Fibromyalgia: What we now know
Patrick B. Wood, MD
Senior Medical Advisor
National Fibromyalgia & Chronic Pain Association
For years, people affected by fibromyalgia have had to contend with being told by well-meaning clinicians that there was "nothing wrong with them" despite the clear indication from their bodies to the contrary. The reason for the apparent contradiction between the experience of symptoms and the lack of pathological findings to which symptoms might be linked stems from limitations inherent to standard laboratory testing and medical imaging. In contrast, we now know that far from having "nothing" wrong, persons with fibromyalgia are affected by several pathophysiological processes that may be linked to symptom development and expression.
The first objective findings were reported in 1975 by Dr. Harvey Moldofsky, who found that patients with fibromyalgia demonstrate abnormal brain activity during sleep. This pattern of activity, known as alpha-delta sleep, is characterized by the occurrence of arousals (represented by alpha wave activity on sleep electroencephalogram, or EEG) during stage III/IV sleep, which is normally characterized by slow, delta brain waves. While not specific to fibromyalgia, this phenomenon occurs with a much higher prevalence among persons with fibromyalgia. Since then, several other sleep abnormalities have also been described.
Fibromyalgia is associated with a disruption of descending noxious inhibitory control (DNIC), the process by which exposure to certain stimuli produces analgesia and lower responses to subsequent painful stimulation. For example, when healthy individuals exercise, they typically experience decreased sensitivity to pain, whereas in fibromyalgia, this phenomenon is frequently lacking. Conversely, when a painful stimulus is repeated, it results in a progressive increase in sensitivity a phenomenon know as "wind up." In fibromyalgia, there is an increase in "wind up" phenomenon that results in a greater degree of pain at lower levels of stimulation. This enhancement of "wind up" has led to the conclusion on many researchers' part that fibromyalgia represents a form of central sensitization, i.e. a greater sensitivity to pain due to changes in the central nervous system.
Abnormalities in the concentration of several neurochemicals have also been described from analysis of cerebrospinal fluid (CSF) from fibromyalgia patients. These include increased concentrations of excitatory neurochemicals, including substance P, glutamate (the chief excitatory neurotransmitter) and nerve growth factor, along with decreased concentrations of dopamine, norepinephrine and serotonin, which participate in descending pain inhibition. Together, these findings suggest an imbalance of excitatory and inhibitory neurotransmitters that may ostensibly contribute to the abnormal pain sensitivity that characterizes the disorder. Paradoxically, increased levels of CSF endorphins have also been described, which appear to indicate a failure of this endogenous analgesic system.
Abnormalities in the function of the primary stress-response systems (i.e. the autonomic nervous system and hypothalamic-pituitary-adrenal [HPA] axis) have also been demonstrated. Fibromyalgia is characterized by an elevation in the baseline function of the sympathetic nervous system, which appears especially pronounced at night. A reduction in responsiveness of the sympathetic nervous system in response to physical or mental challenges has also been found, as has a reduction in the activity of the parasympathetic nervous system. This pattern of dysautonomia may contribute to fatigue, poor exercise tolerance, and orthostatic intolerance, as well as abnormal bowel and bladder function. While data regarding the HPA axis are mixed, in general it appears fibromyalgia may be associated with a mild reduction in cortisol levels (hypocortisolemia). Other abnormalities in neuroendocrine function include a progressive decline in growth hormone levels, which are most pronounced in response to exercise.
Research using neuroimaging technologies has resulted in a number of intriguing findings. The first of these included baseline abnormalities in regional cerebral blood flow in such areas as the cingulate cortex, thalamus and basal ganglia using single positron emission tomography (SPECT). Functional magnetic resonance imaging (fMRI) later revealed abnormal brain responses to noxious stimulation, characterized by hyperactivation within pain-related brain areas in response to low levels of stimuli using pressure or heat. Abnormal brain metabolite levels have been described using magnetic resonance spectroscopy (MRS) in the hippocampus, insula and prefrontal cortex. Studies using positron emission tomography (PET) have demonstrated a reduction in dopamine synthesis and a disruption of dopamine release in response to painful stimulation. A reduction in morphine binding sites has also been described. Together, these findings from PET studies are remarkably consistent with the abnormal chemistry reflected by CSF analysis. Finally, studies using voxel-based morphometry (VBM), which allows characterization of brain shape and volume, have demonstrated that fibromyalgia is associated with reduced concentrations of brain gray matter and reduced total brain volume consistent with an acceleration of normal age-related brain changes.
As the preceding demonstrates, fibromyalgia is associated with several physiologic abnormalities that may be linked to the many symptoms that persons affected by the disorder experience daily. While these findings may seem daunting, there is reason for hope. By uncovering specific abnormalities to characterize the disorder, novel treatments even strategies for prevention may then be developed based on rational therapeutic targets.