FibromyalgiaWRAPFibromyalgiaWRAP

Principles and Practice Strategies for Principles and Practice Strategies for FibromyalgiaFibromyalgia

Fibromyalgia Controversies

► Is it real?Is it real?

► What is the relationship with other functional somatic What is the relationship with other functional somatic syndromes?syndromes?

► Can it be reliably diagnosed?Can it be reliably diagnosed?

► Is it physical or psychological?Is it physical or psychological?

► Is there any effective treatment?Is there any effective treatment?

► Is a diagnosis helpful or harmful?Is a diagnosis helpful or harmful?

► What is role of rheumatology?What is role of rheumatology?

Primary Care and Functional Illnesses

► Account for Account for 30-50%30-50% of office visits of office visits► Medical classification: FM, IBS, irritable Medical classification: FM, IBS, irritable

bladder, vulvodynia, non-cardiac chest pain, bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension TMJ, multiple chemical sensitivity, tension headachesheadaches

► Psychiatric classification: Somatization Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, hypochondriasis, conversion disorder, PTSDdisorder, PTSD

► Commonest primary care problemCommonest primary care problem► Specialty referral based on most distressing Specialty referral based on most distressing

syndromesyndrome

Chronic Pain/Suffering Syndromes

► FM is the prototype for a fundamentally different FM is the prototype for a fundamentally different type of pain syndrome where pain is type of pain syndrome where pain is ● Not due to damage or inflammation of peripheral Not due to damage or inflammation of peripheral

tissues tissues ● Frequently accompanied by a variety of other somatic Frequently accompanied by a variety of other somatic

symptoms and syndromessymptoms and syndromes► There are many different “labels” that one can There are many different “labels” that one can

legitimately use for an individual with this type of legitimately use for an individual with this type of pain (if one decides to use any label)pain (if one decides to use any label)● There is no agreed upon, all encompassing term to There is no agreed upon, all encompassing term to

describe this entire spectrum of illnessdescribe this entire spectrum of illness● No medical specialty has accepted “ownership” of No medical specialty has accepted “ownership” of

these patientsthese patients

American College of Rheumatology (ACR) Diagnostic Criteria for FM

► ACR diagnostic criteriaACR diagnostic criteria● History of chronic History of chronic

widespread pain widespread pain ≥3 ≥3 monthsmonths

● Patients must exhibit Patients must exhibit ≥≥11 11 of 18 tender pointsof 18 tender points

► FM can be identified from FM can be identified from among other rheumatologic among other rheumatologic conditions with use of ACR conditions with use of ACR criteria with criteria with good sensitivity (88.4%) and specificity (81.1%)

FM Diagnosis is Very “Physician Dependent”

Modified from Goldenberg JAMA 2004 6

Rule out other conditions that may present with chronic widespread pain (“Operator dependent”)

History of chronic, widespread pain for ≥3 months

Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18)

General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening

serologic tests)

Confirm diagnosis of fibromyalgia

Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation

History of chronic, widespread pain for ≥3 months

Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18)

General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests)

Confirm diagnosis of fibromyalgia

Problems in Defining Fibromyalgia

► ““Real” if no clear pathophysiologic basis?Real” if no clear pathophysiologic basis?► Gold standard is “expert opinion”Gold standard is “expert opinion”► Tender points, symptoms are subjectiveTender points, symptoms are subjective► Fewer than 11 tender points?Fewer than 11 tender points?► Symptoms are not dichotomousSymptoms are not dichotomous► Same diagnostic criteria and dilemma for any Same diagnostic criteria and dilemma for any

illness lacking objective biologic markers illness lacking objective biologic markers (depression, migraine, IBS, CFS)(depression, migraine, IBS, CFS)

Earlier Diagnosis of Fibromyalgia

Long delay in diagnosis adversely affects outcomeLong delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis:Characteristic symptoms speed diagnosis:

““I hurt all over”I hurt all over” ““It feels like I always have the flu”It feels like I always have the flu” Fatigue, Sleep and Mood disturbancesFatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic IBS, Irritable bladder, multiple other somatic

complaints complaints Exclusion of structural or systemic disease

Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral

Structured Interview for Fibromyalgia

A.A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the bodysegments, plus left and right sides of the body

C.C. At least 4 of the following symptoms At least 4 of the following symptoms1. Generalized fatigue1. Generalized fatigue2. Headaches2. Headaches3. Sleep disturbance 3. Sleep disturbance 4. Neuropsychiatric complaints4. Neuropsychiatric complaints5. Numbness, tingling sensations5. Numbness, tingling sensations6. Irritable bowel symptoms6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Pope HG Jr, Hudson JI. Int J Psychiatry MedInt J Psychiatry Med 1991;21(3):205-232 1991;21(3):205-232

A. Widespread pain (axial + upper and lower + L and R sides)

B. 11 of 18 reproducible tender points

C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints,

numbness/tingling, IBS

Explained by no other condition

Fibromyalgia

OROR

Why Do A Tender Point Exam?

► Confirm Dx impressionConfirm Dx impression

► Proxy for pain sensitivityProxy for pain sensitivity

► Compare to joint tendernessCompare to joint tenderness

► Potential prognostic factorPotential prognostic factor

Who Gets Fibromyalgia?

► No concurrent medical illnessNo concurrent medical illness● Any age, but peak age 40-60Any age, but peak age 40-60

● 60-90% female in clinic, although less gender 60-90% female in clinic, although less gender difference in population-based studiesdifference in population-based studies

► Concurrent medical illness (e.g., SLE, RA, OA, Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain in patients with rheumatic or chronic pain disordersdisorders

► Prior medical illness (e.g., Lyme disease, Prior medical illness (e.g., Lyme disease, viral illness)viral illness)

► Medications (steroid taper)Medications (steroid taper)

Medically Unexplained Illnesses Concurrent With Fibromyalgia

► Chronic fatigue syndromeChronic fatigue syndrome► Irritable bowel syndromeIrritable bowel syndrome► Muscle, migraine headachesMuscle, migraine headaches► Irritable bladder syndromeIrritable bladder syndrome► Mood disturbancesMood disturbances► VulvodyniaVulvodynia► Temporomandibular joint (TMJ) disorderTemporomandibular joint (TMJ) disorder

►IN EACH OF THESE: Diagnosis dependent on:IN EACH OF THESE: Diagnosis dependent on:► Exclusion of diseaseExclusion of disease►Symptoms rather than signsSymptoms rather than signs►No reproducible laboratory findingsNo reproducible laboratory findings►Gold standard is “expert opinion”Gold standard is “expert opinion”

Is FM Physical or Psychological?

► Is it a psychiatric illness?Is it a psychiatric illness?► What is the interaction with depression?What is the interaction with depression?► Is it a maladaptive psychosocial response?Is it a maladaptive psychosocial response?► Is it somatization?Is it somatization?► What is the role of stress?What is the role of stress?

FM and Mood Disorders

► At the time of FM diagnosis, mood disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression.are present in 30-50%, primarily depression.

► Increased prevalence of mood disorders is Increased prevalence of mood disorders is primarily in tertiary-referral patients.primarily in tertiary-referral patients.

► Increased lifetime and family history of mood Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0).disorders in FM vs RA (Odds = 2.0).

► Fibromyalgia co-aggregates with major mood Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01).p=0.01).

Arnold LM et al. Arnold LM et al. J Clin Psychiatry J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. 2006;67:1219–1225, Arnold, et al. Arthritis RheumArthritis Rheum 200; 50:944-952 200; 50:944-952

Is Fibromyalgia a Medical or Psychiatric Illness?

► Harmful and unproductive argumentHarmful and unproductive argument► Fruitless quandary to work out what Fruitless quandary to work out what

came firstcame first► For all patients, symptoms are real and can be For all patients, symptoms are real and can be

disablingdisabling► Need a dual treatment approach targeting both Need a dual treatment approach targeting both

physical and psychological symptomsphysical and psychological symptoms

FM and Fragmented Sleep

► Some patients with FM have Some patients with FM have fragmented fragmented sleepsleep, which is associated with involuntary , which is associated with involuntary sleep-related periodic disturbances during sleep-related periodic disturbances during the night. These disturbances includethe night. These disturbances include

Periodic limb movements (PLMs)Periodic limb movements (PLMs) Restless leg syndrome (RLS)Restless leg syndrome (RLS) Sleep apnea Sleep apnea An underlying periodic arousal disturbance in the An underlying periodic arousal disturbance in the

sleep EEG known as sleep related periodic K-alpha sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating or frequent cyclic alternating EEG sleep pattern EEG sleep pattern (CAP) (CAP)

Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287.Jennum P et al. J Rheumatol. 1993;201756-1759.

EEG, electroencephalogram.CAP, cyclic alternating pattern.

► Both have strong genetic predisposition and similar Both have strong genetic predisposition and similar co-morbidityco-morbidity

► Similar sleep disturbancesSimilar sleep disturbances► Similar cognitive disturbancesSimilar cognitive disturbances► Orthostatic features, ANS dysfunctionOrthostatic features, ANS dysfunction► Childhood abuse, stressChildhood abuse, stress► CatastrophizingCatastrophizing► Imaging studiesImaging studies► Neuroendocrine studiesNeuroendocrine studies

Shared Features of FM and Depression:Clues to Pathophysiology

FM Pathophysiologic Pathways

► Genetic factorsGenetic factors● Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-

degree relatives)degree relatives)● No single candidate gene identifiedNo single candidate gene identified

► Central pain augmentationCentral pain augmentation● CSF substance PCSF substance P● Neuroimaging studiesNeuroimaging studies

► Autonomic/neuroendocrine dysfunctionAutonomic/neuroendocrine dysfunction► Immune dysfunction?Immune dysfunction?► Structural changes?Structural changes?

Genetics of Fibromyalgia

► Familial predispositionFamilial predisposition● Most recent work by Arnold, et al suggests >8 odds Most recent work by Arnold, et al suggests >8 odds

ratio (OR) for first-degree relatives, and much less ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive disorders, much stronger with bipolarity, obsessive compulsive disordercompulsive disorder11

► Genes that may be involvedGenes that may be involved● 5-HT5-HT2A2A receptor polymorphism T/T phenotype receptor polymorphism T/T phenotype22

● Serotonin transporterSerotonin transporter33

● Dopamine D4 receptor exon III repeat Dopamine D4 receptor exon III repeat polymorphismpolymorphism44

● COMT (catecholamine o-methyl transferase)COMT (catecholamine o-methyl transferase)55

1. Arnold LM, et al. 1. Arnold LM, et al. Arthritis RheumArthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. . 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis.Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et 1999;6:433-439. 3. Offenbaecher M, et al. al. Arthritis Rheum.Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry.Mol Psychiatry. 2004;9:730-731. 6. G 2004;9:730-731. 6. Güürsoy S, et al. rsoy S, et al. Rheumatol Int.Rheumatol Int. 2003;23:104-107.2003;23:104-107.

“Pain Matrix” – Pain is Processed in at Least Three Domains in CNS

► Sensory - Where it is and how much it hurtsSensory - Where it is and how much it hurts● Primary and secondary somatosensory corticesPrimary and secondary somatosensory cortices● ThalamusThalamus● Posterior insulaPosterior insula

► Affective – Emotional valence of painAffective – Emotional valence of pain● Anterior cingulate cortexAnterior cingulate cortex● Anterior insulaAnterior insula● AmygdalaAmygdala

► Cognitive – Similar to affective plus pre-frontal Cognitive – Similar to affective plus pre-frontal regionsregions

Melzack et al. Melzack et al. Science.Science. 1965;150:971-979. Casey et al. 1965;150:971-979. Casey et al. Headache.Headache. 1969;8:141-153. 1969;8:141-153.

Specific Underlying Mechanisms in Fibromyalgia

► Global problem with sensory processing (i.e. Global problem with sensory processing (i.e. interoception)interoception)● FM patients equally sensitive to loudness of FM patients equally sensitive to loudness of

auditory tonesauditory tones11

● Insular hyper-reactivity consistently seenInsular hyper-reactivity consistently seen2-42-4

● H-MRS studies of glutamate levels in posterior H-MRS studies of glutamate levels in posterior insulainsula55

1. Geisser et. al. 1. Geisser et. al. J. PainJ. Pain (2008); 2. Gracely et. al. (2008); 2. Gracely et. al. Arthritis Rheum.Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum.Arthritis Rheum. 50, 613-623 (2004); 4. Cook 50, 613-623 (2004); 4. Cook J Rheumatol.J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum.Arthritis Rheum. 58, 58, 903-907 (2008). 903-907 (2008).

Neuroimaging in Fibromyalgia

► Hypoperfusion of thalamus and head of the caudate Hypoperfusion of thalamus and head of the caudate nucleus nucleus

► fMRI of cortical response to pain fMRI of cortical response to pain consistent with consistent with augmentated pain perceptionaugmentated pain perception

► In FM, levels of depression did not modulate the sensory In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. activation in the medial region of the brain.

► Castrophizing correlated with pain response in these Castrophizing correlated with pain response in these medial brain regions.medial brain regions.

► Changes in posterior insula glutamate in PET scansChanges in posterior insula glutamate in PET scans

Gracely et al. Arthritis Rheum. 2002;46:1333-1343.Gracely et al. Arthritis Rheum. 2002;46:1333-1343.

Giesecke, et al Arthritis Rheum 2005 52:1577Giesecke, et al Arthritis Rheum 2005 52:1577

Harris, et al Arthritis Rheum 2008 58, 903-907Harris, et al Arthritis Rheum 2008 58, 903-907

Alterations in Descending Analgesic Activity in FM

OpioidsOpioids► Normal or high levels of Normal or high levels of

CSF enkephalinsCSF enkephalins1 1

► Never administered in Never administered in RCT, but most feel that RCT, but most feel that opioids are ineffective or opioids are ineffective or marginally effectivemarginally effective

► Harris recently used Harris recently used PET to show decreased PET to show decreased mu-opioid receptor mu-opioid receptor binding in fibromyalgiabinding in fibromyalgia22

Noradrenergic/SerotonergicNoradrenergic/Serotonergic► Elevated levels of substance P Elevated levels of substance P

in CSF in fibromyalgiain CSF in fibromyalgia33

► Nearly any class of drug that Nearly any class of drug that raises raises bothboth serotonin and serotonin and norepinephrine levels has norepinephrine levels has demonstrated efficacy in demonstrated efficacy in fibromyalgiafibromyalgia

CSF=cerebrospinal fluid; PET=positron emission tomography.1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556.

Is There Any Effective Management of Fibromyalgia?

► All patientsAll patients● Reassurance re diagnosis Reassurance re diagnosis ● Give explanation, including, but not solely, Give explanation, including, but not solely,

psychological factorspsychological factors● Promote return to normal activity, exercisePromote return to normal activity, exercise

► Most patientsMost patients● Medication trial (esp antidepressants, Medication trial (esp antidepressants,

anticonvulsants)anticonvulsants)● Cognitive behavior therapy, counselingCognitive behavior therapy, counseling● Physical rehabilitationPhysical rehabilitation

Initial Treatment of Fibromyalgia

May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic

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

Provide education about fibromyalgia

Confirm diagnosis

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

Evaluate for comorbid medical and psychiatric disorders

Modified from Arnold LM. Arthritis Res Ther 2006;8:212.

FM: From Mechanism to Treatment

► This is primarily a neural This is primarily a neural disease and “central” factors disease and “central” factors play a critical roleplay a critical role

► This is a polygenic disorderThis is a polygenic disorder► There is a deficiency of There is a deficiency of

noradrenergic-serotonergic noradrenergic-serotonergic activity and/or excess levels of activity and/or excess levels of excitatory neurotransmittersexcitatory neurotransmitters

► Lack of sleep or exercise Lack of sleep or exercise increases pain and other increases pain and other somatic sx, even in normalssomatic sx, even in normals

► How FM patients think about How FM patients think about their pain (cognitions) may their pain (cognitions) may directly influence pain levelsdirectly influence pain levels

► Treatments aimed at the periphery Treatments aimed at the periphery (ie, drugs, injections) are not very (ie, drugs, injections) are not very efficaciousefficacious

► There will be sub-groups of FM There will be sub-groups of FM needing different treatmentsneeding different treatments

► Drugs that raise norepinephrine and Drugs that raise norepinephrine and serotonin, or lower levels of serotonin, or lower levels of excitatory neurotransmitters, will be excitatory neurotransmitters, will be efficacious in someefficacious in some

► Exercise, “sleep hygiene,” and other Exercise, “sleep hygiene,” and other behavioral interventions are effective behavioral interventions are effective therapies for biological reasonstherapies for biological reasons

► Cognitive therapies are effective in Cognitive therapies are effective in FM and have a biological substrateFM and have a biological substrate

Rationale for the Use of Central Nervous System Active Medications in FM

► No evidence for muscle pathologyNo evidence for muscle pathology► Current research supports role of augmented central pain mechanismsCurrent research supports role of augmented central pain mechanisms

● Genetic predispositionGenetic predisposition• 5-HT5-HT2A2A receptor polymorphism receptor polymorphism • ↑ ↑ PPain severity in FM patients with T/T genotype ain severity in FM patients with T/T genotype • ↑ ↑ Frequency of S/S genotype in FM patients compared with healthy Frequency of S/S genotype in FM patients compared with healthy

controlscontrols• ↑ ↑ Incidence of COMT polymorphism in FM patientsIncidence of COMT polymorphism in FM patients

● Substance P increased in CSFSubstance P increased in CSF● 5-HT and NE serum levels decreased in some studies5-HT and NE serum levels decreased in some studies● Imaging studiesImaging studies

► Elevated lifetime rates of mood disorders in patients with FMElevated lifetime rates of mood disorders in patients with FM► Elevated rates of mood disorders in first-degree relatives of FM patientsElevated rates of mood disorders in first-degree relatives of FM patients► Sleep disturbancesSleep disturbancesRussell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. .

Medications in FMS

► Strong evidenceStrong evidence for efficacy for efficacy● Amitriptyline, 25-50 mg at bedtimeAmitriptyline, 25-50 mg at bedtime● Cyclobenzaprine, 10-30 mgs at bedtimeCyclobenzaprine, 10-30 mgs at bedtime● Pregabalin, 300-450 mg/dayPregabalin, 300-450 mg/day● Gabepentin, 1600-2400 mg/dayGabepentin, 1600-2400 mg/day● Duloxetine, 60-120 mg/dayDuloxetine, 60-120 mg/day● Milnacipran, 100-200 mg/dayMilnacipran, 100-200 mg/day

► Modest evidenceModest evidence for efficacy for efficacy● Tramadol, 200-300 mg/dayTramadol, 200-300 mg/day● SSRIs (fluoxetine, sertraline)SSRIs (fluoxetine, sertraline)

► Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine

► No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin guaifenesin

Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95.Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95.

Tricylics in Fibromyalgia

AMITRIPTYLINEAMITRIPTYLINE► Four placebo-Four placebo-

controlled trialscontrolled trials● Goldenberg,1985Goldenberg,1985● Carette,1986Carette,1986● Carette,1994Carette,1994

► Dose 25 – 50 mgDose 25 – 50 mg► Duration 6-26 weeksDuration 6-26 weeks► All showed modest All showed modest

efficacyefficacy

CYCLOBENZAPRINECYCLOBENZAPRINE► Four placebo-controlled Four placebo-controlled

trialstrials● Quimby, 1989Quimby, 1989● Carette, 1994Carette, 1994● Reynolds,1991Reynolds,1991

► Dose 10 – 40 mgDose 10 – 40 mg► Duration 4 – 12 weeksDuration 4 – 12 weeks► 2 showed efficacy2 showed efficacy

Arnold L et al. Arnold L et al. Psychosomatics Psychosomatics 2000;41:104-113.2000;41:104-113.

0

20

40

60

80

100

PBO PGB 150 PGB 300 PGB 450

WorseNo ChangeImproved

Pregabalin in Fibromyalgia

Patient Global Impression of ChangePatient Global Impression of Change

Treatment Group (mg/day)Treatment Group (mg/day)

pp < 0.01 < 0.01 vsvs PBO PBO

% P

atie

nts

% P

atie

nts

pp < 0.01 < 0.01 vsvs PBO PBO

Crofford L, et al. Arth Rheum 2005; 52: 1264-1273

Arnold LM, et al. Arnold LM, et al. Pain Pain 2005; 119:5-15.2005; 119:5-15.

Phase III Study: Female Patients (N=354)Phase III Study: Female Patients (N=354)

-3-3

-2-2

-1-1

0000 11 22 44 66 88 1010 1212

WeeksWeeks

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PlaceboPlacebo

Duloxetine 60 mg QDDuloxetine 60 mg QD

Duloxetine 60 mg BIDDuloxetine 60 mg BID

**PP<.05<.05

******PP≤≤.001 vs placebo.001 vs placebo

****** ******

****** ****** ************

******

** ********

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Improvement in Average Pain Severity with Duloxetine

******

(J Rheumatol 2005;32:1975–85)

Milnacipran (3:1)

Not currently available in US. Hlife 8 h, no liver metab

Milnacipran

Number – 1196Number – 1196Parallel, PL controlled, double blindParallel, PL controlled, double blindRandomized to M 100 or 200 mg or placebo for 3 monthsRandomized to M 100 or 200 mg or placebo for 3 monthsCompleters – 810 (68%)Completers – 810 (68%)

Pain composite – VAS - 30% + very much or much impr on PGICPain composite – VAS - 30% + very much or much impr on PGICFM composite – pain composite + 6 pt impr on PCS of SF36 FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ totalSecondary – PGIC, SF36 (PCS and MCS) and FIQ total

Baseline observation carried forward (BOCF) at 3 mnthsBaseline observation carried forward (BOCF) at 3 mnths 39,46% achieved Pain composite, v 25% PL (0.011, 0.015) 39,46% achieved Pain composite, v 25% PL (0.011, 0.015) 25,26% achieved FM composite, v 13% PL (0.025, 0.004)25,26% achieved FM composite, v 13% PL (0.025, 0.004)

Generally well tolerated (discontinuations 34,35% v 28% PL)Generally well tolerated (discontinuations 34,35% v 28% PL)Common AEs – Common AEs – nausea M – 37%, PL -20%nausea M – 37%, PL -20%(both studies) (both studies) headache M – 18%, PL -14%headache M – 18%, PL -14%

constipation M – 16%, PL -4%constipation M – 16%, PL -4% hyperhidrosis M – 9%, PL - 2%hyperhidrosis M – 9%, PL - 2%

NB – no sig hypertension or wt gainNB – no sig hypertension or wt gain

Milnacipran Phase III (3 months,)Milnacipran Phase III (3 months,)

Milnacipran

Milnacipran Phase III (6 months)Milnacipran Phase III (6 months)

Number – 888

Randomized to M 100 or 200 mg or placebo for 6 months

Completers – 511 (58%)

Pain composite - VAS, 30% + very much or much impr on PGIC

FM composite – pain composite + 6 pt impr on PCS of SF36

Secondary – PGIC, SF36 (PCS and MCS) and FIQ total

Baseline observation carried forward (BOCF) at 6 mnths

44,45% achieved Pain composite, v 28% PL (0.056, 0.032)

33,32% achieved FM composite, v 19% PL (0.028, 0.017)

Milnacipran

Nonpharmacologic Strategies: Evidence of Efficacy

Strong EvidenceStrong EvidenceExerciseExercise

Physical and psychological benefitsPhysical and psychological benefitsMay increase aerobic performance and tender May increase aerobic performance and tender

point pain pressure threshold,point pain pressure threshold,and improve painand improve pain

Efficacy not maintained if exercise stopsEfficacy not maintained if exercise stops

Cognitive-behavioral therapyCognitive-behavioral therapyImprovements in pain, fatigue, mood,Improvements in pain, fatigue, mood,

and physical functionand physical functionImprovement often sustained for monthsImprovement often sustained for months

Patient education/self-managementPatient education/self-managementImproves pain, sleep, fatigue, andImproves pain, sleep, fatigue, and

quality of life quality of life

Combination (multidisciplinary therapy)Combination (multidisciplinary therapy)

Modest EvidenceModest EvidenceStrength trainingStrength trainingAcupunctureAcupunctureHypnotherapyHypnotherapyEMG biofeedbackEMG biofeedbackBalneotherapy (medicinal bathing)Balneotherapy (medicinal bathing)Transcranial electrical stimulationTranscranial electrical stimulation

Goldenberg DL, et al. Goldenberg DL, et al. JAMAJAMA. 2004;292:2388-2395; Williams DA, et al. . 2004;292:2388-2395; Williams DA, et al. J RheumatolJ Rheumatol. 2002;29:1280-. 2002;29:1280-1286; Busch AJ, et al. 1286; Busch AJ, et al. Cochrane Database Syst RevCochrane Database Syst Rev. 2002. 2002

Weak EvidenceWeak EvidenceChiropracticChiropracticManual and massage therapyManual and massage therapyUltrasoundUltrasound

No EvidenceNo EvidenceTender-point injectionsTender-point injectionsFlexibility exerciseFlexibility exercise

FM and Prognosis

► Children and individuals treated in primary care Children and individuals treated in primary care settings and those with recent onset of settings and those with recent onset of symptoms generally have a better prognosissymptoms generally have a better prognosis

► Longer-term studies with larger study Longer-term studies with larger study populations are needed to define risk factors for populations are needed to define risk factors for prognosis and to determine outcome relative to prognosis and to determine outcome relative to those risk factorsthose risk factors

Modified from Horizon A and Weisman MH.Modified from Horizon A and Weisman MH.In In Fibromyalgia and Other Pain Related Syndromes.Fibromyalgia and Other Pain Related Syndromes. 2006, p. 401. 2006, p. 401.

Patient, Family Education

► Primary care or specialist setting.Primary care or specialist setting.► Core set of information should always be provided. Core set of information should always be provided. ► Pathophysiology best based on biopsychological Pathophysiology best based on biopsychological

illness model.illness model.► Anticipate common patient questions and concerns.Anticipate common patient questions and concerns.► Recognize the wealth of patient misinformation.Recognize the wealth of patient misinformation.► Encourage patient participation.Encourage patient participation.

Who Should Treat Fibromyalgia?

► More than 50% of visits are to More than 50% of visits are to primary care physiciansprimary care physicians

► Currently, 16% of FM visits are to Currently, 16% of FM visits are to rheumatologistsrheumatologists

► The American College of Rheumatology suggest that The American College of Rheumatology suggest that rheumatologists serve as consultants (tertiary care)rheumatologists serve as consultants (tertiary care)

► Other specialists should include mental health Other specialists should include mental health professionals, professionals, physiatrists and pain managementphysiatrists and pain management expertsexperts

► Physical medicine/rehabilitationPhysical medicine/rehabilitation● Avoiding inactivityAvoiding inactivity● Analgesic advice and non-pharmacologic Analgesic advice and non-pharmacologic

treatment (trigger point injections)treatment (trigger point injections)● Cardiovascular fitness Cardiovascular fitness ● Stretching, strengtheningStretching, strengthening● OT, work rehab, ergonomicsOT, work rehab, ergonomics

► Mental health professionalMental health professional● PsychopharmacologyPsychopharmacology● CounselingCounseling● CBTCBT

Multidisciplinary FM Treatment

Fibromyalgia Controversies

► Does the diagnostic label promote Does the diagnostic label promote helplessness and disability?helplessness and disability?● Only one controlled study; it didn’tOnly one controlled study; it didn’t● Diagnosis should be reassuring and Diagnosis should be reassuring and

end doctor shoppingend doctor shopping● Only if diagnosis is coupled with Only if diagnosis is coupled with

educationeducation

Fibromyalgia Controversies

► Does the diagnosis promote litigation?Does the diagnosis promote litigation?● Not because of the diagnosis but Not because of the diagnosis but

rather medico-legal misconceptionsrather medico-legal misconceptions● This can lead to symptom This can lead to symptom

amplification and rehabilitation amplification and rehabilitation difficultiesdifficulties

● Problems with “causation” Problems with “causation” ● Use headache or fatigue modelsUse headache or fatigue models

-5 0 5-10Years relative to index date

00

5050

100100

151500

202000 95% CI

CaseControl

Rat

e pe

r 100

per

son-

year

sR

ate

per 1

00 p

erso

n-ye

ars

Hughes G, et al. Hughes G, et al. Arthritis Rheum.Arthritis Rheum. 2006;54:177-183. 2006;54:177-183.

•Total Rate of Diagnostic Tests Total Rate of Diagnostic Tests Performed on FM Cases and on Matched Controls (N=2,260)Performed on FM Cases and on Matched Controls (N=2,260)

Positive Impact of Fibromyalgia Diagnosis in Clinical Practice

The vertical line at 0 indicates the date of fibromyalgia diagnosis

Decrease in diagnostic testing and visit rates following diagnosis

As a first-line approach for patients with moderate to severe pain, trial with evidence-based medications for example: Trial with low-dose tricyclic Trial with low-dose tricyclic

antidepressants, SSRI, SNRI, antiseizure medicationantidepressants, SSRI, SNRI, antiseizure medication

Initial Medication and Non-pharmacologic Treatment of Fibromyalgia

Provide additional treatment for comorbid conditions

Encourage exercise according to fitness level

Stress management techniques

Modified From Arnold LM. Modified From Arnold LM. Arthritis Res TherArthritis Res Ther 2006;8:212. 2006;8:212.

Polypharmacy; for example, trial of SSRI in AM and tricyclic in PM, SNRI in AM and anti-seizure drug in PM

Further Medication and Non-pharmacologic Treatment of Fibromyalgia: Often with Specialists’ Input

Trial of additional analgesics such as tramadol

Comprehensive pain management program

Structured rehabilitation program;

Formal mental health program, such as

CBT for patients with prominent psychosocial stressors, and/or difficulty coping, and/or difficulty functioning

Modified from Arnold LM. Modified from Arnold LM. Arthritis Res TherArthritis Res Ther 2006;8:212. 2006;8:212.

Explaining the Typical Outcome in Fibromyalgia

► FM does not herald the onset of a systemic diseaseFM does not herald the onset of a systemic disease► There is no progressive, structural or organ damageThere is no progressive, structural or organ damage► Most patients in specialty practice have chronic, Most patients in specialty practice have chronic,

persistent symptomspersistent symptoms► Primary care patients more commonly report complete Primary care patients more commonly report complete

remission of symptomsremission of symptoms► Most patients continue to work, but 10-15% are disabledMost patients continue to work, but 10-15% are disabled► There is often adverse impact on work and leisure There is often adverse impact on work and leisure

activitiesactivities► Most patients quality of life improves with medical Most patients quality of life improves with medical

managementmanagement

Granges G, Zilko P, Littlejohn GO.Fibromyalgia syndrome: assessment of the severity of the Granges G, Zilko P, Littlejohn GO.Fibromyalgia syndrome: assessment of the severity of the

condition 2 years after diagnosis. J Rheumatol 21:523-529, 1994 condition 2 years after diagnosis. J Rheumatol 21:523-529, 1994

Felson DT, Goldenberg DL. The natural history of fibromyalgia. Arthritis Rheum. 1986;29:1522-1526.Felson DT, Goldenberg DL. The natural history of fibromyalgia. Arthritis Rheum. 1986;29:1522-1526.

Interdisciplinary Pain Management

Integrated Coordinated

Neurologist

Social Worker

Pain Specialist

Physical Therapist

Psychiatrist

Anesthesiologist

Physiatrist

Psychologist

Nurses

Rheumatologist

Occupational Therapist

Pharmacist

Physician Assistant

Primary

Clinician