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Erschienen in:
01.09.2005 | Adis Drug Evaluation
Modafinil
A Review of its Use in Excessive Sleepiness Associated With Obstructive Sleep Apnoea/Hypopnoea Syndrome and Shift Work Sleep Disorder
Erschienen in: CNS Drugs | Ausgabe 9/2005
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Abstract
Modafinil (Provigil®) is a wake-promoting agent that is pharmacologically distinct from CNS stimulants, such as amfetamine, dexamfetamine and methylphenidate. Modafinil is approved for use in the US and certain European countries for use in patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnoea/hypopnoea syndrome (OSA/HS) or shift work sleep disorder (SWSD).
Oral modafinil promotes wakefulness in patients with OSA/HS and SWSD. It is an effective adjunctive therapy in patients with residual excessive sleepiness associated with OSA/HS who are receiving nasal continuous positive airway pressure (nCPAP) therapy. In SWSD, the drug improves night-time wakefulness without disrupting daytime sleep. Modafinil is generally well tolerated in patients with OSA/HS or SWSD and has a low abuse potential. Thus, modafinil is a valuable new treatment option for use in patients with excessive sleepiness associated with OSA/HS (as an adjunct to nCPAP) or SWSD.
Pharmacological Properties
The exact mechanism by which modafinil promotes wakefulness is unknown, although it appears that it primarily affects areas of the brain involved in controlling wakefulness.
Modafinil increased wakefulness in numerous animal models, including models of sleep deprivation and narcolepsy. Modafinil did not have detrimental effects on subjective and objective measures of nocturnal sleep in healthy volunteers. In sleep-deprived volunteers, modafinil significantly improved mood, fatigue, sleepiness and alertness/vigilance, compared with placebo. In addition, modafinil attenuated the cognitive impairment associated with sleep deprivation and, during laboratory night-shifts, significantly attenuated the decline in cognitive tests versus placebo. Modafinil appears to have a low potential for abuse.
Modafinil is rapidly absorbed; at steady state, a peak plasma concentration of 6.4 μg/mL was reached in 2.7 hours with modafinil 200mg once daily. Approximately 90% of a modafinil dose is metabolised, primarily to two inactive metabolites. The pharmacokinetics of modafinil were altered in older versus younger men nd in patients with chronic hepatic impairment versus healthy volunteers.
Clinical Efficacy
Five randomised, double-blind, placebo-controlled trials examined the efficacy of oral modafinil 200–400mg once daily in patients with excessive sleepiness associated with OSA/HS or SWSD. Two of the OSA/HS trials were of parallel-group design (n = 157 and 309; treatment duration 4 and 12 weeks) and the third was a crossover trial (n = 30; treatment duration 2 weeks). Two studies in SWSD (n = 204 and 278) were of parallel-group design and of 12 weeks’ duration.
In patients with excessive sleepiness associated with OSA/HS who were receiving nCPAP, modafinil 200 or 400 mg/day improved wakefulness, as assessed by Epworth Sleepiness Scale (ESS) scores, to a significantly greater extent than placebo in the parallel-group studies, but not in the smaller crossover study. At study end, sleep-onset latency, assessed by the Maintenance of Wakefulness Test (MWT) or Multiple Sleep Latency Test (MSLT), improved to a significantly greater extent with modafinil 200 or 400 mg/day versus placebo in the parallel-group studies. In the crossover study, sleep-onset latency improved to a significantly greater extent with modafinil 400 mg/day than with placebo according to the MWT, but not the MSLT. Additional analysis of the 4-week parallel-group study found that performance on Psychomotor Vigilance Task (PVT) testing was improved to a significantly greater extent with modafinil 400 mg/day than with placebo.
In the parallel-group studies in patients with OSA/HS, significantly more modafinil 200 or 400 mg/day recipients than placebo recipients experienced clinical improvement. However, in the crossover study, there was no significant between-treatment difference in the proportion of patients whose condition was rated as ‘better’. No reduction in nCPAP use occurred in the parallel-group studies, although a significant reduction in nCPAP use was seen with modafinil 400 mg/day versus placebo in the crossover study. Modafinil did not have an adverse impact on night-time sleep in any of the studies. Moreover, aspects of functional status and health-related quality of life (HR-QOL) were improved to a significantly greater extent with modafinil 200 or 400 mg/day than with placebo in the parallel-group studies, although no such between-treatment difference was seen in the crossover study.
In night-shift workers with SWSD, a significantly greater proportion of modafinil 200 mg/day than placebo recipients experienced clinical improvement according to Clinical Global Impression of Change ratings at the final visit. Improvements in night-time wakefulness (assessed using MSLT sleep-onset latency and Karolinska Sleepiness Scale scores) and performance (PVT testing) were significantly greater in modafinil 200 mg/day than placebo recipients at study end. Modafinil did not have an adverse impact on daytime sleep. Significantly greater improvements in functional status and HR-QOL occurred with modafinil 200 or 300 mg/day than with placebo.
Tolerability
Modafinil was generally well tolerated in patients with excessive sleepiness associated with OSA/HS or SWSD in randomised, double-blind, placebo-controlled studies. Adverse events were generally of mild-to-moderate severity.
In three studies in patients with OSA/HS, the most commonly reported adverse events (i.e. occurring in ≥5% of patients) included headache, infection, nausea, anxiety, accidental injury, diarrhoea, hypertension, nervousness, dizziness, insomnia, rhinitis and dry mouth. Headache, nausea and nervousness occurred significantly more frequently in modafinil than in placebo recipients.
In a study in SWSD, the most commonly reported adverse events (i.e. occurring in ≥5% of patients) in modafinil recipients included headache, nausea, infection, accidental injury, abdominal pain, nervousness, insomnia, dry mouth and tooth disorder; only insomnia occurred in a significantly greater proportion of modafinil than placebo recipients.