MO Karlsson, RC Schoemaker, B Kemp, A Cohen, J van Gerven, M Danhof
Uppsala University and Leiden University
Background: In hypnograms, sleep is continuously monitored and sleep stage is routinely scored every 30 seconds. Direct analysis of such data may provide a source for information of baseline sleep patterns and sedative drug effects.
Methods: Pharmacokinetic and polysomnographic sleep recording data from 21 patients with primary insomnia were collected during a randomized, placebo controlled, cross-over study of 20 mg temazepam. A first-order Markov model was developed to describe the probability of sleep stage changes as a function of time after medication 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. In the primary analysis, a model that distinguished only between being asleep or awake was developed. To obtain more detailed information, awake and five different sleep stages were considered in further analyses.
Results: Temazepam influenced both the probability of falling asleep and awakening with direct and linear relationships on the logit of the probability. There was a distinct difference of temazepams effect on the initial awake state and when patients woke up during the night. The latter state, but not the former, was affected by the drug. A lower risk of waking up during temazepam therapy could be attributed to three mechanisms: (i) transitions to “deeper” sleep was facilitated, (ii) transitions to “lighter” sleep was inhibited,and (iii) regardless of sleep stage, the transition to wake state was inhibited. In addition to dependence on drug concentration, transitions between sleep stages were profoundly influenced by the time of the night and by the time since last change of sleep stage. The effect of temazepam on some sleep transition parameters was correlated to the individual response during a separate day time experiment where saccadic eye movement and EEG changes were monitored.
Conclusions: By the development of a Markov model for these non-ordered 6-categorical data, the effect on the sleep/wake status could be related to temazepam concentration in a detailed manner that agrees with known mechanisms for basic sleep pattern and benzodiazepine pharmacology.
Reference: PAGE 8 () Abstr 135 [www.page-meeting.org/?abstract=135]
Poster: oral presentation