Fibromyalgia Research: From Neurasthenia to Central Processing Abnormalities

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Fibromyalgia Research From Neurasthenia to
Central Processing Abnormalities

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

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Introduction

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

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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

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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

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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

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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)

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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

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Medullary Descending Inhibition
Endocrine, Immune, and Autonomic System Activity
Afferent Input
Pain Perception
Neuromatrix
Pathologic Input
Pain Behavior
Psychosocial and Health Status Factors
Attention
Central Nervous System Plasticity
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Average Pain Threshold Levels Across 5 Bilateral
Tender Points as a Function of Subject Group
(Cianfrini, 2003)
FM lt all other groups (plt.001)
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Mean Thermal Pain Threshold Ratings (SEM) as a
Function of Group
C
p lt 0.01
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Thermal Pain Intensity Ratings in FM Patients and
Healthy Controls
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Altered Temporal Summation of Thermal and
Mechanical Stimulation
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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

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Mean ( SEM) Tender and Control Point Pain
Threshold as a Function of Subject Group
kg / cm2
All FM groups lt Controls, p lt .001
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Mean ( SEM) CSF Levels of Substance P
f moles/ml
All FM groups gt Controls, p lt .05
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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)

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Mean Stress-Induced Changes in Pain
Unpleasantness Ratings as a Function of Thermal
Stimulus and Group
? MVAS Rating (stress - neutral)
45C 47C
49C 51C
Stimulus Temperature
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Mean ( SEM) Plasma Cortisol after Neutral and
Stressful Imagery as a Function of Group

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Altered Biological Factors Associated with Pain
and Distress

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

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Distribution of 5-HTT Promoter Region
Polymorphism in FM Patients and Controls
Cohen et al., Arthritis Rheum, 2002
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Pentazocine analgesia by sex and MC1R genotype
Thermal and Ischemic Stimulation (Mogil et al.,
2003)
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Imaging of Cerebral Responses to Mechanical
Stimulation (Gracely et al., 2002)
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Imaging of Cerebral Responses to Mechanical
Stimulation (Gracely et al., 2002)
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Conclusions

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

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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

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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

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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

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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