668 BRITISH DENTAL JOURNAL VOLUME 189 NO.12 DECEMBER 23 2000 dentistry has been significantly enhanced by flumazenil, largely because of its ability to reverse the cardio-respiratory depressant effects of the benzodiazepines. 4–6 In acute use, flumazenil is nor- mally reserved for use in sedation emergencies, although some clinicians may use it to expedite recovery of ambulatory patients. At the behavioural level, the effects of flumazenil on benzodi- azepine-induced amnesia remain equivocal. For example, it has been reported that flumazenil attenuated, but did not fully reverse, the amnesic effects of diazepam. 7 Similarly, it has been found that while flumazenil reversed the psychomotor impairments induced by midazolam, it had no such effect on amnesia induced by the same compound. 8 The latter authors argued however that flumazenil may demonstrate a differential sequence of reversal, with psychomotor impairments having a lower reversal threshold than any amnesic deficits, resulting in the differential sensitivity of these measures. Similarly, in surgical patients, some studies have also reported that benzodiazepine-induced amnesia may be partly reversed by flumazenil administration. 9 Furthermore, studies using healthy volunteers have shown that the amnesic effects of benzodiazepines can be fully reversed by flumazenil at appropriate doses 10–11 though both of these studies lacked placebo controls. In a well controlled double-blind study, it was reported that a dose of 1.0 mg of flumaze- nil administered intravenously was sufficient to completely reverse midazolam-induced amnesia. 12 Rather more interesting is the possibility of memory enhance- ment following flumazenil administration alone. In a review of the possible intrinsic actions of flumazenil 13 the authors reported that the compound does show intrinsic activity in a variety of behav- ioural, neurological, electrophysiological, and biochemical test situ- ations, in both animals and humans. However, that review did not specifically address cognitive processing. Several other studies have not revealed clear behavioural effects in humans following flumaze- nil administration alone. 3,11–12 Others have indicated that flumaze- nil administration may produce some intrinsic physiological actions 14 but may have little effect on cognitive processing. 3,14 However, it should be pointed out that the tasks described in these studies (i.e. reaction time measures, digit symbol substitution etc) do not typically assess episodic memory. Several laboratory animal studies have indeed shown that flumazenil administration may actually enhance certain types of mnemonic processing. In one such study, rats received post-train- ing intraseptal injections of flumazenil, and this significantly enhanced retention of working memory over a long delay. The authors argued that this facilitation was due to the interaction of flumazenil with the septohippocampal cholinergic system during a critical phase in memory consolidation. 15 In another study using RESEARCH se dat io n Dose-dependent effects of Flumazenil on cognition, mood, and cardio-respiratory physiology in healthy volunteers. N. Neave, 1 C. Reid, 2 A. B. Scholey, 1 J. M. Thompson, 3 M. Moss, 1 G. Ayre, 4 K. Wesnes 4 and N. M. Girdler 2 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. B enzodiazepines are known to produce anxiolytic and amnesic effects in humans across a wide range of behavioural para- digms. 1-2 It is logical to assume that benzodiazepine antagonists should reverse such effects, and indeed, the antagonist flumazenil (formerly known as Ro 15-1788) has been shown to rapidly reverse the sedative and anxiolytic effects of benzodiazepines in a dose- dependent manner. 3 In the clinical environment, flumazenil is an essential component of the emergency armementarium and should be available whenever benzodiazepine sedation is being provided. The safety of benzodiazepine sedation in medicine and 1 Lecturers, Human Cognitive Neuroscience Unit, Division of Psychology, University of Northumbria, Newcastle Upon Tyne. 2 Clinical Assistant; Consultant and Senior Lecturer, Department of Sedation, Newcastle Dental School & Hospital, Newcastle upon Tyne. 3 Research Assistant, Department of Psychiatry, School of Neurosciences and Psychiatry, Royal Victoria Infirmary, Newcastle upon Tyne. 4 Scientific Development Manager; Professor and Director, Cognitive Drug Research Ltd, Reading. Corresponding author: Dr. Nick Neave, Human Cognitive Neuroscience Unit, Division of Psychology, Northumberland Building, University of Northumbria, Newcastle upon Tyne, NE1 8ST, UK. Telephone (0191) 227 4476, Fax (0191) 227 3190, e-mail nick.neave@unn.ac.uk. REFEREED PAPER Received 09.02.00; Accepted 18.07.00 © British Dental Journal 2000; 189: 668–674