Pain Physician 2014; 17:447-457 • ISSN 1533-3159

Epidemiology

Applying Modern Pain Neuroscience in Clinical
Practice: Criteria for the Classification ofCentral Sensitization Pain
Jo Nijs, PhD1,2, Rafael Torres-Cueco, MSc3, C. Paul van Wilgen, PhD4, Enrique Lluch Girbés,
MSc3, Filip Struyf, PhD1,5, Nathalie Roussel, PhD1,5, Jessica Van Oosterwijck, PhD1,6, Liesbeth
Daenen, PhD1,7, Kevin Kuppens, MSc1,5,7, Luc Vanderweeën, MSc1,8, Linda Hermans, MSc6,
David Beckwée, MSc1, Lennard Voogt, PhD1,9, Jacqui Clark, MSc10, Niamh Moloney, PhD1,11,
and Mira Meeus, PhD6,7
From: 1Pain in Motion Research Group,
Departments of Human Physiology andPhysiotherapy, Faculty of Physical Education
and Physiotherapy, Vrije Universiteit
Brussel, Belgium; 2Department of Physical
Medicine and Physiotherapy, University
Hospital Brussels, Belgium; 3Departmentof Rehabilitation, University of Valencia,
Spain; 4Transcare, Transdisciplinairy
Painmanegement Centre, Groningen,
The Netherlands; 5Rehabilitation Sciences
and Physiotherapy, Faculty of Medicine,
Antwerp University, Antwerp, Belgium;
6
Department of Rehabilitation Sciences,Ghent University, Ghent, Belgium;
7
Department of Neurology, Faculty of
Medicine, Antwerp University, Antwerp,
Belgium; 8Private Practice for Spinal Manual
Therapy, Schepdaal-Dilbeek, Belgium;
9
Master Program in Manual Physiotherapy,
Rotterdam University College, The
Netherlands; 10Faculty of Health, Psychology
and Social Care, Manchester Metropolitan
University, United Kingdom; 11Discipline of
Physiotherapy, Faculty of Health Sciences,
The University of Sydney, Australia
Address Correspondence:
Jo Nijs, PhD
Vrije Universiteit Brussel, Building F-Kine
Laarbeeklaan 103, BE-1090
Brussels, Belgium
E-mail: Jo.Nijs@vub.ac.beDisclaimer, Conflicts of Interest on P. 455.
Manuscript received: 02-22-2014
Revised manuscript received: 05-05-2014
Accepted for publication: 06-10-2014
Free full manuscript:
www.painphysicianjournal.com

M

Background: The awareness is growing that central sensitization is of prime
importance for the assessment and management of chronic pain, but its classificationis challenging clinically since no gold standard method of assessment exists.
Objectives: Designing the first set of classification criteria for the classification ofcentral sensitization pain.
Methods: A body of evidence from original research papers was used by 18 pain
experts from 7 different countries to design the first classification criteria for central
sensitization pain.
Results: It is proposed that the classification of central sensitization pain entails 2 major
steps: the exclusion of neuropathic pain and the differential classification of nociceptive
versus central sensitization pain. For the former, the International Association for the
Study of Pain diagnostic criteria are available for diagnosing or excluding neuropathic
pain. For the latter, clinicians are advised to screen their patients for 3 major classification
criteria, and use them to complete the classification algorithm for each individual
patient with chronic pain. The first and obligatory criterion entails disproportionate
pain, implying that the severity of pain and related reported or perceived disability aredisproportionate to the nature and extent of injury or pathology (i.e., tissue damage
or structural impairments). The 2 remaining criteria are 1) the presence of diffuse pain
distribution, allodynia, and hyperalgesia; and 2) hypersensitivity of senses unrelated tothe musculoskeletal system (defined as a score of at least 40 on the Central Sensitization
Inventory).
Limitations: Although based on direct and indirect research findings, the classification
algorithm requires experimental testing in future studies.
Conclusion: Clinicians can use the proposed classification algorithm for differentiatingneuropathic, nociceptive, and central sensitization pain.
Key words: Chronic pain, diagnosis, hypersensitivity, classification, neuropathic pain
Pain Physician 2014; 17:447-457

any chronic pain patients, including thosewith persisting neck pain (1-4), pelvic pain(5,6), low back pain (7-9), fibromyalgia(8,10,11), subacromial impingement syndrome (12),chronic fatigue syndrome (13), tension-type headache(14), migraine (15), osteoarthritis (8,16,17), rheumatoid
arthritis (18), tennis elbow (19,20), nonspecific arm
pain (21), and patella tendinopathy (22) show features

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Pain Physician: September/October 2014; 17:447-457

suggestive of central sensitization (CS), a processcharacterized by generalized hypersensitivity of thesomatosensory system (23-25). According to Woolf(26), CS is “operationally defined as an amplificationof neural signaling within the central nervous systemthat elicits pain hypersensitivity.” These studies provide
evidence supporting the presence of CS in patientswith chronic pain through observational brain imaging
studies, psychophysical testing with various stimuli, andcerebral metabolism studies (5,7,8,12-16,19,20,27).
CS reflects increased activity of pain facilitation
pathways (11,27) and malfunctioning of descending
pain inhibitory pathways which result in dysfunctional
endogenous analgesic control (13). In addition, thepain neuromatrix is likely to be overactive in patientswith CS: Increased activity is present in brain areas
known to be involved in acute pain sensations andemotional representations like the insula, anterior
cingulate cortex, and the prefrontal cortex, but not in
the primary or secondary somatosensory cortex (28).
An overactive pain neuromatrix entails brain activity inregions not involved in acute pain sensations including
various brain stem nuclei, dorsolateral frontal cortex,
and the parietal associated cortex (28). Research findings also suggest a specific role of the brainstem for the
maintenance of CS in humans (29). Furthermore, longterm potentiation of neuronal synapses in the anterior
cingulate cortex (30), nucleus accumbens, insula, andthe sensorimotor cortex, as well as decreased gammaaminobutyric acid-neurotransmission (31) represent 2
potential mechanisms contributing to the overactive
pain neuromatrix.
As mentioned, the concept of CS has been studied
extensively in different patient cohorts (1,2-5,8,1215,18,19,32), showing that CS may modulate the development of pain (e.g., in fibromyalgia) and/or thetransition from acute to chronic pain (e.g., whiplash
associated disorder) (4,33) in patients where an obvious source of nociception is absent. CS in these patientgroups can also mediate treatment responses (2,20) thus
inviting clinicians to consider targeting the processes
underlying CS when treating patients with chronic pain
(24,34). A limited body of evidence suggests that someof the mechanisms underlying CS may be responsive toclinical interventions. For example, there is some evidence to suggest that effective treatment for chronic
low back pain may reverse abnormal brain function(35,36), and that biopsychosocially-driven rehabilitation may reduce central nervous system hyperexcitability (37) and increase prefrontal cortical volume (38)448

in patients with chronic pain although larger trials are
required to further substantiate these findings. Finally,
the clinical importance of CS is supported by findings
in chronic low back pain patients. Compared to thoseclassified as having peripheral neuropathic pain andnociceptive pain, patients with CS reported more severe
pain, poorer general health-related quality of life, andgreater levels of back pain-related disability, depression, and anxiety (39).
In some patient populations, CS may be thecharacteristic feature of the disorder, as is the casewith chronic whiplash, fibromyalgia, chronic fatigue
syndrome, and irritable bowel syndrome (25). Not
all chronic pain patients have CS, but it may underlie
sub-groups of patients with chronic low back pain,
whiplash, osteoarthritis, rheumatoid arthritis, tennis
elbow pain, shoulder pain, and headache (8,12,1418,25,40,41). The reasons for this are unknown, but
may reflect a genetic predisposition and the influenceof other biopsychosocial factors. At the group level,
these populations may be characterized by CS, but at
the individual level definitely not all patients show evidence of CS. Rather, a subgroup of these populations
is characterized by CS. If present, CS may dominate theclinical picture, modulate the transition to chronicity(4,33), and mediate treatment responses (2,20). Therefore, it may be considered important for clinicians to beable to identify or diagnose CS in patient populations
presenting for treatment.
While patients with chronic pain are more likely
to present with CS, CS may not be limited to chronic
pain states. For example, in patients with whiplash associated disorders, abnormal sensory processing may
appear quite rapidly (< 7 days) after the initial whiplash
trauma, and once present, it has an important predictive ability for the development of chronicity (4,42).
Hence, it is important for clinicians to rapidly identify
CS in patients with (sub)acute pain for the early identification of the risk for chronicity.
Although awareness is growing that CS may beof prime importance in the development, persistence,and management of chronic pain, its classification ischallenging clinically since no gold standard methodof assessment exists. In recent years, 2 questionnaires
have been developed for the screening of CS, the Pain
Sensitivity Questionnaire (43) and the Central Sensitization Inventory (44,45). These questionnaires assess
aspects of CS but the inclusion of physical assessment
measures and clinical judgments by health care professionals also offer greater potential for the classificationwww.painphysicianjournal.com

Applying Modern Pain Neuroscience in Clinical Practiceof CS. Guidelines for the recognition of CS in patientswith musculoskeletal pain have been proposed (25),
and although helpful, they are unable to guide clinicians towards clear-cut classification decisions in clinicalpractice. Therefore, a body of evidence from original
research papers was used by 18 pain experts from 7 different countries to design the first classification criteria
for CS pain. Here we propose for the first time a set ofclassification criteria for CS pain as an entity relatively
distinct from other mechanisms-based classifications ofpain such as neuropathic and nociceptive pain.

Excluding or Diagnosing Neuropathic Pain as
the First Important Step
It is proposed that the classification of CS pain entails 2 major steps: the exclusion of neuropathic pain
and the differential classification of nociceptive versus
CS pain.
Neuropathic pain is defined as “pain arising as adirect consequence of a lesion or disease affecting thesomatosensory system” (46). Neuropathic pain can beboth peripheral (i.e., located in a nerve, dorsal root
ganglion, or plexus) and central (located in the brain or
spinal cord). Neuropathic pain is characterized by sensitization as well; peripheral and central (segmentally
related) pain pathways are hyperexcitable in patientswith neuropathic pain (47,48). However, here we focus
on the classification of non-neuropathic CS pain, implying that exclusion of neuropathic pain is required as thefirst step. Indeed, typical CS conditions like fibromyalgia, or any other chronic pain condition not due to alesion or disease of the somatosensory system, do notsatisfy the criteria for the classification of neuropathic

pain. Likewise, some patients with chronic low backpain, tennis elbow, or osteoarthritis may show featuresof CS, but do not fit into the diagnostic criteria forneuropathic pain.
For a detailed description of the diagnostic criteria
and clinical diagnosis of neuropathic pain, the readers
are referred to the relevant international consensus
documents (46,49,50). The main criteria for differentiating between neuropathic and non-neuropathic CS
pain are presented in Table 1.
For the purpose of the present paper, it is important to highlight the issue of sensory dysfunction inneuropathic versus non-neuropathic CS pain. Sensory
testing is of prime importance for the diagnosis of neuropathic pain (46,49). This includes testing of the function of sensory fibers with simple tools (e.g., a tuning
fork for vibration, a soft brush for touch, and cold/warm
objects for temperature), which typically assess therelationship between the stimulus and the perceived
sensation (49). Several options arise here, all suggestiveof neuropathic pain: hyperestesia, hypoestesia, hyperalgesia, hypoalgesia, allodynia, paraesthesia, dysesthesia, aftersensations, etc. Again, the location of thesensory dysfunction is crucial for the differential classification between neuropathic and non-neuropathic
CS pain. While in neuropathic pain the location of
the sensory dysfunction should be neuroanatomically
logical, in non-neuropathic CS pain it should be spreadin nonsegmentally related areas of the body. In fact,clinical examination in non-neuropathic CS pain typically reveals increased sensitivity at sites segmentally
unrelated to the primary source of nociception (25).
Findings of numerous areas of hyperalgesia at sites

Table 1. Criteria for the differential classification between neuropathic (46, 49,50) and non-neuropathic central sensitization (CS)pain.

Neuropathic pain

Non-neuropathic CS pain

History of a lesion or disease of the nervous system

No history of a lesion or disease of the nervous system

Evidence from diagnostic investigations to reveal an abnormality of
the nervous system, or post-traumatic/postsurgical damage to thenervous systemNo evidence from diagnostic investigations, or damage to the nervous
systemOften related to an established medical cause like cancer, stroke,
diabetes, herpes, or neurodegenerative disease

No medical cause for the pain established

Pain is neuroanatomically logicalPain is neuroanatomically illogical, i.e., located at sites segmentally
unrelated to the primary source of nociception

Pain is often described as burning, shooting, or pricking

Pain is not described as burning, shooting, or pricking, but most often
as vague and dull

Location of the sensory dysfunction is neuroanatomically logical

Location of the sensory dysfunction is neuroanatomically illogical,
i.e., numerous areas of hyperalgesia at sites outside and remote to thesymptomatic site – at segmentally unrelated siteswww.painphysicianjournal.com

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outside and remote to the symptomatic site, together
with a nonsegmental general decrease in pressure pain
threshold infers a generalized hyperexcitability of central nociceptive pathways or CS (51).
The presence of neuropathic pain does not exclude
the possibility of CS or vice versa. In fact, some patients
evolve from neuropathic pain with severe but local
signs and symptoms, to a widespread pain condition
that cannot be explained by neuropathic pain solely.
In such cases, CS might account for the evolution to awidespread pain condition.

Classification of Central Sensitization Pain
Once neuropathic pain has been eliminated as areason, 2 options remain: the (chronic) pain arises fromCS (i.e., CS dominates the clinical picture of the patient)or from dominance of peripheral somatic input (i.e.,
nociceptive pain). Some degree of central pain sensitization in response to acute injury may be consideredadaptive in facilitating recovery. Indeed, sensitizationof local tissues is a feature of an acute inflammatory

process (e.g., following an acute ankle sprain or muscle
injury). When tissue is damaged, the responsivenessof polymodal nociceptive endings is enhanced byvarious substances released by various sources (such as
serotonin released by platelets, bradykinin from theplasma, prostaglandins released by damaged cells, substance P released by the primary afferent fibers) (52).
This process is called primary hyperalgesia or peripheral
sensitization of nociceptors, and is a protective actionof the human body to prevent use and consequent
further damage of the traumatized and surrounding
tissues. Secondary hyperalgesia refers to increased
responsiveness of dorsal horn neurons localized in the
spinal segment of the primary source of nociception.
However, clinicians should aim to differentiate between
adaptive peripheral sensitization, for example after anacute inflammatory process, and maladaptative central
sensitization.
We propose the following criteria to facilitate this
distinction clinically. The criteria should be evaluated
together within the classification algorithm (Fig. 1).

Musculoskeletal pain

Disproportionate pain experience?
YES

NO

Diffuse pain distribution?
NO

YES
Central Sensitization

no Central Sensitization

Central Sensitization Inventory ≥ 40 ?

YESCentral SensitizationNO
no Central Sensitization

Fig. 1. Algorithm for the classification of central sensitization (CS) pain.

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Applying Modern Pain Neuroscience in Clinical Practice

These criteria are identifiable from the clinical history
and examination. The underlying clincal rationale ofthese clinical criteria are considered in turn below.

Criterion 1: Pain experience disproportionate
to the nature and extent of injury or
pathology
This criterion is obligatory for the classification of
CS pain. CS is typically characterized by disproportionate pain, implying that the severity of pain and related
reported or perceived disability (e.g., restriction andintolerance to daily life activities, to stress, etc.) are disproportionate to the nature and extent of injury or pathology (i.e., tissue damage or structural impairments)(1,4,7,9,12,13-16,19,32,42,53,54). This contradicts nociceptive pain, where the severity of pain and related
reported or perceived disability are proportionate to
the nature and extent of injury or pathology.
Screening of this first criterion implies that theclinician assesses 1) the patient’s amount of injury, pathology, and objective dysfunctions capable of generating nociceptive input, and 2) the self-perceived pain
and related disability. Next, the clinician then weighs
both in order to answer the following question: Does
this patient presents sufficient evidence of injury, pathology, and/or objective dysfunctions for generating
nociceptive input capable of causing the self-reported
pain and disability? Several answers to this question
are possible:•••

Yes, this patient presents sufficient evidence of
injury, pathology, and/or objective dysfunctions forgenerating nociceptive input capable of causing
the self-reported pain and disability. This would
imply that the patient has nociceptive pain, or atleast a clinical picture dominated by nociceptive
pain (Fig. 1).
No, this patient presents insufficient evidence of
injury, pathology, or objective dysfunctions forgenerating nociceptive input capable of causing
the self-reported pain and disability. This would
imply that the patient fulfills this first out of 3 criteria for CS pain; the patient may have CS pain. We
proceed with screening of the remaining criteria.
There is evidence of injury, pathology, or objective dysfunctions for generating nociceptive input
capable of causing pain and disability, but notenough for explaining the pain and disability experienced by this patient. Again, this would imply
that the patient fulfills this first out of 3 criteria forwww.painphysicianjournal.com

CS pain; the patient may have CS pain. We proceedwith screening of the remaining criteria.
An example of disproprotionate pain may be a apatient with chronic neck pain, who suffered an apparently minor injury, with no structural lesions on
cervical scans, but a complex clinical picture of various
symptoms, including segmentally unrelated pain areasand severe disability. This scenario is typically seen inpatients with chronic whiplash associated disorders(grade 1 – 2) (1,3,4,32).
Patients with osteoarthritis typically have (some)tissue damage (i.e., cartilage distruction), yet standard
radiological findings show little or no association withpain severity or perceived disability (55). At the sametime, mounting evidence supports an important role
for CS in patients with osteoarthritis (8,17,55-58).
In addition, there are patient cohorts with severe
pain in the absence of any discernible tissue damage
or pathology. In this group, nociception is not or has
not been present, and yet they continue to have severe
pain and related disability. This has been shown consistently in studies of various patient populations, including fibromyalgia (53), chronic fatigue syndrome (13,59),
migraine (15), and chronic low back pain (7-9). It is clearthat this group complies with this criterion.
The presence of disproportionate pain implies
some pain of central pain origin, but does not necessarily reflect CS pain. Therefore, additional criteria shouldbe met before one can consider CS as the dominantmechanism explaining the patient’s pain.

Criterion 2: Diffuse pain distribution,
allodynia, and hyperalgesia
This criterion addresses patient self-reported
pain distribution as identified from the clinical history
and/or a body chart (for instance, the Margolis Pain
Diagram uses 2 body outlines, front and back, in which
patients have to shade the body parts were they felt
pain lasting for more than 24 hours in the past 4 weeks(60). At least one of the following, partly overlapping,patterns of pain distribution should be present to fulfill
this criterion:•
bilateral pain/mirror pain (i.e., a symmetrical pain
pattern);•pain varying in (anatomical) location/traveling
pain, including to anatomical locations unrelated
to the presumed source of nociception e.g., hemilateral pain, large pain areas with a nonsegmental(i.e., neuroanatomically illogical) distribution;

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widespread pain (defined as pain located axial, on
the left and right side of the body and above andunder the waist) (61);and/or allodynia/hyperalgesia outside the segmental area of (presumed) primary nociception(3,12,17,19,59).

This overview of patterns of pain distribution is
not comprehensive, but it provides a list of frequently
occurring patterns considered indicative of CS, as theycannot be explained by a local nociceptive source.
Criterion 2 is mainly screened through questioning, although allodynia/hyperalgesia can be examinedon palpation or sensory testing as well (i.e., allodynia
to non-noxious mechanical stimuli such as light touchand hyperalgesia to pin prick or heat and cold). Diffuse/non-anatomic areas of pain/tenderness are typicallyfound on palpation (40). Allodynia and/or hyperalgesia outside the segmental area of primary nociception
has been used for establishing CS in studies of various
chronic pain disorders (including whiplash, epicondylitis, subacromial impingement syndrome, chronic fatigue
syndrome, nonspecific arm pain) (3,12,17,19,21,59). In
addition to manual palpation or assessing pressure pain
thresholds, such allodynia/hyperalgesia outside the segmental area of primary nociception can be establishedthrough history taking or questioning as well. For instance, a low back pain patient reporting that wearing
a necklace is no longer possible as it triggers pain.
Here we propose criterion 1 as a go/no-go for theclassification of CS pain. If criterion 1 and 2 are bothmet, then the classification of CS can be established. If
only the first criterion (disproportionate pain) is met
and not the second criterion, further screening of criterion 3 is required.

Criterion 3: Hypersensitivity of senses
unrelated to the musculoskeletal system
CS may reflect much more than generalized hypersensitivity to pain: It may be characterized by an increased responsiveness to a variety of stimuli in addition
to mechanical pressure (3,12,17,19,21,53,54,59), namely
chemical substances (62), cold (21,42), heat (13,21), electrical stimuli (32,53), stress (31,63-66), emotions, andmental load. Given the overall hyper-responsivenessof central nervous system neurons, CS may explain thehypersensitivity to many environmental (bright light,
cold/heat, sound/noise, weather, stress, food [67-69]),
and chemical stimuli (62,70,71) (odors, pesticides, medication among others). It is therefore recommended to452

question the patients with suspected CS for hypersensitivity to bright light, sound, smell, and hot or cold
sensations. For classification purposes, these symptoms
should not have been present prior to the onset of thepain (disorder) of interest here. However, some of these
could have been present before pain. Their premorbid
presence does not exclude the possibility of CS pain, but
makes them unreliable for diagnosing CS pain.
Still, direct evidence showing that CS explains hypersensitivity to such environmental stimuli is lacking.
This assumption is based on evidence from psychophysiological studies showing hypersensitivity in pain patients to mechanical pressure (3,12,17,19,21,53,54,59),
cold (21,42), heat (13,21), electrical stimuli (32,53), stress(31,63-66), food (67-69), chemical stimuli (62,70,71), anda study in patients with fibromyalgia where low thresholds to auditory tones correlated with pressure pain
thresholds (72). It is therefore recommended to question the patients with suspected CS for hypersensitivity
to bright light, sound, smell, and hot or cold sensations.
The screening of criterion 3 can be done using part
A of the Central Sensitization Inventory (44), whichassesses symptoms common to CS, with total scores
ranging from 0 to 100. Based on a validation study ina sample of 89 CS-pain patients and a 129 non-patientcomparison group, a cutoff score of 40 is recommended(45). A cutoff score of 40 on the Central Sensitization
Inventory provides a clinically relevant guide to alert
health care professionals to the possibility that a patient’s symptom presentation may indicate the presence of CS pain (45). Still, establishing CS pain in clinicalsituations should not rely on self-report only, and there
is currently no published work comparing the Central
Sensitization Inventory between CS and neuropathic
pain patients. Hence, we have no direct evidence tosupport the use of the Central Sensitization Inventory
as the sole criterion for classifying CS pain, and havetherefore chosen to integrate its use in a more comprehensive approach to classifying CS pain.
Here we propose that the combination of a scoreof at least 40 on the Central Sensitization Inventory,
together with disproportionate pain (criterion 1), suffices for the classification of CS pain in patients with
non-neuropathic pain (Fig. 1).

Additional Signs and Symptoms Often Seen
in Patients with CS, but Not Required for theClassification
Clearly, patients with CS typically present with many
more signs and symptoms than those included in the 3

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Applying Modern Pain Neuroscience in Clinical PracticeTable 2. Additional signs and symptoms often seen in patients with central sensitization (CS), but not required for the classificationof CS pain.

Sign or symptom

Assessment

Description

Numbness

Questioning and/or clinical examination

Numbness not localized and with nonsegmental
distribution

Muscle weakness

Questioning and/or clinical examination

Subjective sensation of weakness in whole limb/lackof muscle control in whole limb

Cognitive deficits

Questioning and/or clinical examination

Concentration difficulties, short-term memory
disturbances, latency, difficulties finding the correct
words, “brain fog”

Sleeping difficulties

Questioning

Difficulty falling asleep, frequent awakenings at night,
unrefreshing sleep

Inconsistent clinical examination findings

Clinical examination

Inconsistent findings across clinical tests

Phantom swelling sensation

Questioning and/or clinical examination

Sensation of swollen limb in absence of visualevidence of edema or swelling

Phantom swelling enhancement

Questioning and/or clinical examination

Phantom swelling sensations enhance when thepatients close their eyes

Phantom swelling diminishment

Questioning and/or clinical examination

Phantom swelling sensations decrease or disappear
when they view the affected limb

Altered perception of affected body part

Questioning and/or clinical examination

Perception that the affected body part is smaller orlarger than it should be, or inability to feel part of theaffected body region without visual or tactile input

Impaired tactile localization

Questioning and/or clinical examination

Decreased tactile acuity of (the skin above) the
affected region; increased 2-point discriminationthresholdPhantom stiffness

Questioning and/or clinical examination

Sensation of joint stiffness in absence of objective
signs of decreased mobility

Dyskinaesthesia

Questioning and/or clinical examination

Sensation of clumsiness or poor spatial acuity or lessaware of where their limbs are in spaceclassification criteria for CS. For instance, the longer pain
persists, the more likely CS becomes a more dominantcomponent to the clinical presentation (73). An abnormal timeline is defined as a course over time that deviates from the natural course of the illness or injury. Table
2 lists a number of additional signs and symptoms often
seen in patients with CS pain. Some of them partly overlap with one or more of the classification criteria for CS
pain. Others are totally new and did not make it into theclassification criteria, either because our clinical and research experience indicates that their prevalence among
patients with CS is too low, or because they are notspecific for CS. Taken together, the additional signs andsymptoms have low sensitivity or specificity for patientswith CS, and are mainly included here for clarity reasons.
If present, they may strengthen the classification of CS
pain, but only if they have not been present prior to theonset of the pain (disorder) of interest.
In addition to the signs and symptoms listed in Table
2, it is often informative to question the patient about
the short-term and long-term therapeutic responses towww.painphysicianjournal.com

previous or ongoing treatments. The following options
can be regarded as an abnormal therapeutic response:
nonresponders to nociception-targeted treatments provided, inconsistent or unpredictable response to treatment, intolerance to various treatment approaches, oran acute increase in hypersensitivity to various stimuli
in response to (new) treatment, including symptom
exacerbation beyond what is regularly seen in patientswith local (nociceptive) pain disorders (25,73).
Finally, we acknowledge the close association between CS and maladaptive psychosocial factors (e.g.,
negative emotions, poor self-efficacy, maladaptive
beliefs and pain behaviors), as evidenced in the study
by Smart et al (39). Indeed, “cognitive emotional sensitization” (74) refers to the capacity of forebrain centersof exerting powerful influences on various nuclei of thebrainstem, including the nuclei identified as the originof the descending facilitatory pathways (75). The activity in descending pathways is not constant but can be
modulated, for example by the level of vigilance, catastrophizing, depression, attention, and stress (76,77).

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In spite of the evidence pointing to an importantrole for maladaptive psychosocial and emotional factors in the etiology and maintenance of the process ofCS, we chose against including them in the criteria forclassification of CS pain. The reason is based on researchfindings showing that depressive symptoms, anxiety, or
catastrophizing are neither related to pain sensitivity or
brain activity during experimental pain in chronic pain
patients (78). In addition, the lack of sensitivity andspecificity of maladaptive psychosocial and emotional
factors for the classification of CS pain is an important
issue. Maladaptive psychosocial and emotional factors
can be present in chronic pain patients without CS as
well, making them inappropriate for inclusion as aclassification criterion. Likewise, patients with clear evidence of CS sometimes do not have negative emotions,maladaptive beliefs, or pain behaviors, indicating their
low sensitivity for the classification of CS in patientswith chronic pain. Nevertheless, the authors recognize
the importance of assessing and addressing these psychosocial and emotional factors in the treatment approach of any pain patient.

Discussion
This is the first presentation of criteria and analgorithm for the clinical classification of CS in pain
patients, supported by a large volume of research findings (1-4,8,12,14,15,32,39-42,45,53,59,62,73). Moreover,guidelines for the differential classification between
neuropathic, nociceptive, and CS pain are proposed.
In all 3 pain types a biopsychosocial view is warranted;
in all 3 pain types a multimodal model is necessary to
explain the pain (intensity) and to choose the appropriate treatment.
In addition, criterion 3 from the classification
criteria proposed here is supported by a large validation study of the Central Sensitization Inventory, using
patients with various CS diagnoses like restless leg syndrome, chronic fatigue syndrome, temporomandibular
disorders, tension headaches, migraines, fibromyalgia,
irritable bowel syndrome, and multiple chemical sensitivity syndromes (45). Finally, the classification criteria
are directly substantiated by a study of a large group ofpatients with low back pain (n = 464) (40). Two of the
4 signs/symptoms that differentiated the CS low backpain patients from the neuropathic and nociceptive
pain groups are included in the 4 major classification
criteria for CS: pain disproportionate to the nature andextent of injury or pathology, and diffuse/nonanatomic
areas of pain/tenderness on palpation (40). In addition454

to these 2 signs/symptoms, a third sign (disproportionate, non-mechanical, unpredictable pattern of pain
provocation in response to multiple/nonspecific aggravating/easing factors), although rather specific forspinal pain, is partly included in criteria 2 and 3.
In addition to the scientific evidence presented,
these classification criteria are supported by expert
consensus. Eighteen pain experts from 13 institutions
across 7 countries combine over 100 years of clinical andscientific experience in patients with chronic pain, andover 200 scientific publications in the field of chronic
pain. That said, the classification algorithm still requires
validation in clinical settings, including examination of
its clinical applicability. The inter- and intra-examiner
test-retest reliability, sensitivity, specificity, positive, andnegative likelihood ratios of the classification criteriapresented here remain to be examined. In addition, theclassification algorithm lacks “objective” criteria, but
for the time being there is little proof for an objective
biomarker for CS pain. However, this is the first step
towards a set of classification criteria and a classification algorithm for CS pain. We hope our proposal will
facilitate the acknowledgment and recognition ofCS, research in this area, and eventually adaptation/
improvement of the classification algorithm based on
research data.
If a clinician recognizes CS in a patient with chronic
pain, how does it potentially impact upon treatment?
The presence of CS implies that the brain produces pain,
fatigue, and other warning signs even when there is noreal tissue damage. CS is not a disorder of the mind, butrather a disease of the brain and spinal cord. Hence,
the brain should become an important treatment target. This can be achieved by explaining to the patient
the mechanism of CS with evidence from modern neuroscience, an approach with high patient satisfaction(79-81), and has proven to be effective in a variety ofchronic pain populations (80). Neuroscience education
enables patients to understand the controversy surrounding their pain, including the lack of objective biomarkers, and the need for a time-contingent approachto activity and exercise therapy. A symptom-contingent
approach may facilitate the brain in its production ofnonspecific warning signs, while a time-contingent approach might deactivate brain-orchestrated descending
facilitatory pathways. This view is supported by findingsof reduced central nervous system hyperexcitability(37), and an increase in prefrontal cortical volume (38)in response to time-contingent therapy in chronic pain
(fibromyalgia) patients.

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Applying Modern Pain Neuroscience in Clinical Practice

In addition, centrally-acting drugs, like selective
and balanced serotonin and norepinephrine reuptake
inhibitor drugs, the serotonin precursor tryptophan,opioids, NMDA-receptor antagonists, and calcium
channel a2δ ligands, are indicated for the treatment of
CS (82). For more indepth guidelines on the treatmentof CS in patients with chronic pain, the readers are referred to other sources (16,23,24,56,81,82).

validation work as well. For the latter, clinicians are advised to screen their patients for 3 major classification
criteria, and use them to complete the classification
algorithm for each individual patient with chronic pain.
Although based on both research findings and expert
opinion, the classification algorithm requires experimental testing in future studies.

Disclaimer

Conclusion
The awareness is growing that CS is of prime
importance for the management of chronic pain, but
its classification is challenging clinically since no gold
standard method of assessment exists. It is proposedthat the classification of CS pain entails 2 major steps:
the exclusion of neuropathic pain and the differential
classification of nociceptive versus CS pain. For theformer, the International Association for the Study ofPain diagnostic criteria (46) are available for diagnosing
or excluding neuropathic pain, although they require

There was no external funding in the preparationof this manuscript.

Conflict of interest
Each author certifies that he or she, or a memberof his or her immediate family, has no commercial
association (i.e., consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) thatmight pose a conflict of interest in connection with thesubmitted manuscript.

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