S2 VOLUME 109 SUPPLEMENT 1 AUGUST 2014 nature publishing group

CMErelated editorial on page x

see

American College of Gastroenterology Monograph on

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the Management of Irritable Bowel Syndrome and

Chronic Idiopathic Constipation
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Alexander C. Ford, MB ChB, MD, FRCP1,10, Paul Moayyedi, BSc, MB ChB, PhD, MPH, FACG2,11, Brian E. Lacy, MD, PhD, FACG3,
Anthony J. Lembo, MD4, Yuri A. Saito, MD, MPH5, Lawrence R. Schiller, MD, FACG6, Edy E. Soffer, MD, FACG7, Brennan M.R. Spiegel,
MD, FACG8 and Eamonn M.M. Quigley, MD, FACG9, for the Task Force on the Management of Functional Bowel Disorders
Am J Gastroenterol 2014; 109:S2–S26; doi:10.1038/ajg.2014.187

Irritable bowel syndrome (IBS) and chronic idiopathic constipa- According to Rome III, IBS is defined on the basis of the pres-
tion ((CIC) also referred to as functional constipation) are two ence of:
of the most common functional gastrointestinal disorders world- Recurrent abdominal pain or discomfort at least 3 days/month
wide. IBS is a global problem, with anywhere from 5 to 15% of the in the past 3 months associated with two or more of the following:
general population experiencing symptoms that would satisfy a
definition of IBS (1,2). In a systematic review on the global preva- • Improvement with defecation
lence of IBS, Lovell and Ford (1) documented a pooled prevalence • Onset associated with a change in frequency of stool
of 11% with all regions of the world suffering from this disorder • Onset associated with a change in form (appearance) of stool
at similar rates. Given its prevalence, the frequency of symptoms,
and their associated debility for many patients and the fact that These criteria should be fulfilled for the past 3 months with
IBS typically occurs in younger adulthood, an important period symptom onset at least 6 months before diagnosis (6).
for furthering education, embarking on careers, and/or raising Rome III defines functional constipation as: the presence of
families, the socioeconomic impact of IBS is considerable. These two or more of the following:
indirect medical costs are frequently compounded by the direct
medical costs related to additional medical tests and the use of • Straining during at least 25% of defecations
various medical and nonmedical remedies that may have limited • Lumpy or hard stools in at least 25% of defecations
impact. CIC is equally common; in another systematic review, • Sensation of incomplete evacuation for at least 25% of defeca-
Suares and Ford (3) reported a pooled prevalence of 14%, and also tions
noted that constipation was more common in females, in older • Sensation of anorectal obstruction/blockage for at least 25%
subjects, and those of lower socioeconomic status (3). Chronic of defecations
constipation has also been linked to impaired quality of life (4), • Manual maneuvers to facilitate at least 25% of defecations
most notably among the elderly (5). (e.g., digital evacuation, support of the pelvic floor)
Neither IBS nor CIC are associated with abnormal radiologic • Fewer than three defecations per week
or endoscopic abnormalities, nor are they associated with a
reliable biomarker; diagnosis currently rests entirely, therefore, Furthermore, loose stools are rarely present without the use
on clinical grounds. Although a number of clinical definitions of laxatives and there are insufficient criteria for IBS. Again, these
of both IBS and CIC have been proposed, the criteria developed criteria should be fulfilled for the past 3 months with symptom
through the Rome process, currently in its third iteration, have onset at least 6 months before diagnosis (6).
been those most widely employed in clinical trials and, therefore, In Rome III, IBS is subtyped according to predominant bowel
most relevant to any review of the literature on the management habit as IBS with constipation (IBS-C), IBS with diarrhea (IBS-D),
of these disorders. mixed type (IBS-M), and unclassified (IBS-U). The definition of

1
Leeds Gastroenterology Institute, St James’s University Hospital, Leeds, UK; 2Farncombe Family Digestive Health Research Institute, Division of Gastroenterology,
McMaster University, Hamilton, Ontario, Canada; 3Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA; 4Harvard Medical School, Beth
Israel Deaconess Medical Center, Boston, Massachusetts, USA; 5Mayo Clinic, Rochester, Minnesota, USA; 6Baylor University Medical Center, Digestive Health
Associates of Texas, Dallas, Texas, USA; 7Division of Gastroenterology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA;
8
UCLA School of Medicine, UCLA/VA Center for Outcomes Research and Education (CORE), Los Angeles, California, USA; 9Division of Gastroenterology and
Hepatology, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas, USA; 10First author on the monograph, but is not a member of the
Task Force; 11Conducted systematic reviews with the support of A.C. Ford, and carried out the technical analyses of the data independent of the Task Force.
Correspondence: Eamonn M.M. Quigley, MD, FACG, Chief, Division of Gastroenterology & Hepatology, Houston Methodist Hospital and Weill Cornell Medical
College, Houston, Texas, USA. E-mail: [email protected]

The American Journal of GASTROENTEROLOGY VOLUME 109 | SUPPLEMENT 1 | AUGUST 2014 www.amjgastro.com
 ACG Monograph on IBS and CIC S3

bowel habit type is, in turn, based on the patient’s description of with diarrhea, and mixed IBS), as well as assessing adverse events
stool form by referring to the Bristol Stool Scale (7). The recogni- with therapies for both IBS and CIC.
tion that IBS sufferers segregate into subtypes according to pre-
dominant bowel habit, together with research findings suggesting Systematic review methodology
that IBS-C and IBS-D may be pathophysiologically distinct entities We evaluated manuscripts that studied adults (aged > 16 years)
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(8–10), led to the development of therapies specifically directed at using any definition of IBS or CIC. For IBS, this included a cli-
each of these subtypes. Nonetheless, it is worth noting that symp- nician-defined diagnosis, the Manning criteria (23), the Kruis
toms may not be stable over a lifetime and individuals may exhibit score (24), or Rome I (25), II (26), or III (6) criteria. For CIC,
one IBS subtype during a period, and then a different IBS subtype this included symptoms diagnosed by any of the Rome criteria
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during another period in their lives. (6,25,26), as well as a clinician-defined diagnosis. We included
However, although there is general awareness of the Rome only parallel-group randomized controlled trials (RCTs) com-
criteria, they are infrequently employed in the assessment of paring active intervention with either placebo or no therapy.
IBS and CIC in clinical practice (11). To provide more “clinician Crossover trials were eligible for inclusion, provided extractable
friendly” definitions, as well as to permit inclusion of studies data were provided at the end of the first treatment period, before
that predated the Rome process, American College of Gastro- crossover.
enterology Task Forces suggested the following definitions in For IBS, the following treatments were considered:
prior systematic reviews:
IBS is defined by: abdominal discomfort associated with altered 1. Diet and dietary manipulation
bowel habits (12). 2. Fiber
Constipation is defined as: a symptom-based disorder defined as 3. Interventions that modify the microbiota: probiotics, prebiotics,
unsatisfactory defecation and is characterized by infrequent stools, antibiotics
difficult stool passage, or both. Difficult stool passage includes 4. Antispasmodics
straining, a sense of difficulty passing stool, incomplete evacu- 5. Peppermint oil
ation, hard/lumpy stools, prolonged time to stool, or need for 6. Loperamide
manual maneuvers to pass stool. CIC is defined as the presence of 7. Antidepressants
these symptoms for at least 3 months (13). 8. Psychological therapies, including hypnotherapy
It is important to note that the Rome III criteria state that i 9. Serotonergic agents
ndividuals with chronic constipation do not fulfill criteria for IBS, 10. Prosecretory agents
with pain or discomfort being a major determinant in the latter. 11. Polyethylene glycol
In practice, a clear separation between CIC and IBS with constipa-
tion may be challenging and studies have shown, not only consid- For CIC, the following were considered:
erable overlap between these entities (14–16), but also a significant
tendency for patients to migrate between these diagnoses over 1. Fiber
time (15). It is appropriate therefore that in this update of prior 2. Osmotic and stimulant laxatives
American College of Gastroenterology monographs on IBS and 3. 5-HT4 agonists
CIC, these entities be addressed in the same exercise (12,13,17). 4. Prosecretory agents
The goal of this exercise, therefore, was to update the most recent 5. Biofeedback
systematic reviews commissioned by the American College of 6. Bile acid transporter inhibitors
Gastroenterology on IBS from 2009 (17) and CIC from 2005 (13). 7. Probiotics

Subjects needed to be followed up for at least 1 week. To be

METHODS eligible, trials needed to include one or more of the following
We have conducted a series of systematic reviews on the efficacy outcome measures:
of therapy in IBS and CIC. There have been several systematic
reviews of therapy for IBS and CIC published in the past 5 (i) Global assessment of improvement in IBS or CIC symptoms
years (18–22). There have been considerable data published in (ii) Improvement in abdominal pain for IBS
the intervening time, and hence we have, therefore, updated (iii) Global IBS symptom or abdominal pain scores for IBS
all these systematic reviews of IBS and CIC and synthesized (iv) Mean number of stools per week during therapy for CIC
the data, including the information from new trials, where
appropriate. Search strategy for identification of studies
The primary objective of this exercise was to assess the efficacy MEDLINE (1946 to October 2013), EMBASE and EMBASE
of available therapies in treating IBS and CIC compared with Classic (1947 to October 2013), and the Cochrane central register
placebo or no treatment. The secondary objectives included assess- of controlled trials were searched.
ing the efficacy of available therapies in treating IBS according to Studies on IBS were identified with the terms irritable bowel
predominant stool pattern reported (IBS with constipation, IBS syndrome and functional diseases, colon (both as medical subject

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

 S4 Ford et al.

headings (MeSH) and free text terms), and IBS, spastic colon, irri- For RCTs of pro-secretory agents, these were combined using
table colon, and functional adj5 bowel (as free text terms). the set operator AND with studies identified with the following
For RCTs of dietary manipulation, these were combined using free text terms: linaclotide or lubiprostone.
the set operator AND with studies identified with the terms: diet, For RCTs of polyethylene glycol (PEG), these were combined
fat-restricted, diet, protein-restricted, diet, carbohydrate-restricted, using the set operator AND with studies identified with the term
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diet, gluten-free, diet, macrobiotic, diet, vegetarian, diet, Mediterra- polyethylene glycol (both as a MeSH and free text term).
nean, diet fads, gluten, fructose, lactose intolerance, or lactose (both Studies on CIC were identified with the terms constipation
as MeSH and free text terms), or the following free text terms: or gastrointestinal transit (both as MeSH and free text terms),
FODMAP$, glutens, food adj5 intolerance, food allergy, or food or functional constipation, idiopathic constipation, chronic
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hypersensitivity. constipation, or slow transit (as free text terms). For the search
For RCTs of fiber, antispasmodics, and peppermint oil, these involving biofeedback, the free text terms dyssynergia, pelvic
were combined using the set operator AND with studies identi- floor dysfunction, anismus, and outlet obstruction were also
fied with the terms: dietary fiber, cereals, psyllium, methylcellulose, added.
sterculia, karaya gum, parasympatholytics, hyoscyamine, scopo- For RCTs of fiber, these were combined using the set operator
lamine, trimebutine, muscarinic antagonists, or butylscopolammo- AND with studies identified with the terms: dietary fiber, cellulose,
nium bromide (both as MeSH and free text terms), or the following plant extracts, psyllium, cereals, plantago, or methylcellulose (both
free text terms: bulking agent, psyllium fiber, fiber, husk, bran, as MeSH and free text terms), or the following free text terms: fiber,
ispaghula, wheat bran, calcium polycarbophil, spasmolytics, spas- soluble fiber, insoluble fiber, bran, ispaghula, metamucil, fybogel, or
molytic agents, antispasmodics, mebeverine, alverine, pinaverium ispaghula.
bromide, otilonium bromide, cimetropium bromide, hyoscine butyl For RCTs of osmotic and stimulant laxatives, these were com-
bromide, butylscopolamine, peppermint oil, or colpermin. bined using the set operator AND with studies identified with
For RCTs of probiotics, these were combined using the set oper- the terms: laxatives, cathartics, anthraquinones, phenolphthaleins,
ator AND with studies identified with the terms: Saccharomyces, indoles, phenols, lactulose, polyethylene glycol, senna plant, senna
Lactobacillus, Bifidobacterium, Escherichia coli, or probiotics (both extract, bisacodyl, phosphates, dioctyl sulfosuccinic acid, magne-
as MeSH and free text terms). For RCTs of prebiotics and synbiot- sium, magnesium hydroxide, sorbitol, poloxamer (both as MeSH
ics, these were combined using the set operator AND with stud- and free text terms), or the following free text terms: sodium
ies identified with the term: prebiotic (both MeSH and free text picosulphate, docusate, milk of magnesia, danthron, senna, and
terms) or synbiotic (both MeSH and free text terms). For RCTs of poloxalkol.
antibiotics, these were combined using the set operator AND with For RCTs of 5-HT4 agonists, these were combined using the set
studies identified with the terms: anti-bacterial agents, penicillins, operator AND with studies identified with the terms: serotonin
cephalosporins, rifamycins, quinolones, nitroimidazoles, tetracycline, agonists, receptors, or serotonin, 5-HT4 (both as MeSH and free text
doxycycline, amoxicillin, ciprofloxacin, metronidazole, or tinidazole terms), or the following free text terms: prucalopride, velusetrag, or
(both as MeSH and free text terms), or the following free text naronapride.
terms: antibiotic or rifamixin. For RCTs of pro-secretory agents, these were combined using
For RCTs of loperamide, these were combined using the set the set operator AND with studies identified with the following
operator AND with studies identified with the terms: loperamide free text terms: lubiprostone or linaclotide.
or antidiarrheals (both as MeSH and free text terms), or the follow- For RCTs of biofeedback, these were combined using the set
ing free text terms: imodium or lopex. operator AND with studies identified with the MESH terms
For RCTs of antidepressants and psychological therapies, includ- biofeedback and psychology and the following free text terms:
ing hypnotherapy, these were combined using the set operator biofeedback or neuromuscular training.
AND with studies identified with the terms: psychotropic drugs, For RCTs of bile acid transporter inhibitors, these were com-
antidepressive agents, antidepressive agents (tricyclic), desipramine, bined using the set operator AND with studies identified with
imipramine, trimipramine, doxepin, dothiepin, nortriptyline, the following free text terms: bile acid transporter, elobixibat, or
amitriptyline, selective serotonin reuptake inhibitors, paroxetine, A3309.
sertraline, fluoxetine, citalopram, venlafaxine, cognitive therapy, For RCTs of probiotics, these were combined using the set oper-
psychotherapy, behavior therapy, relaxation techniques, or hypno- ator AND with studies identified with the terms: Saccharomyces,
sis (both as MeSH and free text terms), or the following free text Lactobacillus, Bifidobacterium, E. coli, or probiotics (both as MeSH
terms: behavioral therapy, relaxation therapy, or hypnotherapy. and free text terms). For RCTs of prebiotics and synbiotics, these
For RCTs of serotonergic agents, these were combined were combined using the set operator AND with studies identified
using the set operator AND with studies identified with the with the term: prebiotic (both MESH and free text terms) or synbi-
terms: serotonin antagonists, serotonin agonists, cisapride, recep- otic (both MESH and free text terms).
tors (serotonin, 5-HT3), or receptors (serotonin, 5-HT4) (both The search was limited to humans. No restrictions were
as MeSH and free text terms), or the following free text terms: applied with regard to language of publication. A recursive
5-HT3, 5-HT4, alosetron, cilansetron, ramosetron, prucalopride, search of the bibliography of relevant articles was also conducted.
mosapride, or renzapride. DDW (Digestive Diseases Week) and UEGW (United European

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 ACG Monograph on IBS and CIC S5

Gastroenterology Week) abstract books were hand searched

between 2000 and 2013. Authors of trial reports that did not Box 1. Interpretation of the grading of the quality of evidence
Quality of evidence Interpretation
give enough detail for adequate data extraction were contacted High Further research is very unlikely to change our
and asked to contribute full data sets. Experts in the field were confidence in the estimate of effect.
Moderate Further research is likely to have an important
contacted for leads on unpublished studies.
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impact on our confidence in the estimate of effect

Trials were assessed for risk of bias according to the methods and may change the estimate.
described in the Cochrane handbook [27] using the following Low Further research is very likely to have an important
impact on our confidence in the estimate of effect
characteristics: method used to generate the randomization
and is likely to change the estimate.
schedule, method used to conceal treatment allocation, implemen- Very low The estimate of effect is very uncertain.
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tation of masking, completeness of follow-up, and conduct of an From: http://www.gradeworkinggroup.org.

intention-to-treat analysis.
Eligibility, quality, and outcome data were extracted by the
lead reviewer (Alexander Ford) and by a masked second reviewer
(Paul Moayyedi) on to specially developed forms. Any discrepancy Methodology for assessing levels of evidence and grading
was resolved by discussion between the two reviewers in order recommendations
to reach a consensus. Data were extracted as intention-to-treat We used the GRADE (Grading of Recommendations Assessment,
analyses, where all dropouts were assumed to be treatment failures, Development and Evaluation) system for grading the quality
wherever trial reporting allowed this. of evidence and strength of recommendation for each medical
intervention (32). The system has been widely used in evidence-
Data synthesis based guidelines and is endorsed by all major gastrointestinal
For IBS, whenever possible, any improvement of global IBS societies (http://www.gradeworkinggroup.org). The quality of the
symptoms as a binary outcome was taken as the primary evidence is based on the study design, as well as the extent of risk
outcome measure. If this was not available, improvement in of bias, inconsistency, indirectness, imprecision, and publication
abdominal pain was used. For CIC, any improvement of global bias that exists for the evidence supporting the intervention (33).
CIC symptoms as a binary outcome was taken as the primary Quality of evidence is described as high to very low, depending
outcome measure. The impact of interventions was expressed on the extent to which further evidence would change the esti-
as a relative risk (RR) of IBS or CIC symptoms not improv- mate of treatment effect (Box 1). The grading scheme also classi-
ing, together with 95% confidence intervals (CIs). If there were fies recommendations as strong or weak, according to the quality
sufficient data, RRs were combined using the DerSimonian of the evidence, applicability to all patient groups, balance of
and Laird random effects model (28) to give a more conserva- benefits and risks, patient preferences, and cost. With this graded
tive estimate of the efficacy of individual IBS therapies. For recommendation, the clinician receives guidance about whether
continuous data, such as global IBS symptom scores or indi- or not recommendations should be applied to most patients, and
vidual IBS symptom scores, a standardized mean difference, whether or not recommendations are likely to change in the future
with 95% CIs, was calculated. It should be noted that some after production of new evidence. “Strong” recommendations
treatments may be beneficial in IBS or CIC because of the represent a “recommendation that can apply to most patients in
effects on outcomes other than global symptoms or abdominal most circumstances and further evidence is unlikely to change our
pain, but this was not evaluated and was outside of the scope confidence in the estimate of treatment effect.” The summary of the
of this review. evidence for IBS is presented in Table 1, the reasons for the deci-
Tests of heterogeneity were reported (29). When the test of sion on the quality of that evidence in Table 2, and the reasons
heterogeneity was significant (P < 0.10 and/or I2 > 25%), the for the strength of recommendation in Table 3. Similarly, the
reasons for this were explored by evaluating differences in summary of the evidence for CIC is presented in Table 4, the
study population, study design, or study end points in subgroup reasons for the decision on quality of the evidence in Table 5, and
analyses. Publication bias or other causes of small study effects the reasons for the strength of recommendation in Table 6.
were evaluated using tests for funnel plot asymmetry (30), where
sufficient studies were identified (31).
The number needed to treat (NNT), which is the number of RESULTS
patients who would need to receive active therapy, over and Irritable bowel syndrome
above the control therapy, for one to experience an improvement 1. Diet and dietary manipulation in IBS
in symptoms, and the number needed to harm (NNH), which (a) Role of diet in IBS: Although food intake is one of the most
is the number of patients who would need to receive active common precipitants of symptoms in IBS (34), responses to
therapy, over and above the control therapy, for one to experi- food ingestion and interactions with components of the diet
ence an adverse event were calculated as the inverse of the have not typically undergone rigorous evaluation in the context
risk difference from the meta-analysis and checked using the of a blinded trial. Based on their own experiences, IBS sufferers
formula: NNT = 100 / RRR × BR, where BR is baseline risk and have generated their own theories to explain this phenomenon or
RRR is relative risk reduction. seek guidance from other, usually unsupported, dietary remedies.

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

 S6 Ford et al.

Table 1. Summary of results of monograph on interventions for IBS

No. of No. of RR symptoms NNT Quality of

Statement trials patients (95% CI) (95% CI) Recommendation evidence

Specialized diets may improve symptoms in individual 3 230 NA NA Weak Very low
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IBS patients.
Fiber provides overall symptom relief in IBS. 14 906 0.86 (0.80–0.94) 10 (6–33) Weak Moderate
Psyllium, but not bran, provides overall symptom relief 7 499 0.83 (0.73–0.94) 7 (4–25) Weak Moderate
in IBS (data presented for psyllium).
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There is insufficient evidence to recommend 2 198 NA NA Weak Very low

prebiotics or synbiotics in IBS.
Taken as a whole, probiotics improve global 23 2,575 0.79 (0.70–0.89) 7 (4–12.5) Weak Low
symptoms, bloating, and flatulence in IBS.
Rifaximin is effective in reducing total IBS symptoms 5 1,805 0.84 (0.78–0.90) 9 (6–12.5) Weak Moderate
and bloating in IBS-D.
Certain antispasmodics provide symptomatic 23 2,154 0.69 (0.59–0.81) 5 (4–9) Weak Low
short-term relief in IBS.
Peppermint oil is superior to placebo in improving IBS 5 482 0.51 (0.33–0.79) 3 (2–4) Weak Moderate
symptoms.
There is insufficient evidence to recommend 2 42 0.44 (0.14–1.42) NA Strong Very low
loperamide for use in IBS.
As a class, antidepressants are effective in symptom 17 1,084 0.67 (0.58–0.77) 4 (3–6) Weak High
relief in IBS.
A variety of psychological interventions are effective 32 2,189 0.68 (0.61–0.76) 4 (3–5) Weak Very low
in improving IBS symptoms.
Alosteron is effective in females with IBS-D. 8 4,987 0.79 (0.69–0.90) 8 (5–17) Weak Moderate
Mixed 5-HT4 agonists/5-HT3 antagonists are not more 9 2,905 0.96 (0.83–1.11) NA Strong Low
effective than placebo at improving symptoms of
IBS-C.
Linaclotide is superior to placebo for the treatment 3 2,028 0.80 (0.75–0.85) 6 (5–8) Strong High
of IBS-C.
Lubiprostone is superior to placebo for the treatment 3 1,366 0.91 (0.87–0.95) 12.5 (8–25) Strong Moderate
of IBS-C.
There is no evidence that polyethylene glycol 2 166 NA NA Weak Very low
improves overall symptoms and pain in patients
with IBS.

CI, confidence interval; 5-HT3, serotonin subtype 3; 5-HT4, serotonin subtype 4; IBS, irritable bowel syndrome; IBS-C, IBS with constipation; IBS-D, IBS with diarrhea; NA,
not available; NNT, number needed to treat; RR, relative risk.

Many IBS patients commonly believe that they have an allergy (b) Role of dietary manipulation in IBS: Specialized diets may
to certain foods, although true food allergies are uncommon in improve symptoms in individual IBS patients.
IBS (35). Thus, although the prevalence of true food allergies in Recommendation: weak. Quality of evidence: very low.
Western societies is between 1 and 3% in adults, surveys of gas-
trointestinal clinic patients found that 30–50% believed that their We identified 12 RCTs that evaluated dietary intervention in
symptoms represented food allergy or food intolerance (35–37). IBS (43–54). Following exclusions due to nonextractable data
Most food-related IBS symptoms appear to represent food intol- (46,48,50,52–54), lack of relevant symptom data (45,49,51), and
erance, although only 11–27% of patients can accurately identify an intervention lasting < 1 week (46), three evaluable RCTs
the presumed offending food when re-challenged in a double- involving 230 patients remained (43,44,47).
blind manner (38). Based on their own experiences with food, and The first of these addressed the impact of gluten in IBS. In a
despite a lack of objective evidence to incriminate a specific food, double-blind, placebo-controlled trial, 34 patients with IBS were
studies have shown that a majority of IBS patients institute dietary randomized to either remain on a gluten-free diet or to receive
changes (39–41), sometimes to an extent that may compromise 16 g/day of gluten on completion of an open gluten-free run-in
their nutrition (42). phase (44). In the gluten group, 68% (13/19) reported that their

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Table 2. Reasons for quality of evidence of assessment for IBS data according to GRADE criteria

Statement Quality assessment Study limitations Inconsistency Indirectness of evidence Imprecision Reporting bias
a
Specialized diets may Very low Only one low risk of bias trial Each eligible RCT evaluated a different 3 Only a small number of Not evaluable
improve symptoms in intervention patients studied
individual IBS patients.

Fiber provides overall Moderate Only one low risk of bias trial and two 3 3 3 3
symptom relief in IBS. high risk of bias

Psyllium, but not bran, Moderate Only one low risk of bias trial but this 3 Only one trial compared the 3 3
provides overall symptom contributed to almost half the total two types of fibers. This trial
relief in IBS. number of patients and this trial confirmed the result of the
mirrored the result of the meta-analysis systematic review at week 4
but not at week 12

© 2014 by the American College of Gastroenterology

There is insufficient Very low Only one synbiotic trial with dichoto- Differences in efficacy between the di- 3 Only a small number of Not evaluable
evidence to recommend mous data. Overall result positive. chotomous and continuous data. Each patients studied
prebiotics or synbiotics Meta-analysis of continuous data trial evaluated a different preparation
in IBS. from two trials showed no benefit

Taken as a whole, Low 3 Significant heterogeneity between 3 3 3

probiotics improve global studies that was unexplained. Inconsis-
symptoms, bloating, and tency considered very serious as most
flatulence in IBS. studies evaluated different probiotics

Rifaximin is effective in Moderate 3 3 3 The impact of antibiotics 3

reducing total IBS symp- on IBS symptoms was
toms and bloating in IBS-D. modest

Certain antispasmodics Low All trials unclear risk of bias and the Significant heterogeneity between 3 3 There was funnel plot
provide symptomatic effect on IBS symptoms was marked. studies that was unexplained. Only asymmetry suggesting
short-term relief in IBS. a small number of studies evaluating reporting bias or other
each type of drug small study effects

Peppermint oil is superior Moderate Only one low risk of bias trial and this Significant heterogeneity between stud- 3 3 Not evaluable
to placebo in improving IBS study was the least positive (although ies that was unexplained
symptoms. still showing statistically significant
benefit compared to placebo). Quality
of evidence upgraded as effect on IBS
symptoms marked

There is insufficient Very low Both trials have unclear risk of bias Significant heterogeneity between 3 Effect not significant and Not evaluable
evidence to recommend studies that was unexplained confidence
loperamide for use in IBS. intervals very wide

As a class, antidepressants High Three low risk of bias trials. Meta- 3 3 3 3

are effective in symptom analysis of these showed statistically
relief in IBS. significant effect of antidepressants vs.
placebo

A variety of psychological Very low All trials high risk of bias Significant heterogeneity between stud- Most RCTs did not have an 3 There was funnel plot
interventions are effective in ies that was unexplained adequate control group asymmetry suggesting
improving IBS symptoms. reporting bias or other
small study effects

Alosteron is effective in Moderate Only one trial had low risk of bias but Significant heterogeneity between stud- 3 3 3
females with IBS-D. this trial was also positive and large ies that was unexplained

Table 2 continued on following page

The American Journal of GASTROENTEROLOGY

ACG Monograph on IBS and CIC
S7
 S8 Ford et al.

symptoms were not adequately controlled as compared with 6/15

(40%) in the placebo group. Continuous symptom scores for
Reporting bias

abdominal pain, bloating, satisfaction with stool consistency, and

GRADE, Grading of Recommendations Assessment, Development and Evaluation; 5-HT3, serotonin subtype 3; 5-HT4, serotonin subtype 4; IBS, irritable bowel syndrome; IBS-C, IBS with constipation; IBS-D, IBS with
Not evaluable

Not evaluable
tiredness were statistically significantly better in those who main-
tained a gluten-free diet.
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The second of these studies examined the contribution of food

3

3
allergy or hypersensitivity as assessed, not by immunoglobulin

cant effect on abdominal

of patients studied was

(Ig) E antibodies, but by IgG antibodies (43). In a double-blind,

toms. Overall number

No statistically signifi-

pain or overall symp-

parallel-group trial, 150 IBS patients were randomized to either
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an exclusion diet based on the presence of IgG antibodies to vari-

Effect modest
Imprecision

ous foods or a sham diet. Participants were followed for 12 weeks

and symptoms assessed using a global impact score and the IBS

small
severity score. Compared with 11/66 (17%) in the sham diet
3

group (P = 0.14), 28% (18/65) in the exclusion diet intervention

Indirectness of evidence

arm noted a significant improvement in symptoms. The authors

reported marginal statistical significance in those with high adher-
ence to their diet.
The third study examined the role of FODMAPs (fermentable
oligosaccharides, disaccharides, monosaccharides, and polyols).
Forty-one IBS patients were randomized to a low-FODMAP diet or
3

their regular (habitual) diet for 4 weeks (47). Of those randomized

to the low-FODMAP diet, 68% (13/19) reported adequate control
Significant heterogeneity between stud-

RCTs cannot be combined as different

of their symptoms compared with 5/22 (23%) of the habitual diet

group (P = 0.005). Stool consistency did not differ between groups;
stool frequency was less in the low-FODMAP diet group. A signifi-
ies that was unexplained

cant limitation of this study was the lack of blinding regarding the
dietary intervention.
populations studied

Summary: Belatedly perhaps, the role of dietary components in

Inconsistency

the precipitation of symptoms, or even in the basic pathogenesis

of IBS, is now being addressed. To date, two mechanisms, intole-
rance and hypersensitivity, have been addressed in clinical trials,
3

although it is highly plausible that other mechanisms (e.g., stimu-

lation of gut hormones and interactions with the microbiota) may
Only one trial was low risk of bias and

One other RCT performed but unable

to obtain dichotomous data from the

Both trials are unclear risk of bias

also be relevant to the effects of food or food components. While

recognizing the challenges that any investigation of the role of an
individual’s diet or of a specific food component in IBS present,
this study was negative

the current data provide limited guidance on the role of diet in the
company or authors
Study limitations

management of IBS. Gluten-free and low-FODMAP diets show

promise but their precise role(s) in the management of IBS need
Check marks indicate that the criterion was fulfilled/not a concern.

to be defined.
3

2. Fiber in IBS
Fiber provides overall symptom relief in IBS.
Quality assessment

Recommendation: weak. Quality of evidence: moderate.

Psyllium, but not bran, provides overall symptom relief in IBS.
diarrhea; RCT, randomized controlled trial.

Recommendation: weak. Quality of evidence: moderate.

Moderate

Very low
High
Low

Increased intake of dietary fiber is frequently recommended

to improve bowel function for IBS, particularly for constipation-
Mixed 5-HT4 agonists/5-HT3

improves overall symptoms

Lubiprostone is superior to
placebo for the treatment

placebo for the treatment

antagonists are not more

and pain in patients with

effective than placebo at

Linaclotide is superior to

related symptoms. However, insoluble fibers frequently cause

that polyethylene glycol
improving symptoms of
Table 2. Continued

There is no evidence

bloating and abdominal discomfort.

In updating our prior systematic review (18), we identified
two additional studies for a total of 14 RCTs (55–69) involving
Statement

of IBS-C.

of IBS-C.

906 patients. All but five trials did not differentiate IBS by subtype
IBS-C.

IBS.

and only two restricted recruitment to IBS-C (58,66).

a

The American Journal of GASTROENTEROLOGY VOLUME 109 | SUPPLEMENT 1 | AUGUST 2014 www.amjgastro.com
 ACG Monograph on IBS and CIC S9

Table 3. Reasons for strength of recommendation for IBS therapies according to GRADE criteria

Recom- Quality of
Statement mendation evidence All patient groups Benefits vs. risks Patient values Costa

Specialized diets may improve Weak Very low Likely to relate to only Some diets are very strin- 3b 3
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symptoms in individual IBS some IBS patients gent and difficult to follow
patients.

Fiber provides overall symptom Weak Moderate May only relate to Fiber can cause bloating Some patients do 3
relief in IBS. IBS-C, most trials did and abdominal discomfort not like taking fiber
not state type of IBS supplements
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patient

Psyllium, but not bran, provides Weak Moderate May only relate to Fiber can cause bloating Some patients do 3
overall symptom relief in IBS. IBS-C, most trials did and abdominal discomfort not like taking fiber
not state type of IBS supplements
patient

There is insufficient evidence Weak Very low Likely that only some 3 3 Can be expensive
to recommend prebiotics or patients will respond to patients
synbiotics in IBS.

Taken as a whole, probiotics Weak Low Likely that only some 3 3 Can be expensive
improve global symptoms, bloating, patients will respond to patients
and flatulence in IBS.

Rifaximin is effective in reducing Weak Moderate Likely that only some Antibiotic resistance of 3 Can be expensive
total IBS symptoms and bloating patients will respond GI flora a concern if use to patients
in IBS-D. widespread. Long-term
efficacy uncertain

Certain antispasmodics provide Weak Low 3 3 3 3

symptomatic short-term relief in
IBS.

Peppermint oil is superior to Weak Moderate 3 3 3 3

placebo in improving IBS
symptoms.

There is insufficient evidence to Strong Very low 3 3 3 3

recommend loperamide for use
in IBS.

As a class, antidepressants are Weak High 3 Both TCA and SSRI asso- Some patients do not SSRIs can be
effective in symptom relief in IBS. ciated with adverse events like the idea of taking expensive. TCAs are
with an NNH of 9. antidepressants inexpensive.

A variety of psychological interven- Weak Very low 3 Can be time intensive for Some patients do not Most psychothera-
tions are effective in improving IBS patients like the concept of peutic interventions
symptoms. psychotherapy are expensive

Alosteron is effective in females Weak Moderate 3 Concerns regarding 3 Can be expensive

with IBS-D. ischemic colitis and not freely
available

Mixed 5-HT4 agonists/5-HT3 Strong Low 3 3 3 3

antagonists are not more effective
than placebo at improving symp-
toms of IBS-C.

Linaclotide is superior to placebo Strong High 3 3 3 Expensive

for the treatment of IBS-C.

Lubiprostone is superior to placebo Strong Moderate 3 3 3 Expensive

for the treatment of IBS-C.

There is no evidence that poly- Weak Very low Not clear whether Not clear whether this 3 Can be moderately
ethylene glycol improves overall this intervention is intervention is effective, and expensive for
symptoms and pain in patients effective hence although adverse patients
with IBS. events are rare, cannot
evaluate risks vs. benefits

GI, gastrointestinal; GRADE, Grading of Recommendations Assessment, Development and Evaluation; 5-HT3, serotonin subtype 3; 5-HT4, serotonin subtype 4;
IBS, irritable bowel syndrome; IBS-C, IBS with constipation; IBS-D, IBS with diarrhea; NNH, number needed to harm; SSRI, selective serotonin reuptake inhibitor;
TCA, tricyclic antidepressant.
a
Cost was classified as expensive for the health service if the listed medication cost was > $5 per day. At this level, an economic analysis (289) has shown there is less
certainty that the drug is cost effective, although it is important to emphasize that this will be cost effective for some patients but may not be for those with milder
symptoms.
b
Check marks indicate that the criterion was fulfilled/not a concern.

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

 S10 Ford et al.

Table 4. Summary of results of monograph on interventions for CIC

No. of No. of RR symptoms Quality of

Statement trials patients (95% CI) NNT (95% CI) Recommendation evidence

Some fiber supplements increase stool frequency 3 293 0.25 (0.16–0.37) 2 (1.6–3) Strong Low
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in patients with CIC.

PEG is effective in increasing stool frequency and 4 573 0.52 (0.41–0.65) 3 (2–4) Strong High
improving stool consistency in CIC.
Lactulose is effective in increasing stool frequency 2 148 0.48 (0.27–0.86) 4 (2–7) Strong Low
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and improving stool consistency in CIC.

Sodium picosulfate and bisacodyl are effective 2 735 0.54 (0.42–0.69) 3 (2–3.5) Strong Moderate
in CIC.
Prucalopride is more effective than placebo at 8 3,140 0.81 (0.75–0.86) 5 (4–8) Strong Moderate
improving symptoms of CIC.
Linaclotide is effective in CIC. 3 1,582 0.84 (0.80–0.87) 6 (5–8) Strong High
Lubiprostone is effective in the treatment of CIC. 4 651 0.67 (0.58–0.77) 4 (3–6) Strong High
Biofeedback is effective in CIC patients with 3 216 0.33 (0.22–0.50) 2 (1.6–4) Weak Low
demonstrated evidence of pelvic floor dyssynergia.

CI, confidence interval; CIC, chronic idiopathic constipation; NNT, number needed to treat; PEG, polyethylene glycol; RR, relative risk.

Table 5. Reasons for quality of evidence of assessment of data on CIC according to GRADE criteria

Quality Indirectness
Statement assessment Study limitations Inconsistency of evidence Imprecision Reporting bias

Some fiber supplements Low All trials were unclear End points different even 3a Only a small Not evaluable
increase stool frequency in risk of bias but did in the studies that could be number of patients
patients with CIC. show a marked effect combined studied
PEG is effective in increasing High All RCTs low risk of Moderate heterogeneity 3 3 Not evaluable
stool frequency and improv- bias and demonstrated between studies
ing stool consistency in CIC. strong treatment effect
Lactulose is effective in Low Both trials at high risk Moderate heterogeneity 3 Only a small Not evaluable
increasing stool frequency of bias but there was a between studies number of patients
and improving stool strong treatment effect studied with wide
consistency in CIC. 95% CIs
Sodium picosulfate and Moderate Both trials low risk of Significant heterogeneity 3 Modest number of Not evaluable
bisacodyl are effective in bias and strong treat- between studies patients studied for
CIC. ment effect each intervention
Prucalopride is more Moderate 5/8 Trials were low risk Significant heterogeneity 3 3 3
effective than placebo at of bias and these stud- between studies that was
improving symptoms of CIC. ies were also positive unexplained
Linaclotide is effective in High 3 3 3 3 3
CIC.
Lubiprostone is effective in High Two trials low risk of 3 3 3 Not evaluable
the treatment of CIC. bias, strong treatment
effect
Biofeedback is effective in Low All three trials were End points different even 3 Very modest Not evaluable
CIC patients with demon- high risk of bias but in the studies that could be number of patients
strated evidence of pelvic the treatment effect combined and intervention studied.
floor dyssynergia. was marked slightly different between
studies

CI, confidence interval; CIC, chronic idiopathic constipation; GRADE, Grading of Recommendations Assessment, Development and Evaluation; PEG, poly-
ethylene glycol; RCT, randomized controlled trial.
a
Check marks indicate that the criterion was fulfilled/not a concern.

The American Journal of GASTROENTEROLOGY VOLUME 109 | SUPPLEMENT 1 | AUGUST 2014 www.amjgastro.com
 ACG Monograph on IBS and CIC S11

Table 6. Reasons for strength of recommendation for treatments of CIC according to GRADE criteria

Recommen- Quality of All patient

Statement dation evidence groups Benefits vs. risks Patient values Costa

Some fiber supplements increase stool Strong Low 3b Fiber can cause bloating Some patients do 3
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frequency in patients with CIC. and abdominal discomfort not like taking fiber
supplements
PEG is effective in increasing stool Strong High 3 3 3 Can be expensive
frequency and improving stool to patients
consistency in CIC.
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Lactulose is effective in increasing Strong Low 3 Lactulose can cause 3 3

stool frequency and improving stool bloating
consistency in CIC.
Sodium picosulfate and bisacodyl are Strong Moderate 3 3 3 3
effective in CIC.
Prucalopride is more effective than Strong Moderate 3 3 3 Expensive
placebo at improving symptoms of CIC.
Linaclotide is effective in CIC. Strong High 3 3 3 Expensive
Lubiprostone is effective in the treatment Strong High 3 3 3 Expensive
of CIC.
Biofeedback is effective in CIC patients Weak Low 3 3 Some patients not Expensive
with demonstrated evidence of pelvic receptive to the idea
floor dyssynergia. of biofeedback

CIC, chronic idiopathic constipation; GRADE, Grading of Recommendations Assessment, Development and Evaluation; PEG, polyethylene glycol.
a
Cost was classified as expensive for the health service if the listed medication cost was > $5 per day. At this level, an economic analysis (289) has shown there
is less certainty that drug is cost effective, although it is important to emphasize that this will be cost effective for some patients but may not be for those with
milder symptoms.
b
Check marks indicate that the criterion was fulfilled/not a concern.

In the largest study to date, 275 patients, of whom 53–58% were in IBS. These latter effects appear to transcend expected benefits in
IBS-C and 19–29% were IBS-D, were randomized to one of three terms of relief of constipation.
arms: 10 g of the soluble fiber psyllium, 10 g of the insoluble fiber
bran, or 10 g of a placebo once daily for 12 weeks (57). During the 3. Interventions that modify the microbiota: probiotics, prebiotics,
first month, a significantly greater proportion of patients receiv- and antibiotics
ing psyllium, but not bran, reported adequate symptom relief for The suggestion that the gut bacteria could be relevant to IBS
at least 2 weeks compared with placebo (57% vs. 35% psyllium vs. first came from the observation that a small, although definite,
placebo; RR 1.60, 95% CI 1.13–2.26). Bran was more effective than proportion of individuals who suffer an episode of bacterial
placebo during the third month of treatment only (57% vs. 32%; gastroenteritis will go on to develop IBS de novo; postinfec-
1.70, 1.12–2.57). After 3 months of treatment, symptom severity tious IBS (70). Although bacterial fermentation has been linked
in the psyllium group was reduced by 90 points compared with to bloating and flatulence and changes in the microbiota have
49 points in the placebo group (P = 0.03) and 58 points in the been described in IBS, the contribution of the microbiota to
bran group (P = 0.61 vs. placebo). No differences were found with these, or other symptoms in IBS, is unclear. Thus, although both
respect to quality of life. Dropout was most common in the bran small intestinal bacterial overgrowth (SIBO) (71) and quantita-
group; most commonly because of exacerbation in IBS. tive and qualitative changes in the fecal microbiota (72) have
Data on overall adverse events were only provided by six trials also been linked to IBS (73), the overall contribution of SIBO to
(57,58,60,64,65,69). These trials evaluated 566 patients, but as IBS remains controversial (74), and findings in relation to the
numbers of adverse events were so small in 5 of the trials, pooling microbiota require confirmation in larger patient populations.
of data was not carried out. A total of 130 (38.8%) of 335 patients Prebiotics, probiotics, and prebiotic–probiotic preparations
receiving fiber reported adverse events compared with 63 (27.3%) have been used for decades on an empirical basis by IBS suffer-
of 231 in the placebo arms. ers; they have only recently been subjected to scrutiny in clini-
Summary: Although its use in the management of IBS is time cal trials. The interpretation of probiotic studies in IBS remains
honored, the status of fiber, in general, in IBS, is far from straight- challenging as studies have employed different species, strains,
forward. Insoluble fibers may exacerbate symptoms and provide preparations, and doses in various patient populations and often
little relief; soluble fibers and psyllium, in particular, provide relief in substandard trials.

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

 S12 Ford et al.

Although initial studies, employing the lactulose hydrogen pseudorandomized and included acupuncture in both study arms
breath test, suggested that more than “three quarters” of all (104), and hence we excluded these two studies (103,104). There-
IBS sufferers had SIBO (75), subsequent studies have, in gen- fore, in total, there were 35 RCTs (83–102,105–119), involving
eral, failed to confirm such a high prevalence of SIBO in IBS 3,452 patients. Fourteen trials were at low risk of bias (87,89,91–
(73,74). These divergent results may relate to problems inher- 93,97,99,101,105,109–111,118,119), with the remainder being
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ent to the lactulose breath hydrogen test that may provide an unclear.
overestimation of the true positive rate (73). Nevertheless, this There were 23 RCTs involving 2,575 patients (as reported on
finding provided a rationale for assessing antibiotics in IBS. Table 1) that gave outcomes as a dichotomous variable. Probiotics
Rifaximin, a nonabsorbable antibiotic, has demonstrated effi- were statistically significantly better than placebo (RR of IBS not
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cacy in clinical trials in IBS-D, and although statistically signif- improving = 0.79, 95% CI 0.70–0.89), with the NNT of 7 (95% CI
icant improvements were demonstrated over placebo in global 4–12.5). There was statistically significant heterogeneity between
IBS symptoms as well as in bloating, it is important to note that studies. A further complicating factor in the assessment of probi-
tests for SIBO were not performed in these pivotal trials, leav- otics was the use of a great variety of preparations. Combination
ing the mechanism of action of rifaximin in IBS unclear (76). probiotics, as well as formulations based on specific species (but
widely variable strains); Lactobacillus, Bifidobacterium, Escherichia,
(a) Prebiotics and synbiotics in IBS: There is insufficient evidence to and Streptococcus, were assessed in individual trials. Subanalysis
recommend prebiotics or synbiotics in IBS. only demonstrated a significant effect for combination probiot-
Recommendation: weak. Quality of evidence: very low. ics, Lactobacillus plantarum DSM 9843 and E. coli DSM17252, but
there was significant heterogeneity between studies for the first
(b) Probiotics in IBS: Taken as a whole, probiotics improve global two and only one study for the third.
symptoms, bloating, and flatulence in IBS. There were 24 trials, making 25 comparisons, and assessing
Recommendations regarding individual species, preparations, or 2001 patients who reported improvement in global IBS symp-
strains cannot be made at this time because of insufficient and con- tom scores or abdominal pain scores. There was a statistically
flicting data. significant effect of probiotics in reducing symptoms with
Recommendation: weak. Quality of evidence: low. no significant heterogeneity. Subanalysis, on this occasion,
revealed significant effects for combinations of probiotics, but
(c) Antibiotics in IBS: The poorly absorbable antibiotic rifaximin is not for those containing Lactobacillus spp., Bifidobacterium spp.,
effective at reducing total IBS symptoms and bloating in diarrhea- or Saccharomyces spp.
predominant IBS. There were 17 separate trials, making 18 comparisons and con-
Recommendation: weak. Quality of evidence: moderate. taining 1,446 patients, that reported the effect of probiotics on
bloating symptom scores. Overall, bloating scores were signifi-
We identified one RCT that evaluated the prebiotic trans- cantly reduced with probiotics, but with significant heterogeneity
galactooligosaccharide in IBS (77); this study was excluded from between individual study results.
further analysis as the data were not extractable. In relation to In the 10 trials that assessed this outcome, flatulence scores were
probiotics, it should be noted that changes in diet and intake significantly lower with probiotics compared with placebo with no
of dietary fiber can exert prebiotic effects on gut microbiota; significant heterogeneity detected.
these are addressed in previous sections. We identified two trials There was no apparent benefit detected for probiotics on urgency
assessing 198 IBS patients that evaluated synbiotics vs. control in the six trials that assessed this symptom.
preparations. (78,79) Both studies evaluated different products. Total adverse events were reported by 24 RCTs containing 2,407
We excluded two other RCTs of synbiotics in IBS as data were patients. Overall, 201 (16.5%) of 1,215 patients allocated to probi-
not extractable in one case, (80) and in the second there was no otics experienced any adverse event compared with 164 (13.8%) of
control arm (81). 1,192 assigned to placebo with the NNH of 35 (95% CI 16–362).
There was one study that assessed dichotomous outcomes in We identified 6 RCTs (120–124) involving 1,916 participants
68 patients (79). There were 7 (20.6%) of 34 patients assigned to that evaluated antibiotic therapy in IBS patients. Two trials eval-
synbiotics with persistent symptoms compared with 30 (88.2%) uating metronidazole (125) and rifaximin (126) were excluded
of 34 assigned to control therapy (P < 0.01). Both trials (78,79) as they did not provide extractable data. A further RCT (127)
assessed global IBS symptoms on a continuous scale in 185 assessed Helicobacter pylori eradication therapy but was excluded
patients; there was no statistically significant effect of synbiotics as it assessed symptoms 2 years after a 1-week course of antibi-
in reducing IBS symptom scores, even though both trials were otics. Overall, antibiotic therapy improved IBS symptoms com-
individually positive, again because of significant heterogeneity. pared with placebo, with no significant heterogeneity between
We updated our previous systematic review and meta-analy- studies. One trial (124) evaluated neomycin in 111 patients
sis on probiotics in IBS (22,82), and identified a total of 20 new with a significant effect in favor of neomycin (RR = 0.73, 95%
trials (83–102). However, one of these was a full publication of a CI 0.56–0.96) with the NNT of 5 (95% CI 3–33). The remain-
trial previously included in the original meta-analysis in abstract ing 5 trials (120–123) evaluated rifaximin in 1,805 IBS patients.
form (89,103), and one trial in the original meta-analysis was There was a statistically significant benefit in favor of the anti-

The American Journal of GASTROENTEROLOGY VOLUME 109 | SUPPLEMENT 1 | AUGUST 2014 www.amjgastro.com
 ACG Monograph on IBS and CIC S13

biotic (RR = 0.84, 95% CI 0.78–0.90) with the NNT of 9 (95% CI NNT of 5 (95% CI 4–9). However, the effect of individual anti-
6–12.5). There were three (122,123) low risk of bias trials assess- spasmodics is variable and difficult to interpret, as there are only a
ing 1,330 patients. small number of studies evaluating each of the 12 different drugs
Three RCTs reported adverse events (121,122,124) in 1,456 available for review.
patients. There was no difference in overall adverse events between With respect to individual agents, otilonium (128,129,131,
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the antibiotic and placebo groups (RR of adverse events = 0.70, 132,138), hyoscine bromide (64,67,146), cimetropium bromide
95% CI 0.42–1.16). (130,134,143), pinaverium bromide (133,139,147), and dicyclo-
Summary: Although data accumulate to suggest a role for the mine hydrochloride (142) showed beneficial effects with NNTs of
microbiota in IBS, the primacy of any reported changes in enteric 5, 3, 3, 3, and 4, respectively. However, some of these were evalu-
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populations in the pathogenesis of IBS remains to be confirmed. ated in as few as just one study (142), and for those that were
Although, at this time there is insufficient evidence to permit assessed in multiple studies, heterogeneity was a problem in some
a recommendation on the use of prebiotics or synbiotics in IBS, instances.
aggregated data do indicate a beneficial effect for probiotics, with Mebeverine (one trial), trimebutine (three trials), pirenzipine
bloating and flatulence appearing to be especially responsive. (one trial), alverine (one trial), rociverine (one trial), prifinium
Though recognizing the intrinsic differences that exist between (one trial), and propinox (one trial) did not have a statistically sig-
individual probiotic strains and the consumer’s desire to obtain nificant effect on IBS symptoms, although the numbers of patients
guidance on product selection, limitations intrinsic to available studied were small.
data, as well as a lack of comparative studies, severely limit one’s Fifteen trials included in this review reported adverse events
ability to recommend a particular strain or product at this time. with either active drug or placebo. In total, 144 (16.3%) of 883
The antibiotic rifaximin, although not approved for this indication patients assigned to antispasmodics experienced adverse events
by the Food and Drug Administration, has shown modest but con- compared with 92 (10.4%) of 882 allocated to placebo. When data
sistent efficacy in nonconstipated IBS and seems to be well toler- were pooled, the incidence of adverse events was significantly
ated and, despite concerns regarding the long-term or repeated use higher among those taking antispasmodics as compared with
of an antibiotic, has proven safe at least over the time periods in placebo (RR of experiencing any adverse event = 1.61; 95% CI
which it has been evaluated. 1.08–2.39), with the NNH of 20 (95% CI 9.5–333). The most
common adverse events were dry mouth, dizziness, and blurred
4. Antispasmodics in IBS vision, but there were no serious adverse events reported in either
Antispasmodics have been used for decades on an empirical treatment arm in any of the trials.
basis in the treatment of IBS based on the assumption that gut, Summary: Although many of the relevant clinical trials are old
and especially colonic smooth muscle spasm, contributes to IBS and far from ideal in terms of quality, antispasmodics, as a cate-
symptoms and pain in particular; hence, the term spastic colon. gory, are effective in IBS, though their use may be limited by anti-
Certain antispasmodics (otilonium, hyoscine, cimetropium, pina- cholinergic adverse events. However, not all antispasmodics have
verium, and dicyclomine) provide symptomatic short-term relief in been shown to be effective, and studies on individual agents vary
IBS. Adverse events are more common with antispasmodics than in quality and outcome measures. Furthermore, the availability
placebo. of some of the more effective agents may be limited to certain
Recommendation: weak. Quality of evidence: low. regions.

We identified 23 RCTs (60,64,67,128–147) evaluating 2,154 5. Peppermint oil in IBS

patients with IBS. There was considerable variation between Peppermint oil can be found in various preparations available
the studies concerning diagnostic and inclusion criteria, dosing through conventional or complementary venues. Limited experi-
schedule, and study end points. Only 3 studies used standard- mental data suggest that it can relax smooth muscle, but it may
ized diagnostic criteria (Rome I or II) (131,138,140), whereas also have effects via attenuation of visceral hypersensitivity and
all other 20 studies used author-defined IBS, reflecting the fact modulation of pain sensation, and hence its use for the treatment
that most trials were conducted before Rome definitions were of IBS.
published. The majority of trials did not differentiate between Peppermint oil is superior to placebo in improving IBS symptoms.
the types of IBS patients recruited. Overall, the quality of trials The risk of adverse events is no greater with peppermint oil than with
was poor, with only 4 recruiting more than 100 patients. Only placebo.
four trials (67,131,133,144) reported an adequate method of Recommendation: weak. Quality of evidence: moderate.
randomization and none reported on concealment of alloca-
tion, although all were double blind. Risk of bias was unclear We identified five RCTs (148–152) involving 482 patients.
in all of the trials. Of the drugs used in the various studies, only Most trials did not differentiate between the types of IBS patients
hyoscine (64,67,146) and dicyclomine (142) are available in the recruited, with only one study providing data on this (148). There
United States. was only one RCT at low risk of bias (152), with the remainder
This review shows that as a class, antispasmodic therapy has a being unclear. This RCT reported a less dramatic effect of pepper-
statistically significant effect in improving IBS symptoms with the mint oil on IBS symptoms compared with placebo, but this was

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

 S14 Ford et al.

still statistically significant. Overall, there was a statistically signifi- depressants having persistent abdominal pain following treat-
cant effect in favor of peppermint oil compared with placebo with ment as compared with 123 (72.8%) of 169 subjects allocated to
the NNT of 3 (95% CI 2–4). However, there was significant hetero- placebo, giving a RR of abdominal pain persisting of 0.62 (95% CI
geneity between results. In these studies, an enteric-coated prepa- 0.43–0.88), but with considerable heterogeneity between studies
ration of peppermint oil was employed in doses ranging from 187 (I2 = 72.4%, P = 0.001).
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to 225 mg t.i.d. Tricyclic antidepressants were studied in 11 RCTs involving

When data were pooled, the incidence of adverse events was 744 patients (64,156–158,160,163,165–169), and active therapy
not significantly higher among those taking peppermint oil as was associated with a reduction in IBS symptoms compared with
compared with placebo (RR of experiencing any adverse placebo with the NNT of 4. Selective serotonin reuptake inhibi-
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event = 1.26, 95% CI 0.75–2.12). tors were studied in 7 RCTs involving 356 patients (159,161–164,
Summary: In specific formulations, which may not be univer- 170,171), and active therapy was associated with a reduction in IBS
sally available, peppermint oil is effective in IBS. symptoms compared with placebo with the NNT of 4.
Only seven trials reported on overall adverse events vs. pla-
6. Loperamide in IBS cebo (157–160,162,166,168). In total, 65 (31.3%) of 208 patients
There is insufficient evidence to recommend loperamide for use assigned to antidepressants experienced adverse events as com-
in IBS. pared with 33 (16.5%) of 200 allocated to placebo. When data
Recommendation: strong. Quality of evidence: very low. were pooled, the incidence of adverse events was significantly
higher among those taking antidepressants as compared with
There were two RCTs (153,154) involving 42 patients. There was placebo (RR of experiencing any adverse event = 1.63, 95% CI
no statistically significant effect in favor of loperamide compared 1.18–2.25). The NNH was 9 (95% CI 5–111). Drowsiness and dry
with placebo. Both trials stated the type of IBS patients recruited, mouth were more common in patients taking tricyclic antidepres-
with one study recruiting only IBS-M patients (153) and the other sants than those on placebo.
only IBS-D (154). Summary: Both tricyclic antidepressants and selective seroto-
Data on overall adverse events were provided in both trials. nin reuptake inhibitors are effective in providing global symptom
There were no adverse events in either arm in one trial (153) and relief and reducing pain in IBS. Adverse events and patient, as well
four adverse events in each arm of the other study (154). as physician, acceptability have limited their use and influenced
Summary: Although loperamide is an effective antidiarrheal, our recommendation. Available data, other than adverse event
there is no evidence to support the use of loperamide for relief of profile (e.g., constipating effects of tricyclic antidepressants),
global symptoms in IBS. do not permit guidance on patient selection for antidepressant
therapy.
7. Antidepressants in IBS
Antidepressants were first introduced into the management of 8. Psychological therapies, including hypnotherapy, in IBS
IBS based on the observation that depression and anxiety were A variety of psychological interventions are effective in improving
frequent comorbidities among IBS subjects seen in secondary and IBS symptoms.
tertiary care. Subsequent studies suggested that in subdepression Recommendation: weak. Quality of evidence: very low.
doses these agents were effective in relieving pain of visceral
origin. We updated our previous systematic review and meta-analysis
Antidepressants (tricyclic antidepressants and selective serotonin on psychological therapies in IBS (20,155), and identified a total of
reuptake inhibitors) are effective in symptom relief in IBS. 10 new papers containing 11 separate RCTs, thereby providing in
Side effects are common and may limit patient tolerance. total 30 papers reporting 32 separate trials, involving 2,189 patients
Recommendation: weak. Quality of evidence: high. (167,172–200). The quality of these trials was generally poor, with
only 8 having a sample size of more than 100 (167,174,175,178,18
We updated our previous systematic review and meta-analysis 1,189,191,194). Because of the nature of the intervention, double-
on antidepressants in IBS (20) and identified four further papers blind studies would not have been possible, but only four papers
(155). Overall, there were 17 RCTs (64,156–171) evaluating 1,084 reported that investigators were blinded (167,174,175,192). All of
patients. The majority of trials did not differentiate between the the trials were at high risk of bias.
type of IBS patients recruited, with seven studies providing data There was a statistically significant effect in favor of psycho-
on this (159,161,162,164–166,170), one of which recruited only logical therapies with the NNT of 4 (95% CI 3–5), but with signifi-
IBS-C patients (164) and another only IBS-D patients (165). Only cant heterogeneity between studies.
three of the RCTs were at low risk of bias (167,169,170), with the In terms of the 10 different types of psychological therapies
remainder being unclear. evaluated, the benefits were demonstrated for cognitive behav-
Antidepressants were effective in treating IBS symptoms ioral therapy (NNT of 3 (95% CI 2–6)), hypnotherapy (NNT of
with the NNT of 4 (95% CI 3–6). The effect of antidepressant 4 (95% CI 3–8), multi-component psychological therapy (NNT
therapy on abdominal pain was reported by 7 RCTs (158,159,161, of 4 (95% CI 3–7)), multi-component psychological therapy
164–166,169), with 87 (46.7%) of 182 patients receiving anti- administered via the telephone (NNT of 5 (95% CI 3–17)), and

The American Journal of GASTROENTEROLOGY VOLUME 109 | SUPPLEMENT 1 | AUGUST 2014 www.amjgastro.com
 ACG Monograph on IBS and CIC S15

dynamic psychotherapy (NNT of 3.5 (95% CI 2–25)). No signifi- (a) 5-HT3 antagonists in IBS: Alosteron is effective in females with
cant effects were evident for relaxation therapy, self-administered diarrhea-predominant IBS.
cognitive behavioral therapy, behavioral therapy delivered via the Recommendation: weak. Quality of evidence: moderate.
internet, stress management, or mindfulness meditation training.
However, the latter three have only been tested in one or two We updated our previous systematic review and meta-analy-
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RCTs, and therefore a definite lack of benefit cannot be assumed. sis (19) and identified two new studies providing a total of 13
Only four trials (172,178,184,187) used “sham” or “control” trials eligible containing 8,173 patients for inclusion (208–220).
psychological interventions as a comparison. Only one trial was at low risk of bias (216), with the remainder
Adverse events data were poorly reported by individual RCTs, unclear. All but one recruited nonconstipated IBS. Most trials
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precluding any meaningful analysis. recruited women only, or predominantly women, with the
Summary: Although issues relating to blinding and choice of exception of two Japanese studies where men predominated
control intervention have complicated their evaluation, a variety (218,219), and a US-based trial that recruited only men (213).
of therapeutic approaches, loosely aggregated under the term Overall, there was a statistically significant effect in favor of
“psychological therapies,” have been shown to be effective in IBS. 5-HT3 antagonists with the NNT of 7 and significant hetero-
Availability of skilled therapists experienced in the management geneity.
of IBS greatly limits their use. There appeared to be no difference in efficacy between the three
drugs alosetron (208,210–214,216), cilansetron (209,215,220), and
9. Serotonergic agents ramosetron (218,219) within this class, all proving effective with
Serotonin (5-hydroxytryptamine (5-HT)) plays a critical role in NNTs of 8, 6, and 7, respectively.
gastrointestinal secretion, motility, and sensation (201), and a vari- There were 9 studies (208,210–214,216,218,219) evaluat-
ety of 5-HT receptors have been targets for new drug development ing 5,564 patients that provided total adverse event data. 5-HT3
in functional gastrointestinal disorders (202). The serotonin sub- antagonists had statistically significantly more adverse events
type 3 (5-HT3) receptors have been shown to play an important than placebo (RR of any adverse event = 1.17, 95% CI 1.08–1.25).
role in visceral pain, and 5-HT3 antagonists decrease painful sensa- The NNH was 11 (95% CI 8–17). The main adverse event that
tions from the gut and slow intestinal transit (203,204). Alosetron, was more common with 5-HT3 antagonists than with placebo was
a selective 5-HT3 antagonist, was therefore evaluated in diarrhea- constipation. Ischemic colitis has been reported with alosetron,
predominant IBS and, although it showed efficacy, instances of and it was withdrawn by the FDA in November 2001. In June
severe constipation and ischemic colitis (205) led, initially, to its 2002, the FDA announced the approval of a supplemental
withdrawal by the US Food and Drug Administration (FDA). It New Drug Application that allowed restricted marketing of
was subsequently reintroduced by the FDA in a restricted manner alosetron to treat only women with severe diarrhea-predominant
under a risk management plan for “women suffering with severe IBS. The approval includes a risk management program (termed
diarrhea-predominant IBS that is disabling” (http://www.fda.gov/ a risk evaluation and mitigation strategy since 2010) to ensure
downloads/Drugs/DrugSafety/PostmarketDrugSafetyInforma- patients and physicians are fully informed of the theoretical risks
tionforPatientsandProviders/UCM227960.pdf; accessed June 10th and possible benefits of alosetron (221).
2014). The risk management plan was converted to a risk evalu-
ation and mitigation strategy in 2010. Other 5-HT3 antagonists (b) 5-HT4 agonists in IBS: No further analysis of these agents was
such as cilansetron and ramosetron have never been introduced performed as there were no new data and tegaserod has been with-
into clinical practice. drawn in most areas.
The serotonin subtype 4 (5-HT4) receptors are distributed through-
out the gastrointestinal tract and stimulation of these receptors (c) Mixed 5-HT3 antagonists/5-HT4 agonists: Mixed 5-HT4 ago-
enhances intestinal secretion, augments the peristaltic reflex, and nists/5-HT3 antagonists are not more effective than placebo at
increases gastrointestinal transit (206,207). Tegaserod is an amino- improving symptoms of constipation-predominant IBS.
guanidine-indole categorized as a partial, selective 5-HT4 agonist. The Recommendation: strong. Quality of evidence: low.
FDA granted approval for the use of tegaserod in women with IBS with
constipation in July 2002. Because of possible cardiovascular adverse The complex physiology involved in the generation of IBS symp-
effects, tegaserod was withdrawn from the US market in March 2007. toms is thought to represent an intricate balance of 5-HT receptor
Tegaserod is the only 5-HT4 partial agonist that has been evaluated agonism and antagonism (201,206,207). Several agents classified
in large, prospective, randomized controlled studies in IBS patients. as mixed 5-HT3 antagonists/5-HT4 agonists have been developed
As tegaserod is no longer available in the United States, an updated for the treatment of IBS. These are collectively and individually
analysis of tegaserod efficacy and safety has not been performed. The reviewed below. It should be noted that cisapride has not been
interested reader is referred to the previous systematic review (19). widely available since withdrawal from the US market in July 2000
A number of selective 5-HT4 agonists have been developed and have and that this drug was shown to be not more effective than placebo
shown efficacy in constipation (e.g., prucalopride that is available in in a recent meta-analysis (19).
Canada and the European Union) but no data are, as yet, available on A total of 9 double-blind, placebo-controlled trials involv-
the efficacy or safety of these agents for the treatment of IBS. ing 2,905 patients were eligible for inclusion (222–230). Four

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

 S16 Ford et al.

studies each involved cisapride (223,225,227,228) or renzapride 95% CI 0.96–1.24). However, diarrhea, reported in all three trials,
(222,224,226,229); one study involved mosapride (230). Eight was significantly more likely with linaclotide as compared with
trials recruited patients with constipation-predominant IBS placebo (RR = 6.62, 95% CI 4.39–9.96) with the NNH of 6 (95%
(222–225,227–230) and one mixed IBS (226). The methodological CI 5.5–8). Flatulence, reported in two trials (232,234), was also
quality of trials was low. significantly more common with active therapy (RR = 2.27, 95%
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Analysis of all nine studies revealed no statistically significant CI 1.18–4.36), with the NNH of 50 (95% CI 23–167).
differences between placebo and mixed 5-HT3 antagonists/5-HT4
agonists for the treatment of IBS and significant heterogeneity was (b) Lubiprostone: Lubiprostone is superior to placebo for the treat-
identified between studies. ment of constipation-predominant IBS.
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In terms of individual agents, neither renzapride (222,224,226, Recommendation: strong. Quality of evidence: moderate.
229) in constipation-predominant or mixed IBS nor mosapride
(230) showed significant benefit over placebo. Lubiprostone activates the chloride channel type 2 (CIC-2) on
There was no statistically significant increase in adverse events the apical surface of the intestinal epithelium. This results in chlo-
with mixed 5-HT3 antagonists/5-HT4 agonists as compared with ride and water flux into the intestinal lumen, resulting in faster
placebo. transit through the small and large intestines.
Summary: Of the various agonists and antagonists to serotonergic Four clinical trials of lubiprostone in IBS patients have been
receptors that have been developed and evaluated in IBS, only aloset- reported in three separate papers (235–237). However, one of
ron and ramosetron, both 5-HT3 antagonists, are available (although these was a mixed population of IBS and CIC patients (236).
in certain regions only) and supported by evidence of efficacy. Three studies reported dichotomous data in 1,366 IBS patients
Because of concerns regarding adverse events, the use of alosetron (235,237). All trials were at low risk of bias. There was a statis-
in the United States is limited to women with severe diarrhea-pre- tically significant effect in favor of lubiprostone as compared
dominant IBS and can be prescribed only in the context of a carefully with placebo, with the NNT of 12.5 (95% CI 8–25), and no sig-
monitored program. Ramosetron is approved for the management nificant heterogeneity between the three individual trial results.
of diarrhea-predominant IBS in Japan, Korea, and Thailand. The quality of evidence was graded as moderate according to
GRADE criteria, as the effect on overall IBS symptoms was mod-
10. Prosecretory agents est and the 95% CI for the RR was relatively close to a null effect.
(a) Linaclotide: Linaclotide is superior to placebo for the treatment of Furthermore, dichotomous data for IBS patients from one trial
constipation-predominant IBS. were not available (236).
Recommendation: strong. Quality of evidence: high. Data on overall adverse events were reported in all three trials,
but pooled for the two trials reported in a single paper (235). In the
Linaclotide is a 14-amino acid peptide structurally similar to study by Johanson et al. (237), adverse events were reported by 66%
hormones in the guanylin peptide family. Guanylin peptides are of lubiprostone patients as compared with 58% of placebo, but this
endogenous hormones that assist in the regulation of intestinal difference was not statistically significant. Nausea was also com-
fluid and electrolyte homeostasis by binding to, and activating, moner (17% with lubiprostone compared with 4% with placebo),
guanylate cyclase-C receptors on the lumen of intestinal epithe- but again this was not statistically significant. The only adverse
lium. Activation of guanylate cyclase-C results in an increase of event occurring more frequently among those receiving lubipros-
cyclic guanosine monophosphate that triggers a series of events tone was diarrhea (NNH = 10, 95% CI 5–25). In the two studies
leading to the activation of the cystic fibrosis transmembrane that pooled adverse events data (235), 50% and 51% of IBS patients
conductance regulator that results in secretion of bicarbonate receiving lubiprostone and placebo, respectively, reported at
and chloride into the lumen, followed by sodium and water flux least one adverse event. Diarrhea occurred in 6% of lubiprostone-
into the intestinal lumen, as well as modulation of pain afferent treated patients compared with 4% of those receiving placebo.
sensors (231). Nausea was reported by 8% of those allocated to lubiprostone com-
Three randomized clinical trials in IBS patients were identified pared with 4% of those assigned to placebo.
involving 2,028 combined patients (232–234). All trials were at low Summary: The prosecretory agents linaclotide and lubiprostone
risk of bias, and there was no significant heterogeneity between are effective in constipation-predominant IBS. As both of these agents
individual trial results. were evaluated in comparison with placebo rather than “standard
There was a statistically significant effect in favor of linaclotide therapy,” their position in an IBS treatment algorithm (i.e., for those
compared with placebo with the NNT of 6 (95% CI 5–8), with no who have failed other treatments or as primary therapy) is difficult
significant heterogeneity between studies. There was a statistically to define and complicated by lack of consensus on what “standard”
significant effect in favor of linaclotide compared with placebo on therapy should be in IBS, given the limitations of data on other agents.
abdominal pain (NNT of 8), but with significant heterogeneity
between individual trial results. 11. PEG in IBS
Data on overall adverse events were provided by two of the There is no evidence that PEG improves overall symptoms and pain
three trials (232,234). Overall, adverse event rates were not higher in patients with IBS.
among those taking linaclotide compared with placebo (RR = 1.09, Recommendation: weak. Quality of evidence: very low.

The American Journal of GASTROENTEROLOGY VOLUME 109 | SUPPLEMENT 1 | AUGUST 2014 www.amjgastro.com
 ACG Monograph on IBS and CIC S17

PEG is a large polymer that behaves as an osmotic laxa- Combined data from the three trials (243,245,246) suggested
tive, and although it is approved by the FDA for the treatment that fiber was beneficial compared with placebo with the NNT
of occasional constipation, it has not been extensively studied of 2 (95% CI 1.6–3) and no statistically significant heterogene-
in patients with IBS-C. One open-label study in 27 adolescents ity between studies. Although these trials could be combined for
with IBS-C suggested that PEG improved stool frequency but analysis, the definitions of improvement were all different, and in
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not pain (238). We identified only two RCTs (239,240) of PEG one trial (245) not all patients enrolled in the trial had the outcome
in IBS. In one trial, there was no statistically significant effect on that was used to define treatment success present at baseline. The
bowel movements or discomfort and pain (239). In the second effect size given in this meta-analysis therefore needs to be treated
trial (240), which recruited 139 patients with IBS with constipa- with extreme caution.
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tion, the mean increase in spontaneous bowel movements was In terms of individual formulations, among the three trials
significantly greater with PEG compared with placebo at 4 weeks, (241,243,246) that studied psyllium, including the largest iden-
but there was no difference in effect on abdominal pain or dis- tified RCT conducted by Fenn et al. (243), although outcomes
comfort. Response rates, defined as more than four spontane- varied between these RCTs, all reported significant benefits with
ous bowel movements per week with an increase of two or more psyllium.
from baseline and no worsening of abdominal pain or discom- Lopez Roman et al. (245) used 20 g of a soluble fiber mixture of
fort, were significantly higher with PEG (36.5% vs. 17.5% with inulin and maltodextrin, administered as a dairy preparation, and
placebo, P < 0.05). However, there was no significant difference reported significant reductions in the proportion of patients with
in the proportion of patients with a pain response, defined as a straining during defecation, sensation of incomplete evacuation, or
decrease by 10% or more from baseline (61.9% vs. 47.6%, P > 0.1). sensation of obstruction with soluble fiber. In addition, the number
Adverse event rates were higher with PEG (38.8% vs. 32.9%), but of days between bowel movements was also significantly reduced.
most of these were mild or moderate. Two trials reported on the efficacy of insoluble fiber in CIC
Summary: There is no evidence that PEG formulations alleviate (242,244). The 24 patients recruited were allocated to receive 20 g
pain or provide overall symptom relief in IBS. of bran per day or placebo. No significant benefits were noted with
bran (242) but rye bread was effective (244).
Chronic idiopathic constipation No single study reported total adverse events. One trial reported
1. Fiber in CIC the number of patients in each trial arm who dropped out because
Some medicinal and dietary fiber supplements increase stool of adverse events (one with psyllium and two with placebo) (243).
frequency in patients with chronic idiopathic constipation. Ashraf et al. (241) recorded individual adverse events, with 18%
Recommendation: strong. Quality of evidence: low. of psyllium patients experiencing abdominal pain compared with
0% of placebo patients, but no differences in back pain, bloating,
Dietary fiber is defined as carbohydrate polymers that are or cramping. Finally, there were higher combined symptom scores
incapable of being digested in the normal small intestine and for gastrointestinal side effects such as abdominal pain, flatulence,
are delivered to the colon. Fiber can be part of ingested food or borborygmi, and bloating with rye bread compared with low-fiber
purified and taken as a supplement (“medicinal fiber”). Fiber is toast (244).
classified as “soluble” or “insoluble” depending on its interaction Summary: Fiber and soluble fiber, in particular, are effective
with water. Psyllium is the archetypical soluble fiber; bran is in the management of chronic constipation. Adverse events and
insoluble. bloating, distension, flatulence, and cramping may limit the use
Psyllium husk is the outer coat of the psyllium seed (known of insoluble fiber, especially if increases in fiber intake are not
in India as ispaghula seed) from the plant Plantago ovata. It can introduced gradually.
undergo bacterial fermentation in the colon, thereby producing
gas and bloating. Semisynthetic bulking agents less suscepti- 2. Osmotic and stimulant laxatives in CIC
ble to fermentation include calcium polycarbophil and methyl- Osmotic laxatives contain poorly absorbed ions or molecules that
cellulose. Few studies have been done with bulking agents in retain water in the intestinal lumen. Osmotic agents used with
CIC and the quality of evidence about the use of these agents some frequency include polyethylene glycol, lactulose, magnesium
is very low. hydroxide, magnesium citrate, magnesium sulfate, and sodium
Six trials met the criteria for inclusion in this review (241–246), phosphate.
but a formal meta-analysis was only possible with three trials
(243,245,246), and the remaining studies could not be analyzed (a) Osmotic laxatives in CIC: PEG is effective in improving symp-
because of crossover design (241,242) or a failure to provide toms of CIC.
dichotomous data for extraction (244) with uncertainty regard- Recommendation: strong. Quality of evidence: high.
ing whether the study was truly random. Four of the eligible tri- Lactulose is effective in improving symptoms of CIC.
als used soluble fiber: three used psyllium (241,243,246) and the Recommendation: strong. Quality of evidence: low.
fourth used a combination of inulin and maltodextrose (245). Two
used insoluble fiber: wheat bran in one study (242) and rye bread Five studies compared PEG with placebo (247–251); four
in the other (244). reported dichotomous data in 573 patients (247–250) with the

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

 S18 Ford et al.

NNT of 3 (95% CI 2–4). All trials were at low risk of bias and there Eight of these trials involved prucalopride (257–259,261–265),
was moderate heterogeneity between studies. Two studies (252,253) whereas one trial involved velusetrag (260). Two studies inves-
evaluated lactulose compared with placebo in 148 patients, with tigated the effects of prucalopride in patients either resistant to,
the NNT of 4 (95% CI 2–7). Both trials were at high risk of bias and or dissatisfied with, laxatives (258,264). One study investigated
there was moderate heterogeneity between studies. the effects of prucalopride in patients aged 65 years and older
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Trials with osmotic laxatives did not report on the total number (262). Doses ranged from 0.5 to 4 mg daily; studies lasted from
of adverse events. Where reported (247,248), the incidence of indi- 4 to 12 weeks. Five trials were considered to be at low risk of
vidual adverse events, including abdominal pain, or headache, did bias (257,260,262,263,265).
not differ between active agent and placebo. In an analysis of all 9 trials, 72.3% of patients (1,691/2,339) who
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received 5-HT4 agonists failed to respond to therapy as compared

(b) Stimulant laxatives in CIC: Sodium picosulfate and bisacodyl are with 88.1% (1,059/1,202) of those allocated to placebo, with the
effective in CIC. NNT of 6 (95% CI 5–8). Significant heterogeneity was noted
Recommendation: strong. Quality of evidence: moderate. between the studies.
Analysis of the 8 prucalopride trials revealed that 71.1%
Stimulant laxatives appear to induce fluid and electrolyte (1,454/2,045) of patients treated with prucalopride failed to
secretion by the colon or induce peristalsis in the colon, thereby respond to therapy as compared with 87.4% (957/1,095) of
producing a bowel movement. Stimulant laxatives include senna, those randomized to placebo, with the NNT of 5 (95% CI 4–8).
bisacodyl, castor oil, cascara, rhubarb, and aloe. Significant heterogeneity was identified between studies. One
Both trials of stimulant laxatives, containing 735 patients, study performed a subgroup analysis of those patients treated
reported dichotomous data and had a low risk of bias (254,255). In with prucalopride who had previously failed laxatives (264). The
total, 42.1% of all patients randomized to stimulant laxatives failed authors reported that the effects of prucalopride were similar in
to respond to therapy as compared with 78.0% of those receiving patients who had failed other laxatives compared with the overall
placebo, with the NNT of 3 (95% CI 2–3.5) and with statistically population, although a better comparator would have contrasted
significant heterogeneity between studies. those patients who did not use laxatives before being enrolled in
Only one RCT reported total numbers of adverse events (254); the trial with those who did.
the RR of experiencing any adverse event with laxatives was 1.94 Analysis of the one velusetrag trial revealed that 80.6% (237/294)
(95% CI 1.52–2.47, NNH = 3, 95% CI 2–4). Diarrhea occurred sig- of patients treated with velusetrag failed to respond to therapy as
nificantly more frequently in the two trials (RR = 13.75, 95% CI compared with 95.3% (102/107) of those randomized to placebo;
2.82–67.14, NNH = 3, 95% CI 2–6) (254,255). the NNT was 7 (95% CI 5–11).
Summary: Although supported by varying levels of evidence, the Eight trials reported total numbers of adverse events (257–260,
osmotic laxatives PEG and lactulose and the stimulant laxatives 262–265); these were more common in patients treated with 5-HT4
sodium picosulfate and bisacodyl have been shown to be effec- agonists than with placebo (RR = 1.28, 95% CI 1.11–1.48, NNH = 8;
tive in chronic constipation. Other stimulant laxatives, although 95% CI 5–16). Individual adverse events including headache,
commonly used by sufferers, have not been adequately studied nausea, and diarrhea were all more common in patients who used
and cannot be recommended at this time. Other laxatives have not 5-HT4 agonists compared with placebo. Selective 5-HT4 agonists
been formally tested. were not associated with an increase in serious adverse event rates
(RR = 0.84, 95% CI 0.57–1.25), and only 2 cardiovascular events
3. 5-HT4 agonists in CIC were reported (supraventricular tachycardia in one patient and
Prucalopride is more effective than placebo in improving symptoms electrocardiogram signs of myocardial ischemia in the second)
of CIC. (257,265).
Recommendation: strong. Quality of evidence: moderate. Summary: The 5-HT4 agonists prucalopride and velusetrag are
effective in CIC, with the former supported by considerably more
Serotonin (5-HT) plays a critical role in the gastrointestinal tract data. To date, the cardiac adverse events that bedeviled prior 5-HT4
and influences secretory, motor, and sensory functions (256). There agonists have not emerged as a significant issue; neither is available
are seven major classes of serotonin receptor subtypes (5-HT1 − 7); in the United States at this time.
stimulation of the 5-HT4 receptor enhances intestinal secretion,
augments the peristaltic reflex, and increases gastrointestinal 4. Prosecretory agents in CIC
transit (206,207). The 5-HT4 receptor agonism has the potential (a) Linaclotide: Linaclotide is effective in chronic idiopathic consti-
to improve symptoms of CIC. The selective 5-HT4 agonists pruca- pation. It is generally safe, with the main adverse event being
lopride and velusetrag are reviewed below. Tegaserod, a selective, diarrhea.
partial 5-HT4 agonist, was removed from the US market in March Recommendation: strong. Quality of evidence: high.
2007 because of possible adverse cardiovascular effects, and will
not be discussed further. Review of the literature demonstrated no new randomized
Efficacy: We identified 9 randomized, placebo-controlled trials clinical trials since a previously published systematic review
of 5-HT4 agonists in CIC involving 3,441 patients (257–265). and meta-analysis (21). In total, three trials have been reported

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 ACG Monograph on IBS and CIC S19

in two separate publications (266,267) involving a total of 1,582 internal and external anal sphincters, perineal muscles, as well
CIC patients. All three trials were at low risk of bias. Overall, 860 as the levator ani including the puborectalis muscle (272). Incor-
(79.0%) of 1,089 patients receiving linaclotide failed to respond rect technique, structural abnormalities (e.g., rectocele), and
to therapy as compared with 468 (94.9%) of 493 placebo patients, pudendal and perineal nerve damage can contribute to incom-
with the NNT of 6 (95% CI 5–8). No significant heterogeneity was plete defecation (273). Symptoms and signs include straining,
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observed between studies. incomplete evacuation, and digital maneuvers. Complications

Two of the trials pooled adverse events data together (267), can include rectal prolapse, rectocele, and anal fissures.
precluding meta-analysis. Overall, 58% of linaclotide patients Typical features of pelvic floor dyssynergia include incomplete
experienced any adverse event compared with 52% of placebo relaxation or paradoxical contraction of the anal canal, paradoxical
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patients. In the third trial, adverse event rates were very similar contraction of the puborectalis muscle, or uncoordinated move-
in number in both treatment arms (33.6% linaclotide vs. 31.9% ment of the abdominal, rectal, and anal muscles. As such, the goals
placebo) (266). Separate adverse events data for diarrhea in each of biofeedback are to provide a tailored approach to correction of
trial were obtained from the authors as part of the meta-analysis improper defecatory technique. Trained physical therapists use a
(21). Diarrhea was more common in patients receiving linaclotide variety of techniques and tools to assess and correct underlying
compared with placebo (RR = 3.08, 95% CI 1.27–7.48, NNH = 12; technical abnormalities.
95% CI 7–38.5). Biofeedback, performed by a trained and skilled therapist, is effective
in relief of constipation symptoms in CIC patients with demonstrated
(b) Lubiprostone: Lubiprostone is effective in the treatment of chronic evidence of pelvic floor dyssynergia.
idiopathic constipation. Recommendation: weak. Quality of evidence: low.
Recommendation: strong. Quality of evidence: high.
A total of nine randomized clinical trials (274–282) of patients
We updated a previous meta-analysis on lubiprostone in CIC (21) with CIC with pelvic floor dyssynergia were identified. Six were
that had involved three trials of lubiprostone in CIC (268–270). We excluded because either they did not report a relevant outcome
found two additional clinical trials of lubiprostone (236,271) but (277) or data were not extractable (278) or they compared bio-
these two studies did not provide extractable dichotomous data. feedback with balloon-assisted training or different forms of
After contact with the authors, we obtained dichotomous data for biofeedback (279–282), leaving three randomized clinical trials
one of these studies (271) but not the second (236), despite con- (274–276) that evaluated 216 patients that compared biofeed-
tacting both the original authors and the manufacturers. There- back to a sham therapy or PEG laxative. All trials were unclear
fore, this meta-analysis included four trials of lubiprostone in CIC or at high risk of bias because of inability to blind participants to
involving 651 patients in total. Two trials were at low risk of bias the nature of the interventions, or a lack of reporting of methods
(270,271). used to generate the randomization schedule or conceal allo-
Of the 364 patients receiving lubiprostone, 45.3% failed to cation. There was a statistically significant benefit of biofeed-
respond to therapy compared with 66.9% of 287 placebo patients, back (RR constipation not improved = 0.33, 95% CI 0.22–0.50)
with the NNT of 4 (95% CI 3–6) and no heterogeneity between with the NNT of 2 (95% CI 1.6–4) and no statistically significant
studies. heterogeneity.
Three trials reported adverse events data (268–270). Total num- None of the eligible trials (274–276) reported on adverse
bers of adverse events were significantly higher with lubiprostone events.
(RR = 1.79, 95% CI 1.21–2.65, NNH = 4, 95% CI 3–6). Diarrhea Summary: Although techniques may vary in precise methodo-
and nausea both occurred significantly more frequently with lubi- logical details, biofeedback administered by a skilled and expe-
prostone, but no significant difference in rates of abdominal pain rienced therapist is, in general, effective in the management of
or headache were detected. patients with CIC who have prominent features of pelvic floor
Summary: The prosecretory agents linaclotide and lubiprostone dyssynergia. Access to such expertise limits the usefulness of this
are effective in CIC and are well tolerated. There have been no approach for many patients and their physicians.
comparative studies. As both were evaluated in comparison with
placebo rather than “standard therapy,” a recommendation regard- 6. Bile acid transporter inhibitors in CIC
ing their precise position in a CIC treatment algorithm (i.e., for The ileal bile acid transporter (IBAT) inhibitor A3309 is a promising
those who have failed fiber, osmotic, or stimulant laxatives, or as new therapy for CIC.
primary therapy) cannot be made at this time. Grading not appropriate as no implication for current CIC manage-
ment.
5. Biofeedback in CIC
One of the potential causes of constipation is pelvic floor The IBAT is the most important transporter of the bile acid
dysfunction or dyssynergia. Either alterations in pelvic floor reabsorption loop. IBAT inhibitors selectively inhibit the reuptake
anatomy or function can result in impaired ability to defe- of bile acids in the ileum, resulting in increased secretion and
cate effectively. Defecation requires coordinated activity that motor activity in the colon. Recently, the IBAT inhibitor A3309
includes generation of intrarectal pressure, and relaxation of the has been proposed as a potential treatment for CIC.

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

 S20 Ford et al.

We identified 3 RCTs of the bile acid transporter inhibitor A3309 Potential competing interests: A.C. Ford has received grant/research
in CIC involving 256 patients (283–285). All three trials were at support from Almirall and GE Healthcare, and is a consultant/
low risk of bias. Varying doses of A3309 were employed ranging speaker for Almirall, GE Healthcare, Mayoly Spindler, Merck Sharp
from as low as 0.1 mg to as high as 20 mg. Responses were dose & Dohme, and Shire Pharmaceuticals. B.E. Lacy has served on
dependent. In the largest study to date (283), an increase of ≥1 scientific advisory boards for Ironwood Pharmaceuticals, Takeda,
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complete spontaneous bowel movements per week over baseline Salix, and Prometheus, is a consultant to Furiex, and receives grant
for 4 of the 8 weeks of the study was reported for 58, 64, and 75% support from the NIH for the functional dyspepsia treatment trial.
of those randomized to 5, 10, and 15 mg of A3309, respectively, Y.A. Saito has received research funding from Pfizer and Ironwood
compared with 33% for placebo. Pharmaceuticals, and is on the advisory board of Salix. L.R. Schiller
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Diarrhea was more common in the patients receiving A3309 has served on the speakers’ bureau for Forest Laboratories, Iron-
compared with placebo (RR = 2.62, 95% CI 0.72–9.56). wood Pharmaceuticals, Abbott/Abbvie, Takeda, Salix, and Santarus
Pharmaceuticals. E.E. Soffer has served as a consultant and share-
7. Probiotics in CIC holder for EndoStim. B.M.R. Spiegel has received grant support from
There is insufficient evidence to recommend probiotics in CIC. Takeda, Ironwood Pharmaceuticals, Theravance, Amgen, Shire, and
Recommendation: weak. Quality of evidence: very low. Nestlé Health Sciences, is an advisor to Astellas, and received con-
sulting fees from Ironwood Pharmaceuticals and lecture fees from
We identified three trials evaluating probiotics in 245 CIC patients Takeda. E.M.M. Quigley has served as a consultant and/or on the
(286–288). None of the eligible trials stated the method of randomi- advisory board for Salix, Almirall, Ironwood Pharmaceuticals, For-
zation or concealment and one was an open design. In two trials est Laboratories, Shire/Movetis, Janssen, Rhythm Pharmaceuticals,
(286,288), the risk of bias was deemed to be unclear and one (287) Vibrant, and Alimentary Health, has served as a speaker for Procter
had a high risk of bias. There were two trials (286,287) that reported & Gamble, Almirall, Janssen, Alimentary Health, and Shire, has
on improvement in constipation in 110 CIC patients. Although both received research support from Rhythm, Alimentary Health, Vibrant
trials were positive in favor of probiotics improving constipation, Pharma, and Norgine, and has been a non-executive director, share-
the pooled data were not statistically significant (RR = 0.29, 95% CI holder, and patent holder for Alimentary Health. P. Moayyedi has
0.07–1.12) in a random effects model as there was significant heter- served as a speaker for AstraZeneca, Shire, and Forest Laboratories
ogeneity between the two trials. There were two trials (287,288) that Canada, has served as consultant and/or on the advisory board for
reported on mean number of bowel movements per week in 165 Forest Laboratories Canada, and his Chair at McMaster University
patients. There was a significant improvement in the mean number is funded in part by an unrestricted donation from AstraZeneca to
of bowel movements per week (mean increase in bowel movements McMaster University. A.J. Lembo has served as a consultant and/or
per week in the symbiotic group = 1.49, 95% CI 1.02–1.96). on the advisory board for Ironwood Pharmaceuticals, Forest Labora-
tories, Salix, Prometheus, AstraZeneca, and Furiex, and has received
CONFLICT OF INTEREST research support from Prometheus and Furiex.
Guarantor of the article: Eamonn M.M. Quigley, MD, FACG.
Specific author contributions: A.C. Ford and P. Moayyedi performed REFERENCES
the meta-analyses and participated in writing and reviewing the 1. Lovell RM, Ford AC. Global prevalence of, and risk factors for, irritable bowel
syndrome: a meta-analysis. Clin Gastroenterol Hepatol 2012;10:712–21.
manuscript; E.M.M. Quigley, B.E. Lacy, Y.A. Saito, L.R. Schiller, E.E. 2. Quigley EM, Abdel-Hamid H, Barbara G et al. A global perspective on
Soffer, B.M.R. Spiegel, and A.J. Lembo, together with P. Moayyedi, irritable bowel syndrome: a consensus statement of the World Gastro-
developed all grading and recommendations and contributed to writ- enterology Organisation Summit Task Force on Irritable Bowel Syndrome.
J Clin Gastroenterol 2012;46:356–66.
ing the manuscript. All authors reviewed all drafts of the manuscript 3. Suares NC, Ford AC. Prevalence of, and risk factors for, chronic idiopathic
and agreed with the final version. A.C. Ford is first author on the constipation in the community: systematic review and meta-analysis.
monograph, but is not a member of the Task Force. *P. Moayyedi Am J Gastroenterol 2011;106:1582–91.
4. Belsey J, Greenfield S, Candy D et al. Systematic review: impact of constipa-
conducted systematic reviews with support of A.C. Ford, and carried tion on quality of life in adults and children. Aliment Pharmacol Ther
out the technical analyses of the data independent of the Task Force. 2010;31:938–49.
Financial support: Unrestricted grants have been provided to the 5. Koloski NA, Jones M, Wai R et al. Impact of persistent constipation on
health-related quality of life and mortality in older community-dwelling
American College of Gastroenterology from Forest Laboratories, women. Am J Gastroenterol 2013;108:1152–8.
Ironwood Pharmaceuticals, Nestlé Health Science, and Prometheus 6. Longstreth GF, Thompson WG, Chey WD et al. Functional bowel disorders.
Laboratories. The analysis that supports this monograph and its Gastroenterology 2006;130:1480–91.
7. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit
writing were conducted on behalf of the American College of time. Scand J Gastroenterol 1997;32:920–4.
Gastroenterology and the ACG Institute for Clinical Research & 8. Whitehead WE, Engel BT, Schuster MM. Irritable bowel syndrome: physio-
Education by the ACG Functional Bowel Disorders Task Force, logical and psychological differences between diarrhea-predominant and
constipation-predominant patients. Dig Dis Sci 1980;25:404–13.
which had complete scientific and editorial control of its content and 9. Wouters MM, Lambrechts D, Knapp M et al. Genetic variants in CDC42
whose work was supported exclusively by the ACG Institute. Readers and NXPH1 as susceptibility factors for constipation and diarrhoea
should note that the work of the systematic review was conducted predominant irritable bowel syndrome. Gut 2014;63:1103–11.
10. Hughes PA, Harrington AM, Castro J et al. Sensory neuro-immune inter-
and the writing of the IBS/CIC monograph was completed before actions differ between irritable bowel syndrome subtypes. Gut 2013;62:
funding was obtained. 1456–65.

The American Journal of GASTROENTEROLOGY VOLUME 109 | SUPPLEMENT 1 | AUGUST 2014 www.amjgastro.com
 ACG Monograph on IBS and CIC S21

11. Olafsdottir LB, Gudjonsson H, Jonsdottir HH et al. Irritable bowel syn- 39. Heizer WD, Southern S, McGovern S. The role of diet in symptoms of
drome: physicians’ awareness and patients’ experience. World J Gastroen- irritable bowel syndrome in adults: a narrative review. J Am Diet Assoc
terol 2012;18:3715–20. 2009;109:1204–14.
12. Brandt LJ, Bjorkman D, Fennerty MB et al. Systematic review on the man- 40. Monsbakken KW, Vandvik PO, Farup PG. Perceived food intolerance in
agement of irritable bowel syndrome in North America. Am J Gastroen- subjects with irritable bowel syndrome--etiology, prevalence and conse-
terol 2002;97 (11 Suppl): S7–S26. quences. Eur J Clin Nutr 2006;60:667–72.
13. Brandt LJ, Prather CM, Quigley EM et al. Systematic review on the man- 41. Halpert A, Dalton CB, Palsson O et al. What patients know about irritable
Downloaded from http://journals.lww.com/ajg by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWn

agement of chronic constipation in North America. Am J Gastroenterol bowel syndrome (IBS) and what they would like to know. National Survey
2005;100 (Suppl 1): S5–S21. on Patient Educational Needs in IBS and development and validation of
14. Shekhar C, Monaghan PJ, Morris J et al. Rome III functional constipation the Patient Educational Needs Questionnaire (PEQ). Am J Gastroenterol
and irritable bowel syndrome with constipation are similar disorders within 2007;102:1972–82.
a spectrum of sensitization, regulated by serotonin. Gastroenterology 42. Hayes P, Corish C, O’Mahony E et al. A dietary survey of patients with ir-
2013;145:749–57. ritable bowel syndrome. J Hum Nutr Diet 2014;27 (Suppl 2): 36–47.
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/18/2024

15. Wong RK, Palsson O, Turner MJ et al. Inability of the Rome III criteria to 43. Atkinson W, Sheldon TA, Shaath N et al. Food elimination based on IgG
distinguish functional constipation from constipation-subtype irritable antibodies in irritable bowel syndrome: a randomised controlled trial. Gut
bowel syndrome. Am J Gastroenterol 2010;105:2228–34. 2004;53:1459–64.
16. Zhao YF, Ma XQ, Wang R et al. Epidemiology of functional constipation 44. Biesiekierski JR, Newnham ED, Irving PM et al. Gluten causes gastroin-
and comparison with constipation-predominant irritable bowel syndrome: testinal symptoms in subjects without celiac disease: a double-blind rand-
The Systematic Investigation of Gastrointestinal Diseases in China (SILC). omized placebo-controlled trial. Am J Gastroenterol 2011;106:508–14.
Aliment Pharmacol Ther 2011;34:1020–9. 45. King TS, Elia M, Hunter JO. Abnormal colonic fermentation in irritable
17. Brandt LJ, Chey WD, Foxx-Orenstein AE et al. An evidence-based bowel syndrome. Lancet 1998;352:1187–9.
systematic review on the management of irritable bowel syndrome. Am J 46. Ong DK, Mitchell SB, Barrett JS et al. Manipulation of dietary short chain
Gastroenterol 2009;104 (Suppl I): S8–S35. carbohydrates alters the pattern of gas production and genesis of symptoms
18. Ford AC, Talley NJ, Spiegel BMR et al. Effect of fibre, antispasmodics, and in irritable bowel syndrome. J Gastroenterol Hepatol 2010;25:1366–73.
peppermint oil in irritable bowel syndrome: systematic review and meta- 47. Staudacher HM, Lomer MC, Anderson JL et al. Fermentable carbohydrate
analysis. BMJ 2008;337:1388–92. restriction reduces luminal bifidobacteria and gastrointestinal symptoms
19. Ford AC, Brandt LJ, Young C et al. Efficacy of 5-HT3 antagonists and 5-HT4 in patients with irritable bowel syndrome. J Nutr 2012;142:1510–8.
agonists in irritable bowel syndrome: systematic review and meta-analysis. 48. Bentley SJ, Pearson DJ, Rix KJ. Food hypersensitivity in irritable bowel
Am J Gastroenterol 2009;104:1831–43. syndrome. Lancet 1983;2:295–7.
20. Ford AC, Talley NJ, Schoenfeld PS et al. Efficacy of antidepressants and 49. Carroccio A, Brusca I, Mansueto P et al. Fecal assays detect hypersensitivity
psychological therapies in irritable bowel syndrome: systematic review and to cow’s milk protein and gluten in adults with irritable bowel syndrome.
meta-analysis. Gut 2009;58:367–78. Clin Gastroenterol Hepatol 2011;9:965–71.
21. Ford AC, Suares NC. Effect of laxatives and pharmacological therapies in 50. Shepherd SJ, Parker FC, Muir JG et al. Dietary triggers of abdominal
chronic idiopathic constipation: systematic review and meta-analysis. Gut symptoms in patients with irritable bowel syndrome: randomized
2011;60:209–18. placebo-controlled evidence. Clin Gastroenterol Hepatol 2008;6:765–71.
22. Moayyedi P, Ford AC, Brandt LJ et al. The efficacy of probiotics in the 51. Vazquez Roque MI, Camilleri M, Smyrk T et al. A controlled trial of
treatment of irritable bowel syndrome: a systematic review. Gut 2010;59: gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects
325–32. on bowel frequency and intestinal function. Gastroenterology 2013;144:
23. Manning AP, Thompson WG, Heaton KW et al. Towards positive diagnosis 903–11.
of the irritable bowel. BMJ 1978;277:653–4. 52. Halmos EP, Power VA, Shepherd SJ et al. A diet low in FODMAPs reduces
24. Kruis W, Thieme CH, Weinzierl M et al. A diagnostic score for the irritable symptoms of irritable bowel syndrome. Gastroenterology 2014;146:67–75.
bowel syndrome. Its value in the exclusion of organic disease. Gastro- 53. Biesiekierski JR, Peters SL, Newnham ED et al. No effects of gluten in
enterology 1984;87:1–7. patients with self-reported non-celiac gluten sensitivity after dietary
25. Drossman DA, Thompson WG, Talley NJ. Identification of sub-groups of reduction of fermentable, poorly absorbed, short-chain carbohydrates.
functional gastrointestinal disorders. Gastroenterology Intl 1990;3:159–72. Gastroenterology 2013;145:320–8.
26. Thompson WG, Longstreth GF, Drossman DA et al. Functional bowel 54. Berg LK, Fagerli E, Martinussen M et al. Effect of fructose-reduced diet in
disorders and functional abdominal pain. Gut 1999;45 (Suppl II): II43–7. patients with irritable bowel syndrome, and its correlation to a standard
27. Higgins JPT, Green S. Cochrane handbook for systematic reviews of fructose breath test. Scand J Gastroenterol 2013;48:936–43.
interventions: Version 5.0.2. www.cochrane-handbook.org, 2009. 55. Moayyedi P, Quigley EM, Lacy BE et al. The effect of fiber supplementation
28. Dersimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials on irritable bowel syndrome: A systematic review and meta-analysis.
1986;7:177–88. Am J Gastroenterol 2014 (in press).
29. Higgins JPT, Thompson SG, Deeks JJ et al. Measuring inconsistency in 56. Arthurs Y, Fielding JF. Double blind trial of ispaghula/poloxamer in the
meta-analyses. BMJ 2003;327:557–60. irritable bowel syndrome. Ir Med J 1983;76:253.
30. Egger M, Davey-Smith G, Schneider M et al. Bias in meta-analysis detected 57. Bijkerk CJ, de Wit NJ, Muris JW et al. Soluble or insoluble fibre in irritable
by a simple, graphical test. BMJ 1997;315:629–34. bowel syndrome in primary care? Randomised placebo controlled trial.
31. Sterne JA, Sutton AJ, Ioannidis JP et al. Recommendations for examining BMJ 2009;339:b3154.
and interpreting funnel plot asymmetry in meta-analyses of randomised 58. Fowlie S, Eastwood MA, Prescott R. Irritable bowel syndrome: assessment
controlled trials. BMJ 2011;343:d4002. of psychological disturbance and its influence on the response to fibre
32. Guyatt G, Oxman AD, Akl EA et al. GRADE guidelines: 1. Introduction- supplementation. J Psychosom Res 1992;36:175–80.
GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 59. Jalihal A, Kurian G. Ispaghula therapy in irritable bowel syndrome:
2011;64:383–94. improvement in overall well-being is related to reduction in bowel
33. Balshem H, Helfand M, Schunemann HJ et al. GRADE guidelines: 3. Rat- dissatisfaction. J Gastroenterol Hepatol 1990;5:507–13.
ing the quality of evidence. J Clin Epidemiol 2011;64:401–6. 60. Kruis W, Weinzierl M, Schussler P et al. Comparison of the therapeutic
34. Simren M, Mansson A, Langkilde AM et al. Food-related gastrointestinal effects of wheat bran, mebeverine and placebo in patients with the irritable
symptoms in the irritable bowel syndrome. Digestion 2001;63:108–15. bowel syndrome. Digestion 1986;34:196–201.
35. Rona RJ, Keil T, Summers C et al. The prevalence of food allergy: a meta- 61. Longstreth GF, Fox DD, Youkeles L et al. Psyllium therapy in the irritable
analysis. J Allergy Clin Immunol 2007;120:638–46. bowel syndrome: a double-blind trial. Ann Intern Med 1981;95:53–6.
36. Lack G. Epidemiologic risks for food allergy. J Allergy Clin Immunol 62. Lucey MR, Clark ML, Lowndes JO et al. Is bran efficacious in irritable
2008;121:1331–6. bowel syndrome? A double blind placebo controlled crossover study. Gut
37. Bhat K, Harper A, Gorard DA. Perceived food and drug allergies in 1987;28:221–5.
functional and organic gastrointestinal disorders. Aliment Pharmacol Ther 63. Manning AP, Heaton KW, Harvey RF et al. Wheat fibre and irritable bowel
2002;16:969–73. syndrome: a controlled trial. Lancet 1977;310:417–8.
38. Young E, Stoneham MD, Petruckevitch A et al. A population study of food 64. Nigam P, Kapoor KK, Rastog CK et al. Different therapeutic regimens in
intolerance. Lancet 1994;343:1127–30. irritable bowel syndrome. J Assoc Physicians India 1984;32:1041–4.

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

 S22 Ford et al.

65. Prior A, Whorwell P. Double blind study of ispaghula in irritable bowel irritable bowel syndrome - A randomized, double-blind, controlled study.
syndrome. Gut 1987;28:1510–3. Aliment Pharmacol Ther 2010;31:218–27.
66. Rees G, Davies J, Thompson R et al. Randomised-controlled trial of a fibre 90. Choi CH, Jo SY, Park HJ et al. A randomized, double-blind, placebo-
supplement on the symptoms of irritable bowel syndrome. J R Soc Health controlled multicenter trial of Saccharomyces boulardii in irritable bowel
2005;125:30–4. syndrome: effect on quality of life. J Clin Gastroenterol 2011;45:679–83.
67. Ritchie JA, Truelove SC. Treatment of irritable bowel syndrome with 91. Guglielmetti S, Mora D, Gschwender M et al. Randomised clinical trial:
lorazepam, hyoscine butylbromide, and ispaghula husk. BMJ 1979;278: Bifidobacterium bifidum MIMBb75 significantly alleviates irritable bowel
Downloaded from http://journals.lww.com/ajg by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWn

376–8. syndrome and improves quality of life - a double-blind, placebo-controlled

68. Soltoft J, Krag B, Gudmand-Hoyer E et al. A double-blind trial of the study. Aliment Pharmacol Ther 2011;33:1123–32.
effect of wheat bran on symptoms of irritable bowel syndrome. Lancet 92. Michail S, Kenche H. Gut microbiota is not modified by randomized,
1976;307:270–2. double-blind, placebo-controlled trial of VSL#3 in diarrhea-predominant
69. Cockerell KM, Watkins AS, Reeves LB et al. Effects of linseeds on the irritable bowel syndrome. Probiotics Antimicrob Proteins 2011;3:1–7.
symptoms of irritable bowel syndrome: a pilot randomised controlled 93. Sondergaard B, Olsson J, Ohlson K et al. Effects of probiotic fermented
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/18/2024

trial. J Hum Nutr Diet 2012;25:435–43. milk on symptoms and intestinal flora in patients with irritable bowel
70. Halvorson HA, Schlett CD, Riddle MS. Postinfectious irritable bowel syndrome: a randomized, placebo-controlled trial. Scand J Gastroenterol
syndrome--a meta-analysis. Am J Gastroenterol 2006;101:1894–9. 2011;46:663–72.
71. Lin HC. Small intestinal bacterial overgrowth: a framework for under- 94. Cha BK, Jung SM, Choi CH et al. The effect of a multispecies probiotic
standing irritable bowel syndrome. JAMA 2004;292:852–8. mixture on the symptoms and fecal microbiota in diarrhea-dominant
72. Jeffrey IB, Quigley EM, Ohman L et al. The microbiota link to irritable irritable bowel syndrome: a randomized, double-blind, placebo-controlled
bowel syndrome: an emerging story. Gut Microbes 2012;3:572–6. trial. J Clin Gastroenterol 2012;46:220–7.
73. Spiegel BM. Questioning the bacterial overgrowth hypothesis in irritable 95. Cui S, Hu Y. Multistrain probiotic preparation significantly reduces symp-
bowel syndrome: an epidemiologic and evolutionary perspective. Clin toms of irritable bowel syndrome in a double-blind placebo-controlled
Gastroenterol Hepatol 2011;9:461–9. study. Int J Clin Exp Med 2012;5:238–44.
74. Ford AC, Spiegel BMR, Talley NJ et al. Small intestinal bacterial over- 96. Dapoigny M, Piche T, Ducrotte P et al. Efficacy and safety profile of
growth in irritable bowel syndrome: systematic review and meta-analysis. LCR35 complete freeze-dried culture in irritable bowel syndrome:
Clin Gastroenterol Hepatol 2009;7:1279–86. a randomized, double-blind study. World J Gastroenterol 2012;18:
75. Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial 2067–75.
overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastro- 97. Ducrotte P, Sawant P, Jayanthi V. Clinical trial: Lactobacillus plantarum
enterol 2000;95:3503–6. 299v (DSM 9843) improves symptoms of irritable bowel syndrome. World
76. Menees SB, Maneerattanaporn M, Kim HM et al. The efficacy and safety of J Gastroenterol 2012;18:4012–8.
rifaximin for the irritable bowel syndrome: a systematic review and meta- 98. Farup PG, Jacobsen M, Ligaarden SC et al. Probiotics, symptoms, and
analysis. Am J Gastroenterol 2012;107:28–35. gut microbiota: what are the relations? A randomized controlled trial
77. Silk DB, Davis A, Vulevic J et al. Clinical trial: the effects of a trans-galac- in subjects with irritable bowel syndrome. Gastroenterol Res Pract
tooligosaccharide prebiotic on faecal microbiota and symptoms in irritable 2012;2012:214102.
bowel syndrome. Aliment Pharmacol Ther 2009;29:508–18. 99. Kruis W, Chrubasik S, Boehm S et al. A double-blind placebo-controlled
78. Min YW, Park SU, Jang YS et al. Effect of composite yogurt enriched trial to study therapeutic effects of probiotic Escherichia coli Nissle 1917 in
with acacia fiber and Bifidobacterium lactis. World J Gastroenterol subgroups of patients with irritable bowel syndrome. Int J Colorectal Dis
2012;18:4563–9. 2012;27:467–74.
79. Tsuchiya J, Barreto R, Okura R et al. Single-blind follow up study on the 100. Ringel-Kulka T, Palsson OS, Maier D et al. Probiotic bacteria Lactobacillus
effectiveness of a symbiotic preparation in irritable bowel syndrome. acidophilus NCFM and Bifidobacterium lactis Bi-07 versus placebo for
Chin J Dig Dis 2004;5:169–74. the symptoms of bloating in patients with functional bowel disorders:
80. Bittner AC, Croffut RM, Stranahan MC. Prescript-Assist probiotic-prebi- a double-blind study. J Clin Gastroenterol 2011;45:518–25.
otic treatment for irritable bowel syndrome: a methodologically oriented, 101. Begtrup LM, de Muckadell OB, Kjeldsen J et al. Long-term treatment
2-week, randomized, placebo-controlled, double-blind clinical study. with probiotics in primary care patients with irritable bowel syndrome - a
Clin Ther 2005;27:755–61. randomised, double-blind, placebo controlled trial. Scand J Gastroenterol
81. Andriulli A, Neri M, Loguercio C et al. Clinical trial on the efficacy of 2013;48:1127–35.
a new symbiotic formulation, Flortec, in patients with irritable bowel 102. Roberts LM, McCahon D, Holder R et al. A randomised controlled trial
syndrome: a multicenter, randomized study. J Clin Gastroenterol 2008;42 of a probiotic ‘functional food’ in the management of irritable bowel
(Suppl 3): S218–23. syndrome. BMC Gastroenterol 2013;13:45.
82. Ford AC, Quigley EM, Lacy BE et al. Effect of prebiotics, probiotics, and 103. Simren M, Lindh A, Samuelsson L et al. Effect of yoghurt containing
synbiotics in irritable bowel syndrome and chronic idiopathic constipation: three probiotic bacteria in patients with irritable bowel syndrome (IBS)
systematic review and meta-analysis. Am J Gastroenterol 2014 (in press). - a randomized, double-blind, controlled trial. Gastroenterology 2007;132
83. Enck P, Zimmerman K, Menke G et al. A mixture of Escherichia coli (Suppl 1): A210.
(DSM 17252) and Enterococcus faecalis (DSM 16440) for treatment of the 104. Long ZR, Yu CH, Yang Y et al. [Clinical observation on acupuncture
irritable bowel syndrome - a randomized controlled trial with primary combined with microorganism pharmaceutical preparations for treatment
care physicians. Neurogastroenterol Motil 2008;20:1103–9. of irritable bowel syndrome of constipation type]. Zhongguo Zhen Jiu
84. Zeng J, Li Y-Q, Zuo X-L et al. Clinical trial: effect of active lactic acid bac- 2006;26:403–5.
teria on mucosal barrier function in patients with diarrhoea-predominant 105. Drouault-Holowacz S, Bieuvelet S, Burckel A et al. A double blind rand-
irritable bowel syndrome. Aliment Pharmacol Ther 2008;28:994–1002. omized controlled trial of a probiotic combination in 100 patients with
85. Agrawal A, Houghton LA, Morris J et al. Clinical trial: the effects of a irritable bowel syndrome. Gastroenterol Clin Biol 2008;32:147–52.
fermented milk product containing Bifidobacterium lactis DN-173 010 106. Gade J, Thorn P. Paraghurt for patients with irritable bowel syndrome.
on abdominal distension and gastrointestinal transit in irritable bowel Scand J Prim Health Care 1989;7:23–6.
syndrome with constipation. Aliment Pharmacol Ther 2013;29:104–14. 107. Guyonnet D, Chassany O, Ducrotte P et al. Effect of a fermented milk con-
86. Enck P, Zimmerman K, Menke G et al. Randomized controlled treatment taining Bifidobacterium animalis DN-173 010 on the health-related quality
trial of irritable bowel syndrome with a probiotic E.-coli preparation of life and symptoms in irritable bowel syndrome in adults in primary
(DSM17252) compared to placebo. Z Gastroenterol 2009;47:209–14. care: a multicentre, randomized, double blind, controlled trial. Aliment
87. Hong KS, Kang HW, Im JP et al. Effect of probiotics on symptoms in Pharmacol Ther 2007;26:475–86.
Korean adults with irritable bowel syndrome. Gut Liver 2009;3:101–7. 108. Kajander K, Hatakka K, Poussa T et al. A probiotic mixture alleviates
88. Williams EA, Stimpson J, Wang D et al. Clinical trial: a multistrain symptoms in irritable bowel syndrome patients: a controlled 6-month
probiotic preparation significantly reduces symptoms of irritable bowel intervention. Aliment Pharmacol Ther 2005;22:387–94.
syndrome in a double-blind placebo-controlled study. Aliment Pharmacol 109. Kajander K, Myllyluoma E, Rajilic-Stojanovic M et al. Clinical trial: multi-
Ther 2009;29:97–103. species probiotic supplementation alleviates the symptoms of irritable
89. Simren M, Ohman L, Olsson J et al. Clinical trial: the effects of a bowel syndrome and stabilizes intestinal microbiota. Aliment Pharmacol
fermented milk containing three probiotic bacteria in patients with Ther 2008;27:48–57.

The American Journal of GASTROENTEROLOGY VOLUME 109 | SUPPLEMENT 1 | AUGUST 2014 www.amjgastro.com
 ACG Monograph on IBS and CIC S23

110. Kim HJ, Camilleri M, McKinzie S et al. A randomized controlled trial of a 134. Dobrilla G, Imbibo BP, Piazzi L et al. Long term treatment of irritable
probiotic, VSL#3, on gut transit and symptoms in diarrhea-predominant bowel syndrome with cimetropium bromide: a double blind placebo
irritable bowel syndrome. Aliment Pharmacol Ther 2003;17:895–904. controlled clinical trial. Gut 1990;31:355–8.
111. Kim HJ, Vazquez Roque MI, Camilleri M et al. A randomized control- 135. Fielding JF. Double blind trial of trimebutine in the irritable bowel syn-
led trial of a probiotic combination VSL#3 and placebo in irritable bowel drome. Ir Med J 1980;73:377–9.
syndrome with bloating. Neurogastroenterol Motil 2005;17:687–96. 136. Ghidini O, Saponati G, Intrieri L. Single drug treatment for irritable
Downloaded from http://journals.lww.com/ajg by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWn

112. Kim YG, Moon JT, Lee KM et al. The effects of probiotics on symptoms of colon: rociverine versus trimebutine maleate. Curr Ther Res Clin Exp
irritable bowel syndrome. Korean J Gastroenterol 2006;47:413–9. 1986;39:541–8.
113. Niedzielin K, Kordecki H, Birkenfeld B. A controlled, double blind, rand- 137. Gilvarry J, Kenny A, Fielding JF. The non-effect of pirenzipine in dietary
omized study on the efficacy of Lactobacillus plantarum 299V in patients resistant irritable bowel syndrome. Ir J Med Sci 1989;158:262.
with irritable bowel syndrome. Eur J Gastroenterol Hepatol 2001;13:1143. 138. Glende M, Morselli-Labate AM, Battaglia G et al. Extended analysis of a
114. Niv E, Naftali T, Hallak R et al. The efficacy of Lactobacillus reuteri ATCC double blind, placebo-controlled, 15-week study with otilinium bromide
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/18/2024

55730 in the treatment of patients with irritable bowel syndrome – in irritable bowel syndrome. Eur J Gastroenterol Hepatol 2002;14:1331–8.
a double blind, placebo-controlled, randomized study. Clin Nutr 2005;24: 139. Levy C, Charbonnier A, Cachin M. Pinaverium bromide and functional
925–31. colonic disease (double-blind study). Sem Hop Ther 1977;53:372–4.
115. Nobaek S, Johansson M-L, Molin G et al. Alteration of intestinal microflo- 140. Mitchell SA, Mee AS, Smith GD et al. Alverine citrate fails to relieve
ra is associated with reduction in abdominal bloating and pain in patients the symptoms of irritable bowel syndrome: results of a double-blind,
with irritable bowel syndrome. Am J Gastroenterol 2000;95:1231–8. randomized, placebo-controlled trial. Aliment Pharmacol Ther 2002;16:
116. O’Mahony L, McCarthy J, Kelly P et al. Lactobacillus and bifidobacterium 1187–95.
in irritable bowel syndrome: symptom responses and relationship to 141. Moshal MG, Herron M. A clinical trial of trimebutine (Mebutin) in spastic
cytokine profiles. Gastroenterology 2005;128:541–51. colon. J Int Med Res 1979;7:231–4.
117. Simren M, Syrous A, Lindh A et al. Effects of Lactobacillus Plantarum 142. Page JG, Dirnberger GM. Treatment of the irritable bowel syndrome
299V on symptoms and rectal sensitivity in patients with irritable bowel with Bentyl (dicyclomine hydrochloride). J Clin Gastroenterol 1981;3:
syndrome (IBS) – a randomized double blind controlled trial. Gastroen- 153–6.
terology 2006;130 (Suppl 1): A600. 143. Passaretti S, Guslandi M, Imbibo BP et al. Effects of cimetropium bromide
118. Sinn DH, Song JH, Kim HJ et al. Therapeutic effect of Lactobacillus acido- on gastrointestinal transit time in patients with irritable bowel syndrome.
philus-SDC 2012, 2013 in patients with irritable bowel syndrome. Dig Dis Aliment Pharmacol Ther 1989;3:267–76.
Sci 2008;53:2714–8. 144. Piai G, Mazzacca G. Prifinium bromide in the treatment of the irritable
119. Whorwell PJ, Altringer L, Morel J et al. Efficacy of an encapsulated colon syndrome. Gastroenterology 1979;77:500–2.
probiotic Bifidobacterium infantis 35624 in women with irritable bowel 145. Pulpeiro A, Marti ML, De Los Santos AR et al. Propinox en sindrome de
syndrome. Am J Gastroenterol 2006;101:1581–90. intestino irritable. Prensa Med Argent 2000;87:299–307.
120. Lembo A, Zakko SF, Ferreira NL et al. Rifaximin for the treatment of 146. Schafer VE, Ewe K. The treatment of irritable colon. Efficacy and tolerance
diarrhea-associated irritable bowel syndrome: short term treatment lead- of buscopan plus, buscopan, paracetamol and placebo in ambulatory
ing to long term sustained response. Gastroenterology 2008;134 (Suppl 1): patients with irritable colon. Fortschr Med 1990;108:488–92.
545. 147. Virat J, Hueber D. Colopathy pain and dicetel. Prat Med 1987;43:32–4.
121. Pimentel M, Park S, Mirocha J et al. The effect of a nonabsorbed oral 148. Capanni M, Surrenti E, Biagini M et al. Efficacy of peppermint oil in the
antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a treatment of irritable bowel syndrome: a randomized, controlled trial.
randomized trial. Ann Intern Med 2006;145:557–63. Gazz Med Ital 2005;164:119–26.
122. Pimentel M, Lembo A, Chey WD et al. Rifaximin therapy for patients 149. Cappello G, Spezzaferro M, Grossi L et al. Peppermint oil (Mintoil) in
with irritable bowel syndrome without constipation. N Engl J Med the treatment of irritable bowel syndrome: a prospective double blind
2011;364:22–32. placebo-controlled randomized trial. Dig Liver Dis 2007;39:530–6.
123. Sharara AI, Aoun E, Abdul-Baki H et al. A randomized double-blind 150. Lech Y, Olesen KM, Hey H et al. Treatment of irritable bowel syndrome
placebo-controlled trial of rifaximin in patients with abdominal bloating with peppermint oil. A double-blind investigation with a placebo. Ugeskr
and flatulence. Am J Gastroenterol 2006;101:326–33. Laeger 1988;150:2388–9.
124. Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing 151. Liu J-H, Chen G-H, Yeh H-Z et al. Enteric-coated peppermint-oil capsules
correlates with symptom improvement in irritable bowel syndrome. A in the treatment of irritable bowel syndrome: a prospective, randomized
double-blind, randomized, placebo-controlled study. Am J Gastroenterol trial. J Gastroenterol 1997;32:765–8.
2003;98:412–9. 152. Merat S, Khalili S, Mostajabi P et al. The effect of enteric-coated, delayed-
125. Nayak AK, Karnad DR, Abraham P et al. Metronidazole relieves symp- release peppermint oil on irritable bowel syndrome. Dig Dis Sci 2010;55:
toms in irritable bowel syndrome: the confusion with so-called ‘chronic 1385–90.
amebiasis’. Indian J Gastroenterol 1997;16:137–9. 153. Hovdenak N. Loperamide treatment of the irritable bowel syndrome.
126. Di Stefano M, Tana P, Mengoli C et al. Colonic hypersensitivity is a major Scand J Gastroenterol 1987;130:81–4.
determinant of the efficacy of bloating treatment in constipation-predomi- 154. Lavo B, Stenstam M, Nielsen A-L. Loperamide in treatment of irritable
nant irritable bowel syndrome. Intern Emerg Med 2011;6:403–11. bowel syndrome - a double-blind placebo controlled study. Scand J
127. Moayyedi P, Duffett S, Mason S et al. The influence of antibiotics on Gastroenterol 1987;130:77–80.
irritable bowel syndrome: a randomised controlled trial. Gastroenterology 155. Ford AC, Quigley EM, Lacy BE et al. Effect of antidepressants and psycho-
2002;122 (Suppl 4): A465. logical therapies, including hypnotherapy, in irritable bowel syndrome:
128. Baldi F, Corinaldesi R, Ferrarini F et al. Clinical and functional evaluation systematic review and meta-analysis. Am J Gastroenterol 2014 (in press).
of octilonium bromide in the treatment of irritable bowel syndrome: a 156. Bergmann M, Heddergott A, Schlosser T. Die therapie des colon irritabile
double-blind controlled trial. Clin Trials J 1983;20:77–88. mit trimipramin (Herphonal) - Eine kontrollierte studie. Z Klin Med
129. Castiglione F, Daniele B, Mazzacca G. Therapeutic strategy for the irritable 1991;46:1621–8.
bowel syndrome. Ital J Gastroenterol 1991;23 (Suppl 1): 53–5. 157. Boerner D, Eberhardt R, Metz K et al. Wirksamkeit und vertraglichkeit
130. Centonze V, Imbibo BP, Campanozzi F et al. Oral cimetropium bromide, eines antidepressivuns beim colon irritabile. Therapiewoche 1988;38:
a new antimuscarinic drug, for long-term treatment of irritable bowel 201–8.
syndrome. Am J Gastroenterol 1988;83:1262–6. 158. Heefner JD, Wilder RM, Wilson ID. Irritable colon and depression.
131. Clave P, Acalovschi M, Triantafillidis JK et al. Randomised clinical trial: Psychosomatics 1978;19:540–7.
otilonium bromide improves frequency of abdominal pain, severity of 159. Kuiken SD, Tytgat GNJ, Boeckxstaens GEE. The selective serotonin
distention and time to relapse in patients with irritable bowel syndrome. reuptake inhibitor fluoxetine does not change rectal sensitivity and
Aliment Pharmacol Ther 2011;34:432–42. symptoms in patients with irritable bowel syndrome: a double-blind,
132. D’Arienzo A, D’Agostino L. L’ottilonio bromuro nel trattamento della randomized, placebo-controlled study. Clin Gastroenterol Hepatol
síndrome del colon irritabile. Rass Int Clin Ter 1980;60:649–56. 2003;1:219–28.
133. Delmont J. Interet de l’adjonction d’un antispasmodique musculotrope au 160. Myren J, Groth H, Larssen SE et al. The effect of trimipramine in patients
traitement des constipations douloureuses des colopathies fonctionnelles with the irritable bowel syndrome: a double-blind study. Scand J Gastro-
par le son. Med Chir Dig 1981;10:365–70. enterol 1982;17:871–5.

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

 S24 Ford et al.

161. Tabas G, Beaves M, Wang J et al. Paroxetine to treat irritable bowel 188. Tkachuk GA, Graff LA, Martin GL et al. Randomized controlled trial
syndrome not responding to high fiber diet: a double-blind placebo- of cognitive-behavioral group therapy for irritable bowel syndrome in a
controlled trial. Am J Gastroenterol 2004;99:914–20. medical setting. J Clin Psychol Med Settings 2003;10:57–69.
162. Tack J, Broekaert D, Fischler B et al. A controlled crossover study of the 189. van der Veek PPJ, van Rood YR, Masclee AAM. Clinical trial: short- and
selective serotonin reuptake inhibitor citalopram in irritable bowel syn- long-term benefit of relaxation training for irritable bowel syndrome.
drome. Gut 2006;55:1095–103. Aliment Pharmacol Ther 2007;26:943–52.
Downloaded from http://journals.lww.com/ajg by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWn

163. Talley NJ, Kellow JE, Boyce P et al. Antidepressant therapy (imipramine 190. Vollmer A, Blanchard EB. Controlled comparison of individual versus
and citalopram) for irritable bowel syndrome: a double-blind, rand- group cognitive therapy for irritable bowel syndrome. Behav Ther
omized, placebo-controlled trial. Dig Dis Sci 2008;53:108–15. 1998;29:19–33.
164. Vahedi H, Merat S, Rashidioon A et al. The effect of fluoxetine in patients 191. Craske MG, Wolitzky-Taylor KB, Labus J et al. A cognitive-behavioral
with pain and constipation-predominant irritable bowel syndrome: a double- treatment for irritable bowel syndrome using interoceptive exposure to
blind randomized-controlled study. Aliment Pharmacol Ther 2005;22:381–5. visceral sensations. Behav Res Ther 2011;49:413–21.
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/18/2024

165. Vahedi H, Merat S, Momtahen S et al. Clinical trial: the effect of amitripty- 192. Gaylord SA, Palsson OS, Garland EL et al. Mindfulness training reduces
line in patients with diarrhea-predominant irritable bowel syndrome. the severity of irritable bowel syndrome in women: results of a rand-
Aliment Pharmacol Ther 2008;27:678–84. omized controlled trial. Am J Gastroenterol 2011;106:1678–88.
166. Vij JC, Jiloha RC, Kumar N et al. Effect of antidepressant drug (doxepin) 193. Hunt MG, Moshier S, Milonova M. Brief cognitive-behavioral internet
on irritable bowel syndrome patients. Indian J Psychiatry 1991;33:243–6. therapy for irritable bowel syndrome. Behav Res Ther 2009;47:797–802.
167. Drossman DA, Toner BB, Whitehead WE et al. Cognitive-behavioral 194. Jarrett ME, Cain KC, Burr RL et al. Comprehensive self-management
therapy versus education and desipramine versus placebo for moderate to for irritable bowel syndrome: randomized trial of in-person vs. combined
severe functional bowel disorders. Gastroenterology 2003;125:19–31. in-person and telephone sessions. Am J Gastroenterol 2009;104:3004–14.
168. Abdul-Baki H, El Hajj, ElZahabi L et al. A randomized controlled trial 195. Lackner JM, Jaccard J, Krasner SS et al. Self-administered cognitive
of imipramine in patients with irritable bowel syndrome. World J Gastro- behavior therapy for moderate to severe irritable bowel syndrome:
enterol 2009;15:3636–42. clinical efficacy, tolerability, feasibility. Clin Gastroenterol Hepatol 2008;6:
169. Ghadir MR, Habibinejad H, Heidari A et al. Doxepin is more effective 899–906.
than nortriptyline and placebo for the treatment of diarrhea-predominant 196. Lindfors P, Unge P, Arvidsson P et al. Effects of gut-directed hypnotherapy
irritable bowel syndrome: a randomized triple-blind placebo-controlled on IBS in different clinical settings - results from two randomized,
trial. Tehran Univ Med J 2011;69:352–8. controlled trials. Am J Gastroenterol 2012;107:276–85.
170. Ladabaum U, Sharabidze A, Levin TR et al. Citalopram is not effective 197. Ljotsson B, Falk L, Wibron Vesterlund A et al. Internet-delivered exposure
therapy for nondepressed patients with irritable bowel syndrome. Clin and mindfulness based therapy for irritable bowel syndrome - a rand-
Gastroenterol Hepatol 2010;8:42–8. omized controlled trial. Behav Res Ther 2010;48:531–9.
171. Masand PS, Pae C-U, Krulewicz S et al. A double-blind, randomized, 198. Moser G, Tragner S, Elwira Gajowniczek E et al. Long-term success
placebo-controlled trial of paroxetine controlled-release in irritable bowel of GUT-directed group hypnosis for patients with refractory irritable
syndrome. Psychosomatics 2009;50:78–86. bowel syndrome: a randomized controlled trial. Am J Gastroenterol
172. Blanchard EB, Schwarz SP, Suls JM et al. Two controlled evaluations of 2013;108:602–9.
multicomponent psychological treatment of irritable bowel syndrome. 199. Moss-Morris R, McAlpine L, Didsbury LP et al. A randomized control-
Behav Res Ther 1992;30:175–89. led trial of a cognitive behavioural therapy-based self-management
173. Blanchard EB, Greene B, Scharff L et al. Relaxation training as a treatment intervention for irritable bowel syndrome in primary care. Psychol Med
for irritable bowel syndrome. Biofeedback Self Regul 1993;18:125–31. 2010;40:85–94.
174. Boyce PM, Talley NJ, Balaam B et al. A randomized controlled trial of 200. Shinozaki M, Kanazawa M, Kano M et al. Effect of autogenic training on
cognitive behavior therapy, relaxation training, and routine clinical care general improvement in patients with irritable bowel syndrome: a rand-
for the irritable bowel syndrome. Am J Gastroenterol 2003;98:2209–18. omized controlled trial. Appl Psychophysiol Biofeedback 2010;35:189–98.
175. Creed F, Fernandes L, Guthrie E et al. The cost-effectiveness of psycho- 201. Gershon MD. Review article: serotonin receptors and transporters -- roles
therapy and paroxetine for severe irritable bowel syndrome. Gastro- in normal and abnormal gastrointestinal motility. Aliment Pharmacol
enterology 2003;124:303–17. Ther 2004;20 (Suppl 7): 3–14.
176. Galovski TE, Blanchard EB. The treatment of irritable bowel syndrome 202. Spiller R. Serotonergic modulating drugs for functional gastrointestinal
with hypnotherapy. Appl Psychophysiol Biofeedback 1998;23:219–32. diseases. Br J Clin Pharmacol 2002;54:11–20.
177. Greene B, Blanchard EB. Cognitive therapy for irritable bowel syndrome. 203. Goldberg PA, Kamm MA, Setti-Carraro P et al. Modification of visceral
J Consult Clin Psychol 1994;62:576–82. sensitivity and pain in irritable bowel syndrome by 5-HT3 antagonism
178. Guthrie E, Creed F, Dawson D et al. A controlled trial of psycho- (ondansetron). Digestion 1996;57:478–83.
logical treatment for the irritable bowel syndrome. Gastroenterology 204. Houghton LA, Foster JM, Whorwell PJ. Alosetron, a 5-HT3 receptor
1991;100:450–7. antagonist, delays colonic transit in patients with irritable bowel syndrome
179. Heitkemper M, Jarrett ME, Levy RL et al. Self-management for women and healthy volunteers. Aliment Pharmacol Ther 2000;14:775–82.
with irritable bowel syndrome. Clin Gastroenterol Hepatol 2004;2:585–96. 205. Miller DP, Alfredson T, Cook SF et al. Incidence of colonic ischemia,
180. Keefer L, Blanchard EB. The effects of relaxation response meditation on hospitalized complications of constipation, and bowel surgery in relation
the symptoms of irritable bowel syndrome: results of a controlled treat- to use of alosetron hydrochloride. Am J Gastroenterol 2003;98:1117–22.
ment study. Behav Res Ther 2001;39:801–11. 206. Grider JR, Foxx-Orenstein AE, Jin JG. 5-Hydroxytryptamine4 receptor
181. Kennedy T, Jones R, Darnley S et al. Cognitive behaviour therapy in addi- agonists initiate the peristaltic reflex in human, rat, and guinea pig
tion to antispasmodic treatment for irritable bowel syndrome in primary intestine. Gastroenterology 1998;115:370–80.
care: randomised controlled trial. BMJ 2005;331:435–7. 207. Prather CM, Camilleri M, Zinsmeister AR et al. Tegaserod accelerates
182. Lynch PM, Zamble E. A controlled behavioral treatment study of irritable orocecal transit in patients with constipation-predominant irritable bowel
bowel syndrome. Behav Ther 1989;20:509–23. syndrome. Gastroenterology 2000;118:463–8.
183. Neff DF, Blanchard EB. A multi-component treatment for irritable bowel 208. Bardhan KD, Bodemar G, Geldof H et al. A double-blind, randomized,
syndrome. Behav Ther 1987;18:70–83. placebo-controlled dose-ranging study to evaluate the efficacy of alosetron
184. Payne A, Blanchard EB. A controlled comparison of cognitive therapy in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther
and self-help support groups in the treatment of irritable bowel syndrome. 2000;14:23–34.
J Consult Clin Psychol 1995;63:779–86. 209. Bradette M, Moennikes H, Carter F et al. Cilansetron in irritable bowel
185. Sanders KA, Blanchard EB, Sykes MA. Preliminary study of a self-admin- syndrome with diarrhea predominance (IBS-D): efficacy and safety in
istered treatment for irritable bowel syndrome: comparison to a wait list a 6 month global study. Gastroenterology 2004;126 (Suppl 2): A42.
control group. Appl Psychophysiol Biofeedback 2007;32:111–9. 210. Camilleri M, Mayer EA, Drossman DA et al. Improvement in pain and
186. Shaw G, Srivastava ED, Sadlier M et al. Stress management for irritable bowel function in female irritable bowel patients with alosetron, a 5-HT3
bowel syndrome: a controlled trial. Digestion 1991;50:36–42. receptor antagonist. Aliment Pharmacol Ther 1999;13:1149–59.
187. Simren M, Ringstrom G, Bjornsson ES et al. Treatment with hypnotherapy 211. Camilleri M, Northcutt AR, Kong S et al. Efficacy and safety of alosetron
reduces the sensory and motor component of the gastrocolonic response in women with irritable bowel syndrome: a randomised, placebo-
in irritable bowel syndrome. Psychosom Med 2004;66:233–8. controlled trial. Lancet 2000;355:1035–40.

The American Journal of GASTROENTEROLOGY VOLUME 109 | SUPPLEMENT 1 | AUGUST 2014 www.amjgastro.com
 ACG Monograph on IBS and CIC S25

212. Camilleri M, Chey WY, Mayer EA et al. A randomized controlled clinical trial irritable bowel syndrome and constipation. Gastroenterology 2010;139:
of the serotonin type 3 receptor antagonist alosetron in women with diarrhea- 1877–86.
predominant irritable bowel syndrome. Arch Intern Med 2001;161:1733–40. 234. Rao S, Lembo AJ, Shiff SJ et al. 12-week, randomized, controlled trial
213. Chang L, Ameen VZ, Dukes GE et al. A dose-ranging, phase II study of with a 4-week randomized withdrawal period to evaluate the efficacy
the efficacy and safety of alosetron in men with diarrhea-predominant and safety of linaclotide in irritable bowel syndrome with constipation.
IBS. Am J Gastroenterol 2005;100:115–23. Am J Gastroenterol 2012;107:1714–24.
Downloaded from http://journals.lww.com/ajg by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWn

214. Chey WD, Chey WY, Heath AT et al. Long-term safety and efficacy of 235. Drossman DA, Chey WD, Johanson JF et al. Clinical trial: lubiprostone in
alosetron in women with severe diarrhea-predominant irritable bowel patients with constipation-associated irritable bowel syndrome - results
syndrome. Am J Gastroenterol 2004;99:2195–203. of two randomized, placebo-controlled studies. Aliment Pharmacol Ther
215. Francisconi CF, Drossman DA, Mayer EA et al. Interruption of daily acti- 2009;29:329–41.
vities in cilansetron-treated patients with irritable bowel syndrome with 236. Fukudo S, Hongo M, Kaneko H et al. Efficacy of lubiprostone in patients
diarrhea-predominance (IBS-D): results from a 16-week, placebo-control- with constipation with or without irritable bowel syndrome in Japan:
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/18/2024

led, rerandomization trial. Gastroenterology 2006;130 (Suppl 2): A600. randomized, placebo-controlled and dose-finding study. Gastroenterology
216. Krause R, Ameen V, Gordon SH et al. A randomized, double-blind, 2010;130 (Suppl 1): 1435–6.
placebo-controlled study to assess efficacy and safety of 0.5 mg and 1 mg 237. Johanson JF, Drossman DA, Panas R et al. Clinical trial: phase 2 study
alosetron in women with severe diarrhea-predominant IBS. Am J Gastro- of lubiprostone for irritable bowel syndrome with constipation. Aliment
enterol 2007;102:1709–19. Pharmacol Ther 2008;27:685–96.
217. Lembo T, Wright RA, Lotronex Investigator Team et al. Alosetron controls 238. Khoshoo V, Armstead C, Landry L. Effect of a laxative with and without
bowel urgency and provides global symptom improvement in women tegaserod in adolescents with constipation predominant irritable bowel
with diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol syndrome. Aliment Pharmacol Ther 2006;23:191–6.
2001;96:2662–70. 239. Awad RA, Camacho S. A randomized, double-blind, placebo-controlled
218. Matsueda K, Harasawa S, Hongo M et al. A phase II trial of the novel sero- trial of polyethylene glycol effects on fasting and postprandial rectal sensi-
tonin type 3 receptor antagonist ramosetron in Japanese male and female tivity and symptoms in hypersensitive constipation-predominant irritable
patients with diarrhea-predominant irritable bowel syndrome. Digestion bowel syndrome. Colorectal Dis 2010;12:1131–8.
2008;77:225–35. 240. Chapman RW, Stanghellini V, Geraint M et al. Randomized clinical
219. Matsueda K, Harasawa S, Hongo M et al. A randomized, double-blind, trial: macrogol/PEG 3350 plus electrolytes for treatment of patients with
placebo-controlled clinical trial of the effectiveness of the novel serotonin constipation associated with irritable bowel syndrome. Am J Gastroenterol
type 3 receptor antagonist ramosetron in both male and female Japanese 2013;108:1508–15.
patients with diarrhea-predominant irritable bowel syndrome. Scand J 241. Ashraf W, Park F, Lof J et al. Effects of psyllium therapy on stool character-
Gastroenterol 2008;43:1202–11. istics, colon transit and anorectal function in chronic idiopathic constipa-
220. Miner P, Stanton D, Carter F et al. Cilansetron in irritable bowel syndrome tion. Aliment Pharmacol Ther 1995;9:639–47.
with diarrhea predominance (IBS-D): efficacy and safety in a 3 month US 242. Badiali D, Corazziari E, Habib FI et al. Effect of wheat bran in treatment of
study. Am J Gastroenterol 2004;99 (Suppl): S277. chronic non-organic constipation. A double-blind controlled trial. Dig Dis
221. http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafety Sci 1995;40:349–56.
InformationforPatientsandProviders/UCM227960.pdf (accessed June 10th 243. Fenn GC, Wilkinson PD, Lee CE et al. A general practice study of the effi-
2014). cacy of Regulan in functional constipation. Br J Gen Pract 1986;40:192–7.
222. Camilleri M, McKinzie S, Fox J et al. Effect of renzapride on transit in 244. Hongisto S-M, Paajanen L, Saxelin M et al. A combination of fibre-rich
constipation-predominant irritable bowel syndrome. Clin Gastroenterol rye bread and yoghurt containing Lactobacillus GG improves bowel func-
Hepatol 2004;2:895–904. tion in women with self-reported constipation. Eur J Clin Nutr 2006;60:
223. Farup PG, Hovdenak N, Wetterhus S et al. The symptomatic effect of 319–24.
cisapride in patients with irritable bowel syndrome and constipation. 245. Lopez Roman J, Martinez Gonzalvez AB, Luque A et al. Efecto de la
Scand J Gastroenterol 1998;33:128–31. ingesta de un preparado lacteo con fibra dietetica sobre el estrenimiento
224. George AM, Meyers NL, Hickling RI. Clinical trial: renzapride therapy cronic primario idiopatico]. Nutr Hosp 2008;23:12–9.
for constipation-predominant irritable bowel syndrome - multicentre, 246. Nunes FP, Nunes CP, Levis E et al. A double-blind trial of a celandin,
randomized, placebo-controlled, double-blind study in primary healthcare aloevera and psyllium laxative preparation in adult patients with constipa-
setting. Aliment Pharmacol Ther 2008;27:830–7. tion. Rev Bras Med 2005;62:352–7.
225. Schutze K, Brandstatter G, Dragosics B et al. Double-blind study of 247. Corazziari E, Badiali D, Habib FI et al. Small volume isosmotic polyethyl-
the effect of cisapride on constipation and abdominal discomfort as ene glycol electrolyte balanced solution (PMF-100) in treatment of chronic
components of the irritable bowel syndrome. Aliment Pharmacol Ther nonorganic constipation. Dig Dis Sci 1996;41:1636–42.
1997;11:387–94. 248. Corazziari E, Badiali D, Bazzocchi G et al. Long term efficacy, safety, and
226. Spiller RC, Meyers NL, Hickling RI. Identification of patients with non- tolerability of low daily doses of isosmotic polyethylene glycol electrolyte
D, non-C irritable bowel syndrome and treatment with renzapride: an balanced solution (PMF-100) in the treatment of functional chronic con-
exploratory, multicenter, randomized, double-blind, placebo-controlled stipation. Gut 2000;46:522–6.
clinical trial. Dig Dis Sci 2008;53:3191–200. 249. DiPalma JA, DeRidder PH, Orlando RC et al. A randomized, placebo-
227. Van Outryve M, Milo R, Toussaint J et al. “Prokinetic” treatment of consti- controlled, multicenter study of the safety and efficacy of a new polyethyl-
pation-predominant irritable bowel syndrome: a placebo-controlled study ene glycol laxative. Am J Gastroenterol 2000;95:446–50.
of cisapride. J Clin Gastroenterol 1991;13:49–57. 250. DiPalma JA, Cleveland MV, McGowan J et al. A randomized, multicenter,
228. Ziegenhagen DJ, Kruis W. Cisapride treatment of constipation-predomi- placebo-controlled trial of polyethylene glycol laxative for chronic treat-
nant irritable bowel syndrome is not superior to placebo. J Gastroenterol ment of chronic constipation. Am J Gastroenterol 2007;102:1436–41.
Hepatol 2004;19:744–9. 251. Baldonedo YC, Lugo E, Uzcategui AA et al. Evaluation and use of polyeth-
229. Lembo AJ, Cremonini F, Meyers N et al. Clinical trial: renzapride treat- ylene glycol in constipated patients]. G E N 1991;45:294–7.
ment of women with irritable bowel syndrome and constipation - a 252. Wesselius-De Casparis A, Braadbaart S, Bergh-Bohlken GE et al. Treat-
double-blind, randomized, placebo-controlled, study. Aliment Pharmacol ment of chronic constipation with lactulose syrup: results of a double-
Ther 2010;31:979–90. blind study. Gut 1968;9:84–6.
230. Mansour NM, Ghaith O, El-Halabi M et al. A prospective randomized 253. Sander JF. Lactulose syrup assessed in a double-blind study in elderly
trial of mosapride vs. placebo in constipation-predominant irritable bowel constipated patients. J Am Geriatr Soc 1978;26:236–9.
syndrome. Am J Gastroenterol 2012;107:792–3. 254. Kamm MA, Mueller-Lissner S, Wald A et al. Oral bisacodyl is effective and
231. Forte LR. Guanylin regulatory peptides: structures, biological activities well-tolerated in patients with chronic constipation. Clin Gastroenterol
mediated by cyclic GMP and pathobiology. Regulat Pept 1999;81:25–39. Hepatol 2011;9:577–83.
232. Chey WD, Lembo AJ, Lavins BJ et al. Linaclotide for irritable bowel syndrome 255. Mueller-Lissner S, Kamm MA, Wald A et al. Multicenter, 4-week, double-
with constipation: a 26-week, randomized, double-blind, placebo-controlled blind, randomized, placebo-controlled trial of sodium picosulfate in
trial to evaluate efficacy and safety. Am J Gastroenterol 2012;107:1702–12. patients with chronic constipation. Am J Gastroenterol 2010;105:897–903.
233. Johnston JM, Kurtz CB, MacDougall JE et al. Linaclotide improves 256. Kim DY, Camilleri M. Serotonin: a mediator of the brain-gut connection.
abdominal pain and bowel habits in a phase IIb study of patients with Am J Gastroenterol 2000;95:2698–709.

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

 S26 Ford et al.

257. Camilleri M, Kerstens R, Rykx A et al. A placebo-controlled trial of pruca- 274. Chiarioni G, Whitehead WE, Pezza V et al. Biofeedback is superior to
lopride for severe chronic constipation. N Engl J Med 2008;358:2344–54. laxatives for normal transit constipation due to pelvic floor dyssynergia.
258. Coremans G, Kerstens R, De Pauw M et al. Prucalopride is effective in Gastroenterology 2006;130:657–64.
patients with severe chronic constipation in whom laxatives fail to provide 275. Heymen S, Scarlett Y, Jones K et al. Randomized, controlled trial shows
adequate relief. Digestion 2003;67:82–9. biofeedback to be superior to alternative treatments for patients with
259. Emmanuel AV, Roy AJ, Nicholls TJ et al. Prucalopride, a systemic enterokinetic, pelvic floor dyssynergia-type constipation. Dis Colon Rectum 2007;50:
Downloaded from http://journals.lww.com/ajg by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWn

for the treatment of constipation. Aliment Pharmacol Ther 2002;16:1347–56. 428–41.

260. Goldberg M, Li Y-P, Johanson JF et al. Clinical trial: the efficacy and tolerability 276. Rao SS, Seaton K, Miller M et al. Randomized controlled trial of biofeed-
of velusetrag, a selective 5-HT4 agonist with high intrinsic activity, in chronic back, sham feedback, and standard therapy for dyssynergic defecation.
idiopathic constipation – a 4-week, randomized, double-blind, placebo- Clin Gastroenterol Hepatol 2007;5:331–8.
controlled, dose–response study. Aliment Pharmacol Ther 2010;32:1102–12. 277. Hart SL, Lee JW, Berian J et al. A randomized controlled trial of anorectal
261. Miner PB, Nichols T, Silvers DR et al. The efficacy and safety of prucalo- biofeedback for constipation. Int J Colorectal Dis 2012;27:459–66.
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/18/2024

pride in patients with chronic constipation. Gastroenterology 1999;116 278. Simon MA, Bueno AM. Behavioural treatment of the dyssynergic defeca-
(Suppl): A1043. tion in chronically constipated elderly patients: a randomized controlled
262. Muller-Lissner S, Rykx A, Kerstens R et al. A double-blind, placebo- trial. Appl Psychophysiol Biofeedback 2009;34:273–7.
controlled study of prucalopride in elderly patients with chronic 279. Glia A, Gylin M, Gullberg K et al. Biofeedback retraining in patients
constipation. Neurogastroenterol Motil 2010;22:991–8. with functional constipation and paradoxical puborectalis contraction:
263. Quigley EMM, Vandeplassche L, Kerstens R et al. Clinical trial: the comparison of anal manometry and sphincter electromyography for feed-
efficacy, impact on quality of life, and safety and tolerability of prucalo- back. Dis Colon Rectum 1997;40:889–95.
pride in severe chronic constipation - a 12-week, randomized, double- 280. Koutsomanis D, Lennard-Jones JE, Roy AJ et al. Controlled randomised
blind, placebo-controlled study. Aliment Pharmacol Ther 2009;29:315–28. trial of visual biofeedback versus muscle training without a visual display
264. Tack J, Van Outryve M, Beyens M et al. Prucalopride (Resolor) in the for intractable constipation. Gut 1995;37:95–9.
treatment of severe chronic constipation in patients dissatisfied with 281. Heymen S, Wexner SD, Vickers D et al. Prospective, randomized trial
laxatives. Gut 2009;58:357–65. comparing four biofeedback techniques for patients with constipation.
265. Ke M, Zou D, Yuan Y et al. Prucalopride in the treatment of chronic Dis Colon Rectum 1999;42:1388–93.
constipation in patients from the Asia-Pacific region: a randomized, 282. Pourmomeny AA, Emami MH, Amooshahi M et al. Comparing the
double-blind, placebo-controlled study. Neurogastroenterol Motil efficacy of biofeedback and balloon-assisted training in the treatment of
2012;24:999–e541. dyssynergic defecation. Can J Gastroenterol 2011;25:89–92.
266. Lembo AJ, Kurtz CB, MacDougall JE et al. Efficacy of linaclotide for 283. Chey WD, Camilleri M, Chang L et al. A randomized placebo-controlled
patients with chronic constipation. Gastroenterology 2010;138:886–95. phase IIb trial of a3309, a bile acid transporter inhibitor, for chronic
267. Lembo AJ, Schneier HA, Shiff SJ et al. Two randomized trials of linaclotide idiopathic constipation. Am J Gastroenterol 2011;106:1803–12.
for chronic constipation. N Engl J Med 2011;365:527–36. 284. Simren M, Bajor A, Gillberg PG et al. Randomised clinical trial: the ileal
268. Barish CF, Drossman D, Johanson JF et al. Efficacy and safety of lubiprostone bile acid transporter inhibitor A3309 vs. placebo in patients with chronic
in patients with chronic constipation. Dig Dis Sci 2010;55:1090–7. idiopathic constipation--a double-blind study. Aliment Pharmacol Ther
269. Johanson JF, Ueno R. Lubiprostone, a locally acting chloride channel 2011;34:41–50.
activator, in adult patients with chronic constipation: a double-blind, 285. Wong BS, Camilleri M, McKinzie S et al. Effects of A3309, an ileal bile
placebo-controlled, dose-ranging study to evaluate efficacy and safety. acid transporter inhibitor, on colonic transit and symptoms in females
Aliment Pharmacol Ther 2007;25:1351–61. with functional constipation. Am J Gastroenterol 2011;106:2154–64.
270. Johanson JF, Morton D, Geene J et al. Multicenter, 4-week, double-blind, 286. Koebnick C, Wagner I, Leitzmann P et al. Probiotic beverage containing
randomized, placebo-controlled trial of lubiprostone, a locally-acting Lactobacillus casei Shirota improves gastrointestinal symptoms in patients
type-2 chloride channel activator, in patients with chronic constipation. with chronic constipation. Can J Gastroenterol 2003;17:655–9.
Am J Gastroenterol 2008;103:170–7. 287. Sakai T, Makino H, Ishikawa E et al. Fermented milk containing Lacto-
271. Rao S, Meduri K, Tuteja A et al. Effects of lubiprostone on gastrointestinal bacillus casei strain Shirota reduces incidence of hard or lumpy stools in
symptoms, bowel function, and bowel satisfaction in patients with metha- healthy population. Int J Food Sci Nutr 2011;62:423–30.
nogenic flora and chronic constipation. Am J Gastroenterol 2012;107 288. Yang YX, He M, Hu G et al. Effect of a fermented milk containing
(Suppl 1s): S712–3. Bifidobacterium lactis DN-173010 on Chinese constipated women.
272. Bharucha AE. Pelvic floor: anatomy and function. Neurogastroenterol World J Gastroenterol 2008;14:6237–43.
Motil 2006;18:507–19. 289. Bracco A, Jonsson B, Ricci J-F et al. Economic evaluation of tegaserod
273. Faubion SS, Schuster LT, Bharucha AE. Recognition and management of vs. placebo in the treatment of patients with irritable bowel syndrome: an
nonrelaxing pelvic floor dysfunction. Mayo Clin Proc 2012;87:187–93. analysis of the TENOR study. Value in Health 2007;10:238–46.

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