Chronic administration of and dependence on halazepam, diazepam, and nordiazepam in the dog

Flumazenil-precipitated withdrawal in healthy volunteers following repeated diazepam exposure

“…In general, the symptoms of withdrawal precipitated by flumazenil are similar to the symptoms observed when a benzodiazepine agonist is withdrawn naturally (Woods et al 1987) and, for this reason, flumazenil has been a useful tool in studies evaluating the conditions under which benzodiazepine physical dependence is likely to develop. Preclinical studies of flumazenil-precipitated withdrawal have demonstrated that the dose of the benzodiazepine agonist (Lukas and Griffiths 1984;Sloan et al 1993), the specific pharmacokinetic profile of the agonist (Martin et al 1990;Sloan et al 1991b), the duration of exposure to the agonist Griffiths 1982, 1984;Rosenberg and Chiu 1985;Sloan et al 1991a;Wilson and Gallager 1988;Zharkovskii and Zharkovskaia 1987 as cited in Woods et al 1992; but cf. Kaminski et al 2003), and the dose of flumazenil (Lamb and Griffiths 1987;Martin et al 1990;McNicholas et al 1988;Sannerud et al 1991) all contribute to the intensity of withdrawal.…”