Psychosomatics 44:38-43, February 2003
© 2003 The Academy of Psychosomatic Medicine
A Pilot Randomized Controlled Trial of Dexamphetamine in Patients With Chronic Fatigue Syndrome
L.G. Olson,
A. Ambrogetti, and
D.C. Sutherland
Received Jan. 4, 2002; revision received May 7, 2002; accepted May 22, 2002. From the Department of Respiratory and Sleep Medicine, John Hunter Hospital; and the Faculty of Medicine, University of Newcastle, Newcastle, Australia. Address reprint requests to Dr. Olson, Department of Medicine, John Hunter Hospital, Locked Bag 1, Hunter Region Mail Centre, Newcastle, Australia 2310; lolson{at}mail.newcastle.edu.au (e-mail).
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ABSTRACT
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This study determined whether dexamphetamine improved symptoms and quality of life in patients with chronic fatigue syndrome. The setting was a specialized clinic within a tertiary referral hospital. This was a 6-week parallel-group, placebo-controlled trial with random allocation. There was a 2-week dose-adjustment phase and a 4-week stable treatment period. Outcome measures were the Fatigue Severity Scale, the Medical Outcomes Study 36-item Short-Form Health Survey, and two patient-determined outcomes. Ten patients were randomly assigned to dexamphetamine, and 10 were assigned to placebo. Fatigue Severity Scale scores improved in nine of 10 dexamphetamine and four of 10 placebo patients. The change in mean score was statistically significant. There were large but statistically nonsignificant changes in scores for the Short-Form Health Survey domains vitality and physical functioning. Dexamphetamine may be useful in the management of chronic fatigue syndrome; a larger and longer trial is justified by these results.
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INTRODUCTION
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The management of chronic fatigue syndrome is unsatisfactory. The only approach that has been shown to be effective is cognitive behavior therapy, but it is expensive and requires special skills.1 We have successfully treated with dexamphetamine a number of patients who had received a diagnosis of chronic fatigue syndrome but whose illness satisfied clinical and polysomnographic criteria for narcolepsy or idiopathic hypersomnolence. The possibility that abnormalities of cerebral alerting processes have a role in chronic fatigue syndrome has been recognized previously, and the conclusion that dexamphetamine and similar drugs may be useful in managing chronic fatigue syndrome have been drawn.2 Since dexamphetamine is cheap and simple to use, we conducted a randomized controlled trial of its use in patients with chronic fatigue syndrome who had no evidence of hypersomnolence.
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METHOD
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This was a randomized (allocation concealed) parallel-group trial comparing dexamphetamine with placebo administration. The protocol was approved by the Hunter Area Research Ethics Committee, and all patients gave written informed consent. Recruitment began in May 1998 and ceased in November 1999.
Inclusion and Exclusion Criteria
The principal inclusion criteria were a diagnosis of chronic fatigue syndrome by consensus criteria,3 normal results for an overnight sleep study, and a mean daytime sleep latency of more than 7 minutes (a mildly abnormal result), according to the Multiple Sleep Latency Test. All patients were diagnosed as having chronic fatigue syndrome by a single clinician (D.C.S.) who is believed to see most patients suspected of chronic fatigue syndrome in Newcastle, Australia. Exclusion criteria were a history of alcohol or other substance abuse, a history of epilepsy, a history of myocardial infarction, current hypertension, cardiac arrhythmia, angina pectoris, and coeliac disease (because dexamphetamine tablets contain gluten). All patients were seen by a psychiatrist and were excluded from the study if a psychiatric diagnosis other than depression was made. Although a diagnosis of depression did not require exclusion, use of antidepressant drugs was not permitted because of the risk of interaction with dexamphetamine. Patients were excluded if the psychiatrist believed that antidepressant medication was indicated. Also, because of the risk of drug interaction, use of ß-adrenoreceptor antagonists was not permitted, and patients were warned to discontinue use of herbal and naturopathic preparations.
Outcome Measures
The primary outcome measure was a standard score on the Fatigue Severity Scale.4 Patients with chronic fatigue syndrome who were advising on the trial design considered that any decrease in score on the Fatigue Severity Scale would, in their view, be clinically meaningful, so the primary reported outcome is the proportion of subjects recording a decrease in score on the Fatigue Severity Scale. The secondary outcome measures were the score on the Medical Outcomes Study 36-item Short-Form Health Survey5 quality of life scale and two patient-determined outcomes. These were aspects of the illness that each patient identified in response to the instruction, "Please think of two things you would most like to be able to do that your illness stops you from doing." The ability to perform these tasks was scored by the patients on a 7-point Likert scale at enrollment and at the end of the stable treatment period.
Adverse events were ascertained by asking subjects to list adverse events at the end of the stable treatment period. In addition, a checklist of body parts (hair, eyes, hands, etc.) and body systems (hearing, vision, taste, etc., including "feelings and emotions") was prepared. Subjects were asked, for each body part and system, if anything different or unusual had been experienced, and if they responded "yes," details were sought and recorded.
Group Size and Recruitment
Because the effect size and the variability of response were difficult to estimate in advance, the trial was planned to enroll 20 patients, at which point an initial evaluation was planned to determine the final group size required. Recruitment was slow, and those recruited were a small fraction of those eligible because most patients elected to receive dexamphetamine outside the trial. The trial ended after the first planned evaluation because recruitment had almost ceased, anecdotally because of positive reports of the effects of dexamphetamine from patients outside the trial.
Randomization and Concealment
Opaque envelopes were filled with cards indicating allocation to active or placebo arms and sealed. To ensure an equal number of subjects in each arm at the planned review, 20 envelopes were prepared with 10 active and 10 placebo cards. The envelopes were shuffled and marked with numbers 1 to 20.
The study was carried out at the Newcastle Sleep Disorders Centre, located at the Royal Newcastle Hospital. After informed consent was obtained, patients were allocated the next study number (1–20) in sequence. The sealed envelopes were held at the pharmacy of John Hunter Hospital (approximately 12 kilometers away). Pharmacy staff were notified by telephone of the allocation of a study number, and they prepared an appropriate medication supply for collection by the patient. Active tablets were dexamphetamine, 5-mg tablets. Placebo tablets were identical in appearance.
Study Design
All patients initially took one tablet (5 mg) twice daily, at 8:00 a.m. and 2:00 p.m. After 1 week, they were contacted by telephone by one of us (A.A.) and asked about the efficacy of the medication and about side effects by means of a general question without cueing for specific expected side effects (although likely dexamphetamine side effects were detailed in the information document provided as part of the informed consent procedure). If no satisfactory therapeutic response had been obtained and no troublesome side effects had been observed, the dose was increased to two tablets (10 mg) twice daily. If necessary, adjustments to the timing of doses could be made. After another week, the same procedure was repeated; the dose was increased, if needed, to three tablets (15 mg) twice daily. Patients continued at the dose reached after 2 weeks for another 4 weeks. Tablet containers were retrieved at the end of the study and returned to the John Hunter Hospital pharmacy, where the remaining tablets were counted to estimate compliance.
Outcome measure data were obtained before commencement of study administration and at the end of the 4-week stable treatment period. A second overnight sleep study and Multiple Sleep Latency Test were performed at the end of the treatment period after a day on which trial medication had been taken. Baseline characteristics of the patients are shown in Table 1.
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TABLE 1. Baseline Characteristics of Patients With Chronic Fatigue Syndrome Who Were Randomly Assigned to Dexamphetamine or Placebo for 4 Weeks
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Statistical Methods
Statistical analysis was done with Stata, version 5 (Stata Corporation, College Station, Tex.). Short-Form Health Survey scores were calculated by using software written by Ryan and Wolfe, which also provides physical and mental summary scores specific for Australia.5 All results are presented as means and 95% confidence intervals (CIs). Differences between means were assessed by sign-rank tests for paired data and by rank-sum tests for unpaired data. P values less than 0.05 were significant when isolated or few comparisons were made, and p values less than 0.01 were significant when multiple comparisons were made (as in the case of the multiple domains of the Short-Form Health Survey).
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RESULTS
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Ten subjects received placebo, and 10 received dexamphetamine. Of the subjects receiving placebo, five took three tablets twice daily, and five took one tablet twice daily after the 2-week dose-adjustment phase. Of the subjects receiving dexamphetamine, seven took two tablets (10 mg) twice daily, and three took one tablet (5 mg) twice daily after the dose-adjustment phase.
The Fatigue Severity Scale score improved in nine of 10 subjects receiving dexamphetamine and in four of 10 subjects receiving placebo. In the dexamphetamine group, the mean change in score on the Fatigue Severity Scale was –1.45 (SD=1.09), the median was –1.5, and the range was –3.4 to 0.2. In the placebo group, the mean change was –0.03 (SD=1.11), the median was 0.0, and the range was –1.7 to 1.7. The difference in mean change in score between the dexamphetamine and placebo groups was statistically significant (p<0.02). The mean score on the Fatigue Severity Scale in the dexamphetamine group before treatment was 6.1 (SD=0.7); after treatment it was 4.7 (SD=1.2). In the placebo group, the mean Fatigue Severity Scale score before administration was 5.9 (SD=1.0); after administration it was 5.9 (SD=0.9). The difference in mean score was also statistically significant (p=0.007).
Short-Form Health Survey scores are shown in Table 2 and Table 3. The mean pretreatment and end-of-treatment scores for each domain are shown in Table 2 and the mean change in score in Table 3. Short-Form Health Survey scores for most domains were low and highly variable between subjects and among different variables for the same subject. Scores increased in most domains in placebo subjects. In the domains concerned with emotional and mental functioning, scores increased to a similar extent in dexamphetamine-treated subjects. For physical role and vitality, there were much larger changes associated with dexamphetamine treatment than with placebo administration. None of these changes was statistically significant.
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TABLE 2. Short-Form Health Survey Scores Before and After 4 Weeks of Administration in Patients With Chronic Fatigue Syndrome Who Were Randomly Assigned to Dexamphetamine or Placeboa
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TABLE 3. Mean Change in Short-Form Health Survey Scores During 4-Weeks of Administration in Patients With Chronic Fatigue Syndrome Who Were Randomly Assigned to Dexamphetamine or Placebo
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There were no differences in patient-determined outcomes with either dexamphetamine or placebo administration. No subject in either the dexamphetamine or placebo groups recorded a change of greater than 1 on the 7-point Likert scale for either of their chosen outcomes.
Neither dexamphetamine nor placebo treatment was associated with any change in sleep study variables or in mean daytime sleep latency. The mean sleep latency after treatment in the dexamphetamine-treated group was 13.0 minutes (95% CI=9.1 to 16.9); after treatment in the placebo group it was 11.8 minutes (95% CI=9.1 to 14.4).
The principal adverse event reported was anorexia. Five patients receiving dexamphetamine reported reduced food consumption, three reported weight loss, and one patient receiving placebo reported reduced food consumption. Five placebo-treated patients reported impaired balance. Common sympathomimetic side effects, such as tremor, palpitations, and dry mouth, were not reported by either dexamphetamine or placebo patients.
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DISCUSSION
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Dexamphetamine treatment was associated with a lessened severity of fatigue symptoms and with clinically, but not statistically significant, improvements in quality of life scores. The shortcomings of the trial were its small group size and brief duration and that the blinding during the trial may have been compromised by the familiarity of subjects with the side effects of dexamphetamine. Widespread therapeutic use of dexamphetamine for chronic fatigue syndrome may, for these reasons, be premature, but there is justification for a larger and more prolonged trial.
The brief duration of the trial was decided on in consultation with patients with chronic fatigue syndrome. They concluded that a placebo-controlled trial would be acceptable only if its duration was short. Their view was that if dexamphetamine were superior to placebo after 4 weeks of administration, they would wish to use it, with decisions on the basis of individual response whether worthwhile improvement was maintained during prolonged treatment. Despite our taking into account this preference, recruitment into the trial was slow, and only a small fraction of eligible patients were enrolled. This appears to have been because many patients preferred the immediate chance of whatever benefit dexamphetamine treatment might offer. Because dexamphetamine can be prescribed legally for chronic fatigue syndrome in the jurisdiction in which we practice, we considered that withholding dexamphetamine from patients who elected not to enroll in the trial was coercive and therefore not ethically acceptable merely to encourage enrollment.6
The use of dexamphetamine for chronic fatigue syndrome has a considerable degree of biological plausibility. The ability of dexamphetamine to antagonize the effects of sleep deprivation and increase alertness is among the best known of its actions, and symptoms similar, at least superficially, to those of sleep deprivation are very common in patients with chronic fatigue syndrome. In particular, difficulty sustaining concentration and slow recovery from exertion are among the most disabling symptoms of chronic fatigue syndrome, and the capacity of dexamphetamine to facilitate prolonged concentration and to allow renewed exertion without prolonged rest are prominent aspects of its action. The mechanism by which dexamphetamine might alleviate the symptoms of chronic fatigue syndrome is not clear, however. This is, in part, a consequence of our ignorance of the mechanisms by which the symptoms of chronic fatigue syndrome arise.
The prominence of symptoms similar to those of sleep deprivation in chronic fatigue syndrome has been interpreted as a relationship between the symptoms of chronic fatigue syndrome and a failure of alerting mechanisms in the brain.2 In our subjects, however, daytime sleep latency was normal and did not increase with dexamphetamine treatment. It therefore seems unlikely that dexamphetamine acts simply to reduce the aspects of sleepiness measured by daytime sleep latency. Daytime sleep latency is an incomplete measure of sleepiness7 and a fortiori of "fatigue." Dexamphetamine may be acting to reduce aspects of subjective sleepiness not measured by daytime sleep latency.
Dexamphetamine and methylphenidate have been widely used to treat patients with depressive symptoms in association with medical illness and appear to be beneficial.8 This effect has not been shown to be due to antidepressant effects, however. Antidepressants are not obviously effective in chronic fatigue syndrome,9 and dexamphetamine is therefore unlikely to benefit patients with chronic fatigue syndrome simply because of its antidepressant effect. Dexamphetamine has a well-defined capacity to facilitate the recovery of functional capacity after stroke, which may be because of facilitation of adaptation of previously unused pathways or development of new pathways to replace those damaged.10 Similar effects could account for functional improvement in chronic fatigue syndrome with dexamphetamine if the functional deficits of chronic fatigue syndrome are due to focal dysfunction of neural pathways in the CNS.
The use of dexamphetamine is likely to raise concerns about toxicity. Side effects of dexamphetamine are numerous and well known but are not often troublesome in the doses used in this study.11 The main reason widespread use of dexamphetamine seems imprudent is fear of dependency. However, although dexamphetamine is an important drug of abuse, we are unaware of any evidence that dexamphetamine used for medical illness leads to abuse or dependency. In our experience of the use of stimulant drugs, escalation of use beyond the dose initially established as effective and use at times when alertness is not reasonably necessary is uncommon. We have seen two such cases among more than 400 patients treated with dexamphetamine or methylphenidate.
We conclude that dexamphetamine is a promising drug for the management of chronic fatigue syndrome and that a large trial with a prolonged duration of treatment would be appropriate. Ethical and practical difficulties may be significant obstacles to such a trial, however.
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ACKNOWLEDGMENTS
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The authors thank Jenny McDonald for keeping allocation codes and medications; Stephen Gyulay and Lucy Fong for analyzing polysomnographic data; and Margaret Cole and Kelly Rochow for organizing the data.
Sigma Pharmaceuticals supplied dexamphetamine tablets and matching placebo tablets.
Employees of Sigma Pharmaceuticals had no role in the design or conduct of the study, the analysis of the data, or the preparation of the article. Sigma Pharmaceuticals neither saw the data or the manuscript in advance of publication.
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REFERENCES
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- Krupp LB, La Rocca NG, Muir-Nash J, Steinberg AD: The Fatigue Severity Scale: application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989; 46:1121-1123[Abstract]
- Ryan P, Wolfe F: SF-36: Stata module to calculate summary statistics for the SF-36 Health Survey Instrument. http://netec.wustl.edu/WoPEc/data/Softwares/bocbocodeS377601.html
- Schüklenk U: Access to Experimental Drugs in Terminal Illness: Ethical Issues. New York, Pharmaceutical Products Press, 1998
- Pivik RT: The several qualities of sleepiness: psychophysiological considerations, in Sleep, Sleepiness and Performance. Edited by Monk TH. Chichester, UK, John Wiley & Sons, 1991, pp 3-38
- Block SD: Assessing and managing depression in the terminally ill patient. Ann Intern Med 2000; 132:209-218[Abstract/Free Full Text]
- Vercoulen JHMM, Swanink CM, Zitman FG, Vreden SG, Hoofs MP, Fennis JF, Galama JM, van der Meer JW, Bleijenberg G: Randomised, double-blind, placebo-controlled study of fluoxetine in chronic fatigue syndrome. Lancet 1996; 347:858-861[CrossRef][Medline]
- Walker-Batson D, Smith P, Curtis S, Unwin H, Greenlee R: Amphetamine paired with physical therapy accelerates motor recovery after stroke. Stroke 1995; 26:2254-2259[Abstract/Free Full Text]
- Mitler MM, Aldrich MS: Stimulants: efficacy and adverse effects, in Principles and Practice of Sleep Medicine. Edited by Kryger MH, Roth T, Dement WC. Philadelphia, WB Saunders, 2000, pp 429-440
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ABSTRACT
INTRODUCTION
