# Presentation: 548574

##  Fibromyalgia Research: From Neurasthenia to Central Processing Abnormalities

- Laurence A. Bradley, PhD
- Division of Clinical Immunology and Rheumatology
- University of Alabama at Birmingham

## Introduction

- Fibromyalgia is characterized by several symptoms:
- Widespread pain
- Abnormal pain sensitivity  evoked by diverse stimuli
- Headache
- Fatigue
- Sleep disturbance

## Introduction

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

## Introduction

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

## 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

## Theoretical and Empirical Contributions To Fibromyalgia Research and Clinical Care

- Gate control theory (1965)
- Psychosocial factors influence health care seeking behavior (1988)
- Identification of altered biological factors  associated with pain, distress, and related symptoms in fibromyalgia (1992)

## Gate Control Theory

- Multiple biological and psychosocial factors influence pain perception and pain behavior
- It is no longer appropriate to identify pain and related symptoms as “organic” or “functional”

## Neuromatrix

- 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

## Average Pain Threshold Levels Across 5 Bilateral Tender Points as a Function of Subject Group (Cianfrini, 2003)

- FM < all other groups (p<.001)

## Mean Thermal Pain Threshold Ratings (±SEM) as a Function of Group

-               *p < 0.01

- °C

## Thermal Pain Intensity Ratings in FM Patients and Healthy Controls

##  Altered Temporal Summation of Thermal and Mechanical Stimulation

## Psychosocial Factors and Health Care Behavior 

- Psychological distress or psychiatric illness is associated with greater health care seeking behavior at tertiary care facilities
- Psychological factors are not necessary or sufficient to produce fibromyalgia symptoms

## Slide 14

## Slide 15

## Slide 16

## Slide 17

## Mean (± SEM) Tender and Control Point Pain Threshold as a Function of Subject Group*

- kg / cm2

- * All FM groups < Controls, p < .001

## Mean (±  SEM) CSF Levels of Substance P*

- f moles/ml

- * All FM groups > Controls, p _<_ .05

## 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)

## 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 M****VAS Rating (stress - neutral)**

**Stimulus Temperature**** **

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

## Altered Biological Factors Associated with Pain and Distress

- Genetic influences on pain and analgesia
- Altered central processing of sensory input

## Distribution  of 5-HTT Promoter Region Polymorphism in FM Patients and Controls

- Cohen et al., Arthritis Rheum, 2002

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

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

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

## Conclusions

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

## Conclusions

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

## Conclusions

- Pain sensitivity and CSF substance P do not vary as a function of affective illness (i.e., major depression) or lifetime psychiatric morbidity
- 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

## Implications for Clinical Trials

- 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
- These interventions may also modify pain behavior through alterations in pain intensity and secondary effects on affective disturbance and other psychosocial factors

## Implications for Clinical Trials

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