, Volume 42, Issue 6, pp 1061–1089 | Cite as


A Reappraisal of its Pharmacological Properties and Therapeutic Efficacy as a Benzodiazepine Antagonist
  • Rex N. Brogden
  • Karen L. Goa
Drug Evaluation



Flumazenil is a specific benzodiazepine antagonist which is indicated when the central effects of a benzodiazepine need to be attenuated or terminated. Following intravenous administration of up to 1mg, flumazenil effectively reverses sedation and improves psychomotor performance following administration of short and longer acting benzodiazepines used for sedation, or general anaesthesia supplemented with benzodiazepines. The duration of action is short at generally 30 to 60 minutes and supplemental doses of flumazenil may be needed to maintain the desired level of consciousness in some patients. After poisoning with high dosages of benzodiazepines alone or combined with other drugs, the initial single dose of flumazenil will require supplementing with repeated low intravenous doses or an infusion to maintain wakefulness. In such patients, flumazenil also facilitates differential diagnosis and reduces the necessity for interventions.

Flumazenil thus enhances recovery and allows more rapid discharge of patients sedated with benzodiazepines for diagnostic procedures and facilitates management of patients during the initial recovery period following general anaesthesia supplemented with benzodiazepines, but does not preclude normal monitoring during the recovery period. Flumazenil is clearly very useful in treating drug poisoning when benzodiazepines are a major component.

By virtue of its specific benzodiazepine antagonist effects, flumazenil provides an innovative and well tolerated approach in clinical situations requiring rapid reversal of benzodiazepine-induced central nervous system depressant effects.

Pharmacodynamic Properties

Flumazenil is a benzodiazepine antagonist which inhibits the central effects of benzodiazepine agonists by competing with these drugs for the benzodiazepine receptor. In various tests in mice, rats and cats, flumazenil 0.3 to 30 mg/kg intravenously, 0.5 to. 10 mg/kg intraperitoneally, a total dose of 30 to 100mg orally and of 2.5µg by the intracerebroventricular route, has been shown to antagonise the central effects of benzodiazepine agonists (e.g. diazepam, triazolam, midazolam) and inverse agonists [e.g. dimethoxy-ethyl-carbomethoxy-βr-carboline (DMCM)].

The inhibitory effect of flumazenil is specific for central benzodiazepine receptors. In vitro binding studies of these receptors using positron emission tomography, support the suggestion that in man, as in animals, flumazenil antagonises the central pharmacological effects of the benzodiazepines by interacting with these drugs at the central benzodiazepine receptor binding sites. Numerous studies in healthy subjects have demonstrated that flumazenil 100 to 200mg orally or 2.5 to 20mg intravenously antagonised the pharmacological effects (such as sedation, impaired cognitive and motor function, and anaesthesia) of diazepam, methylclonazepam, flunitrazepam, lorazepam, midazolam and zolpidem when the benzodiazepine agonist and flumazenil were administered concomitantly or separately at various intervals. The degree and duration of flumazenil antagonism of midazolam are dose related.

Although earlier uncontrolled studies suggested that flumazenil reversed ethanol-induced central nervous system depression this has not been confirmed in placebo-controlled trials in healthy volunteers with steady-state plasma ethanol concentrations.

Cardiovascular effects of intravenously administered flumazenil 0.1 to lmg in patients with coronary artery disease sedated with a benzodiazepine derivative are generally slight, but its ventilatory effects are still unclear, with effects varying depending on assessment criteria, and sedative or anaesthetic techniques implemented prior to flumazenil administration. There is some evidence in animal studies that flumazenil prevents benzodiazepine tolerance, dependence and withdrawal, but it is not known whether it is useful clinically in these situations. Early studies suggested that flumazenil was devoid of intrinsic pharmacological activity, but later evidence indicated that, depending on basal conditions, tests, dosage and measurements performed, flumazenil had both weak agonist-like and weak inverse agonist-like properties. Flumazenil has anticonvulsant properties when administered at dosages of 10 to 90mg daily alone or in conjunction with other antiepileptic drugs. Although flumazenil 2mg intravenously precipitated panic attacks in patients with panic disorder, it was without effect in healthy volunteers, and it is improbable that the panic attacks reflected an intrinsic effect of the drug. Apart from its anticonvulsant effect, any weak intrinsic agonist-like or inverse agonist-like pharmacological activity of flumazenil is unlikely to be of clinical importance.

Pharmacokinetic Properties

Peak plasma flumazenil concentrations are attained 20 to 90 minutes after a single 200mg oral dose and oral bioavailability averages 16% because of a high degree hepatic clearance and consequent first-pass metabolism. When administered intravenously, disposition is linear over a dosage range from 2.5 to 40mg, with steady-state concentrations of about 6, 13 and 39 µg/L in fasting volunteers administered a loading dose of 0.5, 1 and 3mg, respectively, followed by an infusion of the same dose hourly. These concentrations are decreased by about one-third by concomitant food ingestion.

Maximum cerebral flumazenil concentrations are attained 5 to 8 minutes after intravenous administration. Protein binding is 40 to 50% and volume of distribution 96 and 77L at steady-state plasma concentrations of 10 and 20 µg/L.

Flumazenil is metabolised principally to the inactive free carboxylic acid and the corresponding glucuronide, has a moderately high total body clearance of 54 to 67 L/h (approximately 13 to 16 ml/min/kg) and a short elimination half-life of 0.8 to 1.16 hours. Elimination half-life and oral bioavailability increased and total body clearance decreased in patients with cirrhosis.

Therapeutic Efficacy

The efficacy of flumazenil in reversing the central effects of benzodiazepines has been clearly shown in placebo-controlled studies. These have mostly been conducted during the recovery period following surgery in hospitalised patients receiving total intravenous anaesthesia using midazolam or flunitrazepam as hypnotics, in outpatients sedated with midazolam, diazepam or flunitrazepam for diagnostic or dental procedures, or in patients sedated with midazolam, flunitrazepam or diazepam who were undergoing various surgical procedures under spinal anaesthesia. Flumazenil administered intravenously at dosages of up to 1mg was consistently superior to placebo in reversing benzodiazepine-induced sedation as evidenced by earlier awakening, orientation in time and space, and cooperation, and improved psychomotor performance. Flumazenil did not eliminate amnesia for the operative procedure, thus retaining this desirable effect, but usually prevented further amnesia after its administration. Residual sedation (re-sedation) was not a clinical problem in patients sedated with single low dosages of midazolam (5 to 11mg) but tended to be more evident after sedation with the longer acting diazepam and flunitrazepam.

Flumazenil also improved postoperative psychomotor performance and shortened recovery time after total intravenous or general anaesthesia employing benzodiazepines, although residual sedation was consistently observed, suggesting the need for repeated flumazenil administration to maintain the desired level of consciousness. Generally, administration of flumazenil did not increase the incidence of postoperative nausea and vomiting or analgesic requirements, and in patients anaesthetised with midazolam/alfentanil appeared to reduce the need for naloxone. Flumazenil was superior to doxapram and physostigmine in improving psychomotor performance and reversing sedation. In 2 studies psychomotor performance was better in patients anaesthetised with propofol than in those administered flumazenil following midazolam anaesthesia; sedation was similar with both regimens 30 minutes after admission to recovery room and at 2 to 4 hours after surgery, but was less evident at 60 minutes with propofol.

Recent double-blind placebo-controlled studies have confirmed the efficacy of flumazenil (≤1mg average) in increasing the level of consciousness, in facilitating differential diagnosis and reducing the necessity of interventions in patients who ingested overdoses of benzodiazepines alone or combined with other drugs. Coma scores increased by a similar amount after flumazenil administration to patients poisoned with benzodiazepines alone or with ethanol and in mixed overdosage, but as would be expected, flumazenil was without effect in poisoning from barbiturates, polycyclic antidepressants or phenothiazines.

Most of the evidence for the efficacy of flumazenil in the treatment of hepatic encephalopathy is anecdotal and in some instances failed to exclude patients treated with benzodiazepines before flumazenil administration. However, in the few that did involve such exclusion, there was transient though distinct improvement in some patients. Preliminary results of controlled studies however, failed to show any therapeutic benefit of flumazenil relative to standard treatment.


Usual therapeutic dosages of flumazenil have been very well tolerated by most patients, particularly when used to reverse sedation for diagnostic procedures. In this setting the incidence of the most commonly reported adverse effects of nausea, dizziness and headache was similar in recipients of flumazenil or placebo. Although the incidence of adverse effects following general anaesthesia has been higher it is difficult to separate adverse effects due to flumazenil from unmasked effects of anaesthetic drugs or underlying disease. Some studies have reported more frequent nausea and/or vomiting with flumazenil than with placebo although others have noted no difference in incidence. There have been few haemodynamic or ventilatory adverse effects. Residual sedation is uncommon following reversal of the effects of single low dosages of midazolam and is more consistently reported following general anaesthesia, but is rarely serious and may be controlled by further administration of flumazenil.

Serious adverse effects possibly, but rarely associated with flumazenil include epileptic or withdrawal seizures, bradycardia, asystole, tachycardia and arrhythmia. Since flumazenil may not completely reverse benzodiazepine-induced respiratory depression, close monitoring is required in such patients.

Dosage and Administration

The dosage of flumazenil should be titrated individually to obtain the desired level of consciousness. Generally, doses of 0.3 to 0.6mg administered intravenously have been adequate to reduce the degree of sedation to the required extent in patients sedated or anaesthetised with benzodiazepines for performing surgery, while doses of 0.5 to 1mg are usually sufficient to abolish the effect of a therapeutic dose of a benzodiazepine in other settings. In patients who are unconscious due to ingestion of an overdose of drugs that have not been positively identified, failure to respond to intravenous doses of 5mg flumazenil may indicate the involvement of intoxicants other than benzodiazepines, or the presence of functional or organic disorders.


Midazolam Hepatic Encephalopathy Flumazenil Flunitrazepam Inverse Agonist 
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© Adis International Limited 1991

Authors and Affiliations

  • Rex N. Brogden
    • 1
  • Karen L. Goa
    • 1
  1. 1.Adis International LimitedAuckland 10New Zealand

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