Journal of

Clinical Medicine

Review
Nociplastic Pain Criteria or Recognition of Central Sensitization?
Pain Phenotyping in the Past, Present and Future
Jo Nijs 1,2,3, * , Astrid Lahousse 1,4 , Eleni Kapreli 5 , Paraskevi Bilika 5 , İsmail Saraçoğlu 6 ,
Anneleen Malfliet 1,2,4 , Iris Coppieters 1,2 , Liesbet De Baets 1 , Laurence Leysen 1 , Eva Roose 1 ,
Jacqui Clark 1,7 , Lennard Voogt 1,8 and Eva Huysmans 1,2,4

1 Pain in Motion Research Group (PAIN), Department of Physiotherapy, Human Physiology and Anatomy,
Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, 1050 Brussels, Belgium;
[email protected] (A.L.); [email protected] (A.M.); [email protected] (I.C.);
[email protected] (L.D.B.); [email protected] (L.L.); [email protected] (E.R.);
[email protected] (J.C.); [email protected] (L.V.); [email protected] (E.H.)
2 Chronic Pain Rehabilitation, Department of Physical Medicine and Physiotherapy,
University Hospital Brussels, 1050 Brussels, Belgium
3 Unit of Physiotherapy, Department of Health and Rehabilitation, Institute of Neuroscience and Physiology,
University of Gothenburg Center for Person-Centred Care (GPCC), Sahlgrenska Academy,
University of Gothenburg, 405 30 Gothenburg, Sweden
4 Research Foundation—Flanders (FWO), 1000 Brussels, Belgium
5 Clinical Exercise Physiology & Rehabilitation Research Laboratory, Physiotherapy Department,
Faculty of Health Sciences, University of Thessaly, 382 21 Lamia, Greece; [email protected] (E.K.);



[email protected] (P.B.)

 6 Kütahya Health Sciences University, Kütahya 43100, Turkey; [email protected]
7 Pains and Brains, Specialist Pain Physiotherapy Clinic, New Plymouth 4310, New Zealand
Citation: Nijs, J.; Lahousse, A.;
8 University of Applied Sciences Rotterdam, 3015 Rotterdam, The Netherlands
Kapreli, E.; Bilika, P.; Saraçoğlu, İ.;
* Correspondence: [email protected]
Malfliet, A.; Coppieters, I.; De Baets,
L.; Leysen, L.; Roose, E.; et al.
Nociplastic Pain Criteria or Abstract: Recently, the International Association for the Study of Pain (IASP) released clinical criteria
Recognition of Central Sensitization? and a grading system for nociplastic pain affecting the musculoskeletal system. These criteria
Pain Phenotyping in the Past, Present replaced the 2014 clinical criteria for predominant central sensitization (CS) pain and accounted
and Future. J. Clin. Med. 2021, 10, for clinicians’ need to identify (early) and correctly classify patients having chronic pain according
3203. https://doi.org/10.3390/ to the pain phenotype. Still, clinicians and researchers can become confused by the multitude of
jcm10153203 terms and the variety of clinical criteria available. Therefore, this paper aims at (1) providing an
overview of what preceded the IASP criteria for nociplastic pain (‘the past’); (2) explaining the new
Academic Editor: Stefan U. Weber
IASP criteria for nociplastic pain in comparison with the 2014 clinical criteria for predominant CS
pain (‘the present’); and (3) highlighting key areas for future implementation and research work
Received: 6 July 2021
in this area (‘the future’). It is explained that the 2021 IASP clinical criteria for nociplastic pain are
Accepted: 19 July 2021
Published: 21 July 2021
in line with the 2014 clinical criteria for predominant CS pain but are more robust, comprehensive,
better developed and hold more potential. Therefore, the 2021 IASP clinical criteria for nociplastic
Publisher’s Note: MDPI stays neutral
pain are important steps towards precision pain medicine, yet studies examining the clinimetric and
with regard to jurisdictional claims in psychometric properties of the criteria are urgently needed.
published maps and institutional affil-
iations. Keywords: nociplastic pain; precision medicine; neuropathic; central sensitization; nociceptive

Copyright: © 2021 by the authors.

1. Introduction
Licensee MDPI, Basel, Switzerland. Chronic pain is the most prevalent disease worldwide, leading to substantial disability
This article is an open access article and enormous socioeconomic burden [1]. Amongst long-term conditions, it is responsible
distributed under the terms and for the highest number of years lived with disability [2,3] and is the most expensive cause
conditions of the Creative Commons of work-related disability [4,5]. Thus, chronic pain can be regarded as a non-communicable
Attribution (CC BY) license (https:// disease with a large impact on public health. Chronic pain is often non-specific, implying
creativecommons.org/licenses/by/ that there is no pathology or tissue damage or that the limited amount of pathology or
4.0/).

J. Clin. Med. 2021, 10, 3203. https://doi.org/10.3390/jcm10153203 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2021, 10, 3203 2 of 14

tissue damage is not severe enough to explain the pain experience. This non-specific nature
accounts for non-cancer pain as well as post-cancer pain (i.e., pain in cancer survivors) [6].
In many people with chronic non-specific pain, central nervous system sensitization
(briefly: central sensitization or CS; the Appendix A provides a terminology overview) can
explain why they suffer from pain in the absence of a clear origin of nociceptive input or in
the absence of enough tissue damage to explain the experienced pain severity, disability
and other symptoms [7,8]. For clinical purposes, CS is defined as an amplification of neural
signalling within the central nervous system that elicits pain hypersensitivity [7]. Under
this definition, it is possible to study CS in humans. However, this is not the case for the
definition provided by the International Association for the Study of Pain (IASP): “an
increased responsiveness of nociceptive neurons in the central nervous system to their
normal or subthreshold afferent input” [9] because in vivo measurements of nociceptive
neuron responses in the central nervous system are impossible. CS encompasses various re-
lated dysfunctions within the central nervous system, including altered sensory processing
in the brain [10] with a disrupted resting state functional connectivity in the default mode
and salience networks [11] and increased brain activity in areas known to be involved in
acute pain sensations (insula, anterior cingulate cortex and prefrontal cortex) as well as in
other regions (various brain stem nuclei, dorsolateral frontal cortex and parietal associated
cortex) [12]. CS also includes altered activity in brain-orchestrated nociceptive facilitatory
pathways [10,13]. CS also implies poor functioning of endogenous analgesia (Appendix A),
which refers to brainstem-originated pathways that release neurotransmitters to inhibit
spinal nociceptive processing [14,15]. Together, these central nervous system dysfunctions
not only contribute to increased responsiveness to a variety of sensory inputs such as
tactile stimuli but can also lead to hypersensitivity to non-musculoskeletal stimuli, such as
chemical substances, light, sound, heat, cold, stress and electricity [16]. The knowledge
regarding CS has revealed a paradigm shift in the understanding and management of
chronic pain that allows clinicians to think beyond muscles and joints and to account for
the role of pain modulation in the central nervous system [17].
In a variety of chronic musculoskeletal pain conditions, CS has been found to be
present in an important subgroup of patients (reviewed in [17]). These conditions include
chronic traumatic neck pain (i.e., whiplash) [18], fibromyalgia [19], osteoarthritis [20],
migraine [21], irritable bowel syndrome [22], chronic fatigue syndrome [23], paediatric
pain [24], low back pain [25], non-traumatic neck pain [26], rheumatoid arthritis [27]
and pain following cancer [6]. CS appears to be less common in patients with tennis
elbow [28], tendinopathies [29] and shoulder pain [30]. This illustrates the need for clinical
recognition of CS in individual patients with chronic pain. Indeed, in conditions, such as
tendinopathies, where CS is present in a minority of patients, the clinical importance of
CS is illustrated by studies showing that the subgroup of the population characterized by
CS is more disabled and suffers more severe pain than those who do not have CS [28,31].
Additionally, the presence of (symptoms of) CS predicts poor treatment outcomes in
patients with a variety of chronic pain conditions [32–36], at least when the treatment targets
the presumed source of nociception. This applies to conservative interventions [35,36] but
also to surgical interventions [37–40]. Again, this shows the need for early recognition of
CS in patients with chronic pain, in combination with tailored treatment [41].
This need for early recognition of CS in patients with chronic pain was picked up
by IASP, who introduced the term “nociplastic pain” in 2017 as a third mechanistic pain
descriptor in addition to nociceptive and neuropathic pain (Appendix A) [42,43]. Noci-
plastic pain is defined by the IASP as “pain that arises from altered nociception despite no
clear evidence of actual or threatened tissue damage causing the activation of peripheral
nociceptors or evidence for disease or lesion of the somatosensory system causing the
pain” (Appendix A) [43]. CS is not part of the definition of nociplastic pain; however,
signs of sensitization are generally present in nociplastic pain conditions [42]. Moreover,
sensitization is the major underlying mechanism of nociplastic pain [44]. Hence, patients
whose clinical picture is dominated by CS are labelled as having nociplastic pain. Recently,
J. Clin. Med. 2021, 10, 3203 3 of 14

the IASP released clinical criteria and a grading system for nociplastic pain affecting the
musculoskeletal system [44]. These criteria replaced the 2014 clinical criteria for predom-
inant CS pain [45] and are embraced by the international community, as they account
for clinicians’ need to (early) identify and correctly classify patients having chronic pain
according to the pain phenotype. Still, clinicians and researchers can become confused
by the multitude of terms (CS, predominant CS pain, nociplastic pain, central sensitivity
syndromes, etc.) and the variety of clinical criteria available. Therefore, the present paper
aims at (1) providing an overview of what preceded the IASP criteria for nociplastic pain
(‘the past’); (2) explaining the new IASP criteria for nociplastic pain in comparison with the
2014 clinical criteria for predominant CS pain (‘the present’); and (3) highlighting key areas
for future implementation and research work in this area (‘the future’).

2. The Past
The first scientific reports that addressed the issue of clinical identification of CS pain in
patients with chronic musculoskeletal pain date back to 2010 [16,46]. A ‘masterclass’ paper
described an initial attempt for supporting clinicians in their clinical reasoning process to
recognize CS in patients with chronic musculoskeletal pain [16], but the first structured
approach to adding CS pain to pain phenotyping in clinical practice was provided in 2010
by Keith Smart et al. [46]. They reported an expert consensus-derived list of clinical criteria
suggestive of a clinical dominance of nociceptive, peripheral neuropathic and ‘central’
mechanisms of musculoskeletal pain [46]. This pioneering work was expanded with the
same group reporting a study of 64 patients with low back and leg pain, where they
identified key symptoms that allowed clinicians to differentiate with a high discriminative
ability [47] CS pain from nociceptive and neuropathic pain [48]: disproportionate, non-
mechanical, unpredictable pattern of pain provocation in response to multiple/non-specific
aggravating/easing factors, pain disproportionate to the nature and extent of injury or
pathology, strong association with maladaptive psychosocial factors and diffuse/non-
anatomic areas of pain/tenderness on palpation.
Based on the work by Smart et al. [46,47], the available literature at that time and
expert consensus, clinical criteria for recognizing predominant CS in patients with chronic
musculoskeletal pain were released in 2014 [45]. These recommendations included the
exclusion of neuropathic pain as the first step. A second mandatory criterion involved
determining if the severe pain can be considered disproportionate to what one would
expect based on the available tissue damage or presumed source of nociception [45]. When
neuropathic pain is not present and the pain is considered disproportionate in nature,
at least one of the two remaining criteria should be met. The first of the two optional
criteria is the diffuse pain distribution, i.e., pain that spreads outside the segmental area of
primary nociception [45,49]. Applied to the example of knee osteoarthritis, this criterion
corresponds to someone having pain referring all over the affected low limb [49]. Pain
drawings can be used to standardize and optimize the assessment of the individual’s
pain distribution in a reliable way. Patients are requested to shade the areas where they
experience pain on an outline of a human figure. The human figure is divided into 45 body
areas. Each body part is equal to a certain percentage of the total body surface [50]. The
more areas are shaded, the more indication for widespread pain. The data obtained
using this tool show acceptable test-retest reliability (r = 0.85) [51]. Furthermore, two-
dimensional computerized methods have been developed for more precise measurement of
pain extent, making interpretation more standardized, presenting excellent intra-rater and
inter-rater reliability (ICC = 0.99–0.97) [52]. The second optional criterion for predominant
CS encompasses a score of 40 or higher on the Central Sensitization Inventory (CSI). The CSI
is a patient-reported outcome measure that has been widely used to study symptoms of CS
in patients with chronic pain. It assesses pain as well as non-pain symptoms considered to
be related to CS (e.g., unrefreshing sleep, sleep problems, sensitivity to light, concentration
difficulties, stress as aggravating factor, sensitivity to odours, restless legs) [53]. The CSI is
available in 18 languages and can be accessed free of charge at » Questionnaires Developed
J. Clin. Med. 2021, 10, 3203 4 of 14

at PRIDE (pridedallas.com, accessed on 9 June 2021). The psychometric properties of

the CSI in patients having non-specific, non-cancer pain are well-established [54]. Taken
together, the 2014 clinical criteria for predominant CS pain suggested that one can expect
the presence of CS in case of a disproportional pain experience combined with a diffuse
pain picture and/or a score above 40/100 on the CSI [45]. Furthermore, the relationship
of the CSI to biopsychosocial aspects of CS pain may be supported based on findings
that the extent of CS symptoms, measured using the CSI in chronic low back pain with
clinically identified CS (2014 criteria), can be predicted by trait anxiety and trait sensory
hyper-sensitivity characteristics [55].
Following its publication in 2014, the clinical criteria for recognizing predominant CS
in patients with chronic musculoskeletal pain [45] were adapted for specific chronic pain
populations such as osteoarthritis [56], low back pain [57], chronic pelvic and perineal pain
criteria [58] and post-cancer pain [6]. Next, the IASP introduced the term “nociplastic pain”
as a third mechanistic pain descriptor [42,43], which brings us to the present situation.

3. The Present
The IASP clinical criteria and grading system for nociplastic pain of the musculoskele-
tal system.
The IASP clinical criteria for nociplastic pain of the musculoskeletal system imply that,
in order to clinically classify nociplastic pain, patients have to:
(1) report pain of at least 3 months duration;
(2) report a regional rather than discrete pain distribution;
(3) report pain that cannot entirely be explained by nociceptive or neuropathic mechanisms;
(4) show clinical signs of pain hypersensitivity (i.e., evoked pain hypersensitivity phe-
nomena such as static or dynamic mechanical allodynia, heat or cold allodynia,
and/or painful after-sensations after any of the mentioned evoked pain hypersensi-
tivity assessments) that are at least present in the region of pain [44].
If these four requirements are met, the patients can be classified as having “possible
nociplastic pain” [44]. In cases where all four requirements are fulfilled, plus the patient
presents with a history of pain hypersensitivity in the region of pain (i.e., sensitivity to
touch, movement, pressure or heat/cold) and at least one of the defined comorbidities
(increased sensitivity to sound, light and/or odours, sleep disturbance with frequent
nocturnal awakenings, fatigue or cognitive problems), the pain is classified as “probable
nociplastic pain” [44]. The presence of nociceptive or neuropathic pain does not exclude
the possibility of concurrence of nociplastic pain, but if nociceptive or neuropathic pain is
present, they cannot be entirely responsible for the pain. For clinicians willing to apply the
IASP clinical criteria for nociplastic pain during their clinical reasoning process, Figure 1
provides a clinical decision-making tree.
The IASP clinical criteria and grading system for nociplastic pain affecting the muscu-
loskeletal system [44] provide the first set of clinical criteria (1) endorsed by a worldwide
scientific organization (i.e., the IASP), and (2) linked to nociplastic pain as the third mecha-
nistic pain descriptor in addition to nociceptive and neuropathic pain. CS is a key underly-
ing mechanism of nociplastic pain [44], yet CS goes beyond the nociceptive system [17].
Within this view, it is considered unfortunate that the IASP chose the term nociplastic
pain and defined it with a focus on the nociceptive system. The IASP nociplastic pain
criteria, however, do appear to account for this shortcoming, as they stress the importance
of assessing comorbidities with non-pain symptoms and sensory (rather than nociceptive)
hypersensitivity being part of the IASP 2021 criteria [44]. It is key for clinicians to under-
stand that non-pain symptoms can result from the same underlying mechanism (i.e., CS),
and the IASP clinical criteria for nociplastic pain facilitate this.
J. Clin.J. Med.
Clin. Med. 10, x10,
2021,2021, FOR3203
PEER REVIEW 5 of 514of 14

Figure
Figure 1. Clinical
1. Clinical decision-makingtree
decision-making tree of
of the
the IASP
IASP clinical
clinicalcriteria
criteriaforfor
nociplastic pain.
nociplastic pain.

Comparing the IASP Clinical Criteria for Nociplastic Pain with the 2014 Clinical Criteria for
The IASP clinical criteria and grading system for nociplastic pain affecting the mus-
Predominant Central Sensitization Pain
culoskeletal system [44] provide the first set of clinical criteria (1) endorsed by a world-
When comparing the 2021 IASP clinical criteria for nociplastic pain of the muscu-
wide scientific organization (i.e., the IASP), and (2) linked to nociplastic pain as the third
loskeletal system with the 2014 clinical criteria for predominant CS pain in patients with
mechanistic pain descriptor
musculoskeletal pain (Table in 1),addition
it becomes toclear
nociceptive
that bothand
setsneuropathic pain.
of criteria focus CS is a key
on chronic
underlying mechanism of nociplastic pain [44], yet CS goes beyond the nociceptive
pain, which is pain of at least three months’ duration. Additionally, both sets target mus- system
[17]. Within this
culoskeletal view,
pain, it is considered
implying that they unfortunate
are not intendedthatfor
thepain
IASPphenotyping
chose the term nociplastic
in patients
pain
with visceral pain. Looking at the individual criteria, the IASP 2021 criterion of the patientpain
and defined it with a focus on the nociceptive system. The IASP nociplastic
criteria, however,
reporting do rather
a regional appear to account
than for this
discrete pain shortcoming,
distribution as theytostress
[44] is similar thecriterion
the 2014 importance
of diffuse pain
of assessing that spreadswith
comorbidities outside the segmental
non-pain symptoms areaand
of primary
sensory nociception
(rather than[45,49]. The
nociceptive)
main difference here is that it is a mandatory criterion in the IASP 2021 criteria,
hypersensitivity being part of the IASP 2021 criteria [44]. It is key for clinicians to under- while it
was an optional criterion in the 2014 criteria. The requirement of excluding
stand that non-pain symptoms can result from the same underlying mechanism (i.e., CS), predominant
neuropathic pain as the underlying mechanism is another agreement between both sets
and the IASP clinical criteria for nociplastic pain facilitate this.
of criteria. In addition, the IASP criteria state that the pain cannot entirely be explained
by nociceptive mechanisms [44], which is a much more straightforward way of what was
Comparing the IASP Clinical Criteria for Nociplastic Pain with the 2014 Clinical Criteria for
intended in the 2014 criteria with ‘disproportionate pain’ [45]. ‘Disproportionate pain’
Predominant
may be viewed Central
as aSensitization Pain
subjective assessment by the therapist, which the 2021 IASP criteria
eliminate. Indeed, disproportionate
When comparing the 2021 IASP pain was defined
clinical criteriaasfor
“the severity ofpain
nociplastic pain of
is dispropor-
the musculo-
tionate to the nature and extent of injury or pathology (i.e., tissue damage
skeletal system with the 2014 clinical criteria for predominant CS pain in patients with or structural
impairments),”pain
musculoskeletal and it was explained
(Table that disproportionate
1), it becomes clear that both setspainof contradicts nociceptive
criteria focus on chronic
pain, which is pain of at least three months’ duration. Additionally, both sets targetormus-
pain, where the severity of pain is proportionate to the nature and extent of injury
pathology [45]. Hence, both sets of criteria stress the importance of differentiating from
culoskeletal pain, implying that they are not intended for pain phenotyping in patients
nociceptive pain by excluding the possibility that nociception is the main driver of the
with visceral pain. Looking at the individual criteria, the IASP 2021 criterion of the patient
experienced pain and consequently used this as a mandatory criterion. Of note is also
reporting
that threea regional rather
out of four than
of the discreteidentified
symptoms pain distribution
by Smart [44]et al.isin
similar to the
2012 [48] 2014 crite-
as having
rion of diffuse pain that spreads outside the segmental area of primary
the ability to differentiate between peripheral neuropathic, nociceptive and CS pain are nociception [45,49].
The main difference
included here is thatinitthe
(in other wordings) is a2021
mandatory criterion
IASP clinical in the
criteria for IASP 2021 criteria,
nociplastic while
pain. It is
it was
worthanmentioning
optional criterion
that more inthan
the 2014 criteria.
one pain The requirement
phenotype can present. of excluding
Taken together,predominant
the 2021
IASP criteria
neuropathic emphasize
pain better the possibility
as the underlying mechanism for mixed types agreement
is another of pain. between both sets
of criteria. In addition, the IASP criteria state that the pain cannot entirely be explained by
nociceptive mechanisms [44], which is a much more straightforward way of what was
intended in the 2014 criteria with ‘disproportionate pain’ [45]. ‘Disproportionate pain’
may be viewed as a subjective assessment by the therapist, which the 2021 IASP criteria
J. Clin. Med. 2021, 10, 3203 6 of 14

Table 1. A comparison of the IASP 2021 clinical criteria for nociplastic pain with the 2014 clinical
criteria for predominant central sensitization pain.

IASP 2021 Clinical Criteria for 2014 Clinical Criteria for Predominant
Nociplastic Pain [44] Central Sensitization Pain [45]
Mandatory criteria
Patients have to report pain of at least Patients have to report pain of at least
3 months duration. 3 months duration.
Patients have to present diffuse pain that
Patients have to report a regional rather than
spreads outside the segmental area of
discrete pain distribution.
primary nociception.
The pain should be considered
Patients have to report pain that cannot entirely disproportionate to what one would expect
be explained by nociceptive mechanisms. based on the available tissue damage or
presumed source of nociception.
Patients have to report pain that cannot entirely Exclusion of neuropathic pain as the dominant
be explained by neuropathic mechanisms. pain mechanism.
Patients have to show clinical signs of pain
hypersensitivity (i.e., evoked pain
hypersensitivity phenomena such as static or
dynamic mechanical allodynia, heat or cold
-
allodynia, and/or painful after-sensations after
any of the mentioned evoked pain
hypersensitivity assessments) that are present
at least in the region of pain.
Optional criteria
Patients present with a history of pain
hypersensitivity in the region of pain (i.e.,
-
sensitivity to touch, movement, pressure or
heat/cold).
Patients present at least one of the defined
comorbidities (increased sensitivity to sound,
A score of at least 40/100 on the Central
light and/or odours, sleep disturbance with
Sensitization Inventory.
frequent nocturnal awakenings, fatigue or
cognitive problems).

A major difference between the 2014 and the 2021 IASP criteria is that the latter de-
mand clinical signs of pain hypersensitivity in at least the region of pain evoked during
clinical assessments of mechanical, heat or cold allodynia [44]. Adding this as a manda-
tory criterion makes a lot of sense considering the body of literature regarding sensory
hypersensitivity in a variety of patients with nociplastic pain [59–62], yet it remains to be
determined whether the outcome of such clinical tests of allodynia in the region of pain
has a discriminative ability with what is seen in patients with nociceptive and neuropathic
pain. In fact, primary hyperalgesia is seen also in inflammatory or nociceptive pain, as
well as in neuropathic pain [63]. Additionally, in the case of chronic, persistent neuropathic
pain, dysfunctions within the central nervous system related to CS may (partly) explain
symptoms in these patients [64]. The discriminative ability of allodynia in areas remote
from the painful region [65–68] may be higher, but this is not addressed in either the 2021
IASP or 2014 clinical criteria. Another key difference between the two sets of criteria
is the use of a grading system in the 2021 IASP criteria, which was not included in the
2014 criteria. We feel this is a very positive evolution, as it is in line with the approach of
grading the likelihood of having neuropathic pain [69] but also as it reflects modesty and
the level of evidence supporting the clinical criteria in individual patients. However, the
additional requirements needed for grading the pain as probable nociplastic pain partly
overlap with the fourth criterion of the 2014 criteria. The 2021 IASP criteria for probable
J. Clin. Med. 2021, 10, 3203 7 of 14

nociplastic pain require that the patient presents with a history of hypersensitivity to touch,
movement, pressure or heat/cold in the region of pain and increased sensitivity to sound,
light and/or odours, sleep disturbance with frequent nocturnal awakenings, fatigue or
cognitive problems [44]. Quantitative sensory testing can be used for assessing hypersensi-
tivity to pressure, heat and cold, but according to the 2021 IASP clinical criteria, this is not
mandatory. While a history of hypersensitivity to touch, movement, pressure or heat/cold
in the region of pain were not included in the 2014 clinical criteria for predominant CS
pain, all the comorbidities of the 2021 IASP clinical criteria for nociplastic pain can be
assessed using the CSI (Table 2). Therefore, even though the CSI was not proposed by
the 2021 IASP criteria, we believe that in the patient interview, most of the CSI items can
assist in querying the history of pain hypersensitivity and non-painful comorbidities. In
addition, the CSI can also provide clinicians information regarding the severity of sensory
hypersensitivity, as it gives a numerical value. A possible limitation of the CSI, where the
CSI score is used to confirm the presence of a predominant CS pain mechanism in the 2014
criteria, is the risk of false negatives, which the IASP 2021 criteria eliminate. For example,
CSI scores may be confounded by individual coping styles with characteristics that tend to
under-report themselves in subjective measures, which they consider might cast them in a
negative light [55]. Taken together, one should keep in mind that the CSI is intended to
assess symptoms of CS and is not meant to be a tool to “diagnose” CS. Therefore, it cannot
be used as a standalone questionnaire for the identification of predominant CS/nociplastic
pain and should always be combined with the assessment of the remaining clinical criteria
for the identification of nociplastic pain.

Table 2. The comorbidities included in the 2021 IASP clinical criteria for nociplastic pain are covered
by items included in the Central Sensitization Inventory. Q = question number.

Comorbidities Included in the 2021 IASP

Central Sensitization Inventory Items
Clinical Criteria for Nociplastic Pain
I am sensitive to bright lights (Q7).
Increased sensitivity to light and/or sound
Certain smells, such as perfumes, make me feel
and/or odours
dizzy and nauseated (Q20).
I feel tired and unrefreshed when I wake up
from sleeping (Q1).
Sleep disturbance with frequent
I do not sleep well (Q12).
nocturnal awakenings
My legs feel uncomfortable and restless when I
am trying to go to sleep at night (Q22).
I get tired very easily when I am physically
Fatigue active (Q8).
I have low energy (Q17).
Cognitive problems such as difficulty to focus I have difficulty concentrating (Q13).
attention, memory disturbances, etc. I have difficulty remembering things (Q23).

Taken together, the 2021 IASP clinical criteria for nociplastic pain of the musculoskele-
tal system are in line with the 2014 clinical criteria for predominant CS pain, but they are
more comprehensive, better developed and hold more potential due to its support from a
large international organization such as the IASP.

4. The Future
4.1. Towards Precision Pain Medicine?
CS facilitates embracing the biopsychosocial model for the assessment, clinical reason-
ing and treatment of patients with chronic pain. In addition, clinical criteria for nociplastic
pain allow clinicians to adopt the treatment according to the pain phenotype. Preci-
sion medicine refers to the ability to classify patients into subgroups that differ in their
susceptibility to, biology, or prognosis of a particular disease, or in their response to a
specific treatment, and thus to tailor treatment to the individual patient characteristics [70].
J. Clin. Med. 2021, 10, 3203 8 of 14

Recent studies suggest that assessment of CS may be used to improve precision pain
medicine for rheumatology practices (reviewed in [17]). This implies that patient education,
management and treatments are adapted to the pain phenotype. For patient education,
this includes explaining the underlying pain mechanism to the patient according to the
relevant pain phenotype (e.g., explaining central sensitization to patients having noci-
plastic pain) [71]. For the management and treatment of pain, it implies that injury- and
pathology-targeted approaches (i.e., classical biomedical treatments such as surgery, joint
treatment and anti-inflammatory drugs) should be preserved to patients having nociceptive
pain, while nociplastic pain requires a broader multimodal approach including patient
education, behavioural graded activity, stress management, exercise therapy, sleep man-
agement, etc. [8,72]. A pitfall for clinicians and patients applying such an approach is that
the focus of the treatment relies too much on improving the underlying pain mechanism
(i.e., decreasing CS in patients with nociplastic pain). Rather, the focus should be to regain
the ability to perform and enjoy the patient’s self-chosen functional activities and hence to
improve quality of life. Another pitfall for clinicians applying a pain phenotyping approach
is that one might neglect the individual variability within one pain phenotype. Therefore,
precision medicine for patients with chronic pain is more than accounting for CS, and it
also implies addressing relevant comorbidities, such as insomnia [73] and obesity [74], and
lifestyle factors that sustain CS, such as stress [75], physical inactivity [76] and unhealthy
diet [77], depending on the individual patient characteristics.
It should be acknowledged that (symptoms of) CS can be present to a varying degree
and may therefore also be present in people whose predominant pain type may not be
nociplastic pain (e.g., in certain people undergoing total knee arthroplasty or surgery to
decompress a spinal nerve). However, in the latter case, accounting for (factors underlying)
CS can still be of relevance due to the known unfavourable influence of CS on therapy
and/or surgical outcomes (refer to the introduction) [35–40]. In that sense, although
differentiating between predominant pain types can be very useful for clinical practice,
clinicians should avoid developing a tunnel view by using such classification criteria.
To facilitate thorough clinical assessment, a guideline for the biopsychosocial assess-
ment of individuals with chronic pain, including the determination of the predominant
pain type, is available [78]. The latter was based on the 2014 criteria but can easily be
replaced by the 2021 IASP clinical criteria. We feel that applying such a comprehensive
biopsychosocial assessment results in a clear overview of the clinical picture of a patient,
facilitating a holistic biopsychosocial approach and decreasing the aforementioned risk for
tunnel vision of the clinician.

4.2. Research Agenda

Still, it is important to stress that research is needed to examine the reliability and
validity of the different sets of clinical criteria for nociplastic pain/predominant CS pain. To
serve this purpose, clinical vignettes may be useful. Clinical vignettes are short scenarios
that describe a situation (i.e., real cases) in which the reader has the opportunity to submit
his or her comments and opinion. Vignettes have been used in social [79] and medical
studies for diagnosis, clinical reasoning and disease management [80,81]. Participants
typically answer a series of open-ended or closed-ended questions related to the scenarios
included in the vignettes [82]. Guidelines are available to ensure internal validity when
developing vignettes [83,84]. One of the advantages of vignettes is that they can present
situations that are influenced by factors that may not be easily accessible for research
purposes in real situations. With this technique, these clinical situations are available
to multiple evaluators simultaneously and identically. This provides the opportunity to
examine the intra- and interrater reliability of the IASP clinical criteria for nociplastic pain
to compare the outcome of the IASP clinical criteria for nociplastic pain with the 2014
clinical criteria for predominant CS pain and to examine the content validity of both sets
of criteria. In addition, developing reliable and valid field-testing procedures would be
valuable for supporting clinicians in applying pain phenotyping in daily practice.
J. Clin. Med. 2021, 10, 3203 9 of 14

As mentioned before, an assessment protocol for allodynia of a remote painful area

could be of added value for clinicians to distinguish the different pain phenotypes [14].
Quantitative sensory testing (QST) is a widely used method that measures patients’ verbal
or behavioural response to quantifiable sensory stimuli, which encompasses broad parame-
ters, such as detection and pain thresholds, temporal summation (TS), and conditioned pain
modulation (CPM) [85]. Patients with chronic conditions show imbalanced pain facilitation
and pain inhibition [86], which are usually assessed, respectively, by TS, controlling for
increasing evoked pain by fixed repetitive stimuli, and CPM, controlling for the ability to
reduce evoked pain by a second stimulus [86]. A dysregulated response was observed in
conditions such as fibromyalgia [87], temporal mandibular disorders [88], irritable bowel
syndrome [88] and osteoarthritis [89]. The strength of these assessments is their ability to
predict the magnitude of post-operative pain and the effect of exercise interventions [90–92].
Unfortunately, until now, it is not realistic to incorporate an elaborated QST protocol in the
clinic. This was also underscored in the paper presenting the 2021 IASP clinical criteria for
nociplastic pain [44]. However, there is growing interest in bedside QST protocols, which
do not require specialized equipment [85]. Some studies provided promising findings re-
garding the validity and reliability of such bedside QST protocols; however, further work is
required, and future research should assess the feasibility in clinical practice, as well as the
added value of such bedside QST protocols to the clinical criteria for nociplastic pain [86].
Another future consideration is that nociplastic pain includes CS within its pheno-
type, but the 2021 IASP criteria do not currently accommodate aspects of sensory hypo-
sensitivity. Aspects of sensory hypo-sensitivity may accompany some nociplastic pain
presentations [93–95], and this warrants further investigation.

5. Conclusions
Pain phenotyping in patients with chronic musculoskeletal pain remains a hot topic.
The initial attempts to develop clinical criteria for patients having a predominant CS type of
pain date back to 2010. In 2017, the IASP introduced the term “nociplastic pain” as a third
mechanistic pain descriptor in addition to nociceptive and neuropathic pain, providing
a label to patients having a predominant CS type of pain. Recently, the IASP released
clinical criteria and a grading system for chronic nociplastic pain of the musculoskeletal
system. These 2021 IASP clinical criteria for nociplastic pain of the musculoskeletal system
are in line with the 2014 clinical criteria for predominant CS pain but are more robust,
comprehensive, better developed and hold more potential due to its support from the
IASP. Therefore, the 2021 IASP clinical criteria for nociplastic pain of the musculoskeletal
system are an important step towards precision pain medicine, yet studies examining the
clinimetric and psychometric properties of the criteria are urgently needed.

Funding: The paper was unfunded. E.H., A.L. and A.M. are research fellows funded by the Research
Foundation Flanders (FWO), Belgium. E.R. is a research fellow funded by Kom op tegen Kanker. J.N.
is the holder of a chair funded by the Berekuyl Academy, The Netherlands.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: J.N. and the Vrije Universiteit Brussel received lecturing/teaching fees from
various professional associations and educational organizations, and J.N. authored a Dutch book on
central sensitization. The remaining authors have nothing to disclose.
J. Clin. Med. 2021, 10, 3203 10 of 14

Appendix A. Terminology (Presented in Alphabetic Order)

Term Explanation
A neurophysiological mechanism, defined as
‘amplification of neural signalling within the central
Central sensitization
nervous system that elicits pain hypersensitivity [7],’
potentially explains chronic, nonspecific pain.
Central nervous system sensitization Refers to ‘central sensitization.’
Chronic pain Pain of at least 3 months duration.
The body’s ability to activate pain relief, with poor
Endogenous analgesia endogenous analgesia considered a feature of
central sensitization [17].
Neuropathic pain Pain due to a lesion or a disease of the nervous system.
Pain due to damage to non-neural tissue
Nociceptive pain
(e.g., musculoskeletal or visceral tissue).
Pain that arises from altered nociception despite no
clear evidence of actual or threatened tissue damage
Nociplastic pain causing the activation of peripheral nociceptors or
evidence for disease or lesion of the somatosensory
system causing the pain [43].
Pain that cannot be explained by tissue damage,
Nonspecific pain
pathology or local dysfunctions.

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