Zolpidem physical dependence assessed across increasing doses under a once-daily dosing regimen in baboons

The current study examined behavioral effects and possible development of physical dependence after once-daily doses of zolpidem (0, 1.0, 3.2, 10.0, 32.0 mg/kg intragastrically [i.g.]) in three baboons. Each dose was administered for 17 days and then the dose was increased; the 32.0 mg/kg dose was administered for 27 days. Baboons had access to food pellets for 20 hr/day beginning 15 min after dosing. Each day, baboons were presented with a fine motor task. Observation sessions were conducted 1 hr after dosing on days 1, 10, 12 and 14 of each dose condition and after termination of drug dosing. On days 10 and 14 of each dose condition, vehicle and flumazenil (5 mg/kg i.m.) were administered, respectively. Zolpidem increased the number of pellets obtained by two of three baboons. Vomit and/or retch and grimace (signs believed to be indicative of abdominal discomfort) were observed in one or two baboons during all zolpidem dose conditions (1.0-32.0 mg/kg). Time to complete the fine motor task increased dose-dependently in all three baboons, and incoordination was observed during the task in two baboons at 10.0 and 32.0 mg/kg. Analysis of blood plasma showed that measurable levels of zolpidem were present 24 hr after dosing in all drug conditions. The signs of flumazenil-precipitated withdrawal were summarized on a 9-point scale. Scores ranged from 1 to 5 in the 1.0 mg/kg condition, from 2 to 5 in the 3.2 and 10.0 mg/kg conditions and from 4 to 6 in the 32.0 mg/kg condition. Signs that were considered intermediate in severity were observed. Specifically, tremor, jerk and/or rigidly braced posture was observed in one baboon at 1.0 mg/kg, two baboons at the next two doses and all three baboons at 32.0 mg/kg. Vomit and/or retch also occurred in two baboons at dose conditions above 1.0 mg/kg. Discontinuation of zolpidem dosing after 78 to 79 days resulted in mild withdrawal signs (e.g., number of pellets obtained were lower and number of 1-min intervals increased in which eyes were closed, or in which lying down, head lower than torso posture and/or withdrawn posture were observed) on the first day in two baboons. The peak withdrawal scores were 4 or 5 on days 5 to 10; two baboons vomited and/or retched and all three baboons showed tremor, jerk and/or rigidly braced posture. Thus, zolpidem produced physical dependence under once-daily dosing conditions, and the severity of the withdrawal syndrome can be characterized as intermediate.