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

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

3. 3 The Normal Pain Processing Pathway 3. ascending 3.A signal is sent via the ascending tract to the brain, and perceived as pain 2. 2.Impulses from afferents depolarize dorsal horn neurons, then, extracellular Ca 2+ diffuse into neurons causing the release of Pain Associated Neurotransmitters 1. 1.Stimulus sensed by the peripheral nerve (ie, skin) descending 4. The descending tract carries modulating impulses back to the dorsal horn Pain Perceived GlutamateGlutamate Substance PSubstance P 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. Glutamate Substance P Postsynaptic neuron Presynaptic neuron

4. 4 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 fMRI data demonstrated that low-intensity stimuli in patients with FM produce pain comparable to high-intensity stimuli in controls 3 Theory of central sensitization is supported by –Increased levels of pain neurotransmitters 4,5 Glutamate Substance P 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 Gracely RH, et al. Arthritis Rheum. 2002;46:1333-1343. 4 Sarchielli P, et al. J Pain. 2007;8:737-745. 5 Vaerøy H, et al. Pain. 1988;32:21-26.

5. 5 Central Sensitization Produces Abnormal Pain Signaling Perceived pain Ascending input Descending modulation Nociceptive afferent fiber Minimal stimuli Perceived pain (hyperalgesia/allodynia) Induction of central sensitization leading to abnormal pain processing 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. Pain stimuli Normal Pain Processing Pain Processing in FM

6. 6 FM: An Amplified Pain Response Painamplificationresponse Subjective Pain Intensity Stimulus Intensity (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 Normal Pain Response Response

7. 7 fMRI = functional magnetic resonance imaging 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 (i.e., 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

8. 8 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 42.843.0 17.0 12.8 19.3 p<0.001 p<0.03 * 1* 2* 3 CSF = cerebrospinal fluid * 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 FM Patients Healthy Control Subjects

9. 9 Patients with FM Have Elevated Pain Neurotransmitter Glutamate in Their CSF CSF = cerebrospinal fluid Sarchielli P, et al. J Pain. 2007;8:737-745. p<0.003 CSF Level of Glutamate (µg/mL) CSF Levels of Glutamate (n=20)

10. 10 FM Pathophysiology: Summary Central sensitization is a leading theory of FM pathophysiology 1 fMRI data supports FM as a disorder of central pain amplification 2 –Areas activated by high intensity stimuli in control patients were activated by low intensity stimuli in patients with FM Elevated pain neurotransmitters in CSF of patients with FM 3-5 –Several studies showed elevated levels of glutamate and substance P –Elevated levels suggest that this may contribute to pain amplification 1 Staud R and Rodriguez ME. Nat Clin Pract Rheum. 2006;2:90-98. 2 Gracely RH, et al. Arthritis Rheum. 2002;46:1333-1343. CSF = cerebrospinal fluid fMRI = functional magnetic resonance imaging 3 Russell IJ, et al. Arthritis Rheum. 1994;37:1593-1601. 4 Bradley LA, et al. Arthritis Rheum. 1996;suppl 9:212. Abstract 1109. 5 Sarchielli P, et al. J Pain. 2007;8:737-745.