fibrositis n : inflammation of white fibrous tissues (especially muscle sheaths)

Fibromyalgia (FM) is a disorder classified by the presence of chronic widespread pain and tactile allodynia. While the criteria for such an entity have not yet been thoroughly developed, the recognition that fibromyalgia involves more than just pain has led to the frequent use of the term "fibromyalgia syndrome". It is not contagious, and recent studies suggest that people with fibromyalgia may be genetically predisposed. The disorder is not directly life-threatening. The degree of symptoms may vary greatly from day to day with periods of flares (severe worsening of symptoms) or remission; however, the disorder is generally perceived as non-progressive.

Signs and symptoms

The defining symptoms of fibromyalgia are chronic, widespread pain and tenderness to light touch. Other symptoms can include moderate to severe fatigue, a heightened and painful response to gentle touch (allodynia), needle-like tingling of the skin, muscle aches, prolonged muscle spasms, weakness in the limbs, nerve pain, functional bowel disturbances, and chronic sleep disturbances. Sleep disturbances may be related to a phenomenon called alpha-delta sleep, a condition in which deep sleep (associated with delta waves) is frequently interrupted by bursts of alpha waves, which normally occur during wakefulness. Slow-wave sleep is often dramatically reduced.

Many patients experience cognitive dysfunction (known as "brain fog" or "fibrofog"), which may be characterized by impaired concentration, problems with short genitourinary symptoms and interstitial cystitis), dermatological disorders, headaches, myoclonic twitches, and symptomatic hypoglycemia. Although fibromyalgia is classified based on the presence of chronic widespread pain, pain may also be localized in areas such as the shoulders, neck, low back, hips, or other areas. Many sufferers also experience varying degrees of facial pain and have high rates of comorbid temporomandibular joint disorder. Not all patients have all symptoms.

Symptoms can have a slow onset, and many patients have mild symptoms beginning in childhood, that are often misdiagnosed as growing pains. Symptoms are often aggravated by unrelated illness or changes in the weather. They can become more tolerable or less tolerable throughout daily or yearly cycles; however, many people with fibromyalgia find that, at least some of the time, the condition prevents them from performing normal activities such as driving a car or walking up stairs. The disorder does not cause inflammation as is characteristic of rheumatoid arthritis, although some non-steroidal anti-inflammatory drugs may temporarily reduce pain symptoms in some patients. Their use, however, is limited, and often of little to no value in pain management.

Variability of symptoms

The following factors have been proposed to exacerbate symptoms of pain in patients:

• Increased psychosocial stress
• Excessive physical exertion (exercise seems to decrease the pain threshold of people with fibromyalgia but increase it in healthy individuals)
• Lack of slow-wave sleep
• Changes in humidity and barometric pressure

Causes

The cause of fibromyalgia is unknown. Fibromyalgia can, but does not always, 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

Fibromyalgia may exhibit a modest genetic component; if one pair of an identical twin has chronic widespread pain, there is a a 15% chance their twin will as well; the risk is only 7% for fraternal twins.

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. Stress can alter the function of the HPA axis and change cortisol levels in the body, leading to widespread pain .

A non-mainstream hypothesis that fibromyalgia may be a psychosomatic illness has been described by John E. Sarno's "tension myositis syndrome", which hypothesizes that chronic pain is caused by the mind's subconscious strategy of distracting painful or dangerous emotions. Education, attitude change, and in some cases, psychotherapy are proposed as treatments.

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.

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).

Comorbidity

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 (or trauma) that likely served to "trigger" the fibromyalgia in the first place. 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.

A large percentage of chronic fatigue syndrome patients are reported to develop fibromyalgia between onset and the second year of illness. Other possible triggers are gluten sensitivity and/or irritable bowel. Irritable bowel is found at high frequency in fibromyalgia, and a large support group survey of adult celiacs revealed that 9% had fibromyalgia.

Dopamine abnormality

Dopamine is a catecholamine neurotransmitter perhaps best known for its role in the pathology of schizophrenia, Parkinson's disease and addiction. There is also strong evidence for a role of dopamine in restless leg syndrome, which is a common co-morbid condition in patients with fibromyalgia. In addition, dopamine plays a critical role in pain perception and natural analgesia. Accordingly, musculoskeletal pain complaints are common among patients with Parkinson's disease, which is characterized by drastic reductions in dopamine owing to neurodegeneration of dopamine-producing neurons, while patients with schizophrenia, which is thought to be due (in part) to hyperactivity of dopamine-producing neurons, have been shown to be relatively insensitive to pain. 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 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; fibromyalgia is associated with stress, chronic exposure to stress results in a disruption of dopamine-related neurotransmission and 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.

In support of the dopamine hypothesis of fibromyalgia, a reduction in dopamine synthesis has been reported by a study that used positron emission tomography (PET) and demonstrated a reduction in dopamine synthesis among fibromyalgia patients in several brain regions in which dopamine plays a role in inhibiting pain perception, including the mesencephalon, thalamus, insular cortex and anterior cingulate cortex. A subsequent PET study demonstrated that, whereas healthy individuals release dopamine into the caudate nucleus and putamen during a tonic experimental pain stimulus (i.e. hypertonic saline infusion into a muscle bed), fibromyalgia patients fail to release dopamine in response to pain and, in some cases, actually have a reduction in dopamine levels during painful stimulation. Moreover, a substantial subset of fibromyalgia patients respond well in controlled trials to pramipexole, a dopamine agonist that selectively stimulates dopamine D2/D3 receptors and is used to treat both Parkinson's disease and restless legs syndrome.

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.

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' posits 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.

Diagnosis is made with a specialized technique called mapping, a gentle palpitation of the muscles to detect lumps and areas of spasm thought to be caused by an excess of calcium in the cytosol of the cells. The mapping technique is notably different from the manual tenderpoint examination upon which a diagnosis of fibromyalgia depends and is purportedly different from the detection of trigger points that characterize the myofascial pain syndrome.

While this hypothesis does not identify the causative mechanism in the kidneys, it proposes a treatment known as guaifenesin therapy. This treatment involves administering the drug guaifenesin to a patient's individual dosage, avoiding salicylic acid in medications or on the skin. Often products for salicylate sensitivity are very helpful. If the patient is also hypoglycemic, a diet is designed to keep insulin levels low.

The phosphate build-up hypothesis explains many of the symptoms present in fibromyalgia.and 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.

Pathophysiology

Diagnosis

There is still debate over what should be considered essential diagnostic criteria. The most widely accepted set of classification criteria for research purposes were elaborated in 1990 by the Multicenter Criteria Committee of the the American College of Rheumatology. These criteria, which are known informally as "the ACR 1990" define fibromyalgia according to the presence of the following criteria:

• A history of widespread pain lasting more than three months—affecting all four quadrants of the body, i.e., both sides, and above and below the waist.
• Tender points—there are 18 designated possible tender or trigger points (although a person with the disorder may feel pain in other areas as well). During diagnosis, four kilograms-force (39 newtons) of force is exerted at each of the 18 points; the patient must feel pain at 11 or more of these points for fibromyalgia to be considered. Four kilograms of force is about the amount of pressure required to blanch the thumbnail when applying pressure. This set of criteria was developed by the American College of Rheumatology as a means of classifying an individual as having fibromyalgia for both clinical and research purposes. While these criteria for classification of patients were originally established as inclusion criteria for research purposes and were not intended for clinical diagnosis, they have become the de facto diagnostic criteria in the clinical setting. It should be noted that the number of tender points that may be active at any one time may vary with time and circumstance.

Prevention

Treatment

As with many other syndromes, there is no universally accepted cure for fibromyalgia, though some physicians claim to have found cures. However, a steady interest in the disorder on the part of academic researchers as well as pharmaceutical interests has led to improvements in its treatment, which ranges from symptomatic prescription medication to alternative and complementary medicine.

The European League Against Rheumatism (EULAR) issued the first guidelines for the treatment of fibromyalgia syndrome (FMS) and published them in the September 17th On-line First issue of the Annals of the Rheumatic Diseases.

Pharmaceutical

Analgesics

A number of analgesics are used to treat the pain symptoms resulting from fibromyalgia. This includes NSAID medications over the counter, COX-2 inhibitors, and tramadol in prescription form for more advanced cases. Recently, pregabalin (marketed as Lyrica) has been given FDA approval for the treatment of diagnosed fibromyalgia.

Muscle relaxants

Muscle relaxants, such as cyclobenzaprine (Flexeril) or tizanidine (Zanaflex), may be used to treat the muscle pain associated with the disorder.

Tricyclic antidepressants

Traditionally, low doses of sedating antidepressants (e.g. amitriptyline and trazodone) have been used to reduce the sleep disturbances that are associated with fibromyalgia and are believed by some practitioners to alleviate the symptoms of the disorder. Because depression often accompanies chronic illness, these antidepressants may provide additional benefits to patients suffering from depression. Amitriptyline is often favoured as it can also have the effect of providing relief from neuralgenic or neuropathic pain. It is to be noted that Fibromyalgia is not considered a depressive disorder; antidepressants are used for their sedating effect to aid in sleep.

Selective serotonin reuptake inhibitors

Research data consistently contradict the utility of agents with specificity as serotonin reuptake inhibitors for the treatment of core symptoms of fibromyalgia. Moreover, SSRIs are known to aggravate many of the comorbidities that commonly affect patients with fibromyalgia including restless legs syndrome and sleep bruxism.

Anti-seizure medication

Anti-seizure drugs are also sometimes used, such as gabapentin and pregabalin (Lyrica). Pregabalin, originally used for the nerve pain suffered by diabetics, has been approved by the American Food and Drug Administration for treatment of fibromyalgia. A randomized controlled trial of pregabalin 450 mg/day found that a number needed to treat of 6 patients for one patient to have 50% reduction in pain.

Dopamine agonists

Dopamine agonists (e.g. pramipexole (Mirapex) and ropinirole(ReQuip)) have been studied for use in the treatment of fibromyalgia with good results. A trial of transdermal rotigotine is currently on going .

Combination therapy

A controlled clinical trial of amitriptyline and fluoxetine demonstrated utility when used in combination.

Central nervous system stimulants

Cognitive dysfunction in fibromyalgia, often referred to as "brain fog," may be treated with low doses of central nervous system (CNS) stimulants such as modafinil, adderall or methylphenidate. These non-amphetamine stimulants are also used to treat the chronic fatigue that is characteristic of fibromyalgia.

Stimulants may be habit forming and can have other serious side effects, so it is important to note that other treatments may be effective. Care should be taken with any prescription, as people with fibromyalgia are known to be sensitive to medications.

Cannabis and cannabinoids

Fibromyalgia patients frequently self-report using cannabis therapeutically to treat symptoms of the disorder. Writing in the July 2006 issue of the journal Current Medical Research and Opinion, investigators at Germany's University of Heidelberg evaluated the analgesic effects of oral THC (∆9-tetrahydrocannabinol) in nine patients with fibromyalgia over a 3-month period. Subjects in the trial were administered daily doses of 2.5 to 15 mg of THC, but received no other pain medication during the trial. Among those participants who completed the trial, all reported a significant reduction in daily recorded pain and electronically induced pain. Previous clinical and preclinical trials have shown that both naturally occurring and endogenous cannabinoids hold analgesic qualities, particularly in the treatment of cancer pain and neuropathic pain, both of which are poorly treated by conventional opioids. As a result, some experts have suggested that cannabinoid agonists would be applicable for the treatment of chronic pain conditions unresponsive to opioid analgesics such as fibromyalgia, and they propose that the disorder may be associated with an underlying clinical deficiency of the endocannabinoid system.

Non-drug treatment

Physical treatments

Studies have found exercise improves fitness and sleep and may reduce pain and fatigue in some people with fibromyalgia. Many patients find temporary relief by applying heat to painful areas. Those with access to physical therapy, massage, or acupuncture may find them beneficial. Most patients find exercise, even low intensity exercise to be extremely helpful. Osteopathic manipulative therapy can also temporarily relieve pain due to fibromyalgia.

A holistic approach—including managing diet, sleep, stress, activity, and pain—is used by many patients. Dietary supplements, massage, chiropractic care, managing blood sugar levels, and avoiding known triggers when possible means living as well as it is in the patient's power to do.

Psychological/behavioral therapies

As the nature of fibromyalgia is not well understood, some physicians believe that it may be psychosomatic or psychogenic. Although there is no universally accepted cure, some doctors have claimed to have successfully treated fibromyalgia when a psychological cause is accepted.

Cognitive behavioral therapy has been shown to improve quality of life and coping in fibromyalgia patients and other sufferers of chronic pain. Reviews of the research indicate that the physiological effect of monosodium glutamate is overstated. There are few other studies linking diet and the disease.

Investigational treatments

Milnacipran, a serotonin-norepinephrine reuptake inhibitor (SNRI), is available in parts of Europe where it has been safely prescribed for other disorders. On May 22nd, 2007, a Phase III study demonstrated statistically significant therapeutic effects of Milnacipran as a treatment of fibromyalgia syndrome. At this time, only initial top-line results are available and further analyses will be completed in the coming weeks. If ultimately approved by the FDA, Milnacipran could be distributed in the United States as early as summer, 2008.

Among the more controversial therapies involves the use of guaifenesin; called St. Amand's protocol or the guaifenesin protocol the efficacy of guaifenesin in treating fibromyalgia has not been proven in properly designed research studies. Indeed, a controlled study conducted by researchers at Oregon Health Science University in Portland failed to demonstrate any benefits from this treatment, and the lead researcher has suggested that the anecdotally reported benefits where due to placebo suggestion. The results of the study have since been contested by Dr St. Amand, who was a co-author or the original research report.

Dextromethorphan is an over-the-counter cough medicine with activity as an NMDA receptor antagonist. It has been used in the research setting to investigate the nature of fibromyalgia pain; however, there are no controlled trials of safety or efficacy in clinical use.

Prognosis

Fibromyalgia can affect every aspect of a person's life. While neither degenerative nor fatal, the chronic pain associated with fibromyalgia is pervasive and persistent. FMS can severely curtail social activity and recreation, and as many as 30% of those diagnosed with fibromyalgia are unable to maintain full-time employment. Like others with disabilities, individuals with FMS often need accommodations to fully participate in their education or remain active in their careers.

In the United States, those who are unable to maintain a full-time job due to the condition may apply for Social Security Disability benefits. Although fibromyalgia has been recognized as a genuine, severe medical condition by the government, applicants are often denied benefits, since there are no formal diagnostic criteria or medically provable symptoms.

In the United Kingdom, the Department for Work and Pensions recognizes fibromyalgia as a condition for the purpose of claiming benefits and assistance.

Epidemiology

Fibromyalgia is seen in about 2% of the general population and affects more females than males, with a ratio of 9:1 by ACR criteria. It is most commonly diagnosed in individuals between the ages of 20 and 50, though onset can occur in childhood.

History

Fibromyalgia has been studied since the early 1800s and referred to by a variety of former names, including muscular rheumatism and fibrositis. The term fibromyalgia was coined in 1976 to more accurately describe the symptoms, from the Latin fibra (fiber) and the Greek words myo (muscle) and algos (pain).

Dr. Muhammad B. Yunus, considered the father of the modern view of fibromyalgia, published the first clinical, controlled study of the characteristics of fibromyalgia syndrome in 1981. Yunus' work validated the known symptoms and tender points that characterise the condition, and proposed data-based criteria for diagnosis. In 1984, Yunus proposed the interconnection between fibromyalgia syndrome and other similar conditions, and in 1986 demonstrated the effectiveness of serotonergic and norepinephric drugs. Yunus later emphasized the "biopsychosocial perspective" of fibromyalgia, which synthesized the contributions of genes, personal and medical history, stress, posttraumatic and mood disorders, coping skills, self-efficacy of pain management and social support towards the functioning and dysfunctioning of the central nervous system in relation to pain and fatigue. an observation that has led to the proposition that current diagnostic criteria are insufficient to differentiate patient groups from each other. Alternatively, there is evidence for the existence of differing pathophysiological processes within the greater fibromyalgia construct, which may be interpreted to represent evidence for the existence of biologically distinct "sub-types" of the disorder akin to conditions such as epilepsy, schizophrenia and major depressive disorder. In a January 14, 2008 article in the New York Times, the controversy of the reality of the disease and its proposed cures are discussed, while citing that the American College of Rheumatology, the Food and Drug Administration and insurers recognize fibromyalgia as a diagnosable disease. Drug companies are aggressively pursuing fibromyalgia treatments, seeing the potential for a major new market.

References

Further reading

• Fibromyalgia for Pharmacists, a medication guide

External links

• American College of Rheumatology Fibromyalgia factsheet
• Living with Fibromyalgia, First Drug Approved at US Food and Drug Administration
• Questions and Answers About Fibromyalgia by the National Institute of Arthritis and Musculoskeletal and Skin Diseases