Alteration in Pain Processing Once fibromyalgia is established, by far the most
consistently detected objective abnormalities involve pain and sensory
processing systems. Because fibromyalgia is defined in part by tenderness,
considerable work has been performed exploring the potential reason for this
phenomenon. As noted earlier, the tenderness in fibromyalgia is not confined to
tender points but instead extends throughout the entire body. Theoretically,
such diffuse tenderness could be due primarily to factors either psychological
(eg, hypervigilance, in which individuals are too attentive to their
surroundings) or neurobiological (eg, the many pathways leading to temporary or
permanent amplification of sensory input).
Two decades of experimental studies in fibromyalgia have shown that
fibromyalgia patients do not detect electrical, pressure, or thermal stimuli at
lower levels than individuals without fibromyalgia, but the point at which these
stimuli cause pain or unpleasantness is lower.[37] These findings are noted even
when stimuli are presented in a random, unpredictable fashion.
These observations suggest that psychological factors such as hypervigilance
play only a minor role in modulating tenderness.[10]
Experimental pain testing has also been used to look for evidence of possible
mechanisms of the widespread allodynia (pain in response to normally nonpainful
stimuli) seen in fibromyalgia. Such studies have suggested that there may be
evidence of a decrease in "descending" neural signals from the brainstem that
normally inhibit the upward transmission of pain.[38,39] Figure 4 depicts these
descending systems, as well as the neurotransmitters that are known to either
facilitate (help to increase pain transmission in the spinal cord) or inhibit
(help to decrease pain transmission in the central nervous system).
Figure 4. Neurotransmitters that are known to play either facilitatory
(indicated in red) or inhibitory (indicated in blue) roles in the central
nervous system. Neuropeptides. Biochemical studies performed on samples from
fibromyalgia patients have supported the notion that there are central changes
in pain processing that may be due to either high levels of pronociceptive
peptides or low levels of antinociceptive peptides. The best supported mechanism
for the hyperalgesia seen in fibromyalgia is that it is due (at least in a
subset of individuals) to attenuated activity in the noradrenergic-serotonergic
descending antinociceptive pathways. Studies have shown that the principal
metabolite of norepinephrine, 3-methoxy-4-hydroxyphenethylene (MPHG), is lower
in the cerebral spinal fluid of fibromyalgia patients than in controls.[40]
Similarly, there are data suggesting low serotonin in this syndrome, manifest by
both reduced levels of serotonin and its precursor,
L-tryptophan, in the serum of patients with fibromyalgia, as well as reduced
levels of the principal metabolite 5-HIAA in the cerebrospinal fluid.[40,41]
Further evidence for this mechanism comes from treatment studies in which nearly
any type of compound that simultaneously raises both serotonin and
norepinephrine has been shown to be efficacious in this condition (discussed
further in the treatment section). By contrast, hypoactivity of the other major
descending antinociceptive pathway in humans, which involves endogenous opioids,
seems less likely to be playing a causative role in fibromyalgia. Cerebrospinal
levels of endogenous opioids are actually elevated in fibromyalgia. Furthermore,
the chronic administration of opioids to patients with fibromyalgia (although
not formally tested in a randomized, controlled trial) appears to have limited
efficacy.[42]
Another neurotransmitter that may play a role in fibromyalgia is substance P,
a pronociceptive peptide. Several studies[43-46] have shown that compared with
controls, patients with fibromyalgia have approximately 3-fold higher
concentrations of substance P in central spinal fluid. Other chronic pain
syndromes, such as osteoarthritis of the hip and chronic low back pain, are also
associated with elevated substance P levels, although chronic fatigue syndrome
(which is not defined on the basis of pain) is not. Of note, once elevated,
substance P levels do not appear to change dramatically and do not rise in
response to acute painful stimuli. Thus, high levels of substance P appear to be
a biological marker for the presence of chronic pain.
Abnormalities on Neuroimaging Functional neuroimaging has been very helpful
in elucidating potential mechanisms in fibromyalgia. Using single photon
emission computed tomography (SPECT), Mountz and colleagues[47] demonstrated
reduced thalamic blood flow under resting conditions (a finding noted in other
chronic pain states). These findings have been replicated by others.[48] Gracely
and colleagues,[49] using functional magnetic resonance imaging (fMRI),
demonstrated that the amount of pressure stimuli required to cause cerebral
activation in pain-processing regions of the brain, such as the primary and
secondary somatosensory cortices, was much lower in fibromyalgia patients than
in healthy controls. This study was the first to corroborate an objective
correlate of the hyperalgesia seen in fibromyalgia; this finding has since been
replicated with both heat and pressure stimuli.[50,51]
Behavioral and Psychological Factors In addition to neurobiological
mechanisms, behavioral and psychological factors also play a role in symptom
expression in many fibromyalgia patients. The rate of current psychiatric
comorbidity in patients with fibromyalgia may be as high as 30% to 60% in
tertiary care settings, and the rate of lifetime psychiatric disorders even
higher.[52,53] Depression and anxiety disorders are most commonly seen. However,
these high rates may be misleading. Most studies have been performed in tertiary
care centers where patients have higher rates of psychiatric conditions.
Individuals identified in the general population who meet ACR criteria for
fibromyalgia do not have nearly as high a rate of identifiable psychiatric
conditions (Figure 5).[13,54]
Figure 5. The relationship between neurobiological factors that initiate or
cause pain and other symptoms and psychological and behavioral factors that
either preexist or develop as a result of pain and can perpetuate or worsen
symptoms. These latter factors increase in frequency as one moves from examining
pain patients in the population to those seen in tertiary care centers. As
already noted, population-based studies have demonstrated that the relationship
between pain and distress is complex and that distress is both a cause and
consequence of pain. In this latter instance, a typical pattern involves
fibromyalgia patients functioning worse as a result of pain and other symptoms.
They may have difficulties with spouses, children, and work inside or outside
the home, which exacerbate symptoms and lead to maladaptive illness behaviors.
These include isolation, cessation of pleasurable activities, and reductions in
activity and exercise. In the worst cases, patients
become involved with disability and compensation systems that almost ensure
that they will not improve.[55]
The complex interaction of biological, psychological, and behavioral
mechanisms is not unique to fibromyalgia. Nonbiological factors play a prominent
role in symptom expression in all rheumatic diseases. In fact, in conditions
such as rheumatoid arthritis and osteoarthritis, nonbiological factors, such as
level of formal education, coping strategies, and socioeconomic variables,
account for more of the variance in pain report and disability than biologic
factors, such as the joint space width or sedimentation rate.[56,57]
Because of the biopsychosocial nature of fibromyalgia, several groups have
attempted to identify subgroups of individuals with this condition who may
present differently or respond differentially to treatment.[58,59] One of these
studies examined how differential degrees of depression, maladaptive cognitions,
and hyperalgesia might interact to lead to different subgroups of patients.
Three identified subgroups can usefully be identified (Figure 6).
Figure 6. Subgroups of fibromyalgia patients based on grouping by
psychological, cognitive, and neurobiological (degree of hyperalgesia) factors.
The first subgroup comprises approximately half of the patients who have low
levels of depression and anxiety, normal cognition regarding pain, and are
mildly tender (although tender enough to meet the ACR criteria). The second
subgroup, representative of "tertiary care" fibromyalgia patients, are slightly
more tender and also display high levels of depression. These patients also have
cognitions associated with a poor prognosis in many pain conditions. These
include an external locus of pain control, defined as feeling that they can do
nothing about their pain, and catastrophizing, defined as having a very negative
and pessimistic view of their pain. The third subgroup, perhaps the most
interesting, are the most tender, but with no negative psychological or
cognitive factors. This suggests that in some "resilient"
individuals, positive psychological and cognitive factors issues may actually
"buffer" neurobiological factors that lead to pain and other symptoms in
fibromyalgia.
Functional imaging studies have been instructive in regard to how these
comorbid mood disorders or cognitions may be influencing pain processing in
fibromyalgia. fMRI undertaken on 30 fibromyalgia patients with variable levels
of depression, with additional experimental pain testing, investigated how the
presence or absence of depression influenced pain report.[60] This study found
that the level of depressive symptomatology did not influence the degree of
neuronal activation in brain regions responsible for coding for the sensory
intensity of pain, the primary and secondary somatosensory cortices. As
expected, the depressed individuals did display greater activations in brain
regions known to be responsible for the affective or cognitive processing of
pain, such as the amygdala and insula. Another study[61] with similar
methodology examined how the presence or absence of catastrophizing might
influence pain report in fibromyalgia. In contrast to the results above, the
presence of catastrophizing was associated with increased neuronal activations
in the sensory coding regions. These studies provide empirical evidence for the
value of treatments such as cognitive-behavioral therapy. This is especially the
case if individuals exhibit cognitions such as catastrophizing which,
independent of other factors, may be capable of increasing pain intensity.




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