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Pathogenesis of fibromyalgia

Author

Don L Goldenberg, MD

Section Editor

Peter H Schur, MD

Deputy Editor

Paul L Romain, MD

Last literature review for
version 16.3: October 1,
2008  |  This topic last
updated: October 6, 2008

INTRODUCTION — Fibromyalgia is a chronic pain disorder with unknown
etiology and unclear pathophysiology [1,2].

There is no evidence that a single event
"causes" fibromyalgia. Rather, many physical
and/or emotional stressors may trigger or aggravate symptoms. These have
included certain infections, such as a viral illness or Lyme
disease as well as emotional or physical trauma [1-3].

The diagnosis is currently based upon the
presence of widespread musculoskeletal pain and excess tenderness in at least
11 of 18 predefined anatomic sites (show
figure 1). A detailed description of the clinical manifestations of fibromyalgia and an approach to the diagnosis of fibromyalgia in adults and children are presented
separately. (See "Clinical manifestations and diagnosis of fibromyalgia in adults" and see "Fibromyalgia in children
and adolescents").

Fibromyalgia is only one of many causes of wide-spread pain. A
discussion of the differential diagnosis of fibromyalgia
and the broad differential diagnosis is presented separately. (See "Differential diagnosis of fibromyalgia").

PATHOGENESIS — Fibromyalgia
is currently considered to be a disorder of pain regulation, classified often
under the term central sensitization [1,2,4]. During much of the 20th century, fibromyalgia was thought to be a muscle disease. However,
controlled trials found no evidence for significant pathologic or biochemical
muscle abnormalities [1-5].
As an example, measures of muscle function, including force generation and
lactate production during exercise, and muscle pain following exertion are
remarkably similar in women with fibromyalgia (FMS)
and sedentary female controls [6,7].
Most investigators now believe that any muscle pathology is secondary to pain
and inactivity rather than primary in nature [1,5-7].

Genetic
predisposition — A number of observational and biologic studies suggest that
chronic widespread pain and fibromyalgia have, in
part, a genetic basis [8].
First degree relatives of patients with FMS are 8.5 times more likely to have
FMS than relatives of patients with rheumatoid arthritis [9].
Familial aggregation of lowered thresholds for pressure-induced pain has been
documented in first-degree relatives of patients. Such reports suggest a shared
hereditary factor that may account for the overlap of chronic pain and mood
disorders in families. However, an association between chronic widespread pain
and any candidate gene has yet been conclusively documented [10].

Candidate
genes — The ability of some antidepressant drugs to improve symptoms
suggested that genes involved in serotonin and/or catecholamine metabolic or
signaling pathways might be candidates for conferring susceptibility.

·
Human serotonin transporter gene — An increased
propensity to have inherited deletions in the gene for the human serotonin
transporter suggests an underlying genetic component for the heightened pain
sensation [11,12]. However, this putative association may
be limited to patients with concommitant affective
disorders, as it was not confirmed in patients with FMS without depression or
anxiety [13].

·
Catecholamine methyltransferase
genes — Catecholamine methyltransferase (COMT)
genes that have been incriminated in predisposition to both pain and depression
have also been implicated in FMS [14].
Variable genetic predisposition may relate to altered kinetics of specific
serotonin transporter density and activity that has been found in patients with
fibromyalgia [15].

·
Monoamine oxidase A gene
polymorphism — Since fibromyalgia is often associated
with anxiety and the monoamine oxidase A polymorphism
has been associated with anxiety, this link was evaluated in patients with fibromyalgia [16].
There was no association of this polymorphism in fibromyalgia
patients compared to controls.

Altered pain
processing — Patients
with fibromyalgia perceive noxious stimuli (eg, heat, electrical current, pressure) as painful at lower
levels of physical stimulation than do healthy controls [1,2,4,17].
Patients with fibromyalgia experience greater spatial
and temporal summation factors compared to normal controls following
mechanically evoked muscle pain [18].

Some differences in pain processing that
may be important in pathogenesis include the following:

·
Upregulation of opioid receptors in the periphery [19],
as well as reduced brain opioid receptors [20].

·
Elevated levels of substance P were found in the
cerebrospinal fluid of FMS patients compared to controls [21].

·
Differences in activation of pain-sensitive areas of the
brain, as determined by increased regional brain blood flow using magnetic
resonance imaging (MRI), and functional MRI (fMRI),
and MR spectroscopy have been noted in FMS [22-24].

Both affective and cognitive factors
influence the brain's response to pain. Patients with fibromyalgia
and comorbid depression demonstrate increased
cerebral blood flow in the amygdala and anterior insula, areas important in affective pain response [23].
Mood disorders such as depression may effect and modulate pain processing [1,2,23].
Reduced regional cerebral blood flow at cortical levels in addition to the
thalamus and the subcortical nucleus has been noted
in those with FM [25].
It was postulated that fibromyalgia patients have
premature aging of the brain with gray matter loss [26].

·
Using MRI morphometric analysis,
fibromyalgia patients have significantly less total
gray matter volume and a 3 times greater age associated decrease in gray matter
than healthy controls. The longer the individuals have fibromyalgia,
the greater the gray matter loss, with each year of fibromyalgia
being equivalent to 9 times the loss expected with normal aging.

·
A pilot study, using positron emission tomography, found
reduced presynaptic dopamine activity in a small
number of fibromyalgia patients compared to controls [27].
These investigators also compared the endogenous release of dopamine in
response to painful and non-painful stimuli [28].
Fibromyalgia patients experienced more pain compared
to controls and did not release dopamine in the basal ganglia as did controls.

·
When fibromyalgia patients
undergo repetitive nonpainful stimulation, they have
an inability to inhibit irrelevant sensory stimuli [29].
This abnormal information processing may be related to a lack of inhibitory
control during stimulus coding and cognitive processing.

Sleep
abnormalities — Underlying central nervous system dysfunction is suggested
by the sleep and mood disturbances noted in the majority of FMS patients [1,2,30].
Phasic alpha sleep activity is most characteristic of
FMS [31].
An increase in cyclic alternating patterns of sleep has been noted in FMS and
correlated with the severity of symptoms [32].
Some data suggest that disordered sleep patterns precede the development of
pain and that abnormal sleep and pain predict depressive symptoms [30].

Neurohormonal perturbations — Hyperactivity of the stress response, demonstrated
by abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis, have been
found using different baseline and provocative testing although the precise
nature of these changes has not been elucidated [33-37].
Among the differences noted are:

·
A correlation between cerebrospinal levels of corticotropin-releasing factor, sensory pain, and variation
in autonomic function in fibromyalgia that was not
associated with chronic fatigue [35].
Altered HPA axis activity may be linked to childhood trauma, especially
physical abuse [36].

·
A strong correlation was found between cortisol
levels and pain upon awakening and one hour after waking in patients with FMS
compared to controls [37].

Abnormal levels of growth hormone have
been found in some, but not all reports [38].
There is no good evidence to suggest that there are alterations of sex hormones
in fibromyalgia [39].

Autonomic
nervous system dysfunction — Abnormal function of the autonomic nervous system in those
with fibromyalgia is suggested by the following:

·
Patients with FMS have been found to have orthostatic
hypotension and increased pain was noted in response to tilt table testing [40,41]. Increased resting supine heart rates and
decreased heart rate variability have been reported in both female [40]
and male patients [41].
(See "Evaluation of parasympathetic nervous system
function").

·
Decreased responsiveness to beta-adrenergic stimulation in
those with FM was demonstrated by in-vitro testing of beta adrenergic receptor
mediated cyclic AMP generation [42].
The alterations of cardiovascular regulation that had been postulated to be
pathologically important in fibromyalgia are
significantly affected by deconditioning [43].

Immune
system changes — There
is little evidence to support the concept that FMS is an immune mediated
disorder [1,2]. Autoantibodies
with affinity for a 68/48 kD
protein have been found in a subset of patients with fibromyalgia,
but not in healthy controls [44].
Other cytokine changes have been reported, but no studies have been consistent nor controlled well for mood disturbances and activity levels [45].

Treatment-induced
effects — One of the most exciting areas of translational research
will be future studies investigating the role of pain perception and neurohormonal factors following various treatment
modalities. For example, changes in salivary cortisol
and corticosteroid receptor alpha mRNA were noted after a 3-week multidisciplinary
treatment program in patients with fibromyalgia [46].

SUMMARY — Despite
the numerous abnormalities described in patients with fibromyalgia,
there is as yet no generally agreed upon explanation for the pathogenesis of
the disorder. The most plausible hypothesis suggests that, in genetically
predisposed individuals, various stressors induce a heightened sense of pain
and hypersensitivity to numerous stimuli [1,2].

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GRAPHICS

Tender points in fibromyalgia

The 18
"tender points" important for the diagnosis of fibromyalgia. Note the bilateral symmetry of the
labeled regions. Tenderness on palpation of at least 11 of these sites in a
patient with at least a three month history of diffuse musculoskeletal pain is
recommended as a diagnostic standard for fibromyalgia.
Adapted
from Goldenberg, DL, Hosp Pract (Off Ed) 1989; 24:39.

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