A pharmacodynamic Markov mixed-effects model for the effect of temazepam on sleep

Background: A hypnogram shows how sleep travels through its various stages in the course of a night. The sleep stage changes can be quantified to stud y sedative drug effects, Methods: Hypnograms from 21 patients with primary insomnia were collected d uring a randomized, placebo-controlled crossover study of 20 mg temazepam, A separate daytime session was performed to determine the pharmacokinetics of 20 mg temazepam and its effect on saccadic eye movement and electroencep halogram. A first-order Markov model was developed to describe the probabil ity of sleep stage changes as a function of time after drug intake and time after last sleep stage change. The influence of temazepam concentration on the probability to change sleep stage was incorporated into the model. Results: Transitions between sleep stages were profoundly influenced by the time of the night and by the time since the last change of sleep stage, Te mazepam reduced the time spent awake, This effect could be attributed to fo ur mechanisms: (1) transition to "deeper" sleep was facilitated, (2) transi tion to "lighter" sleep was inhibited, (3) regardless of sleep stage, the t ransition to wake state was inhibited, and (4) return to sleep was facilita ted. Daytime sensitivities to temazepam, measured with the surrogate marker s saccadic peak velocity and electroencephalogram beta activity, each corre lated with one of the transition probabilities influenced by temazepam, Conclusions: By the development of a Markov model for these non-ordered six categorical data, the effect of temazepam on the sleep-wake status could b e interpreted in terms of known mechanisms for sleep generation and benzodi azepine pharmacology.