1. 1 Fibromyalgia: A Chronic Widespread Neurologic Pain Condition PBP00542 © 2009 Pfizer Inc. All rights reserved. Printed in USA/August 2009 Disease Overview and Diagnosis

2. 22 What is Fibromyalgia? Pathogenesis of Fibromyalgia Clinical Features and Diagnosis of Fibromyalgia Management of Fibromyalgia Summary

3. 3 Categorization of Pain Conditions Courtesy of Woolf C. Ann Intern Med. 2004;140:441-451. Chronic Pain Acute Pain Central Pain Amplification Abnormal pain processing by CNS (ie, Fibromyalgia) Nociceptive Pain Noxious stimuli (ie, Burn) Inflammatory Pain Inflammation (ie, Rheumatoid arthritis) Neuropathic Pain Neuronal damage (ie, Herpes zoster)

4. 4 Fibromyalgia (FM): A Chronic Widespread Neurologic Pain Condition FM is a neurological condition associated with chronic widespread pain (CWP) and tenderness 1 American College of Rheumatology (ACR) criteria for the diagnosis of FM: 2 –Chronic widespread pain Pain for ≥3 months Pain above and below the waist Pain on left and right sides of body and axial skeleton –Pain at ≥11 of 18 tender points when palpated with 4 kg of digital pressure 1. Wolfe F, et al. Arthritis Rheum. 1995;38(1):19-28. 2. Wolfe F, et al. Arthritis Rheum. 1990;33:160-172. Diagram showing 18 tender points ACR criteria are both sensitive (88.4%) and specific (81.1%) 2

5. 5 Epidemiology of FM FM is one of the most common CWP conditions 1 Prevalence in United States is estimated to be 2%-5% of the adult population 1 Prevalence in United States is estimated to be 2%-5% of the adult population 1 Impacts a wide range of patients 2 Most patients are between 25 and 60 years of age Women more likely to be diagnosed than men Impacts a wide range of patients 2 Most patients are between 25 and 60 years of age Women more likely to be diagnosed than men FM is highly underdiagnosed 2 Only 1 in 5 is diagnosedOnly 1 in 5 is diagnosed Diagnosis takes an average of 5 years 3Diagnosis takes an average of 5 years 3 FM is highly underdiagnosed 2 Only 1 in 5 is diagnosedOnly 1 in 5 is diagnosed Diagnosis takes an average of 5 years 3Diagnosis takes an average of 5 years 3 1. Wolfe F, et al. Arthritis Rheum. 1995;38:19-28. 2. Weir PT, et al. J Clin Rheumatol. 2006;12:124-128. 3. National Pain Foundation. Available at: http://nationalpainfoundation.org/articles/849/facts-and-statistics. Accessed July 21, 2009.

6. 6 Risk Factors for FM Genetic factors 1 –Relatives of FM patients are at higher risk for FM First-degree relatives are significantly more likely to have FM (Odds ratio=8.5; P =0.0002) Have significantly more tender points Environmental factors 2 –Physical trauma or injury –Infections (Lyme disease, hepatitis C) –Other stressors (eg, work, family, life-changing events) Gender 3 –Women are diagnosed with FM about 7 times as often as men 1. Arnold LM, et al. Arthritis Rheum. 2004;50(3):944-952. 2. Mease PJ. J Rheumatol. 2005;32(suppl 75):6-21. 3. Arnold LM, et al. Arthritis Rheum. 2004;50(9):2974-2984.

7. 77 What is Fibromyalgia? Pathogenesis of Fibromyalgia Clinical Features and Diagnosis of Fibromyalgia Management of Fibromyalgia

8. 8 The Normal Pain Processing Pathway 3. ascending 3.A signal is sent via the ascending tract to the brain, and perceived as pain 2. GlutamateSubstance P 2.Impulses from afferents depolarize dorsal horn neurons, then, extracellular Ca 2+ diffuse into neurons causing the release of Pain Associated Neurotransmitters – Glutamate and Substance P 1. 1.Stimulus sensed by the peripheral nerve (ie, skin) 1. Staud R and Rodriguez ME. Nat Clin Pract Rheumatol. 2006;2:90-98. 2. Gottschalk A and Smith DS. Am Fam Physician. 2001;63:1979-1984. descending 4. The descending tract carries modulating impulses back to the dorsal horn Pain Perceived Glutamate Substance P

9. 9 Central Sensitization: A Theory for Neurological Pain Amplification in FM Central sensitization is believed to be an underlying cause of the amplified pain perception that results from dysfunction in the CNS 1 –May explain hallmark features of generalized heightened pain sensitivity 2 Hyperalgesia – Amplified response to painful stimuli Allodynia - Pain resulting from normal stimuli Theory of central sensitization is supported by: –Increased levels of pain neurotransmitters 3,4 Glutamate Substance P fMRI data demonstrates low intensity stimuli in patients with FM comparable to high intensity stimuli in controls 5 fMRI = functional magnetic resonance imaging 1. Staud R and Rodriguez ME. Nat Clin Pract Rheumatol. 2006;2:90-98. 2. Williams DA and Clauw DJ. J Pain. 2009;10(8):777-791. 3. Sarchielli P, et al. J Pain. 2007;8:737-745. 4. Vaerøy H, et al. Pain. 1988;32:21-26. 5. Gracely RH, et al. Arthritis Rheum. 2002;46:1333-1343.

10. 10 Central Sensitization Produces Abnormal Pain Signaling After nerve injury, increased input to the dorsal horn can induce central sensitization Perceived pain Ascending input Descending modulation Nerve dysfunction Nociceptive afferent fiber Minimal stimuli Perceived pain (hyperalgesia/allodynia) Induction of central sensitization Increased release of pain neurotransmitters glutamate and substance P Pain amplification 1. Adapted from Gottschalk A and Smith DS. Am Fam Physician. 2001;63:1979-1984. 2. Woolf CJ. Ann Intern Med. 2004;140:441-451. Increased pain perception

11. 11 FM: An Amplified Pain Response Painamplificationresponse Subjective pain intensity Stimulus intensity Normal pain response (when a pinprick causes an intense stabbing sensation) Hyperalgesia 10 8 6 4 2 0 Adapted from Gottschalk A and Smith DS. Am Fam Physician. 2001;63:1979-1986. Allodynia (hugs that feel painful) Pain in FM

12. 12 Gracely RH, et al. Arthritis Rheum. 2002;46:1333-1343. fMRI Study Supports the Amplification of Normal Pain Response in Patients With FM 14 12 10 8 6 4 2 0 4.5 1.52.5 3.5 Stimulus intensity (kg/cm 2 ) Pain intensity FM (n=16) Subjective pain control Stimulus pressure control (n=16) Patients with FM experienced high pain with low grade stimuli Yellow: Area of overlap (ie, area activated at high intensity stimuli in control patients was activated by low intensity stimuli in patients with FM) Green: Activated only at high intensity stimulus in controls Red: Activation at low intensity stimulus in patients with FM fMRI = functional magnetic resonance imaging

13. 13 Patients With FM Have Elevated Pain Neurotransmitter Substance P in Their CSF 1. Russell IJ, et al. Arthritis Rheum. 1994;37:1593-1601. 2. Russell IJ, et al. Myopain 1995: Abstracts from the 3 rd World Congress on Myofascial Pain and Fibromyalgia; July 30 - August 3, 1995; San Antonio, TX. 3. Bradley LA, et al. Arthritis Rheum. 1996;suppl 9:212. Abstract 1109. n=32 n=24 n=14 n=32 n=24 n=14 Substance P concentration (fmoles/mL) † n=30 n=24 n=10 n=30 n=24 n=10 16.3 42.843 17 12.83 19.26 P<0.001 P<0.03 * 1* 2* 3 * CSF sample collected via lumbar puncture in FM and healthy controls and SP levels assessed by radioimmunoassay † fmoles/mL = femtomole/mL = 10-15 mole/mL In 3 separate clinical studies, substance P, a pain neurotransmitter, was elevated in FM patients 1-3 CSF = cerebrospinal fluid

14. 14 Patients With FM Have Elevated Pain Neurotransmitter Glutamate in Their CSF Sarchielli et al measured CSF levels of glutamate in 20 FM patients and 20 age-matched controls Significantly higher levels of glutamate were found in FM patients compared with controls Sarchielli P, et al. J Pain. 2007;8:737-745. P<0.003 CSF level of glutamate (µg/mL) CSF Levels of Glutamate CSF = cerebrospinal fluid

15. 15 FM Pathophysiology: Summary Central sensitization is a leading theory of FM pathophysiology 1 Elevated pain neurotransmitters in CSF of patients with FM 2-4 –Several studies showed elevated levels of glutamate and substance P –Elevated levels suggest that this may contribute to pain amplification fMRI data supports FM as a disorder of central pain amplification 5 –Areas activated by high intensity stimuli in control patients were activated by low intensity stimuli in patients with FM 1. Staud R and Rodriguez ME. Nat Clin Pract Rheum. 2006;2:90-98. 2. Russell IJ, et al. Arthritis Rheum. 1994;37:1593-1601. CSF = cerebrospinal fluid fMRI = functional magnetic resonance imaging 3. Bradley LA, et al. Arthritis Rheum. 1996;suppl 9:212. Abstract 1109. 4. Sarchielli P, et al. J Pain. 2007;8:737-745. 5. Gracely RH, et al. Arthritis Rheum. 2002;46:1333-1343.

16. 16 What is Fibromyalgia? Pathogenesis of Fibromyalgia Clinical Features and Diagnosis of Fibromyalgia Management of Fibromyalgia

17. 17 1. Leavitt F, et al. Arthritis Rheum. 1986;29:775-781. 2. Wolfe F, et al. Arthritis Rheum. 1995;38:19-28. 3. Roizenblatt S, et al. Arthritis Rheum. 2001;44:222-230. 4. Staud R. Arthritis Res Ther. 2006;8(3):208-214. 5. Harding SM. Am J Med Sci. 1998;315:367-376. Chronic Widespread Pain 1,2 CORE criteria of FMCORE criteria of FM Pain is in all 4 quadrants of the body ≥3 monthsPain is in all 4 quadrants of the body ≥3 months Patient descriptors of pain include: 4Patient descriptors of pain include: 4 Aching, exhausting, nagging, and hurtingAching, exhausting, nagging, and hurting Tenderness 2 Sensitivity to pressure stimuliSensitivity to pressure stimuli Hugs, handshakes are painfulHugs, handshakes are painful Tender point exam given to assess tendernessTender point exam given to assess tenderness Hallmark features of FM 4Hallmark features of FM 4 HyperalgesiaHyperalgesia AllodyniaAllodynia Other Symptoms 2,3,5 FatigueFatigue Pain-related conditions/symptomsPain-related conditions/symptoms Chronic headaches/migraines, IBC, IC, TMJ, PMSChronic headaches/migraines, IBC, IC, TMJ, PMS Subjective morning stiffnessSubjective morning stiffness Neurologic symptomsNeurologic symptoms Nondermatomal paresthesiasNondermatomal paresthesias Subjective numbness, tingling in extremitiesSubjective numbness, tingling in extremities Sleep disturbanceSleep disturbance Non-restorative sleep, RLSNon-restorative sleep, RLS Clinical Features of FM Other Symptoms

18. 18 Widespread Pain and Tenderness are the Defining Features of FM Wolfe F, et al. Arthritis Rheum. 1990;33:160-172. * * * * In patients with FM, pain involves more areas than other chronic pain conditions *P<0.001

19. 19 Patients With FM Present With a Global Pain Disorder While the ACR classification criteria focuses on 18 points, patients do not usually speak of tender points 1 This is a pain drawing—a patient colors all areas of the body in which they feel pain 2 The diagram shows that the pain of FM is widespread 1 1. Wolfe F, et al. Arthritis Rheum. 1990:33:160-172. 2. Silverman SL and Martin SA. In: Wallace DJ, Clauws DJ, eds. Fibromyalgia & Other Central Pain Syndromes. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2005:309-319. FrontBack Adapted from pain drawing provided courtesy of L Bateman. ACR = American College of Rheumatology

20. 20 ACR-Recommended Manual Tender Point Survey* for the Diagnosis of FM 1. Adapted from Chakrabarty S and Zoorob R. Am Fam Physician. 2007;76(2);247-254. Manual Tender Points Survey: Presence of 11 tender points on palpation to a maximum of 4 kg of pressure (just enough to blanch examiners thumbnail)Presence of 11 tender points on palpation to a maximum of 4 kg of pressure (just enough to blanch examiners thumbnail) OCCIPUT – At nuchal muscle insertion GLUTEAL – Upper outer quadrant of gluteal muscles GREATER TROCHANTER – Muscle attachments just posterior to GT SUPRASPINATUS – At attachment to medial border of scapula TRAPEZIUS – Upper border of trapezius, midportion LOW CERVICAL – Anterior aspects of C5, C7 intertransverse spaces SECOND RIB SPACE – about 3 cm lateral to sternal border ELBOW – Muscle attachments to Lateral Epicondyle KNEE – Medial fat pad of knee proximal to joint line RIGHT FOREARM FOREHEAD LEFT THUMB Control Points Tender Points *Based on 1990 ACR FM Criteria

21. 21 Patients With FM are More Likely to Have Concomitant Chronic Pain Conditions DMBA = Deseret Mutual Benefits Administration SLE = Systemic lupus erythematosus; RA = Rheumatoid Arthritis; IBS = Irritable Bowel Syndrome *Headache = headache, tension headache, migraine † Baseline from 52,698 females and 52,232 males without FM ‡ Risk ratio = The probability of each condition occurring as compared to a normal, healthy control group (baseline=1) Associations of pain-related conditions among patients diagnosed with FM in the DMBA database between 1997 and 2002 1. Weir PT, et al. J Clin Rheumatology. 2006;12(3):124-128. 2. Wolfe F and Rasker JJ. Fibromyalgia. In: Firestein, ed. Kelly’s Textbook of Rheumatology, 8 th Edition. St. Louis, MO: WB Saunders Co; 2008. FM Patients Female n=906 Male n=1689 Baseline † 20% of patients with SLE, RA and OA have concomitant FM 220% of patients with SLE, RA and OA have concomitant FM 2 Because patients with FM are often diagnosed with other pain-related conditions, FM may go undetectedBecause patients with FM are often diagnosed with other pain-related conditions, FM may go undetected ‡

22. 22 1. Goldenberg DL, et al. JAMA. 2004;292:2388-2395. 2. Wolfe F, et al. Arthritis Rheum. 1990;33:160-172. 3. Adapted from White KP, et al. Arthritis Rheum. 2002;47:260-265. Diagnosis of FM Improves Health Satisfaction Lower number indicates improved patient satisfaction BaselinePost-diagnosis Patient health dissatisfaction * *Statistically significant versus baseline (P value not provided) as a change in the 5-point Likert scale

23. 23 What is Fibromyalgia? Pathogenesis of Fibromyalgia Clinical Features and Diagnosis of Fibromyalgia Summary

24. 24 Summary FM is one of the most common chronic widespread neurologic pain conditions 1 –Associated with hyperalgesia and allodynia 2 –Central sensitization is a leading theory to explain FM 3 –Demonstrated by excessive release of the pain neurotransmitters 3 glutamate and substance P FM is commonly seen with other chronic pain-related conditions 4 ACR criteria for the diagnosis of FM are sensitive and specific 5 –History of CWP ≥3 months –Pain in 4 quadrants and axial skeleton –≥11 of 18 tender points FM diagnosis is a key to successful management 6 1. 1. Wolfe F, et al. Arthritis Rheum. 1995;38(1):19-28. 2. Gottschalk A and Smith DS. Am Fam Physician. 2001;63:1979-1984. 3. Staud R and Rodriguez ME. Nat Clin Pract Rheumatol. 2006;2:90-98. 4. Weir PT, et al. J Clin Rheumatol. 2006;12(3):124-128. 5. Wolfe F, et al. Arthritis Rheum. 1990;33:160-172. 6. Goldenberg DL, et al. JAMA. 2004;292:2388-2395.