EFFECTIVENESS OF FLUMAZENIL (RO 15-1788) IN THE TREATMENT OF BENZODIAZEPINE WITHDRAWAL

Flumazenil (RO 15-1788) was used to treat benzodiazepine (BZD) withdrawal after abrupt cessation of chronic abuse of high-dose flunitrazepam or lormetazepam. Thirty-six patients (18 flunitrazepam and 18 lormetazepam abusers) were randomly divided into 4 groups of 9 subjects: group A: flunitrazepam abusers treated with flumazenil; group B: flunitrazepam abusers treated with placebo; group C: lormetazepam abusers treated with flumazenil; group D: lormetazepam abusers treated with placebo. Fifteen withdrawal symptoms were measured on a four-point scale from 0 (not present) to 3 (severe) every 6 hours. Saline solution was used as the placebo. Mean withdrawal score was significantly higher (P < 0.05) on the first day after cessation of lormetazepam in group D. During the following 2 days the two groups treated with placebo showed a significant increase in mean withdrawal scores (P < 0.001). No rise in mean withdrawal symptom scores was seen in the groups treated with flumazenil. One patient in group B and 2 patients in group D needed diazepam medication 72 hours after withdrawal of BZD. No seizures or other side effects were seen after flumazenil infusion. Our data suggest that high doses of BZD for a prolonged period may induce functional changes in the gamma-aminobutyric acid (GABA)-BZD receptor complex. Flumazenil appears to up-regulate GABA-BZD-receptors and exert a weak agonist action that suppresses BZD withdrawal symptoms.