Modafinil is used orally to improve wakefulness in adults with excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS), and shift work sleep disorder (SWSD). Careful attention to the diagnosis and treatment of the underlying sleep disorder is essential whenever modafinil is used in patients with these conditions.
Modafinil is used in the symptomatic treatment of narcolepsy to improve wakefulness in adults with excessive daytime sleepiness (EDS). Narcolepsy is a CNS disorder characterized by somnolence, often accompanied by sudden attacks of weakness (cataplexy) while awake and disrupted nocturnal sleep, and occasionally by hypnagogic hallucinations and/or sleep paralysis before falling asleep or awakening. The disorder involves dysregulation of wakefulness and sleep.
Efficacy of modafinil has been established in the US in 2 double-blind, multicenter, placebo-controlled clinical trials of 9 weeks' duration. In these and other clinical studies, modafinil 200 or 400 mg daily increased daytime wakefulness and alertness and decreased the number of daytime sleep episodes as determined by several objective (e.g., the Multiple Sleep Latency Test [MSLT], the Maintenance of Wakefulness Test [MWT], the Steer Clear Performance Test [SCPT]) and subjective (e.g., the Epworth Sleepiness Scale [ESS]) measures of sleepiness. Patients showed an enhanced ability to remain awake with both dosages relative to placebo at 3, 6, and 9 weeks, and at study end point (last post-baseline assessment while the patient was in the study) and also greater global improvement in overall disease status (measured by the Clinical Global Impression of Change [CGI-C]). However, despite the clinical improvement, mean objective and subjective measures of sleepiness did not completely normalize with modafinil therapy, with a degree of clinically important physiologic sleepiness persisting despite therapy. The percentage of patients exhibiting any degree of improvement in overall disease status on the CGI-C in the two 9-week studies establishing efficacy in the US was 60-72, 58-64, or 37-38% for the 400-mg regimen, 200-mg regimen, or placebo, respectively. The efficacy of the 2 modafinil dosage regimens was not shown to differ significantly in these studies.
Although the long-term efficacy of modafinil has not been established systematically beyond 9 weeks, improvements in overall disease status on the CGI-C and in subjective measures of sleepiness on the ESS were maintained in a 40-week open-label extension of one of the trials. In this open-label extension, the percentage of patients exhibiting improvement on the CGI-C ranged from 84% after 2 weeks of extension therapy to 91% after 40 weeks. The drug also was well tolerated for up to 40 weeks of therapy, with 11% of patients discontinuing modafinil because of adverse effects and 14% because of inadequate therapeutic effect. Although most patients enrolled in the 2 clinical trials establishing efficacy in the US had histories of cataplexy, those requiring anticataplectic therapy generally were excluded from enrollment. Therefore, current evidence of efficacy for modafinil is limited principally to effects on excessive daytime sleepiness. In one study in a limited number of patients, cataplexy was not affected by modafinil therapy.
Modafinil did not affect the initiation, maintenance, quality, or quantity of nighttime sleep and did not affect the ability to voluntarily sleep (nap) during the daytime. Like other CNS stimulants modafinil can alter mood, perception, thinking, and feelings and can cause psychoactive and euphoric effects. However, in clinical trials, there was no clinically important association between modafanil and the incidence of agitation in patients. In animals, modafinil is reinforcing; however, the somatic effects of the drug were comparable to those of caffeine and differed from those of amphetamine. Although current evidence indicates that the risk of abuse or misuse of modafinil is lower than that associated with some other CNS stimulants (e.g., amphetamines, methylphenidate), caution is recommended in patients with a history of drug or stimulant abuse. Withdrawal of modafinil has not been associated with any manifestations of dependency.
Obstructive Sleep Apnea/Hypopnea Syndrome
Modafinil is used in the symptomatic treatment of OSAHS to improve wakefulness in adults with excessive sleepiness. The drug should be used as an adjunct to standard treatment(s) for the underlying obstruction (e.g., nasal continuous positive airway pressure [CPAP]). If CPAP is considered the treatment of choice for a patient with OSAHS, every effort should be made to optimize CPAP treatment for an adequate period of time prior to initiating modafinil therapy. When modafinil is used adjunctively with CPAP treatment, the encouragement of and periodic assessment of CPAP compliance is necessary.
Efficacy of modafinil in reducing excessive daytime sleepiness in patients with OSAHS was established principally in 2 multicenter, placebo-controlled clinical trials. In both of these studies, enrolled patients met the International Classification of Sleep Disorders (ICSD) criteria for OSAHS, which also are consistent with DSM-IV criteria. These criteria include either excessive sleepiness or insomnia with frequent episodes of impaired breathing during sleep and associated features (e.g., loud snoring, morning headaches, dry mouth upon awakening) or polysomnography demonstrating more than 5 obstructive apneic episodes (each greater than 10 seconds in duration) per hour of sleep and one or more of the following: frequent arousals from sleep associated with the apneic episodes; bradytachycardia; and arterial oxygen desaturation in association with the apneic episodes. In addition, all patients enrolled in these studies had excessive daytime sleepiness as demonstrated by a score of 10 or higher on the Epworth Sleepiness Scale (ESS) despite treatment with CPAP. Evidence that CPAP was effective in reducing the episodes of apnea/hypopnea also was required along with documentation of CPAP use.
In the first multicenter, placebo-controlled study, which was of 12 weeks' duration, patients were randomized to receive modafinil 200 mg daily, modafinil 400 mg daily, or placebo. The majority of patients (80%) in this study were fully compliant with CPAP (defined as CPAP use for more than 4 hours per night on more than 70% of nights); the remainder of patients were partially CPAP compliant (defined as CPAP use for less than 4 hours per night on more than 30% of nights). Efficacy of modafinil was principally evaluated by measurement of sleep latency as assessed by the Maintenance of Wakefulness Test (MWT) and change in the patient's overall disease status as measured by the Clinical Global Impression of Change (CGI-C) at week 12 or at the final visit. The modafinil-treated patients demonstrated a significant improvement in their ability to remain awake as measured by the MWT at the study end point and in their clinical condition as measured by the CGI-C compared with those receiving placebo. The 200- and 400-mg daily doses produced similar clinical efficacy in this study.
In the second multicenter, placebo-controlled study, which was of 4 weeks' duration, patients were randomized to receive either modafinil 400 mg daily or placebo. Documentation of regular CPAP use (for at least 4 hours each night on 70% of nights) was required for all patients. Efficacy in reducing daytime sleepiness was principally assessed by the change from baseline on the ESS at week 4 or the final visit. Patients who received modafinil demonstrated a significant reduction in their ESS score from baseline (mean scores reduced by 4.6) compared with patients receiving placebo (mean scores reduced by 2). In addition, the percentage of patients with normalized daytime sleepiness (ESS score less than 10) was significantly higher for the modafinil group than for those receiving placebo (51 and 27%, respectively). Nighttime sleep as measured by polysomnography was not affected by modafinil administration in these 2 studies.
The manufacturer states that the long-term efficacy (e.g., longer than 12 weeks) of modafinil in OSAHS has not been systematically evaluated in placebo-controlled studies to date. However, a 12-month, noncomparative extension phase of the 12-week, placebo-controlled trial in which patients received modafinil 200, 300, or 400 mg daily demonstrated substantial reductions in ESS scores compared with baseline following 3, 6, 9, and 12 months of therapy. When modafinil is used for extended periods, the need for continued therapy should be reassessed periodically.
Shift Work Sleep Disorder
Modafinil is used in the symptomatic treatment of SWSD to improve wakefulness in adults with excessive sleepiness. Criteria of the International Classification of Sleep Disorders (ICSD-10) for chronic SWSD (which are consistent with DSM-IV criteria for circadian rhythm sleep disorder: shift work type) require a primary complaint of excessive sleepiness or insomnia that is temporally associated with a work period (usually night work) that occurs during the habitual sleep phase or loss of a normal sleep-wake pattern (i.e., disturbed chronobiological rhythmicity) as demonstrated on polysomnography and the Multiple Sleep Latency Test (MSLT) and that the manifestations are not accounted for by another medical or mental disorder and do not meet criteria for any other sleep disorder that produces insomnia or excessive sleepiness (e.g., time zone change [ jet lag] syndrome).
Efficacy of modafinil for excessive sleepiness associated with SWSD was demonstrated in a 12-week, placebo-controlled trial in patients with chronic SWSD who were randomized to receive either modafinil 200 mg daily or placebo. Not all patients engaged in shift work who complain of sleepiness meet the criteria for the diagnosis of SWSD; only patients who were symptomatic for at least 3 months were enrolled in the trial. Patients enrolled in this trial also were required to work a minimum of 5 night shifts per month, have excessive sleepiness at the time of their night shifts (MSLT score of less than 6 minutes), and have daytime insomnia documented by a daytime polysomnogram. Patients who were treated with modafinil demonstrated a significant prolongation of the time to sleep onset compared with those receiving placebo as assessed by the nighttime MSLT; significant improvement in the Clinical Global Impression of Change (CGI-C) also was demonstrated in the modafinil group. Despite these improvements, patients receiving the drug in this study continued to have residual sleepiness and impaired performance at night. (See Persistent Sleepiness under Warnings/Precautions: Warnings, in Cautions.) Daytime sleep measured by polysomnography was not affected by modafinil administration.
The long-term efficacy (e.g., longer than 12 weeks) of modafinil in SWSD has not been systematically evaluated in placebo-controlled studies to date. When modafinil is used for extended periods, the need for continued therapy should be reassessed periodically.