Abstract for: Development of Barbiturate Tolerance and Dependence: A Systems Modeling Approach

A system dynamics model is constructed to study the development of tolerance and dependence to phenobarbital in the long-term. Phenobarbital is a regularly used sedative drug. Its target is the brain. As a side effect, phenobarbital enhances the synthesis of metabolic enzymes in the liver and thus increases its own metabolism rate. Furthermore, in regular use, the brain adapts to the presence of the drug and its sensitivity decreases with time. These factors decrease drug effectiveness and urge the user to increase the dose during continuous use. A feedback loop results as the increased dose affects enzyme and neuroadaptation dynamics. Because adaptive changes persist even after drug intake stops, upon abrupt discontinuation of the drug, the patient experiences rebound effects such as hyperexcitability and seizures. The model incorporates enzyme induction and neuroadaptation dynamics and serves as an experimental platform to study the behavior of the drug user as he/she develops tolerance. Additionally, it is possible to evaluate dosing regimens in order to facilitate gradual withdrawal from the drug so that rebound effects are avoided. Our simulation experiments revealed that whether dependence is partial or complete, the duration of a successful regimen is more than half the duration of regular use.