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The prevailing model for the development of Fibromyalgia (FM) involves:
1. Certain vulnerability elements (female sex, genes, abuse or other
adverse experiences during childhood when the brain is still developing) and
2. Persistent stress or distress. Psychologic variables (eg,
distress, mood and anxiety disorders, personality traits and disorders,
catastrophizing, coping, self-efficacy for pain control) play a central role in the
pain experience, overall morbidity, and prognosis in patients with FM.
High levels of anxiety and distress, less certainty of pain resolution, and a history
of trauma are predictors of whether the acute pain will progress to chronic
pain. Consistent with the relationship between pain and distress is the improvement
in measures of self-efficacy, coping, depression, pain, health status, and disease
activity that accompany the application of stress-management programs.
The International Association for the Study of Pain defines pain as "an unpleasant
sensory and emotional experience associated with actual or potential tissue damage,
or described in terms of such damage" (Merskey, 1986). Implicit here is the
threat associated with pain, which can be trivial or profound. Neurophysiologically,
the pain experience derives from a complex sensation-perception interaction involving
the simultaneous parallel processing of nociceptive input from the spinal cord to
multiple regions of the brain.
In addition to strictly sensory-discriminative elements of pain receptors and
afferent input from somatic reflexes, major contributions from pathways and regions of
the brain that are associated with emotional, motivational, and cognitive aspects of
pain are evident and help determine the subjective intensity of pain. The two
principal effectors of the stress response, the hypothalamic-pituitary-adrenocortical
(HPA) axis and the sympathetic nervous system (SNS), are also activated.
Although normally adaptive, the stress response may become maladaptive in patients
with chronic pain and fatigue syndromes, such as FM.
Negative emotions (eg, depression and anxiety) and other negative psychologic
factors (eg, loss of control, unpredictability in one's environment) and certain
cognitive aspects (eg, negative beliefs and attributions, catastrophizing) can all
function as stressors with actions in these systems.
In some patients with FM, such negative emotional, motivational, and cognitive
stressors may dominate the clinical picture, potentially leading to a
self-sustaining neuroendocrine cascade that contributes to flu-like symptoms,
depressed mood, fatigue, myalgias, cognitive difficulties, and poor sleep. The
important biologic elements here include proinflammatory cytokines, the HPA axis,
other neuroendocrine axes, and the autonomic nervous system. Growth-hormone
abnormalities are also thought to contribute to symptomatology in FM.
Pain in patients with FM derives partly from a generalized decrease in the pain
perception threshold, reflecting discrimination of a nociceptive quality from
a nonnociceptive quality (eg, touch, warmth, cold), and in the threshold for
pain tolerance, reflecting an unwillingness to receive more-intense stimulation.
These phenomena can be demonstrated clinically by pressure algometry (dolorimetry) or
in research settings with quantitative sensory testing (QST) using pressure, heat,
cold, or electricity as stimuli. Underlying these changes in thresholds is
altered processing of nociceptive stimuli in the CNS (central sensitization).
Demonstrated abnormalities in pain processing in FM include:
1) excess excitatory (pronociceptive) neurotransmitters (eg, substance P, glutamate
levels in the insula)
2) low levels of inhibitory neurotransmitters (eg, serotonin and norepinephrine)
in descending antinociceptive pathways in the spinal cord
3) maintained enhancement of temporal summation of second pain
4) altered endogenous opioid analgesic activity in several brain regions known to play
a role in pain modulation, and (5) dopamine dysregulation, among others.
High throughput genotyping is rapidly identifying a series of single
nucleotide polymorphism (SNP) haplotypes that influence neurotransmitter levels
and receptor levels in the brain that contribute to the various abnormalities in
pain processing. Such SNP haplotypes constitute vulnerability elements in
the development of FM and other central sensitivity syndromes. Pharmacologic agents
known to be effective in reducing pain in FM function in this regard by either
increasing levels of inhibitory neurotransmitters (eg, duloxetine) or decreasing levels
of excitatory neurotransmitters, in turn increasing levels of substance P (eg,
gabapentin or pregabalin). Because FM is a polygenic syndrome
with multiple different underlying genetic polymorphisms, genetic testing to tailor
therapy and to predict response to therapy will soon become available.
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