An approach to the modeling of the tolerance mechanism in the drug effect. II: On the implications of compensatory regulation.

In the previous paper (Peper et al., 1987: J. theor. Biol. 127, 413), a model of drug tolerance was developed based on the assumption that the decrease of drug effect after repeated administration of a drug is caused by the involved regulations in the organism adapting themselves to the presence of the drug. In the present paper, the behaviour of the model is studied with respect to the dose-response relation, the drug effect in dependent and non-dependent subjects and withdrawal symptoms. Computer simulations demonstrate the model to be highly sensitive to sudden changes of drug dose. Dependent on the open loop gain of the adaptive mechanism, a sudden decrease of drug dose might result in an effect opposite to the common drug effect. In the model, the rate of decrease of drug dose necessary for optimal drug withdrawal appears to be determined by the same mechanism as the rate of increase of dose necessary for a constant effect at the commencement of treatment. The behaviour of the model suggests the degree of drug dependence in an addicted subject to depend on the extent to which non-somatic factors are involved in the process of initiation of the adaptive mechanisms.