Current issues of ACP Journal Club are published in Annals of Internal Medicine


Review: Behavioral interventions show the most promise for the chronic fatigue syndrome


ACP J Club. 2002 Mar-Apr;136:61. doi:10.7326/ACPJC-2002-136-2-061

Source Citation

Whiting P, Bagnall AM, Sowden AJ, et al. Interventions for the treatment and management of chronic fatigue syndrome. A systematic review. JAMA. 2001 Sep 19;286:1360-8. [PubMed ID: 11560542] (All 2002 articles were reviewed for relevancy, and abstracts were last revised in 2008.)



In patients with the chronic fatigue syndrome (CFS), what is the effectiveness of evaluated interventions?

Data sources

Published and unpublished studies in any language were identified by searching 19 databases, including MEDLINE, EMBASE/Excerpta Medica, PsycLIT, ERIC, Current Contents, and the Cochrane Library (to 2000). The Internet was searched using a meta-search engine; references of retrieved articles were scanned; and individuals and organizations were contacted through a Web site dedicated to the review and through members of 2 advisory panels.

Study selection

Studies were selected if they were randomized controlled trials (RCTs) or controlled clinical trials of any intervention used in the treatment or management of CFS in adults or children. Studies in which diagnoses were based on another syndrome with criteria similar to CFS, such as those of myalgic encephalomyelitis, the chronic fatigue immune deficiency syndrome, or chronic Epstein-Barr virus infection, were included, but studies of fibromyalgia were not.

Data extraction

Data were extracted on study validity (allocation concealment [RCTs], control group and adjustment for confounders [controlled studies]), baseline comparability of groups, blinding, follow-up, dropouts, objectivity of outcome assessment, analysis, sample size, and cointerventions; intervention; diagnostic criteria; duration of follow-up; and outcomes (psychological, physical, quality-of-life and health status, physiologic, and resource use).

Main results

44 studies were included (32 studies enrolled adults, 1 enrolled children, and 2 enrolled adults and children; 9 studies did not give age information) (n = 2801; age range 11 to 87 y, 71% women) with 31 different interventions; 36 studies were RCTs. The studies were grouped by type of intervention (behavioral, immunologic, pharmacologic, supplements, complementary or alternative, and other interventions). 18 trials (41%) showed an overall beneficial effect of the intervention (≥ 1 clinical outcome improved). The results from the RCTs are in the Table. Cognitive behavioral and graded exercise therapies showed beneficial effects. Overall evidence from the other interventions was inconclusive.


In patients with the chronic fatigue syndrome, 31 different interventions show mixed results for effectiveness. Cognitive behavioral therapy and graded exercise therapy show the most promise.

Sources of funding: U.K. Policy Research Programme, Department of Health; Agency for Healthcare Research and Quality; Veterans Evidence-Based Research, Dissemination, and Implementation Center.

For correspondence: Ms. P. Whiting, National Health Service Centre for Reviews and Dissemination, University of York, York, England, UK. E-mail

Table. Interventions from RCTs for the chronic fatigue syndrome*

Interventions Number of RCTs Number of patients Overall effect (improvement vs no difference)
Behavioral 8 883 6 vs 2
Graded exercise 3 350 3 vs 0
CBT 5 533 3 vs 2
Immunologic 9 440 4 vs 5
Pharmacologic 12 896 2 vs 10
Supplements 5 174 2 vs 3
Complementary or alternative 2 84 1 vs 1

*CBT = cognitive behavioral therapy; RCTs = randomized controlled trials. Intervention duration ranged from 2 weeks to 1 year (mean 16 wk); follow-up ranged from 2 weeks to 5 years.


The well-done review by Whiting and colleagues does not help physicians much. In the included studies, the treatment of CFS was done by mental health and other specialists. Thus, as physicians, we must consider the data in terms of whether to refer. Qualified support exists for graded exercise and cognitive behavioral therapies, but it is unknown whether the treatment effect lasts longer than a few months, and some studies reported high dropout rates.

The absence of a standard definition of CFS jeopardizes interpretation. Many researchers have found so much overlap with such other syndromes as the irritable bowel syndrome and fibromyalgia that they posit that any definition of CFS is meaningless (1, 2). They suggest we view syndromes like CFS as artifacts of specialization that obscure the true problem of medically unexplained symptoms, which is the appropriate focus for our research and therapeutic efforts (1, 2).

I was struck by the erratically positive results across many unrelated studies. I suggest that the provider–patient relationship is the common feature, although it was not reported by the authors and I have never seen it reported with controlled interventions in these populations. However, variations in the relationship may account for the variably positive results with so many unrelated treatments. The provider–patient relationship, in any event, is an appropriate focus for physicians in managing patients with CFS and can be useful in arranging referral to mental health specialists (3).

Robert C. Smith, MD
Michigan State University
East Lansing, Michigan, USA


1. Wessely S, Nimnuan C, Sharpe M. Functional somatic syndromes: one or many? Lancet. 1999;354:936-9. [PubMed ID: 10489969]

2. Aaron LA, Burke MM, Buchwald D. Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med. 2000;160:221-7. [PubMed ID: 10647761]

3. Smith RC. Somatization disorder: defining its role in clinical medicine. J Gen Intern Med. 1991;6:168-75. [PubMed ID: 2023026]

Addendum 2007

The Michigan State group has demonstrated in a RCT that primary care providers can manage effectively patients with medically unexplained symptoms (1, 2) without increased costs (3). This can provide direction for primary care providers in managing patients with unexaplined symptoms such as CFS.