Periodic benzodiazepine antagonist administration prevents benzodiazepine withdrawal symptoms in primates.

Daily administration of diazepam (1.5 or 6 mg/kg) in Rhesus monkeys results in the progressive development of physical dependence, as evidenced by Ro15-1788 (5 mg/kg i.m.) precipitated withdrawal symptoms including retching, vomiting, face and limb tremors. Every third day administration of the benzodiazepine antagonist, Ro15-1788, during a similar period of continuous diazepam exposure, significantly decreases withdrawal behaviors. During the course of diazepam exposure (with or without periodic Ro15-1788 administration) effects of chronic diazepam on spontaneously elicited sedative and active behaviors were not altered. It is postulated that physical dependence reverts to a drug naive state after each exposure to the benzodiazepine antagonist. This treatment may represent a possible therapeutic approach for preventing the (time dependent) development of physical dependence and the accompanying severe withdrawal symptoms.