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ProModafinil Has a Role in Management of Sleep ApneaSleep Research Center Stanford University Stanford, California Individuals with commonly occurring cyclical or repetitive obstructive respiratory events during sleep generally suffer a condition known as obstructive sleep apnea (OSA) (1, 2). Frequently, this condition is associated with the complaint of "excessive daytime sleepiness." Indeed, sleepiness occurs with enough frequency that most definitions of the syndrome have required the presence of subjective sleepiness (3). Sleepiness, however, is not reported by all patients with OSA, even when the condition is moderate or severe. Clinical experience and research findings strongly support the notion that adequate treatment of OSA resolves or ameliorates daytime sleepiness, when present, in a substantial subset of patients (4, 5). Yet many patients continue to suffer sleepiness despite what would appear to be adequate treatment of the primary obstructive process (6). The prevalence of such residual sleepiness is unknown. Of important note is that "sleepiness" may not be the best term to describe a patient's experience of daytime function impairment; other terms, such as "lack of energy," "tiredness," or "fatigue" may be more relevant (7). Hence, any estimate of the prevalence of residual impairment in daytime alertness in treated OSA patients may be inaccurate and an underestimate if only "sleepiness" is assessed. Whether sleepiness is actually caused by OSA or simply exacerbated or triggered by OSA in those predisposed is unknown. Studies of induced OSA in normal subjects suggest a causal relationship (8); yet untreated OSA patients without sleepiness are not uncommon (9). Some have postulated that those suffering residual sleepiness following treatment may suffer transient or permanent central nervous system (CNS) malfunction unrelated to acute OSA processes (10, 11). Whatever the cause, many clinicians advocate the use of modafinil to diminish sleepiness in these individuals. To date, at least seven placebo-controlled clinical trials have been conducted to ascertain the potential value of modafinil treatment in patients with OSA and sleepiness. The first two reported studies (n = 6 and 26, respectively) were of crossover design and researchers found statistically significant improvements in subjective and objective measures of daytime sleepiness in untreated OSA patients (12, 13). Subsequent controlled trials in continuous positive airway pressure (CPAP)-treated patients with residual sleepiness have, in general, demonstrated consistent findings of improvement in some or all measures of daytime sleepiness. Investigators of the first of these trials (n = 30) observed a significant improvement in the objective measure of maintenance of wakefulness test and an improvement trend in multiple sleep latency test mean (14). Recently, investigators conducting two multicenter trials found statistically significant improvements in all sleepiness measures assessed. In the first of these (n = 157), modafinil was administered in 400 mg daily doses versus placebo for 4 weeks. The improvements in subjective sleepiness, as measured by the Epworth sleepiness scale, and in objective sleepiness, determined by multiple sleep latency test and psycho-motor vigilance test (PVT), were statistically significant. In addition, nasal CPAP compliance measures during the 4-week trial revealed no differences between groups and no decline in use (15). In the second of these multicenter trials (n = 323), modafinil was administered in 200 mg or 400 mg daily doses versus placebo for 12 weeks. Again, all measures of residual sleepiness, including maintenance of wakefulness test, Epworth sleepiness scale, and PVT, were found to have improved in the modafinil-treated group relative to the placebo group as well as relative to baseline (pretreatment). As was noted in the first multicenter trial, CPAP use remained constant in both modafinil-treated groups and in the placebo-treated group (16). Two further studies, yet unpublished, have been performed—the data from the second of which are undergoing analysis. The former was conducted in a manner providing for rigorous evaluation of the cause of residual sleepiness, which persisted despite regular CPAP use for a minimum of 6 months. All patients underwent esophageal pressure monitoring during CPAP retitration in addition to mask refitting, chin-strap application, and compliance modulation, as needed, to ensure optimal CPAP effect, comfort, and use. Two-thirds of the first 46 patients no longer experienced residual sleepiness following 30 days of subsequent "upgraded" CPAP use. The remaining 15 patients along with 5 additional patients with residual sleepiness participated in a placebo-controlled modafinil trial. Those treated with modafinil exhibited significant improvement in multiple sleep latency test and Epworth sleepiness scale (personal communication, Christian Guilleminault, lead principal investigator for this multicenter study, Stanford University). Of critical importance, this study strongly indicates the need for careful evaluation of the cause of residual sleepiness in treated OSA, but also suggests that a substantial subset of this population remains sleepy despite complete CPAP optimization. To summarize the results of all of these studies, the key and consistent findings are: (1) modafinil treatment improves subjective and objective measures of daytime sleepiness; and (2) modafinil treatment does not compromise CPAP use; additional findings include (3) modafinil-treated patients experience a significant improvement in quality of life measures; and (4) modafinil is generally well tolerated in this population. The arguments for modafinil use in treated OSA patients suffering residual sleepiness are clear and compelling and include, but are not limted to: (1) an improvement in quality of life for the patient; and (2) a potential reduction in the sociologic and economic burden caused by compromised daytime function secondary to residual sleepiness. These findings and factors taken together leave no rational option other than to offer our patients prudent treatment (i.e., modafinil). Some clinicians and investigators have concluded, in haste, that CPAP-treated OSA patients taking modafinil might lose incentive for continued CPAP use. Such a trend would certainly result in unfavorable health outcomes for these patients because untreated OSA is associated with increased risk of hypertension (17, 18), stroke (19), and cardiac disease (19, 20). All evidence thus far, however, suggests otherwise—CPAP-compliant patients taking modafinil do not reduce CPAP use. Moreover, CPAP compliance monitoring is a simple matter with current use-monitoring technology, and physicians could easily limit modafinil access to include only patients who remain CPAP-compliant. Any astute physician would draw the same conclusion: modafinil, and future wake-promoting agents, unquestionably have a role in the treatment of the residual lack of energy, fatigue, tiredness, or sleepiness associated with treated sleep apnea. Furthermore, in light of recent reports of modafinil-enhanced rodent learning and memory, modafinil may prove beneficial for other OSA-related residual cognitive deficits as well. FOOTNOTES Disclaimer: Owing to the fact that Dr. Black has been asked to represent a position in strong favor of the use of a single agent, modafinil, which is the largest revenue generator for Cephalon Inc.; he wishes to state that he holds no shares of Cephalon stock and is in no other way subject to a potential financial conflict of interest. REFERENCES
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