Pathophysiology — central mechanisms

TL;DR — The central-sensitization account of fibromyalgia (FM) rests on three converging lines: psychophysics (lowered pressure-pain thresholds, enhanced temporal summation, impaired conditioned pain modulation — meta-analytic Hedges g ≈ 0.53 and 0.57 respectively, but with large between-study heterogeneity) (O'Brien 2018, PMID 29454976); functional imaging showing that equal stimulus intensity produces greater brain activation in FM than in controls (Gracely 2002, PMID 12115241); and neurochemistry — three-fold elevated CSF substance P (Russell 1994, PMID 7526868), elevated posterior-insula glutamate (Harris 2009, PMID 19790053), reduced µ-opioid receptor binding potential (Harris 2007, PMID 17855614) and widespread elevation of the glial marker TSPO on PET (Albrecht 2019, PMID 30223011). The central weakness of the whole edifice is specificity: nearly every one of these abnormalities has been reported in other chronic pain conditions, and the imaging meta-analyses say so explicitly (Dehghan 2016, PMID 26864780). Most individual findings come from single laboratories with n = 10–37 per group; the multivariate brain classifier reported 92% sensitivity / 94% specificity but only against healthy controls and has not been replicated (López-Solà 2017, PMID 27583567).

0. Evidence at a glance

Sample sizes and replication status matter more here than in most of this wiki, because the central-mechanism literature is dominated by small single-site studies. Read this table before the detail.

Finding	Largest / pivotal evidence	Sample	Replication status
Lowered pressure-pain threshold	Consistent across many labs and criteria sets	Pooled across dozens of studies	Robust; direction never seriously disputed
Enhanced temporal summation	Meta-analysis, g = 0.53 (PMID 29454976)	23 studies, 648 patients / 672 controls (TS + CPM combined)	Replicated; heterogeneity high, protocols non-standardized
Impaired conditioned pain modulation	Meta-analysis, g = 0.57 (PMID 29454976)	as above	Replicated; effect moderated by catastrophizing (PMID 39225326)
Augmented fMRI response at equal stimulus	Gracely 2002 (PMID 12115241)	16 vs 16	Design replicated in spirit by many groups; also demonstrated in vulvodynia (PMID 23578957), so not FM-specific
Elevated CSF substance P	Russell 1994 (PMID 7526868)	32 vs 30	Independently confirmed with a different assay (PMID 10959008); correlates only weakly with tenderness
Elevated CSF excitatory amino acids	Larson 2000 (PMID 10924813)	Multi-group comparison	Not supported — group means did not differ
Elevated posterior-insula glutamate	Harris 2009 (PMID 19790053)	19 vs 14	Same group's longitudinal follow-up n = 10 (PMID 18311814); also elevated in sickle cell disease (PMID 39615812)
Reduced µ-opioid receptor binding	Harris 2007 (PMID 17855614)	17 vs 17	No independent replication located; the same laboratory found the opposite direction (increased thalamic binding) in chronic back pain (PMID 24027273)
rACC failure during evoked pain	Jensen 2009 (PMID 19410366)	16 vs 16	Extended to connectivity by the same group (PMID 22537768)
DMN–insula connectivity tracks pain	Napadow 2010 (PMID 20506181)	18 vs 18	Longitudinal follow-up n = 17 (PMID 22294427); an independent MEG study (28 vs 28) found insula–DMN connectivity decreased in FM (PMID 28831711)
Multivariate brain classifier	López-Solà 2017 (PMID 27583567)	37 vs 35	Not replicated; healthy controls only
Elevated brain TSPO (glial marker)	Albrecht 2019 (PMID 30223011)	31 vs 27 (11 vs 11 for astrocytic tracer)	Two-site pooled design; also elevated in chronic low back pain (PMID 25582579)

1. Quantitative sensory testing (QST)

QST is the oldest and most replicated evidence base, and the reasoning that made it central was explicit from the start: in the absence of demonstrable tissue abnormality, abnormal processing of nociceptive input became the default hypothesis (Staud 2002, PMID 12126581). Three paradigms carry most of the weight.

Paradigm	What it probes	Finding in FM	Effect size / source
Pressure-pain threshold (PPT)	Static mechanical sensitivity	Lowered; FM require significantly less pressure to reach a calibrated pain level	Consistent across labs; e.g. FM required significantly less kPa for VAS 50 (Jensen 2012, PMID 22537768); U = 48, p < .002 in a 16-vs-16 comparison (Jensen 2009, PMID 19410366)
Temporal summation (TS) of second pain / "wind-up"	Dorsal-horn windup, NMDA-dependent amplification	Greater first-stimulus magnitude and greater summation across a series; pain evoked at interstimulus intervals of 2–5 s where controls rarely reported pain above 2 s; after-sensations larger, longer, more often painful	Original demonstration in FM (Staud 2001, PMID 11240089); meta-analytic Hedges g = 0.53 (95% CI 0.23–0.83), described as a 68% relative difference (O'Brien 2018, PMID 29454976)
Conditioned pain modulation (CPM) / DNIC	Descending inhibition	Absent or reduced "pain-inhibits-pain" effect	PPT rose during a tourniquet conditioning stimulus in controls (p < 0.001) but not in FM; between-group difference p < 0.001 in a 10-vs-10 study (Kosek 1997, PMID 9106808). Meta-analytic g = 0.57 (95% CI −0.88 to −0.26; signs as reported in the source), a 65% relative difference (O'Brien 2018, PMID 29454976)

How solid are those effect sizes? The pooled TS/CPM meta-analysis included 23 studies (625 female and 23 male FM patients; 591 female and 81 male controls) and reported large heterogeneity between study protocols; sensitivity analysis and meta-regression identified type and site of stimulation, age, laboratory, sample size and medication control as significant sources of between-study variance, and blinding was frequently absent (O'Brien 2018, PMID 29454976). These are group-level differences with heavily overlapping distributions, not a diagnostic test.

QST is not psychologically inert. A systematic review with meta-regression of 20 studies (n = 1,623) found that higher pain-catastrophizing was associated with less efficient CPM, and higher anxiety and depression with lower pain thresholds; pain threshold rose modestly after FM treatment of any type (effect size 0.29, 95% CI 0.03–0.56), and baseline anxiety predicted smaller threshold improvement (Carneiro 2024, PMID 39225326). Any claim that QST measures "the sensitized nervous system" independently of psychological state is therefore overstated.

2. Landmark functional imaging: augmentation at equal stimulus intensity

The design that made the central-sensitization case persuasive was Gracely's dissociation of stimulus from percept. Sixteen right-handed FM patients and 16 matched controls received pressure to the left thumbnail bed during fMRI. Controls were tested under two conditions: matched pressure and matched subjective pain (Gracely 2002, PMID 12115241).

• At equal subjective pain, activation patterns largely converged: 19 regions of increased signal in controls, 12 in patients, with 7 common regions of increase and 1 of decrease.
• At equal pressure, controls showed only 2 regions of increased signal, neither coinciding with a patient activation.
• Direct group comparison at similar pressures: 13 regions of greater activation in patients versus 1 region greater in controls.

The interpretation — cortical or subcortical augmentation of pain processing rather than exaggerated reporting — is the single most-cited mechanistic result in FM.

Two riders belong with it. First, psychological state modulates the same signal: in 29 FM patients, catastrophizing (residualized for depressive symptoms) correlated with activation in claustrum, cerebellum, dorsolateral prefrontal cortex, parietal cortex, dorsal ACC and medial frontal cortex (r = 0.40–0.51, p < 0.05), and high catastrophizers showed roughly twice the ipsilateral S2 activation of low catastrophizers (Gracely 2004, PMID 14960499). Second, the same augmentation to a remote stimulus (thumb pressure) has been shown in vulvodynia, using FM as the positive control (Hampson 2013, PMID 23578957) — an early sign that augmentation indexes a class of conditions, not FM.

3. Neuroimaging signatures and multivariate classifiers

Resting-state connectivity. In 18 FM and 18 controls, FM showed greater intrinsic connectivity within the default mode network (DMN) and right executive attention network, and greater DMN-to-insula connectivity, with insula–DMN connectivity tracking spontaneous pain intensity (Napadow 2010, PMID 20506181). In a 17-patient longitudinal follow-up, reduction in DMN–insula connectivity after four weeks of non-pharmacologic treatment correlated with reduction in clinical pain (Napadow 2012, PMID 22294427). Connectivity within the descending inhibitory network is reduced: rostral ACC connectivity to amygdala, hippocampus and brainstem, and thalamus–orbitofrontal connectivity, were higher in healthy controls than in FM (28 FM, 14 controls) (Jensen 2012, PMID 22537768). The direction of the insula–DMN result is not method-independent: an independent magnetoencephalography study (28 FM, 28 age- and sex-matched controls) found insula–DMN connectivity decreased in FM in the theta band (4–8 Hz; left p = 0.007, right p = 0.035), with theta connectivity correlating negatively with tender-point count and total tenderness score across the pooled sample, while V1–DMN and S1–DMN control connections were unchanged (Hsiao 2017, PMID 28831711).

Multivariate classification. The most ambitious attempt combined fMRI responses to painful pressure and to non-painful multisensory (visual–auditory–tactile) stimulation in 37 FM and 35 matched controls. FM showed greater responses in the pre-existing Neurologic Pain Signature; a new "FM-pain" pattern showed augmented insula/operculum and medial prefrontal responses with reduced lateral frontal responses; a "multisensory" pattern showed augmented insula/operculum, posterior cingulate and medial prefrontal responses with reduced primary/secondary sensory, basal ganglia and cerebellar responses. Combined, the three patterns classified out-of-sample individuals with 92% sensitivity and 94% specificity (López-Solà 2017, PMID 27583567). Two caveats are essential and are stated by the authors: the comparison group was healthy controls (not other chronic pain), and the paper frames its own conclusions conditionally ("if replicated"). No replication was located in this session's searches.

Structural and coordinate-based meta-analyses. A voxel-based morphometry meta-analysis of 12 studies (289 FM, mean age 47.4 y; 272 controls) found increased grey matter in right postcentral gyrus and left angular gyrus and decreased grey matter in right cingulate/paracingulate, left cerebellum and left gyrus rectus (Xin 2023, PMID 37229427). A coordinate-based activation-likelihood-estimation (ALE) meta-analysis of 37 papers (1,264 subjects, 274 foci) implicated insula, amygdala, anterior/mid-cingulate, superior temporal gyrus, S1, S2 and lingual gyrus (Dehghan 2016, PMID 26864780). A later ALE analysis of 26 publications (1,056 subjects) reported abnormal ACC and insula activity but described the peak effects as reduced relative to healthy individuals, with pain severity negatively correlated with insula activation (Liu 2024, PMID 38294039) — a direction inconsistent with the augmentation literature and a reminder that pooled imaging results in FM are not yet stable.

4. CSF and MRS neurochemistry

Analyte	Direction in FM	Detail	Source
CSF substance P	↑ ~3-fold	32 FM vs 30 controls, p < 0.001; correlated only weakly with tenderness on examination	Russell 1994, PMID 7526868
CSF substance P (independent lab)	↑	Confirmed a significant patient–control difference in CSF substance P and Met-enkephalin-Arg⁶-Phe⁷ using an improved liquid–liquid extraction method	Liu 2000, PMID 10959008
CSF nerve growth factor	↑	41.8 ± 12.7 pg/ml (mean ± SEM) in primary FM vs 9.1 ± 4.1 in controls; not elevated in secondary FM (8.9 ± 4.4) or other painful conditions (16.2 ± 8.4); large variability	Giovengo 1999, PMID 10405946
CSF excitatory amino acids	no group difference	Mean concentrations of most amino acids did not differ between primary FM, secondary FM, other pain, and controls; only within-group correlations with tender-point index (glutamine, asparagine, arginine, glycine, taurine)	Larson 2000, PMID 10924813
Posterior insula glutamate (¹H-MRS)	↑	19 FM vs 14 matched pain-free controls: Glu 8.09 ± 0.72 vs 6.86 ± 1.29 (p = 0.009); Glx 12.38 ± 0.94 vs 10.59 ± 1.48 (p = 0.001). No difference in anterior insula or in other metabolites. Higher Glu/Glx correlated with lower PPT across both groups (r = −0.43, p = 0.012; r = −0.50, p = 0.003)	Harris 2009, PMID 19790053
Insular glutamate, longitudinal	tracks pain	In 10 FM patients scanned before and after a non-pharmacologic intervention, change in Glu/Cr correlated with change in experimental pain threshold (r = −0.95, p < 0.001), change in clinical pain (r = 0.85, p = 0.002) and change in BOLD signal (r = 0.81, p = 0.002)	Harris 2008, PMID 18311814

Two cautions. The substance-P finding is robust in direction but weakly coupled to clinical severity, and the authors themselves concluded that "other abnormalities must exist" (Russell 1994, PMID 7526868). The insular-glutamate longitudinal correlations rest on n = 10 — correlations of r = 0.95 at that sample size are hypothesis-generating, not established. Elevated posterior-insula Glx has since been reported in sickle cell disease (17 patients vs 17 matched controls), i.e. it is not an FM-specific marker (Zhou 2024, PMID 39615812).

5. Descending inhibition: opioidergic and monoaminergic

• Endogenous opioid system. µ-opioid receptor (MOR) PET in 17 FM vs 17 age- and sex-matched controls showed reduced MOR binding potential in nucleus accumbens, amygdala and dorsal cingulate; accumbens binding potential correlated negatively with affective pain ratings (Harris 2007, PMID 17855614). The authors proposed this as one reason exogenous opioids underperform in FM. Two riders: no independent replication in FM was located, and the same laboratory later reported the opposite direction in a different chronic pain condition — baseline increased thalamic MOR availability in 16 patients with chronic non-specific back pain versus 16 matched controls, described by the authors as contrary to their previously studied FM sample (Martikainen 2013, PMID 24027273). The same group also showed that MOR binding potential is dynamically modulable — traditional acupuncture increased short-term MOR binding potential in cingulate, insula, caudate, thalamus and amygdala, and long-term binding potential in cingulate, caudate and amygdala, where sham acupuncture instead produced small reductions (Harris 2009, PMID 19501658).
• Descending network function. During individually calibrated painful pressure, FM patients failed to activate the rostral ACC — the first link in the descending modulatory chain — despite normal activation in attentional and affective regions (16 FM, 16 matched controls) (Jensen 2009, PMID 19410366). Connectivity of the same seed to brainstem and limbic targets is reduced (Jensen 2012, PMID 22537768).
• Serotonergic–noradrenergic. The clinical case for this axis is largely pharmacological (SNRI and tricyclic efficacy) and is treated on the therapy pages; direct human FM evidence for a serotonergic/noradrenergic deficit is older and weaker than the opioidergic PET evidence. Early formulations implicated serotonin alongside substance P, nerve growth factor and dynorphin A as the chemical pain mediators of FM (Russell 1998, PMID 9638894) — treat as historical framing rather than current evidence.

6. Glial activation

The only direct in-vivo human evidence is TSPO PET. Combining datasets from two institutions, 31 FM patients and 27 healthy controls were scanned with [¹¹C]PBR28; FM showed widespread cortical elevations (and no decreases) in both distribution volume and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. A smaller subsample (11 FM, 11 controls) scanned with [¹¹C]-L-deprenyl-D₂ — thought to reflect astrocytic rather than microglial signal — showed no group differences (p ≥ 0.53, uncorrected), suggesting the TSPO elevation is microglia-driven. In exploratory, uncorrected analyses, fatigue ratings correlated with SUVR in anterior and posterior middle cingulate (p < 0.03) (Albrecht 2019, PMID 30223011).

Interpretation limits: TSPO is an indirect marker; the design is cross-sectional; the deprenyl subsample is underpowered to exclude an astrocytic contribution; and elevated brain TSPO is not FM-specific — it was demonstrated earlier in chronic low back pain (9 genotype-, age- and sex-matched patient–control pairs), where thalamic TSPO correlated negatively with clinical pain and circulating IL-6 (Loggia 2015, PMID 25582579). The direction of that correlation complicates any simple "more glia = more pain" reading.

7. Critiques: what central sensitization does and does not establish

1. Specificity. The most explicit statement comes from the imaging meta-analysis itself: because similar alterations have been demonstrated in other chronic pain conditions and most FM studies lack adequate chronic-pain control groups, it is "not clear whether these findings are associated with chronic pain in general" or are FM-specific (Dehghan 2016, PMID 26864780). The vulvodynia study makes the same point experimentally (Hampson 2013, PMID 23578957).
2. Direction of causation. All human data are cross-sectional or short-term interventional. Augmented processing, impaired CPM and altered connectivity could be consequences of chronic pain, sleep loss or distress rather than causes.
3. Sample size and replication. The pivotal studies are single-site with 10–37 patients per arm (Gracely 2002, PMID 12115241; Harris 2007, PMID 17855614; Harris 2009, PMID 19790053; Albrecht 2019, PMID 30223011). The classifier with the best reported discrimination has not been independently replicated (López-Solà 2017, PMID 27583567).
4. Heterogeneity within FM. Meta-regression shows QST results vary by lab, stimulus type and site, and by psychological covariates (O'Brien 2018, PMID 29454976; Carneiro 2024, PMID 39225326).
5. The centre is not the whole story. Peripheral blockade with intramuscular lidocaine reduces both local and remote hyperalgesia in FM, indicating that ongoing peripheral input helps maintain the central state (Staud 2009, PMID 19540671) — see pathophysiology-peripheral.
6. Nosological framing. IASP's nociplastic-pain construct explicitly notes that peripheral and/or central sensitization is "typically present, although not specific for nociplastic pain", and lists both autoreactive antibodies acting at the dorsal root ganglion and aberrant cerebral processing as candidate FM mechanisms (Kosek 2024, PMID 39560415). Reviews from the central-mechanism camp now describe FM as lying on a continuum from peripherally driven to centrally driven (Sluka 2016, PMID 27291641; Clauw 2014, PMID 24737367).

Open questions

• Is any central finding specific to FM rather than to chronic pain in general? No FM neuroimaging study located here used an adequately matched chronic-pain control group as the primary comparator; the meta-analysis names this as the principal unresolved problem (Dehghan 2016, PMID 26864780), and the same augmentation appears in vulvodynia (Hampson 2013, PMID 23578957).
• Does the López-Solà multivariate signature survive replication and a chronic-pain control group? Reported 92%/94% out-of-sample discrimination was against healthy controls only, and the paper's own conclusion is conditional (PMID 27583567).
• Is insular glutamate a state marker or an epiphenomenon? The longitudinal correlations rest on n = 10 (Harris 2008, PMID 18311814), and the cross-sectional elevation is shared with sickle cell disease (Zhou 2024, PMID 39615812).
• Which glial population, and in which direction, is involved? TSPO is elevated but astrocytic tracer signal was not (Albrecht 2019, PMID 30223011), while in chronic low back pain thalamic TSPO correlated negatively with pain (Loggia 2015, PMID 25582579).
• Why do the ALE meta-analyses disagree on the direction of insular/ACC effects? One reports augmentation-consistent involvement (Dehghan 2016, PMID 26864780), another reports reduced activity at insula/ACC peaks and a negative pain–insula correlation (Liu 2024, PMID 38294039).
• Are QST abnormalities trait or state? Pain thresholds rise after treatment of any kind (ES 0.29) and baseline anxiety predicts the size of that change (Carneiro 2024, PMID 39225326), which is hard to reconcile with a fixed structural abnormality.

Related pages

• pathophysiology-peripheral — small-fibre pathology and the peripheral-input evidence that constrains a purely central model.
• autoimmunity-and-inflammation — IgG transfer, anti-satellite-glial-cell antibodies and cytokines; the neuroinflammation link to §6.
• overview — nociplastic framing and the map of the topic.
• history-and-nosology — how "central sensitization" replaced "fibrositis" as the organizing concept.
• biomarkers — why none of the measures on this page qualifies as a validated diagnostic biomarker.
• comorbidities-and-overlap — chronic overlapping pain conditions, the natural comparison group these studies lack.
• pharmacologic-therapy — the opioid-response paradox that the MOR-PET data address.
• sleep-fatigue-cognition — fatigue correlated with cingulate TSPO in exploratory analyses.

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