Fibromyalgia Research: From Neurasthenia to

Central Processing Abnormalities

Laurence A. Bradley, PhDDivision 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”

Pain Perception

Pain Behavior

Neuromatrix

Psychosocial andHealth Status

FactorsAttention

Central NervousSystem Plasticity

PathologicInput

MedullaryDescending

Inhibition

Endocrine, Immune,and AutonomicSystem Activity

AfferentInput

0

2

4

6

8

FM patients DepressedSubjects

Healthycontrols

kg/

1.54

cm

2

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

05

101520253035404550

FM Patients Healthy Controls

*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

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

0.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

Tender Points Control Points

FM Pts (I)

FM Pts (T)

FM Non-Pts (I)

Controls

kg /

cm

2

* All FM groups < Controls, p < .001

Mean (± SEM) CSF Levels of Substance P*

5.00

7.00

9.00

11.00

13.00

15.00

17.00

19.00

21.00

23.00

25.00

FM Pts (I)

FM Pts (T)

FM Non-Pts (I)

Controlsf mol

es/m

l

* 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

-10

-5

0

5

10

FM Patients Healthy Controls

45°C 47°C 49°C 51°C

Δ M

VA

S R

a tin

g (

stre

ss -

ne u

t ra l

)

Stimulus Temperature

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

0

2

4

6

8

10

12

14

FM Patients Healthy Controls

Pla

sma

Cor

tiso

l uG

/dL

Neutral Imagery

Stressful Imagery

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

0

10

20

30

40

50

60

L/L L/S S/S

Fre

quency

(%

)

Controls (559 W/ 0 M)

Patients (99 W/ 0 M)

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