Effects of different rates of absorption of two benzodiazepins on subjective and objective parameters. Significance for clinical use and risk of abuse.

Abstract

Two benzodiazepins with different rates of absorption have been compared in a double-blind cross over study in six healthy subjects using single doses of diazepam (Valium) 2, 5 and 10 mg and oxazepam (Sobril) 15, 25 and 50 mg. Further, oxazepam formulations with different rates of absorption have been compared in 8 healthy subjects. Lastly, the diurnal variation in serum levels during long-term therapy with the benzodiazepins has been followed up in a pilot study in hospital. Drug influence was assessed at intervals and showed that the quantitative and qualitative subjective effects as well as the alteration of reaction time and hand steadiness were more pronounced during the rising phase than in the constant plateau or falling phase of serum drug concentrations. Rapidity of increase in concentration appeared more important than the absolute level. Diazepam has the faster rate of absorption and had a significantly (p<0.05–0.001) greater influence at 30 min, and usually at 90 min, too, than oxazepam or the placebo. Oxazepam, even when administered as a formulation with near-maximal absorption rate, still had not high enough a rate of absorption to produce the distinctly identifiable onset of reactions characteristic of diazepam and did not give noticeable prolongation of reaction time or increased hand unsteadiness even at its maximal serum concentrations. The separate pilot study showed that relatively large diurnal variations in serum concentrations might occur during continuous treatment for more than four weeks and that a preparation with a high rate of absorption (diazepam) could still produce a subjectively apparent experience after each individual dose. It seems reasonable to assume that the risk of abuse, and equally also one of the factors increasing the risk of habituation to psycho-pharmaceutical drugs, is related to subjectively experienced effects, which, as shown above, depend to a large extent on the rate of absorption. For maintenance treatment a steady serum level adapted to the individual is probably to be preferred, while in acute treatment, for example, of attacks of anxiety, a compound with rapid absorption is required, and the therapeutic advantages must then be weighed against the greater risk of abuse.