Download Fibromyalgia Presentation

Fibromyalgia…
Fiend or Feigned?
Ted D. Williams
Pharm D PGY1 Resident
Syracuse VAMC May 2010
Outline
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Spectrum of Disorders
Proposed mechanisms
Co-morbidities
Assessment and diagnosis of fibromyalgia
Evidence review on the treatment of
fibromyalgia
– 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?
Organic
Disease
e.g.
appendicitis
Somatic
Disorders
Myogenic
Disorder
Physical
manifestation
of mental
disturbances
Conscious or
unconscious
Production of
pseudo-neurologic
symptoms
Factitious
Disorders
Or Malingering
Faking for
psychosocial or
financial gain
Disparity between
stated symptoms
and
physical findings
Pain Phases
Limbic
Structures
Periaquiductal
Gray (PAG)
Thalamus
NRPG
1.
2.
3.
4.
Cortex
Initiation
Transmission
Perception
Reaction
NE
(Alpha-2)
NRM
Locus
Ceruleus
NE
5HT
Voltage-Sensitive
Sodium Channels
Stimulus
Dorsal Horn
(Pain Gate)
Nociceptors
Prostaglandins
Proposed Mechanisms of Fibromyalgia
• Intensely studied, poorly understood
• Muscular
– Strength deficits and atrophy are explained by
de-conditioning
• Hyperalgesia
• Hypervigilance
• Somatization
Hyperalgesia
• 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
Hypervigilance
• 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
stimuli
• 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
Fibromyalgia
• 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
Somatization?
• There is good evidence that NE/5HT plays a
important role in management of
Fibromyalgia
• 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%
– Specificity of 81.1%
Applying enough pressure to whiten the
examiner's fingernail bed generates
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)
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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
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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
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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
tachyphylaxis
• Hauser, W, Bernardy, K, Uceyler, N, Sommer, C. Treatment of fibromyalgia syndrome with antidepressants: a meta analysis. JAMA
2009;301:198-209
• Leventhal, LJ. Management of Fibromyalgia. Ann Intern Med. 1999;131:850-858.
SNRIs
• 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
journals
– 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
SSRI
• 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
2009;301:198-209
– 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!
Antiepileptics
• 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.
Opioids
• 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
2005;119:95-103.
– 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
OCD
• Patients may report feeling better, but risk-to-benefit must be
considered
• Tramadol
Synthetic Opioids
– 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
discontinuation
• Tramadol/Acetaminophen 75mg/650mg
4x/day
• Tapentadol – new in 2009
– Has NERT activity, with slight SERT
activity
– 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
Pathways
• Adequate trials 8 weeks
– SSRI Remodeling
– Side effects are bothersome
– Timing, FIQ, and titration are
essential
– If not effective, discontinue
• First Line
– TCA (NE, 5HT, Sleep)
– Gabapentin (VSSC)
• Second Line
– Tramadol (NE, 5HT)
– SSRI (5HT)
– Pregabalin (VSSC)
NE
5HT
VSSC
Amitriptyline 12.5mg QHS
May Titrate to 50mg QHS
SSRI at
Standard
Dose
Tramadol
75mg QID
• Third Line
– Duloxetine (NE)
Venlafaxine is formulary
preferred, but has little evidence
to support its use
Gabapentin
Titrate to
400-600mg TID
Duloxetine 20-120mg QD
Pregabalin
Titrate to
100-200mg TID
Hot Potato –
Who manages Fibromyalgia?
Rheumatology
(+) Diagnosis
(-)No Immunological Component
Behavioral Health
Pain Clinic
(-) Opioids are not useful
(-) Effective pharmacotherapy affects
Behavioral Health treatment
(+) Psychiatric/behavioral comorbidities
(+) Tx are CBT & psychoactive
medications
(-) Patients dislike implications
Summary
• 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