Duration of activity and mode of action of modafinil: Studies on sleep and wakefulness in humans.

The duration of activity of modafinil was investigated in healthy male volunteers in two double-blind crossover studies. Mode of action was explored using a statistical model concerned with the relationship between total sleep duration and that of rapid eye movement (REM) sleep. Nocturnal sleep (23:00-07:00) followed by next-day performance (09:00-17:00) was studied in 12 subjects administered 100, 200, 300 mg modafinil and placebo, 0.5 h before bedtime. Performance overnight (19:00-08:45) followed by sleep (09:15-15:15) was studied in nine subjects administered 100, 200, 300, 400 mg modafinil, 300 mg caffeine and placebo at 22:15. Modafinil dose-dependently reduced sleep duration (nocturnal: 200 mg, p<0.05; 300 mg, p<0.001; morning: 300 and 400 mg, p<0.05) and REM sleep (nocturnal: 300 mg; morning: 400 mg; p<0.05). The statistical model revealed that reduced REM sleep was due to alerting activity, with no evidence of direct suppression of REM sleep, suggesting dopaminergic activity. Enhanced performance with modafinil during overnight work varied with dose (200 mg>100 mg; 300, 400 mg>200, 100 mg, caffeine). However, in the study of next-day performance, the enhancement was attenuated at the highest dose (300 mg) by the greater disturbance of prior sleep. These findings indicate that modafinil has a long duration of action, with alerting properties arising predominantly from dopaminergic activity.