Download Fibromyalgia

Fibromyalgia
Natalie Walker, PharmD
PGY1 Resident, Lexington VAMC
[email protected]
Objectives
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Review the epidemiology of fibromyalgia
Examine pathophysiology
Discuss symptoms
Identify diagnostic criteria
Describe various treatment strategies
Epidemiology
• Affects > 5 million Americans (2-5% of the
population)
▫ Prevalence increases with age
• Affects women more than men
▫ 3.4% vs 0.5%
• Second most common disorder observed by
rheumatologists
▫ As many as 3 of 4 people with the disorder remain
undiagnosed
• Affects adults & children
Clauw DJ, Arnold LM, McCarberg BH. The Science of Fibromyalgia. Mayo Clin Proc. September 2011;86(9):907-911.
Pathophysiology
Bradley LA. Pathophysiology of Fibromyalgia. Am J Med. 2009 December; 122(12 Suppl): S22
Pathophysiology
Bradley LA. Pathophysiology of Fibromyalgia. Am J Med. 2009 December; 122(12 Suppl): S22
Pathophysiology
• Abnormal central pain processing
▫ Pain transmission neurons become augmented
 Over-activation of postsynaptic nitric oxide
production  increase in presynaptic release of
excitatory amino acids
 Allodynia
 Hyperalgesia
▫ Pain inhibition pathway impairment
 Low serum levels of serotonin
 Low CSF levels of metabolites of serotonin,
norepinephrine and dopamine
Bradley LA. Pathophysiology of Fibromyalgia. Am J Med. 2009 December; 122(12 Suppl): S22
Russell IJ, Vaeroy H, Javors M, Nyberg F , et al. Cerebrospinal fluid biogenic amine metabolites in
fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthritis Rheum. 1992 May; 35(5):550-6.
Symptoms
• Musculoskeletal pain
▫ Both sides of the body, above and below the waist
▫ “Hurt all over”
• Fatigue
▫ Nonrestorative sleep
• Cognitive disturbances
▫ Difficulty with attention and rapid thought changes
• Depression and/or anxiety
• Headache
▫ Migraine, tension headache
• Numbness, tingling, burning in arms & legs
Fuller-Thompson E, Nimigon-Young J, Brennenstuhl S. Individuals with fibromyalgia and depression:
findings from a nationally representative Canadian survey. Rheumatol Int. 2012;32:853.
Symptoms
http://www.tipdisease.com/2013/11/fibromyalgia-causes-symptoms-diagnosis.html
Associated conditions
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Rheumatoid arthritis
Major Depressive Disorder
IBS
Abdominal, chest wall pain
Pelvic pain
Bladder
Causes
• Unknown
• Genetic influence?
▫ More frequent occurrence of an abnormality in the
regulatory region of the serotonin transporter
gene
Offenbaecher M, Bondy B, de Jonge S, et.al. Possible association of fibromyalgia with a polymorphism
in the serotonin transporter gene regulatory. Arthritis Rheum. 1999 Nov; 42(11):2482-8.
Triggers
• Physical trauma
▫ Acute illness/infection
▫ Surgery
▫ Physical injury
 MVA
• Psychosocial
▫ Chronic stress
▫ Emotional trauma
▫ Emotional/physical/sexual abuse
Bradley LA. Pathophysiology of Fibromyalgia. Am J Med. 2009 December; 122(12 Suppl): S22
Diagnosis
• 1990 American
College of
Rheumatology
required pain at
≥ 11 of 18 sites
http://www.uspharmacist.com/continuing_education/ceviewtest/lessonid/108249/
Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the
classification of fibromyalgia: report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33:160-172
Diagnosis
• 2010 American College of
Rheumatology
▫ WPI ≥ 7 and SSS ≥ 5
OR
▫ WPI 3-6 and SSS ≥ 9
▫ Widespread pain for ≥ 3 months
 Both sides of the body, above &
below the waist
▫ No disorder that would otherwise
explain the pain
http://www.uspharmacist.com/continuing_education/ceviewtest/lessonid/108249/
Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology Preliminary Diagnostic Criteria for
Fibromyalgia and Measurement of Symptom Severity. Arthritis Care Res (Hoboken). 2010 May; 62(5):600-610.
Treatment
• Goals
▫ Reduce chronic pain
▫ Improve sleep quality to address fatigue
▫ Improve cognitive function
• Start with non-pharmacologic methods
▫ Some patients respond well enough to avoid drug
therapy
▫ Understanding the illness is essential before
prescribing medications
Non-pharmacologic therapy
• EXPRESS
Hassett AL, Clauw DJ. Medscape Education Rheumatology CME/CE. 6/28/10. http://www.Medscape.org/viewarticle/723919. Accessed 12/28/14.
Benefit of exercise
• Fibromyalgia Impact Questionnaire-based randomized
controlled trial
▫ Perceived physical function, pain, fatigue, depression, tenderness
and aerobic endurance
• Groups
▫ 30 minutes of moderate-intensity 5-7 days/week over 12 weeks
 Incorporated in short bouts throughout the day rather than a block
of 30 minutes
▫ Education, no change in exercise
• 92 adults not previously meeting the above exercise
recommendation for the previous 6 months
• Outcome:
▫ Treatment group had significant reductions in FIQ score
(P=0.03) and pain (P=0.006)
Fontaine KR, Conn L, Clauw DJ. Effects of lifestyle physical activity on perceived symptoms and physical
function in adults with fibromyalgia: results of a randomized trial. Arthritis Res Ther. 2010;12:R55.
Pharmacologic therapy
• FDA approved
▫ Pregabalin
▫ Duloxetine
▫ Milnacipran
http://www.medscape.org/viewarticle/723919
Tricyclic Antidepressants
• First line after non-pharmacological methods
• MOA
▫ Increases 5-HT and NE by blocking the membrane
pump responsible for absorption
• Amitriptyline dose
▫ 5-10 mg prior to bedtime initially, titrating by 5
mg every two weeks
• Adverse effects
▫ Anticholinergic
▫ Use with caution in the elderly
Amitriptyline
• Randomized, double-blind, placebo controlled trial
▫ Pain, sleep difficulties, fatigue on awakening, tender point
score
• Treatment groups
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Amitriptyline 25 mg QHS
Naproxen 500 mg BID
Amitriptyline 25 mg QHS + Naproxen 500 mg BID
Placebo
• Outcomes
▫ Amitriptyline group showed significant improvement in all
outcome parameters
▫ Amitriptyline + naproxen showed improvement not
significantly different than amitriptyline alone
Goldenberg DL, Felson DT, Dinerman H. A randomized, controlled trial of amitriptyline and
naproxen in the treatment of patients with fibromyalgia. Arthritis Rheum. 1986 Nov;29(11):1371-7.
Cyclobenzaprine
• Alternative to amitriptyline for mild-moderate
symptoms
▫ Minimal antidepressant effects
• MOA
▫ Similar to TCAs
• Dose
▫ 10 mg near bedtime initially, titrating to effect
• Adverse effects
▫ Anticholinergic
▫ Sedation
Cyclobenzaprine
• Randomized, double-blind, placebo controlled trial
• Groups
▫ Amitriptyline
▫ Cyclobenzaprine
▫ Placebo
• Outcomes
▫ Amitriptyline was superior to placebo (P=0.002)
▫ Cyclobenzaprine was superior to placebo (P=0.02)
▫ Similar side effects between amitriptyline and
cyclobenzaprine
Carette S, Bell MJ, Reynolds WJ, et al. Comparison of amitriptyline, cyclobenzaprine, and placebo in the
treatment of fibromyalgia. A randomized, double-blind clinical trial. Arthritis Rheum. 1994;37:32.
Serotonin-Norepinephrine Reuptake
Inhibitors (SNRIs)
• Duloxetine
▫ Beneficial for severe depression
▫ MOA
 Inhibits 5-HT and NE reuptake
▫ Dose
 12.5 mg day 1  12.5 mg BID days 2-3  25 mg BID
days 4-7 then 50 mg BID titrating to max dose of
100 mg BID
▫ Adverse effects
 Nausea, constipation, headache, insomnia, dry
mouth
Serotonin-Norepinephrine Reuptake
Inhibitors (SNRIs)
• Milnacipran
▫ Beneficial for severe fatigue
▫ MOA
 12.5 mg day 1  12.5 mg BID days 2-3  25 mg BID
days 4-7 then 50 mg BID titrating to max dose of
100 mg BID
▫ Adverse effects
 Nausea, constipation, headache
Duloxetine
• Randomized, double-blind, placebo controlled, 12 week trial
• Groups
▫ Placebo x 1 week, then duloxetine titrated to 60 mg BID
▫ Placebo
• Outcomes
▫ Fibromyalgia Impact Questionnaire (FIQ) total score
▫ FIQ pain score
▫ Tender point threshold, number of tender points, FIQ (fatigue, tiredness on
awakening, stiffness) scores, Clinical Global Impression of Severity scale,
Patient Global Impression of Improvement scale, Brief Pain Inventory
▫ Whether effects of duloxetine were independent of the presence of MDD
• Results
▫ Duloxetine group had significant improvement in FIQ total score (P=0.027)
▫ Duloxetine group had significant improvement in FIQ pain score during
weeks 1-4 only
Arnold LM, Lu Y, Crofford LJ, et.al. A double-blind, multicenter trial comparing duloxetine with placebo in the
treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum. 2004;50:2974.
Anticonvulsants
• Pregabalin
▫ Beneficial for sleep disturbances
▫ MOA
 GABA analog that binds the alpha(2)-delta site of calcium
channels to block the release of excitatory
neurotransmitters
▫ Dose
 75 mg BID initially, increasing to 150 mg BID within a
week to max dose of 225 mg BID
▫ Adverse effects
 Somnolence, dizziness, dry mouth, weight gain,
peripheral edema
Pregabalin
• Randomized, double-blind, placebo
• controlled, 8 week trial
• Groups
▫ 150 mg/day
▫ 300 mg/day
▫ 450 mg/day
▫ Placebo
• Outcomes measured
▫ Pain from 0-10 recorded in a daily diary
▫ Sleep
▫ Fatigue
▫ Health-related quality of life
• Results
▫ 450 mg/day reduced severity of pain (P<0.001), caused ≥50% improvement
in pain (29% vs 13% in placebo; P=0.003), and improved health-related
quality of life
▫ 450 and 300 mg/day caused significant improvement in sleep quality &
fatigue
Crofford LJ, Rowbotham MC, Mease PJ. et.al., Pregabalin for the treatment of fibromyalgia syndrome:
results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52(4):1264
Anticonvulsants
• Gabapentin
▫ Off-label use
 Pros: cost, not considered a controlled substance
 Cons: limited evidence
▫ MOA
 GABA analog that binds the alpha(2)-delta site of calcium
channels to block the release of excitatory
neurotransmitters
▫ Dose
 100 mg at bedtime initially, titrating over six weeks to
max dose of 2400 mg daily (600 mg BID and 1200 mg
QHS)
Gabapentin
• Randomized, double-blind,
placebo controlled, 12 week trial
• Groups
▫ Gabapentin titrated to maximum
tolerated (1,200-2,400 mg/day)
▫ Placebo
• Outcomes
▫ Average pain score (0-10) on Brief Pain Inventory
▫ Response to treatment (reduction of ≥30%)
• Results
▫ Significantly greater improvement in BPI compared to placebo
(P=0.015)
▫ 51% had response to treatment vs. 31% in placebo group
(P=0.014)
Pharmacologic therapy
http://www.rheumatologynetwork.com/sites/default/files/rm/1476008.png
Choosing the right agent
• Individual symptoms
▫ Severe depression  SNRI
▫ Sleep disturbances  anticonvulsant
• Cost
• Potential adverse effects
Questions?
[email protected]