Summary
In anaesthesia and in the intensive care unit, benzodiazepines have proven safe and effective agents for the induction and maintenance of sedation for a variety of therapeutic goals. However, in these contexts, or in benzodiazepine overdose, it is often desirable to be able to terminate or interrupt sedation without waiting for the effect of the benzodiazepine to become dissipated by normal metabolism and excretion.
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. It acts by displacing other benzodiazepines from the receptor site by competitive inhibition. The onset of effect after intravenous administration occurs within 1 to 3 minutes. The optimal dosage is determined for each patient by a dose titration procedure and lies in the range 0.2 to l.Omg in anaesthesiology, and 0.1 to 2.0mg in intensive care use. Despite its short elimination half-life of around 1 hour, after general anaesthesia or conscious to moderate sedation for short procedures, a single dose of flumazenil is usually sufficient to attain and maintain the desired level of consciousness. After intoxication with high benzodiazepine doses, the duration of effect of a single dose of flumazenil is not expected to exceed 1 hour. In such cases, the period of wakefulness can be prolonged as necessary by repeated low intravenous doses of flumazenil or by infusion (0.1 mg/hour).
Flumazenil is well tolerated both systemically and locally. The only adverse events seen with greater frequency after flumazenil compared with placebo were nausea and/or vomiting after general anaesthesia, although the incidence of actual vomiting was not significantly different between the 2 groups. Since these effects were virtually absent in studies of intensive care patients and after sedation for short procedures, and were not seen in tolerability studies in healthy volunteers receiving intravenous bolus doses of up to 100mg, there may be a link between these symptoms and the other agents used in general anaesthesia, some of which have well-known emetic properties.
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. Its reliability of effect, lack of influence on vital functions, and specificity for benzodiazepines also allow its use for diagnostic purposes, e.g. to exclude benzodiazepine intoxication in patients with consciousness impairment of unknown origin.
Similar content being viewed by others
References
Albertson TW, Bowyer JF, Paule MG. Modification of the anti-convulsant efficacy of diazepam by Ro 15-1788 in the kindled amygdaloid seizure model. Life Sciences 31: 1597–1601, 1982
Bonetti EP, Pieri L, Cumin R, Schaffner R, Pieri M, et al. Benzodiazepine antagonist Ro 15-1788: neurological and behavioural effects. Psychopharmacology 78: 8, 1982
Chiolero R, Ravussin P, Chassot P-G, Neff R, Freeman J. Ro 15-1788 for rapid recovery after craniotomy. Anesthesiology 65: Abstract no. A466, 1986
Cowen PJ, Little HJ, Nutt DJ. Functional interactions of benzodiazepine antagonists. British Journal of Pharmacology 75 (Suppl.): 87P, 1982
Darragh A, Lambe R, Kenny M, Brick I. Tolerance of healthy volunteers to intravenous administration of the benzodiazepine antagonist Ro 15-1788. European Journal of Clinical Pharmacology 24: 569–570, 1983
Darragh A, Lambe R, Scully M, Brick I, O’Boyle C, et al. Investigation in man of the efficacy of a benzodiazepine antagonist, Ro 15-1788. Lancet 2: 8–10, 1981
Doenicke A. Modern trends in the investigation of new hypnotics in anaesthesia. In Hindmarch et al. (Eds) Sleep, benzodiazepines and performance, Psychopharmacology (Suppl.), pp. 119–123, Springer, Berlin, 1984
Doenicke A, Suttmann H, Kapp W, Kugler J, Ebentheuer H. Zur Wirkung des Benzodiazepin-Antagonisten Ro 15-1788. Anaesthetist 33: 343–347, 1984
Doenicke A, Suttmann H, Kugler J, Kapp W, Wolf R. Pilot study of a benzodiazepine antagonist. British Journal of Anaesthesia 54: 1131–1133, 1982
Ellmauer S, Müller H, Christen M. Klinische Untersuchungen zur Effektivität und Sicherheit des Benzodiazepin-Antagonisten Ro 15-1788. VII European Congress of Anaesthesiology, 1986. Beiträge zur Anaesthesiologie und Intensivmedizin 17: Abstract no. 128, p. 78, 1986
Forster A, Rouiller M, Morel D, Gemperle M. Double-blind randomized study evaluating a specific benzodiazepine antagonist. Anesthesiology 59: A375, 1983
Gaillard JM, Blois R. Effect of the benzodiazepine antagonist Ro 15-1788 on flunitrazepam-induced sleep changes. British Journal of Clinical Pharmacology 15: 529–536, 1983
Gath I, Weidenfeld J, Collins GI, Hadad H. Electrophysiological aspects of benzodiazepine antagonists, Ro 15-1788 and Ro 15-3505. British Journal of Clinical Pharmacology 18: 541–547, 1984
Geller E, Chernilas J, Halpern P, Niv D, Miller HI. Hemodynamics following reversal of benzodiazepine sedation with Ro 15-1788 in cardiac patients. Anesthesiology 65: Abstract no. A49, 1986a
Geller E, Halpern P, Leykin Y, Rudick V, Sorkine P. Midazolam infusion and benzodiazepine antagonist for sedation in ICU: a preliminary report. Anesthesiology 65: Abstract no. A49, 1986c
Geller E, Halpern P, Weinbrum A, Nevo Y, Niv D, et al. Reversal agents in anesthesia. Acta Anaesthesiologica Scandinavica (in press, 1987)
Geller E, Niv D, Rudick V, Vidne B. Reversal of post-operative benzodiazepine overdose by a specific benzodiazepine antagonist Ro 15-1788. Journal of Bloodless Medicine and Surgery 3: 37–39, 1985a
Geller E, Niv D, Silbiger A, Halpern P, Leykin Y, et al. Ro 15-1788 in the treatment of 34 intoxicated patients. Anesthesiology 63: A157, 1985b
Geller E, Silbiger A, Niv D, Nevo Y, Beihassen B. The reversal of benzodiazepine sedation with Ro 15-1788 in brief procedures. Anesthesiology 65: Abstract no. A357, 1986b
Grecksch G, Prado de Carvalho L, Venault P, Chapouthier G, Rossier J. Convulsions induced by submaximal dose of pentylenetetrazol in mice are antagonised by the benzodiazepine antagonist Ro 15-1788. Life Sciences 32: 2579–2584, 1983
Harrison GG. Death attributable to anesthesia: a 10-year survey (1967-1976). British Journal of Anesthesia 50: 1041–1046, 1978
Hecker WC, Wartotsch A. General survey of the causes of death in patients who died post-operatively in pediatric surgery. Progress in Pediatric Surgery 13: 15–21, 1979
Hennius PJ, van Haastert F, Mulder AJ. Efficacy of Ro 15-1788, a benzodiazepine antagonist, after midazolam-alfentanyl anesthesia in man. VII European Congress of Anaesthesiology, 1986. Beiträge zur Anaesthesiologie und Intensivmedizin 17: Abstract no. 126, p. 76, 1986
Hofer P, Scollo-Lavizzari G. Benzodiazepine antagonist Ro 15-1788 in self-poisoning: diagnostic and therapeutic use. Archives of Internal Medicine 145: 663–664, 1985
Hunkeler W, Möhler H, Pieri L, Bonetti EP, Cumin R, et al. Selective antagonists of benzodiazepines. Nature 290: 514, 1981
Jensen S, Kirkegaard L, Andersen BN. Benzodiazepine antagonist Ro 15-1788 randomized clinical investigation of Ro 15-1788 in reversing the central effects of flunitrazepam. Acta Anaesthesiologica Scandinavica (Suppl.) 29: Abstract no. 162, p. 89, 1985
Jensen LH, Petersen EN, Braestrup C. Audiogenic seizures in DBA/2 mice discriminate sensitively between low efficacy benzodiazepine receptor agonists and inverse agonists. Life Sciences 33: 393–399, 1983
Kajima M, Lasalle GL, Rossier J. The partial benzodiazepine agonist properties of Ro 15-1788 in pentylenetetrazol-induced seizures in cats. European Journal of Pharmacology 93: 113–115, 1983
Klausen NO, Juhl O, Sørensen J, Ferguson H, Neumann PB. Recovery after total intravenous anaesthesia with Midazolam® and Haldid® reversed with a specific benzodiazepine antagonist Ro 15-1788. VII European Congress of Anaesthesiology, 1986. Beiträge zur Anaesthesiologie und Intensivmedizin 17: Abstract no. 131, p. 81, 1986a
Klausen NO, Sörensen J, Ferguson AH, Neumann PB, Larsen C, et al. Stress response during recovery after total intravenous anaesthesia with midazolam and fentanyl reversed by Ro 15-1788. VII European Congress of Anaesthesiology, 1986. Beiträge zur Anaesthesiologie und Intensivmedizin 17: Abstract no. 133, p. 83, 1986b
Kleinberger G, Grimm G, Laggner A, Druml W, Lenz K, et al. Weaning patients from mechanical ventilation by benzodiazepine antagonists Ro 15-1788. Lancet 2: 268–269, 1985
Klotz U, Duka Th, Dorow R, Doenicke A. Flunitrazepam and lormetazepam do not affect the pharmacokinetics of the benzodiazepine antagonist Ro 15-1788. British Journal of Clinical Pharmacology 19: 95–98, 1985a
Klotz U, Ziegler G, Ludwig L, Reimann IW. Pharmacodynamic interaction between midazolam and a specific benzodiazepine antagonist in humans. Journal of Clinical Pharmacology 25: 400–406, 1985b
Knudsen L, Kirkegaard L, Jensen S, Kruse A. Benzodiazepine antagonist Ro 15-1788: antagonism of diazepam sedation in out-patients undergoing gastroscopy. VII European Congress of Anaesthesiology 1986. Beiträge zur Anaesthesiologie und Intensivmedizin 18: Abstract no. 981, p. 268, 1986
Laurian S, Gaillard JM, Le PK. Dose effects of the benzodiazepine antagonist Ro 15-1788 on the auditory evoked potentials (Abstract no. 30). 14th C.I.N.P. Congress. Collegium Internationale Neuropsychopharmacologicum, June 19–23, 1984, Firenze/It, Abstract no. 33, Fidia Research Biomedical Information, 1984
Laurian S, Schöpf J, Le PK, Gaillard JM. The intrinsic pharmacological effect of Ro 15-1788. 7th World Congress of Psychiatry, July 11–16, 1983. Society of Austrian Neurologists and Psychiatrists, Austria. Abstract no. 402, p. 184, 1983
Lauven PM, Schwilden H, Stoeckel H, Greenblatt DJ. The effects of a benzodiazepine antagonist Ro 15-1788 in the presence of stable concentrations of midazolam. Anesthesiology 63: 61–64, 1985
Lauven PM, Stoeckel H, Schwilden H, Arendt R, Greenblatt DJ, et al. Application of a benzodiazepine antagonist Ro 15-1788 under steady-state conditions of midazolam. Anesthesiology 57: A325–A326, 1982
Louis M, Forster A, Suter PM, Gemperle M. Clinical and hemodynamic effects of a specific benzodiazepine antagonist (Ro 15-1788) after open heart surgery. Anesthesiology 61: A61, 1984
Marx M, Cassinelli N, Gonzalez Y, Piriz H, Acuna M, et al. Assessment of the efficacy and safety of Ro 15-1788 (benzodiazepine antagonist) in anaesthetized patients. VII European Congress of Anaesthesiology, 1986. Beiträge zur Anaesthesiologie und Intensivmedizin 17: Abstract no. 132, p. 82, 1986
Mindus P, Ehrin E, Ericsson L, Farde L, Hedström CG, et al. Central benzodiazepine receptor binding studied with 11-C labelled Ro 15-1788 and positron emission tomography. Pharmacopsychiatry 19: 2–3, 1986
Möhler H, Burkard WP, Keller HH, Richards JG, Haefely W. Benzodiazepine antagonist Ro 15-1788 binding characteristics and interaction with drug-induced changes in dopamine turnover and cerebellar cGMP levels. Journal of Neurochemistry 37: 714, 1981
Nicolau E. Anwendung von Anexate (Ro 15-1788) Benzodiazepin Antagonist bei kurzem bis langem Narkoseverfahren. VII European Congress of Anaesthesiology, 1986. Beiträge zur Anaesthesiologie und Intensivmedizin 18: Abstract 979, p. 266, 1986
Nutt DJ, Cowen PhJ. Unusual interaction of benzodiazepine receptor antagonists. Nature 295: 426–438, 1982
O’Boyle C, Darragh A, Lambe R, Brick I, Taffe B, et al. Ro 15-1788 antagonises diazepam induced amnesia without altering bioavailability. Irish Journal of Medical Science 151: 415, 1982
O’Boyle C, Lambe R, Darragh A, Taffe W, Brick I, et al. Ro 15-1788 antagonizes the effects of diazepam in man without affecting its bioavailability. British Journal of Anaesthesia 55: 349–356, 1983
Persson A, Ehrin E, Eriksson L, Farde L, Hedström C-G, et al. Imaging of [11C]-labelled Ro 15-1788 binding to benzodiazepine receptors in the human brain by positron emission tomography. Journal of Psychiatric Research 19: 609–622, 1985
Pieri L. Benzodiazepines: the mechanisms of action. In Rafaelson & Ward (Eds) Benzodiazepines: an update. Where do we go from here? pp. 17–29, Editiones (Roche) 1986
Polc P, Laurent JP, Scherschlicht R, Haefaly W. Electrophysiological studies on the specific benzodiazepine antagonist Ro 15-1788. Naunyn-Schmiedeberg’s Archives of Pharmacology 316: 317, 1981
Ravlo O, Bach V, Lybecker H, Møller JT. Benzodiazepine-antagonist, Ro 15-1788, for reversal of midazolam sedation in patients undergoing broncho- and mediastinoscopic examination. VII European Congress of Anaesthesiology, 1986. Beiträge zur Anaesthesiologie und Intensivmedizin 17: Abstract 130, p. 80, 1986
Richards JG, Schoch P, Möhler H, Haefely W. Benzodiazepine receptors resolved. Experientia 42: 121–126, 1986
Ritz R. Clinical use of Ro 15-1788 in patients receiving benzodiazepines in high therapeutic doses. Presented at the IV World Congress for ICU, Anexate Symposium, June 1985
Jerusalem, Israel Robertson HA. Evidence for distinct benzodiazepine receptors for anticonvulsant and sedative actions: implications for the treatment of temporal lobe epilepsy. Progress in Neuro-Psychopharmacology and Biological Psychiatry 7: 637–640, 1983
Robertson HA, Riives ML. A benzodiazepine receptor for anticonvulsant in an animal model for limbic epilepsy. Brain Research 270: 380–382, 1983
Robertson HA, Riives ML, Black DAS, Petersen MR. A partial agonist at the anticonvulsant benzodiazepine receptor: reversal of the anticonvulsant effects of Ro 15-1788 with CGS-8216. Brain Research 291: 388–390, 1984
Roncari G, Ziegler WH, Guentert TW. Pharmacokinetics of the new benzodiazepine antagonist Ro 15-1788 in man following intravenous and oral administration. British Journal of Clinical Pharmacology 22: 421–428, 1986
Samson Y, Hantraye P, Baron JC, Soussaline F, Comar D, et al. Kinetics and displacement of [11C] Ro 15-1788, a benzodiazepine antagonist, studied in human brain in vivo by positron tomography. European Journal of Pharmacology 110: 247–251, 1985
Schöpf J, Laurian S, Le PK, Gaillard JM. Intrinsic activity of the benzodiazepine antagonist Ro 15-1788 in man: an electrophysiological investigation. Pharmacopsychiatry 17: 79–84, 1984
Schwilden H, Stoeckel H, Lauven PM, Schüttler J. Action of a benzodiazepine antagonist during midazolam infusion in steady state: quantitative EEG studies. Anesthesiology 57: A326, 1982
Scollo-Lavizzari G. First clinical investigation of the benzodiazepine antagonist Ro 15-1788 in comatose patients. European Neurology 22: 7–11, 1983
Scollo-Lavizzari G. The anticonvulsant effect of benzodiazepine antagonist, Ro 15-1788: an EEG study in 4 cases. European Neurology 23: 1–6, 1984
Special Committee Investigating Deaths under Anesthesia Report on 745 classified cases, 1960–1968. Medical Journal of Australia 12: 573–594, 1970
Tolksdorf W, Pirwitz A, Pfeiffer D, Winter D, Mering Th. Wirkungen und Nebenwirkungen des Benzodiazepine antagonisten Ro 15-1788 nach Flunitrazepam-Kombinationsnarkosen im Vergleich zu Placebo: Eine Doppelblindstudie. VII European Congress of Anaesthesiology, 1986. Beiträge zur Anaesthesiologie und Intensivmedizin 17: Abstract 127, p. 77, 1986
Urdinovic S. Anexate (Ro 15-1788), benzodiazepine antagonist, in high risk patients. VII European Congress of Anaesthesiology, 1986. Beiträge zur Anaesthesiologie und Intensivmedizin 18: Abstract 980, p. 267, 1986
Vellucci SV, Webster RA. Antagonism of caffeine-induced seizures in mice by Ro 15-1788. European Journal of Pharmacology 97: 289–293, 1984
Vellucci SV, Webster RA. IS Ro 15-1788: a partial agonist at benzodiazepine receptors. European Journal of Pharmacology 90: 263–268, 1983
Waldvogel HH, Bentzinger C, Favre A. Double-blind placebo-controlled clinical study of the efficacy and safety of the benzodiazepine antagonist Ro 15-1788 in reversing the residual central effects of midazolam used to induce and maintain general anesthesia for short surgical interventions. VII. European Congress of Anaesthesiology, 1986. Beiträge zur Anaesthesiologie und Intensivmedizin 17: Abstract 129, p. 79, 1986
Ziegler WH, Schalch E. Antagonism of benzodiazepine-induced sedation in man. In Sleep 1982, 6th European Congress of Sleep Research, Zürich 1982, pp. 457–429, Karger, Basel, 1983
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Amrein, R., Leishman, B., Bentzinger, C. et al. Flumazenil in Benzodiazepine Antagonism. Med Toxicol Adverse Drug Exp 2, 411–429 (1987). https://doi.org/10.1007/BF03259876
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF03259876