Effect of Modafinil on Fatigue Associated with Neurological Illnesses

J Chronic Fatigue Syndrome, Vol. 8(2) 2001, pp. 65-70

John W. Cochran, MD, FACP

John W. Cochran is affiliated with Drs. Cochran, Eberly &
Howe, PC, 1500 North Beauregard Street, Suite 300, Alexandria, VA 22311
(E-mail: mailto:JackCochranMD@aol.com ).

ABSTRACT.
Fatigue is a common symptom of a variety of neurological illnesses, such
as Alzheimer's disease, chronic fatigue syndrome, multiple sclerosis,
Parkinson's disease, and stroke. Fatigue severely impairs productivity,
performance, social functioning, and quality of life. Modafinil
(PROVIGIL®) has been shown to significantly improve fatigue associated
with multiple sclerosis and depression. Here, a retrospective review of
the medical charts of 25 patients treated with modafinil for fatigue
associated with various neurological illnesses was conducted. Modafinil
was effective for the treatment of fatigue in 21 of 25 patients (84%),
and was well tolerated. Therefore, modafinil appears to be a potentially
attractive candidate for the treatment of fatigue associated with
neurological disorders.


KEYWORDS. Modafinil, fatigue, Alzheimer's disease, neurological
illnesses, stroke


INTRODUCTION

Fatigue, which is often confused with daytime sleepiness, is a common
symptom associated with a variety of neurological illnesses, such as
Alzheimer's disease, chronic fatigue syndrome, multiple sclerosis,
Parkinson's disease, and stroke. Indeed, all patients with chronic
fatigue syndrome (1), up to 96% of patients with multiple sclerosis
(2,3), and 44% of patients with Parkinson's disease (4) experience
persistent, debilitating fatigue. Not only does fatigue severely impair
productivity and performance, but it also has detrimental effects on
social functioning and overall quality of life. Fatigue has been rated as
the worst or one of the worst symptoms by 69% patients with multiple
sclerosis (2).

PROVIGIL® (modafinil) is a novel wake-promoting agent that is chemically
and pharmacologically distinct from other central nervous system
stimulants, such as the amphetamines and methylphenidate. Although the
precise mechanism of action for modafinil is not definitively known,
modafinil is not a direct or indirect acting dopaminergic agent and the
wake-promoting effects of modafinil are not inhibited by dopamine
receptor antagonists or depletion of catecholamines (5,6). Instead,
preclinical studies have demonstrated that modafinil can selectively
activate hypothalamic neurons in both the tuberomamillary nucleus
(histaminergic) and lateral hypothalamus (hypocretin/orexin). These
neurons have substantial projections throughout the cerebral cortex which
can mediate normal wakefulness and enhanced cortical activity (7). This
enhancement of hypothalamo-cortical pathways by modafinil may underlie
its wake-promoting activity.

Modafinil, which significantly improves the excessive daytime sleepiness
(EDS) associated with narcolepsy (8,9), sleep apnea (10), and other
disorders of sleep (11-13), has recently been found to effectively manage
the fatigue associated with multiple sclerosis (14,15) and depression
(16). In a 9-week, forced-titration, placebo-controlled study of 72
patients with multiple sclerosis, 200 mg doses of modafinil taken once
daily were found to significantly improve fatigue as measured by three
different fatigue scales (14). Similar results were obtained during a
12-week, open-label study that evaluated the efficacy of 100 mg doses of
modafinil taken twice daily in 40 patients with multiple sclerosis (15).
Modafinil was found to effectively manage the fatigue in 85% of the
patients and was more effective in patients in the early stages of the
disease. In depression, Menza and coworkers conducted a retrospective
review of the medical charts of 7 patients who had no response or partial
response to treatment with antidepressants (16). Augmentation of their
treatment with modafinil at daily doses of 100 mg or 200 mg resulted in
significant improvements in Hamilton Depression Rating Scale scores, as
well as improvements in fatigue and overall well being. These
improvements generally occurred within one or two weeks after initiating
treatment with modafinil. Taken together, these data suggest that
modafinil may be a viable pharmacotherapeutic option for treatment of
fatigue associated with other neurological illnesses. Here, a case review
of 25 patients was conducted in order to preliminarily determine whether
modafinil was effective for the treatment of fatigue in a variety of
neurological illnesses.

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