© 2003 American Thoracic Society
Should a Pharmaceutical Be Approved for the Broad Indication of Excessive Sleepiness?Division of Sleep Medicine, Department of Medicine, Center for Sleep and Respiratory Neurobiology, University of Pennsylvania, Philadelphia, Pennsylvania Correspondence and requests for reprints should be addressed to Allan I. Pack, M.B., Ch.B., Ph.D., Hospital of the University of Pennsylvania, Center for Sleep and Respiratory Neurobiology, University of Pennsylvania, 991 Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104-4283. E-mail: pack{at}mail.med.upenn.edu In this issue of the AJRCCM (pp. 105–108), there is an interesting Pro/Con debate about whether the drug modafinil (Provigil) has a role (1), or not (2), in the management of obstructive sleep apnea. This is an important debate and the pros and cons are well laid out by Black (1) and Pollak (2). The current issues about use of modafinil, however, include more than its role in sleep apnea. At present it is being proposed that the Food and Drug Administration (FDA) approve modafinil for the broad indication of excessive daytime sleepiness. This raises some interesting medical dilemmas that are the subject of this essay. Modafinil is different from previous medications used for wake promotion, that is, amphetamines and their derivatives. Modafinil lacks abuse potential (3, 4). There are also major differences in recovery sleep that follows a period after an animal has been kept awake for prolonged periods by a pharmacologic agent. With amphetamines, the pressure for sleep (sleep homeostasis) builds up during the induced period of prolonged wakefulness. Hence, when amphetamines are stopped, profound amounts of deep, slow-wave sleep are observed (5, 6). In contrast, when similar studies are done with modafinil, there is limited sleep recovery when modafinil is stopped (5, 6). This has led to the suggestion that modafinil is somnolytic, and that it must act directly to block the sleep-promoting system. Modafinil is a safe compound with only minor side effects such as headache, which is often transient at initiation of therapy (7–10). It has been used in France, where it was discovered, for many years and long-term studies of use reveal a favorable side-effect profile (8). These attributes—demonstrated efficacy in promoting wakefulness, limited and not serious side effects, and lack of abuse potential—suggest that modafinil will be an extremely useful medication. But what will its role be? Originally, modafinil was approved by the FDA for the treatment of narcolepsy on the basis of expensive multicenter studies conducted by its manufacturer, Cephalon (7). Narcolepsy is a life-long condition that usually starts in the teen years or in subjects in their 20s and results in marked excessive sleepiness (for review, see Overeem and coworkers [11]). It does not, however, have a particularly high prevalence, being on the order of 1 in 2,000 (11). Modafinil has quickly become the drug of choice for management of sleepiness in narcolepsy. Although modafinil is acceptable for narcolepsy, the current question concerns whether there are other indications for its use. This is a subject of considerable media interest, with articles in The New Yorker and elsewhere, and stories on major national media outlets, such as CNN. The media attention has presumably contributed to the already widespread off-label use of modafinil in the United States, beyond the prevalence of the approved indication for narcolepsy. As reported by the Washington Post (12), this media attention led the FDA to write to Cephalon in January 2002, warning the company about its promotional materials. The FDA noted that "Provigil is not approved to treat such symptoms as sleepiness, tiredness, decreased activity, lack of energy and fatigue." At present, on the basis of studies such as those on patients 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 bodies in Europe and the United States appear to have made different assessments. In Europe, the proposal is to limit the use of modafinil to narcolepsy and only those patients with sleep apnea who are effectively treated with nasal CPAP. In contrast, in the United States, Cephalon indicates that the FDA is considering a broad indication for excessive sleepiness of any cause. The argument is based on "pseudo-specificity," that is, there is nothing inherently different between the excessive sleepiness of patients with sleep apnea as compared with those with narcolepsy. A broad approval for excessive sleepiness would, in my view, lead to bad medicine. Excessive sleepiness is a symptom with a broad differential diagnosis (see Douglas [14]), for example, sleep apnea; narcolepsy; restless legs syndrome; delayed sleep phase syndrome; sleep disruption secondary to medical causes, for example, pain; secondary to psychiatric disorders, for example, depression; inadequate sleep as a result of voluntarily reducing sleep amounts on a repeated basis (cumulative partial sleep deprivation [15]); and, in rare cases, Kleine–Levin syndrome. Each of these conditions is diagnosed by different strategies. Most importantly, there are specific therapies for several such conditions: for sleep apnea, nasal CPAP and use of intraoral devices, with evidence for both from randomized clinical trials (see, e.g., References 16–25); for restless legs syndrome, use of specific dopamine agonists (26, 27); and for short sleep durations, increased sleep. The widespread use of modafinil for symptomatic management of excessive sleepiness without full evaluation would deny patients with these common disorders access to the effective, specific therapies that have been developed. There is a particular concern for patients with sleep apnea, as the Pro/Con debate illustrates, related to the cardiovascular risk associated with the disorder. There are growing data that untreated sleep apnea is associated with an increased risk of hypertension (28, 29), insulin resistance (30–32), myocardial infarction (33), and stroke (34), and some data that, if not adequately treated, there are worse cardiac outcomes (35). The mechanism of this is likely to be the oxidative stress injury that results from the repeated deoxygenation/reoxygenation with apneic/hypopneic events (36, 37). If modafinil was administered to such patients to ameliorate the symptom of sleepiness, without effectively treating the breathing disturbances during sleep, these data would argue that such patients would remain at risk for serious consequences. There are also concerns about the use of modafinil by normal individuals to maintain alertness, thereby allowing subjects to curtail their sleep. Sleep deprivation is associated with metabolic consequences (38). Specifically, partial sleep deprivation for 10 days in normal, healthy volunteers results in insulin resistance (38). We currently do not know whether subjects who cope with less sleep as a result of modafinil use will have these consequences over the long term. Thus, if modafinil is used for this purpose, we will be engaged in a large, national experiment without data to support it. In conclusion, there is no doubt that modafinil is a useful drug with great potential. There are, however, major questions and we need to think carefully about the indications for its use. We need, I believe, to move cautiously. There is a need for new clinical practice guidelines as to the use of modafinil. The prospect of broad approval by the FDA for this medication for excessive sleepiness is not a desired outcome. One can only hope we will follow the approach being advocated in Europe. The approval of a medication for broad use in excessive sleepiness could lead to millions of Americans receiving symptomatic management for sleepiness when specific therapies are available, and furthermore, leave them at unnecessary risk for adverse cardiovascular and metabolic consequences. FOOTNOTES Conflict of Interest Statement: Dr. Pack was Principal Investigator of a multicenter study funded by Cephalon on the use of modafinil for residual sleepiness in patients with sleep apnea who were effectively treated with nasal CPAP and adherent to therapy (10). Dr. Pack declined to participate in a follow-up study (13) on patients with sleep apnea who were partially compliant with therapy, because of concerns that such patients are left at risk for adverse cardiovascular outcomes. Initially in this study design, patients with sleep apnea not on CPAP were included but later, following pressure from the sleep community, such patients were dropped from the study. Dr. Pack has given occasional talks for Cephalon on the results of the study in which he was involved, and received travel expenses for these talks. He has not accepted personal honoraria. He, with Dr. Leszek Kubin and Dr. Thorarinn Gislason, received an educational grant from Cephalon to be a sponsor for a meeting (the 8th International Meeting on Sleep and Breathing) they jointly organized in Iceland. Dr. Pack is not a consultant for Cephalon. Received in original form November 17, 2002; accepted in final form November 18, 2002 REFERENCES
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