Clinical Evidence Concise

A Publication of BMJ Publishing Group

Chronic Fatigue Syndrome


Am Fam Physician. 2005 Nov 1;72(9):1793-1794.

What are the effects of treatments?


Graded Aerobic Exercise

One systematic review identified three randomized controlled trials (RCTs) that showed that a graded aerobic exercise program improved measures of fatigue and physical functioning compared with flexibility and relaxation training or general advice. The review identified one RCT that showed that an educational package to encourage graded exercise improved measures of physical functioning, fatigue, mood, and sleep at one year compared with written information alone.

Cognitive Behavior Therapy

One systematic review showed that cognitive behavior therapy improved quality of life and physical functioning compared with standard medical care or relaxation therapy. One RCT showed that cognitive behavior therapy administered by therapists who had no experience with treating chronic fatigue syndrome also may be effective compared with guided support groups or no interventions.



Small RCTs provided limited evidence that immunoglobulin G modestly improved physical functioning and fatigue at three to six months compared with placebo, but it was associated with considerable adverse effects. Small RCTs provided insufficient evidence on the effects of interferon alfa or acyclovir compared with placebo. One RCT found that staphylococcus toxoid improved symptoms at six months compared with placebo, although it was associated with local reaction and could cause anaphylaxis.



RCTs provided insufficient evidence about the effects of antidepressants in persons with chronic fatigue syndrome.


RCTs provided insufficient evidence about the effects of corticosteroids in persons with chronic fatigue syndrome.

Oral Nicotinamide Adenine Dinucleotide

One RCT identified by a systematic review provided insufficient evidence about the effects of oral nicotinamide adenine dinucleotide in persons with chronic fatigue syndrome.

Prolonged Rest

We found no RCTs on the effects of prolonged rest. Indirect observational evidence in healthy volunteers and in persons recovering from a viral illness suggests that prolonged rest may perpetuate or worsen fatigue and symptoms.

Dietary Supplements

One small RCT found no significant difference between a nutritional supplement (containing multivitamins, minerals, and coenzymes) and placebo in fatigue severity or functional impairment at 10 weeks.

Magnesium (Intramuscular)

One small RCT found that intramuscular magnesium injections improved symptoms at six weeks compared with placebo. However, we were unable to draw reliable conclusions from this small study.


Chronic fatigue syndrome is characterized by severe, disabling fatigue and other symptoms, including musculoskeletal pain, sleep disturbance, impaired concentration, and headaches. Two widely used definitions of chronic fatigue syndrome (from the U.S. Centers for Disease Control and Prevention1 and from Oxford, United Kingdom2) were developed as operational criteria for research. There are important differences between these definitions. The U.K. criteria insist upon the presence of mental fatigue, whereas the U.S. criteria include a requirement for several physical symptoms, reflecting the belief that chronic fatigue syndrome has an underlying immunologic or infective pathology.


Community- and primary-care–based studies have reported the prevalence of chronic fatigue syndrome to be from 0.007 to 2.8 percent in the general adult population and from 0.006 to 3.0 percent in primary care, depending on the criteria used.3 Population surveys in the United States have found that white individuals have a lower risk of chronic fatigue syndrome compared with Hispanics, blacks, and Native Americans.4,5


Despite considerable research effort and several hypotheses, the cause of chronic fatigue syndrome remains poorly understood. Endocrine and immunologic abnormalities have been found in many persons, although it is unclear whether these changes are causal or part of the course of the syndrome. Women are at higher risk than men (relative risk 1.3 to 1.7, depending on diagnostic criteria used).6


Studies have focused on persons attending specialist clinics. A systematic review of studies of prognosis (search date 1996) showed that children with chronic fatigue syndrome had better outcomes than adults: 54 to 94 percent of children showed definite improvement in symptoms after the follow-up period of six years or less, whereas 20 to 50 percent of adults showed some improvement in the medium term, and only 6 percent returned to premorbid levels of functioning.7 Despite the considerable burden of morbidity associated with chronic fatigue syndrome, we found no evidence of increased mortality. The systematic review showed that a longer duration of illness, fatigue severity, comorbid depression and anxiety, and a physical attribution for chronic fatigue syndrome are factors associated with a poorer prognosis.7

editor’s note: Immunoglobulin G and staphylococcus toxoid are not available in the United States.

search date: September 2004

Adapted with permission from Reid S, Chalder T, Cleare A, Hotopf M, Wessely S. Chronic fatigue syndrome. Clin Evid Concise 2005;13:323–4.



show all references

1. Fukuda K, Straus S, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med. 1994;121:953–9....

2. Sharpe M, Archard LC, Banatvala JE. A report—chronic fatigue syndrome: guidelines for research. J R Soc Med. 1991;84:118–21.

3. Afari N, Buchwald D. Chronic fatigue syndrome: a review. Am J Psychiatry. 2003;160:221–36.

4. Steele L, Dobbins JG, Fukuda K, et al. The epidemiology of chronic fatigue in San Francisco. Am J Med. 1998;105(suppl 3A):S83–90.

5. Jason LA, Richman JA, Rademaker AW, et al. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999;159:2129–37.

6. Wessely S. The epidemiology of chronic fatigue syndrome. Epidemiol Rev. 1995;17:139–51.

7. Joyce J, Hotopf M, Wessely S. The prognosis of chronic fatigue and chronic fatigue syndrome: a systematic review. QJM. 1997;90:223–33.

This is one in a series of chapters excerpted from Clinical Evidence Concise, published by the BMJ Publishing Group, Tavistock Square, London, United Kingdom.



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