Pharmaco-EEG, behavioural methods and blood levels in the comparison of temazepam and flunitrazepam

In a double-blind placebo-controlled cross-over study, the blood levels and pharmacodynamic properties of temazepam were compared with flunitrazepam using quantitative pharmaco-EEG and psychometric methods in ten healthy volunteers. Computer-assisted spectral analysis of the EEG after three doses of temazepam (10 mg, 20 mg and 40 mg) compared with placebo showed statistically significant changes in brain function. These changes were also seen after the administration of the reference drug (flunitrazepam 2 mg) and are typical of anxiolytic sedatives. Psychometric and psychophysiological tests demonstrated significant alterations at the behavioural level, especially after higher doses of temazepam and 2 mg flunitrazepam, as expected. However, low doses or low blood levels of temazepam induced an improvement of performance in certain variables. Dose-efficacy calculations identified 2 mg flunitrazepam and 40 mg temazepam as the most CNS-effective, followed by 20 mg and 10 mg temazepam, while the least changes occurred after placebo. Time-efficacy calculations showed marked inter-drug differences. The pharmacodynamics of both drugs parallel their respective pharmacokinetics. Regression and correlation analyses between blood levels and EEG or psychometric changes revealed that beta activity and the centroid of the EEG were positively correlated with plasma levels, while alpha activity, psychometric variables and skin conductance were negatively correlated. Psychometric variables started to deteriorate above a blood level of approximately 250 ng/ml, while below this level an improvement was seen. Such (sedative) blood levels were only reached after doses higher than 10 mg temazepam. Our findings indicate that 10 mg temazepam has tranquilizing properties, while 20 mg and 40 mg doses exert, in addition, sedative sleep-inducing effects.