Em. Weerts et al., ZOLPIDEM PHYSICAL-DEPENDENCE ASSESSED ACROSS INCREASING DOSES UNDER AONCE-DAILY DOSING REGIMEN IN BABOONS, The Journal of pharmacology and experimental therapeutics, 285(1), 1998, pp. 41-53
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 do
se was administered for 17 days and then the dose was increased; the 3
2.0 mg/kg dose was administered for 27 days. Baboons had access to foo
d pellets for 20 hr/day beginning 15 min after dosing. Each day, baboo
ns were presented with a fine motor task. Observation sessions were co
nducted 1 hr after dosing on days 1, 10, 12 and 14 of each dose condit
ion and after termination of drug dosing. On days 10 and 14 of each do
se condition, vehicle and flumazenil (5 mg/kg i.m.) were administered,
respectively. Zolpidem increased the number of pellets obtained by tw
o of three baboons. Vomit and/or retch and grimace (signs believed to
be indicative of abdominal discomfort) were observed in one or two bab
oons during all zolpidem dose conditions (1.0-32.0 mg/kg). Time to com
plete the fine motor task increased dose-dependently in all three babo
ons, 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 conditi
ons. The signs of flumazenil-precipitated withdrawal were summarized o
n a 9-point scale. Scores ranged from 1 to 5 in the 1.0 mg/kg conditio
n, 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 brac
ed 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 retc
h also occurred in two baboons at dose conditions above 1.0 mg/kg. Dis
continuation of zolpidem dosing after 78 to 79 days resulted in mild w
ithdrawal signs (e,g., number of pellets obtained were lower and numbe
r of 1-min intervals increased in which eyes were closed, or in which
lying down, head lower than torso posture and/or withdrawn posture wer
e observed) on the first day in two baboons. The peak withdrawal score
s 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. T
hus, zolpidem produced physical dependence under once-daily dosing con
ditions, and the severity of the withdrawal syndrome can be characteri
zed as intermediate.