1. Fibromyalgia Natalie Walker, PharmD PGY1 Resident, Lexington VAMC Natalie.Walker@va.gov

2. Objectives Review the epidemiology of fibromyalgia Examine pathophysiology Discuss symptoms Identify diagnostic criteria Describe various treatment strategies

3. 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.

4. Pathophysiology Bradley LA. Pathophysiology of Fibromyalgia. Am J Med. 2009 December; 122(12 Suppl): S22

5. Pathophysiology Bradley LA. Pathophysiology of Fibromyalgia. Am J Med. 2009 December; 122(12 Suppl): S22

6. 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.

7. 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.

8. Symptoms http://www.tipdisease.com/2013/11/fibromyalgia-causes-symptoms-diagnosis.html

9. Associated conditions Rheumatoid arthritis Major Depressive Disorder IBS Abdominal, chest wall pain Pelvic pain Bladder

10. 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.

11. 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

12. 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

13. 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.

14. 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

15. 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.

16. 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.

17. Pharmacologic therapy FDA approved ▫Pregabalin ▫Duloxetine ▫Milnacipran http://www.medscape.org/viewarticle/723919

18. 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

19. Amitriptyline Randomized, double-blind, placebo controlled trial ▫Pain, sleep difficulties, fatigue on awakening, tender point score Treatment groups ▫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.

20. 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

21. 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.

22. 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

23. 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

24. 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.

25. 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

26. 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

27. 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)

28. 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)

29. Pharmacologic therapy http://www.rheumatologynetwork.com/sites/default/files/rm/1476008.png

30. Choosing the right agent Individual symptoms ▫Severe depression  SNRI ▫Sleep disturbances  anticonvulsant Cost Potential adverse effects

31. Questions? Natalie.Walker@va.gov