title: Feasibility of reversing benzodiazepine tolerance with flumazenil.
abstract: To examine whether the benzodiazepine antagonist flumazenil can reverse tolerance to benzodiazepines but without precipitating withdrawal seizures, the antiepileptic effect of flumazenil itself and its ability to reverse tolerance at a dose that would leave sufficient receptors free for the binding of benzodiazepines were investigated. Electroencephalographic studies in 6 patients with partial and 6 with generalised seizures showed that flumazenil had a short (20 min) non-dose-dependent suppressant effect on epileptic discharges in those with partial seizures. Receptor occupancy studies in 12 patients showed that 1.5 mg flumazenil given intravenously occupied 55% receptors, whereas 15 mg occupied nearly all receptors. When 3 patients with partial seizures who had become tolerant to clonazepam were given 1.5 mg flumazenil, they were seizure-free for 6-21 days after the injection. The value of intermittent therapy with a benzodiazepine antagonist for preventing or reversing tolerance to benzodiazepine agonists ought to be investigated further.
authors.affiliation: Department of Clinical Neurophysiology, Karolinska Hospital, Stockholm, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: Savic
authors.forename: L
authors.initials: L
authors.lastname: Widén
authors.forename: S
authors.initials: S
authors.lastname: Stone-Elander
mesh_terms: D000328:Adult; D001569:Benzodiazepines / Q000037:antagonists & inhibitors*; D004361:Drug Tolerance; D004569:Electroencephalography; D004827:Epilepsy / Q000175:diagnosis / Q000188:drug therapy*; D005240:Feasibility Studies; D005442:Flumazenil / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D011963:Receptors, GABA-A / Q000187:drug effects; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil