1. Fibromyalgia Research: From Neurasthenia to Central Processing Abnormalities Laurence A. Bradley, PhD Division of Clinical Immunology and Rheumatology University of Alabama at Birmingham

2. Introduction  Fibromyalgia is characterized by several symptoms: u Widespread pain u Abnormal pain sensitivity evoked by diverse stimuli u Headache u Fatigue u Sleep disturbance

3. Introduction u Fibromyalgia symptoms are associated with several behavioral disturbances: u Reduced activity, social interaction, function u Avoidance of events that evoke pain u Affective distress u Increased usage of health services

4. Introduction u Abnormalities in pain sensitivity, functional ability, and affect, in the absence of biological markers led to different research and clinical pathways: u Search for single source of symptoms u Attribution of symptoms to psychiatric illness

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

6. Theoretical and Empirical Contributions To Fibromyalgia Research and Clinical Care u Gate control theory (1965) u Psychosocial factors influence health care seeking behavior (1988) u Identification of altered biological factors associated with pain, distress, and related symptoms in fibromyalgia (1992)

7. Gate Control Theory u Multiple biological and psychosocial factors influence pain perception and pain behavior u It is no longer appropriate to identify pain and related symptoms as “organic” or “functional”

8. Pain Perception Pain Behavior Neuromatrix Psychosocial and Health Status Factors Attention Central Nervous System Plasticity Pathologic Input Medullary Descending Inhibition Endocrine, Immune, and Autonomic System Activity Afferent Input

9. Average Pain Threshold Levels Across 5 Bilateral Tender Points as a Function of Subject Group (Cianfrini, 2003) FM < all other groups (p<.001)

10. Mean Thermal Pain Threshold Ratings (±SEM) as a Function of Group *p < 0.01 °C

11. Thermal Pain Intensity Ratings in FM Patients and Healthy Controls

12. Altered Temporal Summation of Thermal and Mechanical Stimulation

13. Psychosocial Factors and Health Care Behavior u Psychological distress or psychiatric illness is associated with greater health care seeking behavior at tertiary care facilities u Psychological factors are not necessary or sufficient to produce fibromyalgia symptoms

18. Mean (± SEM) Tender and Control Point Pain Threshold as a Function of Subject Group* kg / cm 2 * All FM groups < Controls, p <.001

19. Mean (± SEM) CSF Levels of Substance P* f moles/ml * All FM groups > Controls, p <.05

20. Effects of Stress on FM Pain  Patients frequently report that their FM symptoms are intensified by physical and emotional stress  Personally-relevant stressful imagery is associated with increased clinical pain in patients with fibromyalgia (Davis et al., 2001)

21. Mean Stress-Induced Changes in Pain Unpleasantness Ratings as a Function of Thermal Stimulus and Group 45°C 47°C 49°C 51°C Δ MVAS Rating (stress - neutral) Stimulus Temperature

22. Mean (± SEM) Plasma Cortisol after Neutral and Stressful Imagery as a Function of Group

23. Altered Biological Factors Associated with Pain and Distress u Genetic influences on pain and analgesia u Altered central processing of sensory input

24. Distribution of 5-HTT Promoter Region Polymorphism in FM Patients and Controls Cohen et al., Arthritis Rheum, 2002

25. Pentazocine analgesia by sex and MC1R genotype: Thermal and Ischemic Stimulation (Mogil et al., 2003)

26. Imaging of Cerebral Responses to Mechanical Stimulation (Gracely et al., 2002)

28. Conclusions u Pain sensitivity, pain-related symptoms, and behavioral disturbances in fibromyalgia are reliably observed: u By different investigators or clinicians u Using different measurement techniques

29. Conclusions u Pain sensitivity and related symptoms are influenced by biological factors: u There may be a genetic predisposition for development of fibromyalgia, headache, and anxiety disorders u Abnormal pain sensitivity is associated with elevated CSF levels of substance P u Abnormal pain sensitivity in fibromyalgia is associated with augmented sensory neural input

30. Conclusions u Pain sensitivity and CSF substance P do not vary as a function of affective illness (i.e., major depression) or lifetime psychiatric morbidity u However, plasma cortisol levels, reports of pain unpleasantness, and other symptoms or behaviors (e.g., function, health care seeking) are influenced by psychosocial factors (e.g., stressors) and affective disturbance

31. Implications for Clinical Trials u Pharmacologic interventions that alter central processing of sensory neural input are likely to modify pain intensity and related symptoms (e.g., sleep, fatigue) in fibromyalgia u These interventions may also modify pain behavior through alterations in pain intensity and secondary effects on affective disturbance and other psychosocial factors

32. Implications for Clinical Trials u Cognitive-behavioral and other psychosocial interventions are likely to modify affective responses, health care behavior, and functional ability u Cognitive-behavioral interventions may prove to be most effective when they are used in conjunction with effective pharmacologic therapy