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Fibromyalgia: from pathophysiology to therapy

Tobias Schmidt-Wilcke and Daniel J. Clauw
Abstract | Individuals with fibromyalgia generally experience chronic widespread pain, which can be accompanied by further symptoms including fatigue, sleep disturbances, cognitive dysfunction, anxiety and depressive episodes. As the recognition and diagnosis of fibromyalgia has improved, the availability of therapeutic options for patients has increased. Furthermore, research into the neurobiological mechanisms that contribute to the chronic pain and concomitant symptoms experienced by patients with fibromyalgia has advanced our understanding of this debilitating disorder. In this Review, we aim to provide an overview of existing pathophysiological concepts. The roles of biological and psychological stress, genetic factors, and pain and sensory processing in the pathophysiology of fibromyalgia and related conditions are discussed. In addition, pharmacological treatments, including monoamine modulators, calcium channel modulators and aminobutyric acid modulators, as well as nonpharmacological treatment options are considered.
Schmidt-Wilcke, T. & Clauw, D. J. Nat. Rev. Rheumatol. 7, 518527 (2011); published online 19 July 2011; doi:10.1038/nrrheum.2011.98

Introduction
Fibromyalgia is characterized by chronic widespread pain (CWP) and is generally accompanied by one or more concomitant symptoms including fatigue, sleep disturbances, cognitive dysfunction, anxiety and/or depressive episodes. 1,2 Considerable overlap exists in both the symptoms and the pathophysiological mechanisms between fibromyalgia and other central pain or functional somatic syndromes, such as irritable bowel syndrome (IBS), interstitial cystitis/painful bladder syndrome, chronic pelvic pain, and temporomandibular joint disorder,3,4 as well as a number of psychiatric disorders, such as depression and anxiety.57 The widespread nature of the pain in fibromyalgia, as well as the low pain thresholds and concomitant symptoms suggest that the central nervous system (CNS) is the primary organ system responsible for the most protean manifestations.8,9 In fact, augmented pain and sensory processing (which are consistently identified via experimental pain testing and functional neuroimaging) are firmly established as contributing to both fibromyalgia and many if not most chronic pain states. This entire spectrum of pain-related illness is better thought of as a biological continuum rather than a series of unconnected syndromes. Indeed, Wolfe and others have shown that the degree of fibromyalgianess, as measured by the widespread nature of pain as well as the presence of comorbid symptoms, is predictive of pain, fatigue, and functional status in nearly all individuals with chronic pain that is attributable to
Competing interests D.J. Clauw declares associations with the following companies: Cypress Bioscience, Eli Lilly and Company, Forest Laboratories, Jazz Pharmaceuticals, Johnson & Johnson, Merck, Nuvo Research, Pfizer, Pierre Fabre Mdicament, Procter & Gamble, and Wyeth Pharmaceuticals. See the article online for full details of the relationships. T. SchmidtWilcke declares no competing interests.

rheumatic disorders.1013 Improved understanding and appreciation of the pathophysiology and treatment of fibromyalgia, therefore, might lead to a better understanding regarding the pathogenesis of pain and other symptoms in nearly any rheumatic disorder. The new (preliminary) American College of Rheumatology (ACR) diagnostic criteria for fibromyalgia, put forth in 2010, allow for the diagnosis of fibromyalgia without a tender point examination, and acknowledge that, in addition to pain, other core symptoms of fibromyalgia include fatigue, unrefreshing sleep and/or cognitive symptoms.14 These new diagnostic guidelines differ from the 1990 ACR criteria (Box1), which required that an individual had both a history of CWP and at least 11 of 18 possible tender points on physical examination.2 Since women are innately more tender than men, the exclusion of the tender point examination from the new diagnostic criteria and the increased emphasis on core symptoms is expected to define far more males as having fibromyalgia than the older criteria. On the basis of the 1990 diagnostic criteria, the prevalence of fibromyalgia is approximately 25% in all populations studied,1518 although the prevalence based on the new criteria is yet to be determined.

Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48106, USA (T.Schmidt-Wilcke, D.J.Clauw). Correspondence to: T. Schmidt-Wilcke tobiass@ med.umich.edu

Pathophysiology of fibromyalgia
Stress and stressors Fibromyalgia can be triggered by a variety of stressors, and for some time fibromyalgia has been assumed to be a stress-related illness. Although this assumption might be justified, the relationship between stress and fibro myalgia is complicated. Indeed, if fibromyalgia can be defined as a stress-related illness, then so can most chronic painstates.19 The question of whether or not stress is a risk factor for fibromyalgia depends on the level and type of stress
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(that is, biological versus psychological stress), and even then only weakly so. Population-based studies showed that individuals with high levels of distress (psychological stress), but without pain, are approximately twofold more likely to develop CWP within the next year as those without psychological distress.20,21 Thus, the relative risk is high, but the absolute risk remains low, and so most individuals that newly develop fibromyalgia do not have prior symptoms of distress. The odds ratio of approximately two is similar to the relative risk of developing fibromyalgia that is attributable to being distressed in a number of other longi tudinal studies.22,23 Overall, having psychologically stressful events in early life, such as the death of a parent, prolonged hospitalization, or being involved in a motor traffic accident, each increase the risk of developing CWP by 50100% in later life.24 In addition to psychological stress, many types of biological stress are associated with the development of fibromyalgia and related conditions. Indeed, 510% of individuals exposed to certain types of infections (for example, Lyme disease, EpsteinBarr virus, parvovirus or Q fever) develop CWP, and infections in other regions of the body can also trigger chronic regional pain. Similarly, 1015% of individuals with acute gastro i ntestinal infections (for example, with Campylobacter spp. , Salmonellaspp. or Shigella spp.) subsequently develop IBS.25 Further more, fibromyalgia or regional chronic pain can be triggered by surgical procedures, deployment to military service, or being involved in physical trauma such as motor vehicle accidents.19,2630 The established link between exposure to stressors and the development of fibromyalgia has led to extensive research into human stress systems in this condition. These studies have generally shown alterations in the hypothalamicpituitary adrenal (HPA) axis and the sympathetic nervous system in fibromyalgia and related conditions,3134 although the findings vary from study to study.
Key points
Fibromyalgia is characterized by chronic widespread pain and is often accompanied by one or more concomitant symptoms including fatigue, sleep disturbances, cognitive dysfunction, anxiety and/or depressive episodes New diagnostic criteria for fibromyalgia have been put forth, both in the USA and in Europe, which do not require the presence of tender points Several risk factors for the development of fibromyalgia, such as certain types of stress, genetic polymorphisms and familial predisposition, have been identified; however, the underlying etiology and pathophysiology remains to be fully elucidated Emerging evidence suggests that both an early and aberrant activation of the pain system, as well as an impaired antinociceptive system, contribute to the development of clinical pain Current treatment recommendations include both pharmacological and nonpharmacological therapies Understanding of, treatment options for and social acceptance of fibromyalgia have improved over the past decade, but fibromyalgia remains a scientific and clinical challenge

Box 1 | Comparison of the 1990 and 2010 diagnostic criteria for fibromyalgia2,14 Criteria for diagnosis of fibromyalgia Fulfillment of the 1990 criteria requires a history of widespread pain for 3months and pain in 11 of 18 specified sites (tender points). By contrast, the 2010 preliminary criteria stipulate that a patients symptoms must meet or exceed thresholds for WPI and SS scale scores (a higher SS scale score is required if the WPI score is intermediate), symptoms are present at a similar level for 3months, and the patient does not have a disorder that would otherwise explain the pain. Definition of widespread pain By the 1990 criteria, pain is considered widespread when present in all of the following: left side of the body, right side of the body, above the waist, and below the waist; axial skeletal pain (that is, pain in the cervical spine, anterior chest, thoracic spine or low back) must also be present. The WPI used in the 2010 criteria provides a score between 0 and 19 that correlates to the number of anatomical areas in which the patient has had pain over the week prior to assessment; these areas include the upper back, lower back, neck, chest and abdomen, and the left and right shoulder girdles, hips, jaws, upper arms, lower arms, upper legs and lower legs. Tender points As mentioned above, central to the 1990 diagnostic criteria is the presence of pain upon digital palpation in 11 of 18 stipulated sites, whereas tender points are not included in the provisional 2010 criteria. Symptom severity scale SS is not included in the 1990 criteria, but in the 2010 provisional criteria is scored as the sum of the severity of fatigue, waking unrefreshed, cognitive symptoms and somatic symptoms, each of which is measured on a 03 scale to give a final score of between 0 and 12.
Abbreviations: SS, symptom severity; WPI, widespread pain index.

Augmented pain and sensory processing The most established underlying pathologic mechanism in fibromyalgia and many other chronic pain states is centrally mediated augmentation of pain and sensory processeswhich exists even in the absence of identifiable psychological factors. Because tender points have been traditionally thought of as a clinical indicator of lowered pain thresholds, they are the measure of tenderness that has been most often assessed in fibro myalgia. However, studies have shown that individuals with fibromyalgia are diffusely tender in all bodily regions (tender points are merely regions where everyone is more tender), even when experimental pain testing paradigms are used that minimize or eliminate the potential role of psychological factors (for example, hypervigilance or expectancy).35,36 Patients with fibromyalgia have also been noted to be more responsive to nearly any type of stimuli, including heat, cold, electrical stimuli and hypertonic saline infusion.37,38 Interestingly, other studies have shown that patients with fibromyalgia display sensitivity to a number of other sensory modalities, such as
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the brightness of light or the loudness of auditory tones, suggesting that fibromyalgia might be associated with a global problem in sensory processing rather than a sp ecific abnormality in pain processing.39 Experimental pain testing has identified attenuated descending analgesic activity as at least one potential reason for the widespread pain sensitivity (that is, diffuse hyperalgesia) in individuals with fibromyalgia (Figure1) . The application of an intense painful stimulus
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a
Inhibition of sensory/nociceptive processing Descending antinociceptive pathways Norepinephrine (2) Serotonin (5HT1a,b) Dopamine Opioids GABA Cannabinoids Adenosine Facilitation of sensory/nociceptive processing Substance P Glutamate and EAA Serotonin (5HT2a,3b) Nerve growth factor CCK Descending inhibitory pathway Ascending nociceptive pathway

Peripheral nociceptive input

Low levels of inhibitory neurotransmitters

Increased levels of neurotransmitters that augment pain transmission in the spine and brain Deficient descending analgesia Hyperalgesia

Attenuation of nociceptive system

Serotonin and norepinephrine reuptake inhibitors

2 ligands

Figure 1 | Pathways of pain processing implicated in chronic pain and fibromyalgia. a | CNS neurotransmitters that are known to either facilitate or inhibit sensory/pain transmission are shown. As indicated by the arrows, the levels of several of these neurotransmitters are either decreased or increased in patients with fibromyalgia. b | Augmented pain processing in fibromyalgia is attributable to an imbalance of several neutrotransmitters that determine the volume control on pain processing. Low levels of inhibitory neurotransmitters might lead to an attenuated antinociceptive system, whereas serotoninnorepinephrine reuptake inhibitors might work to increase antinociceptive activity. Levels of neurotransmitters that augment pain transmission, such as substance P , glutamate/EAA and nerve growth factor, are increased in fibromyalgia, and probably contribute to increased activity in ascending pain transmission pathways. 2 ligands might be working to decrease the release of excitatory neurotransmitters. Abbreviations: 5-HT, 5hydroxytryptamine; CCK, cholecystokinin; CNS, central nervous system; DNIC, diffuse noxious inhibitory control; EAA, excitatory amino acids; GABA, aminobutyric acid. Figure 1a adapted with permission from Elsevier Schmidt-Wilcke, T. & Clauw, D.J. Pharmacol. Ther. 127, 283294 (2010).105

in a healthy individual produces an increase in the pain thresholds in body regions remote from the initial site of nociceptive stimulation, an effect also known as diffuse noxious inhibitory control (DNIC). This analgesic effect has consistently been observed to be attenuated in fibromyalgia, and is also known to be abnormal in other chronic pain states.4043 Interestingly, a decrease in DNIC is not seen in patients with major depressive disorder,44 suggesting that a deficit in pain inhibition is specific to chronic pain states such as fibromyalgia. The DNIC response relies on descending antinociceptive systems (such as the opioidergic and noradrenergic serotonergic systems among others) projecting from the brainstem to the spine and regulating peripheral nociceptive input to the dorsal horn. These systems are in turn under the control of various forebrain structures such as the anterior cingulate cortex, amygdala and frontopolar cortex.45,46 A certain amount of nociceptive signaling (via Cfibers and A-fibers), therefore, might be suppressed at the spinal level in healthy individuals,
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but gain access to the brain in patients with fibromyalgia owing to impaired inhibitory control. Evidence from functional MRI has shown that individuals with fibromyalgia have increased neuronal activation in pain processing regions of the brain following the application of otherwise innocuous stimuli.37,47,48 Similar to the findings from experimental pain tests, these studies have shown that the augmented pain processing in sensory processing regions of the brain is largely independent of the presence of psychiatric factors such as depression.49 Furthermore, brain imaging studies have reported a hypoperfusion of the striatum and thalamus at rest,50 decreased dopamine binding in the striatum in response to experimental pain,51,52 as well as changes in brain structure in the cingulate cortex,53,54 insular cortex, 53,54 striatum 54,55 and thalamus 54,55 in patients with fibromyalgia. Collectively, these findings suggest that functional and morphological changes occur in the forebrain of individuals with fibromyalgia, especially in structures known to be involved in pain systems.
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Whether these changes follow an increased nociceptive input (possibly promoting the process of pain chronification), or whether they actually constitute the primary pathophysiology, remains to be determined. than in controls.74 Furthermore, it could be shown that fibromyalgia patients with a particular poly morphism in the D(3) dopamine receptor gene (which results in the highest receptor functioning) had the highest DNIC efficacy and the highest pain thresholds.75 Low levels or low activity of neurotransmitters such as serotonin, norepinephrine and dopamine, which are capable of altering sensory processing, might have a role in fibromyalgia (Figure1). Many of the neurotransmitters known to facilitate the transmission of pain in the CNS, such as substance P, glutamate and nerve growth factor, are increased in the cerebrospinal fluid of indivi duals with fibromyalgia, whereas levels of metabo lites of neuro transmitters that typically inhibit pain trans mission, such as serotonin, norepinephrine and dopamine, are reduced.7678 Paradoxically, encephalins have been shown to be elevated in patients with fibromyalgia.79 This finding is in line with the results of a PET study that showed decreased opioid receptor availability in the nucleus accumbens and cingulate gyrus in patients with fibro myalgia,80 demonstrating an increased baseline occupancy of opioid receptors. Elevated encephalin levels might result from an ongoing attempt to control nociception in fibromyalgia, and this might explain the anecdotal lack of benefit of exogenous opiate analgesics for fibromyalgia.

Genetics and CNS neurotransmitters Familial predisposition to fibromyalgia is an established phenomenonthe risk of developing fibromyalgia is eightfold higher for first-degree relatives of patients with fibromyalgia than for an unrelated individual. Indeed, family members also have a much higher risk of any type of chronic pain, and are more tender than the family members of control individuals.56 The rates of psychiatric co-morbidity are also high in relatives of patients with fibromyalgia, but this overall risk is approximately twofold compared with control individuals, whereas the excess rate of pain disorders is much higher. Twin studies have demonstrated that there are two somewhat indepen dent but overlapping sets of genetic traits; one related to pain and sensory sensitivity, and the other related to psychiatric comorbidity.5760 Current evidence suggests that genetic factors are responsible for at least 50% of overall sensitivity to experimental pain, and might also make individuals more likely to develop chronic pain over the course of their lifetime. These genetic factors include poly morphisms in genes encoding catecholamineO-methyl-transferase (COMT), a variety of sodium channels, GTP cyclo hydroxylase, and the KCNS potassium channel.6165 Specific genetic polymorphisms associated with an increased risk of developing fibromyalgia pertain to genes involved in serotonin and catecholamine metabolism. The short allele polymorphism in the regulatory region of SLC6A4 (the serotonin transporter [5HTT] gene) occurs more frequently in patients with fibro myalgia than in healthy individuals.66 Of note, the 5HTT gene polymorphism also frequently occurs in patients with depressive disorders, suggesting it to be a risk factor for both diseases.67 Furthermore, a polymorphism in the gene encoding COMT (resulting in a Val158Met polymorphism or a high pain sensitivity haplotype) has been of interest in fibromyalgia research, since it is also implicated in the pathogenesis of other pain syndromes. 68 To date, however, as with genetic findings in other diseases, reports of COMT gene haplotypes in fibromyalgia have been inconclusive.6972 Interestingly, apart from having a direct influence on pain, the role of dopamine (in relation to the COMT polymorphism) is now also discussed as possibly mediating the relationship between pain and daily (maladaptive) coping, suggesting that genetic variation affects pain in fibromyalgia through pathways of pain-related cognition. Polymorphisms of catecholamine receptors have also been investigated, and certain adrenergic receptor haplo types of the 2 and 1A receptor were reported to be more common in fibromyalgia patients as compared with healthy controls.73 With respect to dopamine receptors, a 7-repeat polymorphism in the third exon of the D(4) dopamine receptor gene was observed to occur significantly less frequently in patients with fibromyalgia
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Peripheral abnormalities Some studies have found mild abnormalities in the skeletal muscles of patients with fibromyalgia; however, inconsistencies in these findings are apparent, and such differences might be largely attributable to deconditioning rather than to the illness itself.8183 Nevertheless, small nerve fibers in the skin might be damaged in subsets of individuals with fibromyalgia, as has been seen in patients with other chronic pain conditions.84 Conflicting results have been reported from the use of 31P-spectroscopy to examine muscle metabolism in fibromyalgia; one study compared sedentary controls with fibromyalgia patients and found no differences, whereas another reported lower ATP levels in patients with fibromyalgia.85,86 Other studies suggest that the maintenance of central augmentation requires persistent noxious peripheral input, even in syndromes that are characterized by the absence of well-defined, localized, pain-causing lesions, such as fibromyalgia and IBS.87 A study of patients with fibro myalgia and either myofascial pain syndromes or regional joint pain showed that peripheral trigger point injections and hydroelectrophoresis both ameliorate fibromyalgia pain and increase pain thresholds at sites distant from the therapeutic interventions.88 These findings provide further evidence that painful peripheral stimuli may contribute to the perpetuation of centralaugmentation. The hypothesis that fibromyalgia, IBS and other central pain states are mild inflammatory diseasesan idea that has been in and out of favor over the years is currently being reconsidered, as it seems that some of the symptoms in fibromyalgia might be attributable to subtle inflammatory changes. For example, central
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sensitivity and chronic pain can be augmented in CNS glial cells by proinflammatory cytokine production. Observations such as these might challenge the dichotomic view that classifies pain as being either inflammatory or noninflammatory. as socioeconomic variables, the level of formal education and coping strategies) are known to be responsible for more of the variance in pain reporting and disability than biological factors (such as joint space width or erythrocyte sedimentation rate). 11,101 Subgroups of patients with fibromyalgia can be identified in whom differential psychological factors have a role in symptom expression, including those who seem to be psychologically resilient and whose psychological make-up could, therefore, be a positive factor that might buffer the functional effects of their symptoms.102,103 Functional MRI studies have investigated what influ ence comorbid mood disorders or an individuals thoughts about their pain might have on pain processing in fibromyalgia. One such study found that the level of depres sive symptomatology did not affect the degree of neu ronal activation in brain regions responsible for the sen sory intensity of painthe primary and secondary somatosensory corticesbut did influence neuronal activation in the affective pain processing regions of the brain, such as the amygdala and anterior insula.49 By contrast, another study with a similar methodology reported that the presence of catastrophizing was associated with increased neuronal activations in the sensory coding regions in patients with fibromyalgia.104 Collectively, these studies provide a compelling case for the use of cognitive behavioral therapy in fibromyalgia, especially if individuals exhibit cognitions such as catastrophizing that, independent of other factors, might be capable of increasing pain intensity.

Sleep and activity Disturbed sleep and poor physical function are common symptoms of fibromyalgia. Indeed, the observation that selective sleep deprivation in healthy individuals led to symptoms of fibromyalgia was one of the first biological findings in fibromyalgia and has been replicated by several groups.89,90 However, the electroencephalography abnormalities (termed intrusions) that were thought to be a marker for fibromyalgia in the original study are now known to be present in both healthy individuals and patients with other conditions. 91,92 Polysomnography studies in fibromyalgia demonstrated fewer sleep spindles, an increase in cyclic alternating pattern rate, upper airway resistance syndrome, and/or poor sleep efficiency in patients with fibromyalgia compared with healthy individuals.9395 Overall, no evidence suggests that individuals with suspected fibromyalgia should be screened for sleep disorders unless they have symptoms or risk factors that imply the presence of a sleep disorder. Psychiatric and psychological comorbidities Psychological and behavioral factors have a role in symptom expression in many patients with fibromyalgia, with 3060% experiencing psychiatric comorbidities in tertiary care settings; this rate increases when the rate of lifetime psychiatric disorders (commonly depression and anxiety) is considered.5,96,97 However, these rates might be artifactually elevated by virtue of the fact that most of these studies have been performed in tertiary care centers. By contrast, members of the general population who meet ACR criteria for fibromyalgia, and have not sought care in a tertiary setting, have a lower rate of identifiable psychiatric conditions.98,99 As already noted, the relationship between pain and distress is complex and distress can be both a cause and consequence of pain. In instances where distress is con sidered to be a consequence of pain, individuals with fibromyalgia display a decrease in their ability to undertake everyday roles in their work and family life. For example, relationships with spouses, children and work colleagues can prove difficult to distressed patients with fibro myalgia, a situation that can exacerbate their symptoms and lead to maladaptive illness behaviors, including isolation, cessation of pleasurable activities and reductions in activity and exercise. Indeed, patients who experience these psychiatric conditions can, in the worst cases, come to rely so heavily on disability and compensation systems that an improvement in the co ndition isunlikely.100 The complex interface of biological, psychological and behavioral mechanisms is not unique to fibromyalgia and has an important role in symptom expression in all rheumatic diseases. Indeed, non-biological factors in rheumatoid arthritis and osteoarthritis (such
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Therapy
Pharmacotherapy The number of drugs evaluated for the treatment of fibromyalgia has notably increased over the past decade. Approximately 40 substances have been investigated in that time,105 with a high variation between studies in quality, number of patients enrolled and primary end points. To date, three drugs have been approved by the FDA for the treatment of pain in fibromyalgia: pregabalin, which binds to the 2 subunit of a voltage-dependent, presynaptic calcium channel, and duloxetine and milnacipran, which selectively inhibit reuptake of serotonin and norepinephrine, respectively. A number of other categories of drugs hold promise as future treatments, and generally fall into one of the following categories: monoamine modulators, calcium channel modulators or aminobutyric acid (GABA) receptormodulators.
Monoamine modulators The efficacy of amitriptyline and cyclobenzaprine in treating not only pain, but also fatigue and poor sleep, in fibromyalgia is supported by several randomized controlled trials.106108 Both of these drugs have strong effects on the norepinephrine transporter and moderate effects on 5HTT,109 blocking the reuptake and subsequently increasing the intrasynaptic concentrations of these neurotransmitters. Selective serotonin reuptake inhibitors were found to be less efficacious than the tricyclic compounds or serotoninnorepinephrine compounds,110,111 suggesting
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a critical role for norepinephrine in the analge sic effect in fibromyalgia (and perhaps more broadly in pain). In multicenter trials, duloxetine and milnacipran were shown to be efficacious in a number of outcome variables in fibromyalgia, such as self-reported pain, stiffness, number of tender points, physical functioning and level of fatigue.112,113 Milnacipran treatment was also associated with a durability of improvement and long-term efficacy in fibromyalgia.114 Other mono amine modulators have either failed to demonstrate an over all efficacy (for example, dopamine receptor agonists115117) or are currently not recommended owing to possible severe side effects, such as serotonin syndrome and hypertensive crisis (for example, monoamine oxidase inhi bitors118). A trial published in 2010 also showed that a selective norepinephrine reuptake inhibitor, esreboxe tine, was effective in fibromyalgia, lending further sup port to the notion that norepinephrine is relatively more important than seroton in in the analgesic effects of these compounds.119
Calcium channel modulators Antiepileptic drugs, mainly the 2 calcium channel modulators, are widely used for the treatment of various chronic pain conditions, including postherpetic neuralgia and painful diabetic neuropathy.120 Pregabalin and gabapen tin have both been shown to reduce pain and sleep disturbances in patients with fibromyalgia, but these drugs had no effect on depressed mood.121,122 Both substances bind to the 2 subunit of a voltage- dependent, presynaptic-gated calcium channel and reduce the calcium influx at nerve terminals, probably acting in part by causing a decrease in the release of excitatory neurotransmitters, such as glutamate and substance P. GABA receptor modulators Sodium oxybate (-hydroxybutyric acid) has recently been demonstrated to simultaneously improve pain, fatigue and sleep architecture in several randomized con trolled trials in patients with fibromyalgia.123,124 Sodium oxybate acts as both a GABAB receptor and a hydroxybutyrate receptor agonist. This drug is approved by the FDA for the treatment of narcolepsy and cataplexy but is not likely to be approved for use in fibromyalgia because of safety concerns. Benzodiazepines are GABAA receptor agonists and have both sedative and anxio lytic effects. However, these agents have yielded mixed results in the treatment of fibromyalgia,125,126 and are not generally recommended owing to concerns of substance abuse and a reduction of sleep efficiency.
Initial symptoms of pain, fatigue, etc. Pharmacological therapies to improve symptoms

Function consequences of symptoms Distress Decreased activity Isolation Poor sleep Increased distress Maladaptive illness behaviors

Nonpharmacological therapies to address dysfunction

Figure 2 | Dually focused therapeutic approach to fibromyalgia. The optimum strategy for fibromyalgia management is one that combines the use of pharmacological and nonpharmacological therapies. This approach would be beneficial because nonpharmacological therapies can constitute a rehabilitation model that addresses the many consequences of longstanding pain that can lead to additional pain and other somatic symptoms. The overall outcome of the dually focused therapeutic approach, therefore, would be that pharmacological treatments alleviate the initial symptoms of pain, and nonpharmacological therapies address the functional consequences of the symptoms.

Nonpharmacological therapies Although nonpharmacological therapies for fibromyalgia, such as education, exercise and cognitive behav ioral therapy, have effect sizes that are equal to or exceed the effect sizes of drugs, these therapies are rarely used in current practice.127,128 There are many reasons for this low uptake of nonpharmacological treatments, including the fact that many clinicians do not strongly advocate these therapies, many insurers do not cover the cost of these services, and many patients would rather
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be prescribed a pill that fixes their symptoms. In addition to working well, these nonpharmacological treatments are likely to work on inherently different aspects of fibro myalgia, having more effect on the dysfunction associated with fibromyalgia than purely on symptomatic improvement(Figure2). To increase the use of nonpharmacological treatments, education programs (which are already broadly available) should be given to all patients newly diagnosed with fibromyalgia. The optimal management of fibromyalgia should replicate that of other chronic medical illnesses, using a patient-centric, disease management model. In this putative model, when a patient is newly diagnosed with fibromyalgia, they should receive education about the illness, the available treatments, and the role they must take in managing the condition. This education could occur in group lectures with patients and families, in a series of visits with mid-level providers and/or nurse educators, or by using other models that have been effective for other chronic illnesses. The importance of nonpharmacological therapies should be emphasized and clear expectations on the part of both the patient and the provider should be established. Furthermore, because education, exercise, and/or cognitive behavioral therapy are so inexpensive and effective, all patients diagnosed with fibromyalgia should receive some form of these nonpharmacological treatments.129,130 Research suggests that such therapies might be effective even when administered using minimal or no contact, for example via web-based or smartphone-based programs. Indeed, a randomized controlled trial reported that the use of a free website that educates patients with fibromyalgia on nonpharmacological treatments led to significant improvements in pain and functional status, with effect sizes comparable to those observed with drugs.131 There are few controlled studies that endorse alternative therapies for fibromyalgia, although trigger-point injections, chiropractic manipulation, acupuncture and myofascial release therapy have been explored by patients who decide to manage their own illness. One study showed that treating trigger points with injections in
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fibromyalgia patients with concomitant myofascial pain did lead to an overall improvement in their fibromyalgia symptoms, which is arguably the strongest evidence of the efficacy of this approach to date.88 Tai chi, yoga and a number of other therapies might also be effective,132 but these approaches need to be evaluated in larger studies. fibromyalgia is still lacking and it is likely that diverse mechanisms contribute differently to the clinical picture in individual patients. Although the pharmacological substances used in fibromyalgia are well characterized with respect to their mechanisms of action and binding sites, the exact location in the CNS where they exert their effects remains to be fully eluciated, both from an anatomical perspective and with respect to receptor subtypes. It is not surprising, therefore, that no reliable tools to predict treatment response in individual patients yet exist, and clinical routine largely relies on trial and error. The effect of any single drug examined in groups of individuals is modest, a phenomenon that is no different from analgesics tested in other chronic pain statesNSAIDs and opioids have comparably modest efficacy in conditions such as osteoarthritis or chronic low back pain.136 This situation stresses the need for combined pharmaco therapies and the incorporation of pharmaco therapy into a broader program of education (and other nonpharmaco logical therapies), in addition to sub classification of the fibromyalgia syndrome with the goal of tailored treatment approaches. Furthermore, the majority of individuals with fibromyalgia have unmet needs other than widespread pain, including mood disorders, dyscognitive symptoms, sexual dysfunction and a lack of sociomedical acceptance; aspects that have a deep effect on quality of life and that need to be addressed by future research. As such, fibromyalgia remains a scientif ic and clinical challenge.

Prognosis
The prognosis of fibromyalgia depends largely on where the individual falls on a continuum. On one end of the continuum are individuals in the population who have chronic widespread pain who have not yet sought medical care, or individuals with fibromyalgia that are seen in primary care; the prognosis in these individuals can be quite good.133,134 On the other hand, patients with fibromyalgia seen in tertiary care settings tend to have a poor prognosis, with one study reporting little change in fibromyalgia symptoms over time, and no change in health satisfaction or functional disability.135 All of the studies examining outcomes in patients with fibromyalgia, however, were performed before the approval of pregabalin, duloxetine and milnacipran by the FDA, and before substantial scientific advances in our understanding of this condition. These rapid changes have improved the overall acceptance and recog nition of fibromyalgia, and are likely to be accompanied by improvements in outcomes. Outcomes will be further improved as new drugs are identified that block other molecular targets, and when more clinicians integrate nonpharmacological approaches into their therapeuticarmamentarium.

Conclusions
In this Review, we have aimed to provide an overview of some important aspects of epidemiology, pathophysio l ogy and treatment options in fibromyalgia. Genetic and psychophysiological research, as well as brain imaging and drug trials, have improved both our under standing of the underlying pathophysiology of fibromyalgia and the current treatment options. It must be noted, however, that an overall unifying concept of
1. Bennett, R.M., Jones, J., Turk, D.C., Russell, I.J. & Matallana, L. An internet survey of 2,596 people with fibromyalgia. BMC Musculoskelet. Disord. 8, 27 (2007). Wolfe, F. etal. The American College of Rheumatology criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 33, 160172 (1990). Dadabhoy, D. & Clauw, D.J. Therapy Insight: fibromyalgiaa different type of pain needing a different type of treatment. Nat. Clin. Pract. Rheumatol. 2, 364372 (2006). Huser, W., Trp, J.C., Lempa, M., Wesselmann,U. & Derra, C. Functional somatic pain syndromesnomenclature [German]. Schmerz 18, 98103 (2004). Hudson, J.I., Hudson, M.S., Pliner, L.F., Goldenberg D.L. & Pope, H.G. Jr. Fibromyalgia and major affective disorder: a controlled phenomenology and family history study. Am. J. Psychiatry 142, 441446 (1985). 6.

Review criteria
We searched PubMed for original articles focusing on fibromyalgia published between 1985 and 2010. The combinations of search terms used were fibromyalgia and epidemiology, fibromyalgia and pathophysiology, and fibromyalgia and therapy. Given the large number of publications identified and space restrictions of this article, we selected a subset of articles for inclusion in this Review on the basis of conceptual influence and study quality.

2.

3.

4.

5.

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