Fibromyalgia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Proposed causes and pathophysiology

The cause of fibromyalgia is unknown. In fact it may not be due to a singular cause at all, but rather due to a multiplicity of causes [2]. Fibromyalgia can, but most often does not, start as a result of some trauma such as a traffic accident, major surgery, or disease. Some evidence shows that Lyme Disease may be a trigger of fibromyalgia symptoms. Another study suggests that more than one clinical entity may be involved, ranging from a mild, idiopathic inflammatory process to clinical depression

Genetics

By using self-reported "Chronic Widespread Pain" (CWP) as a surrogate marker for fibromyalgia, the Swedish Twin Registry found that a modest genetic contribution may exist:

• Monozygotic twins with CWP have a 15% chance that their twin sibling has CWP
• Dizygotic twins with CWP have a 7% chance that their twin sibling has CWP

Stress

Studies have shown that stress is a significant precipitating factor in the development of fibromyalgia, and that PTSD is linked with fibromyalgia. The Amital study found that 49% of PTSD patients fulfilled the criteria for FMS, compared with none of the controls.

A non-mainstream hypothesis that fibromyalgia may be a psychosomatic illness has been described by John E. Sarno's "tension myositis syndrome". He believes many cases of chronic pain result from changes in the body caused by the mind's subconscious strategy of distracting painful or dangerous emotions. Education, attitude change, (and in some cases, psychotherapy) are treatments proposed to stop the brain from using that strategy. Robert G. Schwartz, MD has proposed an alternative view where in mind-body connections may play an important role in chronic disease (not just fibromyalgia) [3]. Through his Challenge and Choice program strategies to align incentives are offered.

Dopamine abnormality

Dopamine is a catecholamine neurotransmitter perhaps best known for its role in the pathology of schizophrenia, Parkinson's disease and addiction. As is the case with several of the neurotransmitters, there is evidence for a role of dopamine in restless leg syndrome , which is a common co-morbid condition in patients with fibromyalgia. Interestingly, patients with restless legs syndrome have also been demonstrated to have hyperalgesia to static mechanical stimulation.

Fibromyalgia has been commonly referred to as a "stress-related disorder" due to its frequent onset and worsening of symptoms in the context of stressful events. It was therefore proposed that fibromyalgia may represent a condition characterized by low levels of central dopamine that likely results from a combination of genetic factors and exposure to environmental stressors, including psychosocial distress, physical trauma, systemic viral infections or inflammatory disorders (e.g. rheumatoid arthritis, systemic lupus erythematosus). This conclusion was based on three key observations: (1) fibromyalgia is associated with stress; (2) chronic exposure to stress results in a disruption of dopamine-related neurotransmission; and (3) dopamine plays a critical role in modulating pain perception and central analgesia in such areas as the basal ganglia including the nucleus accumbens, insular cortex, anterior cingulate cortex, thalamus, periaqueductal gray, and spinal cord .

Serotonin

Serotonin is a neurotransmitter that is known to play a role in regulating sleep patterns, mood, feelings of well-being, concentration and descending inhibition of pain. Accordingly, it has been hypothesized that the pathophysiology underlying the symptoms of fibromyalgia may be a dysregulation of serotonin metabolism, which may explain (in part) many of the symptoms associated with the disorder. This hypothesis is derived in part by the observation of decreased serotonin metabolites in patient plasma and cerebrospinal fluid. However, selective serotonin reuptake inhibitors (SSRIs) have met with limited success in alleviating the symptoms of the disorder, while drugs with activity as mixed serotonin-norepinephrine reuptake inhibitors (SNRIs) have been more successful. Accordingly, duloxetine (Cymbalta), a SNRI originally used to treat depression and painful diabetic neuropathy, has been demonstrated by controlled trials to relieve symptoms of some patients. Eli Lilly and Company, the manufacturer of duloxetine has submitted a supplementary new drug application (sNDA) to the FDA for approval of it use in the treatment of FM. The relevance of dysregulated serotonin metabolism to the pathophysiology is a matter of debate. Ironically, one of the more effective types of medication for the treatment of the disorder (i.e. serotonin 5-HT3 antagonists) actually block some of the effects of serotonin.

Sleep disturbance

Electroencephalography studies have shown that people with fibromyalgia lack slow-wave sleep and circumstances that interfere with stage four sleep (pain, depression, serotonin deficiency, certain medications or anxiety) may cause or worsen the condition. According to the sleep disturbance hypothesis, an event such as a trauma or illness causes sleep disturbance and possibly initial chronic pain that may initiate the disorder. The hypothesis supposes that stage 4 sleep is critical to the function of the nervous system, as it is during that stage that certain neurochemical processes in the body 'reset'. In particular, pain causes the release of the neuropeptide substance P in the spinal cord which has the effect of amplifying pain and causing nerves near the initiating ones to become more sensitive to pain. Under normal circumstances, areas around a wound to become more sensitive to pain but if pain becomes chronic and body-wide this process can run out of control. The sleep disturbance hypothesis holds that deep sleep is critical to reset the substance P mechanism and prevent this out-of-control effect.

The sleep disturbance/substance P hypothesis could explain "tender points" that are characteristic of fibromyalgia but which are otherwise enigmatic, since their positions don't correspond to any particular set of nerve junctions or other obvious body structures. The hypothesis proposes that these locations are more sensitive because the sensory nerves that serve them are positioned in the spinal cord to be most strongly affected by substance P. This hypothesis could also explain some of more general neurological features of fibromyalgia, since substance P is active in many other areas of the nervous system. The sleep disturbance hypothesis could also provide a possible connection between fibromyalgia, chronic fatigue syndrome (CFS) and post-polio syndrome through damage to the ascending reticular activating system of the reticular formation. This area of the brain, in addition to apparently controlling the sensation of fatigue, is known to control sleep behaviors and is also believed to produce some neuropeptides, and thus injury or imbalance in this area could cause both CFS and sleep-related fibromyalgia.

Critics of the hypothesis argue that it does not explain slow-onset fibromyalgia, fibromyalgia present without tender points, or patients without heightened pain symptoms, and a number of the non-pain symptoms present in the disorder.

Human growth hormone

An alternate hypothesis suggests that stress-induced problems in the hypothalamus may lead to reduced sleep and reduced production of human growth hormone (HGH) during slow-wave sleep. People with fibromyalgia tend to produce inadequate levels of HGH. Most patients with FM with low IGF-I levels failed to secrete HGH after stimulation with clonidine and l-dopa.

This view is supported by the fact that those hormones under the direct or indirect control of HGH, including IGF-1, cortisol, leptin and neuropeptide Y are abnormal in people with fibromyalgia, In addition, treatment with exogenous HGH or growth hormone secretagogue reduces fibromyalgia related pain and restores slow wave sleep though there is disagreement about the proposition.

Deposition disease

The 'deposition hypothesis of fibromyaglia' poses that fibromyalgia is due to intracellular phosphate and calcium accumulations that eventually reaches levels sufficient to impede the ATP process, possibly caused by a kidney defect or missing enzyme that prevents the removal of excess phosphates from the blood stream. Accordingly, proponents of this hypothesis suggest that fibromyalgia may be an inherited disorder, and that phosphate build-up in cells is gradual but can be accelerated by trauma or illness. Calcium is required for the excess phosphate to enter the cells. The additional phosphate slows down the ATP process; however the excess calcium prods the cell to continue producing ATP.

The phosphate build-up hypothesis explains many of the symptoms present in fibromyalgiaand proposes an underlying cause. The guaifenesin treatment, based on this hypothesis, has received mixed reviews, with some practitioners claiming many near-universal successes and others reporting no success. Of note, guaifenesin is also a central acting muscle relaxant used in veterinary anaesthesia that is structurally related to methocarbamol, a property that might explain its utility in some fibromyalgia patients. A controlled trial of guaifenesin for the treatment of fibromyalgia demonstrated no evidence for efficacy of this medication. However, this study has been criticized by the chief proponent of the deposition hypothesis for not limiting salicylic acid exposure in patients, and for studying the effectiveness of only guaifenesin, not the entire treatment method. As of 2005, further studies to test the protocol's effectiveness are in the planning stages, with funding for independent studies largely collected from groups which advocate the hypothesis. It should be noted that nothing in the scientific literature supports the proposition that fibromyalgia patients have excessive levels of phosphate in their tissues.

Other hypotheses

Other hypotheses have been proposed related to various toxins from the patient's environment, viral causes such as the Epstein-Barr Virus, growth hormone deficiencies possibly related to an underlying (maybe autoimmune) disease affecting the hypothalamus gland, an aberrant immune response to intestinal bacteria, neurotransmitter disruptions in the central nervous system, and erosion of the protective chemical coating around sensory nerves. A 2001 study suggested an increase in fibromyalgia among women with extracapsular silicone gel leakage, compared to women whose implants were not broken or leaking outside the capsule. This association has not repeated in a number of related studies, and the US-FDA concluded "the weight of the epidemiological evidence published in the literature does not support an association between fibromyalgia and breast implants." Due to the multi-systemic nature of illnesses such as fibromyalgia and chronic fatigue syndrome (CFS/ME), an emerging branch of medical science called psychoneuroimmunology (PNI) is looking into how the various hypotheses fit together.

Another hypothesis on the cause of symptoms in fibromyalgia states that patients suffer from vasomotor dysregulation causing improper vascularflow and hypoperfusion (decreased blood flow to a given tissue or organ).

Always a comorbid disease?

Cutting across several of the above hypotheses is the proposition that fibromyalgia is almost always a comorbid disorder, occurring in combination with some other disorder that likely served to "trigger" the fibromyalgia in the first place. Two possible triggers are gluten sensitivity and/or irritable bowel. Irritable bowel is found at high frequency in fibromyalgia, and a large coeliac support group survey of adult celiacs revealed that 7% had fibromyalgia and also has a co-occurrence with chronic fatique.

According to this hypothesis, some other disorder (or trauma) occurs first, and fibromyalgia follows as a result. In some cases, the original disorder abates on its own or is separately treated and cured, but the fibromyalgia remains. This is especially apparent when fibromyalgia seems triggered by major surgery. In other cases the two disorders coexist. Since it can be extremely complex to treat the source of fibromyalgia, and since it is most probably a multifactoral disorder that is different from one afflicted patient to the next, the concept of Reducing Total Load has been proposed. In this instance the total number of things that does not allow a patient to get well is treated, one at a time, taking into consideration the unique conditions of that individual patient.