1. Muscle Pain Sally Kendall Parker InstituteSK 2004

2. Muscle pain 15% of adult population report chronic pain in the musculoskeletal system DIKE Danish Health and Morbidity Survey 1994 10% adult US population widespread pain, 20% chronic regional pain Wolfe et al J Rheumatology 1997

3. FM Prevalence: ”The end of the continuum?” tenderness % 2- 4% population Clauw 2001

4. Fibromyalgia What is fibromyalgia? How do we diagnose fibromyalgia? What causes fibromyalgia? What is the frequency of FM? How can we treat FM?

5. What is fibromyalgia? Painful, non-articular condition involving muscles Widespread musculoskeletal pain Associated with fatigue, non-refreshing sleep May be part of a wider syndrome

6. Important symptoms in fibromyalgia Muscle pain Decreased endurance Fatigue and Poor sleep ”Exercise” intolerance

7. How do we diagnose fibromyalgia? ACR-1990 Criteria: History of widespread pain Pain in both sides of the body Pain above and below the waist Axial skeletal pain Present for at least three months Wolfe F. et al.Arthritis&Rheumatism, 1990

8. Digital palpation Approximate force of 4 kg A tenderpoint has to be painful at palpation not just ”tender” ACR-1990

9. Fib.Reum.Klin.BDS Pain in 11 of 18 tender points Suboccipital muscle insertions Anterior aspects of lig. intertransverse C5-C7 Midpoint of the upper border of mm. Trapezius Supraspinatus at origins above the scapula Second rib - costochondrale junction 2 cm distal to the laterale epikondyles The upper outer quadrats of buttocks Posterior to the trochanteric prominence Mediale fat pad proximal to the joint line

11. What causes fibromyalgia?

12. Fibromyalgia is a syndrome! Predisposition Key events Mechanisms

13. Predisposition Polygenic predisposition + environment

14. Key events Infections Physical trauma* Psychological stress Hormonal dysfunction Drugs Catastrophes* *Events perceived as stressful

15. Mechanisms Muscle Pain Lund et al Scand J Rheumatol 2003 32 138-45 Nørregaard et al Clin Physiol 1994 14 159-67 Lund et al Scand J Rheumatol 1986 15 165-173 Sensory processing

16. Autonomic dysfunction Backman et al Acta Neurol Scand 1988 77 187-91 Neuroendocrine dysfunction Væroy et al Pain 1988 21-26 Russell et al Arthritis Rheum 1994 37:1593-601

17. Muscle Pain Smerter-en lærebog 2003

18. From Smerte En Lærebog: Graven- Nielsen et al 1997 Referred pain

19. Sensory processing Interaction between ascending and descending pathways Evidence for abnormal central processing of noxious stimuli at cortical and sub-cortical levels leading to allodynia and hyperalgesia Mountz et al Arthritis Rheum 199538: 926-38 Lautenbacher & Rollman Clin J Pain 1997 13 189-96 Kosek et al Pain 1996 2-3 375-83 Bendtsen et al Arthritis Rheum 1997 40 98-102 Gracely et al Arthritis Rheum 2002 36: 1333-43

20. Allodynia Hyperalgesia

21. Autonomic dysfunction Heart rate variability Impaired Stress response: noradrenaline and adrenaline Petzke & Clauw Curr Rheumatol Rep 2000 2: 116-23 review

22. Neuroendocrine dysfunction Serotonin : low in blood Substance P : CSF  Nerve growth factor : CSF  Dynorfin : CSF  Probably NOT causes

23. What is the frequency of FM? Prevalence in the community: 1-3% Primary healthcare 2-6% Rheumatology practices up to 20% 80-90% women

24. Prevalence: ”The end of the continuum?” tenderness % 2- 4% population Clauw 2001

25. Age curve

26. FM och multi-symptom illnesses Overlap! FM 2-4% Chronic Fatigue Syndrome 1% multiple chemical sensitivity exposure syndromes f.eks Gulf War syndrom, silicon breast implanter, sick building syndrome Somatoform disorders 4% Clauw 2001

27. Overlap! Chronic Fatigue Syndrome 21-80% Irritabel Bowel Syndrome 32-80% Temporomandibular Disorder 75% Tension/Migraine Headache 10-80% Multiple Chemical Sensitivities 33-55% Interstitial Cystitis 13-21% Chronic Pelvic Pain 18% Aaron & Buchvald Best Practice & Res 2003 17: 563-74

28. Important symptoms in fibromyalgia patients: 2 Depression 1,2 2-34% Anxiety 2 27% 1 Krag et al Acta Psychiatr Scand 1994 89 370-5 2.Epstein et al Psychomatics 1999 40 57-63

29. Most experimental evidence against pain response bias by hypervigilance BUT psychological factors alter pain reporting and pain behaviour Villemure & Bushnell Pain 2002 95: 195-9 Petzke et al J Rheumatol 2003 30:567-74

30. What treatment is available? Physical therapy Education and cognitive restructuring Multidisciplinary long-term treatment Myofascial therapy Aerobic exercise Drugs

31. Analgesia t Analgesia targets Peripheral pain generators Central pain processes Windup: an increase in pain sensation with time when given repetitive painful stimuli Temporal summation: the additive feeling of pain unpleasantness when painful stimuli continue NMDA receptor: important role in central sensitization DNIC: a system that sends inhibitory signals from the brain stem to the spinal cord => inhibits or filters out ascending pain signals

32. Rao Rheum Dis Clin NA 2003 The Dorsal Horn

33. Paracetamol vs anti inflammatory drugsParacetamol vs anti inflammatory drugs self-rated effectiveness N=1042 Wolfe et al, Arthritis Rheum 2000 43: 378-385

34. Tramadol Rationale opioid μ receptor binding + monoamine reuptake inhibition RCT Russell et al, A&R 1997 40:S117 Effective Biasi et al, Int J Clin Pharm 1998 XV111 13-19  pain Clinical use Bennett et al, Am J Med 2003 114:537-545 Combination with paracetamol effective

35. Opioids Rationale Act on ascending and descending pathways Fentanyl Staud et al Pain 2002 95:195-9 single dose inhibits wind up

36. Opioids Little FM data Problems with side effects and addiction issues Which aspects of pain processing and experience are the target? Fillingim Pain 2003 105: 385-6 Staud et al Pain 2002 95:195-9

37. Meta-analysis tricyclics Rationale increase CNS concentrations by blocking 5-HT- and/or NA-mediated neurotransmission, antihistamine and anticholinergic effects 9 TCA studies »16  14 PBO controlled [5 insufficient data] Duration »3-26 weeks [1 >12 weeks] Arnold et al Psychosomatics 2000 41:104-113

38. Meta-analysis tricyclics Sample size »9-98 /group Effect size »Moderate overall »Best on sleep / less on pain Response »35-37%

39. Fib.Reum.Klin.BDS Comparison Between Fibromyalgia and Depression Patients with FM had more tender points (16,5) than depressed patients (1,3) Fassbender et al Clin Rheum 1997

40. SSRIs Rationale 5-HT reuptake inhibition Fluoxetine Wolfe et al, Scan J Rheum, 1994 23:255-259 no efficacy cf PBO Goldenberg et al, A&R 1996 39:1852-1859 Ami + Fluox  improvements cf monotherapy/PBO Citalopram (most selective) Norregaard et al, Pain 1995 61:445-449 No efficacy cf PBO Anderberg et al, Eur J Pain 2000 4:27-35  depressive symptoms No other efficacy cf PBO

41. Pain transmission modulators: SSRIs Sertraline Alberts et al, A&R 1998 41:S259  pain threshold Celiker et al ACR 2000 Ser 50mg/d compared to Ami 25mg/d Both  pain,fatigue,sleep disturbance,stiffness, tender point count Fluvoxamine Nishikai et al, J Rheum 2003 30:1124-25 As effective as Ami  pain

42. NA/5HT reuptake blockers Venlaxafine Dwight et al, Psychosomatics 1998, 39:14-17 6/11 improved 50% in 55% small numbers, open study, max. tolerated dosage Sayar et al J Psychosomatic Res 2003 55:147-8 Pain, function, depression, anxiety improved small numbers, open study Zijlstra et al Arthritis Rheum 2002 46: S105 RCT no effect (lower dosage)

43. Reboxetin Browne & Chong 10th World Congresson Pain report 2002 Open label, 25 patients better pain and fatigue

44. Target:Sleep Zopiclone Drewes et al, Scan J Rheum 1991,20:288-293 sleep better, pain + stiffness same Zolpidem Moldofsky et al, J Rheum 1996, 23:529-533 sleep better, pain + TePs + stiffness same

45. Side Effects Tramadol: nausea, vomiting, CNS, pruritus, rash TCA: urinretention, ileus, dry mouth SSRI : nausea, vomiting,CNS, sexual dysfunction, hyponatremi, serotonergic syndrome (hyperthermia + muscle spasmer +CNS/autonomic symptoms)

46. Future therapies? Gabapentin Cation channel blocker, GABAergic transmission enhancer role in FM? Case reports Pregabalin (anti eptileptic drug) Crofford et al, 2002 ACR S613 RCT dose-response 8wk trial effective  pain,fatigue,sleep disturbance,global assessment Milnacipran Gendreau et al, J of Pain 2003 4: Supp 1:80 NA+5-HT blockade + NMDA antagonism Phase 11 trials published Better pain, fatigue, mood

47. Future therapies? Rationale 5-HT3 antagonists Tropisetron Samborski et al Materia Medica Polona 1996 28: 17-9 19 in open trial  pain and tenderness,  vegetative symptoms Ondansetron Stratz et al Zeischrift fur Rheumatologie 1994 53: 335-8 crossover design  pain and tenderness in 14/34

48. Future therapies? NMDA antagonists NK 1 antagonists α 2 agonists

49. In the morning they asked her how she had slept. ”Dreadfully!” said the princess. ”I hardly got a wink of sleep all night! Goodness knows what can have been in the bed! There was something hard in it and now I´m just black and blue all over! It is really dreadful!” ……Only a real princess could be so tender as that. The princess and the pea by Hans Christian Andersen

50. Parker Instituttet