Evidence from research conducted the last three decades has revealed abnormalities within the central nervous system affecting brain regions that may be linked both to clinical symptoms and research phenomena.[8] These studies show a correlation, but not causation.[11] Some research suggests that alterations in the central nervous system might be the result of childhood stress, or prolonged or severe stress.[8]
Historically, fibromyalgia has been considered either a musculoskeletal disease or neuropsychiatric condition. Although there is as yet no cure for fibromyalgia, some treatments have been demonstrated by controlled clinical trials to be effective in reducing symptoms, including medications, behavioral interventions, patient education, and exercise.[12][13][14][15][16][17] The most recent approach of a diagnosis of fibromyalgia involves pain index and a measure of key symptoms and severity. [18]
Fibromyalgia is considered a controversial diagnosis, due to lacking scientific consensus to its cause.[19] Not all members of the medical community consider fibromyalgia a disease because of a lack of abnormalities on physical examination and the absence of objective diagnostic tests.[11][19][20]
Signs and symptoms The defining symptoms of fibromyalgia are chronic, widespread pain, fatigue, and heightened pain in response to tactile pressure (allodynia). Other symptoms may include tingling of the skin, prolonged muscle spasms, weakness in the limbs, nerve pain, muscle twitching, palpitations[21], functional bowel disturbances,[3] and chronic sleep disturbances.[22]
Many patients experience cognitive dysfunction[6] (known as "brain fog" or "fibrofog"), which may be characterized by impaired concentration,[23] problems with short[23][7] and long-term memory, short-term memory consolidation,[7] impaired speed of performance,[23][7] inability to multi-task, cognitive overload,[23][7] and diminished attention span. Fibromyalgia is often associated with anxiety, and depressive symptoms.[7]
Causation hypotheses The cause of fibromyalgia is currently unknown. However, several hypotheses have been developed including "central sensitization". This theory proposes that fibromyalgia patients have a lower threshold for pain because of increased sensitivity in the brain to pain signals. [26]
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.[27][28] The mode of inheritance is currently unknown, but it is most probably polygenic.[29] Research has also demonstrated that fibromyalgia is potentially associated with polymorphisms of genes in the serotoninergic,[30] dopaminergic[31] and catecholaminergic systems.[32] However, these polymorphisms are not specific for fibromyalgia and are associated with a variety of allied disorders (e.g. chronic fatigue syndrome,[33] irritable bowel syndrome[34]) and with depression.[35]
Stress Stress may be an important precipitating factor in the development of fibromyalgia.[36] Fibromyalgia is frequently comorbid with stress-related disorders such as chronic fatigue, posttraumatic stress disorder, irritable bowel syndrome and depression[8]. Two studies that employed single-voxel magnetic resonance spectroscopy (1H-MRS) reported metabolic abnormalities within the hippocampal complex in patients with fibromyalgia. As the hippocampus plays crucial roles in maintenance of cognitive functions, sleep regulation, and pain perception, it was suggested that metabolic dysfunction of the hippocampus may be implicated in the appearance of these symptoms.[37][38]
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.[39]
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. Insufficient dopamine in a part of the body is termed hypodopaminergia. Dopamine is a catecholamineneurotransmitter with roles in pain perception and natural analgesia. There is also strong evidence for a role of dopamine in restless leg syndrome,[40] which is a condition found frequently in patients with fibromyalgia.[41] 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.[42]
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.[22] In 1992, decreased serotonin metabolites in patient blood samples[43] and cerebrospinal fluid were reported.[44] 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.[45] In controlled trials funded by Eli Lily, Duloxetine (Cymbalta), an SNRI originally used to treat depression and painful diabetic neuropathy, was demonstrated to relieve fibromyalgia symptoms in some women, however male subjects failed to improve significantly.[46] . The Food and Drug Administration regulators approved the drug for the treatment of fibromyalgia in June 2008[47]. However, the relevance of dysregulated serotonin metabolism to pathophysiology is a matter of debate.[48] 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.[49]
Deficient growth hormone (GH) secretion Levels of hormones under the direct or indirect control of growth hormone (GH), including IGF-1, cortisol, leptin and neuropeptide Y may be abnormal in people with fibromyalgia,[50] 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".[51] There is disagreement about the role of HGH in fibromyalgia.[52][53][54][55]
Psychological factors There is strong evidence that major depression is associated with fibromyalgia[56], 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.[57] 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 indicates that the amplification of the sensory dimension of pain in fibromyalgia occurs independently of mood or emotional processes.[58]
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.[59]
Other hypotheses have been proposed. One of these is an aberrant immune response to intestinal bacteria.
Psychological/behavioural therapies Cognitive behavioural therapy (CBT) and related psychological/behavioral therapies are evidence-based treatments which have shown to be moderately effective in randomized controlled trials.[99] The greatest benefit occurs when CBT is used along with exercise.[12][100] Some physicians believe fibromyalgia may be psychosomatic or psychogenic.[101] Accordingly, some doctors say they have successfully treated fibromyalgia when the patient accepts a psychological cause.[102]
Pharmaceutical Some medications have reduced symptoms in some patients, but the results of pharmacological interventions must be weighed against side effects. In review in the 2009 Journal of Rheumatology, fibromyalgia researcher H.A. Smythe writes, “patients receive some benefit, but when side effects make the patient dull, lethargic, or fat, neither their goals nor those of society are satisfactorily met”.[103]
Antidepressants A 2009 meta-analysis in the Journal of the American Medical Association reported that some antidepressants were effective, but with small effect sizes, against pain, fatigue, sleep disturbance, and depression in fibromyalgia. The analysis found “strong evidence against a favorable effect of antidepressants on fatigue”.[104] 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)[105] 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.[106] 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.[107] 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.”[108]