Dogs, surgically implanted with a
gastric fistula, were chronically dosed with
diazepam or
lorazepam.
Diazepam (60 mg/kg/day) or
lorazepam (100 mg/kg/day) was administered intragastrically in four divided daily doses. Beginning no less than 2 weeks after the attainment of stabilization doses, dogs underwent withdrawal experiments, repeated at 2-week intervals. At a time of withdrawal determined by a Latin square crossover design, dogs were observed for 8 hr for signs of abstinence. Both
diazepam and
lorazepam caused a withdrawal abstinence syndrome to appear upon abrupt discontinuation of the
drug. The two abstinence syndromes had many signs in common, including
tremor, hot foot walking, rigidity and decreased food intake, but the
lorazepam withdrawal abstinence syndrome was much less intense and had a shorter latency to onset than the
diazepam abstinence syndrome, which also included clonic and
tonic-clonic convulsions and was lethal in two dogs. Furthermore, the
diazepam withdrawal abstinence syndrome was biphasic, the first phase apparent by 24 hr and a second phase beginning at 48 hr, whereas the
lorazepam syndrome was not.
Diazepam suppressed the major signs of
diazepam abstinence in a dose-related manner, but failed to completely suppress all signs of abstinence.
CGS-8216, a pyrazoloquinoline
benzodiazepine antagonist, precipitated abstinence in the
diazepam-dependent dog, but did not precipitate
tonic-clonic seizures. No abstinence syndrome was precipitated in the
lorazepam-dependent dog. These results would suggest that whereas
diazepam and
lorazepam both cause physical dependence the two syndromes are not the same and, furthermore, that physical dependence on, and withdrawal from,
diazepam involves at least two separate mechanisms with different selectivity for
benzodiazepine agonists and antagonists.