Should a Pharmaceutical Be Approved for the Broad Indication of Excessive Sleepiness

In this issue of the AJRCCM (pp. 105–108), there is an interesting These attributes—demonstrated efficacy in promoting wakePro/Con debate about whether the drug modafinil (Provigil) has fulness, limited and not serious side effects, and lack of abuse a role (1), or not (2), in the management of obstructive sleep potential—suggest that modafinil will be an extremely useful apnea. This is an important debate and the pros and cons are medication. But what will its role be? well laid out by Black (1) and Pollak (2). The current issues Originally, modafinil was approved by the FDA for the treatabout use of modafinil, however, include more than its role in ment of narcolepsy on the basis of expensive multicenter studies sleep apnea. At present it is being proposed that the Food and conducted by its manufacturer, Cephalon (7). Narcolepsy is a Drug Administration (FDA) approve modafinil for the broad life-long condition that usually starts in the teen years or in indication of excessive daytime sleepiness. This raises some intersubjects in their 20s and results in marked excessive sleepiness esting medical dilemmas that are the subject of this essay. (for review, see Overeem and coworkers [11]). It does not, howModafinil is different from previous medications used for wake ever, have a particularly high prevalence, being on the order of promotion, that is, amphetamines and their derivatives. Modafi1 in 2,000 (11). Modafinil has quickly become the drug of choice nil lacks abuse potential (3, 4). There are also major differences for management of sleepiness in narcolepsy. in recovery sleep that follows a period after an animal has been Although modafinil is acceptable for narcolepsy, the current kept awake for prolonged periods by a pharmacologic agent. question concerns whether there are other indications for its With amphetamines, the pressure for sleep (sleep homeostasis) use. This is a subject of considerable media interest, with articles builds up during the induced period of prolonged wakefulness. in The New Yorker and elsewhere, and stories on major national Hence, when amphetamines are stopped, profound amounts of media outlets, such as CNN. The media attention has presumably deep, slow-wave sleep are observed (5, 6). In contrast, when contributed to the already widespread off-label use of modafinil similar studies are done with modafinil, there is limited sleep in the United States, beyond the prevalence of the approved recovery when modafinil is stopped (5, 6). This has led to the indication for narcolepsy. As reported by the Washington Post suggestion that modafinil is somnolytic, and that it must act (12), this media attention led the FDA to write to Cephalon directly to block the sleep-promoting system. in January 2002, warning the company about its promotional Modafinil is a safe compound with only minor side effects materials. The FDA noted that “Provigil is not approved to treat such as headache, which is often transient at initiation of therapy such symptoms as sleepiness, tiredness, decreased activity, lack (7–10). It has been used in France, where it was discovered, for of energy and fatigue.” many years and long-term studies of use reveal a favorable sideAt present, on the basis of studies such as those on patients effect profile (8). with obstructive sleep apnea with residual sleepiness, who were effectively being treated with nasal continuous positive airway pressure (CPAP) (9, 10, 13), the potential role of modafinil in other conditions is being considered. Interestingly, regulatory