A Systematic Review of Modafinil: Potential Clinical Uses and Mechanisms of Action

Jacob S. Ballon, M.D., and David Feifel, M.D., Ph.D.

Background: Modafinil is a novel wake-promoting agent that has U.S. Food and Drug Administration approval for narcolepsy and shift work sleep disorder and as adjunctive
treatment of obstructive sleep apnea/hypopnea syndrome. Modafinil has a novel mechanism
and is theorized to work in a localized manner, utilizing hypocretin, histamine, epinephrine,
gamma-aminobutyric acid, and glutamate. It is a well-tolerated medication with low propensity for abuse and is frequently used for off-label indications. The objective of this study was to systematically review the available evidence supporting the clinical use of modafinil.

Data Sources: The search term modafinil OR Provigil was searched on PubMed. Selected articles were mined for further potential sources of data. Abstracts from major scientific conferences were reviewed. Lastly, the manufacturer of modafinil in the United States was asked to provide all publications, abstracts, and unpublished data regarding studies of modafinil.

Data Synthesis: There have been 33 double-blind, placebo-controlled trials of modafinil. Additionally, numerous smaller studies have been performed, and case reports of modafinil's use abound in the literature.

Conclusions: Modafinil is a promising drug with a large potential for many uses in psychiatry and general medicine. Treating daytime sleepiness is complex, and determining the precise nature of the sleep disorder is vital. Modafinil may be an effective agent in many sleep conditions. To date, the strongest evidence among off-label uses exists for the use of modafinil in attention-deficit disorder, postanesthetic sedation, and cocaine dependence and withdrawal and as an adjunct to antidepressants for depression.

(J Clin Psychiatry 2006;67:554-566)

Received Feb. 13, 2005; accepted Jan. 30, 2006. From the Department of Psychiatry, University of California, San Diego, San Diego (Drs. Ballon and Feifel); and the Department of Psychiatry and Behavioral Science, Stanford University, Stanford, Calif. (Dr. Ballon).

Drs. Ballon and Feifel report no financial affiliations or other relationships relevant to the subject of this article.

Corresponding author and reprints: David Feifel, M.D., Ph.D., 200 West Arbor Dr., San Diego, CA 92103-8218 (e-mail: dfeifel@ucsd.edu).