A biological basis for fibromyalgia

Fibromyalgia has long been difficult to explain. Patients experience widespread pain, fatigue, poor sleep, cognitive difficulties and heightened sensitivity, often without tissue damage that seems sufficient to account for the severity of their symptoms. Some called it lack of “biological essence”. A major genetic study involving more than 2.5 million people from the US and Europe provides some of the strongest evidence yet that fibromyalgia is fundamentally linked to how the nervous system processes pain and sensory information.

Fibromyalgia is commonly described as a nociplastic pain condition. Unlike nociceptive pain, where pain arises primarily from actual or threatened tissue damage, or neuropathic pain caused by damage to the somatosensory nervous system, nociplastic pain reflects altered processing of sensory information. The nervous system becomes more responsive to incoming signals, producing hyperalgesia—greater pain from normally painful stimuli—and allodynia, where normally non-painful stimuli become painful.

The new study strengthens this model considerably. Researchers identified 26 independent genetic loci associated with fibromyalgia, providing robust evidence that susceptibility to the condition has a measurable biological and genetic basis.

Importantly, the genetic signals were not distributed evenly throughout the body. Fibromyalgia heritability was strongly and almost exclusively enriched in brain and neuronal tissues. Five significantly enriched human tissues were all brain regions, while 12 of 13 significantly enriched cell types were neuronal.

For therapists, this supports an important shift in perspective: chronic widespread pain in fibromyalgia should not necessarily be interpreted as evidence of widespread musculoskeletal damage. The tissues may hurt, but the mechanisms maintaining that pain appear to involve altered sensory processing across the nervous system.

Pain is real, even when tissue pathology is limited

This distinction is clinically important. Saying that pain is generated or amplified by the nervous system does not mean that the pain is imaginary or psychological. Pain is always ultimately produced through neural processing.

In fibromyalgia, genetic susceptibility appears to influence neural systems involved in sensory interpretation, pain modulation, cognition and emotional processing. The strongest cell-type signal occurred in neurons of the hippocampal dentate gyrus, a region involved in contextualising sensory experience. Other associations involved cortical, striatal, interneuronal and enteric nervous-system pathways.

Several of the genes highlighted in the study also have roles in neural development, synaptic signalling or regulation of neuronal excitability. These include HTT, DCC, MDGA2, DRD2 and CELF4. The CELF4 finding is especially interesting because experimental work indicates that it regulates sensory-neuron excitability and sensitivity to mechanical and thermal stimulation.

Despite large sex differences in fibromyalgia prevalence, the genetic architecture of fibromyalgia was nearly identical between males and females

The emerging picture is therefore not simply of an overly sensitive muscle or fascia, but of a sensory system whose gain may be turned up.

Fibromyalgia extends beyond musculoskeletal pain

Therapists frequently encounter clients with fibromyalgia who also report migraine, irritable bowel symptoms, sleep problems, fatigue, anxiety or other seemingly unrelated complaints. The new genetic findings suggest that some of these associations may reflect shared biological vulnerability.

Researchers found substantial genetic overlap between fibromyalgia and numerous pain conditions, including low-back pain, joint pain, migraine and widespread musculoskeletal disorders. There were also strong genetic correlations with conditions including post-traumatic stress disorder, depression, irritable bowel syndrome and functional dyspepsia.

The authors propose that fibromyalgia may partly represent a transdiagnostic nervous-system vulnerability affecting sensory and affective regulation. Depending on genetic, biological and environmental influences, this vulnerability might manifest as widespread pain, gastrointestinal symptoms, fatigue, migraine or other syndromes.

This helps explain why treatment aimed exclusively at a painful anatomical structure often produces incomplete or temporary results.

Is fibromyalgia autoimmune?

There has been considerable debate over whether fibromyalgia should instead be regarded as an autoimmune condition.

The new genetic evidence does not strongly support that interpretation. Researchers found no major genetic signal within the major histocompatibility complex and no significant enrichment of fibromyalgia heritability within peripheral immune cells or glia. Genetic overlap with autoimmune diseases existed, but was considerably weaker than that observed for pain and nervous-system-related conditions.

This does not exclude immune or neuroimmune involvement. Rather, the study suggests that classical peripheral autoimmunity is unlikely to be the primary mechanism driving fibromyalgia.

What does this mean for manual and movement therapists?

These findings do not suggest that hands-on therapy is irrelevant. They suggest that the explanation for why it may help needs to change.

A therapist may still identify painful muscles, restricted movement, protective guarding or altered movement strategies. These peripheral inputs can contribute to the sensory information entering the nervous system. But in fibromyalgia, the intensity of pain cannot necessarily be inferred from the amount of local tissue dysfunction.

This has several practical consequences.

Avoid chasing every painful structure.
Multiple tender areas do not necessarily represent multiple independent injuries. Widespread tenderness may partly reflect altered amplification of sensory information.

Dose treatment according to sensitivity.
When the nervous system is highly responsive, aggressive treatment intended to “break adhesions”, release deep restrictions or provoke a corrective response may instead increase nociceptive input. Treatment tolerance may therefore be more important than treatment intensity.

Use touch as sensory input rather than as structural correction.
Manual therapy can provide graded, non-threatening sensory information. Its value may lie partly in changing perception, reducing protective responses and enabling comfortable movement rather than mechanically correcting every painful tissue.

Combine treatment with movement.
Movement provides the nervous system with repeated information that an activity can be performed safely. Gradual exposure to movement and load may therefore be particularly important for rebuilding tolerance.

Recognise the whole clinical picture.
Sleep disturbance, fatigue, cognitive symptoms, gastrointestinal complaints and psychological stressors are not peripheral distractions from the “real” musculoskeletal problem. They may be part of the same broader biological system influencing pain sensitivity.

Genetics does not mean destiny

The genetic component should also not be overstated. The study estimated observed fibromyalgia heritability at approximately 10.4%, and genetic risk scores had only modest predictive accuracy.

Genes therefore contribute to vulnerability rather than determining whether an individual will develop fibromyalgia. Environmental exposure, illness, stress, sleep, physical activity, injury and other biological factors are still likely to influence how the condition develops and persists.

Interestingly, although fibromyalgia is diagnosed much more frequently in women, the study found that its genetic architecture was essentially the same in men and women. The difference in prevalence therefore appears unlikely to result simply from sex-specific genetic variants.

A different clinical question

Perhaps the most useful consequence of this research is a change in the question therapists ask.

Instead of continually asking:

“Which structure is causing this person’s pain?”

fibromyalgia may require us to ask:

“Why is this person’s sensory system responding so strongly, and how can we help it regain tolerance?”

That shift does not remove muscles, joints, fascia or movement from treatment. It places them within a larger nervous-system context.

The study concludes that fibromyalgia has a robust genetic basis and that its genetic architecture predominantly implicates neuronal systems, providing strong support for the concept of fibromyalgia as primarily a central nervous-system disorder.

For therapists, the practical message is therefore not that the body should be ignored, but that pain cannot always be read directly from the tissues. In fibromyalgia especially, effective care is likely to depend on working with the nervous system as well as with the structures through which patients experience their pain.