Elsevier

The Lancet

Volume 353, Issue 9151, 6 February 1999, Pages 455-458
The Lancet

Early Report
Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial

https://doi.org/10.1016/S0140-6736(98)04074-4Get rights and content

Summary

Background

Reports of mild hypocortisolism in chronic fatigue syndrome led us to postulate that low-dose hydrocortisone therapy may be an effective treatment.

Methods

In a randomised crossover trial, we screened 218 patients with chronic fatigue. 32 patients met our strict criteria for chronic fatigue syndrome without co-morbid psychiatric disorder. The eligible patients received consecutive treatment with low-dose hydrocortisone (5 mg or 10 mg daily) for 1 month and placebo for 1 month; the order of treatment was randomly assigned. Analysis was by intention to treat.

Findings

None of the patients dropped out. Compared with the baseline self-reported fatigue scores (mean 25·1 points), the score fell by 7·2 points for patients on hydrocortisone and by 3·3 points for those on placebo (paired difference in mean scores 4·5 points [95% CI 1·2–7·7], p=0·009). In nine (28%) of the 32 patients on hydrocortisone, fatigue scores reached a predefined cut-off value similar to the normal population score, compared with three (9%) of the 32 on placebo (Fisher's exact test p=0·05). The degree of disability was reduced with hydrocortisone treatment, but not with placebo. Insulin stress tests showed that endogenous adrenal function was not suppressed by hydrocortisone. Minor side-effects were reported by three patients after hydrocortisone treatment and by one patient after placebo.

Interpretation

In some patients with chronic fatigue syndrome, low-dose hydrocortisone reduces fatigue levels in the short term. Treatment for a longer time and follow-up studies are needed to find out whether this effect could be clinically useful.

Introduction

Chronic fatigue syndrome affects up to 2·6% of people who attend primary care in the UK1 and is also encountered in many medical specialties. Patients with chronic fatigue syndrome have a poor outcome: only 3% of patients spontaneously recover at 18 months of follow-up.2

About 50% of patients with chronic fatigue syndrome have co-morbid major depression.3 However, the results from placebo-controlled trials of antidepressants differ; some studies show moderate efficacy,4 whereas others do not.5 Controlled studies suggest that graded exercise therapy6 and cognitive behavioural therapy7, 8 are effective treatments, but are relatively expensive and not widely available because of a shortage of adequately trained therapists. In addition, many patients are wary of the rationale behind these treatments. Alternative effective treatments for chronic fatigue syndrome are needed.

Studies of the hypothalamo-pituitary adrenal (HPA) axis in chronic fatigue syndrome show a mild hypocortisolism of central origin, in contrast to the hypercortisolism of major depression.9, 10, 11, 12 Given the overlap between the symptoms of Addison's disease and chronic fatigue syndrome, Demitrack and colleagues9 postulated that this hypocortisolism may be important in the mediation of central fatigue.9 There are suggestions that this underactivity of the HPA axis could result from factors that are secondary to the primary aetiology of chronic fatigue syndrome, such as sleep disturbance.13 Whatever the origin, one possibility is that low circulating cortisol could act as a biological factor that contributes to fatigue chronicity and interacts adversely with perpetuating cognitive and behavioural processes.14 Thus, a rise in cortisol concentrations might improve fatigue.

We set out to test the hypothesis that low-dose hydrocortisone therapy would improve fatigue in chronic fatigue syndrome using a randomised, double-blind, placebo-controlled, crossover design.

Section snippets

Patients

Between November, 1995, and February, 1997, we recruited patients in London and Cambridge from established clinics that specialise in chronic fatigue syndrome. The study was approved by both local ethical committees. We included patients who fulfilled both international consensus criteria for chronic fatigue syndrome.15, 16 All patients underwent medical screening that included physical examination and relevant investigation, with a minimum of urine analysis, full blood count, measurement of

Results

The trial profile shows the numbers of patients throughout the trial (figure 1). None of the 32 valid patients who started treatment dropped out. Thus, our analysis is both on an intention to treat and treatment completers basis. Our compliance assessment suggested that no patient missed more than two doses of trial medication. The mean age of the 32 patients was 35·3 (range 19–58) years and 20 were women. Nine (28%) patients had a history of psychiatric illness, whereas 19 (59%) related the

Discussion

This study shows that low-dose hydrocortisone results in significant reductions in self-rated fatigue and disability in patients with chronic fatigue syndrome. Moreover, about a third of patients had a clinically significant reduction in fatigue, most to a level at or below that of the general population, with accompanying reductions in disability.

The effect of low-dose hydrocortisone was to increase the overall 24 h cortisol output after 28 days of treatment. When taken together with the

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