Amantadine for fatigue in multiple sclerosis

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Abstract
Background Fatigue is one of the most common and disabling symptoms of people with Multiple Sclerosis (MS). The effective management of fatigue has an important impact on the patient's functioning, abilities, and quality of life. Although a number of strategies have been devised for reducing fatigue, treatment recommendations are based on a limited amount of scientific evidence. Many textbooks report amantadine as a first‐choice drug for MS‐related fatigue because of published randomised controlled trials (RCTs) showing some benefit. We performed a systematic review in order to gather existing evidence, and contribute to the topic. Objectives To determine the effectiveness and safety of amantadine in reducing fatigue in people with MS. Search methods We searched MEDLINE (January 1966 to May 2002), EMBASE (1988 to May 2002), bibliographies of relevant articles and handsearched relevant journals. We also contacted drug companies and researchers in the field. Selection criteria Randomised, placebo or other drugs‐controlled, double‐blind trials of amantadine in MS people with fatigue. Data collection and analysis Three reviewers selected studies for inclusion in the review and they extracted the data reported in the original articles. We requested missing and unclear data by correspondence with the trial's principal investigator. A meta‐analysis was not performed due to the inadequacy of available data, heterogeneity of outcome measures. Main results Out of twelve pertinent publications, four trials met the criteria for inclusion in this review: one study was a parallel arms study, and three were crossover trials. The number of randomised participants ranged between 10 and 115, and a total of 236 MS patients were studied. Overall the quality of the studies considered was poor and all trials were open to bias. All studies reported small and inconsistent improvements in fatigue, whereas the clinical relevance of these findings and the impact on patient's functioning and health related quality of life remained undetermined. The number of participants reporting side effects during amantadine therapy ranged from 10% to 57%, without significant differences between treatment and placebo. The side effects reported were generally mild, and discontinuation of the drug due to side effects occurred in less than 10% of the patients. Authors' conclusions Amantadine treatment is generally well tolerated, however its efficacy in reducing fatigue in people with MS is poorly documented. It is advisable to: (1) improve knowledge on the underlying mechanisms of MS‐related fatigue; (2) achieve an agreement on accurate, reliable and responsive outcome measures of fatigue; (3) perform good quality RCTs.