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Physical dependence to barbital compared to pentobarbital. IV. Influence of elimination kinetics.

The withdrawal characteristics of barbital and pentobarbital after "chronically equivalent" treatment suggested that the longer acting barbital was less liable to produce physical dependence. Therefore, to distinguish this potential pharmacodynamic difference from the known pharmacokinetic differences between the two drugs, the rate of elimination of each was adjusted to mimic that of the other. The rate of barbiturate elimination after chronically equivalent pentobarbital dosing was reduced by barbital substitution or by first-order pentobarbital dose reduction, with the result that withdrawal signs became mild and appeared later (3 days postdrug). The rate of barbiturate elimination after chronically equivalent barbital dosing was increased by pentobarbital substitution or by peritoneal dialysis of barbital, with the result that withdrawal signs became severe and appeared sooner (within 1 day). These findings conclusively support the key role of the rate of barbiturate elimination to expose underlying physical dependence to barbiturates. Furthermore, "physical dependence" and its expression in "withdrawal" must be regarded separately to evaluate and compare critically the dependence capability of different drugs.