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Fibromyalgia (new lat., fibro-, fibrous tissue, Gk. myo-, muscle, Gk. algos-, pain), meaning muscle and connective tissue pain (also referred to as FM or FMS), is a disorder classified by the presence of chronic widespread pain and a heightened and painful response to pressure (allodynia). Other core symptoms are debilitating fatigue, sleep disturbance, and joint stiffness. Other symptoms include difficulty with swallowing, bowel and bladder abnormalities, numbness and tingling (paresthesia), and cognitive dysfunction. An increased prevalence of affective- and anxiety-disorders is also well known. Because fibromyalgia involves more than just pain, the term "fibromyalgia syndrome" is often used. However, not all affected persons experience all associated symptoms.

While historically considered either a musculoskeletal disease or neuropsychiatric condition, evidence from research conducted in the last three decades has demonstrated abnormalities within the central nervous system affecting brain regions that may be linked both to clinical symptoms and research phenomena. Despite these abnormalities, fibromyalgia might be the result of childhood stress or prolonged or severe stress rather than a primary disorder of the brain. There is no recognized cure for fibromyalgia, but some treatments have been demonstrated by controlled clinical trials to be effective in reducing symptoms, including medications, patient education, exercise, and behavioral interventions.

Fibromyalgia is a controversial diagnosis. Many members of the medical community consider fibromyalgia a ‘non-disease’ because of a lack of abnormalities on physical examination, the absence of objective diagnostic tests, and extensive overlap with other proposed conditions like chronic fatigue syndrome and multiple chemical sensitivity. Although several brain imaging studies have show evidence for possible neurological differences in fibromyalgia and healthy controls, these studies may show only correlation, not causation, and fibromyalgia might be the result of childhood stress or prolonged or severe stress rather than a primary disorder of the brain.

Signs and symptoms

The defining symptoms of fibromyalgia are chronic, widespread pain, fatigue, and heightened pain in response to pressure (allodynia). Other symptoms may include tingling of the skin, prolonged muscle spasms, weakness in the limbs, nerve pain, functional bowel disturbances, and chronic sleep disturbances.

Many patients experience cognitive dysfunction (known as "brain fog" or "fibrofog"), which may be characterized by impaired concentration, problems with short and long-term memory, short-term memory consolidation, impaired speed of performance, inability to multi-task, cognitive overload, diminished attention span, anxiety, and depressive symptoms.

Other symptoms often attributed to fibromyalgia that may possibly be due to a comorbid disorder include myofascial pain syndrome also referred to as Chronic Myofascial Pain, diffuse non-dermatomal paresthesias, functional bowel disturbances and irritable bowel syndrome (possibly linked to lower levels of ghrelin, 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.

An epidemiology study consisting of an internet-based survey of 2,596 people with fibromyalgia reported that the most frequently cited factors perceived to worsen fibromyalgia symptoms were emotional distress (83%), weather changes (80%), sleeping problems (79%), strenuous activity (70%), mental stress (68%), worrying (60%), car travel (57%), family conflicts (52%), physical injuries (50%) and physical inactivity (50%). Other factors included infections, allergies, lack of emotional support, perfectionism, side effects of medications, and chemical exposures.

Causation hypotheses

The cause of fibromyalgia is currently unknown. However, several hypotheses have been developed.

Genetic predisposition

There is evidence that genetic factors may play a role in the development of fibromyalgia. For example, there is a high aggregation of fibromyalgia in families. The mode of inheritance is currently unknown, but it is most probably polygenic. Research has demonstrated that fibromyalgia is associated with polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems. However, these polymorphisms are not specific for fibromyalgia and are associated with a variety of allied disorders (e.g. chronic fatigue syndrome, irritable bowel syndrome) and with depression.

Stress-induced pathophysiology

Studies have shown that stress is a significant precipitating factor in the development of fibromyalgia. Accordingly, it has been proposed that fibromyalgia may result from stress-induced changes in the function and integrity of the hippocampus. This proposition was based in part on the observation that preclinical studies in non-human primates have shown that exposure to psychosocial duress results in material changes to the very tissues of the brain, including atrophic and metabolic changes in the hippocampal complex. Evidence in support of this hypothesis have been generated by two studies that employed single-voxel magnetic resonance spectroscopy (1H-MRS) to demonstrate metabolic abnormalities within the hippocampal complex in patients with fibromyalgia with significant correlations between hippocampal metabolic abnormalities and severity of clinical symptoms.

Other authors have proposed that, because exposure to stressful conditions can alter the function of the hypothalamic-pituitary-adrenal (HPA) axis, the development of fibromyalgia may stem from stress-induced disruption of the HPA axis. This proposition is supported in part by a prospective epidemiology study which found that variations in HPA function characterized by high levels of circulating cortisol following dexamethasone suppression testing, low levels of morning salivary cortisol and high levels of evening salivary cortisol are all associated with the development of chronic widespread pain.

Central dopamine dysfunction (hypodopaminergia)

The 'dopamine hypothesis of fibromyalgia’ proposes that the central abnormality responsible for symptoms associated with fibromyalgia is a disruption of normal dopamine-related neurotransmission. Dopamine is a catecholamine neurotransmitter with roles in pain perception and natural analgesia. There is also strong evidence for a role of dopamine in restless leg syndrome, which is a condition found frequently in patients with fibromyalgia. Some fibromyalgia patients responded 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 leg syndrome.

Abnormal serotonin metabolism

In 1975, researchers hypothesized that serotonin, a neurotransmitter that regulates sleep patterns, mood, concentration and pain, could be involved in the pathophysiology of fibromyalgia-associated symptoms. In 1992, decreased serotonin metabolites in patient blood samples and cerebrospinal fluid were reported. 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. 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. However, the relevance of dysregulated serotonin metabolism to pathophysiology is a matter of debate. Complicating the analysis, one of the more effective types of medication for the treatment of the disorder (i.e. serotonin 5-HT3 antagonists) actually blocks some of the effects of serotonin.

Deficient human growth hormone (HGH) secretion

Levels of hormones under the direct or indirect control of human growth hormone (HGH), including IGF-1, cortisol, leptin and neuropeptide Y may be abnormal in people with fibromyalgia, but supplementing growth hormone in patients does not have large effects, and a 2007 literature review reported a need for "further study before any solid recommendations can be made." There is disagreement about the role of HGH in fibromyalgia.

Psychological factors

There is strong evidence that major depression is associated with fibromyalgia, although the nature of the association is controversial. A comprehensive review into the relationship between fibromyalgia and major depressive disorder (MDD) found substantial similarities in neuroendocrine abnormalities, psychological characteristics, physical symptoms and treatments between fibromyalgia and MDD, but currently available findings do not support the assumption that MDD and fibromyalgia refer to the same underlying construct or can be seen as subsidiaries of one disease concept. Indeed, the sensation of pain has at least two dimensions: a sensory dimension which processes the magnitude of the pain, and an affective-motivational dimension which processes the unpleasantness. Accordingly, a study that employed functional magnetic resonance imaging to evaluate brain responses to experimental pain among fibromyalgia patients found that depressive symptoms were associated with the magnitude of clinically-induced pain response specifically in areas of the brain that participate in affective pain processing, but not in areas involved in sensory processing which indicate that the amplification of the sensory dimension of pain in fibromyalgia occurs independently of mood or emotional processes.

An alternative hypothesis regarding the development of fibromyalgia in relationship to psychological conflict proposes that the disorder may be a psychosomatic illness as described by John E. Sarno's writing related to "tension myositis syndrome," in which chronic pain is proposed to be a psychic diathesis of the mind's subconscious strategy of distracting painful or dangerous emotions. Education, attitude change, and in some cases, psychotherapy are proposed as treatments.

Other hypotheses

Other hypotheses have been proposed. One of these is an aberrant immune response to intestinal bacteria.

While there is, as yet, no cure for fibromyalgia, advances in the understanding of the pathophysiology of the disorder have led to improvements in treatment, which include prescription medication, behavioral intervention, exercise, and alternative and complementary medicine. Integrated treatment plans that incorporate medication, patient education, aerobic exercise and cognitive-behavioral therapy have been shown to be most effective at alleviating pain and other fibromyalgia-related symptoms. In 2005, the American Pain Society produced the first comprehensive guidelines for patient evaluation and management.

Pathophysiology

Sleep disturbances

The first objective findings associated with the disorder were reported in 1975 by Moldofsky and colleagues, who reported the presence of anomalous alpha wave activity (typically associated with arousal states) on sleep electroencephalogram (EEG) during non-rapid-eye-movement sleep. By disrupting stage IV sleep consistently in young, healthy subjects, the researchers reproduced a significant increase in muscle tenderness similar to that experienced in fibromyalgia but which resolved when the subjects were able to resume their normal sleep patterns. In 1995, additional EEG sleep abnormalities were reported in fibromyalgia patients.

Poly-modal sensitivity

Results from studies examining responses to experimental stimulation have shown that fibromyalgia patients display sensitivity to pressure, heat, cold, electrical and chemical stimulation. Experiments examining pain regulatory systems have shown that fibromyalgia patients also display a dysregulation of diffuse noxious inhibitory control, an exaggerated wind-up in response to repetitive stimulation, and an absence of exercise-induced analgesic response. Together these results point to dysregulation of the nociceptive system at the central level.

Neuroendocrine disruption

Patients with fibromyalgia have been demonstrated to have a disruption of normal neuroendocrine function, characterized by mild hypocortisolemia, hyperreactivity of pituitary adrenocorticotropin hormone release in response to challenge, and glucocorticoid feedback resistance. A progressive reduction of serum growth hormone levels has also been documented—at baseline in a minority of patients, while most demonstrate reduced secretion in response to exercise or pharmacological challenge. Other abnormalities include reduced responsivity of thyrotropin and thyroid hormones to thyroid-releasing hormone, a mild elevation of prolactin levels with disinhibition of prolactin release in response to challenge and hyposecretion of adrenal androgens. These changes might be attributed to the effects of chronic stress, which, after being perceived and processed by the central nervous system, activates hypothalamic corticotrophin-releasing hormone neurons. Thus, the multiple neuroendocrine changes evident in fibromyalgia have been proposed to stem from chronic overactivity of corticotropin-releasing hormone releasing neurons, resulting in a disruption of normal function of the pituitary-adrenal axis and an increased stimulation of hypothalamic somatostatin secretion, which, in turn, inhibits the secretion of a multiplicity of other hormones.

Sympathetic hyperactivity

Functional analysis of the autonomic system in patients with fibromyalgia has demonstrated disturbed activity characterized by hyperactivity of the sympathetic nervous system at baseline with reduced sympathoadrenal reactivity in response to a variety of stressors including physical exertion and mental stress. Fibromyalgia patients demonstrate lower heart rate variability, an index of sympathetic/parasympathetic balance, indicating sustained sympathetic hyperactivity, especially at night. In addition, plasma levels of neuropeptide Y, which is co-localized with norepinephrine in the sympathetic nervous system, have been reported as low in patients with fibromyalgia, while circulating levels of epinephrine and norepinephrine have been variously reported as low, normal and high. Administration of interleukin-6, a cytokine capable of stimulating the release of hypothalamic corticotropin-releasing hormone which in turn stimulates activity within the sympathetic nervous system, results in a dramatic increase in circulating norepinephrine levels and a significantly greater increase in heart rate over baseline in fibromyalgia patients as compared to healthy controls.

Cerebrospinal fluid abnormalities

The most reproduced laboratory finding in patients with fibromyalgia is an elevation in cerebrospinal fluid levels of substance P, a putative nociceptive neurotransmitter. Metabolites for the monoamine neurotransmitters serotonin, norepinephrine, and dopamine—all of which play a role in natural analgesia—have been shown to be lower, while concentrations of endogenous opioids (i.e., endorphins and enkephalins) appear to be higher. The mean concentration of nerve growth factor, a substance known to participate in structural and functional plasticity of nociceptive pathways within the dorsal root ganglia and spinal cord, is elevated. There is also evidence for increased excitatory amino acid release within cerebrospinal fluid, with a correlation demonstrated between levels for metabolites of glutamate and nitric oxide and clinical indices of pain.

Brain imaging studies

Evidence of abnormal brain involvement in fibromyalgia has been provided via functional neuroimaging. The first findings reported were decreased blood flow within the thalamus and elements of the basal ganglia and mid-brain (i.e., pontine nucleus). Differential activation in response to painful stimulation has also been demonstrated. Brain centers showing hyperactivation in response to noxious stimulation include such pain-related brain centers as the primary and secondary somatosensory cortex, anterior cingulate cortex and insular cortex, while relative hypoactivation at subjectively equal pain levels appears to occur within the thalamus and basal ganglia. Patients also exhibit neural activation in brain regions associated with pain perception in response to nonpainful stimuli in such areas as the prefrontal, supplemental motor, insular, and cingulate cortices. Evidence of hippocampal disruption indicated by reduced brain metabolite ratios has been demonstrated by studies using single-voxel magnetic resonance spectroscopy (1H-MRS). A significant negative correlation was demonstrated between abnormal metabolite ratios and a validated index of the clinical severity (i.e. the Fibromyalgia Impact Questionnaire). Correlations between clinical pain severity and concentrations of the excitatory amino acid neurotransmitter glutamate within the insular cortex have also been demonstrated using 1H-MRS. An acceleration of normal age-related brain atrophy has been demonstrated using voxel-based morphometry (VBM) with areas of reduced gray matter located in the cingulate cortex, insula and parahippocampal gyrus. Studies utilizing positron emission tomography have demonstrated reduced dopamine synthesis in the brainstem and elements of the limbic cortex. A significant negative correlation between pain severity and dopamine synthesis was demonstrated within the insular cortex. A subsequent study demonstrated gross disruption of dopaminergic reactivity in response to a tonic pain stimulus within the basal ganglia with a significant positive correlation between the defining feature of the disorder (i.e. tender point index) and dopamine D2 receptor binding potential specifically in the right putamen. Finally, reduced availability of mu-opioid receptors in the ventral striatum/nucleus accumbens and cingulate cortex has been demonstrated, with a significant negative correlation between affective pain levels and receptor availability in the nucleus accumbens.

Diagnosis

There is still debate over what should be considered essential diagnostic criteria. The difficulty with diagnosing fibromyalgia is that, in most cases, laboratory testing appears normal and that many of the symptoms mimic those of other rheumatic conditions such as arthritis or osteoporosis. In general, most doctors diagnose patients with a process called differential diagnosis, which means that doctors consider all of the possible things that might be wrong with the patient based on the patient's symptoms, gender, age, geographic location, medical history and other factors. They then narrow down the diagnosis to the most likely one. The most widely accepted set of classification criteria for research purposes was 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.

Treatment

While there is, as yet, no cure for fibromyalgia, advances in the understanding of the pathophysiology of the disorder have led to improvements in treatment, which include prescription medication, behavioral intervention, exercise, and alternative and complementary medicine. Integrated treatment plans that incorporate medication, patient education, aerobic exercise and cognitive-behavioral therapy have been shown to be most effective at alleviating pain and other fibromyalgia-related symptoms. In 2005, the American Pain Society produced the first comprehensive guidelines for patient evaluation and management.

Pharmaceutical

Antidepressants

A 2009 meta analysis in the Journal of the American Medical Association reported that some antidepressants were effective, but with small effect sizees, against pain, fatigue, sleep disturbance, and depression in fibromyalgia. The analysis found “strong evidence against a favorable effect of antidepressants on fatigue.” The authors conclude that the goal of antidepressants in fibromyalgia should be, at most, a “possible symptom reduction,” and the results must be balanced against side effects. Tricyclic antidepressants were the most effective against pain, fatigue, and sleep problems, but have many side effects due to interaction with adrenergic, cholinergic or histaminergic receptors, and sodium channels. Selective serotonin reuptake inhibitors (SSRIs) and Serotonin-norepinephrine reuptake inhibitors (SNRIs) had lower effects.

Anti-seizure medication

The anti-seizure drugs gabapentin (Neurontin) and pregabalin (Lyrica) have been tested. Gabapentin is approved for use in treatment of neuropathic pain but not fibromyalgia. Pregabalin, originally labeled for the treatment of nerve pain suffered by diabetics, has been cleared by the US Food and Drug Administration for treatment of fibromyalgia. A randomized controlled trial of pregabalin 450 mg/day found that 6 patients is the number needed to treat for one patient to have a 50% reduction in pain. A Cochrane Database analysis of pregabalin use in chronic pain concluded that “A minority of patients will have substantial benefit with pregabalin, and more will have moderate benefit. Many will have no or trivial benefit, or will discontinue because of adverse events.”

Dopamine agonists

Dopamine agonists (e.g. pramipexole (Mirapex) and ropinirole (ReQuip) resulted in some improvement in a minority of patients, but numerous side effects, including the onset of impulse control disorders like compulsive gambling and shopping, have led to concern about this approach. A trial of transdermal rotigotine is currently ongoing.

Investigational medications

Investigational medications include cannabinoids and the 5-HT3 receptor antagonist tropisetron. A controlled study of guaifenesin failed to demonstrate any benefits from this controversial 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 and Chiropractic manipulative therapy can also temporarily relieve pain due to fibromyalgia.

Psychological/behavioural therapies

Cognitive behavioural therapy has been shown to alleviate fibromyalgic symptoms, although it is not curative. The greatest benefit occurs when CBT is used along with exercise. Self-management techniques such as pacing and stress management may also be helpful for some patients. Because the nature of fibromyalgia is not well understood, some physicians believe that it may be psychosomatic or psychogenic. Accordingly, some doctors have claimed to have successfully treated fibromyalgia when a psychological cause is accepted.

Prognosis

Although neither degenerative nor fatal, the chronic pain of fibromyalgia is pervasive and persistent. Most fibromyalgia patients report that their symptoms do not change over time. An evaluation of 332 consecutive new fibromyalgia patients found that, out of 15 factors, pain levels, self-assessed inability to work, psychological distress, pending litigation, helplessness, level of education, and coping ability had a significant and independent association with symptom severity and function.

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

Many names, including “muscular rheumatism,” “fibrositis,” “psychogenic rheumatism,” and “neurasthenia” were applied historically to symptoms resembling those of fibromyalgia. The term fibromyalgia was coined in 1976 from the Latin fibra (fiber) and the Greek words myo (muscle) and algos (pain).

Historical perspectives on the development of the fibromyalgia concept note the “central importance” of a 1977 paper by Smythe and Moldofsky on fibrositis. The first clinical, controlled study of the characteristics of fibromyalgia syndrome was published in 1981, providing support for symptom associations. In 1984, an interconnection between fibromyalgia syndrome and other similar conditions was proposed, and in 1986, trials of the first proposed medications for fibromyalgia were published.

A 1987 article in the Journal of the American Medical Association used the term "fibromyalgia syndrome" while saying it was a "controversial condition." The American College of Rheumatology (ACR) published its first classification criteria for fibromyalgia in 1990, although these are not strictly diagnostic criteria.

Controversies

Fibromyalgia continues to be a disputed diagnosis. Many members of the medical community consider fibromyalgia a ‘non-disease’ because of a lack of abnormalities on physical examination, the absence of objective diagnostic tests, and extensive overlap with other proposed conditions like chronic fatigue syndrome.

Several controversial issues exist with regard to fibromyalgia that range from questions regarding the validity of the disorder as a clinical entity, to issues regarding primary pathophysiology and the potential existence of fibromyalgia subtypes.

According to Frederick Wolfe, the most-cited fibromyalgia researcher and lead author of the 1990 paper that first defined the ACR fibromyalgia classification criteria, “the large majority of physicians, sociologists, and medical historians” are skeptical about the validity of fibromyalgia as a clinical entity. Some call fibromyalgia a “non-disease” and “an over-inclusive and ultimately meaningless label.” Wolfe now questions the validity of fibromyalgia as a disease. He considers fibromyalgia a physical response to stress, depression, and economic and social anxiety, and believes the associated symptoms are a normal part of everyday life. In 2009, he wrote, "the tendency to respond with distress to physical and mental stressors is part of the human condition." Wolfe and other opponents of the fibromyalgia concept say that labeling fibromyalgia as a "disease" simply legitimizes patients’ sickness behavior, slowing their recovery and harming them.

In a study of 100 individuals identified as having fibromyalgia, physical functioning decreased significantly over time, and individuals who had been diagnosed earlier had larger numbers of reported symptoms and greater severity. However, there was also a statistically significant improvement in satisfaction with health following classification. The authors of the study concluded that the ‘fibromyalgia label’ does not have a meaningful adverse affect on clinical outcome over the long term. It is however possible that these results can be accounted for by Regression toward the mean.

The validity of fibromyalgia as a unique clinical entity is also a matter of contention because "no discrete boundary separates syndromes such as FMS, chronic fatigue syndrome, irritable bowel syndrome, or chronic muscular headaches." Because of considerable symptomatic overlap, some researchers believe that fibromyalgia and other medically unexplained syndromes should be referred to collectively as functional somatic syndromes.

Some researchers believe that differences in psychological and autonomic nervous system profiles among affected individuals may indicate the existence of fibromyalgia subtypes. A 2007 review divides individuals with fibromyalgia into four groups as well as “mixed types”:

1. “extreme sensitivity to pain but no associated psychiatric conditions” (may respond to medications that block the 5-HT3 receptor)
2. “fibromyalgia and comorbid, pain-related depression” (may respond to antidepressants)
3. “depression with concomitant fibromyalgia syndrome” (may respond to antidepressants)
4. “fibromyalgia due to somatization” (may respond to psychotherapy).

See also

• Living With Fibromyalgia, documentary film

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External links

• Fibromyalgia Topics A-Z from the National Fibromyalgia Association
• Fibromyalgia Professional Resource Center from the National Fibromyalgia Association
• Fibromyalgia Continuing Medical Education Program FAME Project, Unihealth Foundation grant
• American College of Rheumatology Fibromyalgia factsheet
• Living with Fibromyalgia: Two Drugs Approved at US Food and Drug Administration
• Questions and Answers About Fibromyalgia by the National Institute of Arthritis and Musculoskeletal and Skin Diseases
• Template:Dmoz
• Arthritis - Types - Fibromyalgia by the CDC
• Fibromyalgia Treatment Guidelines Published by US Department of Health & Human Resources

• Rheumatology
• Diseases involving the fasciae
• Syndromes
• Ailments of unknown etiology