Fibromyalgia

1. Fibromyalgia Manfred Harth MD FRCPC Professor Emeritus U.W.O

2. Potential Conflicts of Interest Honoraria from : Solvay Jansen-Ortho Pfizer, Bristol-Myers Squibb Boehringer Ingelheim Review board for a Fralex trial Grant support from Eli Lilly. IMEs for several legal firms ,insurance companies,and WSIAT.

3. The Patient Betty M., a 50 year old woman, has developed pain in her neck, shoulders, elbows, forearms, low back, thighs, knees, ankles and feet over the past year. She has fatigue, and a non-refreshing sleep.

4. We therefore immediately suspect that Betty has: a) Polymyalgia Rheumatica b)Rheumatoid Arthritis c) Fibromyalgia d) Galloping hypochondriasis

5. Fibromyalgia (Fibromyalgia Syndrome) is a condition characterized by chronic pain, fatigue, and a non-refreshing sleep.

6. So, she has Fibromyalgia ? Prove it !

7. FMS ACR Classification Criteria At least 3 regions of chronic pain (> 3 months) : 1 above the waist ; 1 below the waist ; 1 on each side of the body ; 1 in the centre of the body.

8. + > 11/18 tender points

9. Betty M has 16 TPs Betty M has Fibromyalgia

10. FM occurs in all ethnic groups, all over the world. Its prevalence is 2-4% About 85% of patients are women The highest prevalence is between 40-60 years of age.

11. Associated Disorders Chronic Fatigue Syndrome Migraine Irritable bowel syndrome Irritable bladder Restless leg syndrome Anxiety state Depression

12. Associated Diseases Endometriosis RA SLE AIDS Lyme Disease Hepatitis C

13. Where is the Problem ?

14. Pathogenesis

15. Central Nervous System Sensitization • Refers to hyperexcitablility of certain spinal cord nerve cells • Characterized by  spontaneous activity, enlarged receptive fields and increased response to sensory input • Pain related to central sensitization does not follow the normal pattern of “nerve territories” (dermatomal distribution)

16. hyperexcitable Second Order Nerve Cerebral Cortex Sensory Nerve (First Order) Thalamus Nociceptors Spinal Cord

17. Normal Sensitized

18. Central Sensitization (cont’d) • Is relevant to FM because it is often associated with extensive secondary hyperalgesia and allodynia Allodynia = pain due to a stimulus that doesn’t normally provoke pain • Several studies (e.g., Staud et al., 2002; 2003) suggest abnormalities in spinal cord processes in FM

19. Quantitative Sensory Testing uses the nociceptive flexion reflex R-III (NFR) • Stimulate Sural nerve (pain pathway) • Measure latency of biceps femoris response

20. Median NFR: • FMS patients median threshold = 22.7 mA (range 17.5-31.7) • Normal controls median threshold = 33 mA (range 28.1-41.0) • FMS vs NC : p<0.001 • Suggest hyperexcitability of spinal cord pain mechanisms in FMS (allodynia)

21. Brain Imaging Research in FM

22. fMRI response to painful heat Normal Control Fibromyalgia DB Cook et al J Rheumatol 2004; 31:364-78

23. Normal Control Fibromyalgia

24. Deficient in FM

26. Pain inhibition Normal controls show activation of rostral anterior cingulate cortex (A), and pulvinar nucleus of thalamus (B) during painful stimulation. K B Jensen et al Pain 2009;144:95-100;

28. Adapted from I J Russell et al Arthritis Rheum 1994;37:1593-1601

29. Nerve growth factor in CSF Adapted from SL Giovengo et al J Rheumatol 1999;26:1564-9

30. 24 hour growth hormone (GH) levels A Leal-Cerro et al J Clin Endocrinol Metab 1999; 84:3378-81

31. Effects of IL-6 on NE blood levels FMS Normal controls DJ Torpy et al Arthritis Rheum 2000; 43: 872-80

32. Brain activity and sleep in FMS Half the patients with FMS have phasic alpha sleep (compared to 7% of controls). All of these have a non-refreshing sleep.* * S Roizenblatt et al Arthritis and Rheum 2001; 44:222-30

33. Other Actors Serotonin, Dopamine, GABA, Glutamate etc…

34. Therapy

35. Betty does not want to use medications at this stage. " What else can I do other than take drugs ??? "

36. Aerobic Exercise ENERGY, PAIN RELIEF,WORK CAPACITY L Brosseau, Wells GA, Tugwell P et al. Physical Thrapy 2008; 88: 857-71

37. Brosseau L et al. Ottawa Panel evidence-based clinical practice guidelines for strengthening exercises in the management Phys Ther. 2008 Jul;88(7):873-86 Strengthening Exercise Pain, Disability, Depression

38. Exercise • Includes aerobic exercise, flexibility and strength training • No consensus about what type,duration or intensity are best

39. Cognitive behavioural therapy ( CBT ) Kati Thieme,Dennis Turk,Herta Flor Arthritis Care Res 2007;57:830-6 3 FM groups (40-43) CBT, OBT, Attention placebo(AP) CBT:focus on patient thinking, problem solving, relaxation. Operant-behavioural therapy : focus on pain behaviour rather than on thought. 15 weekly sessions of 2 hrs each

40. p<0.001 % ge with clinically significant reduction or increase in pain at 12 months p<0.005 % ge with clinically significant reduction or increase in physical impairment at 12 months

41. Betty improves somewhat, but still complains of pain and fatigue. She is ready now to accept the use of medications "What choices have I got ? "

42. TRAMADOL μ opioid receptor agonist Has GABAergic, serotonergic and noradrenergic effects

43. Tramadol • Acts on opioid receptors in brain • Inhibits serotonin and norepinephrine reuptake,therefore interferes with pain transmission in spinal cord • Available in Canada as Tramadol slow release, or with acetaminophen (Tramacet)

44. Tramadol and Acetaminophen Effect on pain Pain score in mm p < 0.001< T+A Placebo RM Bennett et al Am J Med 2003;114:537-45

45. Tricyclic antidepressants AMITRIPTYLINE CYCLOBENZAPRINE & FRIENDS

46. Placebo Cyclobenzaprine Amitriptyline Placebo Cycl Ami S Carette et al Arthritis Rheum 1994; 37:32-40

47. Gabapentin and Pregabalin BLOCK Blockage of α2δ subunit in Ca channel. Reduced release of glutamate,serotonin,noradrenalin,dopamine, substance P.

48. Pregabalin 13 weeks PAIN PJ Mease et al J Rheumatol 2008; 35:502-14

49. Patient global impression of change-PGIC Dropouts 33-41%

50. FIQ improved in 1 trial Pregabalin: Adverse Effects Dizziness Somnolence Headaches Weight gain Edema