Development of tolerance and dependence in barbiturate use: a systems modeling approach

Abstract

A system dynamics model is constructed to study the development of tolerance and dependence to phenobarbital in prolonged use. Phenobarbital is a sedative barbiturate drug whose target of action is the brain. Although its use has decreased over the years, phenobarbital is still being prescribed to many patients. As a side effect, phenobarbital enhances the synthesis of its own metabolic enzymes in the liver. This enzyme induction problem causes increased tolerance to phenobarbital over time. Moreover, the brain adapts to the presence of the drug and its sensitivity decreases with time. The resulting decrease in drug effectiveness urges the drug user to increase the dose. A feedback loop results, as the increased dose in turn leads to more metabolic induction and neuroadaptation. Furthermore, the brain’s adaptation to the drug plays a major role in rendering the user dependent on the drug hence complicating withdrawal from the drug. Because adaptive changes persist even after drug intake stops, upon abrupt discontinuation to the drug, the user experiences unwanted rebound effects. The model incorporates phenobarbital absorption, distribution, metabolism, and elimination processes with enzyme induction and neuroadaptation related structures. We start with validating the model by assuming a normal person. We then consider three scenarios: An epilepsy patient, a normal person taking an enzyme inhibitor drug concurrently with phenobarbital, and a normal person adopting different dosing schemes. We finally search for dosing regimens that facilitate gradual withdrawal from the drug so that rebound effects are avoided. Results show that an epilepsy patient is more prone to developing tolerance and dependence. Also, it is shown that concurrent intake of an enzyme inhibitor drug weakens rebound effects after sudden discontinuation since phenobarbital is cleared slower. Experiments with dosing frequencies show that the patient is more prone to tolerance and dependence development if dosing frequency is decreased. Finally, experiments confirm that in order to withdraw from the drug safely, doses should be reduced gradually.