Nociplastic Pain: A Contemporary Narrative Review of Mechanisms, Clinical Assessment, Controversies, and Management

Chronic pain is a major global health burden, with population-level estimates ranging from approximately 20% to over 30% of adults experiencing moderate-to-severe chronic pain, depending on the population and case definition used. 1 , 2 It is the leading cause of years lived with disability and imposes a substantial socioeconomic and personal burden. 1 Despite decades of progress in nociceptor biology and neuropathic pain pharmacology, a large proportion of patients with persistent pain cannot be adequately accounted for by ongoing tissue damage or by identifiable lesions of the somatosensory nervous system. To bridge this conceptual and clinical gap, the International Association for the Study of Pain (IASP) introduced the term nociplastic pain in 2017 as a third mechanistic descriptor, complementary to nociceptive and neuropathic pain. 3 , 4 The present review provides a critical, clinically oriented synthesis of evidence from January 2016 to June 2026. We address the definition and historical evolution, epidemiology, neurobiology, clinical assessment, prototypical disorders, comorbidities, treatment, controversies, and research priorities of nociplastic pain. Throughout, we emphasize a balanced reading of the evidence and explicitly identify unresolved questions. Three syntheses are central to the current literature: Fitzcharles et al mapped the clinical features and treatment of nociplastic pain conditions; 5 Kaplan et al synthesized mechanisms and risk factors and proposed top-down and bottom-up nociplastic subtypes 6 and the Häuser and Kosek perspective cautioned against conflating nociplastic pain with central sensitization or chronic primary pain. 7 Three needs remain unmet. First, the distinction these works defend in principle has not been rendered operational: clinicians still lack a single framework that separates mechanism, descriptor, and diagnosis at the point of care. Second, the rapidly accumulating 2024–2026 validation evidence for the 2021 IASP criteria (Vervullens 2024. 8 Bilika 2025. 9 Schmidt 2025) 10 has not been critically appraised against the limits of those criteria. Third, no structured research agenda yet specifies how the criteria should be tested in the visceral, headache, cancer, pediatric, and geriatric domains in which they are currently unvalidated, or how a mixed-state nociplastic contribution should be quantified. Accordingly, this review aims to close these three gaps, with the primary purpose of providing a clinically usable framework; the critical appraisal of the recent validation evidence and the structured research agenda serve this primary clinical aim. The review is timely because the 2021 criteria are increasingly applied well beyond the musculoskeletal population from which they were derived. This is a narrative review. We searched PubMed/MEDLINE, Embase, Scopus, and the Cochrane Library for English-language publications issued between January 2016 and June 2026. The electronic search was supplemented by selected seminal publications predating 2016 and by hand-searching the reference lists of major reviews and relevant documents issued by the International Association for the Study of Pain (IASP), the European Alliance of Associations for Rheumatology (EULAR), and other professional societies. Search terms included “nociplastic pain”, “central sensitization” or “central sensitisation”, “chronic primary pain”, “central sensitivity syndrome”, and “fibromyalgia”, combined with terms relating to “criteria”, “mechanisms”, “diagnosis”, “neuroimmune”, and “treatment”. The final search of all databases was completed on June 30, 2026. As an example, the full PubMed/MEDLINE strategy was: (“nociplastic pain”[Title/Abstract] OR “central sensitization”[Title/Abstract] OR “central sensitisation”[Title/Abstract] OR “chronic primary pain”[Title/Abstract] OR “central sensitivity syndrome”[Title/Abstract] OR fibromyalgia[Title/Abstract]) AND (criteria[Title/Abstract] OR mechanism*[Title/Abstract] OR diagnosis[Title/Abstract] OR neuroimmune[Title/Abstract] OR treatment[Title/Abstract]), restricted to English-language publications dated January 1, 2016 to June 30, 2026; this strategy was adapted to the syntax of the other databases. The searches, title-and-abstract screening, and full-text assessment were performed by two authors (C.-C.C. and Y.-T.L), who also verified all references against the primary sources; disagreements were resolved by discussion with the senior author (J.-J.W). Priority was given to IASP definitions and professional-society guidelines, systematic reviews and meta-analyses, randomized controlled trials, and mechanistic human studies with direct relevance to the conceptualization, diagnosis, and management of nociplastic pain. Selected foundational references published before 2016 were retained when they provided essential historical, conceptual, or mechanistic context for which no recent equivalent was available. Non-English-language publications and conference abstracts without an accessible full-text report were excluded. After removing duplicate records, the retrieved citations were screened by title and abstract for relevance; potentially eligible reports were then assessed in full text, and the final body of evidence was selected by author consensus on the basis of clinical relevance, methodological quality, and thematic fit. Methodological quality was appraised informally according to a design hierarchy (IASP documents and professional-society guidelines, systematic reviews and meta-analyses, randomized controlled trials, then mechanistic human studies) rather than with a defined critical-appraisal framework. Consistent with the narrative design of this review, no formal systematic-review protocol, dual independent screening, quantitative study-count reporting, or formal risk-of-bias/quality assessment was undertaken; these are limitations of the narrative design. During the preparation of this work the authors used a generative AI tool (Claude, Fable 5, Anthropic) to improve the clarity, structure, and English-language readability of the manuscript, and to assist with reference cross-checking. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article. Generative AI was not used to generate scientific content, analyses, or citations, and is not listed as an author. All references were verified by the authors against the primary sources. Over the past half-century, mechanistic pain classification has evolved from a dichotomous (nociceptive vs neuropathic) framework toward a more nuanced, mechanism-based scheme. Revisions of IASP terminology by Loeser and Treede, the IASP neuropathic pain grading system (Treede et al 2008; 11 updated by Finnerup et al 2016), 12 and subsequent IASP–ICD-11 collaborations together shaped the contemporary classification. By the mid-2010s, however, it had become evident that a substantial subset of patients (particularly those with fibromyalgia, chronic widespread pain, and overlapping chronic pain conditions) did not fit into either category despite strong evidence of altered central nociceptive processing. 13 , 14 In 2016, Kosek et al formally proposed the need for a third mechanistic descriptor for these chronic pain states. 3 The proposal was adopted by the IASP Council in 2017 and entered the IASP terminology in 2017–2018, defined 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. 4 In parallel, the IASP Task Force developed a new ICD-11 chronic pain classification, defining chronic pain as pain persisting or recurring for more than three months and distinguishing chronic primary pain (a disease in its own right) from chronic secondary pain (a symptom of another disease). 15 , 16 Dedicated companion papers operationalized the chronic secondary categories, including visceral, musculoskeletal, and neuropathic pain, 17–19 and showed that the mechanistic (nociplastic) and etiologic/clinical (chronic primary pain) frameworks overlap but are not equivalent, a distinction often blurred in clinical practice and recent literature. 7 In 2021, the IASP further refined the concept by publishing clinical criteria and a grading system for nociplastic pain affecting the musculoskeletal system; these give a structured decision-tree approach for the field. 20 Criteria for visceral and other non-musculoskeletal pain are still under development. The concept has continued to be refined, accompanied by recurrent calls for broader validation and critical re-examination. 7 , 21 , 22 Recent commentary notes the risk that nociplastic pain may become an over-inclusive diagnostic catch-all, that it overlaps incompletely with ICD-11 chronic primary pain, and that the term may obscure undetected peripheral drivers. 7 , 21 A vignette-based validation study by Bilika et al subsequently demonstrated satisfactory reliability and criterion validity, particularly after rater familiarization, while calling for further evaluation in real-world clinical settings. 9 A cohort study by Vervullens et al in knee osteoarthritis proposed additional operational criteria to refine the grading system. 8 The IASP defines nociplastic pain as pain arising from altered nociception, in the absence of clear evidence of actual or potential tissue damage that activates peripheral nociceptors, and without disease or lesion of the somatosensory nervous system that would explain the pain. 4 Critically, nociplastic pain is conceptualized as a mechanism, not a diagnosis. It can occur in isolation or coexist with nociceptive and/or neuropathic components in a mixed pain state. 4 , 5 , 7 Conditions historically described as “functional pain,” “central sensitivity syndromes”, “medically unexplained pain,” or “chronic primary pain” often correspond to this phenotype. 4 , 14 , 20 , 23 Fibromyalgia, irritable bowel syndrome (IBS), temporomandibular disorders (TMD), chronic primary low back pain, and chronic primary headache are frequently cited examples; of these, fibromyalgia is the prototype, whereas in the remaining conditions nociplastic mechanisms are proposed to contribute, often alongside nociceptive or neuropathic components. 4 , 5 Three conceptual features deserve emphasis. First, nociplastic pain is mechanism-based rather than syndrome-based: patients with osteoarthritis, rheumatoid arthritis, or chronic low back pain may primarily exhibit nociceptive pain but also carry a nociplastic component that modulates pain intensity, distribution, and treatment response. 5 , 6 Second, nociplastic pain implies maladaptive plasticity within nociceptive pathways, encompassing both central pathways and peripheral pathways that are now also recognized. 6 , 24 Third, the descriptor is not synonymous with “unexplained pain” or “psychogenic pain”; it explicitly requires positive clinical features rather than serving as a diagnosis of exclusion. 22 Nociplastic pain is not synonymous with central sensitization. Central sensitization refers to a specific neurophysiological phenomenon characterized by enhanced responsiveness of central nociceptive neurons, demonstrable through enhanced temporal summation, secondary hyperalgesia, and impaired conditioned pain modulation. 25–27 Although central sensitization is a principal contributor to nociplastic pain, the two concepts operate at different levels: central sensitization is a mechanism, nociplastic pain is a clinical–mechanistic description, and chronic primary pain is a diagnostic entity. 7 , 22 To reduce the persistent conflation of these terms, Table 1 sets out an explicit comparison across the dimensions most relevant to clinical and research use, including, in the final row, a practical bedside cue for recognizing each construct. Table 1 Conceptual Disambiguation of Central Sensitization, Nociplastic Pain, and Chronic Primary Pain Dimension Central Sensitization Nociplastic Pain Chronic Primary Pain Construct type Neurophysiological mechanism / process Clinical–mechanistic descriptor of pain Diagnostic entity (a disease in its own right) Core definition Enhanced responsiveness of central nociceptive neurons to normal or subthreshold input Pain from altered nociception without clear tissue damage or somatosensory lesion Chronic pain ≥ 3 months with distress/disability, not better accounted for by another condition Level Cellular / circuit Whole-person pain phenotype Nosological / classification How established Psychophysics (temporal summation, secondary hyperalgesia, impaired CPM); human and animal models Positive clinical features plus IASP 2021 criteria ICD-11 clinical diagnosis (etiology-agnostic) Relationship to the others A principal contributor to nociplastic pain, but not all CS is nociplastic Often underpinned by CS but broader (neuroimmune, descending, peripheral) Many chronic primary pain conditions are predominantly nociplastic, yet the sets are not identical Typical examples Secondary hyperalgesia after injury; experimental sensitization Fibromyalgia, IBS, TMD, chronic primary headache Fibromyalgia, chronic primary low back pain, chronic primary visceral/headache (ICD-11) Principal clinical use Explains amplification; target for normalizing therapies Guides mechanism-based phenotyping and treatment selection Provides recognition, diagnosis, and coding Bedside cue / what to do (added) Test temporal summation and CPM; look for secondary hyperalgesia around an injury Map pain distribution; screen for evoked hypersensitivity and the comorbidity cluster (sleep, fatigue, cognition, sensory) Confirm ≥3 months, distress/disability, and that no other diagnosis better explains the pain; assign an ICD-11 code Principal references [ 25–27 ] [ 3 , 4 , 7 , 20 , 22 ] [ 15 , 16 ] Abbreviations : CPM, conditioned pain modulation; CS, central sensitization; IBS, irritable bowel syndrome; TMD, temporomandibular disorder. Conceptual Disambiguation of Central Sensitization, Nociplastic Pain, and Chronic Primary Pain Abbreviations : CPM, conditioned pain modulation; CS, central sensitization; IBS, irritable bowel syndrome; TMD, temporomandibular disorder. Reliable population-level estimates of nociplastic pain are constrained by inconsistent definitions and the limited time elapsed since the publication of operational criteria. Indirect estimates derived from prototypical disorders nevertheless provide useful context. Fibromyalgia affects approximately 2–4% of the general population. 28 , 29 IBS, 5–10%; TMD, 5–12%; migraine approximately 14%; and chronic primary low back pain affects several percent of adults at any given time. 1 , 5 , 30 , 31 Nociplastic pain disproportionately affects women, with female-to-male ratios of approximately 2:1 to 9:1 depending on the condition. 5 , 6 Risk factors associated with the development of nociplastic pain include female sex, adverse childhood experiences, psychological trauma, insufficient sleep, sedentary lifestyle, genetic predisposition, and chronic stress. 6 Genetic and transcriptomic evidence indicates that chronic overlapping pain conditions share common underlying biological signatures. 32 The clinical and economic burden is substantial. Patients typically report multifocal pain, severe fatigue, sleep disturbance, cognitive dysfunction, affective dysregulation, and reduced work capacity. 5 , 6 Healthcare utilization is high, and interventions targeting peripheral tissues alone (e.g joint surgery, injection therapy) frequently disappoint when a nociplastic component goes unrecognized. 5 , 6 These observations point to the need for greater clinical awareness and a shift toward mechanism-based management. Critical implications for the nociplastic pain concept . These prevalence figures are necessarily indirect: because operational criteria are recent and musculoskeletal-specific, all population estimates of nociplastic pain are extrapolated from prototypical disorders rather than measured directly. This circularity, inferring the prevalence of a mechanism from the diagnoses presumed to embody it, is itself a limitation of the construct and a priority for criterion-based epidemiology. Central sensitization, the amplification of neural signaling within the central nervous system that elicits pain hypersensitivity, is widely regarded as a principal, but not the sole, mechanism contributing to nociplastic pain. 25–27 At the spinal level, enhanced synaptic efficacy, loss of inhibitory tone, and altered glutamatergic signaling produce hyperalgesia, enlarged receptive fields, and secondary hyperalgesia. 27 Supraspinally, functional and structural neuroimaging studies of fibromyalgia and related conditions consistently demonstrate enhanced activation of pain-processing regions (insula, anterior cingulate cortex, somatosensory cortex), 33 altered default-mode network connectivity, 34 and elevated intra-insular glutamate concentrations, 35 with progressive structural and network reorganization during chronification. 36 Dysfunction of descending pain modulation is another prominent feature. Impaired conditioned pain modulation, a psychophysical indicator of endogenous inhibitory pathways, has been demonstrated in nociplastic conditions, and inadequate diffuse noxious inhibitory control has been associated with pain chronification and treatment response. 37 Consistent with this, a controlled psychophysical study demonstrated a deficit of endogenous pain inhibition in patients with fibromyalgia relative to both chronic low back pain patients and healthy controls. 38 Dysregulation of monoaminergic (serotonergic and noradrenergic) descending pathways provides a mechanistic rationale for the efficacy of serotonin–noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants in these disorders. 39 , 40 Additional contributors include hyperalgesic priming, brain network reorganization favoring affective over sensory pain circuits, and alterations in autonomic and stress-response systems (hypothalamic–pituitary–adrenal axis dysfunction). 6 The dichotomy between “central” and “peripheral” mechanisms is now widely regarded as artificial: peripheral nociceptor sensitization, small-fiber pathology, and even autoimmune-driven peripheral sensitization have been described in fibromyalgia and complex regional pain syndrome, indicating bidirectional peripheral–central interactions. 24 , 41 , 42 An integrated view of these mechanisms is summarized in Figure 1 , and assessment across chronic pain conditions has been reviewed by Arendt-Nielsen et al, 43 and, in the context of precision medicine, by Nijs et al 44 Figure 1 Principal pathophysiological mechanisms of nociplastic pain. Central sensitization is depicted as a principal, but not the sole, central mechanism of nociplastic pain: four interacting mechanistic domains converge on central sensitization, and neuroimmune/glial and peripheral mechanisms can additionally contribute to the clinical phenotype through pathways at least partly independent of central sensitization (thin lateral arrows). All four domain–central sensitization interactions are bidirectional (double-headed arrows): deficient descending modulation both permits sensitization and can itself result from the ongoing pain state, as shown by normalization of conditioned pain modulation after surgical pain relief 37 , 45 , 46 structural and network reorganization in the brain is driven by persistent nociceptive activity while contributing to the maintenance of chronic pain; 36 neuron–glia signaling at the neuroimmune interface is reciprocal; 47–49 and peripheral and central mechanisms interact in both directions. 24 , 41 , 42 The vertical double-headed arrow linking central sensitization to the clinical manifestations denotes a bidirectional relationship: central sensitization generates the clinical phenotype, while the clinical manifestations, particularly disrupted sleep, feed back to impair descending inhibition and further sustain sensitization. 6 , 50 Within the boxes, upward (↑) and downward (↓) arrows denote increased and decreased activity, signaling, or neurotransmitter levels, respectively (e.g, ↑ NMDA receptor activation; ↓ serotonin and noradrenaline). The reference numbers shown within each element of the figure indicate the supporting sources. Author-created original schematic; it is not reproduced or adapted from any single previously published figure, and the mechanisms depicted are based on evidence from references, 5 , 6 , 20 , 24 , 26 , 27 , 32–42 and. 44–54 A diagram of nociplastic pain mechanisms, showing central sensitization and its interactions with various domains. A diagram outlines the key mechanisms of nociplastic pain, focusing on central sensitization and its interaction with four domains: deficient descending modulation, altered brain structure, neuroimmune activation and peripheral contributions. Each domain has a bidirectional relationship with central sensitization. Deficient modulation involves impaired inhibition and reduced pain modulation. Altered brain structure includes increased pain processing and gray matter changes. Neuroimmune activation involves microglial activity and pro-inflammatory cytokines. Peripheral contributions cover small-fiber pathology and autoimmune influences. Clinical symptoms like widespread hyperalgesia and sleep issues can occur independently of central sensitization. Arrows indicate changes in activity, signaling, or neurotransmitter levels. Abbreviations : ACC, anterior cingulate cortex; BDNF, brain-derived neurotrophic factor; CPM, conditioned pain modulation; GABA, γ-aminobutyric acid; IgG, immunoglobulin G; IL, interleukin; NMDA, N-methyl-D-aspartate; S1, primary somatosensory cortex; TNF-α, tumor necrosis factor alpha. Principal pathophysiological mechanisms of nociplastic pain. Central sensitization is depicted as a principal, but not the sole, central mechanism of nociplastic pain: four interacting mechanistic domains converge on central sensitization, and neuroimmune/glial and peripheral mechanisms can additionally contribute to the clinical phenotype through pathways at least partly independent of central sensitization (thin lateral arrows). All four domain–central sensitization interactions are bidirectional (double-headed arrows): deficient descending modulation both permits sensitization and can itself result from the ongoing pain state, as shown by normalization of conditioned pain modulation after surgical pain relief 37 , 45 , 46 structural and network reorganization in the brain is driven by persistent nociceptive activity while contributing to the maintenance of chronic pain; 36 neuron–glia signaling at the neuroimmune interface is reciprocal; 47–49 and peripheral and central mechanisms interact in both directions. 24 , 41 , 42 The vertical double-headed arrow linking central sensitization to the clinical manifestations denotes a bidirectional relationship: central sensitization generates the clinical phenotype, while the clinical manifestations, particularly disrupted sleep, feed back to impair descending inhibition and further sustain sensitization. 6 , 50 Within the boxes, upward (↑) and downward (↓) arrows denote increased and decreased activity, signaling, or neurotransmitter levels, respectively (e.g, ↑ NMDA receptor activation; ↓ serotonin and noradrenaline). The reference numbers shown within each element of the figure indicate the supporting sources. Author-created original schematic; it is not reproduced or adapted from any single previously published figure, and the mechanisms depicted are based on evidence from references, 5 , 6 , 20 , 24 , 26 , 27 , 32–42 and. 44–54 Importantly, the interactions between central sensitization and each of these mechanistic domains appear to be reciprocal rather than strictly unidirectional. Deficient descending modulation is not only a premorbid, trait-like vulnerability that permits sensitization but can also be a state consequence of the ongoing pain itself: the impaired conditioned pain modulation observed in painful hip and knee osteoarthritis normalizes after surgical pain relief. 37 , 45 , 46 Similarly, structural and network reorganization in the brain is driven by persistent nociceptive activity while in turn contributing to the maintenance of chronic pain, 36 and the characteristic clinical manifestations can themselves feed back into the process, as disrupted sleep impairs descending inhibition, enhances pain facilitation, and thereby further sustains sensitization. 6 , 50 The neuroimmune interface is likewise characterized by reciprocal neuron–glia crosstalk, in which neuronal activity engages glial activation whose mediators in turn amplify neuronal excitability (see Section 7). 47–49 These bidirectional relationships are depicted in Figure 1 . Whether central sensitization can sustain pain autonomously in the absence of ongoing peripheral input remains debated. Critics argue that experimental and clinical evidence largely supports the requirement for ongoing nociceptive input to maintain sensitization, and that “autonomous” central sensitization may be more theoretical than demonstrable. 21 This unresolved issue has direct implications for therapeutic strategy. Preclinical and clinical evidence implicates neuroimmune mechanisms in the initiation and maintenance of nociplastic pain. 47–49 Central glial cell activation, particularly of microglia and astrocytes, drives the release of pro-inflammatory cytokines (e.g interleukin-1β, tumor necrosis factor-α, brain-derived neurotrophic factor) that enhance excitatory neurotransmission, reduce GABAergic (γ-aminobutyric acid) and glycinergic inhibition, and promote plasticity within spinal and supraspinal pain circuits. 47–49 Consistent with these mechanisms, a multiplex proteomic study identified concurrent cerebrospinal-fluid and plasma inflammatory signatures, including elevated fractalkine (CX3CL1), a neuron-derived chemokine that signals to microglia, and interleukin-8, in patients with fibromyalgia, providing direct human evidence of combined neuroinflammation and systemic inflammation. 51 Glial activation has been demonstrated in vivo in patients with fibromyalgia and chronic low back pain using translocator protein positron emission tomography; this is one of the first objective neuroimaging indicators of neuroinflammation in nociplastic pain states, although it is not validated as a diagnostic biomarker for nociplastic pain. 52 , 53 Peripheral immune signatures, including autoantibodies capable of inducing fibromyalgia-like behavior in animal models, further support a role for adaptive immunity: passive transfer of immunoglobulin G from patients with fibromyalgia reproduces sensory hypersensitivity in mice, in part by targeting satellite glial cells. 54 These findings have prompted interest in glia-targeting and immunomodulatory therapies, although translation into clinically validated treatments remains at an early stage. 6 The relevance of neuroinflammation to nociplastic pain helps reconcile the apparent paradox of pain without overt structural damage, and matches the broader phenotype of fatigue, cognitive dysfunction, and sleep disturbance characteristic of these disorders, features consistent with widespread neuroimmune dysregulation. 6 , 49 The 2021 IASP clinical criteria for nociplastic pain affecting the musculoskeletal system provide a structured, stepwise decision-tree. 20 To meet the criteria for possible nociplastic pain, a patient must demonstrate (i) chronic pain (≥3 months); (ii) regional rather than discrete distribution; (iii) pain not fully explained by nociceptive or neuropathic mechanisms; and (iv) clinical evidence of evoked pain hypersensitivity (allodynia, hyperalgesia, after-sensation) at least in the painful region. 20 To progress to probable nociplastic pain, additional features are required: a history of pain hypersensitivity in the region of pain, and at least one comorbidity from a defined list (sleep disturbance, fatigue, cognitive dysfunction, or hypersensitivity to non-painful sensory stimuli such as light, sound, and odors). 20 A practical, clinically oriented decision pathway that integrates these criteria with the peripheral-pathology safety checks emphasised throughout this review is summarised in Figure 2 . Figure 2 Clinical decision pathway for recognising a nociplastic pain contribution. Author-created schematic based on the IASP terminology 4 and the 2021 IASP clinical criteria and grading system for nociplastic pain affecting the musculoskeletal system, 20 with additional peripheral-pathology safety checks and referral prompts derived from the evidence synthesised in this review. 5–7 , 12 , 21 , 24 , 41 , 42 , 55 It is not an official IASP algorithm and is intended to support, not replace, individualised clinical judgment. The reference numbers shown within each element of the figure indicate the supporting sources. The 2021 criteria are validated for musculoskeletal pain and remain unvalidated in visceral, headache, and other non-musculoskeletal domains. A flowchart for assessing nociplastic pain in adults with chronic pain over 3 months. The flowchart begins with ′Adult with chronic pain (greater than or equal to 3 months)′. It proceeds to ′Clinical evaluation: history, pain distribution, sensory and neurological examination; screen for tissue damage or a somatosensory lesion′. If ′Red flags or focal peripheral/neural signs?′ are present, it leads to ′Targeted investigation and specialist referral; do not let a nociplastic label mask treatable peripheral or neural pathology′. If not, it asks ′Is the pain fully explained by nociceptive and/or neuropathic mechanisms?′ If yes, it suggests managing as nociceptive and/or neuropathic pain. If no, it checks for ′Regional, multifocal or widespread pain AND evoked hypersensitivity′. If yes, it indicates ′POSSIBLE nociplastic pain′. If no, it states ′Criteria for nociplastic pain not met′. For ′POSSIBLE nociplastic pain′, it checks ′History of pain hypersensitivity in the region AND greater than or equal to 1 comorbidity′. If yes, it leads to ′PROBABLE nociplastic pain′. If no, it remains ′POSSIBLE nociplastic pain′. The final step considers mixed pain and suggests mechanism-based management. Abbreviations : CPM, conditioned pain modulation; IASP, International Association for the Study of Pain; QST, quantitative sensory testing; SNRI, serotonin–noradrenaline reuptake inhibitor; TCA, tricyclic antidepressant. Clinical decision pathway for recognising a nociplastic pain contribution. Author-created schematic based on the IASP terminology 4 and the 2021 IASP clinical criteria and grading system for nociplastic pain affecting the musculoskeletal system, 20 with additional peripheral-pathology safety checks and referral prompts derived from the evidence synthesised in this review. 5–7 , 12 , 21 , 24 , 41 , 42 , 55 It is not an official IASP algorithm and is intended to support, not replace, individualised clinical judgment. The reference numbers shown within each element of the figure indicate the supporting sources. The 2021 criteria are validated for musculoskeletal pain and remain unvalidated in visceral, headache, and other non-musculoskeletal domains. Adjunctive assessment tools include questionnaires such as the Central Sensitization Inventory and the Fibromyalgia Survey Questionnaire, body pain diagrams, and psychophysical testing including quantitative sensory testing, temporal summation, and conditioned pain modulation. These instruments are useful adjuncts but should not replace clinical evaluation. 6 , 25 A comprehensive biopsychosocial assessment, including screening for sleep disturbance, mood, fatigue, sensory hypersensitivity, and adverse experiences, is essential. 6 Quantitative sensory testing (QST), temporal summation, and conditioned pain modulation (CPM) are useful for characterizing central pain processing but remain primarily research tools. They are most informative when (i) the diagnosis is uncertain in a specialist setting, (ii) one wishes to document deficient endogenous inhibition (e.g impaired CPM) to support a nociplastic phenotype, or (iii) stratifying patients for mechanism-based trials or, potentially, treatment selection; baseline CPM may predict SNRI (duloxetine) response, as shown in painful diabetic neuropathy. 56 They are least useful as stand-alone diagnostic tests: there are no universally accepted clinical cut-offs, protocols are not standardized across centers, and results must be interpreted alongside the clinical picture rather than replacing it. 6 , 25 , 43 In primary care, where full QST is rarely available, questionnaire-based instruments (Central Sensitization Inventory, Fibromyalgia Survey Questionnaire), a body pain diagram, and simple bedside testing (palpation tenderness, after-sensation) are reasonable screening substitutes; referral to a pain center with QST/CPM capability is appropriate when these screens suggest a substantial central component yet the diagnosis remains uncertain or treatable peripheral drivers must be excluded. Although nociceptive, neuropathic, and nociplastic pain differ mechanistically, they frequently coexist in the same patient, contributing to refractory chronic pain. 5 , 6 Differential diagnosis requires careful integration of history, physical examination, and targeted investigations where appropriate. The principal differentiating features are summarized in Table 2 . Nociceptive pain typically results from identifiable tissue injury or inflammation, is well localized, responsive to anti-inflammatory treatment, and tracks the temporal course of tissue damage. Neuropathic pain arises from a demonstrable lesion or disease of the somatosensory nervous system, conforms to a neuroanatomically plausible distribution, and is supported by confirmatory testing per the IASP grading system. 11 , 12 Table 2 Comparison of Nociceptive, Neuropathic, and Nociplastic Pain Feature Nociceptive Pain Neuropathic Pain Nociplastic Pain Underlying mechanism Peripheral nociceptor activation (injury/inflammation) 12 Lesion/disease of peripheral or central somatosensory pathways 12 Central sensitization; dysfunctional descending inhibition; neuroimmune activation; maladaptive plasticity 6 , 26 , 27 , 37 , 47 Distribution Localized to site of injury Neuroanatomically plausible (dermatomal/nerve-territory) 12 Regional, multifocal, or widespread; not anchored to peripheral pathology 5 , 20 Pain quality Aching, throbbing, sharp Burning, lancinating, electric, allodynia 12 Diffuse, deep, often migratory; widespread hypersensitivity 5 , 6 Sensory exam Tenderness at injured site; otherwise normal Sensory loss/gain in a neuroanatomical distribution 12 Diffuse hyperalgesia/allodynia; heightened sensitivity to non-painful stimuli 6 , 20 Comorbid features Limited, proportionate to injury Often paresthesia, autonomic dysfunction Fatigue, sleep disturbance, cognitive/mood disturbance, sensory hypersensitivity 5 , 6 , 20 Diagnostic confirmation Imaging/clinical signs of injury IASP neuropathic grading; 12 nerve conduction, imaging, sensory testing IASP clinical criteria; 20 clinical assessment; adjunctive QST/CPM 6 , 25 First-line treatment NSAIDs, paracetamol, anti-inflammatory, topical Gabapentinoids, TCAs, SNRIs, topical agents 57 SNRIs, TCAs, α2δ ligands (evidence largely from fibromyalgia); 5 , 39 , 58 exercise, CBT, education; multidisciplinary rehabilitation 58 Opioid response Effective short-term but limited Not first-line; tramadol second-line and strong opioids third-line (weak recommendations) 57 Generally ineffective; risk of opioid-induced hyperalgesia 5 , 6 Prototypical conditions Osteoarthritis, postoperative, inflammatory arthritis Diabetic polyneuropathy, postherpetic neuralgia, radiculopathy 12 Fibromyalgia, IBS, TMD, chronic primary low back pain, migraine 5 , 31 Mixed-state clues Pain disproportionate to imaging; spread beyond the injured site; poor response to local treatment Pain extends beyond the nerve territory; widespread tenderness; allodynia outside the lesion Persistent residual pain after a structural lesion is treated; non-painful sensory hypersensitivity 5 , 6 , 20 Common pitfalls / over-call risk Attributing all pain to imaging findings Diagnosing without confirmatory testing Using the label as a diagnosis of exclusion, masking small-fiber or autoimmune pathology 21 Abbreviations : CBT, cognitive behavioral therapy; CPM, conditioned pain modulation; IBS, irritable bowel syndrome; NSAID, non-steroidal anti-inflammatory drug; QST, quantitative sensory testing; SNRI, serotonin–noradrenaline reuptake inhibitor; TCA, tricyclic antidepressant; TMD, temporomandibular disorder. Comparison of Nociceptive, Neuropathic, and Nociplastic Pain Abbreviations : CBT, cognitive behavioral therapy; CPM, conditioned pain modulation; IBS, irritable bowel syndrome; NSAID, non-steroidal anti-inflammatory drug; QST, quantitative sensory testing; SNRI, serotonin–noradrenaline reuptake inhibitor; TCA, tricyclic antidepressant; TMD, temporomandibular disorder. By contrast, nociplastic pain is regional or multifocal, lacks an unambiguous anatomical correspondence to peripheral injury or neural pathology, and is accompanied by evoked sensory hypersensitivity and characteristic comorbidities such as fatigue, sleep disturbance, cognitive dysfunction, and hypersensitivity to non-painful stimuli. 4 , 6 , 20

Treatment of nociplastic pain can be broadly divided into pharmacological and non-pharmacological strategies ( Table 5 ). Because most randomized evidence derives from fibromyalgia, extrapolation of these recommendations to other conditions with a presumed nociplastic component should be cautious and made on a condition-by-condition basis. Table 5 Pharmacological and Non-Pharmacological Treatment Strategies for Nociplastic Pain Category Intervention Evidence/Comments Refs Pharmacological: first-line Duloxetine/milnacipran (SNRIs) Cochrane (Welsch 2018): combined NNTB 11 (≥50%) and 10 (≥30%); low-quality evidence; clinically relevant at ≥30% and for patient global impression [ 39 , 58 ] Amitriptyline (TCA, low-dose) Used in fibromyalgia, IBS, TMD, chronic primary headache [ 5 , 58 ] Pregabalin (α2δ ligand) Cochrane (Derry 2016): reduced pain, improved sleep vs placebo; FDA-approved for fibromyalgia; dose comparison in network meta-analysis (Migliorini 2022) [ 69 , 70 ] Gabapentin (α2δ ligand) Off-label; weaker evidence [ 58 ] Pharmacological: emerging Low-dose naltrexone RCT/crossover data; may modulate glial activity [ 6 , 71 ] Cannabinoids Limited, mixed evidence in fibromyalgia [ 72 ] Ketamine/NMDA antagonists Preliminary; non-routine use [ 6 , 68 , 72 ] Generally not recommended Long-term opioids Opioid-induced hyperalgesia; minimal efficacy [ 5 , 6 ] NSAIDs / corticosteroids Usually ineffective in predominantly nociplastic pain [ 5 , 6 ] Non-pharmacological: strong Pain neuroscience education Reduces fear-avoidance; supports engagement [ 58 ] Graded aerobic/ resistance exercise Sustained benefit on pain, function, fatigue [ 58 , 73 ] Cognitive behavioral therapy Improves coping, mood, function [ 58 , 74 ] Multidisciplinary rehabilitation Largest effect size in complex phenotypes [ 5 , 6 , 58 ] Non-pharmacological: supportive MBSR/ACT/tai chi/yoga Improve catastrophizing, function, pain [ 6 , 58 ] Sleep optimization Bidirectional link with pain [ 6 , 75 ] Emerging/under investigation rTMS/tDCS Promising but not yet mature [ 6 ] Glia-targeted/ autoantibody-directed Preclinical and early clinical [ 6 , 24 , 47 , 54 ] Digital therapeutics/ virtual reality Growing evidence base [ 6 ] Abbreviations : ACT, acceptance and commitment therapy; FDA, US Food and Drug Administration; IBS, irritable bowel syndrome; MBSR, mindfulness-based stress reduction; NMDA, N-methyl-D-aspartate; NNTB, number needed to treat for benefit; NSAID, non-steroidal anti-inflammatory drug; RCT, randomized controlled trial; rTMS, repetitive transcranial magnetic stimulation; SNRI, serotonin–noradrenaline reuptake inhibitor; tDCS, transcranial direct-current stimulation; TCA, tricyclic antidepressant; TMD, temporomandibular disorder. Pharmacological and Non-Pharmacological Treatment Strategies for Nociplastic Pain Abbreviations : ACT, acceptance and commitment therapy; FDA, US Food and Drug Administration; IBS, irritable bowel syndrome; MBSR, mindfulness-based stress reduction; NMDA, N-methyl-D-aspartate; NNTB, number needed to treat for benefit; NSAID, non-steroidal anti-inflammatory drug; RCT, randomized controlled trial; rTMS, repetitive transcranial magnetic stimulation; SNRI, serotonin–noradrenaline reuptake inhibitor; tDCS, transcranial direct-current stimulation; TCA, tricyclic antidepressant; TMD, temporomandibular disorder. Pharmacological management of nociplastic pain differs substantially from that of nociceptive or neuropathic pain. 5 , 6 Anti-inflammatory agents (NSAIDs, corticosteroids) and opioids are typically ineffective or harmful in predominantly nociplastic conditions and may exacerbate central sensitization, notably through opioid-induced hyperalgesia. 5 , 6 Among nociplastic disorders, the best-supported pharmacological agents, largely derived from fibromyalgia trials, act centrally to modulate descending inhibition and neuronal excitability: Serotonin–noradrenaline reuptake inhibitors (duloxetine, milnacipran): the Cochrane review by Welsch et al (2018) reported, for duloxetine and milnacipran combined, a number-needed-to-treat for benefit (NNTB) of 11 (95% CI 9–14) for 50% pain reduction in fibromyalgia and an NNTB of 10 (95% CI 8–12) for 30% pain reduction, with low-quality evidence; the benefit met pre-defined clinical relevance at the ≥30% threshold and for patient global impression, but not at the ≥50% threshold. 39 , 58 Baseline conditioned pain modulation may help predict SNRI response. 56 Tricyclic antidepressants (low-dose amitriptyline): widely used; the evidence of benefit is strongest in fibromyalgia, with condition-specific evidence in IBS, TMD, and chronic primary headache, and limited direct evidence in other presumed nociplastic conditions. 5 , 58 α2δ ligands (pregabalin, gabapentin): pregabalin reduces pain and improves sleep in fibromyalgia, as established in the Cochrane review by Derry et al (2016); 69 a Bayesian network meta-analysis by Migliorini and colleagues (2022) compared 300/450/600 mg/day doses to inform dose selection. 70 Gabapentin is used off-label with weaker evidence. 58 Combination of pregabalin with SNRIs may provide additive benefit. 76 Low-dose naltrexone: used off-label, with randomized crossover data in fibromyalgia and emerging evidence of modulation of glial activity. 6 , 71 Serotonin–noradrenaline reuptake inhibitors (duloxetine, milnacipran): the Cochrane review by Welsch et al (2018) reported, for duloxetine and milnacipran combined, a number-needed-to-treat for benefit (NNTB) of 11 (95% CI 9–14) for 50% pain reduction in fibromyalgia and an NNTB of 10 (95% CI 8–12) for 30% pain reduction, with low-quality evidence; the benefit met pre-defined clinical relevance at the ≥30% threshold and for patient global impression, but not at the ≥50% threshold. 39 , 58 Baseline conditioned pain modulation may help predict SNRI response. 56 Tricyclic antidepressants (low-dose amitriptyline): widely used; the evidence of benefit is strongest in fibromyalgia, with condition-specific evidence in IBS, TMD, and chronic primary headache, and limited direct evidence in other presumed nociplastic conditions. 5 , 58 α2δ ligands (pregabalin, gabapentin): pregabalin reduces pain and improves sleep in fibromyalgia, as established in the Cochrane review by Derry et al (2016); 69 a Bayesian network meta-analysis by Migliorini and colleagues (2022) compared 300/450/600 mg/day doses to inform dose selection. 70 Gabapentin is used off-label with weaker evidence. 58 Combination of pregabalin with SNRIs may provide additive benefit. 76 Low-dose naltrexone: used off-label, with randomized crossover data in fibromyalgia and emerging evidence of modulation of glial activity. 6 , 71 Cannabinoids, low-dose ketamine, and other glutamatergic modulators have drawn research interest, but evidence remains preliminary. 68 , 72 Polypharmacy and high-dose monotherapy carry a meaningful adverse-event burden and should be weighed against clinical benefit. Treatment selection should consider comorbid sleep, mood, and cognitive dysfunction. 5 , 6 Non-pharmacological interventions are central to nociplastic pain management and are generally recommended as first-line treatment. 5 , 6 , 58 EULAR fibromyalgia guidelines and related recommendations support a stepped, biopsychosocial, multimodal approach. 58 Key strategies include patient and pain neuroscience education to reduce fear-avoidance and improve treatment engagement; 58 graded aerobic and resistance exercise to improve pain, function, and fatigue; 58 , 73 cognitive behavioral therapy and acceptance and commitment therapy to enhance coping, mood, and function; 58 , 74 mind–body therapies, such as mindfulness-based stress reduction, yoga, and tai chi; 6 , 58 and sleep optimization, given the bidirectional relationship between sleep disturbance and nociplastic pain. 6 , 75 Multidisciplinary pain rehabilitation programs integrating these elements demonstrate the largest effect sizes in complex nociplastic phenotypes, although access remains limited globally. 5 , 6 , 58 Peripheral interventions such as surgery and injection therapy often disappoint and may cause iatrogenic harm when offered for a predominantly nociplastic pain state; they may nevertheless remain appropriate when clinically relevant peripheral pathology coexists. 5 , 6 Multiple emerging treatment strategies are under active investigation. Non-invasive brain stimulation (repetitive transcranial magnetic stimulation and transcranial direct-current stimulation) has shown promising efficacy in fibromyalgia and related disorders, although optimal protocols remain undefined. 6 Agents targeting glial cells and modulating neuroinflammation (including selective microglial inhibitors and cytokine antagonists) are in preclinical and early clinical development. 6 , 47 Building on emerging evidence for autoimmune mechanisms, autoantibody-directed therapies for fibromyalgia and complex regional pain syndrome represent a new therapeutic direction. 6 , 24 , 54 Other areas of innovation include digital therapeutics (app-based cognitive behavioral therapy, virtual reality interventions), personalized exercise programs, microbiome-targeted strategies (particularly for IBS-associated pain), and psychedelic-assisted therapies, although the latter remain at a highly preliminary stage. 6 Objective biomarkers, including translocator protein PET imaging for neuroinflammation, quantitative sensory testing profiles, multimodal neuroimaging signatures, and emerging genomic and transcriptomic markers, may ultimately enable mechanism-based patient stratification. 6 , 32 , 52

Fibromyalgia is the prototypical nociplastic pain disorder. Characterized by widespread musculoskeletal pain, fatigue, poor sleep quality, and cognitive dysfunction, it has been one of the principal drivers of the nociplastic pain concept. 28 , 31 , 59 , 60 The 2010 ACR criteria introduced the Widespread Pain Index and Symptom Severity Score, and the 2016 revisions consolidated this shift from a tender-point–based model toward a syndrome-level construct consistent with central pain mechanisms. 31 , 61 EULAR (European League Against Rheumatism) recommendations support a stepped, multimodal management approach with non-pharmacological strategies as first-line. 58 Critical implications for the nociplastic pain concept . Fibromyalgia is the strongest empirical anchor for the construct: augmented central pain processing, 33–35 glial activation on TSPO-PET, 52 , 53 and passive transfer of sensory hypersensitivity by patient IgG 54 together provide convergent mechanistic support. Yet fibromyalgia also exposes the construct’s central tension: small-fiber pathology in a substantial subset 41 , 42 shows that a “nociplastic” label can coexist with, and risk obscuring, identifiable peripheral pathology. 21 The diagnostic limitation is circularity: the 2016 ACR criteria and the IASP 2021 criteria share symptom domains (widespread pain, fatigue, sleep, cognition), so fibromyalgia partly defines, rather than independently validates, the nociplastic phenotype. The research gap is a biomarker that separates predominantly top-down from peripherally driven cases, 6 which current criteria cannot do. IBS is frequently cited as an example of predominantly nociplastic pain in the visceral domain, although the 2021 IASP criteria have not been validated in visceral pain. Patients exhibit visceral hypersensitivity, aberrant brain–gut axis signaling, and central sensitization, accompanied by affective and cognitive symptoms. 5 , 6 Although gut microbiota dysbiosis and altered gut immune signaling also contribute, evidence indicates that altered central processing is a principal determinant of the pain experience. 5 Critical implications for the nociplastic pain concept . IBS extends the construct beyond the musculoskeletal system into the viscera, where visceral hypersensitivity and altered brain–gut processing parallel the central features seen in fibromyalgia. 5 , 6 This is precisely where the construct is most useful conceptually but least validated operationally: the 2021 IASP criteria were derived for musculoskeletal pain and have not been calibrated for visceral pain, in which “regional” distribution and “evoked hypersensitivity” on examination do not map cleanly. IBS therefore both motivates and constrains the nociplastic label: it is a key test case for whether the criteria generalize, and shows that gut microbial and mucosal immune drivers may carry a peripheral component that a central label can mask. Painful TMD often demonstrates features of central sensitization, with widespread hyperalgesia, headache and fibromyalgia comorbidity, and shared genetic and psychosocial risk factors with other chronic overlapping pain conditions. 32 The OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment) cohort and subsequent studies have provided much of the evidence supporting TMD as a nociplastic phenotype. 13 , 32 Critical implications for the nociplastic pain concept . TMD supplies some of the most rigorous prospective evidence for the construct: the OPPERA cohort demonstrated that pre-existing pain amplification and psychological factors predict TMD onset, which points to a central, trait-like vulnerability shared across overlapping conditions. 13 , 32 This strengthens the argument that nociplasticity is a continuous, pre-morbid susceptibility rather than a discrete diagnostic category. The limitation is that painful TMD frequently has a genuine peripheral nociceptive generator (eg joint or muscle pathology); classifying it as nociplastic without quantifying the mixed contribution risks the very over-inclusiveness the concept’s critics warn against. 7 , 21 A substantial proportion of chronic low back pain, particularly when it persists after adequate conservative or surgical management, exhibits features of altered nociception. Functional imaging studies indicate that with chronification, pain representation shifts from sensory to affective brain networks. 6 , 36 , 55 Integrating mechanism-based phenotyping into chronic low back pain assessment is now widely advocated. 25 , 55 Critical implications for the nociplastic pain concept . Chronic low back pain is the clearest illustration of nociplasticity as an additive, mixed-state component rather than a stand-alone entity: imaging shows a shift from sensory to affective-circuit representation with chronification, 36 , 55 yet most patients retain plausible peripheral contributors. This challenges the IASP requirement to “exclude” nociceptive and neuropathic mechanisms before assigning a nociplastic label. 7 The practical implication is decisional rather than nosological: recognizing a nociplastic component should recalibrate expectations of surgery and injections, 55 not replace structural assessment. The research gap is a validated way to weight the nociplastic contribution in an individual mixed-pain patient. Chronic migraine, particularly when accompanied by cutaneous allodynia, exhibits hallmarks of central sensitization, including trigeminovascular hyperexcitability and altered descending modulation. 5 , 6 Although migraine pathophysiology is complex and includes specific neurovascular components, the nociplastic descriptor captures the chronified phenotype and informs preventive therapy with agents such as tricyclic antidepressants and SNRIs. 5 , 6 Critical implications for the nociplastic pain concept . Chronic migraine with cutaneous allodynia displays central sensitization of trigeminovascular pathways and deficient descending modulation, fitting the nociplastic phenotype for the chronified state. 5 , 6 However, migraine also has disorder-specific neurovascular and channelopathic mechanisms and a dedicated, mechanism-targeted therapeutic class (CGRP pathway agents) that lie outside the nociplastic framework. Migraine is therefore a boundary case: it shows the descriptor’s reach into headache, but also that “nociplastic” should describe a component of a condition with its own primary biology, not subsume the diagnosis. Whether the IASP criteria should be applied to headache at all is an open validation question. Nociplastic mechanisms are also implicated in several other conditions, including complex regional pain syndrome, vulvodynia, interstitial cystitis/bladder pain syndrome, endometriosis-associated pain, persistent postsurgical pain, and a considerable subset of patients with rheumatoid arthritis and osteoarthritis. 5 , 6 The peripheral risks that may coexist with, and be obscured by, a predominantly nociplastic label across the prototypical and related conditions discussed above are consolidated in Table 3 , together with the corresponding assessment priorities and referral considerations. Table 3 Prototypical Nociplastic-Pain Conditions and Coexisting Peripheral Risks or Pathology to Consider Disease/Clinical Condition Predominant Pain Phenotype Relevant Peripheral Risk/Pathology to Consider Assessment Priority Red Flags/Referral Considerations Refs Fibromyalgia Nociplastic (prototype) Small-fibre pathology in a subset; autoantibody-mediated peripheral sensitisation may coexist Examine for length-dependent sensory loss; consider skin biopsy or autoimmune work-up if focal neurological signs are present New or progressive focal neurological deficit → neurology referral [ 21 , 24 , 41 , 42 , 51 ] Irritable bowel syndrome (visceral) Nociplastic, visceral domain Ongoing visceral nociceptive input; gut microbial and mucosal-immune drivers may contribute Exclude alarm features; the 2021 musculoskeletal criteria are not calibrated for visceral pain GI alarm features (bleeding, weight loss, anaemia, nocturnal symptoms) → gastroenterology [ 5 , 6 , 17 ] Temporomandibular disorders Mixed (nociplastic + nociceptive) A genuine intra-articular or masticatory-muscle nociceptive generator is common Quantify the mixed contribution; do not assign a nociplastic label without orofacial/dental assessment Joint locking, malocclusion, or structural joint disease → orofacial/dental referral [ 7 , 13 , 21 , 32 ] Chronic primary low back pain Mixed; additive nociplastic component Persistent structural or radicular peripheral contributors frequently remain A recognised nociplastic component should recalibrate expectations of surgery/injection, not replace structural assessment Progressive neurological deficit, cauda equina, or features of malignancy/infection → urgent imaging/referral [ 6 , 25 , 36 , 55 ] Chronic migraine Nociplastic component of a primary neurovascular disorder Disorder-specific neurovascular and channelopathic mechanisms lie outside the nociplastic frame Apply headache classification first; CGRP-targeted therapy addresses mechanisms outside the nociplastic construct New or changed headache pattern, thunderclap onset, or focal deficit → neuroimaging/neurology [ 5 , 6 ] Complex regional pain syndrome Nociplastic with prominent peripheral/immune features Small-fibre and autoantibody-mediated peripheral mechanisms have been described Do not let a nociplastic label mask potentially treatable peripheral or immune pathology Rapidly worsening dystonia, infection, or fracture non-union → specialist referral [ 21 , 24 , 41 , 51 ] Persistent post-surgical and cancer-survivor pain Mixed; a nociplastic component may be present (evidence remains limited) Ongoing tissue or treatment damage, chemotherapy-induced peripheral neuropathy, or nerve entrapment Screen for a nociplastic component but attribute cautiously; the criteria are unvalidated in these settings Recurrence red flags, new mass, or progressive deficit → oncology/surgical review [ 5 , 6 ] Notes : In this table, “peripheral risk or pathology” denotes identifiable or suspected peripheral nociceptive or neural contributors — for example ongoing nociceptive input, small-fibre pathology, entrapment or chemotherapy-induced neuropathy, and autoimmune or peripheral sensitisation — that may coexist with, and be obscured by, a predominantly nociplastic label. Associations are drawn from the evidence discussed in the main text and are, in several instances, proposed rather than established; entries phrased with “may”, “proposed”, or “evidence remains limited” should be read accordingly. Abbreviations : CGRP, calcitonin gene-related peptide; GI, gastrointestinal; IASP, International Association for the Study of Pain. Prototypical Nociplastic-Pain Conditions and Coexisting Peripheral Risks or Pathology to Consider Notes : In this table, “peripheral risk or pathology” denotes identifiable or suspected peripheral nociceptive or neural contributors — for example ongoing nociceptive input, small-fibre pathology, entrapment or chemotherapy-induced neuropathy, and autoimmune or peripheral sensitisation — that may coexist with, and be obscured by, a predominantly nociplastic label. Associations are drawn from the evidence discussed in the main text and are, in several instances, proposed rather than established; entries phrased with “may”, “proposed”, or “evidence remains limited” should be read accordingly. Abbreviations : CGRP, calcitonin gene-related peptide; GI, gastrointestinal; IASP, International Association for the Study of Pain. Nociplastic pain is closely associated with psychological and psychiatric comorbidities including depression, anxiety, post-traumatic stress disorder, somatic symptom disorder, and adverse childhood experiences. 5 , 6 , 62 These comorbidities should not be interpreted simplistically as the cause of pain within a psychogenic model; rather, they reflect shared neurobiological vulnerabilities, including dysregulation of stress-response systems, monoaminergic signaling, and neuroimmune pathways, that may also drive pain chronification. 6 Pain catastrophizing, hypervigilance, kinesiophobia, and pain-related fear-avoidance contribute to pain-related disability and are associated with poorer treatment outcomes. 6 , 58 , 63 These cognitive–affective dimensions are targets for cognitive behavioral therapy, acceptance and commitment therapy, and pain neuroscience education. 58 Psychological treatment of nociplastic pain should be framed as addressing biologically modifiable risk factors rather than as confirming psychogenic pain, a framing that may lead to stigmatization and reduced engagement. Despite the explanatory power of the nociplastic construct, several substantive controversies persist. First, much of the literature blurs the boundaries between nociplastic pain, chronic primary pain, and central sensitization, leading to imprecise use of terminology. Nociplastic pain is a mechanistic descriptor; chronic primary pain is a diagnostic entity; and central sensitization is a specific neurophysiological process ( Table 1 ). 7 , 22 A recent perspective by Häuser and Kosek (2026), summarizing a main session at the European Pain Federation (EFIC) Congress in Lyon (26 April 2025), explicitly cautions against conflating these terms. 7 Second, critics argue that nociplastic pain risks becoming a clinical and conceptual residual category invoked when nociceptive and neuropathic mechanisms cannot be established. 21 Applied uncritically, the diagnosis may obscure occult peripheral or neural pathology, particularly in heterogeneous conditions such as fibromyalgia and complex regional pain syndrome, in which small-fiber neuropathy, autoantibody-mediated mechanisms, and other peripheral factors are now recognized. 21 , 24 , 41 , 54 Macionis (2025) has explicitly warned that the descriptor may reduce diagnostic vigilance for undiagnosed causes of pain. 21 Third, the requirement to exclude nociceptive and neuropathic pain before diagnosing nociplastic pain has been questioned. Nociplasticity may represent a continuous, additive component of pain rather than a discrete category, as illustrated by patients with painful osteoarthritis or rheumatoid arthritis with prominent superimposed central sensitization. 5–7 Fourth, the reliability and validity of the IASP criteria are still being investigated. The vignette-based study by Bilika et al showed satisfactory reliability and criterion validity with high positive and negative predictive values, 9 while the prospective cohort study by Vervullens et al in knee osteoarthritis proposed additional operational criteria to refine application. 8 A field study by Schmidt et al demonstrated reasonable discrimination between chronic primary and chronic secondary pain mechanisms. 10 Whether vignette-based reliability estimates are trustworthy has itself been debated: a published commentary questioned whether raters could consistently assess evoked hypersensitivity from written vignettes, to which the original authors replied defending their methodology. 64 , 65 These studies converge on the view that the criteria perform reasonably in expert hands but require further refinement and additional validation in primary-care and non-musculoskeletal contexts. Fifth, the term itself has been criticized on linguistic and biological grounds: “plasticity” in biology typically denotes adaptive change, whereas nociplastic pain implies maladaptive plasticity. 7 , 21 , 66 Alternative terms have been proposed but no consensus has emerged. These controversies do not invalidate the construct, but they show that the concept is still maturing and calls for careful, mechanism-based application. 67 , 68 Because the nociplastic descriptor, the ICD-11 classification, and disorder-specific management guidelines are frequently cited side by side yet serve different purposes, Table 4 compares the major frameworks directly. The IASP 2017 descriptor names the mechanism; the IASP 2021 grading system operationalizes it for the musculoskeletal system; ICD-11 provides an etiology-agnostic diagnostic classification in which chronic primary pain is a disease in its own right; and the EULAR recommendations translate these concepts into stepped, multimodal management for fibromyalgia. Recognizing the complementary scope and limitations of each framework helps avoid the common error of treating a mechanism as though it were a diagnosis, or a single-disorder guideline as though it were a general classification. 7 , 15 , 16 , 20 , 58 Table 4 Major Classification and Guideline Frameworks Relevant to Nociplastic Pain Framework/Source Year & Body Nature Defining Feature Role, Limitation, and What it Cannot Tell You IASP nociplastic descriptor 3 , 4 2017, IASP Mechanistic descriptor Third pain mechanism; altered nociception without tissue or nerve lesion Reframes “functional” pain mechanistically; not operational by itself; cannot grade or diagnose an individual IASP grading criteria 8–10 , 20 , 64 , 65 2021, Kosek et al Operational diagnostic criteria (MSK) Possible/probable nociplastic pain via a decision tree First operational tool; musculoskeletal-only; reliability debated in 2024–2026 validation work; cannot be assumed valid in visceral/headache pain ICD-11 chronic primary pain 15 , 16 2019, IASP/WHO Diagnostic classification Chronic pain as a disease in its own right Enables recognition and coding; etiology-agnostic; overlaps imperfectly with nociplastic pain; cannot specify mechanism EULAR fibromyalgia recommendations 58 2017, Macfarlane et al Management guideline Stepped, multimodal care for fibromyalgia Non-pharmacological first-line; fibromyalgia-specific; predates 2021 criteria; cannot be generalized to all nociplastic conditions Abbreviations : IASP, International Association for the Study of Pain; MSK, musculoskeletal; WHO, World Health Organization. Major Classification and Guideline Frameworks Relevant to Nociplastic Pain Abbreviations : IASP, International Association for the Study of Pain; MSK, musculoskeletal; WHO, World Health Organization.

Nociplastic pain has emerged as the third recognized mechanistic descriptor, describing a large and previously under-recognized population with altered central nociceptive processing. We close with four clinical messages and a single research priority. Consider a nociplastic contribution in any patient with chronic regional or widespread pain that is disproportionate to identifiable tissue or nerve pathology, especially when accompanied by fatigue, poor sleep, cognitive symptoms, and sensory hypersensitivity. For nociplastic-predominant pain, prioritize, as first line, exercise, psychological therapy, pain neuroscience education, and multidisciplinary rehabilitation, and consider centrally acting agents (SNRIs, low-dose tricyclic antidepressants, α2δ ligands), recognizing that the pharmacological evidence derives largely from fibromyalgia and that treatment should be individualized to the underlying disorder, comorbidities, and mixed pain mechanisms; avoid reflexive opioids and anti-inflammatory drugs, and weigh peripherally directed procedures cautiously, reserving them for patients with clinically relevant coexisting peripheral pathology. Apply “nociplastic” as a continuous, mechanism-based component of mixed pain, not as a fixed diagnostic label, and do not allow the label to reduce vigilance for treatable peripheral or neural drivers. Communicate explicitly that nociplastic pain is consistent with recognized neurobiological mechanisms and is not psychogenic in origin, to support engagement and reduce stigma. Consider a nociplastic contribution in any patient with chronic regional or widespread pain that is disproportionate to identifiable tissue or nerve pathology, especially when accompanied by fatigue, poor sleep, cognitive symptoms, and sensory hypersensitivity. For nociplastic-predominant pain, prioritize, as first line, exercise, psychological therapy, pain neuroscience education, and multidisciplinary rehabilitation, and consider centrally acting agents (SNRIs, low-dose tricyclic antidepressants, α2δ ligands), recognizing that the pharmacological evidence derives largely from fibromyalgia and that treatment should be individualized to the underlying disorder, comorbidities, and mixed pain mechanisms; avoid reflexive opioids and anti-inflammatory drugs, and weigh peripherally directed procedures cautiously, reserving them for patients with clinically relevant coexisting peripheral pathology. Apply “nociplastic” as a continuous, mechanism-based component of mixed pain, not as a fixed diagnostic label, and do not allow the label to reduce vigilance for treatable peripheral or neural drivers. Communicate explicitly that nociplastic pain is consistent with recognized neurobiological mechanisms and is not psychogenic in origin, to support engagement and reduce stigma. Overriding research priority . Prospective validation of the IASP criteria beyond the musculoskeletal system, in the visceral, headache, cancer, pediatric, geriatric, and mixed-state domains addressed by the six research questions above, coupled with objective biomarkers, so that phenotype-stratified trials can establish whether mechanism-based treatment improves outcomes. A balanced, mechanism-oriented approach, treating nociplastic features as a continuous component of complex pain states, is most likely to translate the concept into measurable gains in personalized pain medicine.

The introduction and operationalization of nociplastic pain gave a mechanism-based framework to a large clinical population previously excluded from formal classification or stigmatized by the “functional” label. By stressing central sensitization, dysfunctional descending modulation, neuroimmune activation, and maladaptive neuroplasticity, the concept brings clinical practice into line with three decades of neurobiological evidence and supports a shift from peripherally focused to centrally focused, biopsychosocially integrated care. 5 , 6 , 26 , 27 What this review adds . The synthesis presented above translates the three gaps identified at the outset into concrete, reusable tools rather than restating them. The conceptual disambiguation of central sensitization, nociplastic pain, and chronic primary pain is rendered decision-usable at the bedside ( Table 1 ); the frameworks that are habitually cited together are appraised side by side, with the scope and blind spot of each made explicit ( Table 4 ); the principal mechanistic evidence is consolidated into a single integrative schematic ( Figure 1 ); and the 2024–2026 validation literature 8–10 , 64 , 65 is critically appraised, its open problems reframed as explicit, testable research questions for the non-musculoskeletal domains in which the criteria remain unvalidated (Section 17). The cumulative effect is a shift in emphasis from describing the construct to operationalizing it: clarifying, for the clinician, when a nociplastic contribution should change a decision, and, for the researcher, which questions must be answered before the label can be applied with confidence beyond the musculoskeletal system. Nevertheless, the concept is far from mature, and several issues warrant careful reflection. Despite repeated cautions from its proponents, the boundary between nociplastic pain as a mechanism and as a diagnosis is frequently blurred in clinical and research practice. 7 , 22 The relationship between nociplastic pain and central sensitization requires careful distinction: not all central sensitization constitutes nociplastic pain, and not all nociplastic phenotypes can be fully explained by central sensitization. 7 , 22 Furthermore, overuse of the descriptor may erode diagnostic vigilance, particularly in heterogeneous disorders where small-fiber neuropathy or other peripheral factors might respond to specific therapy. 6 , 21 , 41 The IASP clinical criteria are useful but require continued validation across different populations and in visceral and non-musculoskeletal domains. Existing evidence indicates acceptable criterion validity and reliability in expert hands, with uncertain performance in primary care and across cultural contexts. 8–10 Conceptual disagreement persists regarding whether “exclusion” of nociceptive and neuropathic mechanisms is appropriate, given that nociplasticity may operate as a persistent coexisting factor. 7 Finally, the term itself remains contested on linguistic and biological grounds. 7 , 21 , 66 Whether the term “nociplastic” persists or is replaced by a semantically more accurate alternative, the underlying clinical reality, that a large group of patients exhibit maladaptive central pain processing, is well established and supported by an increasing body of evidence. Existing reviews converge on broad future tasks: biomarkers, phenotype-stratified trials, mechanism-specific therapies, and terminological refinement. 6 , 7 To move from vision to testable science, and to address the domains in which the IASP criteria are not yet validated, we frame the principal priorities as explicit research questions in PICO form. RQ1 (Visceral / IBS) . P: adults with chronic primary visceral pain (e.g IBS) meeting symptom thresholds I: a visceral-adapted version of the IASP 2021 criteria C: the unmodified musculoskeletal criteria and clinician gestalt O: criterion validity, inter-rater reliability, and ability to predict response to centrally acting therapy. RQ2 (Headache / chronic migraine) . P: patients with chronic migraine with and without cutaneous allodynia I: QST/CPM-based nociplastic phenotyping C: standard headache classification alone O: whether the nociplastic phenotype predicts preventive-therapy response independent of CGRP-targeted treatment. RQ3 (Cancer pain) . P: cancer survivors with persistent pain after curative treatment I: screening for a nociplastic component using IASP-derived criteria C: pain attributed solely to tissue or treatment damage O: prevalence of a nociplastic component and its association with opioid non-response. RQ4 (Pediatric) . P: adolescents with chronic widespread or primary pain I: an age-adapted nociplastic criteria set C: adult criteria applied unmodified O: feasibility, developmental validity, and longitudinal prediction of persistence into adulthood. RQ5 (Geriatric) . P: older adults with chronic pain and multimorbidity I: nociplastic phenotyping incorporating cognitive and sensory screening C: usual mechanism-agnostic assessment O: diagnostic accuracy where peripheral pathology is highly prevalent and may confound the label. RQ6 (Mixed-state quantification) . P: patients with osteoarthritis or chronic low back pain I: a continuous index weighting the nociplastic contribution C: binary present/absent classification O: whether the continuous index outperforms binary classification in predicting surgical and injection outcomes. A concrete testable hypothesis follows from RQ1 and reference: 56 in chronic primary visceral pain, deficient conditioned pain modulation at baseline predicts greater pain reduction with duloxetine than preserved conditioned pain modulation. Alongside these domain-specific questions, terminology and classification require continued international consensus so that future revisions of IASP terminology and the ICD-11 chronic pain classification clearly articulate the relationships among mechanism, diagnosis, and underlying pathophysiology. 7 , 15