This article is part of the Expert Guide “Understanding Pain”.

Why Does Some Pain Persist Without Any Nociceptive or Neuropathic Lesion?

Why does this article matter?

We have seen that pain can be explained by tissue damage or by demonstrated involvement of the nervous system. Yet some people continue to suffer even though neither of these two explanations is sufficient any longer. Test results are normal. The nerve appears intact. The tissues seem to have healed. And yet the pain is still very much there.

For a long time, this situation had no real pathophysiological framework, which fueled the mistaken idea of “imaginary” or purely psychological pain. In recent years, however, a third mechanism has been recognized by the international scientific community: nociplastic pain.

In 2016, an international working group proposed this mechanism to name what was neither nociceptive nor neuropathic (Kosek et al., 2016). The IASP formally adopted it in November 2017. Understanding this mechanism helps avoid two mirror-image errors: searching endlessly for a lesion that does not exist, or giving up on explaining very real pain for lack of a visible lesion.

The absence of an identifiable lesion does not mean the absence of a mechanism. It means that the mechanism lies in the processing of pain-related information, not in the tissue that originally triggered it.

We now know that neuropathic painNeuropathic painNeuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system.Read the full entry : Neuropathic pain implies demonstrated involvement of the nervous system. But what happens to pain when no lesion, whether tissue or nerve, is enough to explain it? This is precisely what the definition of nociplastic pain seeks to clarify.

1. What exactly is nociplastic pain?

This definition rests on a double exclusion: no clearly identified nociceptive mechanism, and no demonstrated neuropathic mechanism. What remains, once these two causes have been ruled out, is altered nociceptive processing: pain signals are amplified, poorly filtered, or generated in excess relative to the information actually transmitted from the periphery (Fitzcharles et al., 2021). Indeed, the nervous system more broadly and progressively changes the way it processes sensory information: stimuli that were previously filtered out become significant, while the usual modulation mechanisms lose part of their effectiveness.

Nociplastic pain is therefore not the absence of a mechanism. It is a mechanism in its own right, rooted in altered nociceptive processing rather than in ongoing tissue damage or a lesion of the nerve itself.

Figure 1 — The three mechanisms of chronic painChronic painPain is called chronic when it persists or recurs for more than three months. It may accompany an identified disease or be a condition in its own right.Read the full entry : Chronic pain. Nociceptive, neuropathic, and nociplastic pain correspond to three distinct biological mechanisms that can exist separately or combine in the same person.

Three mechanisms, three different logics

In practice, then, this classification does not always close neatly: the same person may simultaneously present a nociceptive component, a neuropathic component already documented in the previous article, and a superimposed nociplastic component.

This definition, however, does not yet say anything about what actually happens in the central nervous system. What biological mechanisms produce this amplification of the pain signal?

2. What biological mechanisms underlie nociplastic pain?

The precise mechanisms that lead to this sensitization are still partly debated. One widely accepted hypothesis is that they correspond to plasticity phenomena in the nervous system originally intended to strengthen the body’s protection (Latremoliere & Woolf, 2009). When these adaptations persist after the initial threat has diminished, they may themselves contribute to maintaining the pain. Several phenomena, often intertwined, reflect this shift in concrete terms.

Central sensitization

Neurons in the dorsal horn of the spinal cord and certain brain relays gradually become more excitable. A previously neutral stimulus can then trigger pain (allodyniaAllodyniaAllodynia is pain caused by a stimulus that is normally not painful: a light touch, the contact of clothing, gentle pressure. It is a descriptive clinical term: it describes what the person feels, without by itself designating a mechanism.Read the full entry : Allodynia), and a mildly painful stimulus can produce an excessive response (hyperalgesiaHyperalgesiaHyperalgesia is an increased pain response to a normally painful stimulus. In other words, a stimulus that is already painful causes abnormally amplified pain. It is a descriptive clinical term that does not, on its own, designate a mechanism.Read the full entry : Hyperalgesia). This phenomenon involves a lasting strengthening of the synapses involved in pain transmission, comparable to a self-sustaining memory of pain (Latremoliere & Woolf, 2009).

Figure 2 — Central sensitizationCentral sensitizationCentral sensitization refers to an amplification of the central nervous system's response to sensory signals: pain can then be more intense, more widespread or longer-lasting than the state of the tissues would suggest.Read the full entry : Central sensitization: when the nervous system amplifies itself. Central circuits gradually become hypersensitive, amplifying and prolonging pain signals, even when the peripheral threat has disappeared or diminished.

Associated peripheral sensitization

Established central sensitization can indeed be accompanied by a lowering of the firing threshold of peripheral receptors, even in the absence of active tissue damage. This mechanism notably explains the intestinal hypersensitivity observed in irritable bowel syndrome (Fitzcharles et al., 2021).

Dysfunction of descending inhibitory pathways

The central nervous system normally has circuits that dampen pain transmission. When these inhibitory pathways, which originate in the brainstem, work less effectively, the natural modulation of pain decreases and nociceptive signals are less filtered (Latremoliere & Woolf, 2009).

Changes in brain connectivity

Functional imaging studies report altered connectivity between the insula, the anterior cingulate cortex, and pain-modulation networks in people with fibromyalgiaFibromyalgiaFibromyalgia is a chronic pain syndrome combining persistent widespread pain, fatigue, sleep disturbances and often difficulty concentrating, with no tissue damage that could on its own explain the intensity of the symptoms.Read the full entry : Fibromyalgia. These changes do not prove a single cause, but they support the hypothesis of a persistently altered central processing of pain (Ricci et al., 2022).

Once established, these mechanisms are not visible to the naked eye or on standard imaging. Under these conditions, how is a diagnosis of nociplastic pain actually made?

3. How is nociplastic pain recognized?

There is no blood test, no imaging, and no biological marker that can, on its own, confirm nociplastic pain. The assessment is therefore clinical: it combines positive features of altered nociception with verification that nociceptive or neuropathic mechanisms do not sufficiently explain the pain.

A diagnosis that begins by ruling out the other mechanisms

Before a nociplastic mechanism is considered, an active nociceptive cause (inflammation, structural lesion) and a demonstrable neuropathic cause must first have been reasonably ruled out, according to the criteria already described in the previous article. Nociplastic pain is therefore not a diagnosis of convenience: it is a positive conclusion, based on a set of consistent signs, not on the mere absence of an abnormality.

Characteristic clinical signs

Several features point toward this mechanism, although none is sufficient on its own: chronic pain lasting more than three months, a widespread distribution or one disproportionate to what the tissues would lead one to expect, allodynia or hyperalgesia, and associated symptoms such as chronic fatigue, sleep disturbances, difficulty concentrating, or anxiety (Fitzcharles et al., 2021).

Figure 3 — How can nociplastic pain be recognized? Its diagnosis relies on clinical reasoning that combines the absence of an explanatory lesion, suggestive features, and a context compatible with central sensitization.

Validated questionnaires to support clinical judgment

The Central Sensitization Inventory (CSI), is a 25-item self-report questionnaire assessing symptoms frequently associated with central sensitization. A score of 40/100 has historically been proposed as a clinically relevant cutoff in chronic pain populations, but the CSI does not directly measure central sensitization and cannot diagnose nociplastic pain on its own (Mayer et al., 2012; Neblett et al., 2013). The FiRST (Fibromyalgia Rapid Screening Tool), which is more specific to fibromyalgia screening, consists of six questions; a score of five or more positive answers strongly points toward this diagnosis, with a sensitivity of 90.5% and a specificity of 85.7% (Perrot et al., 2010). These tools guide clinical judgment; they do not replace the clinical examination.

Making this diagnosis is not enough to explain why certain conditions illustrate it more than others. Fibromyalgia and endometriosisEndometriosisEndometriosis is a chronic inflammatory disease in which tissue similar to the lining of the uterus grows outside the uterine cavity. It can cause severe pelvic pain and infertility.Read the full entry : Endometriosis offer two particularly well-documented examples.

4. Fibromyalgia and endometriosis: two common expressions of the nociplastic mechanism

Fibromyalgia affects about 2% of the general population, with a clear female predominance, according to a meta-analysis covering more than 3.6 million people (Heidari et al., 2017). The diagnosis is based on the revised American College of Rheumatology criteria, which combine widespread pain and somatic symptoms, without a specific structural lesion (Wolfe et al., 2016).

Endometriosis, by contrast, is very often accompanied by actual, identifiable tissue damage. But a notable proportion of affected women develop, in addition to this nociceptive component, a superimposed central sensitization: a recent review reports associated fibromyalgia in about 7% of women with endometriosis, with peripheral, central, and cross-sensitization mechanisms described between the two conditions (McNamara et al., 2021).

An overlap that complicates the clinical picture

In the same person, pelvic pain may therefore combine active tissue damage, possible involvement of the pudendal nervePudendal nerveThe pudendal nerve arises mainly from the sacral roots S2 to S4. It provides a large share of the sensory and motor innervation of the perineum and the external genitalia.Read the full entry : Pudendal nerve already described in the previous article, and superimposed central sensitization. Treating only one of these components then improves only part of the picture, which partly explains the treatment failures reported in these complex situations.

Figure 4 — The three mechanisms can coexist. Chronic pain frequently results from the interaction of several mechanisms whose relative importance varies from person to person and over time.

Once these mechanisms are recognized, the question becomes a practical one: how is nociplastic pain managed once it has been identified?

5. How is nociplastic pain managed?

The EULAR recommendations for fibromyalgia, the most robust reference available for this mechanism, emphasize a multimodal, individualized approach (Macfarlane et al., 2017).

Physical activity: the only recommendation backed by a high level of evidence

Of all the interventions evaluated, physical exercise is the only one to receive a strong recommendation based on meta-analyses. Adapted, progressive activity, rather than intense activity, thus helps reduce central sensitization over time (Macfarlane et al., 2017).

Mind-body approaches and therapeutic patient education

Cognitive behavioral therapy and therapeutic patient education help limit the vicious cycle of catastrophizing, avoidance, and worsening pain. Their benefit, however, mainly concerns quality of life and functional impact, rather than pain intensity alone.

Medications: a real but modest benefit

Duloxetine and pregabalin are the most extensively studied medications. The available Cochrane reviews show significant pain relief in roughly one person in ten, with no consistent benefit on the other associated symptoms (Derry et al., 2016; Welsch et al., 2018). Conventional anti-inflammatory drugs and corticosteroids, on the other hand, have not demonstrated efficacy, since there is no inflammatory tissue mechanism to target.

The interpretation proposed by the Blue Portance model

The Blue Portance model proposes a reading of the factors that may help maintain central sensitization in certain chronic situations. This interpretive framework organizes the interactions between mechanical stresses, pain history, adaptive behaviors, and postural variabilityPostural variabilityPostural variability refers to fluctuations in posture over time. It is measured in particular through displacements of the center of pressure and is neither good nor bad in itself.Read the full entry : Postural variability, without replacing either the IASP definition of nociplastic pain or medical diagnostic reasoning. In concrete terms, it helps organize four areas:

Figure 5 — Blue Portance model: a reading of the factors that sustain central sensitization. This interpretive framework proposes an integrative reading of the biological, mechanical, behavioral, and environmental factors that may help maintain nociplastic pain.

1. Sensitization history: has the pain evolved from an initial nociceptive or neuropathic event toward a more widespread and less proportionate picture?
2. Maintaining factors: disrupted sleep, a sedentary lifestyle, chronic stress, emotional burden — these factors did not cause the sensitization, but they may help maintain it.
3. Associated mechanisms: does an already identified nociceptive or neuropathic component coexist with central sensitization?
4. Postural and behavioral variability: do prolonged positions and lack of movement reduce the nervous system’s natural regulatory capacities?

This reading cannot be used to diagnose nociplastic pain. It does, however, help distinguish between what stems from a modifiable maintaining factor, what corresponds to an already established central mechanism, and what requires medical reassessment.

This interpretive framework includes postural variability among the maintaining factors. What, more precisely, is the link between sitting and nociplastic pain?

6. Nociplastic pain and sitting: what is the link?

It is important to be precise here so as not to distort the mechanism: sitting does not, on its own, cause central sensitization. Nociplastic pain is not mechanical in origin, and no seat, however well designed, directly “treats” altered nociceptive processing.

The link is indirect, but real. Prolonged sitting with little variation promotes a sedentary lifestyle, reduces opportunities for movement, and may limit the natural production of endorphins associated with physical activity — and physical activity is precisely the only intervention supported by a high level of evidence in the management of this mechanism. Prolonged sitting may therefore act as one maintaining factor among others, without being a cause of the nociplastic mechanism itself.

In addition, a genuine mechanical component — pudendal nerve involvement, for example — can coexist with central sensitization in the same person. Changing how one sits may then reduce an active nociceptive or neuropathic component, without resolving the associated nociplastic component, which requires specific management.

It remains to clarify the limits of what science currently establishes about this mechanism, in order to avoid the most common shortcuts.

7. Controversies and limitations of current knowledge

Another limitation stems from the absence of a single biological marker: the diagnosis remains clinical, which partly explains the diagnostic odyssey often reported by patients before a nociplastic mechanism is considered.

8. Practical implications for understanding a situation

When faced with chronic pain that is not sufficiently explained by a lesion, several questions structure the analysis:

• Exclusion: have the nociceptive and neuropathic mechanisms been reasonably ruled out or documented?
• Distribution: is the pain widespread or disproportionate to what the tissues would lead one to expect?
• Associated symptoms: is the pain accompanied by fatigue, sleep disturbances, cognitive difficulties, or anxiety?
• Maintaining factors: can a sedentary lifestyle, chronic stress, or disrupted sleep be identified and modified?
• Associated mechanisms: does a nociceptive or neuropathic component coexist with central sensitization?
• Response to movement: does adapted, progressive physical activity bring any improvement, even a modest one?

Rapid worsening, unexplained weight loss, a decline in general health, or the onset of new neurological signs should prompt medical reassessment, because they cannot be explained by a nociplastic mechanism alone.

Note: this content explains general mechanisms established in the scientific literature. It cannot be used to make a diagnosis remotely or to replace a medical evaluation. Widespread or unexplained chronic pain should be discussed with a healthcare professional.

© Gil Ayache. The concepts, diagrams, terminology, and principles presented on this page constitute a work protected by copyright. They are made available to Blue Portance under an intellectual property license agreement, without transfer of economic rights or of authorship.