Effect of dosing frequency on the development of physical dependence and tolerance to pentobarbital

Many studies have suggested the importance of the rate of drug elimination in the development of pharmacodynamic tolerance and physical dependence to sedative-hypnotic drugs. Our previous study demonstrated that the role of individual variation in elimination kinetics played an important part in producing pharmacodynamic tolerance and physical dependence when the drug was given at a fixed dose-frequency schedule. The present study investigated the effect of various dose-frequency schedules on the production of tolerance and physical dependence. Controlling the frequency of administration was thought to be the most rational clinical approach in avoiding the production of tolerance and physical dependence with repeated sedative-hypnotic medication. Groups of animals were treated with Na pentobarbital according to the "maximally tolerable" dosing schedule described previously, except that with different dose-frequency schedules, i.e., twice a day, once every day, once every 1.5 days and once every other day for 70 consecutive doses and then withdrawn abruptly. The relationship between the number of Na pentobarbital doses under each dose-frequency schedule and the pharmacokinetic and pharmacodynamic tolerance production, plus the intensity of withdrawal, were studied. The withdrawal intensity was further correlated to the time lag between each drug administration by estimating the maximal time allowed between doses that does not produce any spontaneous withdrawal convulsions and overt withdrawal signs. It was concluded that the time required for repeated Na pentobarbital administration that does not produce withdrawal convulsion and overt withdrawal signs was 4.9 and 5.7 times the average pentobarbital half-life, respectively.