nature rev rheumatol - fibromyalgia - from pathophysiology to therapy - 2011

8/12/2019 Nature Rev Rheumatol - Fibromyalgia - From Pathophysiology to Therapy - 2011

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Chronic Pain andFatigue ResearchCenter, Department ofAnesthesiology,University of Michigan,24 Frank Lloyd WrightDrive, Ann Arbor, MI48106, USA(T. Schmidt-Wilcke,D. J. Clauw).

Correspondence to:T. Schmidt [email protected]

Fibromyalgia: from pathophysiology to therapyTobias 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 widespreadpain (CWP) and is generally accompanied by one ormore concomitant symptoms including fatigue, sleepdisturbances, cognitive dysfunction, anxiety and/ordepressive episodes.1,2Considerable overlap exists inboth the symptoms and the pathophysiological mecha-nisms between fibromyalgia and other central pain orfunctional somatic syndromes, such as irritable bowelsyndrome (IBS), interstitial cystitis/painful bladder syn-drome, chronic pelvic pain, and temporomandibular

joint disorder,3,4as well as a number of psychiatric dis-orders, such as depression and anxiety.57The widespreadnature of the pain in fibromyalgia, as well as the low painthresholds and concomitant symptoms suggest that thecentral nervous system (CNS) is the primary organsystem responsible for the most protean manifestations.8,9In fact, augmented pain and sensory processing (whichare consistently identified via experimental pain testingand functional neuroimaging) are firmly established ascontributing to both fibromyalgia and many if not mostchronic pain states. This entire spectrum of pain-relatedillness is better thought of as a biological continuumrather than a series of unconnected syndromes. Indeed,

Wolfe and others have shown that the degree of fibro-myalgianess, as measured by the widespread nature ofpain as well as the presence of comorbid symptoms, ispredictive of pain, fatigue, and functional status in nearlyall individuals with chronic pain that is attributable to

rheumatic disorders.1013Improved understanding andappreciation of the pathophysiology and treatment offibromyalgia, therefore, might lead to a better under-standing regarding the pathogenesis of pain and othersymptoms in nearly any rheumatic disorder.

The new (preliminary) American College of Rheuma-tology (ACR) diagnostic cr iteria for fibromyalgia, putforth in 2010, allow for the diagnosis of fibromyalgiawithout a tender point examination, and acknowledgethat, in addition to pain, other core symptoms of fibro-

myalgia include fatigue, unrefreshing sleep and/or cogni-tive symptoms.14These new diagnostic guidelines differfrom the 1990 ACR criteria (Box 1), which required thatan individual had both a history of CWP and at least 11of 18 possible tender points on physical examination.2Since women are innately more tender than men, theexclusion of the tender point examination from the newdiagnostic criteria and the increased emphasis on coresymptoms is expected to define far more males as havingfibromyalgia than the older criteria. On the basis of the1990 diagnostic criteria, the prevalence of fibromyalgiais approximately 25% in all populations studied,1518although the prevalence based on the new criteria is yet

to be determined.

Pathophysiology of fibromyalgia

Stress and stressors

Fibromyalgia can be triggered by a variety of stressors,and for some time fibromyalgia has been assumed tobe a stress-related illness. Although this assumptionmight be justified, the relationship between stress andfibromyalgia is complicated. Indeed, if fibromyalgia canbe defined as a stress-related illness, then so can mostchronic pain states.19

The question of whether or not stress is a risk factorfor fibromyalgia depends on the level and type of stress

Competing interests

D. J. Clauw declares associations with the following companies:Cypress Bioscience, Eli Lilly and Company, Forest Laboratories,Jazz Pharmaceuticals, Johnson & Johnson, Merck, NuvoResearch, Pfizer, Pierre Fabre Mdicament, Procter & Gamble,and Wyeth Pharmaceuticals. See the article online for fulldetails of the relationships. T. Schmidt-Wilcke declares nocompeting interests.

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2011 Macmillan Publishers Limited. All rights reserved
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(that is, biological versus psychological stress), and eventhen only weakly so. Population-based studies showedthat individuals with high levels of distress (psycho-logical stress), but without pain, are approximately two-fold more likely to develop CWP within the next yearas those without psychological distress.20,21Thus, therelative risk is high, but the absolute risk remains low,and so most individuals that newly develop fibromyalgiado not have prior symptoms of distress. The odds ratioof approximately two is similar to the relative risk ofdeveloping fibromyalgia that is attributable to being dis-tressed in a number of other longitudinal studies.22,23Overall, having psychologically stressful events in earlylife, such as the death of a parent, prolonged hospital-ization, 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 ofbiological stress are associated with the developmentof fibromyalgia and related conditions. Indeed, 510%of individuals exposed to certain types of infections (for

example, Lyme disease, EpsteinBarr virus, parvovirus orQ fever) develop CWP, and infections in other regions ofthe body can also trigger chronic regional pain. Similarly,1015% of individuals with acute gastrointestinalinfections (for example, with Campylobacter spp.,Salmonella spp.or Shigella spp.) subsequently developIBS.25Furthermore, fibromyalgia or regional chronicpain can be triggered by surgical procedures, deploymentto military service, or being involved in physical traumasuch as motor vehicle accidents.19,2630The establishedlink between exposure to stressors and the developmentof fibromyalgia has led to extensive research into humanstress systems in this condition. These studies have gen-

erally shown alterations in the hypothalamicpituitaryadrenal (HPA) axis and the sympathetic nervous systemin fibromyalgia and related conditions,3134although thefindings vary from study to study.

Augmented pain and sensory processing

The most established underlying pathologic mechanismin fibromyalgia and many other chronic pain states iscentrally mediated augmentation of pain and sensoryprocesseswhich exists even in the absence of identifi-able psychological factors. Because tender points havebeen traditionally thought of as a clinical indicator oflowered pain thresholds, they are the measure of tender-

ness that has been most often assessed in fibromyalgia.However, studies have shown that individuals with fibro-myalgia are diffusely tender in all bodily regions (tenderpoints are merely regions where everyone is moretender), even when experimental pain testing paradigmsare used that minimize or eliminate the potential roleof psychological factors (for example, hypervigilanceor expectancy).35,36Patients with fibromyalgia have alsobeen noted to be more responsive to nearly any typeof stimuli, including heat, cold, electrical stimuli andhypertonic saline infusion.37,38Interestingly, other studieshave shown that patients with fibromyalgia display sensi-tivity to a number of other sensory modalities, such as

the brightness of light or the loudness of auditory tones,suggesting that fibromyalgia might be associated witha global problem in sensory processing rather than aspecific abnormality in pain processing.39

Experimental pain testing has identified attenuateddescending analgesic activity as at least one poten-tial reason for the widespread pain sensitivity (that is,diffuse hyperalgesia) in individuals with fibromyalgia(Figure 1) . The application of an intense painful stimulus

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 beenidentified; 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 for3 months 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 levelfor 3 months, 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 ofthe 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 numberof 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 togive a final score of between 0 and 12.

Abbreviations: SS, symptom severity; WPI, widespread pain index.

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in a healthy individual produces an increase in the painthresholds in body regions remote from the initial site ofnociceptive stimulation, an effect also known as diffusenoxious inhibitory control (DNIC). This analgesiceffect has consistently been observed to be attenuatedin fibromyalgia, and is also known to be abnormal inother chronic pain states.4043Interestingly, a decrease

in DNIC is not seen in patients with major depressivedisorder,44suggesting that a deficit in pain inhibition isspecific to chronic pain states such as fibromyalgia. TheDNIC response relies on descending antinociceptivesystems (such as the opioidergic and noradrenergicserotonergic systems among others) projecting from thebrainstem to the spine and regulating peripheral noci-ceptive input to the dorsal horn. These systems are inturn under the control of various forebrain structuressuch as the anterior cingulate cortex, amygdala andfrontopolar cortex.45,46A certain amount of nociceptivesignaling (via C-fibers and A-fibers), therefore, mightbe suppressed at the spinal level in healthy individuals,

but gain access to the brain in patients with fibromyalgiaowing to impaired inhibitory control.

Evidence from functional MRI has shown that indivi-duals with fibromyalgia have increased neuronal activa-tion in pain processing regions of the brain following theapplication of otherwise innocuous stimuli.37,47,48Similarto the findings from experimental pain tests, these

studies have shown that the augmented pain process-ing in sensory processing regions of the brain is largelyindependent of the presence of psychiatric factors suchas depression.49Furthermore, brain imaging studies havereported a hypoperfusion of the striatum and thalamusat rest,50decreased dopamine binding in the striatum inresponse to experimental pain,51,52as well as changesin brain structure in the cingulate cortex,53,54insularcortex,53,54striatum54,55and thalamus54,55in patientswith fibromyalgia. Collectively, these findings suggestthat functional and morphological changes occur in theforebrain of individuals with fibromyalgia, especiallyin structures known to be involved in pain systems.

Descending

inhibitory

pathway

Ascending

nociceptive

pathway

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

a

Attenuation ofnociceptive system

Deficient descendinganalgesia Hyperalgesia

b

Serotonin andnorepinephrine

reuptake inhibitors

2ligands

Low levels of inhibitoryneurotransmitters

Increased levels ofneurotransmitters that

augment pain transmissionin the spine and brain

Peripheralnociceptive input

Figure 1 | Pathways of pain processing implicated in chronic pain and fibromyalgia. a| CNS neurotransmitters that areknown to either facilitate or inhibit sensory/pain transmission are shown. As indicated by the arrows, the levels of severalof these neurotransmitters are either decreased or increased in patients with fibromyalgia. b| Augmented pain processingin fibromyalgia is attributable to an imbalance of several neutrotransmitters that determine the volume control on painprocessing. Low levels of inhibitory neurotransmitters might lead to an attenuated antinociceptive system, whereasserotoninnorepinephrine reuptake inhibitors might work to increase antinociceptive activity. Levels of neurotransmittersthat 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. 2ligands might beworking to decrease the release of excitatory neurotransmitters. Abbreviations: 5-HT, 5-hydroxytryptamine; 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

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Whether these changes follow an increased nociceptiveinput (possibly promoting the process of pain chronifica-tion), or whether they actually constitute the primarypathophysiology, remains to be determined.

Genetics and CNS neurotransmitters

Familial predisposition to fibromyalgia is an establishedphenomenonthe risk of developing fibromyalgia iseightfold higher for first-degree relatives of patients withfibromyalgia than for an unrelated individual. Indeed,family members also have a much higher risk of any typeof chronic pain, and are more tender than the familymembers of control individuals.56The rates of psychi-atric co-morbidity are also high in relatives of patientswith fibromyalgia, but this overall risk is approximatelytwofold compared with control individuals, whereasthe excess rate of pain disorders is much higher. Twinstudies have demonstrated that there are two somewhatindependent but overlapping sets of genetic traits; onerelated to pain and sensory sensitivity, and the otherrelated to psychiatric comorbidity.5760

Current evidence suggests that genetic factors are res-ponsible for at least 50% of overall sensitivity to experi-mental pain, and might also make individuals more likelyto develop chronic pain over the course of their lifetime.These genetic factors include polymorphisms in genesencoding catecholamine-O-methyl-transferase (COMT),a variety of sodium channels, GTP cyclohydroxylase,and the KCNS potassium channel.6165Specific geneticpolymorphisms associated with an increased r isk ofdeveloping fibromyalgia pertain to genes involved inserotonin and catecholamine metabolism. The shortallele polymorphism in the regulatory region of SLC6A4(the serotonin transporter [5-HTT] gene) occurs more

frequently in patients with fibromyalgia than in healthyindividuals.66Of note, the 5-HTT gene polymorphismalso frequently occurs in patients with depressive dis-orders, suggesting it to be a risk factor for both diseases.67Furthermore, a polymorphism in the gene encodingCOMT (resulting in a Val158Met polymorphism ora high pain sensitivity haplotype) has been of interestin fibromyalgia research, since it is also implicated inthe pathogenesis of other pain syndromes.68To date,however, as with genetic findings in other diseases,reports of COMT gene haplotypes in fibromyalgia havebeen inconclusive.6972Interestingly, apart from having adirect influence on pain, the role of dopamine (in rela-

tion to the COMT polymorphism) is now also discussedas possibly mediating the relationship between pain anddaily (maladaptive) coping, suggesting that genetic vari-ation affects pain in fibromyalgia through pathways ofpain-related cognition.

Polymorphisms of catecholamine receptors havealso been investigated, and certain adrenergic receptorhaplotypes of the

2and

1Areceptor were reported to

be more common in fibromyalgia patients as comparedwith healthy controls.73With respect to dopamine recep-tors, a 7-repeat polymorphism in the third exon of theD(4) dopamine receptor gene was observed to occur sig-nificantly less frequently in patients with fibromyalgia

than in controls.74Furthermore, it could be shown thatfibromyalgia patients with a particular polymorphismin the D(3) dopamine receptor gene (which results inthe highest receptor functioning) had the highest DNICefficacy and the highest pain thresholds.75

Low levels or low activity of neurotransmitters suchas serotonin, norepinephrine and dopamine, whichare capable of altering sensory processing, might havea role in fibromyalgia (Figure 1). Many of the neuro-transmitters known to facilitate the transmission ofpain in the CNS, such as substance P, glutamate andnerve growth factor, are increased in the cerebrospinalfluid of individuals with fibromyalgia, whereas levels ofmetabolites of neurotransmitters that typically inhibitpain transmission, such as serotonin, norepinephrineand dopamine, are reduced.7678Paradoxically, encepha-lins have been shown to be elevated in patients withfibromyalgia.79This finding is in line with the resultsof a PET study that showed decreased -opioid recep-tor availability in the nucleus accumbens and cingulategyrus in patients with fibromyalgia,80demonstrating

an increased baseline occupancy of opioid receptors.Elevated encephalin levels might result from an ongoingattempt to control nociception in fibromyalgia, and thismight explain the anecdotal lack of benefit of exogenousopiate analgesics for fibromyalgia.

Peripheral abnormalities

Some studies have found mild abnormalities in theskeletal muscles of patients with fibromyalgia; however,inconsistencies in these findings are apparent, and suchdifferences might be largely attributable to decondition-ing rather than to the illness itself.8183Nevertheless, smallnerve fibers in the skin might be damaged in subsets of

individuals with fibromyalgia, as has been seen in patientswith other chronic pain conditions.84Conflicting resultshave been reported from the use of 31P-spectroscopy toexamine muscle metabolism in fibromyalgia; one studycompared sedentary controls with fibromyalgia patientsand found no differences, whereas another reportedlower ATP levels in patients with fibromyalgia.85,86

Other studies suggest that the maintenance of centralaugmentation requires persistent noxious peripheralinput, even in syndromes that are characterized by theabsence of well-defined, localized, pain-causing lesions,such as fibromyalgia and IBS.87A study of patients withfibromyalgia and either myofascial pain syndromes

or regional joint pain showed that peripheral triggerpoint injections and hydroelectrophoresis both ameli-orate fibromyalgia pain and increase pain thresholdsat sites distant from the therapeutic interventions.88These findings provide further evidence that painfulperipheral stimuli may contribute to the perpetuation ofcentral augmentation.

The hypothesis that fibromyalgia, IBS and othercentral pain states are mild inflammatory diseasesanidea that has been in and out of favor over the yearsis currently being reconsidered, as it seems that someof the symptoms in fibromyalgia might be attributableto subtle inflammatory changes. For example, central

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sensitivity and chronic pain can be augmented in CNSglial cells by proinflammatory cytokine production.Observations such as these might challenge the dichoto-mic view that classifies pain as being either inflammatoryor noninflammatory.

Sleep and activity

Disturbed sleep and poor physical function are commonsymptoms of fibromyalgia. Indeed, the observation thatselective sleep deprivation in healthy individuals led tosymptoms of fibromyalgia was one of the first biologicalfindings in fibromyalgia and has been replicated byseveral groups.89,90However, the electroencephalographyabnormalities (termed intrusions) that were thoughtto be a marker for fibromyalgia in the original study arenow known to be present in both healthy individuals andpatients with other conditions.91,92Polysomnographystudies in fibromyalgia demonstrated fewer sleep spin-dles, an increase in cyclic alternating pattern rate, upperairway resistance syndrome, and/or poor sleep efficiencyin patients with fibromyalgia compared with healthy

individuals.9395Overall, no evidence suggests that indivi-duals with suspected fibromyalgia should be screened forsleep disorders unless they have symptoms or risk factorsthat imply the presence of a sleep disorder.

Psychiatric and psychological comorbidities

Psychological and behavioral factors have a role in symp-tom expression in many patients with fibromyalgia, with3060% experiencing psychiatric comorbidities in ter-tiary care settings; this rate increases when the rate oflifetime psychiatric disorders (commonly depression andanxiety) is considered.5,96,97However, these rates mightbe artifactually elevated by virtue of the fact that most of

these studies have been performed in tertiary care cen-ters. By contrast, members of the general population whomeet ACR criteria for fibromyalgia, and have not soughtcare in a tertiary setting, have a lower rate of identifiablepsychiatric conditions.98,99

As already noted, the relationship between pain anddistress is complex and distress can be both a causeand consequence of pain. In instances where distressis considered to be a consequence of pain, individualswith fibromyalgia display a decrease in their ability toundertake everyday roles in their work and family life.For example, relationships with spouses, children andwork colleagues can prove difficult to distressed patients

with fibromyalgia, a situation that can exacerbate theirsymptoms and lead to maladaptive illness behaviors,including isolation, cessation of pleasurable activities andreductions in activity and exercise. Indeed, patients whoexperience these psychiatric conditions can, in the worstcases, come to rely so heavily on disability and compen-sation systems that an improvement in the conditionis unlikely.100

The complex interface of biological, psychologicaland behavioral mechanisms is not unique to fibro-myalgia and has an important role in symptom expres-sion in all rheumatic diseases. Indeed, non-biologicalfactors in rheumatoid arthritis and osteoarthritis (such

as socioeconomic variables, the level of formal educationand coping strategies) are known to be responsible formore of the variance in pain reporting and disability thanbiological factors (such as joint space width or erythro-cyte sedimentation rate).11,101Subgroups of patientswith fibromyalgia can be identified in whom differentialpsychological factors have a role in symptom expression,including those who seem to be psychologically resilientand whose psychological make-up could, therefore, be apositive factor that might buffer the functional effects oftheir symptoms.102,103

Functional MRI studies have investigated whatinfluence comorbid mood disorders or an individualsthoughts about their pain might have on pain process-ing in fibromyalgia. One such study found that the levelof depressive symptomatology did not affect the degreeof neuronal activation in brain regions responsible forthe sensory intensity of painthe primary and secon-dary somatosensory corticesbut did influence neuronalactivation in the affective pain processing regions of thebrain, such as the amygdala and anterior insula.49By con-

trast, another study with a similar methodology reportedthat the presence of catastrophizing was associated withincreased neuronal activations in the sensory codingregions in patients with fibromyalgia.104Collectively,these studies provide a compelling case for the use ofcognitive behavioral therapy in fibromyalgia, especiallyif individuals exhibit cognitions such as catastrophizingthat, independent of other factors, might be capable ofincreasing pain intensity.

Therapy

Pharmacotherapy

The number of drugs evaluated for the treatment of

fibromyalgia has notably increased over the past decade.Approximately 40 substances have been investigatedin that time,105with a high variation between studies inquality, number of patients enrolled and primary endpoints. To date, three drugs have been approved by theFDA for the treatment of pain in fibromyalgia: pregabalin,which binds to the

2 subunit of a voltage-dependent,

presynaptic calcium channel, and duloxetine and mil-nacipran, which selectively inhibit reuptake of serotoninand norepinephrine, respectively. A number of othercategories 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) receptor modulators.

Monoamine modulators

The efficacy of amitriptyline and cyclobenzaprine in treat-ing not only pain, but also fatigue and poor sleep, in fibro-myalgia is supported by several randomized controlledtrials.106108Both of these drugs have strong effects onthe norepinephrine transporter and moderate effectson 5-HTT,109blocking the reuptake and subsequentlyincreasing the intrasynaptic concentrations of these neuro-

transmitters. Selective serotonin reuptake inhibitors werefound to be less efficacious than the tricyclic compoundsor serotoninnorepinephrine compounds,110,111suggesting

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a critical role for norepinephrine in the analgesic effectin fibromyalgia (and perhaps more broadly in pain). Inmulticenter trials, duloxetine and milnacipran wereshown to be efficacious in a number of outcome varia-bles in fibromyalgia, such as self-reported pain, stiffness,number of tender points, physical functioning and levelof fatigue.112,113Milnacipran treatment was also associ-ated with a durability of improvement and long-termefficacy in fibromyalgia.114Other monoamine modu-lators have either failed to demonstrate an overall effi-cacy (for example, dopamine receptor agonists115117) orare currently not recommended owing to possible severeside effects, such as serotonin syndrome and hypertensivecrisis (for example, monoamine oxidase inhibitors118). Atrial published in 2010 also showed that a selective norepi-nephrine reuptake inhibitor, esreboxetine, was effectivein fibromyalgia, lending further support to the notionthat norepinephrine is relatively more important thanserotonin in the analgesic effects of these compounds.119

Calcium channel modulators

Antiepileptic drugs, mainly the 2 calcium channelmodulators, are widely used for the treatment of variouschronic pain conditions, including postherpetic neuralgiaand painful diabetic neuropathy.120Pregabalin and gaba-pentin have both been shown to reduce pain and sleepdisturbances in patients with fibromyalgia, but thesedrugs had no effect on depressed mood.121,122Both sub-stances bind to the

2 subunit of a voltage-dependent,

presynaptic-gated calcium channel and reduce thecalcium influx at nerve terminals, probably acting inpart by causing a decrease in the release of excitatoryneurotransmitters, such as glutamate and substance P.

GABA receptor modulatorsSodium oxybate (-hydroxybutyric acid) has recently beendemonstrated to simultaneously improve pain, fatigueand sleep architecture in several randomized controlledtrials in patients with fibromyalgia.123,124Sodium oxybateacts as both a GABA

Breceptor and a -hydroxybutyrate

receptor agonist. This drug is approved by the FDA forthe treatment of narcolepsy and cataplexy but is not likelyto be approved for use in fibromyalgia because of safetyconcerns. Benzodiazepines are GABA

Areceptor agonists

and have both sedative and anxiolytic effects. However,these agents have yielded mixed results in the treatmentof fibromyalgia,125,126and are not generally recommended

owing to concerns of substance abuse and a reduction ofsleep efficiency.

Nonpharmacological therapies

Although nonpharmacological therapies for fibro-myalgia, such as education, exercise and cognitivebehavioral therapy, have effect sizes that are equal to orexceed the effect sizes of drugs, these therapies are rarelyused in current practice.127,128There are many reasonsfor this low uptake of nonpharmacological treatments,including the fact that many clinicians do not stronglyadvocate these therapies, many insurers do not cover thecost of these services, and many patients would rather

be prescribed a pill that fixes their symptoms. In addi-tion to working well, these nonpharmacological treat-

ments are likely to work on inherently different aspectsof fibromyalgia, having more effect on the dysfunctionassociated with fibromyalgia than purely on symptomaticimprovement (Figure 2).

To increase the use of nonpharmacological treatments,education programs (which are already broadly available)should be given to all patients newly diagnosed withfibromyalgia. The optimal management of fibromyalgiashould replicate that of other chronic medical illnesses,using a patient-centric, disease management model. Inthis putative model, when a patient is newly diagnosedwith fibromyalgia, they should receive education aboutthe illness, the available treatments, and the role they

must take in managing the condition. This educationcould occur in group lectures with patients and fami-lies, in a series of visits with mid-level providers and/ornurse educators, or by using other models that have beeneffective for other chronic illnesses. The importance ofnonpharmacological therapies should be emphasizedand clear expectations on the part of both the patientand the provider should be established. Furthermore,because education, exercise, and/or cognitive behav-ioral therapy are so inexpensive and effective, all patientsdiagnosed with fibromyalgia should receive some formof these nonpharmacological treatments.129,130Researchsuggests that such therapies might be effective even when

administered using minimal or no contact, for examplevia web-based or smartphone-based programs. Indeed,a randomized controlled trial reported that the use of afree website that educates patients with fibromyalgiaon nonpharmacological treatments led to significantimprovements in pain and functional status, with effectsizes comparable to those observed with drugs.131

There are few controlled studies that endorse alterna-tive therapies for fibromyalgia, although trigger-pointinjections, chiropractic manipulation, acupuncture andmyofascial release therapy have been explored by patientswho decide to manage their own illness. One studyshowed that treating trigger points with injections in

Pharmacological therapiesto improve symptoms

Nonpharmacologicaltherapies to address dysfunction

Initial symptoms of pain, fatigue, etc.

Function consequences of symptomsDistressDecreased activity IsolationPoor sleepIncreased distress

Maladaptive illness behaviors

Figure 2 | Dually focused therapeutic approach to fibromyalgia. The optimumstrategy for fibromyalgia management is one that combines the use ofpharmacological and nonpharmacological therapies. This approach would bebeneficial because nonpharmacological therapies can constitute a rehabilitationmodel that addresses the many consequences of longstanding pain that can leadto additional pain and other somatic symptoms. The overall outcome of the duallyfocused therapeutic approach, therefore, would be that pharmacologicaltreatments alleviate the initial symptoms of pain, and nonpharmacologicaltherapies address the functional consequences of the symptoms.

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fibromyalgia patients with concomitant myofascial paindid lead to an overall improvement in their fibromyalgiasymptoms, which is arguably the strongest evidence ofthe efficacy of this approach to date.88Tai chi, yoga and anumber of other therapies might also be effective,132butthese approaches need to be evaluated in larger studies.

Prognosis

The prognosis of fibromyalgia depends largely onwhere the individual falls on a continuum. On one endof the continuum are individuals in the population whohave chronic widespread pain who have not yet soughtmedical care, or individuals with fibromyalgia that areseen in primary care; the prognosis in these individualscan be quite good.133,134On the other hand, patients withfibromyalgia seen in tertiary care settings tend to have apoor prognosis, with one study reporting little changein fibromyalgia symptoms over time, and no change inhealth satisfaction or functional disability.135

All of the studies examining outcomes in patientswith fibromyalgia, however, were performed before

the approval of pregabalin, duloxetine and milnacipranby the FDA, and before substantial scientific advancesin our understanding of this condition. These rapidchanges have improved the overall acceptance andrecognition of fibromyalgia, and are likely to be accom-panied by improvements in outcomes. Outcomes willbe further improved as new drugs are identified thatblock other molecular targets, and when more cliniciansintegrate nonpharmacological approaches into theirtherapeutic armamentarium.

Conclusions

In this Review, we have aimed to provide an overview

of some important aspects of epidemiology, patho-physiology and treatment options in fibromyalgia.Genetic and psychophysiological research, as well asbrain imaging and drug trials, have improved both ourunderstanding of the underlying pathophysiology offibromyalgia and the current treatment options. It mustbe noted, however, that an overall unifying concept of

fibromyalgia is still lacking and it is likely that diversemechanisms contribute differently to the clinical picturein individual patients. Although the pharmacologicalsubstances used in f ibromyalgia are well characterizedwith respect to their mechanisms of action and bindingsites, the exact location in the CNS where they exerttheir effects remains to be fully eluciated, both froman anatomical perspective and with respect to recep-tor subtypes. It is not surprising, therefore, that no reli-able tools to predict treatment response in individualpatients yet exist, and clinical routine largely relies ontrial and error. The effect of any single drug examinedin groups of individuals is modest, a phenomenon that isno different from analgesics tested in other chronic painstatesNSAIDs and opioids have comparably modestefficacy in conditions such as osteoarthritis or chroniclow back pain.136This situation stresses the need forcombined pharmacotherapies and the incorporation ofpharmacotherapy into a broader program of education(and other nonpharmacological therapies), in additionto subclassification of the fibromyalgia syndrome with

the goal of tailored treatment approaches. Furthermore,the majority of individuals with fibromyalgia have unmetneeds other than widespread pain, including mood dis-orders, dyscognitive symptoms, sexual dysfunction and alack of sociomedical acceptance; aspects that have a deepeffect on quality of life and that need to be addressedby future research. As such, fibromyalgia remains ascientific and clinical challenge.

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 ar ticle, we selected a subset

of articles for inclusion in this Review on the basis of

conceptual influence and study quality.

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fibromyalgia symptom variables: evidence thatfibromyalgia is not a discrete disorder in theclinic.Ann. Rheum. Dis.56, 268271 (1997).

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22. McLean, S. A., Williams, D. A. & Clauw, D. J.Fibromyalgia after motor vehicle collision:

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26. Buskila, D., Neumann, L., Vaisberg, G.,Alkalay, D. & Wolfe, F. Increased rates of

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32. Qiao, Z. G., Vaery, H. & Mrkrid, L.Electrodermal and microcirculatory activity inpatients with fibromyalgia during baseline,acoustic stimulation and cold pressor tests.

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34. Martnez-Lavn, M., Hermosillo, A. G., Rosas M &Soto, M. E. Circadian studies of autonomic

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35. Petzke, F., Clauw, D. J., Ambrose, K., Khine, A. &Gracely, R. H. Increased pain sensitivity infibromyalgia: effects of stimulus type and modeof presentation.Pain105, 403413 (2003).

36. Petzke, F., Gracely, R. H., Park, K. M.,Ambrose, K. & Clauw, D. J. What do tenderpoints measure? Influence of distress on 4

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38. Geisser, M. E. et al.Perception of noxious andinnocuous heat stimulation among healthywomen and women with fibromyalgia:association with mood, somatic focus, andcatastrophizing.Pain102, 243250 (2003).

39. Geisser, M. E. et al.A psychophysical study ofauditory and pressure sensitivity in patients withfibromyalgia and healthy controls.J.Pain9,417422 (2008).

40. Lautenbacher, S. & Rollman, G. B. Possibledeficiencies of pain modulation in fibromyalgia.Clin.J.Pain13, 189196 (1997).

41. Kosek, E. & Hansson, P. Modulatory influence onsomatosensory perception from vibration andheterotopic noxious conditioning stimulation(HNCS) in fibromyalgia patients and healthysubjects. Pain70, 4151 (1997).

42. Julien, N., Goffaux, P., Arsenault, P. &Marchand, S. Widespread pain in fibromyalgia isrelated to a deficit of endogenous paininhibition. Pain114, 295302 (2005).

43. Wilder-Smith, C. H. & Robert-Yap, J. Abnormalendogenous pain modulation and somatic andvisceral hypersensitivity in female patients withirritable bowel syndrome. WorldJ. Gastroenterol.13, 36993704 (2007).

44. Normand, E. et al.Pain inhibition is deficient inchronic widespread pain but normal in majordepressive disorder.J.Clin.Psychiatry72,

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47. Gracely, R. H., Petzke, F., Wolf, J. M. &Clauw, D. J. Functional magnetic resonanceimaging evidence of augmented pain processingin fibromyalgia.ArthritisRheum.46, 13331343(2002).

48. Cook, D. B. et al.Functional imaging of pain inpatients with primary fibromyalgia.J.Rheumatol.31, 364378 (2004).

49. Giesecke, T. et al.The relationship betweendepression, clinical pain, and experimental painin a chronic pain cohort.ArthritisRheum.52,15771584 (2005).

50. Mountz, J. M. et al.Fibromyalgia in women.Abnormalities of regional cerebral blood flow inthe thalamus and the caudate nucleus areassociated with low pain threshold levels.

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54. Lutz, J. et al.White and gray matterabnormalities in the brain of patients withfibromyalgia: a diffusion-tensor and volumetricimaging study.ArthritisRheum.58, 39603969(2008).

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AcknowledgmentsTobias Schmidt-Wilcke is supported by a grant fromthe Deutsche Forschungsgemeinschaft (DFG, GZ:SchM 2665/1-1).

Author contributions

T. Schmidt-Wilcke and D. J. Clauw contributed equallyto researching data for, discussing the content of andwriting the article, and reviewing/editing of themanuscript before submission.

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nature rev rheumatol - fibromyalgia - from pathophysiology to therapy - 2011

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