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

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. Regional or Organ-Specific Symptoms and Syndromes Related to CMI 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 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 PAINNON-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 Stimulus Spinal cord Brain from Robert Bennett, MD A-delta – 1 st sharp C fiber – 2 nd burning, throbbing Willis 1985

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

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

21. Pain fiber Touch fiber Convergence onto a “sensitized” WDR neuron Allodynia

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

24. Thermal pain 42 43 44 45 46 47 48 49 50 51 52 53 ThresholdTolerance Temperature (ºC) Fibromyalgia Control P<0.01 P<0.05 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. SI IPL SII STG, Insula, Putamen

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. Cognitive Changes Across the Lifespan 0 0.4 0.8 1.2 20's30's40's50's60's70's80's Digit Symbol Letter Comparison Pattern Comparison Letter Rotation Line Span Computation Span Reading Span Benton Rey Cued Recall Free Recall Shipley Vocabulary Antonym Vocabulary Synonym Vocabulary Age Groups Z-scores n = 350

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

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

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. Pituitary ACTH Stress Cortisol 20 0 700 1300 1900 100 700 10 Slow wave sleep Time Cortisol  g/dL Hypothalamus Adrenal Cortex CRH CircadianRhythm

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

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

51. The Physiological / Psychobehavioral Continuum Physiologic factors Abnormal sensory processing Autonomic and HPA axis dysfunction Smooth muscle dysmotility Psychosocial factors General “distress” Mood disorders (e.g., depression) Cognitions Maladaptive illness behaviors Secondary gain issues Population Primary Care Tertiary Care

52. Symptoms Psychological and behavioral consequences Decreased activity Poor sleep Increased distress Maladaptive illness behaviors Dually focused treatment TRIGGERS POOR ENVIRONMENT BAD GENES

53. Our advice to FM/CFS patients: 1.Focus on what you need to do to get better, not what caused your illness l Look forward, not backwards 2.Look for treatments, not “cures” l We cure very few chronic medical illnesses; FM/CFS is not likely to be one of them 3. Find a health care provider who will work with you l Explain, don’t complain l Suggest a series of short visits each addressing specific issues l Gently educate, with credible sources of information (i.e. scientific articles) l Understand where they’re coming from. 4.Try exercise and CBT l People who recommend them don’t think you’re lazy (exercise) or crazy (CBT)

54. Our advice to FM/CFS patients: 5.Try tested therapies before untested 6.When trying any therapies (tested or untested), do your own personal “clinical trial” 7.When you get worse, don’t assume it is because a treatment has stopped working, and stop your existing treatments, or look to add new treatments l The natural history of these illnesses is to wax and wane l Look for stressors or changes in behavior that may have made symptoms worse instead

55. Our advice to FM/CFS patients 8.When a treatment improves symptoms, you must correspondingly increase function 9.Think very carefully about disability or litigation Almost always is permanent Almost always makes people worse

56. Our advice to FM/CFS patients 10.There is hope! l Most individuals who are treated with existing treatments that are know to work get better, and can live normal lives l There is significant interest by the NIH, pharmaceutical industry in this spectrum of illness. The more money that is spent on studying these illnesses, the more effective we will be at treating them