 120
agomelatine, 432 cognitive and emotional arousal, 118–119
esmirtazapine, 432 cortical arousal and autonomic activation,
5-HT2A antagonists 119–120
eplivanserin, 430 current and past treatments, 121–122
pimavanserin, 430 diathesis-stress model, 118
pruvanserin, 430 nocturnal symptom phenotypes, 120–121
ritanserin, 430 definition, 113
volinanserin, 430 diagnostic assessment
GABA agonistic modulators, 427–428 daytime symptoms, 117, 117t
melatonin agonists, 431 diagnosis, 115–116, 116f
orexin antagonists, 428–429 nocturnal symptoms, 116, 117t
tricyclic medications, 431 sleep-related behaviors, 116
Piper methysticum, 421 management, 122–123
PIRS-20. See Pittsburgh insomnia rating scale, polysomnographic findings, 122
20-item version subtypes
Pittsburgh insomnia rating scale, 20-item version, idiopathic insomnia, 114
91 inadequate sleep hygiene, 115
Pittsburgh sleep diary, 94t paradoxical insomnia, 114
Pittsburgh sleep quality index, 27, 37, 78, 92, 293 psychophysiological insomnia, 113
PLM. See Periodic limb movements Primary sleep disorder, 106, 228. See also under
PLMD. See Periodic limb movement disorder Psychiatric disorders, insomnia in
PLMS. See Periodic limb movements in sleep Profile of mood states, 11, 47
PMR. See Progressive muscle relaxation Progressive muscle relaxation, 290–291
Polysomnography Progressive supranuclear palsy, 158
catecholamines, 71 Proinflammatory cytokines, 71–72
history taking in insomnia, 87 Prophylactic napping, 192
hypothalamic–pituitary–adrenal axis, 68 Protective-preventative techniques, 299
Parkinson’s disease, 158 Pruvanserin, 430
periodic limb movement disorder, 199 PSA. See power spectral analysis
primary insomnia, clinical assessment of, 122 PSG. See Polysomnography
sleep, 51 PSP. See Progressive supranuclear palsy
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PSQI. See Pittsburg sleep quality index gamma frequency range, 54

PSWQ. See Penn state worry questionnaire power spectral analysis, 54
Psychiatric disorders, 140, 147, 227 Quetiapine, 174, 393, 402
assessment, 126 Quinine, 206
bipolar disorders, 129–130
depressive disorder, 128–129 Ramelteon, 412–413
generalized anxiety disorder, 130 Randomized clinical trials, 353, 356
panic disorder, 130–131 for comorbid insomnia, 354t
posttraumatic stress disorder, 131 for late-life insomnia, 358t
schizophrenia, 131–132 Rapid eye movement
behavioral factors, 132–133, 133t latency, 51
primary sleep disorder human sleep neuroimaging, 78
circadian rhythm disorders, 133t, 135–136 sleep EEG, 52, 53t
obstructive sleep apnea, 133t, 135 onset latency, 165
sleep-related movement disorders, 133t, 135 sleep
psychotropic medications, 133 antidepressants, 134
antidepressants, 133t, 134 chronic obstructive pulmonary disease, 153
antipsychotics, 133t, 134 depressive disorder, 128
stimulants, 133t, 134 schizophrenia, 131
Psychiatric illness. See under Insomnia as risk factor stimulants, 134
Psychobiological inhibition model, 45
Psychological models RCT. See Randomized clinical trials
affect, 46–47 RDC-I. See Research diagnostic criteria for insomnia
contextual factors, 47–48 Real sleep deficit, 46
environmental factors, 47–48 Rebound insomnia, 389, 390, 394
Espie’s psychobiological inhibition model, 45 Recuperative napping, 192
Harvey’s cognitive model, 45–46 Relaxation techniques
hybrid cognitive-behavioral model biofeedback, 291
Lundh and Broman, 44 multimodal CBT, 345
Morin’s, 43–44 progressive muscle relaxation, 290–291
neurocognitive model, 44 Relaxation training, 343t
personality, 46–47 REM. See Rapid eye movement
stimulus control model, 42–43 Research
three-P model, 42, 43t on brief treatment, 312t–323t
Psychomotor impairment, 387–388, 394 on group treatment, 331t–337t
Psychomotor performance. See Objective daytime Research diagnostic criteria for insomnia, 106
consequences Restless leg syndrome, 134
Psychophysiological insomnia, 104t, 113, 238t chronic kidney disease, 154
Psychotropic medications. See under Psychiatric pediatric insomnia, 237
disorders, insomnia in See also under Movement disorders
PTIB. See Prescribed time-in-bed Rhythmic masticatory muscle activity, 204
PTSD. See Posttraumatic stress disorder Rhythmic movement disorder, 205
Public health, insomnia and. See Socioeconomic Ritanserin, 430
impact of insomnia RLS. See Restless legs syndrome
Pulsatile analysis, 68 RMD. See Rhythmic movement disorder
RMMA. See Rhythmic masticatory muscle activity
QEEG. See Quantitative electroencephalography ROL. See Rapid eye movement onset latency
QOL. See Quality of life
Quality of life Sandalwood (aromatherapy), 294
congestive heart failure, 12 SCG. See Superior cervical ganglia
impact of insomnia, 26–27 Scheduling, sleep, 263–264, 270
in insomnia scale, 12 Schizophrenia, 131–132
insomnia severity index, 12 School-aged children, sleep pattern of, 236
job performance, 13 SCN. See Suprachiasmatic nucleus
medical outcomes study short form (SF-36), 12 Screening measures
scale Hotel Dieu-16 (HD-16), 27–28 bipolar disorders, 127t, 129–130
sleep in comorbid insomnia, 27 depressive disorders, 127t, 128–129
in treatment of insomnia, 27 generalized anxiety disorder, 127t, 130
Quantitative electroencephalography, 59 panic disorder, 127t, 131
beta frequency activity, 54, 55f posttraumatic stress disorder, 127t, 131
digital period analysis, 54 schizophrenia, 127t, 132
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SCT. See Stimulus control therapy education, 300

Secondary insomnia, 51 efficacy
Secondary sleep disorders, 102, 106 amitriptyline, 401
Sedation, daytime, 382–383 doxepin, 401
Sedative hypnotics, 77, 78, 229, 230, 368 lorazepam, 403–404
Sedatives, 217 mirtazapine, 402
Selective serotonin reuptake inhibitors, 134, 251 nortriptyline, 401
Self-medication, 392–393 olanzapine, 403
Self-report outcomes, 256 quetiapine, 402
Self-report questionnaires trazodone, 399–400
Athens insomnia scale, 91 efficiency, 68, 70
dysfunctional attitudes and beliefs about sleep, self-reported, 37
92 utilization, 286–287, 287f
insomnia severity index, 90–91 fragmentation, 228
Pittsburgh insomnia rating scale, 20-item history. See History-taking process in insomnia
version, 91 hygiene, 85, 104t, 230, 357
Pittsburgh sleep quality index, 92 inadequate, 115, 173
sleep hygiene awareness and practices scale, 92 for children, 242t
Spielman insomnia symptom questionnaire, 91 logs, 173
women’s health initiative insomnia rating scale, maintenance, 227, 376t, 378t
91 medicines, 368, 370–37, 458–459
Self-report screening measures, 128 normal. See under Pediatric insomnia
Self-reported sleep efficiency, 37 objective measures of. See Neurobiology of
Self-reported sleep quality, 37 insomnia
Serotonin-norepinephrine reuptake inhibitors, onset, 57, 58t
251 patterns, 85
SHE. See Sleep hygiene education patterns, basic. See Basic sleep patterns
Shift work disorder, 190 Pittsburgh, 94t
combination treatment, 193 quality, self-reported, 37
pharmacologic symptom control, 192 questionnaire, 311
prescribed sleep scheduling, 192 regulation (night shift worker), 183f
timed light exposure, 191 restriction, 42, 230, 343t
timed melatonin administration, 191–192 restriction therapy, 283t
Short-term memory, 13 cognitive behavior therapy, 281t
Short-term treatment approach cost/benefit model, 286–287, 287f
brief interventions development, 277, 279t–280t
alternate formats, using, 324 implementation, 285–286
dose-response effects, 324–325 method, 283f
4–5 sessions, 310–311 rationale, 282–285, 282f
integration of findings, 325 sleep efficiency utilization, 286–287, 287f
∼2 sessions, 311 three-P model, 284f
with PTSD patients and caregivers, 324 schedules, 263–264, 270
research on brief treatment, 312t–323t schedules, prescribed, 187, 189, 190, 192, 194,
SHPS. See Sleep hygiene practice scale 195, 195–196
SII. See Substance-induced insomnia testing, daytime, 72
SL. See Sleep latency Sleep hygiene awareness and practices scale, 92
Sleep Sleep hygiene education, 310–311, 319t, 343t,
ability, 225 345
aids, 20, 422 Sleep hygiene practice scale, 133
architecture, 50n, 52–53, 53t, 59, 166t–167t, Sleep latency, 14, 50n, 53
224–225 menopause, 73
compression, 230 in primary insomnia, 52f
continuity, 50n, 51, 59, 166t–167t Sleep onset latency, 165
deprivation, 225, 277, 391 Sleep state misperception, 66, 105, 114
diary, 93, 94t, 184, 285 Sleep-disruptive practices, 344
graphic, 94t Sleepiness, 14, 166t–167t
difficulties, 85, 147 Sleepiness measurement, 11, 14
disorders, 166t–167t, 228–229 Sleeping pills, 456
limit-setting, 105 Sleep-interfering processes, 44
secondary, 102, 106 Sleep-onset association disorder, 105
symptoms of, 86t Sleep-onset efficacy, 376t, 378t
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478 Index

Sleep-promoting substance, 260 SOL. See Sleep onset latency

Sleep-related behaviors, 85–86 Somatic arousal, 44
Sleep-related breathing disorder Somnambulism, 391
clinical recommendations, 220 Somnolence, 382
definition Spielberger state-trait anxiety inventory, 11, 47,
assessment, 212 95
causes, 21 Spielman insomnia symptom questionnaire,
clinical presentation, 21 91
epidemiology of, 211 Spielman model. See Three-P model
hypopnea, 211f SRBD. See Sleep-related breathing disorder
sequelae, 210–211 SRT. See Sleep restriction therapy
treatment, 212–213 SSRI. See Selective serotonin reuptake inhibitors
insomnia and SRBD, 215t St. John’s wort, 421–422
central sensitization, 215–216 Stanford sleepiness scale, 10, 11
comorbid insomnia, 215 Stimulants, 133t, 134
insomnia complaints, 213–214, 214t Stimulus control, 230, 343t, 357
older adults, 214–215 Stimulus control model, 42–43
treatment Stimulus control therapy
in chronic insomnia, 218t effectiveness, 270
drugs, application of. See Drug effects on OSA instructions, 268–270
in insomnia, 216–217 multicomponent treatments, 270–271
medication on respiration, 219t treatment
Sleep-related hypoxemia, 153 acceleration of improvement, 272–273
Sleep-related movement disorders, 133t, 135 mindfulness meditation, integrated, 273
Sleep–wake regulation, melatonin in. See reaching more patients, 271–272
Melatonin for insomnia treatment self-help treatments, 272
Slow wave sleep, 51, 53t Strokes, 159
Small fiber neuropathy, 200 Subjective daytime consequences
SNRI. See Serotonin-norepinephrine reuptake anxiety, 11
inhibitors depression, 11
Social function, 147–148 mood, 10–11
Socioeconomic impact of insomnia quality of life, 12
comorbidities work performance, 13
with depression and anxiety, 21 Subjective insomnia, 114
and health care use, 23–24 Subjective-objective discrepancies, 51, 52t
costs Sub-ob discrepancies, 52f
direct, 24–25 Substance abuse disorders, 35–36
evaluation, 25 Substance, sleep-promoting, 260
indirect, 25 Substance-induced insomnia
epidemiology epidemiology
international comparisons, 19 alcohol, 165–169, 168f
at national level, 19 amphetamines, 172
help seekers caffeine, 169–170
diagnosis, 21 cocaine, 171–172
insomniacs, 20 ecstacy, 171
multivariate logistic regression analyses, 21 marijuana, 170
nonprescription medication, 20 nicotine, 169
prescription medication, 20 opioids, 170–171
quality of life evaluation
Hotel Dieu-16 scale, 27–28 differential diagnoses, 173
impact of insomnia, 26–27 preliminary assessment, 172–173
sleep in comorbid insomnia, 27 nonpharmacological treatments, 175
treatment, 27 pharmacological treatments, 173
sociodemographics factors anticonvulsants, 174
among women, 20 antidepressants, 174
job stress, 20 antipsychotics, 174
socioeconomical status, 20 benzodiazepine receptor agonists, 174
at workplace benzodiazepines, 174
absenteeism, 21 hypnotics, 174
accidents, 22–23 substances of abuse, 166t–167t
efficiency, 22 Suicide and suicidality, 34
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Superior cervical ganglia, 410, 411t Urinary free cortisol, 68

Suprachiasmatic nucleus (SCN), 182f, 183f, 184, Uvulopalatopharyngoplasty, 213
225, 292, 410, 411t
SWD. See Shift work disorders Valerian, 421
SWS. See Slow wave sleep Valeriana officinalis, 421
Symptoms of insomnia, daytime, 85, 117t Valproic acid, 405
Syndromal insomnia measures, 380–381 Ventral emotional system, 79
Synucleinopathies, 158–159 Verapamil, 206
Vigilance, 14
Tasimelteon, 413, 431 Vitamin, 422
Tauopathies, 157–158 Volinanserin, 430
TBI. See Traumatic brain injury
Temazepam, 383 WA. See Work accidents
Temporomandibular joint disorder, 143 Wake after sleep onset, 50n, 52f, 431
Test-retest reliability, 107t Wake time after sleep onset, 67, 71, 71f
Tetrahydrocannabinol, 170 Waking ERPs, 57, 58
Thalamocortical activity, 80 Waking symptoms measurement, 257
Thalomid, 437 WASO. See Wake after sleep onset
THC. See Tetrahydrocannabinol White-collar workers, 20
Thermodynamic hypothesis, 292–293 Whole body metabolic rate, 66–67
Three-factor model. See Three-P model Wiley Act, 436
Three-P model Withdrawal effects
perpetuating factors, 42, 43t alcohol, 166t, 168
precipitating factors, 42, 43t amphetamines, 167t, 172
predisposing factors, 42, 43t caffeine, 166t, 170
Tiagabine, 405 cocaine, 167t, 172
TIB. See Time-in-bed ecstacy, 166t, 171
Time in bed, 277, 287 marijuana, 166t, 170
Timed light exposure, 184, 188, 190, 191, 193, 194, nicotine, 166t, 169
195 opioids, 166t, 170–171
Timed melatonin administration, 185, 188–189, 190, Women’s health initiative insomnia rating scale, 91
191–192, 193–194, 194, 195 Work accidents, 23
Tiredness symptoms scale, 11 Work limitations questionnaire, 13
TMD. See Temporomandibular joint disorder Workplace, insomniacs at, 13
TNF ␣. See Tumor necrosis factor ␣ absenteeism, 21
Toddlers, sleep habits of, 235 accidents, 22–23
Total costs of insomnia, 25 efficiency, 22
Total sleep time, 50n, 68, 70f, 122 WTASO. See Wake time after sleep onset
Total wake time, 68
Traffic accidents on sleep, 85 Yoga for insomnia, 291
Transient insomnia model, 442 Young children, sleep pattern of, 236
Traumatic brain injury, 160
Trazodone, 174, 251, 393, 399–400, 431 Zaleplon, 369, 443
Triazolam, 56, 77, 382, 389 Z-drugs, 369
Tricyclic antidepressants, 251, 400 Zeitgebers, 225, 226, 263
Tricyclic medications, 431 Zolpidem, 369, 382, 383, 388, 428, 441, 442
TSS. See Tiredness symptoms scale Zolpidem
TST. See Total sleep time Alzheimer’s disease, 157
Tumor necrosis factor ␣, 71–72, BzRA therapy, 380
72f cyclic alternating pattern rate, 56
TWT. See Total wake time medication on respiration, 219t
mood, 11
UFC. See Urinary free cortisol somnambulism, 391
Untreated insomnia, 392 work performance, 13
UPPP. See Uvulopalatopharyngoplasty Zopiclone, 56, 389