Off-Label Uses of Modafinil

The Letter to the Editor (Am J Psychiatry 2001; 158:970–971) by Edward Teitelman, M.D., should have had as its title “Off-Label Uses of Modafinil.” The letter with the correct title appears below.

To the Editor: Modafinil, a wakefulness-promoting oral agent, is approved for the treatment of the excessive daytime sleepiness associated with narcolepsy. It is thought to work by means of the hypocretin-orexin system in the hypothalamus (1). A class IV drug, it is only minimally stimulating in the traditional manner. These facts suggested that it might be useful in treating the excessive daytime sleepiness often seen as a side effect of the neuroleptic treatment of psychosis or depression and in closed-head brain injury (dementia due to head trauma). In both cases the somnolence can be severely disabling and the use of traditional psychostimulants is cumbersome and may be risky or impractical.

I report the successful open-label clinical use of modafinil in 10 outpatients with closed-head brain injury and excessive daytime sleepiness and in two patients with somnolence due to sedating psychiatric drugs. In these instances, it either replaced a schedule II agent or was used as the initial treatment for excessive daytime sleepiness.

The patients ranged in age from 42 to 72 years. All were outpatients whose excessive daytime sleepiness limited their activity and quality of life. The patients were informed that the drug had been approved for other uses, but it seemed to have benefits that might serve their needs. They were informed of possible side effects, including overstimulation. In these individuals, modafinil was well tolerated at doses of 100–400 mg taken once every morning; effectiveness lasted all day and resulted in an apparently normal nighttime sleep. With proper titration, excessive daytime sleepiness was markedly decreased in nine patients and moderately decreased in three; all changes were felt to be beneficial by the patients.

At prescribed doses, there was increased wakefulness and feelings of normality. Some patients noticed a greater sense of attention and other cognitive benefits. The results have often been rapid (within 1–2 hours of taking modafinil) and dramatic and have frequently led to a sense of relief and increased well-being. It is not clear if there is a direct effect on affect or if the patients simply responded to their increased quality of life and function—or both.

To date, my patients have used modafinil between 5 and 13 months, and there has been no evidence of tolerance or decreased effectiveness and no apparent adverse interactions with concurrent medications. Side effects, when present, have usually been mild and transient, primarily complaints of stimulation or gastrointestinal upset. It should be noted, however, that outside of this group, two middle-aged brain-injured women with multiple other complications and medications could not tolerate modafinil. This was due to strong feelings of emotional instability brought on soon after taking the first dose of 100 mg. Both reported similar reactions to many other medications and felt they were generally hypersensitive to drugs. No further trials were made at a lower dose.

Modafinil appears to be useful in the treatment of excessive daytime sleepiness associated with closed-head brain injury and with sedating psychiatric drugs, facilitating rehabilitation and enhancing quality of life. However, adequately controlled clinical trials will be needed to fully determine the role of modafinil in the treatment of excessive daytime sleepiness associated with these and other medical conditions apart from narcolepsy.

The author is currently a consultant to Cephalon, Inc., maker of ProVigil (brand name of modafinil). Compensation has been limited to attendance at the Cephalon regional consultants’ meeting, Feb. 11–13, 2000.