Question: Which drug should be used as an antidote in benzodiazepine overdose?

Context:
Benzodiazepine (BZD) overdose (OD) continues to cause significant morbidity and mortality in the UK. Flumazenil is an effective antidote but there is a risk of seizures, particularly in those who have co-ingested tricyclic antidepressants.
Flumazenil was administered to 80 patients in 4504 BZD-related enquiries, 68 of whom did not have ventilatory failure or had recognised contraindications to flumazenil.
Flumazenil is used infrequently in the management of BZD OD in the UK.
Flumazenil is a benzodiazepine antagonist. It is widely used as an antidote in comatose patients suspected of having ingested a benzodiazepine overdose.
Flumazenil is very useful in reversing benzodiazepine-induced sedation as well as to diagnose or treat benzodiazepine overdose.
Flumazenil is indicated for reversal of sedation from benzodiazepines administered during therapeutic or diagnostic procedures and during induction or maintenance of general anesthesia, as well as for benzodiazepine overdose.
When measures are required to ensure adequate recovery of a patient's respiratory function and mental awareness, such as in patients with benzodiazepine toxicity, consideration of continuous-infusion flumazenil is warranted.
Flumazenil is a potent benzodiazepine antagonist that competitively blocks the central effects of benzodiazepines. It can reverse the sedative effects of benzodiazepines occurring after diagnostic or therapeutic procedures or after benzodiazepine overdose.
A 54-y-old man ingested 2 g of bulk laboratory diazepam and was treated with activated charcoal, enhanced diuresis and flumazenil infusion.
Flumazenil is a specific and competitive antagonist at the central benzodiazepine receptor, reversing all effects of benzodiazepine agonists without tranquillising or anticonvulsant actions.
Incremental intravenous bolus injections of flumazenil 0.1 to 0.3 mg are the most effective and well tolerated in the diagnosis and treatment of pure benzodiazepine overdose; additional boluses or an infusion (0.3 to 0.5 mg/h) can be given to prevent patients from relapsing into coma.
Flumazenil is a competitive benzodiazepine antagonist that acts to reverse their sedative and hypnotic effects. It is indicated in the management of benzodiazepine overdose, but its role in the routine reversal of endoscopic conscious sedation has not been defined.
To develop clinical rules for the safe and effective use of flumazenil in suspected benzodiazepine overdose.
Unconscious patients (n = 110) suspected of benzodiazepine overdose, graded 2 to 4 on the Matthew and Lawson coma scale, were treated with flumazenil, the specific benzodiazepine receptor antagonist.
Fourteen of 17 double-blind, flumazenil-treated patients woke after a mean of 0.8 +/- 0.3 (SD) mg vs. one of 14 placebo patients (p < .001). Seventy-five percent of the aggregated controlled and uncontrolled patients awoke from coma scores of 3.1 +/- 0.6 to 0.4 +/- 0.5 (p < .01) after the injection of 0.7 +/- 0.3 mg of flumazenil. These patients had high benzodiazepine serum blood concentrations.
Flumazenil is effective in preventing recurrence of benzodiazepine-induced coma.
Flumazenil is best left for reversal of therapeutic conscious sedation and rare select cases of benzodiazepine overdose.
Flumazenil interacts at the central benzodiazepine receptor to antagonize or reverse the behavioral, neurologic, and electrophysiologic effects of benzodiazepine agonists and inverse agonists.
It improves the level of consciousness in patients with benzodiazepine overdose; however, resedation may occur within one to two hours after administration, so repeated doses or a continuous infusion may be required to maintain therapeutic efficacy.
Flumazenil has been shown to reverse sedation caused by intoxication with benzodiazepines alone or benzodiazepines in combination with other agents, but it should not be used when cyclic antidepressant intoxication is suspected.
Flumazenil, a specific benzodiazepine antagonist, was evaluated as adjunctive therapy in the management of benzodiazepine overdose.
The mean CGIS score at 10 minutes for benzodiazepine-positive patients treated with flumazenil was 1.95 versus 3.58 for those given placebo.
Among the benzodiazepine-positive patients, 9 (53%) of 17 patients from the flumazenil group responded to the additional flumazenil, and 58 (81%) of patients previously given placebo responded.
The results of this study confirm published reports of the efficacy of flumazenil in reversing benzodiazepine-induced sedation in patients with benzodiazepine overdose.
Flumazenil, a specific benzodiazepine antagonist, is useful in reversing the sedation and respiratory depression that often occur when benzodiazepines are administered to patients undergoing anesthesia or when patients have taken an intentional benzodiazepine overdose.
Flumazenil rapidly and effectively reverses the clinical signs and symptoms of a BDZ overdose.
Flumazenil is a benzodiazepine antagonist that is highly effective in reversing the central nervous system effects of benzodiazepine overdose.
In the setting of isolated benzodiazepine overdose, flumazenil is capable of completely reversing coma within one to two minutes, with this effect lasting between one and five hours.
Fifteen comatous patients with suspected sedatives/hypnotics overdose were included in this study and flumazenil 0.25 mg per dose was administrated intravenously. The average score of Glasgow Coma Scale increased from 7.13 +/- 2.92 to 10.93 +/- 3.67 after one dose of flumazenil. Clear consciousness was restored after multiple doses of flumazenil administration.
We concluded that flumazenil is an excellent antidote for benzodiazepine overdose and valuable for differentiating the patients in comatose.
Patients with benzodiazepine overdose who received 5 mg flumazenil regained consciousness about 1-2 min after the end of injection.
We conclude that flumazenil is an effective and safe drug in the treatment of benzodiazepine overdose.
Flumazenil is the first benzodiazepine antagonist which can be used in humans and is a well established for treatment of benzodiazepine overdose.
Flumazenil, a 1,4-imidazobenzodiazepine, is a highly effective, specific benzodiazepine antagonist which is indicated for use when the effect of a benzodiazepine must be attenuated or terminated at short notice.
Thus, flumazenil provides a safe and effective means of attenuating or reversing the CNS-depressant effects of benzodiazepines whenever indicated, e.g. following benzodiazepine-induced general anaesthesia, conscious sedation, or after benzodiazepine overdose, either alone or in combination with other agents.
Flumazenil is safe when administered cautiously, even in patients with coma caused by a mixed overdose of benzodiazepine plus tricyclic antidepressants.
The mean +/- SD CGIS score at ten minutes for BDZ-positive patients was 1.41 +/- 0.72 for patients who received flumazenil and 3.41 +/- 0.91 for the placebo group (P < .01). There was no difference in the mean CGIS score between the flumazenil (3.25 +/- 1.15) and placebo (3.75 +/- 0.69) groups in BDZ-negative patients. The GCS and NAS were also significantly better in patients who were BDZ-positive and received flumazenil.
In 23 patients admitted to the Intensive Care Unit with coma due to overdose with benzodiazepines or other sedatives, flumazenil i.v. (up to 2 mg or placebo) was given. In 13 patients given flumazenil the Glasgow Coma Scale (GCS) increased significantly from 4.9 to 7.8 (p less than 0.05). Six of these 13 patients, including mainly benzodiazepine mono-intoxications, needed only one series of injections (up to 1.0 mg flumazenil); the GCS increased thereby from 4.5 to 10.7 within a maximum of 5 min (p less than 0.01).
The efficacy and safety of flumazenil were assessed in comparison to placebo in a double-blind randomised study of 31 adults intoxicated with benzodiazepines. The criteria of efficacy were the degree of sedation, and orientation in time and space. Patients who received flumazenil awoke within minutes but central depression returned partly one hour later, which reflects the short elimination half-life of the drug.
Side effects were few and the results indicate that flumazenil is effective in the primary management of benzodiazepine overdose and in states where benzodiazepines have been taken with other drugs.
Flumazenil (Ro 15-1788) proved to be a very efficacious competitive antagonist of benzodiazepines that reliably counteracts their pharmacological actions within 1-2 min as could be demonstrated in clinical and EEG studies.
In intensive care medicine, the antagonist may be used in the treatment of benzodiazepine overdose as well as in the differential diagnosis of a coma of unknown origin.

Answer: Flumazenil should be used in all patients presenting with suspected benzodiazepine overdose. Flumazenil is a  potent benzodiazepine receptor antagonist that competitively blocks the central effects of benzodiazepines and reverses behavioral, neurologic, and electrophysiologic effects of benzodiazepine overdose. Clinical efficacy and safety of flumazenil in treatment of benzodiazepine overdose has been confirmed in a number of rigorous clinical trials. In addition, flumazenil is also useful to to reverse benzodiazepine induced sedation and to and to diagnose benzodiazepine overdose.
Exact answer: flumazenil