Fibromyalgia

Fibromyalgia (new Latin, fibro-, fibrous tissues, Gk. myo-, muscle, Gk. algos-, pain, meaningmuscle and connective tissue pain; also referred to as FM or FMS) is a medical disordercharacterized by chronic widespread pain and allodynia, a heightened and painful response to pressure.^[1] Fibromyalgia symptoms are not restricted to pain, leading to the use of the alternative term fibromyalgia syndrome for the condition. Other symptoms include debilitatingfatigue, sleep disturbance, and joint stiffness. Some patients^[2] may also report difficulty with swallowing,^[3] bowel and bladder abnormalities,^[4] numbness and tingling,^[5] and cognitive dysfunction.^[6] Fibromyalgia is frequently comorbid with psychiatric conditions such asdepression and anxiety and stress-related disorders such as posttraumatic stress disorder.^[7][8]Not all people with fibromyalgia experience all associated symptoms.^[9] Fibromyalgia is estimated to affect 2–4% of the population,^[7] with a female to male incidence ratio of approximately 9:1.^[10]

Evidence from research conducted in 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 orneuropsychiatric 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]

Contents  [hide] 1 Signs and symptoms 2 Causation hypotheses 2.1 Genetic predisposition 2.2 Stress 2.3 Dopamine dysfunction (hypodopaminergia) 2.4 Abnormal serotonin metabolism 2.5 Deficient growth hormone (GH) secretion 2.6 Psychological factors 2.7 Physical trauma 2.8 Other hypotheses 3 Pathophysiology 3.1 Sleep disturbances 3.2 Poly-modal sensitivity 3.3 Neuroendocrine disruption 3.4 Sympathetic hyperactivity 3.5 Cerebrospinal fluid abnormalities 3.6 Brain imaging studies 4 Diagnosis 5 Treatment 5.1 Psychological/behavioural therapies 5.2 Pharmaceutical 5.2.1 Antidepressants 5.2.2 Anti-seizure medication 5.2.3 Dopamine agonists 5.2.4 Muscle relaxants 5.2.5 Opioids 5.3 Investigational medications 5.4 Physical treatments 6 Costs of fibromyalgia 7 Prognosis 8 Epidemiology 9 History 10 Controversies 11 See also 12 References 13 External links

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^[7][23] and long-term memory, short-term memory consolidation,^[7] impaired speed of performance,^[7][23]inability to multi-task, cognitive overload,^[7][23] and diminished attention span. Fibromyalgia is often associated with anxiety, and depressivesymptoms.^[7]

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^[24]), 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. 20–30% of patients with rheumatoid arthritis andsystemic lupus erythematosus may also have fibromyalgia.^[25]

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 catecholamine neurotransmitter 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 painfuldiabetic 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

Controversial theories propose that fibromyalgia is a psychosomatic illness.^[56] There is strong evidence that major depression is associated with fibromyalgia,^[57] although the nature of the association is debated. 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.^[58] Indeed, the sensation of pain has at least two dimensions: a sensory dimension which processes the magnitude and location 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.^[59]

Physical trauma

Neck trauma seems to increase the risk of developing fibromyalgia.^[60]

Other hypotheses

Other hypotheses have been proposed. One of these is an aberrant immune response to intestinal bacteria.^[61]

Pathophysiology

Sleep disturbances

In 1975, Moldofsky and colleagues reported the presence of anomalous alpha wave activity (typically associated with arousal states) measured by electroencephalogram (EEG) during non-rapid eye movement sleep of "fibrositis syndrome" patients.^[22] By disrupting stage IV sleep consistently in young, healthy subjects, the researchers reproduced a significant increase in muscle tenderness similar to that experienced in "neurasthenic musculoskeletal pain syndrome" but which resolved when the subjects were able to resume their normal sleep patterns.^[62]

Poly-modal sensitivity

Results from studies examining responses to experimental stimulation suggest that fibromyalgia patients may have heightened sensitivity of the nociceptive system, which senses pressure, heat, cold, electrical and chemical stimulation.^[63] Experiments examining pain regulatory systems have shown that fibromyalgia patients display an exaggerated wind-up in response to repetitive stimulation^[64] and an absence of exercise-induced analgesic response.^[65]

Neuroendocrine disruption

Patients with fibromyalgia may have alterations of normal neuroendocrine function, characterized by mild hypocortisolemia,^[66] hyperreactivity of pituitary adrenocorticotropin hormone release in response to challenge, and glucocorticoid feedback resistance.^[67] Low insulin-like growth factor 1 (IGF-1) levels in some fibromyalgia patients have led to the theory that these patients may actually have a different, treatable syndrome, adult growth hormone deficiency.^[68] Other abnormalities include reduced responsivity of thyrotropin and thyroid hormones to thyroid-releasing hormone,^[69] a mild elevation of prolactin levels with disinhibition of prolactin release in response to challenge^[70] and hyposecretion of adrenal androgens.^[71]

These changes might result from chronic stress, which, after being perceived and processed by the central nervous system, activates hypothalamic corticotrophin-releasing hormone neurons. Chronic overactivity of these neurons could disrupt normal function of the pituitary-adrenal axis and cause an increased stimulation of hypothalamic somatostatin secretion, which, in turn, could inhibit the secretion of other hormones.^[72]

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^[73] with reduced sympathoadrenal reactivity in response to a variety of stressors including physical exertion and mental stress.^[74][75] Fibromyalgia patients demonstrate lower heart rate variability, an index of sympathetic/parasympathetic balance, indicating sustained sympathetic hyperactivity, especially at night.^[76] 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,^[50] while circulating levels of epinephrine and norepinephrine have been variously reported as low, normal and high.^[77][78]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.^[79]

Cerebrospinal fluid abnormalities

One of the most reproduced laboratory finding in patients with fibromyalgia is an elevation in cerebrospinal fluid levels of substance P, a putative nociceptive neurotransmitter.^[80][81][82] Metabolites for the monoamine neurotransmitters serotonin, norepinephrine, and dopamine—all of which play a role in natural analgesia—have been shown to be lower,^[44] while concentrations of endogenous opioids (i.e., endorphins and enkephalins) appear to be higher.^[83] 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.^[84] 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.^[85]

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).^[86][87] Differential activation in response to painful stimulation has also been demonstrated.^[88][89] Brain centers showing hyperactivation in response to noxious stimulation include such pain-related brain centers as the primary and secondary somatosensory cortices, anterior cingulate cortex, andinsular cortex. 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).^[37][38] A significant negative correlation was demonstrated between abnormal metabolite ratios and a validated index of the clinical severity (i.e. the Fibromyalgia Impact Questionnaire).^[90] Correlations between clinical pain severity and concentrations of the excitatory amino acid neurotransmitterglutamate within the insular cortex have also been demonstrated using 1H-MRS.^[91] 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. Grey matter loss appears to increase 9.5 times the normal rate with each year.^[92] Studies utilizing positron emission tomography have demonstrated reduced dopamine synthesis in the brainstem and elements of the limbic cortex.^[93] 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.^[94] 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.^[95]

Diagnosis

There is no one test that fully shows if someone has fibromyalgia. There is still debate over what should be considered essential diagnostic criteria and whether objective diagnosis is possible. 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 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 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.^[96] Four kilograms of force is about the amount of pressure required to blanch the thumbnail when applying pressure.

The ACR criteria for classification of patients were originally established as inclusion criteria for research purposes and were not intended for clinical diagnosis but have now 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. A controversial study done by a legal team looking to prove their client's disability based primarily on tender points and their widespread presence in non-litigious communities prompted the lead author of the ACR criteria to now question the useful validity of tender points in diagnosis.^[97] Since the ACR criteria were originally published, research with mechanical devices that exert defined pressure indicate that diagnosis of fibromyalgia cannot be done objectively by machine and require a physician's subjective estimate of how much pressure should be exerted.

Treatment

As with many other medically unexplained syndromes, there is no known cure or universally accepted treatment for fibromyalgia, and treatment is typically aimed at symptom management. Developments 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. Indeed, integrated treatment plans that incorporate medication, patient education, aerobic exercise and cognitive-behavioral therapy have been shown to be effective in alleviating pain and other fibromyalgia-related symptoms.^[12] In 2005, the American Pain Society produced comprehensive guidelines for patient evaluation and management.^[98] More recently, the European League Against Rheumatism (EULAR) issued updated treatment guidelines.^[99]

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.^[100] The greatest benefit occurs when CBT is used along with exercise.^[12][101]

Pharmaceutical

There are three medications that have been approved by the FDA for treatment of Fibromyalgia. Lyrica was approved in June, 2007, Cymbaltawas approved in June, 2008, and Milnacipran was approved in January, 2009.^[102] Cymbalta and Lyrica were shown to reduce pain in a substantial number of patients with fibromyalgia, but there were others who didn't benefit.^[102]

Antidepressants

A 2009 meta-analysis in the Journal of the American Medical Association concluded that antidepressants were "associated with improvements in pain, depression, fatigue, sleep disturbances, and health-related quality of life in patients with FMS." ^[103] The authors also stated that the goal of antidepressants in fibromyalgia should be “possible symptom reduction”, and if used long term, their effects should be evaluated 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 side effects.

Anti-seizure medication

The anti-seizure drugs gabapentin (Neurontin)^[104] 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.^[105] 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.^[106] 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.”^[107]

Dopamine agonists

Dopamine agonists (e.g. pramipexole (Mirapex) and ropinirole (ReQuip) resulted in some improvement in a minority of patients,^[42] but numerous side effects, including the onset of impulse control disorders like compulsive gambling and shopping, have led to concern about this approach.^[108] A trial of transdermal rotigotine is currently ongoing.^[109]

Muscle relaxants

Cyclobenzaprine is a muscle relaxant medication used to relieve skeletal muscle spasms and associated pain in acute musculoskeletal conditions. It is the most well-studied drug for this application,^[110] and it also has been used off-label for fibromyalgia treatment.^[111]

Tizanidine (brandnames Zanaflex, Sirdalud) is a muscle relaxant centrally acting α-2 adrenergic agonist. It is used to treat the spasms, cramping, and tightness of muscles caused by medical problems such as multiple sclerosis, spastic diplegia, back pain, or certain other injuries to the spine or central nervous system. It is also prescribed off-label for some symptoms of fibromyalgia.^[112]

Opioids

According to a 2004 review of fibromyalgia treatment studies, there is moderate evidence to support the effectiveness of Tramadol by itself or combined with acetaminophen, although the long-term effectiveness and tolerability are unknown. The review also stated that opioids other than Tramadol have not had random controlled trials, and "should be considered only after all other medicinal and nonmedicinal therapies have been exhausted".^[113] Other opioids are widely used by fibromyalgia patients despite a lack of clinical trials and the potential for addiction and abuse. An analysis of insurance claims by 52,000 fibromyalgia patients showed that 40% had received opioids in any given year, predominantly short-acting agents.^[114]

Investigational medications

Investigational medications include cannabinoids and the 5-HT3 receptor antagonist tropisetron.^[115] A controlled study of guaifenesin failed to demonstrate any benefits from this treatment.^[116][117]

Physical treatments

Exercise improves fitness and sleep and may reduce pain and fatigue in some people with fibromyalgia.^[118][119] In particular, there is strong evidence that cardiovascular exercise is effective for some patients.^[113] Chiropractic care of fibromyalgia lacks scientific evidence^[120] and treatment is not currently supported.^[121]

Costs of fibromyalgia

Patients with fibromyalgia have higher health care costs and utilization. A study of almost 20,000 Humana members enrolled in Medicare Advantage and commercial plans compared costs and medical utilizations and found that persons with fibromyalgia used twice as much pain-related medication as those without fibromyalgia. Furthermore, the use of medications and medical necessities increased markedly across many measures once diagnosis was made.^[122]

Prognosis

Although in itself neither degenerative nor fatal, the chronic pain of fibromyalgia is pervasive and persistent. Most fibromyalgia patients report that their symptoms do not improve over time. An evaluation of 332 consecutive new fibromyalgia patients found that disease-related factors such as pain and psychological factors such as work status, helplessness, education, and coping ability had an independent and significant relationship to FM symptom severity and function.^[123]

Epidemiology

Fibromyalgia is seen in about 2% of the general population^[124] and affects more females than males, with a ratio of 9:1 by ACR criteria.^[125]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.^[126] The term fibromyalgia was coined by researcher Mohammed Yunus as a synonym for fibrositis and was first used in a scientific publication in 1981.^[127] Fibromyalgia is from the Latin fibra (fiber)^[128] and the Greek words myo(muscle)^[129] and algos (pain).^[130]

Historical perspectives on the development of the fibromyalgia concept note the “central importance” of a 1977 paper by Smythe and Moldofsky on fibrositis.^[11][131] The first clinical, controlled study of the characteristics of fibromyalgia syndrome was published in 1981,^[132]providing support for symptom associations. In 1984, an interconnection between fibromyalgia syndrome and other similar conditions was proposed,^[133] and in 1986, trials of the first proposed medications for fibromyalgia were published.^[133]

A 1987 article in the Journal of the American Medical Association used the term "fibromyalgia syndrome" while saying it was a "controversial condition".^[134] The American College of Rheumatology (ACR) published its first classification criteria for fibromyalgia in 1990,^[1] although these are not strictly diagnostic criteria.^[135]

Controversies

Fibromyalgia continues to be a disputed diagnosis. Many members of the medical community do not consider fibromyalgia a disease because of a lack of abnormalities on physical examination, and the absence of objective diagnostic tests.^[11][19]

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, highly 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"^[11] are skeptical about the validity of fibromyalgia as a clinical entity.^[136] Some call fibromyalgia a “non-disease”^[19] and “an over-inclusive and ultimately meaningless label.”^[137] Wolfe now questions the validity of fibromyalgia as a disease. He considers fibromyalgia a physical response to stress, depression, and economic and social anxiety,^[138] 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."^[139] Wolfe notes that opponents of the fibromyalgia concept say that labeling fibromyalgia as a "disease" simply legitimizes patients’ sickness behavior, slowing their recovery and harming them.^[19]

In a study of 100 individuals identified as having fibromyalgia, physical functioning decreased slightly 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.^[140] The authors of the study concluded that the ‘fibromyalgia label’ does not have a meaningful adverse effect on clinical outcome over the long term.

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."^[113][141] Because of this considerable symptomatic overlap, some researchers have proposed that fibromyalgia and other syndromes with overlapping symptoms be classified as functional somatic syndromes for some purposes.^[142]

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”:^[135]

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).

Other researchers have suggested that depression may be a result of coping with the disabling impacts of a, thus far, incurable disease.