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Fatigue is a perplexing and at times incapacitating symptom in multiple sclerosis. It has both physical and cognitive components and its severity is not closely related to the extent of neurological disability, nor to clinical or laboratory measures of inflammatory activity, nor to depression.1,2 Treatment is unsatisfactory, with few controlled studies and with interpretation of results hindered by somewhat blunt clinical scales to measure effects. Evidence is accumulating that fatigue in multiple sclerosis is due to dysfunction of the CNS,3,4 but lack of understanding of the underlying pathophysiology makes a rational approach to treatment difficult. The paper by Rammohan et al5 (this issue, pp 179–183) is a useful addition to the limited literature on the subject. It demonstrates improvement in fatigue in patients with multiple sclerosis taking 200 mg modafinil a day.
Modafanil stimulates wakefulness and, compared with amphetamines, has a more selective action in the brain and fewer side effects. It is an α-1 adrenergic agonist with complex actions also on other neurotransmitter systems. A relatively long half life makes single daily dosing practicable. Interest in its effect on fatigue was stimulated by a study showing effectiveness in reducing daytime sleepiness in narcolepsy—at the same time measures of fatigue were improved. There is clearly overlap between fatigue and sleepiness, but in many patients the symptoms can be distinguished reasonably well.
Limitations of the present report in patients with multiple sclerosis are the single blind design, a standard dose titration sequence for modafinil and placebo and, especially, the short time on active treatment. Although 200 mg modafinil a day was of benefit, a higher dose of 400 mg was not. Increased side effects on the higher dose is a more likely explanation than loss of responsiveness to the treatment after 2 weeks. It was noted that some patients did better on the higher dose, and it would be expected that there may be considerable variation among patients in the doses producing both side effects and improvement in symptoms.
Further studies on modafinil for fatigue in multiple sclerosis are warranted, with the need for a double blind study assessing treatment for longer periods, with titration of the dose for individual patients. Potential for habituation with modafinil seems relatively low but needs careful assessment.
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