1. Fibromyalgia --- from pathophysiology to evidence-based treatment 財團法人為恭紀念醫院 精神科 鄧方怡醫師

2. Conceptual evolution

3. The misnomer of “fibrositis”  Clinical descriptions of fibromyalgia have been reported since mid-1800s  In 1904, Sir William Gowers introduced the term "Fibrositis" to describe the inflammation of fibrous tissue in his description of low back pain.  Also In 1904, Ralph Stockman first reported evidence of inflammatory changes in the fibrous, intra-muscular septa on biopsies from patients

4. The misnomer of “fibrositis”  However, subsequent studies of muscle biopsies have failed to reproduce Stockman’s findings.  Various terms, included neurasthenia, fibrositis, fibromyositis, psychogenic, psychosomatic, muscular rheumatism, had been applied in subsequent years.  Yet the term fibrositis has been most resilient and "eventually became synonymous with idiopathic local or diffuse musculoskeletal pain of any type"

5. Recent development  In the 1970’s, Hench first introduced the term "fibromyalgia".  In the 1980’s, Yunus, proposed the need for a unified classification system as well as the first diagnostic criteria.  Finally, in 1990, the American College of Rheumatology established firm criteria for the classification and diagnosis of fibromyalgia

6. Diagnostic Labels For Fibromyalgia Syndrome  DaCosta Syndrome/Shell Shock (brain)  Neurasthenia (nerves)  Chronic Brucellosis (viral)  Failure to Cope (psychological)  Fibrositis (muscle inflammation)  Affective Spectrum Disorder (depressive disorder)  Fibromyalgia

7. The ACR criteria  1. History of widespread pain for 3 months in combination with  2. Tenderness at 11 or more of 18 specific tender points sites when digitally palpated with about 4 kg/1.4cm2 per unit area of force  3. No exclusions are made for the presence of concomitant radiographic or laboratory abnormalities

8. Location of tender points. * Represents "control" points.

9. Clinical presentation

10. What is Fibromyalgia  Pain ---Clinical and experimental ---Lower pain threshold, allodynia, and hyperalgesia ---Involves musculoskeletal structures, skin, and in some cases, viscera  Behavioral disturbances: ---Reduced activity, social interaction, function ---Avoidance of events that evoke pain ---Affective distress ---Increased usage of health services

11. Neuropsychological symptoms %

12. The Criticism of ACR criteria  Many patients with chronic widespread pain may have les than the 11 of 18 tender points  Artificially increase the female predominance  Select for individuals with higher levels of disease-related distress  Fail to capture the “essence”

13. Epidemiology

14. Prevalence  10~11% of the population has chronic widespread pain at ay given time  1/5 of above meet the ACR criteria of fibromyalgia  3.4% in women versus 0.5% in men  It occurs in 5%~6% of adult patients presenting at general medical practice and in 10%~20% of adult patients presenting to rheumatologists.  2nd most common disorder observed by rheumatologists

15. Comorbidity  80%:chronic fatigue syndrome  80%:have headaches  75%:temporomandibular disorders  60%:irritable bowel syndrome

16. FMS is Multi-system—not just muscles  Chronic Fatigue Syndrome  Non-restorative Sleep  Cognitive Problems (“fibro fog”)  Irritable bowel  Irritable bladder  Chronic headache  Vulvodynia  Orthostatic Hypotension  Postural Orthostatic Tachycardia (POTS)  Anxiety  Depression  Delayed Post Exertional Flare-Up

17. Disability  25.3% of patients received disability payments. However, only 25% of these were specifically for the diagnosis.  31% of patients employed prior to onset of their FM reported loss of employment due to their disease  The disability associated with FM does not change substantially over time according to one 7 year cohort study

18. Pathophysiology

19. Aberrant pain processing?

20. Temporal summation/Wind-up  Pain increases in intensity when painful stimuli are applied repetitively.  Only repetitive stimuli at shorter interval(3 s) resulted in a significant increase in pain ratings.

21. Central sensitization  Hyperalgesia: augmentation of pain sensation  Allodynia: lowered pain threshold  It is associated with enlarged receptive fields and is often occur as a consequence of temporal summation

23. Greater windup in patients with FM

24. Prolonged and more intense after-sensations

25. Evidence from fMRI  Patients display a normal “detection” threshold to sensory stimuli, but exhibit a decreased “noxious threshold”  This phenomenon is independent of psychological factors such as expectancy or hypervigilance  Increased activity of cerebral pain processing areas on fMRI

26. Evidence from fMRI  Decreased thalamic activity on functional brain scans  fMRI/SPECT studies support the hypothesis that fibromyalgia is characterized by cortical or sub- cortical augmentation of pain processing Gracely R, et. al. Arthritis Rheum. 2002 Gracely R, et. al. Bet Pract res Clin rheum, 2003

28. Effects of stress  Symptom onset and exacerbation during periods of stress  Clinical response of symptoms to therapeutic agents that alter stress mediators(exercise, TCA, SSRI)  FM has been reported to occur at increased frequency in PTSD patients  Some authors have suggested that it is stress itself that provides the etiology for FM

30. Disturbance in HPA axis  Healthy HPA axis: circadian variation with high cortisol in AM and low cortisol in PM  FM patients: abnormally elevated plasma cortisol concentration in the evening  It may be related to reduced levels of 5-HT

31. Disturbance in HPA axis  Marked hypersecretion of ACTH in response to severe acute stressors.  This has been suggested to result from chronic hyposecretion of CRH  HPA abnormalities may be related to depressed autonomic nervous system function.

32. Common biological pathways shared in FM and psychiatric disorder  FM patients’ response to dexamethasone suggests similarity with PTSD  Increased “drive” to activity of the HPA axis in melancholic depression

33. Biochemical abnormalities underlying FM  Levels of 5-HT & primary metabolites of NE and 5- HT are both reduced in patients with FM  Reduced levels of 5-HIAA and tryptophan were associated with increased pain in FM patients  5-HT inhibits the release of neurotransmitters involved in pain processing (substance P, excitatory amino acids)

34. Biochemical abnormalities underlying FM  Measures of pain intensity in FM patients are positively correlated with the levels of glutamate and aspartate metabolites, glycine, and taurine.  The level of substance P,NGF,glutamate, and aspartate is elevated in CSF of FM patients  Above changes lead to decrease in presynaptic inhibition of pain-related primary afferent neurons

35. Biochemical abnormalities underlying FM  Low levels of 5-HIAA and high concentrations of substance P were both positively correlated with more severe sleep disturbance  Dysregulation of 5-HT has been associated with depression and anxiety.

36. Behavior and psychological factors  Psychological distress or psychiatric illness is associated with greater health careseeking behavior at tertiary care facilities  Psychological factors are not necessary or sufficient to produce fibromyalgia.  The most common psychiatric conditions observed in patients with FM include depression (current:30%, life time:60%), dysthymia (10%), panic disorder (7%), and simple phobia (12%)

37. The Neurobiological / Psychobehavioral Continuum Neurobiological factors  Abnormal sensory processing  Biochemical dysfunction  HPA dysfunction  ? Peripheral factors Psychobehavioral factors  General “distress”  Cognitive factors  Psychiatric comorbidities  Maladaptive illness behaviors  Secondary gain issues Population Primary Care Tertiary Care Definition factors (e.g., tender points)

38. Treatment

39. Pharmacotherapy  Wind-up is dependent on the activation of NMDA receptors by glutamate and substance P  NMDA receptor blockers (ketamine and dextromethorphan) have prove benefit in pain control  NE and 5-HT release from the descending tract and down-regulate dorsal neuron excitability.

41.  Anti-seizure medications are beneficial in inhibiting the release of glutamate and substance P  Medications that block the re-uptake of both NE and 5-HT appear to be more effective than SSRI

42. Medical strategy  Anti-inflammatory [NSAID, Prednisone]-Failed  Block substance P receptor-Failed  Inhibit nerve signal conduction-success  Correct insomnia-Success  Augment descending inhibition-Success ---Increase 5-HT synthesis and /or NE-like ---Decrease 5-HT and/or NE reuptake

43. Treatment of Fibromyalgia Syndrome Medications Stron g Evidence for Efficacy Amitriptyline: often helps sleep a n d overall well-being; dose, 25-50 mg at bedtim e. Cyclobenzaprin e : similar response and adverse effects; dose, 10-30 mg at bedtim e. Modest Evidence for Efficacy Tramadol: long-term efficacy and tolerabil i ty unknown; administered with or without acetaminophen; dose, 200- 3 00 mg /d. Serotonin reuptake inhibitors (SSRIs): Fluoxet i ne (only one carefully evaluated at this time): dose, 20-80 m g; may be used with tricyclic given at bedtime; uncontrolled rep o rt of efficacy using sertrali ne. Dual-reuptake inhibit o rs (SNRIs): Venlafaxine: 1 RCT ineffective but 2 case repo r ts found higher dose effecti ve. Milnacipran: effective in single R CT. Duloxetine: effective in single R CT. Pregabal i n: second-generation anticonvulsant; effective in single R CT. Weak Evidence for Efficacy Growth hormone: modest improvemen t in subset of patients with FMS with low growth hormone level s at basel in e. 5-Hydroxytryptamine (serotonin): methodolog i cal probl ems. Tropisetron: not commercially availa bl e. S-adenosyl-methion i ne: mixed resu lt s. Goldenberg et al. JAMA. 2004

44. No Evidence for Efficacy Opioids, corticosteroids, nonsteroidal anti-inflammatory drugs, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, calcitonin, thyroid hormone, guaifenesin, dehydroepiandrosterone, magnesium. Nonmedicinal Therapies Strong Evidence for Efficacy (Wait-List or Flexibility Controls But Not Blinded Trials) Cardiovascular exercise: efficacy not maintained if exercise stops. CBT: improvement often sustained for months. Patient education: group format using lectures, written materials, demonstrations; improvement sustained for 3 to 12 months. Multidisciplinary therapy, such as exercise and CBT or education and exercise. Moderate Evidence for Efficacy Strength training, acupuncture, hypnotherapy, biofeedback,balneotherapy. Weak Evidence for Efficacy Chiropractic, manual, and massage therapy; electrotherapy, ultrasound. No Evidence for Efficacy Tender (trigger) point injections, flexibility exercise. Goldenberg et al. JAMA. 2004

45.  Evidence for treatment efficacy was ranked as:  Strong: positive results from a meta-analysis or consistently positive results from more than 1 RCT  Moderate : positive results from 1 RCT or largely positive results from multiple RCTs or consistently positive results from multiple non-RCT studies  Weak:positive results from descriptive and case studies, inconsistent results from RCTs, or both Goldenberg et al. JAMA. 2004

46.  Stepwise Fibromyalgia Management  Step 1  Confirm the diagnosis.  Explain the condition.  Evaluate and treat comorbid illness, such as mood disturbances and primary sleep disturbances.  Step 2  Trial with low-dose tricyclic antidepressant or cyclobenzaprine.  Begin cardiovascular fitness exercise program.  Refer for cognitive behavior therapy or combine that with exercise.

47.  Step 3  Specialty referral (eg, rheumatologist, physiatrist, psychiatrist, pain management).  Trials with selective serotonin reuptake inhibitor, serotonin and norepinephrine reuptake inhibitor, or tramadol.  Consider combination medication trial or anticonvulsant.

48. Thanks for your concentration