Fibromyalgia Fibromyalgia… Fiend or Feigned Ted D

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Fibromyalgia Fibromyalgia… Fiend or Feigned Ted D Powered By Docstoc
Fiend or Feigned?
     Ted D. Williams
 Pharm D PGY1 Resident
Syracuse VAMC May 2010
•   Spectrum of Disorders
•   Proposed mechanisms
•   Co-morbidities
•   Assessment and diagnosis of fibromyalgia
•   Evidence review on the treatment of
    – Non-pharmacotherapy
    – Pharmacotherapy
            What is Fibromyalgia?
• Chronic Pain Syndrome
   – A group of symptoms
      • Generalized pain
      • Specific trigger points
• Etiology poorly understood
• Treatments are of questionable efficacy
• Several new medications have received FDA indications
  for the treatment of Fibromyalgia
   – Duloxetine (Cymbalta®)
   – Pregabalin (Lyrica®)
   – How do these Non-Formulary medications compare with
     formulary alternatives?
               Spectrum of Disorders

    Where does fibromyalgia fit?

                 Somatic          Myogenic             Disorders
Organic                           Disorder           Or Malingering
                 Disorders                                Faking for
Disease                             Conscious or
                   Physical                           psychosocial or
   e.g.          manifestation                          financial gain
                                   Production of
appendicitis      of mental                          Disparity between
                 disturbances                        stated symptoms
                                     symptoms                and
                                                      physical findings
                          Pain Phases
                                                  1.   Initiation
                                                  2.   Transmission
                                                  3.   Perception
Thalamus                   Gray (PAG)             4.   Reaction
                                              Ceruleus                   Stimulus

                                    Dorsal Horn
                                    (Pain Gate)            Nociceptors
   Sodium Channels                                          Prostaglandins
Proposed Mechanisms of Fibromyalgia
• Intensely studied, poorly understood
• Muscular
  – Strength deficits and atrophy are explained by
• Hyperalgesia
• Hypervigilance
• Somatization
   • Studies extensively
   • Literature replete with positive findings
   • Results have poor repeatability, many confounders, small
     sample size, etc.

• Lautenbacher S; Rollman GB. Possible deficiencies of pain modulation in fibromyalgia. Clinical Journal of Pain. 1997;13:189-96
• Staud, Roland. Abnormal Pain Modulation in Patients with Spatially Distributed Chronic Pain: Fibromyalgia. Rheum Dis Clin North
  Am. 2009;35: 263–274
• Generalized Hypervigilance Hypothesis (GHH)
       – Theorizes that all noxious stimuli (tactile, auditory,
         etc) are amplified
       – Centrally mediated process, rather than peripheral
         pain derangement
       – Some support, but mixed results on non-tactile

• Lollins, M, Harper, D, Gallagher, S et al. Perceived Intensity and Unpleasantness of Cutaneous and Auditory Stimuli: An
  Evaluation of the Generalized Hypervigilance Hypothesis. Pain 2009;141;215-221
                                           Comorbidities of
      • Mood Disturbances
             – Concurrent depression at diagnosis 30%
             – Lifetime prevalence
                    • Depression 74%
                    • Anxiety Disorder 60%
      • Non-Restorative sleep nearly universal
      • Veterans
             – OR 2.32 in deployed vs. non-deployed Gulf War veterans
               after 10 years
             – OR 3.00 in female veterans with PTSD vs. without PTSD

• Perrot, S., et al. Fibromyalgia: Harmonizing science with clinical practice considerations. Pain Practice 2008;8:177-189
• Eisen, et al. Gulf war Veteran’s Health: Medical evaluation of a U.S. cohort. Annals of Internal Medicine 2005:142:881-890
• Dobie, et al. Posttraumatic Stress Disorder in female veterans: Association with self-reported health problems and functional impairment.
  Archives of Internal Medicine 2004;164:394-400
• There is good evidence that NE/5HT plays a
  important role in management of
• Are there underlying genetic polymorphisms
  in NE and 5HT receptors or reuptake inhibitors
  or metabolism that make patients susceptible
  to both mood disturbances and fibromyalgia?
• The debate rages on…
        Summary of Fibromyalgia
      Pathophysiology and Etiology
• Fibromyalgia pain appears to be mediated by
  neurotransmitters (NE,5HT) involved mood
  and sleep
• Fibromyalgia pain manifests peripherally, but
  appears to be centrally mediated
• Rational pharmacotherapy should focus on
  targets of norepinephrine, serotonin, and
  voltage-gated sodium channels
       Diagnostic Criteria of Fibromyalgia
    • 1990 ACR Criteria
            – The combination of
                   • widespread pain
                   • mild or greater
                     tenderness in 11 of
                     18 tender points
            – Sensitivity of 88.4%                                     Applying enough pressure to whiten the
                                                                       examiner's fingernail bed generates
            – Specificity of 81.1%                                     approximately 4 kg/cm2 of pressure

• Wolfe, A. et al. The american college of rheumatology 1990 criteria for the classification of fibromyalgia. Arthritis and Rheumatism 1990;
  33:160 - 172
       Adding Fibromyalgia to the
              problem list
• Fibromyalgia is not equal to generalized pain
• Treatment of fibromyalgia is different than
  other pain syndromes
• Verify the source of the problem list item
  – Chart Lore
  – Patient Reports
  – Specialty clinics
     • Diagnosis should come from Rheumatology
           Fibromyalgia Prognosis
• “Patient with established fibromyalgia, seen in
  rheumatology centers in which there is a special interest in
  the disease and followed up for as long as 7 years, have
  markedly abnormal scores for pain, functional disability,
  fatigue, sleep disturbance, and psychological status, and
  these values do not change substantially over time.”
   – Wolfe, A. et al. Health status and disease severity in
     fibromyalgia. Arthritis and Rheumatism 1997;40:1571-1579
• “If treatments do not work in a sustained and useful way,
  they should not be used.”
   – Wolfe, A. Letter to the editor regarding: Management of
     Fibromyalgia. Annals of Internal Medicine 1999;131:850-858
               Assessment of Fibromyalgia
 • Fibromyalgia Impact Questionnaire (FIQ)
        –    Activities of Daily Living (ADLs)
        –    Pain at various times
        –    Fatigue
        –    Anxiety
        –    Mood
 • Self assessment
 • Easy to use, and provides more information than simple
   pain scores
 • Very sensitive to changes in perceived pain and
   functional status
• Bennett, R. The Fibromyalgia Impact Questionnaire (FIQ): a review of its development, current version, operating characteristics and
  uses. Clinical and experimental rheumatology 2005:S154-162
                    Goals of Fibromyalgia Therapy
        • Primary Goal:
                 – Improve Functional Status
        • Secondary Goals:
                 – Reduce Pain
                 – Streamline therapy
        • Tertiary Goals:
                 – Manage resource utilization
                          • e.g. limit unnecessary testing,
                            and visits
                          • Usually involved setting up
                            scheduled, frequent visits with
                            the appropriate provider
• Perrot, S. Dickenson, AH, Bennett, RM. Fibromyalgia: Harmonizing Science with Clinical Practice Considerations. Pain Practice 2008;8:177–189
• Wolfe, A. et al. Health status and disease severity in fibromyalgia. Arthritis and Rheumatism 1997;40:1571-1579
• Hughes G, Martinez C, Myon E, Taieb C, Wessely S. The impact of a diagnosis of fibromyalgia on health care resource use by primary care patients in the UK: an
  observational study based on clinical practice. Arthritis Rheum.2006;54:177–183.
          Treatment Strategies
• Non-Pharmacological
  – Patient Education
  – Cognitive Behavioral Therapy (CBT)
  – Sleep Hygiene
  – Occupational/Physical Therapy
• Pharmacological
  – Depression/Anxiety Management
  – Pain Management
                  Non-Pharmacological Treatment –
                     Primary Treatment Mode
       • Patient Education
               – Nature of the disease and disease course
               – Modes of therapy (Physical, behavioral, pharmacologic)
               – Goals of therapy (ADL, pain)
       • Cognitive Behavioral Therapy (CBT)
               – Improvements in sleep (50% reduction in sleep disturbances)
               – Improvements in functional status
               – Effects persist while therapy continues
       • Sleep Hygiene
               – Simple sleep hygiene counseling improves symptoms, but not as much
                 as more intensive CBT
       • Physical Therapy
               – Improves functional status but not mood
               – Effects more persistent after discontinuation of therapy than CBT

• Thompson, PA, et al. Effects of a 1.5 day multidisciplinary outpatient treatment program for fibromyalgia. American Journal of Medical Rehabilitation 2003;82:186-191
• Edinger, JD et al. Behavioral Insomnia therapy for fibromyalgia patients. Archives of Internal Medicine 2005;165:2527-2535
• Redondo, JR. et al. Long-term efficacy of therapy in patients with fibromyalgia: A physical exercise-based program and a cognitive-behavioral approach. Arthritis and
  Rheumatism. 2004;51:184-192
    Pharmacological Treatment
• Mood Management
• Pain Management
       Formulary Requirements
• For moderate-to-severe fibromyalgia:
  – Pregabalin
     • restricted to non-response to
         –   max-tolerated gabapentin up to 3,600mg/day
         –   Amitriptyline
         –   Fluoxetine
         –   Venlafaxine
         –   Tramadol + APAP
     • along with exercise and cognitive behavioral program
  – Duloxetine
     • For moderate-to-severe fibromyalgia:
     • Pregabalin is preferred
• Let’s see what the evidence supports…
                      Tricyclic Antidepressants
   • JAMA 2009 Meta Analysis
          – Doses studies were amitriptyline 12.5mg-50mg daily
                 • One nortriptyline study
          – Strong evidence for reduction in
                 •   pain
                 •   fatigue
                 •   mood
                 •   sleep disturbances
          – TCAs had the largest effect size of all antidepressants
          – Durability of Response
                 • Most studies were less than 12 weeks
                 • One study of 26 weeks found no significant change in pain vs. placebo
                 • Leventhal suggested a “holiday” to restore efficacy in case of

• Hauser, W, Bernardy, K, Uceyler, N, Sommer, C. Treatment of fibromyalgia syndrome with antidepressants: a meta analysis. JAMA
• Leventhal, LJ. Management of Fibromyalgia. Ann Intern Med. 1999;131:850-858.
• Duloxetine
       – 2009 JAMA meta analysis of antidepressants in fibromyalgia
                • Improvements found in
                         – Pain
                         – Mood
                         – Sleep
                • No effects found on
                         – Fatigue
                • Effect size smallest in SNRIs and SSRI
       – Russell, IJ, et al. Pain 2008
                • No clear dose-response relationship between 20mg, 60mg and 120mg daily doses
• Venlafaxine
       – Cites a single RCT showing no benefit
                • Phantom Reference , no such article in the journal +/- 2 years, nothing in OVID search of all
       – Open label trials suggest possible benefit
       – Evidence is lacking

 • Hauser, W, Bernardy, K, Uceyler, N, Sommer, C. Treatment of fibromyalgia syndrome with antidepressants: a meta analysis. JAMA 2009;301:198-209
 • Russell, IJ, et al. Efficacy and safety of duloxetine for treatment of fibromylagia in patients with or without major depressive disorder: Results from a 6
   month, randomized, double-blind, placebo-controlled, fixed dose trial. Pain 2008;136:432-444
 • Goldenberg, et al. Management of Fibromyalgia Syndrome. JAMA 2004;292:2388-2395
• 2009 JAMA meta analysis of antidepressants in fibromyalgia
   – Hauser, W, Bernardy, K, Uceyler, N, Sommer, C. Treatment of
     fibromyalgia syndrome with antidepressants: a meta analysis. JAMA
   – Studies were of
       • Fluoxetine 20-80mg
       • Paroxetine (mean 40mg)
       • Citalopram 20-40mg
   – Improvements found in
       • Pain
       • Mood
   – No effects found on
       • Fatigue
       • Sleep
   – Effect size smallest in SNRIs and SSRI
   – These data suggest it isn’t just a mood disorder, otherwise SSRIs would
     be great!
    • Pregabalin FDA Approved
           – Doses below 300mg daily ineffective
           – Most sustained effect at 450-600mg daily
    • Gabapentin off label
           – 1200-2400mg daily
    • Hauser, W. et al 2009
           – 30% pain reduction NNT
                   • Gabapentin 5
                   • Pregabalin (>=300mg/day) 6.6-9.4
           – Significant improvement in pain and FIQ for both
             gabapentin and pregabalin
• Hauser, W. Bernardy, K, Uceyler, Sommer. Treatment of fibromyalgia syndrome with gabapentin and pregabalin – a meta-analysis of
  randomixed controlled trials. Pain 2009;145:69-81.
• No studies have demonstrated efficacy of opioids for the treatment
  of neuropathic or fibromyalgia pain
• Sullivan, MD, Edlund, MJ, Steffick, D, Unutzer, J. Regular use of prescribed
  opioids: association with common psychiatric disorders. Pain
   – Presence of mood disorders is a strong predictor of opioid use
        • (OR 3.15 CI 1.69-5.88, p<0.001)
    – Presence of Panic disorder OR 8.46
        • PTSD not reported
    – Drug abuse disorder OR 4.75
• Mood disorders were historically treated with opioids
• Some evidence for efficacy of opioids for refractory depression and

• Patients may report feeling better, but risk-to-benefit must be
                                 Synthetic Opioids
• Tramadol
     – Has SNRI activity
            • R,R (+) isomer
                   – SERT antagonist
            • S,S (-) isomer
                   – NERT antagonist
     – Low opioid activity
     – Demonstrated superior to placebo in
       improving FIQ and time to
            • Tramadol/Acetaminophen 75mg/650mg
• Tapentadol – new in 2009
     – Has NERT activity, with slight SERT
     – Strong opioid affinity
     – No studies in neuropathic or
       fibromyalgic pain
• Bennett, RM, Kamin, M, Karim, R, Rosenthal, N. Tramadol and Acetaminophen Combination Tablets in the Treatment of Fibromyalgia
  Pain: A Double-Blind, Randomized, Placebo-Controlled Study. The American Journal of Medicine 2003;114:537-545
         NSAIDs & Prednisone
• Goldenberg DL; Burckhardt C; Crofford L.
  Management of Fibromyalgia Syndrome.
  JAMA 2004;292(19):2388-95.
  – No more effective than placebo
             Other Agents
• Pramipexol
• Carisoprodol
• Sodium oxybate
           EBM & Formulary Synthesis
• Parallel, complimentary
• Adequate trials 8 weeks                           NE
    – SSRI Remodeling                               5HT
    – Side effects are bothersome
    – Timing, FIQ, and titration are
    – If not effective, discontinue     Amitriptyline 12.5mg QHS      Gabapentin
• First Line                            May Titrate to 50mg QHS        Titrate to
    – TCA (NE, 5HT, Sleep)                                           400-600mg TID
    – Gabapentin (VSSC)                   SSRI at
• Second Line                            Standard
                                                          75mg QID
    – Tramadol (NE, 5HT)                   Dose
    – SSRI (5HT)                                                        Titrate to
    – Pregabalin (VSSC)                                              100-200mg TID
• Third Line
    – Duloxetine (NE)
   Venlafaxine is formulary
   preferred, but has little evidence    Duloxetine 20-120mg QD
   to support its use
                 Hot Potato –
           Who manages Fibromyalgia?
                                            (+) Diagnosis
                                    (-)No Immunological Component

                                                                        Behavioral Health
            Pain Clinic                                             (+) Psychiatric/behavioral co-
      (-) Opioids are not useful
                                                                    (+) Tx are CBT & psychoactive
(-) Effective pharmacotherapy affects                                        medications
     Behavioral Health treatment
                                                                    (-) Patients dislike implications
• Therapy Goals
   – Fibromyalgia is a chronic pain disorder with a poor prognosis
   – Therapy goals should be improvements in ADL, not necessarily pain score
   – Sleep and mood management are essential
• Pharmacotherapy
   –    Complimentary mechanisms of action should be used in accordance with
        Formulary Guidelines
       • TCAs and Gabapentin
       • SSRI/SNRI/Tramadol and Pregabalin
   –    Opioids have no place in fibromyalgia therapy
       • No demonstrated efficacy in reducing pain scores
       • But patients do feel better
• Therapy Management
   – Assessment tools like FIQ are easy to use and can help compare overall
     function from one medication to the next
   – If an agent isn’t effective after 8-12 weeks, discontinue, don’t just add on
   – Multidisciplinary coordination is essential to provide maximum benefit
     and to control healthcare utilization

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