Persistent Pain in Patients with Chronic
A. Bradley, PhD University of
Widespread and persistent pain is very
common in people with chronic fatigue syndrome (CFS). A recent population-based
study revealed that 94 percent of patients report muscle aches and pains, 84
percent report joint pain or morning stiffness and 19 percent report jaw
pain.1,2 Indeed, there is a high degree of overlap between CFS and
other syndromes that are characterized by recurrent or persistent
For example, clinic-based
investigations suggest that among people with CFS, 35–70 percent meet criteria
for fibromyalgia (FM)3,4 and 36–63 percent meet criteria for
irritable bowel syndrome.3,5 There also is evidence that four to
eight percent of patients with CFS report that they have received diagnoses of
interstitial cystitis, chronic tension-type headache, persistent pelvic pain and
multiple chemical sensitivities.3
The overlap between CFS and FM is
especially important because individuals who meet standard diagnostic criteria
for both disorders experience debilitating fatigue and widespread pain, and
experience allodynia, pain in response to stimuli such as pressure or heat that
do not evoke pain in healthy persons.6 The enhanced pain sensitivity
may increase the likelihood of experiencing very high levels of disability and
Unfortunately, little is known regarding
the etiopathogenesis of persistent pain or allodynia in people with CFS.
Moreover, investigators have not measured changes in pain in studies of medical
and behavioral treatments for CFS. This paper will review the current literature
concerning factors that may contribute to persistent pain or allodynia in CFS,
and will recommend that investigators evaluate various combinations of
pharmacological, immunological and behavioral therapies in order to identify the
most effective treatment approaches for reducing pain in subgroups of patients
factors Numerous investigators have proposed that there may
be a genetic component to the development of painful symptoms in persons with
CFS.7 However, well-designed investigations of genetic and
environmental factors that may contribute to CFS have just begun to appear.
While these findings are very exciting, it is not yet known whether there are
specific genes that might predispose individuals with CFS to experience
allodynia or enhanced sensitivity to pain.
It is interesting to note that a study
that patients with FM, compared to healthy persons, were significantly more
likely to exhibit a functional polymorphism in the regulatory region of the
serotonin promoter gene.8 Serotonin is a neurotransmitter that is
involved in the pain inhibition system involving the brain and the spinal cord.
Thus, the genetic abnormality identified in persons with FM might contribute to
the abnormal levels of serotonin and allodynia associated with this disorder. It
would be interesting to determine whether a greater number of individuals with
both CFS and FM, compared to those with CFS alone, show the same abnormality.
functions Efforts to understand
the symptoms of CFS have led researchers to study the neuroendocrine function in
samples of patients with CFS. Most of these investigations have focused on the
function of the hypothalamic-pituitary-adrenal (HPA) axis, which is activated by
stressors such as exhaustion, pain and perceived threats.9
exposure to stressors, the hypothalamus increases the production of
corticotropin releasing hormone (CRH), which stimulates the pituitary gland to
release adrenocorticotropic hormone (ACTH). ACTH, in turn, activates the adrenal
gland to release cortisol.
This sequence of events has important
implications for the pain associated with CFS.10 For example, CRH
enhances the actions of descending pathways from the brain to the spinal cord
that are involved in pain inhibition through their effects on the sympathetic
nervous system and the secretion of opioid peptides in the
hypothalamus.7,10 CRH also may diminish pain through its facilitating
effects on production of cortisol and other substances that inhibit
pain.9,10 There is consistent evidence that patients with CFS are
characterized by low hypothalamic levels of CRH11 and some studies
indicate that these patients also exhibit low cortisol levels.12,13
A number of abnormalities in immune
function have been identified in people with CFS.14,15 It has been
consistently found that patients with CFS tend to exhibit elevated levels of
cytokines that promote inflammation, such as interleukin-1-alpha (IL-1 alpha) in
blood plasma.15 These pro-inflammatory cytokines may interact with
the central nervous system in ways that have important implications for
Neuropeptides related to
pain Serotonin regulates the
circadian fluctuations of the HPA axis19 and probably plays a role in
stimulating the release of CRH from the hypothalamus.20 Moreover, it
contributes to the activation of descending antinociceptive pathways from the
brain to the spinal dorsal horns.7 Several investigators have sought
to determine whether low serotonin production might be associated with the
painful symptoms of CFS. It has generally been found that patients with CFS,
compared to healthy controls, show higher blood plasma levels of the serotonin
metabolite 5-HIAA21 and a prolactin response to buspirone indicative
of enhanced serotonin neurotransmission.22 In contrast, patients with FM, compared
to controls, show lower blood serum levels of serotonin and lower cerebrospinal
fluid (CSF) levels of the serotonin metabolite
Psychiatric comorbidity Many people
with CFS experience significant psychological distress. Studies using structured
psychiatric interviews indicate that up to one-half of patients with CFS meet
standard criteria for major depression.6
It does not appear
that depression is
a major factor in the development of persistent fatigue and pain. However, it is
important to acknowledge that depression and other emotional and cognitive
factors influence the transmission and modulation of pain in the central nervous
system and, thus, affect our perceptions of the intensity, sensory qualities and
the unpleasantness of pain.24
implications Little is known
regarding the effects of medical and behavioral interventions for pain in people
with CFS. Investigators have focused on fatigue, functional ability and general
quality of life as the primary outcomes of controlled trials of these
interventions.25,26 At present, then, it is not possible to make any
meaningful conclusions regarding the effects of immunological, behavioral or
pharmacological therapies on pain in persons with CFS.
Given the similarities in HPA axis
dysregulation among people with CFS and FM, it is worthwhile to examine the
outcomes of medical and behavioral interventions on pain in persons with FM. Our
laboratory recently reviewed the outcomes of pharmacologic approaches to FM pain
and concluded: amitriptyline and cyclo-benzaprine are superior to placebo in
producing improvements in pain, sleep quality, and fatigue, although the
efficacy of these pharmacologic agents appear to diminish over time; and studies
of the effects of selective serotonin reuptake inhibitors (e.g., sertraline
hydrochloride, fluoxetine) are limited and have produced both positive and
negative results.27 Given that patients with CFS tend to show normal
blood levels of serotonin, the efficacy of these interventions for pain
management in CFS may be limited primarily to those individuals who meet
criteria for both CFS and FM.
Our review of behavioral approaches
management in FM led to conclusions similar to those concerning the effects of behavioral
interventions on fatigue and quality of life in the CFS literature.25
That is, although there is a large amount of variation in the quality of
study designs, structured, graded exercise programs that emphasize improvements
in aerobic fitness tend to produce significant and sustained reductions in pain
among persons with FM.28 However, in contrast to the literature on
patients with CFS, all adequately designed studies of the effects of
cognitive-behavioral therapies on pain have shown that these interventions do
not produce reductions in pain greater than those achieved by
Conclusions Available evidence suggests that there are complex
mechanisms underlying persistent pain in persons with CFS. Although little is
known about the effects of current treatment interventions on pain in CFS, it is
reasonable to suggest that it will be necessary to evaluate various combinations
of pharmacological, immunological and behavioral therapies30 in order to identify the
treatment approaches that are most effective for various subgroups of patients
(e.g., persons with CFS only vs. those with CFS and FM).
Laurence A. Bradley, PhD, is
Professor of Medicine in the Division of Clinical Immunology and Rheumatology at
the University of
Bradley also serves as the head of the Neurobehavioral Medicine Working Group in
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