[ viewpoint ]

HUBERT VAN GRIENSVEN, MSc (Pain), PhD, MCSP, DipAc1 • ANNINA SCHMID, M Manip Ther, PhD, MMACP, MCSP2
TEODORA TRENDAFILOVA, BSc (Hons)2 • MATTHEW LOW, BSc (Hons), MSc, MMACP, MCSP3,4

Central Sensitization in Musculoskeletal

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Pain: Lost in Translation?

P
sychosocial factors and sensory neuroplasticity associated neurobiological changes in dorsal horn
with persistent pain entered physical therapy parlance in the neurons such as increased excitability,
1990s, driving improved understanding of the wide range of strengthened synaptic transmission, and
reduced inhibition. These changes can be
influences on pain and a movement away from the biomedical explained by changes in the expression
view that pain equals tissue damage. This paradigm shift has meant and function of proteins (eg, ion chan-
that many patients have received more holistic and effective care. One nels) and the structure of the neurons
aspect of persistent pain is central sensitization, defined as increased (FIGURE 1).
responsiveness of nociceptive neurons to central sensitization: The brain can modulate dorsal horn
Copyright © 2020 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved.

in the central nervous system to their 1. What is the original description of sensitization through top-down mecha-
normal or subthreshold afferent input.5 central sensitization? nisms that augment spinal excitability.
Central sensitization is a neurophysio- 2. What findings may be suggestive These include increased descending fa-
logical mechanism that currently cannot of central sensitization in clinical cilitation or decreased descending inhi-
be directly determined clinically. Certain practice? bition. Peripheral input is also important
signs and symptoms, such as allodynia 3. What are the challenges of applying for the initiation and maintenance of
and widespread hyperalgesia, may sug- the concept of central sensitization in central sensitization. For instance, skin
gest its presence.1 clinical practice? anesthesia reduces pain behavior, and
Given that central sensitization was low-level activity of the peripheral af-
Journal of Orthopaedic & Sports Physical Therapy®

first described almost 4 decades ago, it is What Is the Original Description ferents in dorsal root ganglia contributes
time to reflect on challenges associated of Central Sensitization? to sustained pain behavior in preclinical
with its clinical application. This View- Central sensitization is a neurophysiolog- models of central sensitization. There
point aims to stimulate debate by ad- ical phenomenon that is adaptive, activ- is convincing preclinical evidence that
dressing 3 important questions related ity dependent, and dynamic. It comprises activity-dependent synaptic plasticity in
the dorsal horn responsible for central
U SYNOPSIS: Central sensitization is a physi- poses 6 challenges associated with the application sensitization is reversible once peripher-
ological mechanism associated with enhanced of central sensitization concepts in clinical practice al nociceptive input is removed (see the
sensitivity and pain responses. At present, central and makes suggestions for assessment, treatment, APPENDIX, available at www.jospt.org, for
sensitization cannot be determined directly in and use of terminology. Physical therapists are further references).
humans, but certain signs and symptoms may asked to be mindful of central sensitization and
be suggestive of it. Although central sensitization consider potential top-down as well as bottom-up
has received increasing attention in the clinical What Findings May Be Suggestive of
drivers, in the context of a person-centered bio-
literature, there is a risk that certain distinctions Central Sensitization in Clinical Practice?
psychosocial approach. J Orthop Sports Phys Ther
are being lost. This paper summarizes current
2020;50(11):592-596. doi:10.2519/jospt.2020.0610 Although there is no specific clinical test
knowledge of the physiology of central sensitiza- for central sensitization, signs and symp-
tion and its possible manifestations in patients, U KEY WORDS: central sensitivity syndrome,
toms like ongoing, spontaneous, and wide-
in order to inform a debate about the relevance central sensitization, nociplastic pain, pain assess-
of central sensitization for physical therapists. It ment, pain physiology spread pain, or severe and prolonged pain
following a seemingly innocuous stimulus,

1
School of Health and Social Work, University of Hertfordshire, Hatfield, United Kingdom. 2Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United
Kingdom. 3The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Bournemouth, United Kingdom. 4Orthopaedic Research Institute, Bournemouth University,
Bournemouth, United Kingdom. Dr Schmid is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are
those of the author and not necessarily those of the NHS, the NIHR, or the Department of Health. Teodora Trendafilova is supported by the Wellcome Trust OXION studentship. The
authors certify that they have no affiliations with or financial involvement in any organization or entity with a direct financial interest in the subject matter or materials discussed in
the article. Address correspondence to Dr Hubert van Griensven, School of Health and Social Work, University of Hertfordshire, College Lane, Hatfield, Hertfordshire AL10 9AB UK.
E-mail: [email protected] t Copyright ©2020 Journal of Orthopaedic & Sports Physical Therapy®

592 | november 2020 | volume 50 | number 11 | journal of orthopaedic & sports physical therapy

 raise clinical suspicion. An example of a lished normative reference values where What Are the Challenges of
clinical surrogate marker for central sen- available. Applying the Concept of Central
sitization is quantitative sensory testing Dynamic mechanical allodynia is ex- Sensitization in Clinical Practice?
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(QST), which comprehensively evaluates amined by brushing the skin. It may be a There have been large strides in our un-
sensitivity to a range of stimuli, specifically sign of central sensitization but could be derstanding of central sensitization from
heightened responsiveness (FIGURE 2).10 caused by peripheral drivers.8 a mechanistic and clinical standpoint,
To identify secondary hyperalgesia Temporal summation manifests as an but implementation in clinical practice
(increased pain sensitivity in undamaged increasing response to repeated nocicep- remains a challenge for the following
tissue away from the site of a painful le- tive stimulations (eg, sharpness) within reasons.
sion), nociceptive stimuli are applied in the same receptive field.1 Absence of Biomarkers to Help Diagnose
an area innervated by a different seg- Spatial summation reflects a height- Central Sensitization  Quantitative sen-
mental level, for example, QST of the ip- ened pain intensity experienced with sory testing is a promising surrogate mea-
silateral masseter muscle in patients with stimulation of wider areas, for example, sure to identify central sensitization, but
shoulder pain.1 using an increasing area of simultaneous it evaluates evoked responses rather than
Tertiary hyperalgesia (increased pain pinprick stimulation.1 clinically characteristic spontaneous pain.
sensitivity on the contralateral side of Conditioned pain modulation may Quantitative sensory testing mostly relies
a painful lesion) has been reported in reflect the efficacy of descending pain on testing skin sensitivity, rather than the
several conditions (eg, unilateral neuro- inhibition by testing to what extent one deep pain often experienced by patients
pathic pain and knee osteoarthritis).1,6 noxious stimulus invokes the inhibition with suspected central sensitization (eg,
Copyright © 2020 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved.

The contralateral side may therefore of another.9 This approach shows prom- fibromyalgia). It also requires time and
not be a true control in a patient,13 so ise for groups but remains difficult to in- resources. Objective markers of central
QST values should be compared to pub- terpret in individuals. sensitization such as functional neuroim-

Evidence for Mg2+ block

reversibility if
Early changes Functional and structural peripheral input
Fast reversal to changes in the spinal corda removed
normal NMDA receptor AMPA receptor
Journal of Orthopaedic & Sports Physical Therapy®

NMDA receptor activation in Yes

response to strong membrane Prolonged stimulation
depolarization
Mg2+ block
Increased intracellular calcium Yes removed Increased
(sources: NMDA, AMPA, membrane
voltage-gated Ca2+ channels, excitability
intracellular stores) NMDA receptor
AMPA receptor

Prolonged
Ca2+-driven phosphorylation Yes Strengthened
nociceptive
1. Further activation of NMDA and synapses
stimulation
AMPA receptors
2. Increased recruitment of receptors
to the membrane
Reduced
3. Activation of PKC—reduction of
inhibition
GABA and glycine neurotransmitter
release (reduced inhibition) NMDA receptor
AMPA
receptor

Transcriptional and translational Yes

changes through different
cascades
Transcriptional changes

Anatomical changes—changes in Not yet available

Late changes dendritic spine structure and
Slow reversal density
back to normal Modulation of spine
structure and density

FIGURE 1. A selection of neurobiological changes implicated in central sensitization at the spinal cord level. Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid; Ca2+, calcium ion; GABA, gamma aminobutyric acid; Mg2+, magnesium ion; NMDA, N-methyl-D-aspartate; PKC, protein kinase C. aReferences can be
found in the APPENDIX.

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 [ viewpoint ]
aging are still under development.2 a recent study3 challenged their construct anxiety) can have a direct influence on
Limitations of Questionnaires to Iden- validity. Neither of these questionnaires the nervous system. They may influence
tify Central Sensitization  Central sen- was associated with widespread pain sen- central sensitization through descending
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sitization screening questionnaires (eg, sitivity, and both showed a stronger asso- modulation. However, central sensitiza-
the Central Sensitization Inventory and ciation with psychological measures than tion and psychology are distinct and not
Pain Sensitivity Questionnaire) have with markers for central sensitization.3 linked predictably. We suggest judicious
good clinical measurement properties Central Sensitization Is Not Synony- and systematic evaluation of physiologi-
(eg, validity and reliability).11,12 However, mous With Psychological Problems  Psy- cal changes as well as psychosocial as-
they must be interpreted with caution, as chological factors (eg, depression and pects when examining patients, in order

Measurement Properties of
Clinical Tests Compared to
Clinical Sign Semi-objective Test (QST) Clincial Test Interpretation Semi-objective Tests
Cold/heat hyperalgesia Thermal tester Cold/hot test tubes Presence of secondary or Agreement rates (Zhu et al):
tertiary hyperalgesia raises Cold tube: 45.0%-69.7%
suspicion of contribution of Hot tube: 45.0%-69.2%
central mechanisms Cold tube: high test-retest
reliability (Cathcart and Pritchard,
Tilley and Bisset)
Mechanical hyperalgesia Weighted pinprick stimulators, blunt Toothpick/neurotip, blunt pressure Presence of secondary or Agreement rates (Zhu et al):
Copyright © 2020 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved.

pressure algometer (thumb, eraser) tertiary hyperalgesia raises Toothpick: 52.6% -84.6%
suspicion of contribution of Thumb pressure: 57.5%-86.8%
central mechanisms Eraser pressure: 60.0%-84.2%
Nerve palpation: high test-­retest reli-
ability (Pedersini et al, Fingleton
et al)

Dynamic mechanical Cotton wool tip, soft brush Cotton wool tip, soft brush Pain elicited on light touch Good to high intertester reliability of
allodynia raises suspicion of contribu- allodynia tests (Geber et al)
tion of central mechanisms
Journal of Orthopaedic & Sports Physical Therapy®

Temporal summation Repeated nociceptive stimulation (eg, Repeated pinprick stimulation with Exacerbation of pain ratings for Agreement rates (Zhu et al):
pinprick, thermal, electrical) toothpick/neurotip a train of stimuli compared Toothpick: 47.5%-76.5%
to a single stimulus raises Wind-up with pinprick moderate
suspicion of contribution test-retest reliability (Geber et al)
of central mechanisms.
Also observe for painful
aftersensations (prolonged
pain after repeated stimuli
have stopped)
Spatial summation Different sizes of thermodes, different numbers of pressure probes Presence raises suspicion
of contribution of central
mechanisms
Descending inhibition Conditioned pain modulation (conditioning and test stimulus over different areas, Presence raises suspicion Test-retest reliability: good to excel-
for example, one foot immersed in ice water and pressure pain threshold over of contribution of central lent (Kennedy et al)
the contralateral foot) mechanisms

FIGURE 2. Clinical correlates of central sensitization: clinical alternatives to semi-objective tests, with their interpretation and measurement properties. The measurement
properties and diagnostic accuracy of clinical tests for central sensitization are largely unknown. Here, we indicate the emerging evidence related to concurrent validity
(agreement rates of clinical tests with semi-objective QST) and test-retest reliability of clinical tests. Abbreviation: QST, quantitative sensory testing. References can be found in
the APPENDIX. All images taken by Dr Liam Peck, Dr Annina Schmid, and Guan Cheng Zhu. ©The Authors. Used with permission.

594 | november 2020 | volume 50 | number 11 | journal of orthopaedic & sports physical therapy

 to establish a comprehensive impression over the next decade is fibromyalgia. that targets psychological, behavioral,
of their persistent pain problems. This condition is traditionally associated and social components, as well as any pe-
Consider Peripheral Drivers of Central with central sensitization, as no patho- ripheral drivers of central sensitization, is
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Sensitization  Pain scientists are debating physiological driver is apparent. There required. Therapeutic approaches may be
whether central sensitization maintains is convincing evidence that fibromyalgia chosen for their potential to activate de-
itself in the absence of peripheral drivers, is associated with small-fiber degenera- scending inhibitory systems and reduce
but preclinical and preliminary human tion and spontaneous neural activity and nociceptive input. Importantly, the his-
research suggests a role for peripheral hyperexcitability.4 There may be an au- tory of medicine suggests that we should
drivers in the initiation, maintenance, toimmune component in some patients. proceed with epistemic humility, recog-
and modulation of central sensitization. While this is an area of ongoing develop- nizing that knowledge is never complete.
For example, local anesthetic blocks can ment, clinicians must be prepared to re-
abolish allodynia and spontaneous pain evaluate their understanding of central Key Points
in patients with persistent complex re- sensitization in persistent pain condi- • Central sensitization is a physiological
gional pain syndrome, with symptoms tions to benefit patients. and reversible mechanism associated
returning after the anesthesia wanes. Re- Using Clinically Relevant Terminol- with enhanced sensitivity and pain
moving peripheral drivers of sensitization ogy  Perhaps the term central sensitiza- responses.
(eg, by replacing an arthritic joint) may tion should be reserved for physiological • Until better markers are available,
reverse even structural brain changes (eg, changes, as originally described. In clini- detection of central sensitization in
thalamic atrophy). cal practice, the term central sensitivity humans remains tentative.
Copyright © 2020 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved.

We acknowledge that central sensi- syndrome has been introduced to de- • We must be careful that the concept
tization may not always be dependent scribe a group of overlapping conditions of central sensitization is not used
on an obvious peripheral driver, but ad- with heightened sensitivity.15 Diagnosis interchangeably with psychological
vocate careful assessment of potential is conducted by excluding specific pa- manifestations.
sources of nociception alongside psy- thologies rather than by positive iden- • Let us keep an open mind about cen-
chological, behavioral, and social com- tification, as in nonspecific low back tral sensitization as our knowledge
ponents. Given the complex interplay of pain, fibromyalgia, and chronic fatigue about this intriguing concept contin-
bottom-up and top-down mechanisms in syndrome. Another example is the term ues to evolve. t
central sensitization, effective treatment nociplastic pain, which is pain that arises
Journal of Orthopaedic & Sports Physical Therapy®

may require a combination of strategies.14 from altered nociception despite no clear STUDY DETAILS
Epistemic Humility Scientific under- evidence of actual or threatened tissue AUTHOR CONTRIBUTIONS: All authors met
standing of central sensitization is damage causing the activation of periph- full criteria to be designated as authors.
evolving. With the availability of re- eral nociceptors or evidence of disease or DATA SHARING: There are no data in this
fined diagnostic methods and deeper lesion of the somatosensory system caus- manuscript.
knowledge, we may realize that certain ing the pain.5 While these terms are open PATIENT AND PUBLIC INVOLVEMENT: There
conditions that are currently labeled as to criticism, they may be more clinically were no patients involved.
central sensitization are driven by spe- relevant than “central sensitization.”
cific pathomechanisms. One example is
small-fiber neuropathy, which is charac- Summary REFERENCES
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our understanding may be challenged multimodal person-centered approach

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@ MORE INFORMATION
7. Liu X, Treister R, Lang M, Oaklander AL. IVIg for chronic pain patients. Pain. 2012;153:1210-1218.
apparently autoimmune small-fiber polyneu- https://doi.org/10.1016/j.pain.2012.02.025
ropathy: first analysis of efficacy and safety. Ther 12. Scerbo T, Colasurdo J, Dunn S, Unger J, Nijs J, WWW.JOSPT.ORG
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published articles by Previous Issues with accompanying volume and issue
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APPENDIX
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ADDITIONAL REFERENCES
Recommended Reading
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Harte SE, Harris RE, Clauw DJ. The neurobiology of central sensitization. J Appl Biobehav Res. 2018;23:e12137. https://doi.org/10.1111/jabr.12137
Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10:895-926. https://doi.org/
10.1016/j.jpain.2009.06.012
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McCall WD, Tanner KD, Levine JD. Formalin induces biphasic activity in C-fibers in the rat. Neurosci Lett. 1996;208:45-48. https://doi.
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References for Figure 1
Journal of Orthopaedic & Sports Physical Therapy®

NMDA Receptor Activation in Response to Strong Membrane Depolarization: Evidence for Phenomenon
Ma QP, Woolf CJ. Noxious stimuli induce an N-methyl-D-aspartate receptor-dependent hypersensitivity of the flexion withdrawal reflex to touch: implica-
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Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10:895-926. https://doi.org/
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Increased Intracellular Calcium: Evidence for Phenomenon
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Guo W, Wei F, Zou S, et al. Group I metabotropic glutamate receptor NMDA receptor coupling and signaling cascade mediate spinal dorsal horn
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Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10:895-926. https://doi.
org/10.1016/j.jpain.2009.06.012
Vikman KS, Rycroft BK, Christie MJ. Switch to Ca2+-permeable AMPA and reduced NR2B NMDA receptor-mediated neurotransmission at dorsal horn
nociceptive synapses during inflammatory pain in the rat. J Physiol. 2008;586:515-527. https://doi.org/10.1113/jphysiol.2007.145581
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10.1016/j.jpain.2009.06.012

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APPENDIX
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Ca2+-driven Phosphorylation: Evidence for Phenomenon

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Abbreviation: NMDA, N-methyl-D-aspartate.

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