Nociplastic Pain

Abstract

Nociplastic pain is a type of pain: pain that arises from altered nociception despite no clear evidence of tissue damage activating nociceptors and no lesion of the somatosensory nervous system. It is the third mechanistic descriptor in the modern taxonomy of pain, set against nociceptive pain, which follows the activation of nociceptors by tissue injury, and neuropathic pain, which follows a lesion of the somatosensory system. Coined in 2016 and adopted by the International Association for the Study of Pain, the term names the mechanism behind conditions such as fibromyalgia in which pain is real but the peripheral cause the other two categories require is absent. Because its engine is the central nervous system rather than the periphery, nociplastic pain is the mechanistic category in which cognitive and affective processes are not merely modulators of pain but constituents of it.

Keywords: nociplastic pain, central sensitization, mechanistic taxonomy, augmented pain processing, fibromyalgia

Nociplastic pain is the pain that has no wound. A patient with fibromyalgia hurts diffusely and severely, yet no imaging, no blood test, and no nerve study finds the injury or the lesion that ought to be generating the signal. For most of the history of medicine such pain was treated as a puzzle to be explained away, its reality doubted precisely because the periphery looked intact. The mechanistic taxonomy of pain resolves the puzzle by naming a third route to pain that does not require a peripheral cause at all: a nervous system whose own processing of nociceptive signals has been turned up, so that pain is generated and amplified centrally. Fixing this category matters clinically, because a pain with no peripheral driver will not yield to an anti-inflammatory or a nerve block and needs instead treatments aimed at the central nervous system and the cognition riding on it (Kosek et al., 2016).

What Nociplastic Pain Is

Nociplastic pain is defined, like the other mechanistic categories, by its mechanism rather than by its location, severity, or duration. The International Association for the Study of Pain defines it as pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors, and no evidence of disease or lesion of the somatosensory system causing the pain (Kosek et al., 2016). The double negative in the definition is the whole of its content: nociplastic pain is what remains when the peripheral cause required by nociceptive pain and the neural lesion required by neuropathic pain are both absent, yet pain is undeniably present. The word itself, from nociception and plasticity, marks the claim that the pain is a product of the nervous system's capacity to change its own responsiveness.

That the category had to be invented at all reflects a long clinical embarrassment. Conditions such as fibromyalgia, irritable bowel syndrome, and much chronic low back pain produce severe, disabling pain with no proportionate peripheral pathology, and for want of a mechanism they were often labeled psychogenic or functional, with the implication that the pain was less than real (Fitzcharles et al., 2021). Naming nociplastic pain as a genuine mechanism rather than a diagnosis of exclusion changed the terms of the discussion: the pain is real, it has a physiological basis in altered central processing, and the absence of a wound is a feature of the mechanism rather than evidence against the complaint. This reframing is the reason the concept was adopted so quickly across pain medicine.

The conceptual foundation beneath the category is the distinction between nociception and pain. Nociception is the neural detection and transmission of noxious stimuli; pain is the conscious experience the brain constructs. In nociceptive pain the two travel together, so the distinction is easy to overlook. Nociplastic pain is the case that forces the distinction into view, because here there is pain with little or no nociception to construct it from: the experience is generated largely by the processing itself. Holding nociception and pain apart is exactly what makes room for a pain that is centrally manufactured, and it is the move that places nociplastic pain squarely within cognitive psychology rather than at its periphery.

The Mechanistic Taxonomy of Pain

Nociplastic pain acquires its meaning only within the taxonomy that opposes it to the other two mechanisms by which pain is generated. That taxonomy has three terms. Nociceptive pain arises from the activation of nociceptors by actual or threatened damage to non-neural tissue, in a somatosensory system that is itself intact. Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system itself, so that the alarm is generated by damage to the signaling apparatus rather than to the tissue it monitors. Nociplastic pain arises from altered nociception despite neither a peripheral injury activating nociceptors nor a lesion of the somatosensory system, and it names the mechanism behind pain that the first two categories cannot explain (Treede et al., 2019).

The third category was not a philosopher's tidy addition but a clinical necessity, argued for on the ground that a large fraction of chronic pain fit neither of the two existing descriptors (Kosek et al., 2016). The logic of the whole taxonomy is that mechanism, not location or duration, should guide treatment: a drug that quiets sensitized nociceptors is the right tool for a nociceptive pain and the wrong one for a nociplastic pain whose driver is central. The categories are descriptors of mechanism rather than mutually exclusive diagnoses, and a single patient can carry more than one, which is why the modern framing speaks of a predominant or mixed mechanism rather than a single label; a patient with osteoarthritis, for instance, may have nociceptive pain from the joint together with a nociplastic component from a centrally sensitized nervous system (Trouvin & Perrot, 2019). Table 1 sets the three categories side by side, and Figure 1 places them on the axes that separate them.

Figure 1

The Three Mechanistic Categories of Pain

Central Sensitization and Augmented Processing

The physiological substrate of nociplastic pain is central sensitization: an increase in the excitability and responsiveness of nociceptive neurons in the central nervous system, such that their output is amplified relative to their input (Woolf, 2011). Where a normal nervous system passes a nociceptive signal upward at roughly unity gain, a sensitized one multiplies it, so that a small peripheral input, or in the limit no peripheral input at all, produces a large felt pain. The mechanism was first characterized as a use-dependent increase in the gain of the pain system driven by activity, capable of turning up the volume on nociception well beyond what the stimulus warrants (Woolf & Salter, 2000). Nociplastic pain is what central sensitization looks like when it becomes the dominant, self-sustaining source of the pain rather than a temporary amplifier of a real injury.

The clinical signatures of central sensitization are the observable face of this amplified gain. Patients show widespread hypersensitivity, with lowered pain thresholds at body sites far from any lesion and allodynia, pain evoked by light touch and other stimuli that do not normally hurt, together with enhanced temporal summation, the progressive escalation of pain under a train of identical stimuli that a normal nervous system would report as unchanging (Clauw, 2014). Fibromyalgia is the prototype: a condition of chronic widespread pain in which quantitative sensory testing reveals augmented central pain processing rather than any peripheral abnormality, and which serves as the reference disorder for the nociplastic mechanism as a whole (Clauw, 2014). The first of the two demonstrations that follow makes the central gain itself tangible. It lets the peripheral nociceptive input and the central gain be set independently, showing how a fixed input yields a mild pain in a normal system and a severe one in a sensitized system, and how a sensitized system can generate substantial pain from almost no input at all.

The second observable signature is temporal, and it is the clearest bedside evidence that the amplification is central. When a normal nervous system receives a train of identical noxious pulses at a steady rate, the felt intensity stays roughly constant. A sensitized nervous system instead winds up: each successive pulse is felt as more painful than the last, even though the stimulus never changes, because the central circuits are summing rather than resetting between inputs. This enhanced temporal summation is a direct behavioral readout of increased central gain, and it is one of the psychophysical tests used to detect nociplastic processing. The second demonstration contrasts a normal and a sensitized response to the same train of pulses, letting the degree of sensitization be varied to show how windup emerges as gain rises.

Central sensitization is also the mechanism that blurs the boundary the taxonomy draws. A pain that begins as cleanly nociceptive — the legible response of an intact system to a real injury — can, under sustained input, drive the central changes that outlast and outgrow the injury, so that what remains when the tissue has healed is a nociplastic pain riding on a nervous system the original injury sensitized (Woolf, 2011). This is why the categories are better understood as a spectrum of predominant mechanisms than as sealed boxes, and why chronic pain so often carries a nociplastic component regardless of how it started.

Identifying Nociplastic Pain

Because no imaging finding, blood test, or nerve study confirms nociplastic pain, its identification rests on recognizing a clinical pattern rather than reading a biomarker. A working group led by Kosek proposed a set of clinical criteria and a grading system for nociplastic pain affecting the musculoskeletal system, precisely to give the concept the diagnostic rigor a mechanism used to guide treatment requires (Kosek et al., 2021). The criteria turn on a small number of features: pain that is regional rather than discrete, of at least several months, that cannot be explained by a nociceptive or neuropathic source, and that is accompanied by clinical signs of hypersensitivity and by common comorbidities (Kosek et al., 2021).

The comorbidities are diagnostically informative rather than incidental. Nociplastic pain travels with fatigue, disturbed and unrefreshing sleep, and cognitive difficulty, the cluster patients describe as mental fog, and this co-travel is itself a clue that the problem lies in central processing shared across these domains rather than in any one painful part (Fitzcharles et al., 2021). The grading of possible, probable, or definite nociplastic pain then accumulates these features: a regional distribution and evoked hypersensitivity move a case from possible toward probable, and the presence of the characteristic comorbidities strengthens it further. There remains active debate over whether the nociplastic criteria capture anything beyond the older construct of central sensitization, or whether they usefully reframe it for clinical use (Nijs et al., 2021). The third demonstration builds this reasoning into an interactive tool, letting the presence of regional pain, evoked hypersensitivity, and comorbidities be set to see how the clinical grading of nociplastic pain shifts.

Worked Example

Consider the central gain the first demonstration computes, and use it to show why nociplastic pain can be severe with little or no peripheral input. Model the felt pain intensity as a product of peripheral nociceptive input and central gain: let the peripheral input be I on a zero-to-ten scale, the central gain be G, and the felt intensity be P = G × I × 10, capped at 100 on a zero-to-hundred scale. A normal nervous system passes the signal at unity gain, G = 1.

Apply a mild peripheral input, I = 2, the sort of low-grade signal that ordinary tissue generates all the time. In a normal system, P = 1 × 2 × 10 = 20: a mild, unremarkable ache, correctly scaled to a minor input. Now hold the input fixed and place it in a sensitized system with a central gain of G = 3, in the range quantitative sensory testing finds in nociplastic conditions. Now P = 3 × 2 × 10 = 60: the identical peripheral input produces a severe pain, three times as intense, with nothing changed in the periphery at all.

The defining case is the one where the input nearly vanishes. Let the peripheral input fall to I = 0.5, close to the background chatter of a body with no injury, and keep the sensitized gain G = 3: P = 3 × 0.5 × 10 = 15, a genuine, felt pain generated from almost nothing. Push the input to I = 0 and P = 0, so the model is honest that some input is needed, but the lesson stands: as central gain rises, the pain a person feels decouples from the state of their tissue and becomes a function of the nervous system's own processing. This is the mechanistic content of nociplastic pain, and it is why treatments aimed at the periphery fail against it while those aimed at the central nervous system and the cognition that sets its gain can succeed (Fitzcharles et al., 2021).

Discussion

The arc of nociplastic-pain research is the conversion of a clinical embarrassment into a mechanism. For most of the twentieth century, pain out of proportion to any findable cause was explained by exclusion and often by insinuation, its sufferers suspected of exaggeration. The characterization of central sensitization gave the missing mechanism a physiology, showing that the nervous system can amplify and sustain pain on its own (Woolf & Salter, 2000). Naming nociplastic pain as a formal third descriptor then gave that physiology a place in the taxonomy that governs how pain is classified and treated, and did so on the explicit argument that the two existing categories left too much real pain unaccounted for (Kosek et al., 2016).

The clinical stakes are large and specific. Chronic pain imposes an enormous individual and societal burden, and the treatments that work for nociceptive and neuropathic pain — anti-inflammatories, nerve-targeted drugs, procedures aimed at a peripheral generator — are largely ineffective against a pain whose driver is central, while opioids are not only ineffective but harmful in this setting (Cohen et al., 2021). Correctly identifying a pain as nociplastic redirects care toward what does help: exercise, sleep and mood treatment, centrally acting medications, and psychological therapies that act on the very processes that set central gain (Fitzcharles et al., 2021). But the deepest implication is conceptual, and it is what keeps nociplastic pain at the center of cognitive psychology: here is a pain that is, in large part, a product of information processing rather than of tissue, and understanding it means understanding the brain that makes it.

Cognitive Implications

In nociceptive pain, cognition modulates a signal that originates in the periphery; in nociplastic pain, cognition is closer to a source of the signal itself, because the central processing that cognition shapes is the mechanism generating the pain. Attention is the clearest case. Pain has an interruptive function, built to seize attention and hold it, and this competition for limited attentional resources amplifies an attended pain and diminishes an ignored one (Eccleston & Crombez, 1999). In a sensitized nervous system, whose gain is already high, this attentional amplification acts on a signal that is being manufactured centrally, so the vigilance that nociplastic pain provokes feeds the very processing that sustains it.

The appraisal of pain matters even more. Pain catastrophizing — an exaggerated negative orientation toward actual or anticipated pain, marked by rumination, magnification, and helplessness — amplifies both the intensity and the disabling impact of pain and is among the most robust psychological predictors of poor pain outcomes (Sullivan et al., 1995). In nociplastic conditions catastrophizing is not a reaction to a peripheral injury but an input to the central gain, one of the cognitive-affective factors that turn the amplification up and keep it there. These effects are built into the circuitry: the brain's cognitive and emotional control systems, acting through descending pathways, physically set how much a nociceptive signal is amplified or suppressed, and human neuroimaging traces nociplastic pain as a distributed, modifiable cerebral signature rather than a fixed reading of any peripheral gauge (Apkarian et al., 2005). This is the mechanistic content of the claim that nociplastic pain is where the biopsychosocial model of pain is most fully realized, because in no other category are psychological and social factors so directly constitutive of the pain rather than commentary upon it (Cohen et al., 2021).

Current Directions

Current research on nociplastic pain runs along two fronts, one diagnostic and one conceptual. On the diagnostic side, the effort is to convert a pattern-recognition diagnosis into something more objective, refining the clinical criteria and grading system so that nociplastic pain can be identified reliably and, ideally, measured (Kosek et al., 2021). Quantitative sensory testing, which quantifies hypersensitivity and temporal summation, and functional neuroimaging, which visualizes augmented central processing, are the leading candidates for a biomarker, though none is yet a settled test, and much recent work aims at validating them against the clinical criteria (Trouvin & Perrot, 2019).

On the conceptual side, the open question is whether nociplastic pain is genuinely a new category or a rebranding of central sensitization, and where a persistently amplified nociceptive pain stops being nociceptive and becomes nociplastic (Nijs et al., 2021). Because the categories overlap and coexist, and because a nociplastic component can ride on any chronic pain regardless of its origin, distinguishing the mechanisms in an individual patient remains difficult, and resolving the boundaries is a matter of treatment rather than nomenclature (Fitzcharles et al., 2021). The enduring lesson is the one the concept began with: pain can be manufactured by the nervous system itself, and understanding that pain means understanding the processing, and the cognition riding on it, that sets the gain.

Common Misconceptions

Nociplastic pain is pain with no real cause, or pain that is imagined.

Nociplastic pain has a real physiological cause: central sensitization, an amplification of nociceptive processing in the central nervous system. The absence of a peripheral wound is a feature of the mechanism, not evidence that the pain is unreal or psychogenic (Kosek et al., 2016).

Nociplastic pain is just another name for central sensitization.

Central sensitization is the physiological mechanism; nociplastic pain is the clinical category defined by that mechanism together with a recognizable pattern of symptoms and comorbidities. Whether the clinical concept adds to the physiological one is an active debate, not a settled equivalence (Nijs et al., 2021).

A pain is either nociplastic or it is not.

The mechanistic categories are descriptors, not exclusive diagnoses. A single patient can have nociceptive, neuropathic, and nociplastic mechanisms at once, and a long-standing pain of any origin can acquire a nociplastic component as central sensitization develops (Trouvin & Perrot, 2019).

Glossary

Allodynia.

Pain evoked by a stimulus that does not normally provoke pain, such as light touch; a common sign of the hypersensitivity that accompanies central sensitization.

Augmented pain processing.

The amplification of nociceptive signals within the central nervous system, so that felt pain exceeds what the peripheral input would warrant; the functional core of nociplastic pain.

Central sensitization.

An increase in the excitability and responsiveness of nociceptive neurons in the central nervous system that amplifies pain from within; the physiological substrate of nociplastic pain.

Descending modulation.

Control of spinal pain transmission by pathways descending from the brain, the route through which attention, expectation, and emotion set central gain.

Fibromyalgia.

A condition of chronic widespread pain, fatigue, and cognitive difficulty marked by augmented central pain processing; the prototype disorder of the nociplastic mechanism.

Mechanistic taxonomy.

The classification of pain by its underlying mechanism — nociceptive, neuropathic, or nociplastic — rather than by its location, duration, or cause, adopted for ICD-11 because mechanism guides treatment.

Neuropathic pain.

Pain caused by a lesion or disease of the somatosensory nervous system itself, as in diabetic neuropathy or nerve injury; the second mechanistic category.

Nociception.

The neural process by which noxious stimuli are detected, transduced, and transmitted toward the central nervous system; the physiological substrate of, but not identical to, pain.

Nociceptive pain.

Pain arising from actual or threatened damage to non-neural tissue through the activation of nociceptors, in a somatosensory system that is itself intact; the first mechanistic category.

Nociplastic pain.

Pain arising from altered nociception with no evident tissue damage activating nociceptors and no lesion of the somatosensory system; the third mechanistic category.

Pain catastrophizing.

An exaggerated negative orientation toward actual or anticipated pain, marked by rumination, magnification, and helplessness; a cognitive input to central gain and a robust predictor of poor outcomes.

Quantitative sensory testing.

A set of standardized psychophysical tests that measure pain thresholds and temporal summation, used to detect the hypersensitivity characteristic of central sensitization.

Temporal summation.

The progressive escalation of felt pain under a train of identical noxious stimuli, a behavioral readout of increased central gain and a bedside sign of central sensitization.

Windup.

The spinal-cord phenomenon underlying temporal summation, in which repeated C-fiber input produces a progressively larger response in dorsal-horn neurons rather than resetting between stimuli.

Key Researchers

Daniel J. Clauw (contemporary). Physician-researcher at the University of Michigan and director of its Chronic Pain and Fatigue Research Center whose work on fibromyalgia established it as the prototype of augmented central pain processing. ORCID - Google Scholar - Faculty page

Eva Kosek (contemporary). Pain researcher at Karolinska Institutet and Uppsala University who led the working group that coined the term nociplastic pain and later proposed its clinical criteria and grading system. Faculty page - Research group

Ronald Melzack (1929-2019). McGill psychologist whose gate control and neuromatrix theories established that pain is generated and modulated by the central nervous system, the conceptual groundwork on which the nociplastic category rests. Wikipedia - Wikidata

Jo Nijs (contemporary). Professor of physiotherapy and physiology at Vrije Universiteit Brussel who leads the Pain in Motion group and has pressed the question of how the nociplastic criteria relate to central sensitization. ORCID - Faculty page

Rolf-Detlef Treede (contemporary). Neurophysiologist at Heidelberg University who led the IASP Classification of Chronic Pain for ICD-11, formalizing the nociceptive, neuropathic, and nociplastic mechanistic descriptors. ORCID - Faculty page

Clifford J. Woolf (contemporary). Neurobiologist at Harvard Medical School and Boston Children's Hospital who characterized central sensitization, the physiological mechanism that underlies nociplastic pain. ORCID - Wikipedia - Wikidata

Frequently Asked Questions

What is nociplastic pain? Nociplastic pain is pain that arises from altered nociception without evident tissue damage activating nociceptors and without a lesion of the somatosensory nervous system. It is the third mechanistic category of pain, and it names the mechanism behind conditions such as fibromyalgia, in which pain is real but has no proportionate peripheral cause (Kosek et al., 2016).

How is nociplastic pain different from nociceptive and neuropathic pain? The three are mechanistic categories. Nociceptive pain comes from nociceptors detecting tissue damage; neuropathic pain comes from a lesion of the somatosensory nervous system; and nociplastic pain comes from altered central processing with neither tissue damage nor a nerve lesion. Mechanism, not location or duration, is what distinguishes them, because it guides treatment (Treede et al., 2019).

What causes nociplastic pain? Its physiological basis is central sensitization, an increase in the gain of nociceptive processing in the central nervous system. A sensitized nervous system amplifies, and can even generate, pain from little or no peripheral input, which is why the pain can be severe without a findable injury (Woolf, 2011).

Is nociplastic pain real, or is it psychological? It is real and has a physiological cause. The absence of a peripheral wound reflects the central mechanism rather than the absence of pain. Psychological factors such as attention and catastrophizing do contribute, but as inputs to the central processing that generates the pain, not as evidence that the pain is imagined (Kosek et al., 2016).

What conditions involve nociplastic pain? Fibromyalgia is the prototype. Irritable bowel syndrome, some chronic low back pain, some chronic primary headache, and other conditions of pain without proportionate peripheral pathology are also understood as predominantly nociplastic, and a nociplastic component can accompany many other chronic pains (Fitzcharles et al., 2021).

How is nociplastic pain diagnosed? There is no single confirmatory test, so diagnosis rests on a clinical pattern: pain that is regional rather than discrete, present for months, unexplained by a nociceptive or neuropathic source, with signs of hypersensitivity and comorbidities such as fatigue, poor sleep, and cognitive difficulty. A grading system rates the case as possible, probable, or definite (Kosek et al., 2021).

Why do standard painkillers often fail against nociplastic pain? Anti-inflammatories, nerve blocks, and other peripherally aimed treatments target a peripheral generator that nociplastic pain does not have, and opioids are both ineffective and harmful in this setting. Treatment instead targets the central nervous system and the cognition that sets its gain, through exercise, sleep and mood treatment, centrally acting drugs, and psychological therapy (Cohen et al., 2021).

Can a nociceptive pain become nociplastic? Yes. Sustained nociceptive input can drive the central sensitization that outlasts and outgrows the original injury, so that a pain which began as nociceptive acquires a nociplastic component. This is one reason chronic pain so often carries a nociplastic element regardless of how it started (Trouvin & Perrot, 2019).

References