fibromyalgia drug treatment

PRETEST AND OBJECTIVES

Prim Care Companion J Clin Psychiatry 2008;10(2) 91PSYCHIATRIST.COM

Articles are selected for credit designation on the basis of the CME Institutesassessment of the needs of readers of The Primary Care Companion, with the purposeof providing readers with a curriculum of CME articles on a variety of topics throughouteach volume. There are no prerequisites for participation in this CME activity.To obtain credit, read the material and complete the Posttest and Registration Formon pages 175176 or go to PSYCHIATRIST.COM and take the Posttest online.CME ObjectivesAfter studying the ACADEMIC HIGHLIGHTS by Goldenberg et al. and Culpepper et al.,you should be able to:

Diagnose fibromyalgia and its co-occurring conditions in primary care and employappropriate pharmacologic and nonpharmacologic treatment strategies to optimizepatients outcomes.

Recognize depressive and anxiety symptoms in primary care and formulate anindividualized treatment plan that utilizes the most appropriate agents to addresspatients mental and physical health care needs.

Accreditation StatementThe CME Institute of Physicians Postgraduate Press, Inc., is accredited by theAccreditation Council for Continuing Medical Education to provide continuingmedical education for physicians.Credit DesignationThe CME Institute of Physicians Postgraduate Press, Inc., designates this educationalactivity for a maximum of 2.5 AMA PRA Category 1 Credits. Physicians should onlyclaim credit commensurate with the extent of their participation in the activity.Date of Original Release/ReviewThis educational activity is eligible for AMA PRA Category 1 Credit throughApril 30, 2011. The latest review of this material was February 2008.

Financial DisclosureIn the spirit of full disclosure and in compliance with all ACCME Essential Areasand Policies, the faculty for this CME activity and CME Institute staff were asked tocomplete a statement regarding all relevant personal financial relationships betweenthemselves or their spouse/partner and any commercial interest. The CME Institute hasresolved any conflicts of interest that were identified. No member of the CME Institutestaff reported any relevant personal financial relationships. Faculty financial disclosureappears with each article.

This pretest is designed to facilitate your study of the material.1. Fibromyalgia is an illness that primarily affects the _____.

a. Peripheral nervous systemb. Central nervous systemc. Musculoskeletal systemd. Neuroendocrine system

2. Mixed anxiety and depression is a condition characterized by:a. Meeting the full diagnostic criteria for both an anxiety disorder and major

depressive disorder (MDD)b. Meeting the full diagnostic criteria for MDD but having subthreshold symptoms

of anxietyc. Having subsyndromal symptoms of both anxiety and depressiond. None of the above

For Pretest answers and Posttest, see pages 175176.

To receive yourcredit certificate

immediately for free,complete this

activity online.

Keyword: PCC2

90

ACADEMIC HIGHLIGHTS


An Introduction to Fibromyalgia and Its Related Disorders

effects of fibromyalgia on cognition.Specific pharmacologic treatment rec-ommendations were given by Daniel J.Clauw, M.D., while Dr. Goldenbergconcluded with a discussion of non-pharmacologic therapeutic options.

The spectrum of fibromyalgiaranges from mild symptomatology, re-quiring no medical attention, to severe,with disabling widespread pain andexhaustion. The progression from mildto severe symptoms is not well under-stood but does involve personalpsychosocial factors. Therefore, pri-mary care physicians should considerthe psychosocial as well as the physi-ologic aspects of fibromyalgia and itsrelated disorders to provide patientswith a comprehensive treatment planthat includes pharmacologic and non-pharmacologic treatment options.

Understanding Fibromyalgia and Its Related Disorders

his ACADEMIC HIGHLIGHTS section of ThePrimary Care Companion to The Journalof Clinical Psychiatry presents the

highlights of the planning teleconference seriesUnderstanding Fibromyalgia and Its RelatedDisorders, which was held in October andNovember 2007. This report was prepared by theCME Institute of Physicians Postgraduate Press,Inc., and was supported by an educational grantfrom Eli Lilly and Company.

The planning teleconference was chaired by DonL. Goldenberg, M.D., Department of Medicine andthe Department of Rheumatology, Newton-WellesleyHospital, Newton, Mass. The faculty were LaurenceA. Bradley, Ph.D., Division of Clinical Immunologyand Rheumatology, Department of Medicine, and theCenter for Education and Research on Therapeuticsof Musculoskeletal Disorders, University ofAlabama, Birmingham; Lesley M. Arnold, M.D.,Director of Womens Health Research Program,Department of Psychiatry, University of CincinnatiCollege of Medicine, Cincinnati, Ohio; Jennifer M.Glass, Ph.D., Substance Abuse Section, Departmentof Psychiatry, and the Institute for Social Research,University of Michigan Medical School, Ann Arbor;and Daniel J. Clauw, M.D., Division ofRheumatology, Department of Internal Medicine,and the Michigan Institute for Clinical and HealthResearch, University of Michigan Medical School,Ann Arbor.

Financial disclosure: Dr. Goldenberg is aconsultant for Eli Lilly, Pfizer, Merck, CypressBioscience, and Forest. Dr. Bradley is a consultantfor Eli Lilly, Pfizer, and Forest; has received grant/research support from the National Institutes ofHealth, the Agency for Healthcare Research andQuality, Eli Lilly, Pfizer, and the AmericanFibromyalgia Syndrome Association; has receivedhonoraria from Eli Lilly, Pfizer, Forest, and theSociety for Womens Health Research; is a memberof the speakers/advisory board for Pfizer; and hasreceived royalties from UpToDate Rheumatology.Dr. Arnold has received grant/research support fromEli Lilly, Pfizer, Cypress Bioscience, Wyeth, Sanofi-Aventis, Boehringer Ingelheim, Allergan, and Forest;is a consultant for Eli Lilly, Pfizer, CypressBioscience, Wyeth, Sanofi-Aventis, BoehringerIngelheim, Sepracor, Forest, Allergan, Vivus, andOrganon; and is a member of the speakers bureausfor Eli Lilly and Pfizer. Dr. Glass has received grant/research support from the National Institute on DrugAbuse, the National Institute of Alcohol Abuse andAlcoholism, and the Department of Defense and hasreceived honoraria from Pierre Fabre. Dr. Clauw isa consultant for and a member of the speakers/advisory boards for Cypress Bioscience, Forest,Wyeth, Pfizer, and Eli Lilly and has received grant/research support from Cypress Bioscience.

The opinions expressed herein are those of thefaculty and do not necessarily reflect the views of theCME provider and publisher or the commercialsupporter.

TFibromyalgia, an illness character-

ized by chronic, widespread pain andtenderness,1 is estimated to affect about5 million U.S. adults.2 Fibromyalgiawas formerly classified as an inflam-matory musculoskeletal disease but isnow considered to be an illness thatprimarily affects the central nervoussystem.

Don L. Goldenberg, M.D., chairedthe discussion and along with the fac-ulty outlined the diagnosis, course, andcurrent treatment of fibromyalgia andits related disorders. Laurence A. Bra-dley, Ph.D., reviewed factors that con-tribute to fibromyalgia and commonlyco-occurring disorders. Lesley M.Arnold, M.D., focused on the relation-ship between chronic pain disorderslike fibromyalgia and mood disorders.Jennifer M. Glass, Ph.D., discussed the

Pathophysiologic Mechanisms of Fibromyalgiaand Its Related Disorders

Understanding the pathophysiologyof fibromyalgia and co-occurring dis-orders may help clinicians provide themost appropriate treatment to their pa-tients, began Dr. Bradley. The patho-physiology of fibromyalgia involvesfamily and genetic factors, environ-mental triggers, and abnormalities inthe neuroendocrine and autonomic ner-vous systems. Many of these risk fac-tors are similar to those for other ill-nesses characterized by recurrent orpersistent pain and affective distressthat are frequently comorbid withfibromyalgia, such as irritable bowelsyndrome, chronic fatigue syndrome,tension or migraine headaches,temporomandibular disorder, andmajor depressive disorder (MDD).3Fibromyalgia may also be comorbid

with hypothyroidism4 and chronicautoimmune diseases such as rheuma-toid arthritis and systemic lupuserythematosus.5

Biological and Genetic FactorsDr. Bradley explained that fibro-

myalgia may be part of a group ofaffective spectrum disorders (ASD).The ASD hypothesis proposed byHudson and colleagues6 suggests thatthis group includes, but is not limitedto, 10 psychiatric and 4 medical disor-ders (Table 1) that share 1 or morephysiologic abnormalities important totheir etiology. These include inheritedfactors that may contribute to enhancedpain sensitivity, diminished pain in-hibitory function, or mood disorders.Studies6,7 of patients, as well as their

ACADEMIC HIGHLIGHTS

Prim Care Companion J Clin Psychiatry 2008;10(2)134 PSYCHIATRIST.COM

first-degree relatives, with fibromyal-gia or rheumatoid arthritis have pro-vided evidence to support the ASD hy-pothesis. For example, Arnold et al.7reported that the first-degree relativesof patients with fibromyalgia, com-pared with those of patients with rheu-matoid arthritis, more frequently metdiagnostic criteria for fibromyalgia orMDD and exhibited a greater numberof sensitive tender points (i.e., en-hanced pain sensitivity). Hudson et al.6further examined data from this familystudy and found that fibromyalgia co-aggregated with 1 or more other formsof ASD whether mood disorders wereincluded (p = .004) or not (p = .012).These findings suggest that, consistentwith the ASD hypothesis, (1) heritableas well as environmental factors maycontribute to family aggregation ofpain sensitivity in fibromyalgia, (2)fibromyalgia co-aggregates with otheraffective spectrum disorders, and (3)these disorders may share heritablephysiologic abnormalities.

One heritable factor that may beshared by several affective spectrumdisorders is a single nucleotide poly-morphism in the regulatory region ofthe serotonin transporter (5-HTT)gene.8 This polymorphism is foundmore frequently in patients with fibro-myalgia9,10 and in patients with MDD11compared with healthy controls. Thereis also some evidence that it is foundmore frequently among patients withdiarrhea-predominant irritable bowelsyndrome (IBS).12,13 This polymor-phism, then, may represent a heritable

risk factor for the development of theseaffective spectrum disorders. How-ever, there currently are no data re-garding the frequency of this polymor-phism among first-degree relatives ofpatients with fibromyalgia or IBSor the extent to which it may beassociated with enhanced pain sensi-tivity among patients and their familymembers.

Environmental TriggersDr. Bradley described environmen-

tal triggers that may also be involvedin the pathophysiology of fibro-myalgia, especially in combinationwith other risk factors. These triggersinclude mechanical or physicaltrauma or injury and psychosocialstressors.1416

A number of variables involvingmanual work, such as heavy lifting,repetitive motions, or squatting for ex-tended periods of time, have been sig-nificantly associated with the occur-rence of several musculoskeletal painconditions, including widespreadpain.15 But workers reports of dissat-isfaction with the amount of psychoso-cial support they received at their jobsites as well as descriptions of work asmonotonous also were associated witha higher risk of onset of widespreadpain. Several other environmental fac-tors such as working in hot conditionsalso increased the risk, although notsignificantly, of developing wide-spread pain.

Exposure to brief psychosocialstressors also may affect individuals

perceptions of pain associated withfibromyalgia. Dr. Bradley cited astudy16 of women with fibromyalgia orosteoarthritis. Following exposure to anegative mood induction procedure(i.e., reading sad text) and a psychoso-cial stressor, (i.e., discussing a stress-ful life event), women with fibromyal-gia reported greater increases in painseverity than did women with osteoar-thritis. Even during the post-stressorrecovery period, pain severity ratingsremained elevated in the women withfibromyalgia. However, exposure to aneutral mood induction procedure (i.e.,relaxation) prior to the psychosocialstressor did not alter the pain severityratings of women with fibromyalgia orknee osteoarthritis. These findings sug-gest that, although repetitive exposureto psychosocial stressors in the work-place increases the risk of onset ofwidespread pain, both negative moodand exposure to psychosocial stressorsare required to alter perceptions ofpain severity among patients withfibromyalgia.

Neuroendocrine AbnormalitiesDr. Bradley stated that fibromyal-

gia is generally considered to be astress-related disorder characterized byabnormal functioning in the hypothala-mic-pituitary-adrenal axis, such as theinability to suppress cortisol, a neu-roendocrine abnormality that has alsobeen found in patients with psychiatricdisorders. Patients with fibromyalgiatend to exhibit higher peak and troughlevels of cortisol than patients withrheumatoid arthritis.17 These patientsalso display a diminished response toan ovine corticotropin-releasinghormone that typically evokes a sub-stantial stress response in healthyindividuals.18

Autonomic Nervous SystemAbnormalities

Abnormalities are also present inthe function of the autonomic nervoussystem of patients with fibromyalgia.These abnormalities include decreasedmicrocirculatory vasoconstriction,19

Table 1. Affective Spectrum Disorders Hypothesized to Share Common PhysiologicAbnormalitiesa

Psychiatric Conditions Medical ConditionsAttention-deficit/hyperactivity disorder FibromyalgiaBulimia nervosa Irritable bowel syndromeDysthymic disorder MigraineGeneralized anxiety disorder CataplexyMajor depressive disorderObsessive-compulsive disorderPanic disorderPosttraumatic stress disorderPremenstrual dysphoric disorderSocial phobiaaBased on Hudson et al.6

ACADEMIC HIGHLIGHTS


increased hypotension,20 variations inheart rate,21 and sleep disturbance.22,23Dr. Bradley noted that heart rate vari-ability in fibromyalgia patients may bedifferent in men and women,22,24 andthat diminished heart rate variability inpatients with fibromyalgia may be dueto an abnormal chronobiology that mayalso contribute to sleep disturbanceand fatigue.21 Dr. Bradley explainedthat fibromyalgia is often associatedwith sleep disturbances, such as non-restorative sleep, insomnia, earlymorning awakening, and poor qualityof sleep.23 Moreover, sleep disturbancemay contribute to pain experienced bypatients with fibromyalgia through re-duced production of growth hormoneand insulin-like growth factor thatare necessary for repairing musclemicrotrauma.25

Enhanced Pain PerceptionPatients with fibromyalgia show en-

hanced sensitivity to a wide array ofstimuli. Carli et al.26 studied pain sen-sitivity to 5 sensory testing tasks andfound that patients with fibromyalgiashowed lower pain thresholds thanhealthy controls on all 5 tests. In con-trast, patients with multiregional painor widespread pain displayed enhancedpain sensitivity to 1 to 3 of the stimula-tion sources.26

Dr. Bradley stated that central sen-sitization may underlie the enhancedsensitivity to low-intensity stimuli thatis exhibited by patients with fibromyal-gia.27,28 However, in both animal andhuman models of central sensitization,the stimulus is identified (e.g., nerveinjury), and pain sensitivity is reducedif the source of sensory input is elimi-nated. In contrast, among patients withfibromyalgia, the source of sensory in-put remains unknown. For this reason,most fibromyalgia researchers refer tocentral augmentation of sensory inputrather than central sensitization whendiscussing the pathophysiology offibromyalgia.

Recent documentation of stimulus-evoked changes in brain activity usingfunctional magnetic resonance imag-

ing (fMRI) has illustrated the phenom-enon of central augmentation of sen-sory input among patients with fibro-myalgia. For example, patients withfibromyalgia reported moderate levelsof pain intensity (i.e., 11 on a 20-pointscale) at about one-half the stimulusintensity required to evoke the sameresponse in healthy persons. Neverthe-less, both patients and healthy indi-viduals show significant increases infunctional brain activity in the samebrain regions in response to these dis-parate stimulus intensities.29 The fMRIfindings, then, strongly suggest thatenhanced pain sensitivity among pa-tients with fibromyalgia is due to cen-tral augmentation of sensory input tothe brain rather than somatization or asimilar tendency to report pain or otherunpleasant perceptions in response tolow intensity sensory input.

Neuroimaging procedures are alsobeing used to document alterations inbrain inhibitory function of patientswith fibromyalgia. For example, Woodet al.30 used ligand positron emissiontomography (PET) to compare dopa-mine receptor availability in healthycontrols and patients with fibromyal-gia. In response to stimulation that pro-duced pain in the anterior tibialismuscle, the patients reported higherlevels of pain intensity than the healthycontrols. However, only the healthycontrols exhibited significant reduc-tions in binding potential at dopaminereceptors in basal ganglia structures.In other words, only healthy personsshowed evidence of endogenous opi-oid release in brain regions that areinvolved in pain processing and arehighly innervated by dopamine recep-tors. These findings suggest that bothcentral augmentation of sensory inputand diminished function of central paininhibitory functions contribute to theabnormal pain sensitivity and persis-tent pain experienced by patients withfibromyalgia.

ConclusionDr. Bradley concluded that factors

that contribute to the pathophysiology

of fibromyalgia include biologic andgenetic influences, environmental trig-gers, and abnormal function of the neu-roendocrine and autonomic nervoussystems. These factors are frequentlyshared by persons with disorders thatco-occur with fibromyalgia, such aschronic fatigue syndrome, irritablebowel syndrome, and MDD. Enhancedpain sensitivity occurs not only in pa-tients with fibromyalgia but also morefrequently in their first-degree relativesthan in the relatives of both healthypeople and persons with other painfulillnesses. Both central augmentation ofsensory input and deficits in centralpain inhibitory mechanisms appear tocontribute to enhanced pain sensitivityin persons with fibromyalgia.

Management of Fibromyalgiaand Comorbid PsychiatricDisorders

Depressive and anxiety symptomsare common and frequently severe inpatients with fibromyalgia.31 Because,as Dr. Bradley described, fibromyalgiamay share underlying pathophysi-ologic links with mood and anxietydisorders, Dr. Arnold recommendedthat patients with fibromyalgia be rou-tinely evaluated for the presence ofpsychiatric comorbidity.

Impact of Psychiatric Comorbidityon Fibromyalgia

The presence of psychiatric symp-toms has a profound impact on the se-verity and the course of fibromyalgia.High levels of depression and anxietyin patients with fibromyalgia havebeen found to be associated with morephysical symptoms and poorer func-tioning than low levels of depressionand anxiety.31 In fact, the presence ofpsychological symptoms in these pa-tients is a predictor of persistent pain.32Therefore, in treating patients withfibromyalgia, identifying and address-ing psychiatric comorbidity mayimprove the long-term outcome ofpatients.

ACADEMIC HIGHLIGHTS


Clinical PresentationsAlthough only widespread pain and

tenderness are included in the Ameri-can College of Rheumatology (ACR)criteria,1 Dr. Arnold noted that severalother symptom domains commonlyoccur in patients with fibromyalgia,such as fatigue, sleep disturbance,morning stiffness, paresthesias, head-ache, and depressive and anxietysymptoms.33 Other clinical features offibromyalgia include cognitive prob-lems, such as trouble concentrating,forgetfulness, and disorganized think-ing,33 addressed later by Dr. Glass.

A structured interview was de-signed by Pope and Hudson34 to helpclinicians diagnose fibromyalgia. Theinterview requires widespread pain for3 months or longer, like the ACR crite-ria.1 However, the interview allows theclinician to either conduct the ACRtender point exam or collect at least 4other commonly reported symptoms(Table 2). The clinician must also ruleout other systemic conditions thatmight be contributing to the patientssymptoms.

Treating Fibromyalgia in thePresence of Psychiatric Symptoms

The treatment of fibromyalgia com-monly includes the use of antidepres-sant medications, addressed later byDr. Clauw. The use of antidepressantmedication, said Dr. Arnold, is espe-cially useful in patients with comorbidmood and anxiety symptoms. The pos-sibility of a common pathophysiologiclink between mood disorders and fibro-myalgia6 suggests why these agentsmay affect both mood and pain.

Tricyclic antidepressants (TCAs),such as amitriptyline, and serotonin-norepinephrine reuptake inhibitors(SNRIs), such as venlafaxine,35milnacipran,36 or duloxetine,37,38 mayhave a therapeutic effect on pain that isindependent of their effects on moodas a result of their serotonin- and nor-epinephrine-mediated effects on thedescending pain-inhibitory pathwaysin the brain and spinal cord.39 Medica-tions with both serotonin and norepi-

nephrine activity may have more con-sistent benefits than other antidepres-sants, such as selective serotonin re-uptake inhibitors (SSRIs), in the reliefof persistent pain associated withchronic pain conditions, includingfibromyalgia.39

Comorbid MDD or anxiety. Dr.Arnold stated that, during evaluationof patients with fibromyalgia, deter-mining whether they have a currentcomorbid mood disorder is important,as well as screening for a past mooddisorder. If a patient has a historyof MDD, an SNRI may be preferableto an SSRI because of the more con-sistent effect of SNRIs on painreduction.

When using antidepressants to treatpatients with fibromyalgia, an ad-equate therapeutic dosage should betried for an adequate duration (about46 weeks) to allow for a response. Ifthe patient does not fully respond, theclinician should switch to a differentantidepressant or add another agent tothe antidepressant. One combinationof medications that has been foundeffective is an SSRI and a TCA (fluox-etine and amitriptyline).40 However,Dr. Arnold cautioned that some SSRIsand SNRIs may elevate blood TCAlevels, so adverse drug interactionsshould be carefully monitored. An-other effective combination may be anantidepressant and an anticonvulsantmedication such as gabapentin orpregabalin. Pregabalin is currently theonly agent approved for the treatmentof fibromyalgia by the U.S. Food andDrug Administration (FDA). More

study of the treatment of fibromyalgiaand comorbid MDD is needed.

In patients with fibromyalgia andeither current or lifetime anxiety disor-ders, antidepressants are potentially ef-fective for both the painful symptomsof fibromyalgia and the anxiety symp-toms. Dr. Arnold noted that pregabalinand gabapentin also have anxiolyticproperties.41

Comorbid bipolar disorder. The op-tions for treating fibromyalgia and co-morbid bipolar disorder may be morelimited because of the dearth of avail-able studies on bipolar disorder in pa-tients with fibromyalgia. If antidepres-sants are used to manage pain inpatients with fibromyalgia and co-occurring bipolar disorder, Dr. Arnoldwarned that these agents should beused in combination with mood stabi-lizers to lessen the patients risk ofswitching to a manic phase and toavoid the induction of rapid cycling.Patients with type II bipolar disordermay respond to low doses of antide-pressant monotherapy, but they mustbe observed carefully for developmentof mood instability.3 Gabapentin orpregabalin are alternatives to antide-pressants in the treatment of comorbidbipolar disorder and fibromyalgiabut, like antidepressants, should alsobe used in combination with well-established mood stabilizers.

Comorbid sleep disorders. Sleepdisorders are common in patients withfibromyalgia. One treatment option,Dr. Arnold suggested, is to use a sedat-ing agent at bedtime. Studies42,43 of theshort-term treatment of fibromyalgia

Table 2. Criteria for Fibromyalgiaa

American College of RheumatologyCriteria for Fibromyalgia1 Pope and Hudson Criteria for Fibromyalgia34

Widespread pain 3 months duration Widespread pain 3 months durationPain at 11 of 18 tender points Pain at 11 of 18 tender points or

4 of 6 of the following symptoms:Generalized fatigueHeadachesSleep disturbanceNeuropsychiatric complaintsNumbness or tingling sensationsIrritable bowel symptoms

aBased on Wolfe et al.1 and Pope and Hudson.34

ACADEMIC HIGHLIGHTS


with non-benzodiazepine sedatives,such as zolpidem and zopiclone, haveshown benefits for sleep and daytimeenergy, but not for pain. Therefore,they have limited usefulness as mono-therapy in patients with fibromyalgia,and there are no data on their long-term use in fibromyalgia.

An alternative to the sedating agentsis prescribing TCAs, such as amitripty-line at a dose of between 10 mg and 25mg at bedtime.44 This strategy can beused as monotherapy or as adjunctivetreatment. Gabapentin and pregabalinalso have sedative effects and havedemonstrated an increase in sleep qual-ity and enhanced slow-wave sleep.4548

NonpharmacologicTreatment Options

Dr. Arnold described nonpharma-cologic treatments of fibromyalgia,

which include cognitive-behavioraltherapy (CBT), education, and aerobicexercise, addressed later by Dr.Goldenberg. Cognitive-behavioraltherapy has demonstrated positive ef-fects on patients ability to cope withpain associated with fibromyalgia andfeelings of control over pain, although

these effects were not superior to thoseproduced by education,49 which sug-gests that education itself can be thera-peutic. Cognitive-behavioral therapy isalso an effective treatment for moodand anxiety disorders.50,51 Dr. Arnoldstated that evidence also supports theuse of aerobic exercise for the treat-ment of fibromyalgia52 and for the treat-ment of mild to moderate depression.53

Stepwise Treatment PlanComorbid mood and anxiety disor-

ders in patients with fibromyalgia canpresent diagnostic dilemmas and cannegatively impact the course of fibro-myalgia. The presence of comorbidpsychiatric disorders may require addi-tional pharmacologic and nonpharma-cologic treatments. Therefore, Dr.Arnold reviewed a stepwise treatmentplan (Figure 1).54 Once a diagnosis offibromyalgia is confirmed and comor-bid disorders have been identified, aclinician should educate the patient andbegin treatment with evidence-basedmedications and appropriate nonphar-macologic treatments.

ConclusionDr. Arnold stressed the importance

of obtaining a thorough patient andfamily history in patients with fibro-myalgia, paying particular attention toreports of mood or anxiety disorders.Using medications to treat fibromyal-gia as well as comorbid psychiatric dis-orders and incorporating appropriatenonpharmacologic therapies should op-timize patients overall outcomes.

Figure 1. Stepwise Treatment for Fibromyalgiaa

aAdapted with permission from Arnold.54

Identify important symptom domains,their severity, and level of patient function

Evaluate for comorbid medical and psychiatric disorders

Confirm diagnosis of fibromyalgia

May require referral to aspecialist for full evaluation

Assess psychosocial stressors,level of fitness, and barriers to treatment

Provide education about fibromyalgia

Review treatment options

As a first-line approach for patientswith moderate to severe pain, trial with

evidence-based medications

Adjunctive cognitive behavioraltherapy for patients with prominent

psychosocial stressors and/ordifficulty coping and/or functioning

Encourage exercise according tofitness level

Fibromyalgia and CognitionFibrofog is a term coined by patient

support groups to describe cognitivecomplaints associated with fibromyal-gia. Dr. Glass explained that patientswith fibromyalgia experience a de-crease in memory, loss of vocabulary,and a lack of concentration, which areexacerbated in stressful work environ-ments. She reported that her patientshave often complained that the cogni-

tive symptoms of fibromyalgia weremore disturbing than the physicalsymptoms.

Self-Reported Cognitive ProblemsClinical observations of cognitive

problems in fibromyalgia patients werecorroborated by a study55 of 100women with fibromyalgia and chronicfatigue syndrome. Of the women

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sampled, 95% reported concentrationdifficulties and 93% reported failingmemory. In a survey of more than 2500people with fibromyalgia,56 respon-dents reported that concentration andmemory were the most common prob-lems after pain, fatigue, muscle ten-sion or stiffness, and sleep problems.Dr. Glass noted that fibromyalgia pa-tients have more self-reported cogni-tive problems than patients with otherrheumatic disorders.57 Additionally,fibromyalgia patients report lowermemory capacity and more deteriora-tion in memory over time comparedwith 2 healthy control groups (one ofwhich was 20 years older than the pa-tient group).58 Fibromyalgia patientsalso reported having less control overmemory function (self-efficacy) andhigher anxiety about memory perfor-mance than age-matched controls, al-though they were more motivated andreported using more strategies to boosttheir memory performance.58

Objective Measuresof Cognitive Function

Objective measures of cognitivefunction have shown differences be-tween fibromyalgia patients and con-trols, particularly with memory andattention.59,60

Memory. Short-term memory, epi-sodic long-term memory, and seman-tic memory access are particularlytroublesome for patients with fibro-myalgia. Working memory combinesshort-term memory (memory of lessthan about 30 seconds) with othermental processes for tasks such asmental arithmetic. Episodic long-termmemory is the ability to remember par-ticular episodes, such as items on agrocery list or personal experiences.Semantic memory involves facts andknowledge about the world. Dr. Glassreported that objective tests have re-vealed that the level of impairment inworking memory, episodic long-termmemory (free recall), and semanticmemory (verbal fluency) in fibromyal-gia patients mimics about 20 years ofaging.61

Attention. Dr. Glass explained thatresults of attention tests in patientswith fibromyalgia are consistent withthose of working memory tests be-cause the attention tests require peopleto store some information for a shortperiod of time and also process dis-tracting information. Studies60,62 exam-ining attentional functioning in pa-tients with fibromyalgia reported thatthey scored substantially worse thanpain-free controls in selective atten-tion and auditory-verbal workingmemory. Dividing attention had costsfor both controls and fibromyalgia pa-tients, but the greatest cost incurredwas among the fibromyalgia patientswhen attention was divided duringboth the learning and recall phases oftesting. These results may explain whyfibromyalgia patients report poormemory performance in real-world en-vironments.63 Dr. Glass said that thecost in accuracy on attention tests wasgreatest when fibromyalgia patientshad to switch between complex rules.64These results confirm patients ac-counts that they are most aware of theircognitive problems when tasks are dif-ficult, multiple tasks are required, andthere is a lot of distraction.

Factors That Contribute to FibrofogSeveral factors may contribute to

cognitive problems in patients withfibromyalgia, said Dr. Glass. Thesefactors include comorbid depression,sleep problems, neuroendocrine ab-normalities, pain, and central augmen-tation of sensory input.

Psychiatric comorbidity. Dr. Glassnoted that while other researchers65,66have reported a correlation betweendepressive symptoms and cognitivefunction in patients with fibromyalgia,she and her colleagues61 did not find acorrelation between psychiatric symp-toms and results on cognitive tests.She said that although depression oranxiety could be related to cognitivefunction in some fibromyalgia pa-tients, these symptoms do not explainall of their memory and attentionproblems.

Sleep disturbances. Fibromyalgiapatients usually have sleep problemsand, even in healthy subjects, insuffi-cient sleep impairs learning andmemory.67 However, Dr. Glasss re-search61 did not produce any corre-lation between sleep and cognitiveperformance. As is the case with de-pression, poor sleep undoubtedly con-tributes to some of the cognitive diffi-culties of fibromyalgia patients but isnot a sole cause.

Neuroendocrine abnormalities. Dr.Glass stated that stress-level cortisoldoses have been shown to decreasememory function in healthy adults,68and elevated levels of cortisol wereassociated with lower performance oncognitive tests in those with Cushingsdisease.69 Conversely, other research70found that higher salivary cortisol lev-els correlated with better visual-spatialmemory. Neuroendocrine functionseems to have some effect on memoryfunction, but exactly how this mayaffect fibromyalgia patients is stillunclear.

Pain. Chronic pain has been associ-ated with impairment in attention71 andmay contribute to fibrofog. Cognitivefunction has been correlated with bothself-reported and evoked pain in fibro-myalgia,61,72 so pain likely contributesto the cognitive problems experiencedby fibromyalgia patients, according toDr. Glass.

Central augmentation of sensoryinput. Central processing abnormali-ties may interfere with the abilityto maintain focus.29 Dr. Glass statedthat enhanced processing of sensorysignals may lead to increaseddistractibility.

Tests Versus Self-Reportin Clinical Practice

Dr. Glass said that physicians oftenask how cognitive function in fibro-myalgia patients should be measuredin clinical practice. Her answer wasthat, generally, neuropsychologicaland cognitive tests are extensive andtime-consuming and may not be fea-sible in practice. Many of the tests that

ACADEMIC HIGHLIGHTS


are sensitive to the problems that fibro-myalgia patients experience are notstandardized, and some of the standardneuropsychological tests may miss theattention difficulties of fibromyalgiapatients. No quick and easy test of cog-nitive function in fibromyalgia patientsexists yet. Dr. Glass suggested that, inthe clinic, self-report may be the bestand quickest measure of cognitiveproblems in fibromyalgia patients. Per-formance on an objective memory re-call task correlated with fibromyalgiapatients perceived capacity, achieve-ment motivation, and self-efficacy.58

ConclusionResearch using objective tests

has verified fibromyalgia patientsself-report of cognitive difficulties. Asno simple and quick test exists forevaluating cognitive problems in pa-tients with fibromyalgia, patient self-report can be used in clinical practice.More research is needed to delineatethe exact nature of cognitive difficul-ties. Uncovering causes of cognitiveimpairment in fibromyalgia patientsmay lead to treatments that will im-prove cognitive function.

diazepines, hypnotics, and sedativesalso have not been shown to be effica-cious in treating fibromyalgia.

Drugs With Strong Evidenceof Efficacy

TCAs. TCAs have been found to beefficacious in the treatment offibromyalgic pain, fatigue, and sleepdisturbances44 but are associated withsome safety concerns. Adverse eventsinclude dry mouth, sedation, weightgain, urinary retention, constipation,and tachycardia.73 Patients with car-diac problems or narrow-angle glau-coma should not take TCAs. Elderlypatients should not take amitriptylinedue to the risk of anticholinergic sideeffects.

To minimize the incidence of sideeffects associated with TCAs, Dr.Clauw suggested that a low doseshould be used at the beginning oftherapy, and the dose should be titratedup slowly.74 For example, amitripty-line can be started at 10 mg/day takenseveral hours before bedtime and betitrated by about 10 to 25 mg per weekto a maximum of 70 or 80 mg/day orthe highest therapeutic dose that thepatient will tolerate.73 Cyclobenzaprineshould usually be started at 5 mg sev-eral hours before bedtime and esca-lated up to 20 mg/day or the maxi-mally tolerated dose.75

SNRIs. SNRIs tend to increase nor-epinephrine and serotonin without pro-ducing the cardiac side effectsassociated with TCAs.74 Dr. Clauwreported that both duloxetine37 andmilnacipran76 were shown to diminishfibromyalgic pain as well as fatigue,stiffness, and function. Like withTCAs, duloxetine and milnacipran cansometimes be effective for treatingfibromyalgia at or below the doses rec-ommended for depression when testedin patients with fibromyalgia (60120mg/day for duloxetine37 and 100200mg/day for milnacipran76), giving thesedual reuptake inhibitors the added ad-vantage of treating the comorbid de-pression that sometimes exists in indi-viduals with fibromyalgia. Side effects

associated with both drugs includeconstipation, nausea, palpitations,dizziness, insomnia, and dry mouth.73Again, Dr. Clauw recommended slowdose titration because side effects areoften most pronounced when the drugis first administered and with doseescalation. Taking this class of drugswith food will also aid gastrointestinaltolerability.

2 Ligands. The 2 ligands gaba-pentin46 and pregabalin45 have similar,if not identical, mechanisms of action,and both drugs have demonstratedefficacy in fibromyalgia treatment.Gabapentin was effective when usedwith a dose range of 1200 to 2400mg/day.46 Both 300 mg and 450mg/day of pregabalin have been ap-proved by the FDA for use in fibro-myalgia. According to Dr. Clauw,these drugs are often better tolerated ifa higher percentage of the daily dose istaken at bedtime, such as 600 mg ofgabapentin in the morning and 1200mg at night. Similarly, pregabalincould be divided into 100 mg in themorning and 200 mg at night or 150mg in the morning and 300 mg at night.Adverse events may include fatigue,sedation, nausea, drowsiness, dizzi-ness, and weight gain.73

Possibly EffectiveTreatment Options

Other drugs, such as the dual-reuptake inhibitor/atypical opioid tra-madol,77 the older SSRIs such as fluox-etine,40 GHB,78 and the dopamineagonist pramipexole79 appear to bebeneficial in fibromyalgia despite lesscompelling evidence. Tramadol seemsto be safe and effective for most pa-tients as both monotherapy77 and incombination with acetaminophen.80Dr. Clauw mentioned that the side ef-fect profile for combined tramadol/acetaminophen includes nausea, dizzi-ness, headache, pruritus, constipation,and somnolence, which is similar tothat of tramadol as monotherapy.81

Older SSRIs such as fluoxetine40and paroxetine74 have been foundeffective in some patients with

Pharmacotherapy forPatients With Fibromyalgia

Pharmacotherapy plays an integralrole in the management of fibromyal-gia, but, Dr. Clauw stressed, the mosteffective treatment approach combinespharmacotherapy with adjunctive non-pharmacologic programs. Dr. Clauwstated that 3 classes of drugs havestrong evidence supporting their effi-cacy in fibromyalgia: TCAs, SNRIs,and 2 ligands. Other drugs that maybe efficacious, although the evidenceis less compelling, include tramadol,the older SSRIs, -hydroxybutyrate(GHB), and dopamine agonists. Non-steroidal anti-inflammatory drugs(NSAIDs) and opioids are probably noteffective in the treatment of fibromyal-gia, despite their routine use. Benzo-

ACADEMIC HIGHLIGHTS


fibromyalgia either as monotherapy82,83or in combination with TCAs.40 Fluox-etine monotherapy84 and cycloben-zaprine monotherapy85 have been effi-cacious for certain outcome measuresin fibromyalgia, but the combinationof fluoxetine and cyclobenzaprinedemonstrated the most effective re-sults.85 Amitriptyline is also effectiveas monotherapy treatment for fibro-myalgia, but the combination withfluoxetine was more effective than ei-ther medication on its own.40 Fluoxe-tine and paroxetine are often dosed at10 to 20 mg/day when used for depres-sion, but in fibromyalgia higher dosesmight be required, necessitating dosesas high as 80 mg/day.73 In contrastto TCAs, higher doses of SSRIs aremore useful as analgesics, again be-cause of the enhanced noradrenergicproperties at higher doses.39 Themost common side effects for theseSSRIs include nausea, sedation, head-ache, weight gain, decreased libido,and sexual dysfunction.73

Dr. Clauw described other agentswith mixed reports of efficacy in treat-ing fibromyalgia. The newer SSRI ci-talopram appears to be less effective inthe fibromyalgic population,86 perhapsbecause the older drugs have noradren-ergic activity, especially at higherdoses.39 -Hydroxybutyrate may be ef-ficacious in reducing pain and fatiguebut is most effective in reducing sleepabnormalities associated with fibro-myalgia78; however, GHB is a sched-uled substance because of its abuse po-tential. Pramipexole has also beenshown to be moderately effective inreducing pain and fatigue while im-proving function and global status forpatients with fibromyalgia who weredisabled and/or required narcoticanalgesia.79 Dr. Clauw noted thatpramipexole was associated withweight loss and transient anxiety.

Drugs to AvoidDr. Clauw has observed in routine

clinical practice that NSAIDs and opi-oids are not particularly efficacious,unless the individual has a comorbid

peripheral pain condition, but never-theless these drugs are often used astreatment for fibromyalgia. These an-algesics can be quite helpful in allevi-ating acute pain and so-called periph-eral or nociceptive pain, such as thatwhich occurs with osteoarthritis or ten-donitis, but they are not nearly as effi-cacious for central or neuropathic pain,such as that which occurs in fibromyal-gia.74 An additional risk with opioidtherapy is the development of a sub-stance use disorder.87 Likewise, ben-zodiazepines, hypnotics, and sedativesshould be avoided, as they have notbeen shown to be efficacious in thetreatment of fibromyalgia.

Integrated Treatment ApproachDr. Clauw emphasized the impor-

tance of approaching the treatment offibromyalgia and other chronic painsyndromes with a rehabilitation modelrather than a classic biomedical model,integrating pharmacologic treatmentwith nonpharmacologic therapies.Pharmacologic therapies primarily ad-dress pain or pain processing, whereasnonpharmacologic therapies address

the functional consequences of the pain,such as disability. Strong evidence sup-ports education, aerobic exercise, andCBT as effective treatments for patientswith fibromyalgia,88 addressed later byDr. Goldenberg. Strength training89 andhypnotherapy90 may provide some ben-efit. Dr. Clauw mentioned that tenderpoint injections, despite routine clinicaluse, have not been shown to be effec-tive in the treatment of fibromyalgia.74

ConclusionTricyclic antidepressants often can

lead to global improvements in pain,fatigue, sleep, and other symptoms offibromyalgia. If tricyclic monotherapyis ineffective or intolerable, it shouldbe augmented or replaced with SNRIsand/or 2 ligands. Dr. Clauw statedthat, in many cases, all 3 of these classesof drugs can be used together, with clearsalutary effects from each. Some com-bination of the effective nonpharmaco-logic therapies should also be imple-mented. Effective use of an integratedtreatment plan will have a significant,positive impact on the lives of patientswith fibromyalgia.

Multidisciplinary Modalitiesin the Treatment of Fibromyalgia

Dr. Goldenberg asserted that adiagnosis of fibromyalgia should beenabling rather than disabling, al-though this is an area of controversy.91Some people believe that fibromyal-gia symptoms, such as widespreadpain and fatigue, are a part of dailylife, and pathologizing them may in-crease symptomatology, health careutilization, or anxiety. Dr. Goldenbergstated the diagnosis is only harmfulwhen the patient does not receiveappropriate information about the con-dition. With any chronic symptom-atology, labeling the symptoms is re-assuring, and patients typically stopundergoing multiple diagnostic testswith the fear that something is beingmissed.

Once the patient has been diag-nosed, treatment can begin. Dr.Goldenberg echoed Dr. Clauws as-sertion that the most effect treatmentregimens integrate pharmacologic andnonpharmacologic modalities thatare appropriate to the patient. Dr.Goldenberg described nonpharmaco-logic treatments in greater detail.

Nonpharmacologic TreatmentsSeveral types of nonpharmacologic

strategies for treating fibromyalgiahave been examined, but many studiestested more than 1 strategy at a timeand/or were not controlled. However,patient education, exercise, and CBThave individually or in combinationbeen found to improve mood, physical

ACADEMIC HIGHLIGHTS


functioning, sleep, and self-efficacyand to lessen fatigue and pain.

Education. Education has beenfound to improve self-efficacy andquality of life in patients with fibro-myalgia.92 However, finding enoughtime to properly educate patients withfibromyalgia is challenging for clini-cians. Dr. Goldenbergs time-savingmethod is to schedule several patientswith fibromyalgia on the same day sothat he and/or his staff can lead a groupdiscussion that includes both patientsand family members. The small-groupformat with a didactic lecture followedby questions and discussion is recom-mended.93 After the group meeting, theclinician should allow any patientswho want one-on-one treatment adviceto ask more questions. The group set-ting helps patients learn from theirpeers, and often they establish contactsand bond with other patients.

Common patient questions includethe following:

What is wrong with me? Why do I hurt all over? Why am I so exhausted? Why wont anyone believe me? How did I get fibromyalgia? How is fibromyalgia treated? When will fibromyalgia go

away?

Dr. Goldenberg recommended ad-dressing these questions by discussingpotential pathophysiologic mecha-nisms in fibromyalgia using a bio-psychological model. The clinicianmust dispel the notion that absence oforganic disease means the symptomsare psychogenic.

Dr. Goldenberg recommendedavoiding structural or causation labels.Structural labels used for neck pain,such as torticollis and occipital neu-ralgia, or for back pain, such as sacro-iliac dysfunction, do not have any cre-dence in pathophysiologic models offibromyalgia. Rather, the appropriateterms fibromyalgia or chronic wide-spread pain do not explain illnessbased on structure. Patients shouldknow that they do not have structural

abnormalities, nor is fibromyalgia typi-cally a prodromal phase of another dis-ease. Also, using labels linked to pos-sible causes, such as posttraumaticfibromyalgia, postinfectious fibromyal-gia, or environmental fibromyalgia,should be avoided unless a clear linkexists between the symptoms and thecause, which typically is not the case.

Describing the prognosis and theclinical course is important. Dr.Goldenberg recommending telling pa-tients that, although fibromyalgia is achronic disorder, a waxing and waningcourse is typical. The condition canimprove but only with hard work andself-management on the patients part.A problem that clinicians face whileadvising patients with fibromyalgia ispatient access to pervasive misinfor-mation in commercial books and onthe Internet. He recommended that cli-nicians provide patients with trustwor-thy literature and Web site addresses.

Exercise. Exercise has been shownto be an effective intervention in fibro-myalgia. Patients demonstrated im-provement not only in walking dis-tances but also in Fibromyalgia ImpactQuestionnaire scores, anxiety and de-pression scale scores, and self-efficacyfollowing an exercise regimen of three30-minute exercise classes per weekfor 23 weeks, while patients who didnot participate in the exercise regimentdeclined.94

Because many patients with fibro-myalgia are sedentary, Dr. Goldenbergsaid that the word exercise should bereplaced with activity in the earlystages of treatment. Patients should beinstructed to avoid inactivity and pushfor gradual cardiovascular fitness,stretching, and strengthening. Patientsshould be warned that their pain mightinitially worsen as physical exertionincreases. A general goal is to achievemoderate exercise levels, such as 60%to 75% of their age-adjusted maximumheart rate at least 3 times weekly for atleast 30 to 40 minutes.

CBT. Cognitive-behavioral therapyhas been shown to be effective in themanagement of fibromyalgia.95 Cogni-

tive-behavioral therapy not only im-proves mood and function but alsodecreases pain and fatigue.96 Group orindividual CBT sessions may be used.Dr. Goldenberg explained that CBTcan address bad habits that patientsmay have developed to manage theirillness that actually worsen it, such astrying to do too much on a day theyfeel well and then paying the conse-quences for their overactivity the nextday. Balancing their daily activitylevel can have a salutary effect onpatients overall symptomatology.

Other Nonpharmacologic TherapiesSome complementary and alterna-

tive therapies, including acupunc-ture,97 trigger point injections,98manual treatment including chiroprac-tic99 and massage100 therapies, hypno-therapy,90 biofeedback,101 tai-chi,102and yoga,103 may be effective treat-ments for some patients with fibro-myalgia. Dr. Goldenberg stressed thatthe evidence is tentative and more re-search is needed.

ConclusionDr. Goldenberg concluded that

successfully managing the physicaland mental symptoms of patients withfibromyalgia and related disorders re-quires integrated pharmacologic andnonpharmacologic therapy that is tai-lored to a patients needs. While manytreatments have some data showingefficacy when used alone, multi-disciplinary strategies generally pro-vide better outcomes than monothera-pies.104 Deciding which clinicianshould take charge in the multi-disciplinary treatment of fibromyal-gia is necessary for optimal patientcare.

Drug names: acetaminophen/tramadol(Ultracet and others), citalopram (Celexa andothers), cyclobenzaprine (Amrix, Flexeril,and others), duloxetine (Cymbalta),fluoxetine (Prozac and others), gabapentin(Neurontin and others), paroxetine (Paxil,Pexeva, and others), pramipexole (Mirapexand others), pregabalin (Lyrica), tramadol(Ultram and others), venlafaxine (Effexor andothers), zolpidem (Ambien and others),zopiclone (Lunesta),

ACADEMIC HIGHLIGHTS


Disclosure of off-label usage: The chair hasdetermined that, to the best of his knowledge,citalopram, cyclobenzaprine, duloxetine,fluoxetine, gabapentin, paroxetine,pramipexole, tramadol, venlafaxine,amitriptyline, milnacipran, and-hydroxybutyrate are not approved bythe U.S. Food and Drug Administrationfor the treatment of fibromyalgia.

REFERENCES

1. Wolfe F, Smythe HA, Yunus MB, et al.The American College of Rheumatology1990 Criteria for the Classification ofFibromyalgia. Report of the MulticenterCriteria Committee. Arthritis Rheum1990;33:160172

2. Lawrence RC, Felson DT, Helmick CG, etal. for the National Arthritis DataWorkgroup. Estimates of the prevalence ofarthritis and other rheumatic conditions inthe United States, pt 2. Arthritis Rheum2008;58:2635

3. Arnold LM, Hudson JI, Keck PE, et al.Comorbidity of fibromyalgia and psychiat-ric disorders. J Clin Psychiatry 2006;67:12191225

4. Garrison RL, Breeding PC. A metabolicbasis for fibromyalgia and its related disor-ders: the possible role of resistance to thy-roid hormone. Med Hypotheses2003;61:182189

5. Weir PT, Harlan GA, Nkoy FL, et al. Theincidence of fibromyalgia and its associ-ated comorbidities: a population-based ret-rospective cohort study based on Interna-tional Classification of Diseases, 9thRevision codes. J Clin Rheumatol2006;12:124128

6. Hudson JI, Arnold LM, Keck PE, et al.Family study of fibromyalgia and affectivespectrum disorder. Biol Psychiatry2004;56:884891

7. Arnold LM, Hudson JI, Hess EV, et al.Family study of fibromyalgia. ArthritisRheum 2004;50:944952

8. Wolfe F, Russell IJ, Vipraio G, et al. Sero-tonin levels, pain threshold, and fibromyal-gia symptoms in the general population.J Rheumatol 1997;24:555559

9. Cohen H, Buskila D, Neumann L, et al.Confirmation of an association betweenfibromyalgia and serotonin transporter pro-moter region (5-HTTLPR) polymorphism,and relationship to anxiety-related person-ality traits. Arthritis Rheum 2002;46:845847

10. Offenbaecher M, Bondy B, de Jonge S, etal. Possible association of fibromyalgiawith a polymorphism in the serotonintransporter gene regulatory region. Arthri-tis Rheum 1999;42:24822488

11. Hoefgen B, Schulze TG, Ohlraun S, et al.The power of sample size and homogenoussampling: association between the 5-HTTLPR serotonin transporter polymor-phism and major depressive disorder. BiolPsychiatry 2005;57:247251

12. Yeo A, Boyd P, Lumsden S, et al. Associa-tion between functional polymorphism inthe serotonin transporter gene and diar-rhoea predominant irritable bowl syndromein women. Gut 2004;53:14521458

13. Camilleri M. Is there a SERT-ain associa-

tion with IBS? Gut 2004;53:1396139914. Al-Allaf AW, Dunbar KL, Hallum NS, et

al. A case-control study examining the roleof physical trauma in the onset of fibro-myalgia syndrome. Rheumatology (Ox-ford) 2002;41:450453

15. Harkness EF, Macfarlane GJ, Nahit E, etal. Mechanical injury and psychosocial fac-tors in the work place predict the onset ofwidespread body pain. Arthritis Rheum2004;50:16551664

16. Davis MC, Zautra AJ, Reich JW. Vulner-ability to stress among women in chronicpain from fibromyalgia and osteoarthritis.Ann Behav Med 2001;23:215226

17. McCain GA, Tilbe KS. Diurnal hormonevariation in fibromyalgia syndrome:a comparison with rheumatoid arthritis.J Rheumatol Suppl 1989;19:154157

18. Crofford LJ, Pillemer SR, Kalogeras KT, etal. Hypothalamic-pituitary-adrenal axisperturbations in patients with fibromyalgia.Arthritis Rheum 1994;37:15831592

19. Vaery H, Qiao ZG, Mrkrid L, et al. Al-tered sympathetic nervous system responsein patients with fibromyalgia (fibrositissyndrome). J Rheumatol 1998;16:14601465

20. Bou-Holaigah I, Calkins H, Flynn JA, et al.Provocation of hypotension and pain dur-ing upright tilt table testing in adults withfibromyalgia. Clin Exp Rheumatol1997;15:239246

21. Martnez-Lavn M, Hermosillo AG, RosasM, et al. Circadian studies of autonomicnervous balance in patients with fibromyal-gia: a heart rate variability analysis. Arthri-tis Rheum 1998;41:19661971

22. Stein PK, Domitrovich PP, Ambrose K, etal. Sex effects on heart rate variability infibromyalgia and gulf war illness. ArthritisRheum 2004;51:700708

23. Roizenblatt S, Moldofsky H, Benedito-Silva AA, et al. Alpha sleep characteristicsin fibromyalgia. Arthritis Rheum2001;44:222230

24. Martnez-Lavn M, Hermosillo AG,Mendoza C, et al. Orthostatic sympatheticderangement in subjects with fibromyalgia.J Rheumatol 1997;24:714718

25. Harding SM. Sleep in fibromyalgia pa-tients: subjective and objective findings.Am J Med Sci 1998;315:367376

26. Carli G, Suman AL, Biasi G, et al. Reactiv-ity to superficial and deep stimuli in pa-tients with chronic musculoskeletal pain.Pain 2002;100:259269

27. Ledeboer A, Liu T, Shumilla JA, et al. Theglial modulatory drug AV411 attenuatesmechanical allodynia in rat models of neu-ropathic pain. Neuron Glia Biol2007;2:279291

28. Watkins LR, Milligan ED, Maier SF. Glialproinflammatory cytokines mediate exag-gerated pain states: implications for clini-cal pain. Adv Exp Med Biol 2003;521:121

29. Gracely RH, Petzke F, Wold JM, et al.Functional magnetic resonance imagingevidence of augmented pain processing infibromyalgia. Arthritis Rheum2002;46:13331343

30. Wood PB, Patterson JC II, Sunderland JS,et al. Reduced presynaptic dopamine activ-ity in fibromyalgia syndrome demonstratedwith positron emission tomography: a pilot

study. J Pain 2007;8:515831. White KP, Nielson WR, Harth M, et al.

Chronic widespread musculoskeletal painwith or without fibromyalgia: psychologi-cal distress in a representative communityadult sample. J Rheumatol 2002;29:588594

32. MacFarlane GJ, Thomas E, PapageorgiouAC, et al. The natural history of chronicpain in the community: a better prognosisthan in the clinic? J Rheumatol 1996;23:16171620

33. Mease PJ, Clauw DJ, Arnold LM, et al.Fibromyalgia syndrome. J Rheumatol2005;32:22702277

34. Pope HG Jr, Hudson JI. A supplementalinterview for forms of affective spectrumdisorder. Int J Psychiatry Med1991;21:205232

35. Sayar K, Aksu G, Ak I, et al. Venlafaxinetreatment of fibromyalgia. AnnPharmacother 2003;37:15611565

36. Gendreau RM, Thorn MD, Gendreau JF,et al. Efficacy of milnacipran in patientswith fibromyalgia. J Rheumatol 2005;32:19751985

37. Arnold LM, Lu Y, Crofford LJ, et al, forthe Duloxetine Fibromyalgia Trial Group.A double-blind, multicenter trial compar-ing duloxetine with placebo in the treat-ment of fibromyalgia patients with or with-out major depressive disorder. ArthritisRheum 2004;50:29742984

38. Arnold LM, Rosen A, Pritchett YL, et al.A randomized, double-blind, placebo-controlled trial of duloxetine in the treat-ment of women with fibromyalgia withor without major depressive disorder.Pain 2005;119:515

39. Fishbain D. Evidence-based data on painrelief with antidepressants. Ann Med2000;32:305316

40. Goldenberg D, Mayskiy M, Mossey C, etal. A randomized, double-blind crossovertrial of fluoxetine and amitriptyline in thetreatment of fibromyalgia. Arthritis Rheum1996;39:18521859

41. Mula M, Pini S, Gassano GB. The role ofanticonvulsant drugs in anxiety disorders: acritical review of the evidence. J ClinPsychopharmacol 2007;27:263272

42. Drewes AM, Andreasen A, Jennum P, et al.Zopiclone in the treatment of sleep abnor-malities in fibromyalgia. Scand JRheumatol 1991;20:288298

43. Moldofsky H, Lue FA, Mously C, et al.The effect of zolpidem in patients withfibromyalgia: a dose ranging, double blind,placebo controlled, modified crossoverstudy. J Rheumatol 1996;23:529533

44. Arnold LM, Keck PE Jr, Welge JA. Anti-depressant treatment of fibromyalgia: ameta-analysis and review. Psychosomatics2000;41:104113

45. Crofford LJ, Rowbotham MC, Mease PJ,et al. Pregabalin for the treatment of fibro-myalgia syndrome: results of a random-ized, double-blind, placebo-controlled trial.Arthritis Rheum 2005;52:12641273

46. Arnold LM, Goldenberg DL, Stanford SB,et al. Gabapentin in the treatment of fibro-myalgia: a randomized, double-blind,placebo-controlled, multicenter trial.Arthritis Rheum 2007;56:13361344

47. Hindmarch I, Dawson J, Stanley N. Adouble-blind study in healthy volunteers

ACADEMIC HIGHLIGHTS


to assess the effects on sleep of pregabalincompared with alprazolam and placebo.Sleep 2005;28:187193

48. Foldvary-Schaefer N, De Leon Sanchez I,Karafa M, et al. Gabapentin increasesslow-wave sleep in normal adults.Epilepsia 2002;43:14931497

49. Nicassio PM, Radojevic V, Weisman MH,et al. A comparison of behavioral and edu-cational interventions for fibromyalgia.J Rheumatol 1997;24:20002007

50. Gloaguen V, Cottraux J, Cucherat M, et al.A meta-analysis of the effects of cognitivetherapy in depressed patients. J AffectDisord 1998;49:5972

51. Gould RA, Otto MW, Pollack MP, et al.Cognitive-behavioral and pharmacologicaltreatment of generalized anxiety disorder:a preliminary meta-analysis. Behav Ther1997;28:285305

52. Busch AJ, Barber KA, Overend TJ, et al.Exercise for treating fibromyalgia syn-drome. Cochrane Database Syst Rev2007;4:CD003786

53. Dunn AL, Trivedi MH, Kampert JB, et al.Exercise treatment for depression: efficacyand dose response. Am J Prev Med2005;28:18

54. Arnold LM. Biology and therapy of fibro-myalgia: new therapies in fibromyalgia.Arthritis Res Ther 2006;8:212

55. Zachrisson O, Regland B, Jahreskog M, etal. A rating scale for fibromyalgia andchronic fatigue syndrome (the FibroFatiguescale). J Psychosom Res 2002;52:501509

56. Bennett RM, Jones J, Turk DC, et al. Aninternet survey of 2596 people with fibro-myalgia. BMC Musculoskelet Disord2007;9:27. doi: 10.1186/1471-2474-8-27.Available at http://www.biomedcentral.com/1471-247/8/27. Accessed on Nov 2,2007

57. Katz RS, Heard AR, Mills M, et al. Theprevalence and clinical impact of reportedcognitive difficulties (fibrofog) in patientswith rheumatic disease with and withoutfibromyalgia. J Clin Rheumatol 2004;10:5358

58. Glass JM, Park DC, Minear M, et al.Memory beliefs and function in fibromyal-gia patients. J Psychosom Res2005;58:263269

59. Glass JM, Park DC. Cognitive dysfunctionin fibromyalgia. Curr Rheumatol Rep2001;3:123127

60. Dick B, Eccleston C, Crombez G. Atten-tional functioning in fibromyalgia, rheuma-toid arthritis, and musculoskeletal pain pa-tients. Arthritis Rheum 2002;47:639644

61. Park DC, Glass JM, Minear M, et al. Cog-nitive function in fibromyalgia patients.Arthritis Rheum 2001;44:21252133

62. Glass JM, Park DC, Minear M. Memoryperformance with divided attention infibromyalgia patients. Arthritis Rheum2004;50(suppl 9):S489

63. Leavitt F, Katz RS. Distraction as a keydeterminant of impaired memory in pa-tients with fibromyalgia. J Rheumatol2006;33:127132

64. Glass JM, Park DC, Crofford LJ, et al.Fibromyalgia patients show reducedexecutive/cognitive control in a task-switching test. Arthritis Rheum 2006;54(suppl 9):S610

65. Suhr JA. Neuropsychological impairment

in fibromyalgia: relation to depression,fatigue, and pain. J Psychosom Res2003;55:321329

66. Landro NI, Stiles TC, Sletvold H. Memoryfunctioning in patients with primary fibro-myalgia and major depression and healthycontrols. J Psychosom Res 1997;42:297306

67. Banks S, Dinges DF. Behavioral and physi-ological consequences of sleep restriction.J Clin Sleep Med 2007;3:519528

68. Newcomer JW, Selke G, Melson AK, et al.Decreased memory performance in healthyhumans induced by stress-level cortisoltreatment. Arch Gen Psychiatry1999;56:527533

69. Starkman MN, Giordani B, Berent S, et al.Elevated cortisol levels in Cushings dis-ease are associated with cognitive decre-ments. Psychosom Med 2001;63:985993

70. Sephton SE, Studts JL, Hoover K, et al.Biological and psychological factors asso-ciated with memory function in fibromyal-gia syndrome. Health Psychol2003;22:592597

71. Hart RP, Martelli MF, Zasler ND. Chronicpain and neuropsychological functioning.Neuropsychol Rev 2000;10:131149

72. Glass J, Williams D, Gracely R, et al.Myofascial pain and fibromyalgia relation-ship of self-reported pain, tender pointcount, and evoked pressure pain sensitivityto cognitive function in fibromyalgia.J Pain 2004;5(suppl 1):S38

73. Maizels M, McCarberg B. Antidepressantsand antiepileptic drugs for chronic non-cancer pain. Am Fam Physician2005;71:483490

74. Dadabhoy D, Clauw DJ. Therapy insight:fibromyalgiaa different type of pain need-ing a different type of treatment. Nat ClinPract Rheumatol 2006;2:364372

75. Flexeril (cyclobenzaprine) [package insert].West Point, Pa: Merck; 2001 http://www.fda.gov/cder/foi/label/2003/017821s045lbl.pdf. Accessed on Dec 18,2007

76. Vitton O, Gendreau M, Gendreau J, et al. Adouble-blind placebo-controlled trial ofmilnacipran in the treatment of fibromyal-gia. Hum Psychopharmacol 2004;19(suppl1):S27S35

77. Russell I, Kamin M, Bennett RM, et al. Ef-ficacy of tramadol in treatment of pain infibromyalgia. J Clin Rheumatol2000;6:250257

78. Scharf MB, Baumann M, Berkowitz DV.The effects of sodium oxybate on clinicalsymptoms and sleep patterns in patientswith fibromyalgia. J Rheumatol2003;30:10701074

79. Holman AJ, Myers RR. A randomized,double-blind, placebo-controlled trial ofpramipexole, a dopamine agonist, in pa-tients with fibromyalgia receiving concomi-tant medications. Arthritis Rheum2005;52:24952505

80. Bennett RM, Kamin M, Karim R, et al. Tra-madol and acetaminophen combination tab-lets in the treatment of fibromyalgia pain: adouble-blind, randomized, placebo-con-trolled study. Am J Med 2003;114:537545

81. Bennett RM, Schein J, Kosinski MR, et al.Impact of fibromyalgia pain on health-related quality of life before and after treat-ment with tramadol/acetaminophen.

Arthritis Rheum 2005;53:51952782. Arnold LM, Hess EV, Hudson JI, et al. A

randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine inthe treatment of women with fibromyal-gia. Am J Med 2002;15:191197

83. Patkar AA, Masand PS, Krulewicz S, etal. A randomized, controlled, trial of con-trolled release paroxetine in fibromyalgia.Am J Med 2007;120:448454

84. Wolfe F, Cathey MA, Hawley DJ. Adouble-blind placebo controlled trial offluoxetine in fibromyalgia. Scand JRheumatol 1994;23:255259

85. Cantini F, Bellandi F, Niccoli L, et al.Fluoxetine combined withcyclobenzaprine in the treatment of fibro-myalgia. Minerva Med 1994;85:97100

86. Anderberg UM, Marteinsdottir I, vonKnorring L. Citalopram in patients withfibromyalgia: a randomized, double-blind,placebo-controlled study. Eur J Pain2000;4:2735

87. Fleming MF, Balousek SL, Klessig CL, etal. Substance use disorders in a primarycare sample receiving daily opioidtherapy. J Pain 2007;8:573582

88. Staud R. Treatment of fibromyalgia andits symptoms. Expert Opin Pharmacother2007;8:16291642

89. Busch A, Schachter CL, Peloso PM, et al.Exercise for treating fibromyalgia syn-drome. Chochrane Database Syst Rev2002;3:CD003786

90. Haanen HC, Hoenderdos HT, vanRomunde LK, et al. Controlled trial ofhypnotherapy in the treatment of refrac-tory fibromyalgia. J Rheumatol1991;18:7275

91. White KP, Nielson WR, Harth M, et al.Does the label fibromyalgia alter healthstatus, function, and health service utiliza-tion? a prospective, within-group com-parison in a community cohort of adultswith chronic widespread pain. ArthritisRheum 2002;47:260265

92. Burckhardt CS, Mannerkorpi K,Hedenberg L, et al. A randomized, con-trolled clinical trial of education andphysical training for women with fibro-myalgia. J Rheumatol 1994;21:714720

93. Mannerkorpi K, Henriksson C. Non-pharmacological treatment of chronicwidespread musculoskeletal pain. BestPract Res Rheumatol 2007;21:513534

94. Gowans SE, deHueck A, Voss A, et al.Effect of a randomized, controlled trial ofexercise on mood and physical function inindividuals with fibromyalgia. ArthritisRheum 2001;45:519529

95. Williams DA, Cary MA, Groner KH, etal. Improving physical function status inpatients with fibromyalgia: a brief cogni-tive behavioral intervention. J Rheumatol2002;29:12801286

96. Goldenberg DL, Burckhardt C, CroffordL. Management of fibromyalgia syn-drome. JAMA 2004;292:23882395

97. Duncan B, White A, Rahman A. Acu-puncture in the treatment of fibromyalgiain tertiary care: a case series. AcupunctMed 2007;25:137147

98. Staud R. Are tender point injections ben-eficial: the role of tonic nociception infibromyalgia. Curr Pharm Des2006;12:2327

ACADEMIC HIGHLIGHTS


99. Hains G, Hains F. A combined ischemiccompression and spinal manipulation inthe treatment of fibromyalgia: a prelimi-nary estimate of dose and efficacy.J Manipulative Physiol Ther 2000;23:225230

100. Field T, Diego M, Cullen C, et al. Fibro-myalgia pain and substance P decreaseand sleep improves after massage therapy.J Clin Rheumatol 2002;8:7276

101. Babu AS, Mathew E, Danda D, et al.Management of patients with fibromyal-gia using biofeedback: a randomizedcontrol trial. Indian J Med Sci 2007;61:455461

102. Taggart HM, Arslanian CL, Bae S, et al.Effects of Tai Chi exercise on fibromyal-gia symptoms and health-related qualityof life. Orthop Nurs 2003;22:353360

103. da Silva GD, Lorenzi-Filho G, Lage LV.

Effects of yoga and the addition of TuiNa in patients with fibromyalgia.J Altern Complement Med 2007;13:11071114

104. Sarzi-Puttini P, Buskila D, Carrabba M, etal. Treatment strategy in fibromyalgiasyndrome: where are we now? [publishedonline ahead of print Oct 30, 2007].Semin Arthritis Rheum 2007. doi:10.1016/j.semarthrit.2007.08.008

For the CME Posttest for this ACADEMIC HIGHLIGHTS, see pages 175176.

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for this activity online.To receive up to 2.5 AMA PRA Category 1 CreditsTM, take theextended Posttest online at PSYCHIATRIST.COM, keyword:PCC2. You must complete the entire evaluation onlineto receive the maximum credit.To receive up to 2.0 AMA PRA Category 1 CreditsTM, take thePosttest and send the completed Registration Form to the addressor fax number listed.You must correctly answer at least 70% of the questions in thePosttest to be awarded credit. Unanswered questions will beconsidered incorrect and so scored. Answer sheets, once graded,will not be returned. All replies and results are confidential.The CME Institute of Physicians Postgraduate Press, Inc., willkeep only a record of participation, which indicates that youcompleted the activity and the number of AMA PRA Category 1Credits you have been awarded. Correct answers to the Posttestwill be available upon request after the submission deadline.

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Answers to Pretest: 1. b 2. c

ACADEMIC HIGHLIGHTSGoldenberg et al. pp. 133144

1. According to Bradley, the proposed _____ includes 10psychiatric disorders and 4 medical disorders, whichshare 1 or more physiologic abnormalities importantto their etiology.a. Bipolar disorder spectrumb. Fibromyalgic spectrumc. Affective disorder spectrumd. Rheumatic spectrum

2. Patients with fibromyalgia and a history of majordepressive disorder (MDD) may benefit from treatmentwith serotonin-norepinephrine reuptake inhibitors because,as Arnold mentioned, the dual effects of serotonin andnorepinephrine may be beneficial for both pain and mood.a. Trueb. False

3. Glass stated that all of the following are factors thatcontribute to cognitive problems in patients withfibromyalgia except:a. Psychiatric comorbidityb. Vision problemsc. Sleep disturbancesd. Neuroendocrine abnormalities

4. Which of the following drugs, according to Clauw,have strong evidence to support their efficacy in treatingfibromyalgia?a. Tricyclic antidepressantsb. Nonsteroidal anti-inflammatory drugsc. Opioid antagonistsd. Hypnotics

5. As outlined by Goldenberg, which of the followingnonpharmacologic treatments have the strongest evidencesupporting their effectiveness for the treatment offibromyalgia?a. Cognitive-behavioral therapyb. Exercisec. Group therapyd. All of the above

ACADEMIC HIGHLIGHTSCulpepper et al. pp. 145152

6. The 2 cardinal symptoms of depression include which oneof the following, as noted by Clayton?a. Loss of interest and pleasure in activities that were

previously enjoyableb. Changes in appetite or weightc. Concentration, memory, or decision-making problemsd. Excessive worry

7. Epidemiologic research has found that, among patients withMDD who have a comorbidity, anxiety disorders accountedfor _____% of the 12-month or lifetime comorbid disorders,according to Clayton.a. Less than 10b. 25c. 45d. More than 50

8. Susman stated that the Patient Health Questionnaire(PHQ-9):a. Is tedious to fill outb. Can ascertain whether a patient has depression but should

not be used to assess response during the course of therapyc. Can be self-administeredd. Is the only acceptable diagnostic tool to measure depressive

symptoms in primary care

9. Culpepper stated that depression and/or anxiety may worsenthe course of medical disorders such as arthritis, diabetes,stroke, and cardiovascular disease, but they cannot increasea patients risk of developing these medical disorders.a. Trueb. False

10. According to Lieberman, the mnemonic device BATHEis a technique to help clinicians:a. Remember the secondary symptoms in the criteria for MDDb. Encourage their patients to remain compliant with treatmentc. Elicit psychosocial dimensions of a patients presentationd. None of the above

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