Abstract
Objectives To assess the possible effects of flumazenil on cognitive processing, physiology, and mood.
Design A double-blind, placebo controlled, four-way cross-over study, using healthy volunteers.
Methods On each of 4 separate visits, 16 participants received 0.5mg, 2.5mg, 5.0mg of flumazenil, or normal saline. They then performed a computerised test battery assessing cognitive function. Measures of pulse rate, arterial oxygen saturation and mean arterial pressure were also taken. Finally, participants completed visual analogue scales assessing their subjective mood state.
Results The majority of cognitive tasks showed dose-dependent declines in performance. Mean arterial pressure was significantly reduced, as was pulse rate. Subjective alertness showed a similar decline.
Conclusions Flumazenil has been clinically described as an agent with few intrinsic properties, whose primary effect lies in its ability to reverse benzodiazepine-induced states. This study has shown that flumazenil does possess intrinsic activity which have a significant effect on cognition, cardiovascular physiology and mood. Clinicians need to be aware of these effects.
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References
Ghoneim M M, Mewaldt S P . Benzodiazepines and human memory: a review. Anesthesiol 1990; 72: 926–938.
Thompson J M, Neave N, Moss M C, Scholey A B, Wesnes K, Girdler N M . Cognitive properties of sedation agents: comparison of the effects of nitrous oxide and midazolam on memory and mood. Br Dent J 1999; 187: 557–562.
Darragh A, Lambe R, O'Boyle C, Kenny M, Brick I . Absence of central effects in man of the benzodiazepine antagonist Ro 15-1788. Psychopharmacol 1983; 80: 192–195.
Rosenbaum N L, Hooper P A . The use of flumazenil as an antagonist to midazolam in intravenous sedation for dental patients. Eur J Anaesthesiol 1988; S2: 183–190.
Hunter K M, Zacharias M, Parkinson R, Luyk N H . Effect of flumazenil on the recovery from intravenous sedation. New Zealand J Dent 1994; 90: 9–12.
Girdler N M, Hill C M . Sedation in dentistry. Oxford: Butterworth Heinemann, 1998.
O'Boyle C, Lambe R, Darragh A, Taffe W, Brick I, Kenny M . Ro15-1788 antagonizes the effects of diazepam in man without affecting its bioavailability. Br J Anaesth 1983; 55: 349–355.
Birch B, Curran H V . The differential effects of flumazenil on the psychomotor and amnesic actions of midazolam. J Psychopharmacol 1990; 4: 29–34.
Ghoneim M M . The reversal of benzodiazepine-induced amnesia by flumazenil: a review. Curr Ther Res 1992; 52: 757–767.
Gentil V, Gorenstein C, Camargo C H P, Singer J M . Effects of flunitrazepam on memory and their reversal by two antagonists. J Clin Psychopharmacol 1989; 9: 191–197.
Dorow R, Berenberg D, Duka T, Sauerbrey N . Amnestic effects of lormetazepam and their reversal by the benzodiazepine antagonist Ro 15-1788. Psychopharmacol 1987; 93: 507–514.
Ghoneim M M, Block R I, Sum Ping S T, El-Zahaby H M, Hinrichs J V . The interactions of midazolam and flumazenil on human memory and cognition. Anesthesiol 1993; 79: 1183–1192.
File S E, Pellow S . Intrinsic actions of the benzodiazepine receptor antagonist Ro 15-1788. Psychopharmacol 1986; 88: 1–11.
Higgitt A, Lader M, Fongay P . The effects of the benzodiazepine antagonist Ro 15-1788 on psychophysiological performance and subjective measures in normal subjects. Psychopharmacol 1986; 89: 395–403.
Herzog C D, Stackman R W, Walsh T J . Intraseptal flumazenil enhances, while diazepam binding inhibitor impairs, performance in a working memory task. Neurobiol Learn Mem 1996; 66: 341–352.
McNamara R K, Skelton R W. . (1993) Benzodiazepine receptor antagonists flumazenil and CGS 8216 and inverse-agonist (β-CCM enhance spatial learning in the rat: dissociation from anxiogenic actions). Psychobiol 1993; 21: 101–108.
Çelik T, Deniz G, Uzbay I T, Palaoglu O, Ayhan I H . The effects of flumazenil on two way active avoidance and locomotor activity in diazepam-treated rats. Eur Neuropsychopharmacol 1999; 9: 45–50.
Hantraye P, Brouillet E, Kukuda H, et al. Benzodiazepine receptors studied in living primates by positron emission tomography: antagonist interactions. Eur J Pharmacol 1988; 153: 25–32.
Wesnes K, Simpson P M, Christmas L . The assessment of human information processing abilities in psychopharmacology. In Hindmarch I, Stonier P D (Ed's). Human psychopharmacology: measures and methods, Vol. I. Chichester: Wiley, 1987.
O'Neil W M, Hanks G W, White L, Simpson P, Wesnes K . The cognitive and psychomotor effects of opioid analgesics I. A randomised controlled trial of single doses of dextropoxyphrene, lorazepam and placebo in healthy subjects. Eur J Clin Pharmacol 1995; 48: 447–453.
Bond A, Lader M . The use of analogue scales in rating subjective feelings. Br J Med Psychol 1974; 47: 455–460.
McCormack H M, Horne D J, Sheather S . Clinical applications of visual analogue scales: a critical review. Psychol Med 1988; 18: 1007–1019.
Smolink R, Pietrowsky R, Fehm H L, Born J . Enhanced selective attention after low-dose administration of the benzodiazepine antagonist flumazenil. J Clin Psychopharmacol 1998; 18: 241–247.
Ströhle, Kellner M, Holsboer F, Wiedemann K . Behavioural, neuroendocrine, and cardiovascular response to flumazenil: no evidence for an altered benzodiazepine receptor sensitivity in panic disorder. Biol Psychiat 1999; 45: 321–326.
Finder R L, Moore P A . Benzodiazepines for intravenous conscious sedation: agonists & antagonists. Compendium, 1993; 14: 972–780.
Rosenburg H C, Chiu T . Blood pressure response to Ro15-1788, a benzodiazepine antagonist. Life Sciences 1985; 36: 781–787.
Shannon M, Alberds G, Burkhart K, et al . Safety and efficacy of flumazenil in the reversal of benzodiazepine-induced conscious sedation. J Paediatr 1997; 131: 582–586.
Acknowledgements
The authors would like to express their thanks to: the volunteers for their participation in this study; the Sedation Department nurses for their kind assistance; Dr C Dracup at the University of Northumbria for statistical advice and the anonymous referees for their constructive comments on the preparation of this manuscript. This study was undertaken as part of the Diploma in Conscious Sedation programme run by the Northern Deanery Postgraduate Institute for Medicine and Dentistry (University of Newcastle).
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Neave, N., Reid, C., Scholey, A. et al. Dose-dependent effects of Flumazenil on cognition, mood, and cardio-respiratory physiology in healthy volunteers. Br Dent J 189, 668–674 (2000). https://doi.org/10.1038/sj.bdj.4800860
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DOI: https://doi.org/10.1038/sj.bdj.4800860
