Feasibility of reversing benzodiazepine tolerance with flumazenil

  title={Feasibility of reversing benzodiazepine tolerance with flumazenil},
  author={Ivanka Savic and Lennart Wid{\'e}n and Sharon Stone-Elander},
  journal={The Lancet},
Effects of flumazenil in the treatment of benzodiazepine withdrawal – a double-blind pilot study
There was an overall difference between patients and controls, with patients scoring higher on negative and somatic items and lower on positive psychological items, and flumazenil reduced symptoms thought to be important in withdrawal in patients treated for benzodiazepine dependency.
Pharmacology of flumazenil
The existence of flumazenil is important, with implications for future research and the development of minimally invasive therapy and day‐case surgery, and with increasing pressures on non‐anaesthetically trained practitioners to perform sedation, it has important implications for safety.
Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebo‐controlled study
The effectiveness of FLU may reflect its capacity to upregulate BZD receptors and to reverse the uncoupling between the recognition sites of BzD and GABA, on the GABA A macromolecular complex, that has been reported in tolerant subjects.
Oral Flumazenil in the Treatment of Epilepsy
No adequately designed long-term trials have been conducted on treatment of epilepsy using flumazenil, rendering evaluation of its use as a single-agent antiepileptic difficult.
Benzodiazepine dependence and its treatment with low dose flumazenil
Preliminary in vitro water bath and in vivo biocompatibility data in sheep show that such an implant is feasible and so is likely to be used in clinical trials in the near future, and could be capable of managing both acute and longer term benzodiazepine withdrawal sequelae.
A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal
The benefits last between a few hours and several days despite flumazenil's otherwise short duration of action, however, symptoms did return to varying degrees in most cases, suggesting the need for repeated doses.
Flumazenil-precipitated withdrawal in healthy volunteers following repeated diazepam exposure
These findings support previous human research studies indicating that flumazenil precipitates withdrawal after short chronic exposure to benzodiazepines and suggests that duration of exposure does not influence the intensity of withdrawal beyond the first week of exposure.
Benzodiazepine Receptor Antagonists
Flumazenil represents a promising tool for pharmacological investigations of the GABAergic system and for imaging of the benzodiazepine receptor, and as a neuronal marker in epilepsy and cerebral ischaemia.


The anticonvulsant effect of the benzodiazepine antagonist, Ro 15-1788: an EEG study in 4 cases.
This investigation would suggest further study of Ro 15-1788 in epileptic patients for clarification of its anticonvulsant properties and evaluation of its action on the sedation caused by benzodiazepine antiepileptic medication is suggested.
Chronic benzodiazepine treatment decreases postsynaptic GABA sensitivity
Electrophysiological evidence for decreased postsynaptic sensitivity to GABA following chronic benzodiazepine administration is presented as measured by the direct iontophoretic application of GABA and serotonin onto serotonergic cells in the midbrain dorsal raphe nucleus (DRN), known to receive GABAergic input.
Precipitated withdrawal by a benzodiazepine receptor antagonist (Ro 15-1788) after 7 days of diazepam.
Baboons implanted with intragastric catheters were given diazepam twice daily for 45 consecutive days and intramuscular injections of the benzodiazepine receptor antagonist Ro 15-1788 were given on days 7 and 35.
Benzodiazepine receptor occupancy in vivo: correlation with brain concentrations and pharmacodynamic actions.
The correlation between receptor occupancy and the pharmacodynamic actions of these drugs in blocking pentylenetetrazol seizures and inducing rotarod ataxia indicated that ED50 for these effects occurred at receptor occupancy of 30 to 60% for both drugs.
Partial agonists of the benzodiazepine receptor: from animal data to results in patients.
  • W. Haefely
  • Biology
    Advances in biochemical psychopharmacology
  • 1988
Concepts are presented here that could explain the modulatory function of the BZR, and a number of factors are proposed to determine the pharmacological and therapeutic profile of B zR ligands: intrinsic efficacy at the BzR, density of GABAA-BZR on neurons, functional reserve in GAB AA-BzRs, the intensity of the GABAergic input to a neuron, and the excitatory neuronal state.