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Summer 2002

Persistent Pain in Patients with Chronic Fatigue Syndrome
By Laurence A. Bradley, PhD
University of Alabama at Birmingham

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 pain.

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 psychological distress.

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 with CFS.

Genetic 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 performed in Germany found 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.

Neuroendocrine and  immune 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 During 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 system 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 pain.15–18

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 5-HIAA.23

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

Treatment 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 to pain 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 placebo.29

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 Alabama at Birmingham. Dr. Bradley also serves as the head of the Neurobehavioral Medicine Working Group in the Division's NIH-supportedMultidisciplinaryClinicalResearchCenter.

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