Flunitrazepam and nordiazepam slowly released from silastic capsules induce physical dependence in rat

The rates of in vitro release of flunitrazepam (FN), nordiazepam (ND) and diazepam (DZ) from silastic capsules were compared and found to be in the following order: DZ > FN > ND. Rats that were implanted subcutaneously with capsules filled with FN or ND for 5 to 7 weeks before administering flumazenil (FLU) (40 mg/kg, i.v.) showed precipitated abstinence as measured by the Precipitated Abstinence Score (PAS) which included a rapid onset of clonic and tonic-clonic convulsions. Rats implanted with DZ also demonstrated significant PAS and seizures. Implantation of similar doses of DZ, FN and ND resulted in different plasma levels of parent benzodiazepines and their metabolites that corresponded with their in vitro release: DZ > FN > ND. These data indicate that, as for DZ, the capsule implantation is an effective method of producing physical dependence on FN and ND in the rat.