Fibromyalgia

The term, “Fibromyalgia Syndrome,” is the modern name for a complex, multifactorial disorder characterized by chronic, widespread pain, and heightened pain response to tactile pressure. Fibromyalgia sufferers often present chronic fatigue syndrome, bowel disturbances, cognitive dysfunctions, anxiety, sleep disturbances, and multiple chemical sensitivities. (Aaron & Buchwald) Although the term itself is modern, the chronic pain and fatigue have been recognized for centuries. The Biblical figure Job suffered from symptoms similar to fibromyalgia. (Bible) In the later part of the 19th century, Florence Nightingale suffered from chronic, widespread pain and fatigue until her death in 1910. (Richards)

The term “fibromyalgia” is derived from Latin, fibro-, and Greek, myo- and algos-, to mean “muscle and fibrous tissue pain,” but the ailment has been known by several different names since the 1600s, including muscular rheumatism, fibrositis, and neurasthenia. (Wikipedia, “Fibromyalgia”) In 1816, Dr. William Balfour at the University of Edinburgh gave the first medical description of the syndrome. Eight years later, he identified a series of tender points associated with the syndrome. In 1904, Sir William Gowers changed the name to fibrositis in order to match the apparent inflammation of the tender points. In 1972, Dr. Hugh Smythe described the widespread pain associated with the tender points, and in 1975, he and Dr. Harvey Moldofsky used sleep electroencephalograms to describe the characteristic sleep disturbances accompanying the syndrome. In 1981, the researcher Mohammed Yunus first used the term “fibromyalgia” in a published paper. By 1987, the American Medical Association considered fibromyalgia to be a real, physical condition. In 1990, an official diagnostic criteria was developed by the American College of Rheumatology, known as “the ACR 1990.”. This criteria, while controversial, helped bring an awareness of the fibromyalgia into the medical field. (“Fibromyalgia History”)

Fibromyalgia affects several times more women than men, and is usually diagnosed around middle age. The symptoms affect children and men, although more rarely. The cause is unknown, and it can develop spontaneously, although many people associate the development of fibromyalgia with emotional stress, traumatic events, repetitive stress, or illness. It is not fatal, and often does improve over time. (Ader)

Because the cause is unknown, current treatment utilizes an array of tools, some of which work better for some people than others. Many varieties of drugs can be used, include analgesics, NSAIDs, tricyclic antidepressants, SSRIs, SNRIs, or benzodiazepines. Additionally, a range of medications regularly used to treat irritable bowel syndrome may be utilized to treat comorbid intestinal dysfunctions. Fibromyalgia patients may also benefit from physical and occupational therapy, instruction in pain management, and balanced rest and activity. (Ader)

There are no known physical abnormalities to indicate fibromyalgia, making diagnosis difficult. Instead, there appear to be many factors that may contribute to the symptoms. (Wikipedia, “Fibromyalgia”) The ACR 1990 diagnostic criteria defines a set of symptoms that a patient must present in order be diagnosed with fibromyalgia syndrome. This criteria specifies that, for fibromyalgia to be considered, the patient must have widespread pain in all four quadrants of the body, and have specific tender areas at 11 of 18 defined points on the body. (Ader)

Stress appears to play a significant role in fibromyalgia. Fibromyalgia is often comorbid with stress-related diagnoses such as chronic fatigue, post traumatic stress disorder, irritable bowel syndrome, and depression, leading to the potential conclusion that fibromyalgia may be a “consequence of early life stress or prolonged or severe stress.” (Schweinhardt) 

Fibromyalgia has been correlated to metabolic dysfunction in the hippocampus (Emad). Stress can directly influence the hippocampus; indeed, long term stress results in atrophy of the hippocampus due to neurotoxic effects of glucocorticoid hormones, which weaken neurons in the hippocampus, increasing their sensitivity to metabolic insult. (Sapolsky) The hippocampus normally has important roles in sleep regulation, cognitive functions, and pain perception. It generates the hippocampal theta waves, which appear to be vital to REM sleep. (Wikipedia, “Hippocampus”) It is possible that atrophy of the hippocampus reduces theta rhythms in the brain, resulting in the common sleep disturbances experienced by fibromyalgia patients. The hippocampus also has important roles in cognitive functions, including association and memory; atrophy of the hippocampus could result in the cognitive and memory difficulties that many fibromyalgia patients know as “fibro-fog.”

Genetics appear to have some role in fibromyalgia. Fibromyalgia is known to be clustered in families (Stormorken & Brosstad), and there is a moderate tendency for twins to share the symptoms. (Kato et al.) In one study, researchers discovered the prevalence of fibromyalgia among blood relatives of female fibromyalgia patients to be 26 percent, while the prevalence among their husbands was found to be 19 percent. The genetic component of fibromyalgia appears to be polygenic, and only one of many potential contributing factors. (Buskila & Neumann)

Fibromyalgia has been associated a mutation of the serotonin transporter (SERT) gene, SLC6A4. The studied region, 5-HTTLPR, has two common variants, long and short. The short allele has been associated with fibromyalgia, although the effect appears to be indirect. (Cohen & Buskila)

The long and short alleles appear to correspond to different transcription rates of SERT mRNA, with the short allele having a lower transcription rate. (Praschak-Rieder et al.) SERT is an integral membrane protein that transports serotonin from synaptic spaces into presynaptic neurons. Fewer transporter proteins should affect the rate of serotonin reuptake into the presynaptic neurons. The implication is that serotonin will remain for a longer period in the synaptic cleft in people having the short 5-HTTLPR allele. This neurochemical behavior has been hypothesized to combine with other factors to result in fibromyalgia.

Fibromyalgia has also been associated with the “DRD4 long” or “7R” mutation in the dopamine receptor, DRD4. (Buskila et al.) In normal physiology, DRD4 is a G-protein-coupled receptor. Dopamine binds to the receptor, which then undergoes a conformational change resulting in the production of cAMP inside the cell. The DRD4 long receptor is significantly less sensitive to dopamine, resulting in decreased cAMP production inside the cell. (Asghari et al.) The implication is that this inhibition of dopamine sensitivity could be a potential factor in fibromyalgia as well.

The pain associated with fibromyalgia has been associated with the val158met polymorphism of the catechol-O-methyltransferase, or COMT, gene. (Zubieta et al.) COMT is involved in the breakdown of catecholamines in the synaptic cleft. Individuals with val158met polymorphism are able to catabolize dopamine much faster than normal, reducing the overall availability of dopamine to postsynaptic neurons. COMT is particularly important in the breakdown of catecholamines in the frontal lobes of the brain, so the val158met polymorphism should have particular effect in that area. (Wikipedia, “Catechol-O-methyl transferase”)

Many fibromyalgia patients suffer from restless leg syndrome, which has been associated with a heightened sensitivity to dopamine. This heightened sensitivity is theorized to be caused by either higher dopamine receptor densities, or lower levels of endogenous dopamine. (Cervenka et al.) Additionally, dopamine appears to play a very significant role in pain perception and analgesia in many parts of the nervous system. It has been shown that abnormalities in dopaminergic neurotransmission are associated with the pain of fibromyalgia, as well as other painful neurologic diseases. (Wood)

Serotonin, norepinephrine, and dopamine metabolites have all been shown to be lower in the cerebrospinal fluid of fibromyalgia patients. (Russell & Vaeroy et al.) Serotonin metabolites have been shown to be lower in the blood serum of fibromyalgia patients. (Russell & Michalek et al.) One theory concerning the cause of fibromyalgia involves a deficiency of serotonin in the nervous system; supporting this theory is the observation that induced neurological serotonin deficiency results in symptoms similar to fibromyalgia. (Moldofsky et al.) However, SSRI drugs, which should increase the overall availability of serotonin in the synaptic cleft, and therefore alleviate the symptoms of serotonin deficiency, have failed to adequately address the symptoms of fibromyalgia, and have many potent side effects. Instead, benefits arising from SSRI administration seem to result from sleep quality improvements due to their sedative effects. SNRI drugs are much more specific in targeting neurotransmitters, and therefore lack the adrenergic, cholinergic, and histaminergic side effects of SSRIs. SNRI drugs have been met with limited success in treating the symptoms of fibromyalgia. (Arnold)

The complexity of the role of serotonin in fibromyalgia syndrome is made evident by the fact that antagonists of one particular serotonin receptor, 5-HT3, are effective in treating some cases of fibromyalgia. (Späth) 5-HT3 receptors are particularly prevalent in the gut, in terminals of the vagus nerve. (Wikipedia, “5-HT3 receptor antagonist”) This may implicate a different model for fibromyalgia syndrome.

In normal human physiology, digestion of chyme in the stomach takes 3 to 4 hours, at a pH of 1-3. Gastric acid production is stimulated by acetylcholine release from parasympathetic nerve fibers. (Wikipedia, “Digestion”) Once the duodenum begins to fill, the enterogastric reflex is triggered, which stimulates sympathetic nerve fibers to reduce gastric motility and close the pyloric sphincter, allowing the duodenum time to process its contents. (Wikipedia, “Regulation of gastric function”) As the process of digestion continues, peristalsis moves food into the colon, emptying the duodenum and allowing it accept more chyme from the stomach. (Wikipedia, “Enterogastric reflex”) It is important to note that peristalsis is stimulated by the parasympathetic nervous system, and inhibited by the sympathetic nervous system.

Many fibromyalgia patients link the onset of their symptoms with stressful events, such as car accidents, emotional stress, repetitive stress, or other traumatic events. (Ader) Many of these phenomena activate the “fight or flight” response, activating the sympathetic nervous system. Activation of the sympathetic nervous system reduces acid, bicarbonate, and mucus production in the gastrointestinal tract. (Wikipedia, “Gastric acid”) It also reduces intestinal motility.

Over time, the stagnation of digestion and dysfunctions of digestive secretions can form an excellent growing media for harmful bacteria. Patients with extended gastric emptying time have been shown to have a tendency to develop small intestinal bacterial overgrowth, or SIBO. (Reddymasu & McCallum). Using a lactulose breath test, researchers have determined that there can be a strong correlation between SIBO and irritable bowel syndrome, and an even stronger correlation between SIBO and fibromyalgia. In fact, abnormality on the breath test correlated directly with somatic pain. (Pimentel et al.) 

Once an inflammatory condition develops in the gut, nociceptive reflexes will work to activate muscular guarding reactions, keeping the smooth muscle of the gastrointestinal tract in a state of spasm. (Buskirk) If gut inflammation is the original cause of the smooth muscle spasms, then a positive feedback loop could develop, permanently locking the gut into a dysfunctional state.

Serotonin is a primary neurotransmitter of the sympathetic nervous system. Since the 5-HT3 serotonin receptor is found primarily in the gut, blocking the 5-HT3 receptor should inhibit the effect of the sympathetic nervous system on the gut, allowing the parasympathetic and enteric nervous systems to exert more influence. Indeed, certain 5-HT3 antagonists have been shown to reduce gastric emptying time. (Akkermans et al.) Increasing intestinal motility should reduce the amount of time food stagnates in the intestinal tract, which should reduce SIBO, and reduce SIBO-related inflammation.

If the gut is overly stimulated by the sympathetic nervous system, the associated deficiency in mucus production should result in gastric acid insult to the sensory receptors in the stomach. Endogenous gastric acid in the stomach is known to modulate the sensory gain of acid-sensitive vagal afferents. (Holzer) These acid-sensitive receptors are nociceptive, but the associated afferent pathways do not project into the insular cortex; instead, these signals project into the solitary nucleus, the hypothalamic paraventricular nucleus, the central amygdala, the medial/lateral habenula, and other structures. (Michl et al.)

These areas of the nervous system have important functions, many of them potentially relevant to fibromyalgia. The solitary nucleus handles motility and secretory reflexes in the gastrointestinal tract, and therefore may include a feedback loop involving gastric acid production. (Wikipedia, “Solitary Nucleus”). The hypothalamic paraventricular nucleus is involved in the secretion of corticotropin-releasing hormone, involved in the release of cortisol; and vasopressin, involved in blood pressure regulation. (Wikipedia, “Paraventricular nucleus of hypothalamus”) The habenula outputs to many regions of the midbrain involved in releasing serotonin, dopamine, and norepinephrine. (Wikipedia, “Habenula”)

When stimulated, the habenula is a powerful inhibitor of dopamine production in the substantia nigra pars compacta and the ventral tegmental area. (Christoph et al.) The habenula also inhibits serotonin-producing neurons in the raphe nuclei. (Wang & Aghajanian) 

It is possible that excessive vagal stimulation of the habenula, caused by long-term inflammation in the gut, may inhibit a significant portion of the body’s endogenous secretion of dopamine and serotonin in the brain, thereby resulting in the long term dopamine and serotonin dysfunctions associated with fibromyalgia. This specific mechanism involving the visceral afferent pathway of the vagus nerve does not appears to have been investigated as a primary cause of fibromyalgia.

Mild stimulation of the vagus nerve, using an implanted electrode, has shown promising results in the treatment of fibromyalgia. One study with fourteen patients measured significant benefits associated with vagus nerve stimulation; five patients showed therapeutic efficacy of the treatment after three months, and two of those had improved to the point that they no longer met the diagnostic criteria for fibromyalgia. The therapeutic effect seemed to increase over time, with other patients showing marked improvement eight months after cessation of vagus nerve stimulation. (Lange et al.)

The physiological basis for the efficacy of vagus nerve stimulation likely does not involve adding additional stimulation to the afferent pathways into the brain, since those pathways are likely undergoing hyperactivation due to inflammatory conditions in the gut. Instead, vagus nerve stimulation likely involves activation of the efferent pathways of the vagus nerve. The vagus nerve, being a branch of the parasympathetic nervous system, stimulates intestinal motility. Electrical stimulation of the vagus nerve should therefore reduce gut spasms, and help move material through the intestines. Once the gut is functioning properly, the enteric nervous system should be able to take over, leading to slow improvement over time.

Exercise remains one of the most consistent and powerful forms of treatment for fibromyalgia. (Ader) Physiologically, exercise lowers stress hormone levels, and reduces inflammation. Lowering stress hormone levels should lower the glucocorticoid neurotoxicity in the hippocampus, allowing it to slowly regain normal function. This should result in a slow diminishing of “fibro-fog.” Reducing overall inflammation should decrease the inflammatory afferent activity in the vagus nerve. In turn, this should reduce activation of the habenula, thereby decreasing inhibition of serotonin and dopamine production in the brain.

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