Workshop agenda

1. Workshop agenda • Welcome and Introductions • Fibromyalgia: What do we know? • Stretch break • Non-drug Treatment of Fibromyalgia • Pharmacologic Treatment of Fibromyalgia • Questions & Answers

2. Fibromyalgia: What do we know? Leslie J. Crofford, M.D. Gloria W. Singletary Professor Chief, Division of Rheumatology & Women’s Health Director, Center for the Advancement of Women’s Health University of Kentucky

3. Fibromyalgia:1990 American College of Rheumatology Criteria • Chronic widespread pain in all four quadrants of the body and the axial skeleton • 11 / 18 tender points (patient experiences pain with 4 kg of pressure)

4. Fibromyalgia Syndrome • Symptoms • Widespread chronic pain • Fatigue • Unrefreshing sleep • Cognitive dysfunction • Depression and anxiety • Regional musculoskeletal pain • Visceral pain

5. Overlapping Systemic Syndromes MULTIPLE CHEMICAL SENSITIVITY - symptoms in multiple organ systems in response to multiple substances FIBROMYALGIA 2 - 4% of population; defined by widespread pain and tenderness CHRONIC FATIGUE SYNDROME 1% of population; fatigue and 4/8 “minor criteria” SOMATOFORM DISORDERS 4% of population; multiple unexplained symptoms - no “organic” findings EXPOSURE SYNDROMES e.g. Gulf War Illnesses, silicone breast implants, sick building syndrome

6. Chronic Multi-symptom Illnesses (CMI) • Term coined by the CDC in 1999 to describe multiple somatic symptoms in Gulf War veterans (Fukuda et. al. JAMA 1999) • This study and subsequent studies in the general population using factor analytic techniques (e.g., Doebbling et. al. Am J Med 2000) identified 3 – 4 symptom factors that cluster in the populations • Multifocal pain • Fatigue • Cognitive difficulties • Psychological symptoms • This and subsequent studies demonstrated that approximately 10 – 15% of the population suffers from a syndrome characterized by two or more of these symptoms

7. Symptom Syndromes • Overlapping syndromes • systemic • regional • Epidemiological studies • Insights into mechanisms • Treatment

8. Tension/migraine headache Affective disorders Temporomandibular joint syndrome Constitutional Weight fluctuations Night sweats Weakness Sleep disturbances Cognitive difficulties ENT complaints (sicca sx., vasomotor rhinits, accommodation problems) Vestibular complaints Multiple chemical sensitivity, “allergic” symptoms Esophageal dysmotility Neurally mediated hypotension, mitral valve prolapse Non-cardiac chest pain, dyspnea due to respiratory mm. dysfunction Interstitial cystitis, female urethral syndrome, vulvar vestibulitis, vulvodynia Regional or Organ-Specific Symptoms and Syndromes Related to CMI Irritable bowel syndrome Nondermatomal paresthesias

9. Many symptoms … Many doctors

10. What causes fibromyalgia and other CMI? • Genetics • “Triggers” • Mechanisms • Disordered sensory processing • Autonomic/neuroendocrine dysfunction • Relationship between physiologic and psychologic factors

11. What causes CMI? • Genetics • “Triggers” • Mechanisms • Disordered sensory processing • Autonomic/neuroendocrine dysfunction • Relationship between physiologic and psychologic factors

12. “Stressors” capable of triggering these illnesses – supported by case-control studies • Infections (e.g., parvovirus, EBV, Lyme, Q fever; not common URI) • Physical trauma (automobile accidents) • Psychological stress / distress • Hormonal alterations (e.g., hypothyroidism) • Drugs • Vaccines • Certain catastrophic events (war, but not natural disasters)

14. FMS symptom domains PAIN NON-PAIN - Generalized - Regional - Visceral - Fatigue - Cognitive Dysfunction - Sleep Disturbance - Depression/Anxiety

15. PAIN

16. Definition of pain “An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage” – International Association for the Study of Pain, 1994

17. What causes fibromyalgia? • Genetics • “Triggers” • Mechanisms • Disordered sensory processing • Autonomic/neuroendocrine dysfunction • Relationship between physiologic and psychologic factors

18. Mechanisms of Pain Brain A-delta – 1st sharp C fiber – 2nd burning, throbbing Willis 1985 Stimulus Spinal cord from Robert Bennett, MD

19. Mechanisms of Pain Chronic pain Central factors typically predominate Acute pain Peripheral nociceptive input from thermal, chemical or mechanical nociceptors Brain Stimulus Spinal cord from Robert Bennett, MD

20. Convergence onto a wide dynamic range neuron (WDR) Touch fiber(myelinated) Brain WDR Pain fiber(unmyelinated)

21. Convergence onto a “sensitized” WDR neuron Allodynia Painfiber Touchfiber

22. Sensory processing in CMI A problem with the “volume control” • Patients display a normal “detection threshold”, but an increased sensitivity, to noxious levels of not only pressure, but also other stimuli, e.g. heat, noise, electrical stimulation. • The general increase in sensory sensitivity could theoretically be due to psychological or physiological factors including: • expectancy • hypervigilance • central changes in nociceptive processing (e.g., sensitization or reduced descending pain inhibition)

23. 450 Fibromyalgia Control 400 350 P<0.001 Pressure (pascals) 300 P<0.001 250 200 150 Tender points Control points Pressure pain Geisser et al. Pain 2003.

24. 53 Fibromyalgia 52 Control 51 P<0.05 50 49 Temperature (ºC) P<0.01 48 47 46 45 44 43 42 Threshold Tolerance Thermal pain Geisser et al. Pain 2003.

25. Functional MRI in chronic pain It is “all in your head” • fMRI takes advantage of magnetic moment of deoxygenated blood, and thus can detect neuronal activations associated with stimuli • Most imaging sequences take advantage of “on-off” paradigms, where the difference between the blood flow in a “neutral” condition (e.g. touch) and pain is imaged • PET and fMRI have identified a number of brain regions involved in pain processing

26. Functional MRI in Fibromyalgia

27. SII SI STG, Insula, Putamen IPL

28. Other fMRI findings • Depression isn’t causing pain • Cognitive factors, i.e. how someone views their pain or reacts to it, are very important • Locus of control • Catastrophizing

29. FMS pain is not “normal” pain, but “central” pain • Clear difference in pain threshold in research studies comparing FMS and normal subjects • Patients’ pain complaints confirmed by studies using objective measures of brain activation • Pain cannot be explained by tissue damage • Pain does not respond well to usual pain treatments • Strong evidence for central factors in FMS pain

30. Treatment Implications for Concept of Central Pain • Treatments usually used for musculoskeletal pain do not work well in most FMS patients • Treatments must address the problems: • Altered pain processing in the spinal cord • Altered descending inhibition of pain signals

31. FATIGUE

32. Chronic Fatigue Syndrome • Chronic fatigue severe enough to limit daily activity and four or more of the following • Myalgia , Arthralgia • Headache • Tender nodes • Sore throats • Unrefreshing sleep • Post exertional malaise • Difficulty with concentration

34. What does “fatigue” mean? • General • Decreased energy, need to rest, sleepiness or unrefreshing sleep, struggle to overcome inactivity • Physical • Weakness, limb heaviness, post-exertional malaise • Emotional • Decreased motivation/interest • Mental (cognitive) • Diminished concentration/memory • Functional • Difficulty completing daily tasks

35. Possible causes of fatigue in fibromyalgia • Sleep disturbance • Pain • Depression/anxiety • Medications • Deconditioning/muscle metabolism • Neurally-mediated hypotension

36. Fatigue clusters with other FMS symptoms N=524-529. Fatigue=Multidimensional Assessment of Fatigue Global Index; Pain=Pain VAS; Sleep=Sleep Problems Index; Dep=HADS Depression; Anxiety=HADS Anxiety. All correlations significant at P>0.0001.

37. COGNITIVE DYSFUNCTION

38. -0.4 -0.8 -1.2 Cognitive Changes Across the Lifespan Digit Symbol Letter Comparison 1.2 Pattern Comparison 0.8 Letter Rotation Line Span 0.4 Computation Span Z-scores Reading Span 0 Benton Rey Cued Recall Free Recall n = 350 Shipley Vocabulary Antonym Vocabulary 20's 30's 40's 50's 60's 70's 80's Synonym Vocabulary Age Groups

39. 32 30 p < .039 28 FM vs AMC 26 24 22 Number Correct Trials 20 18 16 14 12 10 FM Older Age-Matched Controls Controls Working memory

40. p = .80 150 FM vs AMC 140 130 120 Number Correct 110 100 90 80 FM Older Age-Matched Controls Controls Information processing speed

41. Cognitive function in fibromyalgia • Cognitive complaints are accurate • Working memory, “effortful” short-term memory, vocabulary • Unlikely to be explained on the basis of depression or due to global brain dysfunction • Processing speed normal • Depression, anxiety, and sleep measures do not correlate with cognitive performance

42. PSYCHOLOGICAL DISTRESS

43. What causes fibromyalgia? • Genetics • “Triggers” • Mechanisms • Disordered sensory processing • Autonomic/neuroendocrine dysfunction • Relationship between physiologic and psychologic factors

45. Stress-response and fibromyalgia • Symptom onset and exacerbation during periods of stress • Clinical response of symptoms to therapeutic agents that alter stress mediators • Symptoms of FMS can be reproduced by altering HPA axis physiology • Evidence of HPA axis and ANS dysfunction

46. Hypothalamus Pituitary Adrenal Cortex Slow wave sleep Circadian Rhythm Stress CRH ACTH Cortisol 20 Cortisol mg/dL 10 0 700 1300 1900 100 700 Time

47. Central ¯ Reproduction ¯ Slow Wave Sleep ­ Grooming ­ Neophobia ­ Pyramidal Cell FR ­ Locus Coeruleus FR « Eating « Immune Function Stress Hippocampus Amygdala PVN - Hypothalamus Pituitary CRH ACTH Locus Coeruleus Norepinephrine SNS ­ Blood Pressure ­ Heart Rate ¯ Blood Sugar ¯ GI Blood Flow PNS Modulatory Cortisol HPA Axis ­ Gluconeogenesis ­ Lipolysis ­ Proteolysis ­ Insulin Resistance ¯ Inflammation Epinephrine

48. Factors that influence physiologic effects of stress …a stress is not always the same stress • Control • Support • Predictability • Directionality

49. What causes fibromyalgia? • Genetics • “Triggers” • Mechanisms • Disordered sensory processing • Autonomic/neuroendocrine dysfunction • Relationship between physiologic and psychologic factors

50. Depression and anxiety • Mood disturbance is a normal response to feeling unwell and not being capable of functioning at the desired level • Depression is neither necessary nor sufficient for having FMS or a related syndrome • Some of the neurobiologic abnormalities seen in FMS are shared with depression • Can be a barrier to treatment