IPCS/CEC EVALUATION OF ANTIDOTES SERIES VOLUME 1 NALOXONE, FLUMAZENIL AND DANTROLENE AS ANTIDOTES IPCS/CEC Evaluation of Antidotes Series IPCS International Programme on Chemical Safety CEC Commission of the European Communities Volume 1 Naloxone, flumazenil and dantrolene as antidotes Volume 2 Antidotes for poisoning by cyanide This important new series will provide definitive and authoritative guidance on the use of antidotes to treat poisoning. The International Programme on Chemical Safety (IPCS) and the Commission of the European Communities (CEC) (ILO/UNEP/WHO) have jointly undertaken a major programme to evaluate antidotes used clinically in the treatment of poisoning. The aim of this programme has been to identify and evaluate for the first time in a scientific and rigorous way the efficacy and use of a wide range of antidotes. This series will therefore summarise and assess, on an antidote by antidote basis, their clinical use, mode of action and efficacy. The aim has been to provide an authoritative consensus statement which will greatly assist in the selection and administration of an appropriate antidote. This scientific assessment is complemented by detailed clinical information on routes of administration, contraindications, precautions and so on. The series will therefore collate a wealth of useful information which will be of immense practical use to clinical toxicologists and all those involved in the treatment and management of poisoining. Scientific Editors T.J. MEREDITH Department of Health, London, United Kingdom D. JACOBSEN Ulleval University Hospital, Oslo, Norway J.A. HAINES International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland J-C. BERGER Health and Safety Directorate, Commission of the European Communities, Luxembourg EUR 14797 EN Published by Cambridge University Press on behalf of the World Health Organization and of the Commission of the European Communities CAMBRIDGE UNIVERSITY PRESS The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Neither the Commission of the European Communities nor any person acting on behalf of the Commission is responsible for the use which might be made of the information contained in this report. (c) World Health Organization, Geneva, 1993 and ECSC-EEC-EAEC, Brussels-Luxembourg, 1993 First published 1993 Publication No. EUR 14797 EN of the Commission of the European Communities, Dissemination of Scientific and Technical Knowledge Unit, Directorate-General Information Technologies and Industries, and Telecommunications, Luxembourg ISBN 0 521 45459 X hardback CONTENTS PREFACE ABBREVIATIONS 1. INTRODUCTION TO THE SERIES 2. NALOXONE 2.1. Introduction 2.2. Name and chemical formula 2.3. Physico-chemical properties 2.4. Pharmaceutical formulation and synthesis 2.5. Analytical methods 2.5.1. Quality control 2.5.2. Identification 2.5.3. Quantification of the antidote 2.5.4. Analysis of toxic agents 2.6. Shelf-life 2.7. General properties 2.8. Animal studies 2.8.1. Pharmacodynamics 2.8.2. Pharmacokinetics 2.8.3. Toxicology 2.9. Volunteer studies 2.9.1. Pharmacokinetics 2.9.2. Pharmacodynamics 2.9.3. Effects of high doses of naloxone 2.10. Clinical studies - clinical trials 2.10.1. Effects in therapeutic use of opioids 2.10.2. Effects in acute opioid poisoning 2.11. Clinical studies - case reports 2.11.1. Naloxone in clonidine poisoning 2.12. Summary of evaluation 2.12.1. Indications 2.12.2. Advised routes and dose 2.12.3. Other consequential or supportive therapy 2.12.4. Areas where there is insufficient information to make recommendations 2.12.5. Proposals for further studies 2.12.6. Adverse effects 2.12.7. Restrictions of use 2.13. Model information sheet 2.13.1. Uses 2.13.2. Dosage and route 2.13.3. Precautions/contraindications 2.13.4. Adverse effects 2.13.5. Use in pregnancy and lactation 2.13.6. Storage 2.14. References 3. FLUMAZENIL 3.1. Introduction 3.2. Name and chemical formula of antidote 3.3. Physico-chemical properties 3.4. Pharmaceutical formulation and synthesis 3.5. Analytical methods 3.5.1. Identification of the antidote 126.96.36.199 Infrared spectroscopy 188.8.131.52 Ultraviolet absorption 184.108.40.206 Thin-layer chromatography 3.5.2. Quantification of the antidote in biological samples 3.5.3. Analysis of the toxic agent in biological samples 3.6. Shelf-life 3.7. General properties 3.8. Animal studies 3.8.1. Pharmacodynamics 3.8.2. Pharmacokinetics 220.127.116.11 Absorption 18.104.22.168 Distribution 22.214.171.124 Elimination 3.8.3. Toxicology 126.96.36.199 Acute toxicity 188.8.131.52 Subacute toxicity 184.108.40.206 Chronic toxicity 220.127.116.11 Embryotoxicity 18.104.22.168 Mutagenicity 3.9. Volunteer studies 3.9.1. Pharmacodynamics 22.214.171.124 BZD antagonist effect 126.96.36.199 Intrinsic effects 3.9.2. Pharmacokinetics 188.8.131.52 Absorption 184.108.40.206 Distribution 220.127.116.11 Elimination 3.9.3. Tolerance of flumazenil 3.9.4. Other studies 3.10. Clinical studies - clinical trials 3.10.1. Anaesthesiology 18.104.22.168 General anaesthesia 22.214.171.124 Conscious sedation 3.10.2. Benzodiazepine overdose or intoxication 3.11. Clinical studies - case reports 3.12. Summary of evaluation 3.12.1. Indications 3.12.2. Dosage and route 3.12.3. Other consequential or supportive therapy 3.12.4. Areas where there is insufficient information to make recommendations 3.12.5. Proposals for further study 3.12.6. Adverse effects 3.12.7. Restrictions of use 3.13. Model information sheet 3.13.1. Uses 3.13.2. Dosage and route 3.13.3. Precautions/contraindications 126.96.36.199 Pharmaceutical precautions 188.8.131.52 Other precautions 3.13.4. Adverse effects 3.13.5. Use in pregnancy and lactation 3.13.6. Storage 3.13.7. Special risk groups 3.14. References 4. DANTROLENE SODIUM 4.1. Introduction 4.2. Name and chemical formula of antidote 4.3. Physico-chemical properties 4.4. Pharmaceutical formulation and synthesis 4.5. Analytical methods 4.5.1. Identification and quantification of dantrolene sodium and its formulation 4.5.2. Quantification of dantrolene in body fluids 184.108.40.206 Spectrofluorimetry 220.127.116.11 High-performance liquid chromatography 4.6. Shelf life 4.7. General properties 4.8. Animal studies 4.8.1. Pharmacodynamics 18.104.22.168 Effect on skeletal muscle 22.214.171.124 Effects on other tissues 126.96.36.199 Studies in malignant hyperthermia- susceptible pigs 4.8.2. Pharmacokinetics 4.8.3. Toxicology 188.8.131.52 Acute toxicity 184.108.40.206 Subacute toxicity 220.127.116.11 Chronic toxicity 18.104.22.168 Teratogenicity 4.9. Volunteer studies 4.9.1. Administration and plasma concentrations 4.9.2. Distribution 22.214.171.124 Distribution to the fetus and newborn baby 4.9.3. Elimination 4.9.4. Human in vitro pharmacodynamics 4.10. Clinical studies - clinical trials 4.11. Clinical studies - case reports 4.11.1. Use in malignant hyperthermia 126.96.36.199 Prophylaxis of malignant hyperthermia 188.8.131.52 Prophylaxis of malignant hyperthermia during pregnancy 4.11.2. Use in neuroleptic malignant syndrome 4.11.3. Use in other drug-induced hyperthermia 4.12. Summary of evaluation 4.12.1. Indications 184.108.40.206 Treatment of malignant hyperthermia 220.127.116.11 Treatment of neuroleptic malignant syndrome 18.104.22.168 Treatment of hyperthermia induced by muscle rigidity in poisoning 4.12.2. Advised routes and doses 22.214.171.124 Treatment of severe drug-induced hyperthermia, including malignant hyperthermia 126.96.36.199 Prophylaxis of malignant hyperthermia prior to anaesthesia in susceptible patients 4.12.3. Other consequential or supportive therapy 4.12.4. Controversial issues and areas of insufficient information 4.12.5. Proposals for further studies 4.12.6. Adverse effects 188.8.131.52 Hepatoxicity 184.108.40.206 Interaction with calcium antagonists 4.12.7. Restrictions for use 4.13. Model information sheet 4.13.1. Uses as an antidote 4.13.2. Dosage and route 4.13.3. Precautions and contraindications 4.13.4. Pharmaceutical incompatibilities and drug interactions 4.13.5. Adverse effects 4.13.6. Use in pregnancy and lactation 4.13.7. Storage 4.14. References APPENDIX I List of antidotes APPENDIX II Principles for the evaluation of antidotes APPENDIX III Proforma for monographs on antidotes for specific toxic agents WORKING GROUP ON VOLUME 1, EVALUATION OF ANTIDOTES Members Dr D.N. Bateman, Department of Clinical Pharmacology, University of Newcastle, Newcastle-upon Tyne, United Kingdom Professor C. Bismuth, Hôpital Fernand Widal, Paris, France Dr R.E. Ferner, West Midlands Poisons Unit, Dudley Road Hospital, Birmingham, United Kingdom (Joint Rapporteur) Dr T.J. Meredith, Department of Health, London, United Kingdom Dr H. Persson, Poison Information Centre, Karolinska Sjukhuset, Stockholm, Sweden (Joint Chairman) Professor L. Prescott, Scottish Poison Information Service, The Royal Infirmary, Edinburgh, Scotland (Joint Chairman) Dr M.-L. Ruggerone, Ospedale Niguarda, Centro Antiveleni, Milan, Italy Dr H. Smet, Centre Belge Anti-Poisons, Brussels, Belgium Dr U. Taitelman, National Poisons Information Centre, Rambam Medical Centre, Haifa, Israel Dr W. Temple, National Toxicology Group, Otago University Medical School, Dunedin, New Zealand (Joint Rapporteur) Professor A.N.P. van Heijst, Bosch en Duin, The Netherlands Dr G. Volans, Poisons Unit, New Cross Hospital, London, United Kingdom Dr E. Wickstrom, National Poison Centre, Oslo, Norway Observer Dr G. Olibet, Centro Antiveleni, Milan, Italy Secretariat Dr J.-C. Berger, Health and Safety Directorate, Commission of the European Communities, Luxembourg Dr J.A. Haines, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland Dr M. ten Ham, Pharmaceuticals Programme, World Health Organization, Geneva, Switzerland PREFACE At a joint meeting of the World Federation of Associations of Clinical Toxicology and Poison Control Centres, the International Programme on Chemical Safety (IPCS), and the Commission of the European Communities (CEC), held at the headquarters of the World Health Organization in October 1985, the evaluation of antidotes used in the treatment of poisonings was identified as a priority area for international collaboration. During 1986, the IPCS and CEC undertook the preparatory phase of a joint project on this subject. For the purpose of the project an antidote was defined as a therapeutic substance used to counteract the toxic action(s) of a specified xenobiotic. Antidotes, as well as other agents used to prevent the absorption of poisons, to enhance their elimination and to treat their effects on body functions, were listed and preliminarily classified according to the urgency of treatment and efficacy in practice. With respect to efficacy in practice, they were classified as: (1) those generally accepted as useful; (2) those widely used and considered promising but not yet universally accepted as useful and requiring further research concerning their efficacy and/or their indications for use; and (3) those of questionable usefulness. Additionally, certain antidotes or agents used for specific purposes were considered to correspond to the WHO criteria for essential drugs (see Criteria for the Selection of Essential Drugs, WHO Technical Report Series 722, Geneva, 1985). A methodology for the principles of evaluating antidotes and agents used in the treatment of poisonings and a proforma for preparing monographs on antidotes for specific toxins were drafted (Appendices II and III respectively). Monographs are being prepared, using the proforma, for those antidotes and agents provisionally classified in category 1 as regards efficacy in practice. For those classified in categories 2 and 3, where there are insufficient data or controversy regarding efficacy in practice, it was agreed that further study was necessary. Accordingly, several were selected for initial review and evaluation, among which were naloxone as an antagonist for opioids, flumazenil as a benzodiazepine antagonist and dantrolene for malignant hyperthermia. The review and evaluation of these antidotes was initiated at a joint meeting of the IPCS and the CEC, organized by the Northern Poisons Unit and held at the Medical School of the University of Newcastle-upon-Tyne, United Kingdom, 13-17 March 1989. In preparation for this meeting, monographs were drafted, using the proforma, on naloxone by Dr D.N. Bateman, on flumazenil by Dr A. Brovard and Professor C. Bismuth and on dantrolene by Dr H. Smet and Professor C. Bismuth. The draft document on naloxone was reviewed by a working group consisting of Professor L.F. Prescott (Chairman), Dr W. Temple (Rapporteur), Dr D. Bateman, Dr M. Ten Ham, Dr A.N.P. van Heijst, Dr G.N. Volans and Dr E. Wickstrom. The draft documents on flumazenil and dantrolene were reviewed by a working group consisting of Dr H. Persson (Chairman), Dr R.E. Ferner (Rapporteur), Dr J.-C. Berger, Professor C. Bismuth, Dr G. Olibet, Dr M.-L. Ruggerone, Dr H. Smet and Dr U. Taitelman. Following the meeting further drafting work was undertaken by the authors, with the assistance of Drs R.E. Ferner, B. Britt (Department of Anaesthesia, Faculty of Medicine, University of Toronto, Canada), and T. Fagerlund (Institute of Medical Genetics, University of Oslo, Norway) in the redrafting of the dantrolene monograph. Draft texts were further revised by the series editors (Dr T.J. Meredith, Dr D. Jacobsen, Dr J.A. Haines, and Dr J.-C. Berger), who also prepared an introduction to the series. This introduction summarizes the results of the preparatory phase and indicates the volumes currently planned for this series. The efforts of all who helped in the preparation and finalization of this volume are gratefully acknowledged. ABBREVIATIONS BZD benzodiazepine CAT computer-assisted tomography CNS central nervous system GABA gamma-aminobutyric acid GLC gas-liquid chromatography HIV human immunodeficiency virus HPLC high-performance liquid chromatography LSD lysergic acid diethylamide RIA radio-immunoassay TLC thin-layer chromatography UV ultraviolet 1. INTRODUCTION TO THE SERIES Antidotes play a vital role in the treatment of poisoned patients. Good supportive care, directed particularly at the cardiac and respiratory systems, and the use of elimination techniques when indicated, enable the majority of poisoned patients to make a full recovery. However, in certain circumstances the use of antidotes can be life-saving, and in other circumstances the use of antidotes may reduce morbidity as well as medical and other resources required in the care of a patient. In areas remote from hospital care, and particularly in developing countries where facilities for supportive care outside hospital are often limited, the availability of certain antidotes is even more essential for the successful treatment of a poisoned patient. However, there remains controversy about the clinical efficacy and indications for use of many of the antidotes conventionally employed in the treatment of poisoning. There is also sometimes difficulty in obtaining antidotes in an emergency situation, particularly if the substance in question is not available as a pharmaceutical preparation. The need for an international evaluation of the clinical efficacy of antidotes and other substances used in the treatment of poisoning was first recognized at a joint meeting of the World Federation of Associations of Clinical Toxicology Centres and Poisons Control Centres, the International Programme on Chemical Safety (IPCS) and the Commission of the European Communities (CEC), held at WHO headquarters, Geneva, 6-9 October 1985. At the same time, the need to encourage the more widespread availability of those antidotes that are effective was also recognized. As a result, a joint IPCS/CEC project was subsequently initiated to address these problems. In a preparatory phase of the project, an antidote was defined for working purposes as a therapeutic substance used to counteract the toxic action(s) of a specified xenobiotic. A preliminary list of antidotes for review, as well as of other agents used to prevent the absorption of poisons, to enhance their elimination and to treat their effects on body functions, was established. For the purposes of the review process, antidotes and other substances were classified according to the urgency with which treatment with the antidote was thought on current evidence to be required and the (currently judged) clinical efficacy of the antidote in practice. Those corresponding to the WHO concept of an essential drug were designated as such. Some have already been incorporated into the WHO list of essential drugsa. Antidotes and similar substances for veterinary use were a WHO (1988) Use of Essential Drugs. Model list of essential drugs (fifth list). Third Report of the WHO Expert Committee. WHO Technical Report Series 770, Geneva World Health Organization. also listed. A methodology on the principles for evaluation of antidotes and other agents used in the treatment of poisonings was developed and this has subsequently been used as a framework for drafting monographs on specific antidotes. The list of antidotes and other agents established as a result of the preparatory phase and the preliminary classification is given in Appendix I. The principles for evaluation are detailed in Appendix II. Early during the course of the preparatory phase, it became apparent that the availability of antidotes differed from one country to another. Problems of availability fell into three interrelated categories, namely: * scientific, technical and economic aspects; * regulatory and administrative requirements; * geospatial and time considerations. Problems of availability of antidotes used in the treatment of poisonings were therefore examined by an IPCS/CEC Working Group, hosted by the Norwegian National Poisons Information Centre and held in Oslo, 20-22 June 1988. The record of this meeting is given in ICS/88.44. In preparation for this meeting, a preliminary survey was undertaken of selected poisons control centres in order to identify more precisely the practical difficulties encountered in obtaining antidotes. The survey showed that, in general, poisons centres in industrialized countries had few problems in obtaining most antidotes, although lack of suitable preparations/importers/manufacturers together with administrative difficulties did hinder access to certain antidotes. In contrast, centres in developing countries reported many problems in obtaining even those antidotes that are readily available elsewhere. A report was prepared by the IPCS/CEC Working Group setting out the problems associated with the availability of antidotes and suggesting ways in which the availability of antidotes might be ensured for the treatment of poisoned individuals. In due course, it is intended that this report will be brought to the attention of all relevant national drug regulatory and importation authorities, pharmaceutical manufacturers, distributors of pharmaceutical materials, and all poisons control centres. The IPCS Guidelines for Poisons Control summarize the problems and issues of availability identified by the Working Groupb. b WHO (in press) - Guidelines for Poisons Control, Part II, section 6 Geneva, World Health Organization Aspects of the evaluation of antidotes The development and evaluation of substances to counteract the toxic action(s) of a xenobiotic is principally a task for the scientific community, particularly those working in experimental pharmacology, toxicology and clinical medicine. The efficacy of a substance intended for use as an antidote must first be demonstrated in an appropriate animal model. The next step, demonstration of efficacy in humans, it is often more difficult because there is rarely an opportunity for controlled clinical trials. Even if a substance is shown to be effective as an antidote, the potential intrinsic toxicity of the substance also needs to be considered prior to its more widespread use, and, as with all drugs, the possibility of an adverse drug reaction should be considered. A clinician is more likely to be prepared to use a relatively "non-toxic" antidote (even one whose efficacy has still to be established with certainty) than one with intrinsic toxicity. An antidote which is potentially toxic should only be used if it is therapeutically effective and the indication for use is clear. Although possible long-term adverse effects and chronic toxicity need to be considered, they are usually of less consequence than for an ordinary pharmaceutical agent because treatment with an antidote is rarely required more than once in any particular individual. A final consideration in the use of an antidote is that increased toxicity should not result from mobilization of the toxin from tissue stores or from changes in tissue distribution. The concept of relative "efficacy" of antidotes It is important that clinicians employing antidotes in the treatment of poisoned patients recognize that the clinical "efficacy" of antidotes varies considerably. On the one hand there are antidotes whose clinical effect is both rapid and dramatic. Examples would be naloxone or flumazenil, which act as very specific competitive antagonists at opioid and benzodiazepines receptors, respectively. On the other hand, there are antidotes that are able to counter only some of the toxic effects of a particular compound; if the dose of the compound in question is sufficiently high then the patient is likely to die despite the use of an antidote. Chelating agents provide good examples of antidotes that fall into this category of efficacy. Nevertheless, chelating agents have a valuable role to play in the treatment of heavy metal poisoning, and many are recommended for this purpose in volume V of this series. Some agents are loosely termed antidotes even though they may have little or no true antidotal effect; they may nonetheless form valuable adjuncts to treatment. Diazepam, used in the treatment of organophosphate poisoning (volume IV), is one such example. Provisional list of volumes in the IPCS/CEC antidotes series It is intended that the IPCS/CEC series of monographs on antidotes will cover all antidotes that are commonly employed - or which have been proposed for use - in the treatment of human poisoning. Once this aim has been achieved, it is intended that the volumes will be periodically updated in order to meet the needs of health care professionals. At present, the proposed volumes for this series include: Volume 2 Evaluation of antidotes for cyanide poisoning: * oxygen * sodium thiosulfate * hydroxocobalamin * dicobalt edetate * amyl nitrite * sodium nitrite * 4-dimethylaminophenol * antidotes to methaemoglobin-forming agents (methylene blue, toluidine blue) * analytical methods for cyanide alone and in combination with cyanide antidotes Volume 3 Evaluation of antidotes for paracetamol poisoning * overview * N-acetylcysteine * methionine Volume 4 Evaluation of antidotes for organophosphate poisoning * overview * atropine * diazepam * obidoxime * pralidoxime Volume 5 Evaluation of chelating agents for heavy metal poisoning * overview * deferoxamine * prussian blue * trientine * calcium disodium edetate * DTPA * DMPS * DMSA * dimercaprol * penicillamine and N-acetyl penicillamine Volume 6 Antidotes for methanol and ethylene glycol poisoning. Volume 7 Antidotes for amatoxin, gyrometrine and isoniazid poisoning Volume 8 Evaluation of the various pharmaceutical substances used for enhanced elimination and prevention of absorption. Further volumes are planned for: * General antidotes and sorbents * Antidotes based on immunotoxicology International evaluation process Experts are requested by the IPCS to prepare draft monographs on specific antidotes or agents, or on specific aspects associated with their therapeutic use. Original literature references must be used according to the criteria established for Environmental Health Criteria documents. In order to ensure that monographs are written according to agreed standards, a common format has been established following the methodology on principles for evaluation of antidotes (Appendix II) and the guidelines to authors (Appendix III). The series editors examine the drafts to ensure that they conform to the standard format and are of acceptable quality for peer review. For certain volumes a guest editor is also appointed. The IPCS sends the drafts to selected experts for comment and for possible additional information. A working group of authors and experts in the field is then convened by the IPCS and CEC. The task of this group is to: (i) examine the literature referred to in the monographs for its relevance, including case data experience; (ii) identify any gaps in knowledge or scientific unknowns; (iii) make an evaluation of the clinical efficacy of the antidote for a particular poisoning or pathological condition resulting from the poisoning; (iv) provide guidance on the treatment regimens, under various conditions of use of the antidote, including, where appropriate, field and primary health care use, advise on the accompanying supportive care, and give particular attention to paediatric doses, contraindications and special considerations. Following the working group meeting further drafting may need to be undertaken by the original author in consultation with the series and guest editors. An overview chapter summarizing the issues and giving the evaluation of a series of antidotes for specific types of poisoning cases is drafted by the editors or invited experts. The IPCS and CEC may convene a further editorial meeting to finalize the monographs for a particular volume and to approve the overview chapter. The volume is then processed by the WHO editor for publication by Cambridge University Press. 2. NALOXONE 2.1 Introduction Naloxone is an opioid antagonist acting at all three types of opioid receptors. It appears devoid of agonist activity (Martin, 1976). Naloxone is indicated in the treatment of opiate poisoning. Although naloxone has also been reported to be of benefit as an antidote in benzodiazepine (BZD) poisoning (Bell, 1975), other workers failed to demonstrate an effect in a double-blind study of diazepam-induced sedation (Christensen & Huttel, 1979). However, Jordan (1980) demonstrated some reversal of diazepam-induced respiratory depression by naloxone. Thus there is a need for further controlled studies, particularly in cases of poisoning. Naloxone has also been claimed to have an effect on ethanol-induced central nervous system (CNS) depression, and in one study appeared to cause an improvement in 20% of treated cases (Jefferys et al., 1980). However, this finding has not been confirmed by other workers (Handal et al., 1983; Nuotto et al., 1984). The possible beneficial effects of naloxone in non-opiate poisoning probably reflect the involvement of endogenous opioids in the depressant action of some non-opioid drugs (McNicholas & Martin, 1984). 2.2 Name and Chemical Formula Naloxone 6-Allylnoroxymorphone 17-Allyl-6-deoxy-7,8-dihydro-14-hydroxy-6-oxo-17-normorphone Empirical formula: C19 H21 NO4 Relative molecular mass: 327 CAS number: 465-65-6 Trade names: Narcan, Nalone, Narcanti (Du Pont Pharmaceuticals) Naloxone is available for clinical use as the hydrochloride salt, which may be anhydrous (CAS-357-08-4) or contain 2 molecules of water of hydration (CAS 51481-60-8). The relative molecular mass of the free base is 327.37 and of the anhydrous salt 363.84. Conversion table: 1 g = 3.1 mmol 1 mmol = 327.4 mg 1 mg/ml = 3.1 mmol/l 1 mmol/l = 0.33 mg/ml The molecular structure of naloxone hydrochloride is shown below. 2.3 Physico-chemical Properties Naloxone hydrochloride has a melting range of 200-205 °C. It is soluble in water, dilute acids and strong alkalis, and is slightly soluble in alcohol but practically insoluble in ether. Aqueous solutions are acidic (pH 3 to 4.5) (United States Pharmacopeia, 1980) and an 8.08% solution in water is isotonic with serum (Hassan et al., 1985). A 25% solution of naloxone hydrochloride rotates light between -170 and -181. Naloxone crystals from ethyl acetate have a specific optical rotation at 20 °C ([alpha]D20; 9.3 g/l chloroform) of -194.5 ° (Windholz, 1983). Naloxone has a pKa (20 °C) values for the nitrogen and phenolic H groupings of 7.94 and 9.44, respectively (Kaufman et al., 1975). On drying at 105 °C, the anhydrous form loses not more than 0.5% and the hydrated form not more than 11% of its weight. The solution for injection is made up in water and should be protected from light. Naloxone can be diluted in 0.9% saline or 5% dextrose and should then be used within 24 h. It should not be mixed in solutions containing metasulfite, metabisulfite, or long-chain or high relative molecular mass anions, or in those with an alkaline pH. 2.4 Pharmaceutical Formulation and Synthesis Three synthetic routes for the production of naloxone have been reported (Hassan et al., 1985). Oxymorphone is a starting point for two of the synthetic processes and 14-hydroxycodeinone for the third. Noroxymorphone hydrochloride is a potential impurity from the manufacturing process. 2.5 Analytical Methods 2.5.1 Quality control Naloxone hydrochloride can be assayed by gas chromatography with flame ionization detection (United States Pharmacopeia, 1980). 2.5.2 Identification About 150 mg of the unknown substance is dissolved in 25 ml of water and a few drops of 6N ammonium hydroxide are added. Three 5-ml portions of chloroform are used for extraction and the extract is filtered. The filtrate is collected, evaporated to dryness using a steam bath, and dried at 105 °C for one hour. The infrared absorption spectrum of a 1-in-50 solution of the residue obtained in chloroform will have maxima at the same wavelengths as those of a similar solution of naloxone reference standard. The addition of one drop of ferric chloride solution to 1 ml of a 1-in-100 solution of naloxone hydrochoride results in a clear purplish-blue colour. 2.5.3 Quantification of the antidote Assay methods for naloxone in biological fluids employing gas-liquid chromatography (GLC) (Meffin & Smith, 1980), radio-immunoassay (RIA) (Berkowitz et al., 1975; Hahn et al., 1983) and high-performance liquid chromatography (HPLC) (Asali, 1983; Terry et al., 1984) have all been reported. The GLC method involves derivatization and the specific antibody for the RIA is not widely available. The HPLC methods reported appear sensitive and reproducible, and are therefore probably the methods of choice. 2.5.4 Analysis of toxic agents In the majority of cases in which naloxone is used as an antidote, there is no way of measuring the level of the opioid poison. Present assay techniques for many opiates are difficult, and RIA suffers from lack of specificity in many cases. Some opiates, e.g., morphine, also appear to have active metabolites (Bodd et al., 1990). The most widely used method for opioid detection is RIA of urine. 2.6 Shelf-life The shelf-life of naloxone for intravenous injection in temperate countries is 3 years and has a similar length in tropical countries. 2.7 General Properties Naloxone is a specific opioid antagonist (Martin, 1976) and it is for this reason that it is used in the treatment of poisoning. There are reports that it may reverse the central effects of ethanol and BZD poisoning in man. However, these are experimental uses that remain unproven, and any observed effects probably reflect the involvement of endogenous opioids in the nonspecific depressant action of those agents (McNicholas & Martin, 1984). 2.8 Animal Studies 2.8.1 Pharmacodynamics Naloxone is a competitive antagonist at opiate receptors, and appears to be effective at all three types of receptor (mu, kappa and sigma) (Martin, 1976). It does not produce habituation in animal or human models of opiate tolerance and appears to be free of agonist activity in most laboratory test models (Jasinski, 1967; McNicholas & Martin, 1984). It produces a parallel shift in the in vitro dose- response effects of pure agonist opioids, such as morphine, and partial agonists, such as pentazocine (Smits & Takemori, 1970), buprenorphine and dextropropoxyphene. Since the range and relative quantities of opioid receptors vary in different animal tissues, a range of concentrations of naloxone is required to antagonize opioid effects in different test systems. Confusion has arisen as to whether naloxone is a pure antagonist. This is because some opioid receptors act as modulators and enhance nociceptive stimuli. Thus, in some animal models naloxone appears to possess agonist effects, but this is in fact incorrect (Sawynok et al., 1979). Naloxone has also been observed in some experiments to antagonize the antinociceptive effects of some non-opiate drugs. Again it seems likely that this reflects an involvement of opioid receptors in the mechanism of action of these drugs (Sawynok et al., 1979). However, in a recent study in rats, Kotlinska & Langwinski (1990) failed to find any evidence for the participation of the opioid system in the mediation of acute ethanol effects in rats. Naloxone has been reported to either decrease or have no influence on barbiturate-induced anaesthesia. This paradox may be a result of the dose-response relationship of the effects of naloxone, which at high doses may have a potentiating effect (Sawynok et al., 1979). Naloxone has some activity as a GABA antagonist and may thus have convulsant activity. However, this is likely to be at much higher concentrations that those encountered clinically (Dingledine et al., 1978), since in mice a dose of 100 mg/kg was required to produce convulsions. Naloxone has also been shown to have a number of biochemical effects in the rat, including inhibition of lipolysis and a subsequent increase in circulating free tryptophan (Badawy et al., 1983). 2.8.2 Pharmacokinetics Naloxone appears to be readily absorbed after oral administration but undergoes extensive first-pass hepatic metabolism, which results in a very low bioavailability (Misra, 1978). Studies of the pharmacokinetics of intravenous naloxone have been performed in a variety of animal species including the rat, rabbit and dog. Many of these studies are based on radio-immunoassay of naloxone. The serum concentration of naloxone found 5 min after injection was similar (5 mg/kg) in the rat and the dog (Ngai et al., 1976; Pace et al., 1979). The half-life of the parent drug in the rat (30 min) was approximately half that in the dog (71 min). Ngai et al. (1976) also examined the brain:serum ratio of naloxone and found this to vary in the rat between 2.7:1 and 4.6:1. Intravenously administered naloxone acts rapidly on the brain. The brain:serum ratio was higher, however, when the naloxone was administered subcutaneously. These workers also studied, in a parallel group of animals, the distribution of morphine and noted that the brain:serum ration was 1:10. The initial distribution of naloxone may account for the rapid onset of its reversal of opiate effects when it is given intravenously. The major metabolite of naloxone is the glucuronide. Naloxone-3-glucuronide has been found, for example, in the rabbit (Fujimoto, 1969). A conjugated 6-hydroxy product of naloxone, N-allyl-14-hydroxy-7,8-dihydronormorphine-3-glucuronide was identified in the chicken by Fujimoto (1969); this conjugate was also identified in the rabbit by Weinstein et al. (1974) but only in small amounts. The relatively short action of naloxone appears to result from the ease with which it enters the brain after intravenous dosing and the subsequent rapid redistribution, elimination and consequent fall in brain naloxone levels (Berkowitz, 1976). Hydroxylated metabolites of naloxone appear to possess narcotic antagonist activities, but their potencies are much weaker than the parent compound. Thus they are unlikely to be of significance in view of the small amounts produced (Fujimoto et al., 1975). The distribution of naloxone has not been found to be altered by a 25-fold range of morphine concentration in the rat (Fishman et al., 1975). 2.8.3 Toxicology Acute toxicity studies with naloxone have been performed in mice, rats and dogs. The LD50 for intravenous administration was 150 mg/kg in mice, 109 mg/kg in rats and 80 mg/kg in dogs (Social Welfare Board, 1976). For 24-h-old rats the LD50 was 260 mg/kg when given subcutaneously (Blumberg et al., 1966). The maximum nontoxic subcutaneous dose in rats was found to be of the order of 50 mg/kg (Blumberg et al., 1966). This dose was tolerated for 24 days, whereas 200 mg/kg resulted in tremor, convulsions and salivation. Daily doses of 0.2 mg/kg given intravenously to dogs for 16 days and 5 mg/kg given subcutaneously to monkeys for 30 days caused no toxicity. However, a subcutaneous dose of 20 mg/kg resulted in lethargy and tremor in monkeys. No teratogenic effects were observed in mice, rats or rabbits when naloxone was given parenterally over the period of organogenesis (Social Welfare Board, 1976). No studies on mutagenicity have been published. 2.9 Volunteer Studies Studies of the pharmacokinetics and pharmacodynamics of naloxone have been performed in volunteers. 2.9.1 Pharmacokinetics Using an RIA assay, the pharmacokinetics of naloxone were found to fit a two-compartment model, with a rapid distribution phase and a slower elimination phase, having a half-life of 64 min (Ngai et al., 1976). More recent studies using HPLC to assay naloxone suggest that the apparent volume of distribution, half-life and clearance all show differences within groups of normal volunteers. Thus Aitkenhead et al. (1984) reported a mean apparent volume of distribution at steady state of 3.65 l/kg (range 1.43-7.05 l/kg) and a mean half-life of 151.2 min (range 47.1-313.2 min). Using an HPLC assay, Goldfrank et al. (1986) found less variability in patients (half-life 28-55 min). The kinetics of naloxone in infants appear similar to those in adults (Stile et al., 1984). Orally administered radiolabelled naloxone undergoes extensive first-pass metabolism in normal subjects (Fishman et al., 1973). After intravenous administration, most (70%) of the radioactivity was recovered in urine, the major part of which was conjugated as the glucuronide. In addition other metabolites were found in small quantities, i.e. the glucuronide conjugates of 7,8-dihydro-14-hydroxy- normorphine, and N-allyl-7,8-dihydro-14-hydroxy-normorphine (Weinstein et al., 1971). As a consequence of the high hepatic clearance of naloxone and relatively weak agonist activity of its metabolites, it is unlikely that dose adjustments would be necessary in cases of renal failure. Naloxone is only 54% protein-bound in adult plasma (61.5% in fetal plasma), and this binding is not concentration-dependent over the range 9 ng/ml to 2.5 µg/ml (Asali & Brown, 1984). Thus protein- binding interactions seem unlikely. The elimination of naloxone might be altered in patients with liver disease, but no studies appear to have been performed. 2.9.2 Pharmacodynamics Studies have been conducted on the duration of action and potency of naloxone in reversing respiratory depression induced by morphine (intravenous doses of 5 mg plus 10 mg) in volunteers (Kaufman et al., 1981). The effect of naloxone against this therapeutic dose of morphine reached a peak at around 30 min, which was equatable with the probable peak in brain concentration. It should be noted that the times of onset and peak effect of naloxone differed. The duration of action of naloxone appeared to be about 1.5 h in this experimental model. Johnstone (1974) examined the effects of an infusion of naloxone in volunteers who had received 2 mg/kg morphine intravenously and been anaesthetized for 5 h. Intravenous naloxone given to these volunteers at a rate of 40 µg/kg over a 10-h period reversed the central depressant effects of morphine on respiratory function (measured by CO2 responsiveness) and higher functions (assessed by a vigilance test). No tachyphalaxis to the effects of naloxone was observed over this period (Johnstone et al., 1974). It has been suggested that ethanol may exert some of its effects via the endogenous opiate system, as illustrated by the study by Jeffferys et al. (1980) and Jeffcoate et al. (1979) where naloxone was found to antagonize some of the ethanol effects. However, these findings could not be confirmed by Handal et al. (1983) or Nuotto et al. (1984). In the latter study, the effect of naloxone on ethanol- induced impairment of psychomotor performance was first studied in two placebo-controlled, double-blind, cross-over trials in 17 healthy male volunteers. The main conclusion was that naloxone (intravenous doses of 0.4 plus 2 mg) had no significant antagonizing effects on the impairment induced by ethanol (1.5 g/kg). However, a slight but significant effect on ethanol-induced nystagmus was noted. A placebo- controlled, double-blind study was subsequently conducted on male alcoholics admitted for acute ethanol intoxication (the mean blood ethanol level was 2.9 g/l (64 mmol/l)). In this case, neither naloxone (intravenous doses of 0.4 plus 2 mg; n=11) nor saline (n=7) had any effect, as judged from a clinical inebriation test (Nuotto et al., 1984). 2.9.3 Effects of high doses of naloxone Naloxone has been administered to healthy volunteers at dose levels of 0.3-4 mg/kg. These high dose levels produced dose-dependent dysphasia and memory impairment. In addition, increases in blood pressure and respiratory rate were noted, together with increases in cortisol and growth hormone levels (Cohen et al., 1983). These findings have been used to support the hypothesis that endogenous opioids play a normal regulatory physiological role, but obviously have potential therapeutic implications if large doses of naloxone are used to treat poisoned patients. 2.10 Clinical Studies - Clinical Trials Naloxone has been investigated in clinical studies on both patients who have received a therapeutic dose of an opiate (see section 2.9) and those who have been poisoned with opiates. Since naloxone is a competitive antagonist, the dose required to reverse the clinical effects of a specific opiate will depend on the dose of the opiate, its duration of action, and its pharmacological properties, particularly whether it has partial agonist activity or shows selectivity at one type of opioid receptor subgroup (Martin, 1976). 2.10.1 Effects in therapeutic use of opioids An alternative method of studying the response to naloxone was reported by Drummond et al. (1977). They studied patients who had been anaesthetized and had received the synthetic opiate fentanyl. Naloxone produced a dose-dependent increase in respiratory function (measured as minute volume or respiratory rate) with intravenous doses of 0.1, 0.2 and 0.4 mg. Hatano et al. (1975) reported an open study on 80 patients undergoing a variety of surgical procedures including cardiopulmonary bypass. Premedication included pethidine (meperidine) and induction was achieved with pentazocine and diazepam. The doses of pentazocine in males were 2 mg/kg and females 1.5 mg/kg, and those of diazepam were 0.4 and 0.3 mg/kg, respectively. The authors used a stepwise increment of naloxone (0.2-mg intravenous boluses) to achieve reversal of the opiate effect of pentazocine at the end of the operative procedure and noted a stepwise reversal of the opiate effects in their patients as the opiate dose was increased (the average total dose given was 2.5 mg/kg body weight). The duration of action of naloxone in reversing the effects of morphine (5 or 10 mg, intramuscular) in patients recovering from surgery is relatively short (Longnecker et al., 1973). The authors suggested that the use of a combination of intravenous and intramuscular naloxone might be an appropriate regimen in the post- operative situation; this has also been suggested for the treatment of acute overdoses in heroin addicts (see sections 2.12.2 & 2.13.2). 2.10.2 Effects in acute opioid poisoning Two important studies have demonstrated the efficacy of naloxone in reversing opiate poisoning. Evans et al. (1973) reported a study in which naloxone (0.4-1.2 mg, intravenous) resulted in recovery of consciousness within 1-2 min in nine patients with a history of opiate ingestion. This was associated with improvement in respiratory function in the six patients in whom this could be measured with minute volume and respiratory rate. The opiates taken by these patients were reported as dipipanone (3), pethidine (2), dihydrocodeine (2), pentazocine (1) and heroin (1). In contrast, none of 13 patients overdosed with a variety of other central nervous system depressants showed improvement after having been given a total intravenous dose of 1.2 mg naloxone. This rapid and clear benefit of therapy was also reported by Buchner et al. (1972), who studied the effects of naloxone (0.005 to 0.01 mg/kg) in 10 children with methadone poisoning. Although they did not study a control group, they did confirm the presence of methadone in biological fluids in some of their patients. These authors stress the importance of an adequate period of observation for patients poisoned with long-acting opiates and the necessity of repeated doses of naloxone. Since the onset of the effects of naloxone is so rapid, it has proved relatively easy to confirm its effectiveness in opiate poisoning at restoring consciousness and improving respiration. Further extensive clinical trials in opiate poisoning have, therefore, not been performed. Henry & Volans (1984) have stressed the importance of classifying drugs correctly as opioids. A list of opioids is a useful reminder (Table 1) that agents such as loperamide and diphenoxylate may produce significant systemic toxicity in overdose. One particular aspect of naloxone use that requires consideration is that of the most appropriate dosage regimen. Early human studies confirmed that the duration of action of naloxone was shorter than might have been expected from its plasma half-life (Berkowitz et al., 1975). The long duration of action of some opiates is also a factor in the need to repeat the initial dose of naloxone in poisoned patients (Gober et al., 1979). As an alternative to repetitive dosing, several research workers have suggested that intravenous loading doses followed by a steady-state infusion of the drug would be appropriate both in children (Gourlay & Coulthard, 1983; Tenenbein, 1984) and in adults (Bradberry & Raebel, 1981; Goldfrank et al., 1986) suffering opiate poisoning. These regimens have appeared safe and effective in clinical use, but do not obviate the need for close monitoring during treatment of respiratory function, conscious level and cardiovascular function. It is important to remember that some synthetic opioids, e.g., dextropropoxyphene, have been reported to produce toxic effects at high doses, which are not reversible by naloxone (Barraclough & Lowe, 1982). These effects may be due to a direct action of dextropropoxyphene on cardiac cell membranes. Table 1. Alphabetical list of opioid drugsa Alletorphine Levorphanol Alphaprodine Loperamide Anileridine Meptazinol Azidomorphine Methadone Bezitramide Metofoline Buprenorphine Morphine Butorphanol Nalbuphine Codeine Norpipanone Dextromoramide Opium Dextropropoxyphene Oxycodone Diamorphine (Heroin) Oxymorphone Difenoxin Papaveretum Dihydrocodeine Pentazocine Diphenoxylate Pethidine (Meperidine) Dipipanone Phenadoxone Ethoheptazine Phenazocine Ethylmorphine Phenoperidine Etorphine Piminodine Fentanyl Piritramide Hydrocodone Thebacon Hydromorphone Tilidate Ketobemidone Tramadol Levomethadyl Trimeperidine a From Martindale (1982). Some of these drugs may be marketed as part of a combination preparation. 2.11 Clinical Studies - Case Reports Individual published case reports have confirmed efficacy for the majority of opiates (Handal et al., 1983). In patients who are narcotic addicts, naloxone may precipitate features of acute opiate withdrawal. Doses of up to 20 mg naloxone have been used in children without associated adverse effects (Handal et al., 1983). If patients with acute renal failure are given morphine over several days for various reasons (e.g., for sedation while on a respirator), opioid toxicity may occur due to accumulation of the active metabolite morphine-6-glucuronide, which is renally excreted (Bodd et al., 1990). In such cases, the opioid toxicity may last for up to two weeks after the cessation of morphine therapy, and the patient will need naloxone infusion in order to avoid respiratory depression. 2.11.1 Naloxone in clonidine poisoning Clonidine hydrochloride is a central and peripheral alpha-adrenergic antagonist that is still used in the treatment of hypertension. It has also been suggested for the treatment of opiate withdrawal (Gold et al., 1980). The mechanism for this effect and for the claimed effect of naloxone in some cases of clonidine poisoning (North et al., 1981; Kulig et al., 1982) is not clear, but the involvement of endogenous opioids has been suggested. However, the effect of naloxone in clonidine poisoning could not be confirmed by Banner et al. (1983). In a retrospective study of 47 consecutive children admitted for clonidine poisoning (Wiley et al., 1990), only 3 out of the 19 given naloxone showed a temporary response. One child had an episode of severe hypertension associated with naloxone administration (0.1 mg/kg). Thus, there is no clear documentation for the beneficial effect of naloxone in clonidine poisoning. 2.12 Summary of Evaluation 2.12.1 Indications Naloxone has been reported to significantly antagonize acute opioid toxicity and opioid effects within anaesthesia. Its high therapeutic index and possible beneficial effect in other poisonings allow for diagnostic use in critically ill patients when opioid poisoning may be a differential diagnosis. 2.12.2 Advised routes and dose In patients with definite opiate poisoning, naloxone should be given by the intravenous route until an improvement in conscious level and respiration is observed. This may involve the administration of several milligrams of naloxone if partial opioid agonists are given, but 0.8-1.2 mg is usually sufficient in morphine or heroin poisonings. It is important to stress that a pharmacologically active dose of naloxone in opiate poisoning may be more than that normally recommended in anaesthetic practice. In patients with suspected opiate poisoning, an intravenous injection of up to 2 mg naloxone should be administered and the patient's response closely monitored. If there is improvement in conscious level, respiratory rate or cardiovascular parameters, further doses of naloxone should be administered. The effect of naloxone should be visible within 1 to 2 min after administration. Once a patient has regained consciousness, it is necessary to continue to monitor respiration and cardiovascular status at regular intervals. In the patient who has taken a large opiate overdose or an overdose of a long-acting opiate, it may be necessary to repeat dosing with naloxone. This may be conveniently done by establishing an intravenous infusion of naloxone. A guide to the required dosage has been suggested by Goldfrank et al. (1986). From studies of the pharmacokinetics of naloxone in patients suffering opiate poisoning, they calculated that an hourly infusion of two-thirds of the dose required initially to reverse the effects of the opiate would maintain naloxone levels at approximately those present 30 min after the initial bolus administration. Another approach to opioid poisoning that may sometimes be usefully employed in addicts is to give 0.8-1.2 mg naloxone intramuscularly before awakening the patient with an intravenous naloxone dose of 0.4-0.8 mg (higher doses are rarely needed) (personal communication by D. Jacobsen, 1991). This has been shown to be a useful practical approach, since many addicts leave the hospital immediately following the effect of the intravenous dose. Since naloxone has a shorter duration of action than the opiate, patients are commonly readmitted within one hour with miosis, coma and impaired respiration. This approach to treatment, however, requires adequate ventilatary support for the patient because of the short delay before the intravenous dose is given. Naloxone may also be given as a continuous intravenous infusion (about 0.5 mg/h in isotonic saline) to counteract effects of morphine metabolites in patients with acute renal failure (Bodd et al., 1990). 2.12.3 Other consequential or supportive therapy Since many of these patients suffer from impaired respiration or respiratory arrest, it is extremely important to give oxygen and to support ventilation immediately while waiting for naloxone to be available for injection. If ventilation is under control and cyanosis is regressing, one should consider giving an intramuscular dose of naloxone before the intravenous dose (see section 2.12.2). Pulmonary congestion or oedema is occasionally seen in opioid (heroin) poisoning. It is usually transient and responds to supportive therapy (oxygen and ventilation support) and naloxone. 2.12.4 Areas where there is insufficient information to make recommendations There are anecdotal reports of beneficial effect of naloxone in other types of acute poisoning, e.g., with ethanol or clonidine. In the case of ethanol, these results have not been confirmed in well- controlled studies on volunteers or in intoxicated patients (Nuotto et al., 1984). The claimed effect in clonidine poisoning has also been challenged (Wiley et al., 1990). There are insufficient data to recommend the use of naloxone in poisonings other than those involving opioids. 2.12.5 Proposals for further studies Studies of the effect of naloxone in other acute poisonings should be encouraged. It could, however, be argued that enough studies have been performed on the use of naloxone in ethanol intoxication to rule out a possible beneficial effect. On the other hand, there is certainly a lack of controlled studies on the possible effect of naloxone in clonidine poisoning. If effects of naloxone are observed in patients assumed to have been poisoned by non-opioids, urine specimens should be collected and analysed by RIA for presence of opioids. Otherwise such "case reports" are of little value. 2.12.6 Adverse effects Naloxone possesses a high therapeutic index, but it may provoke withdrawal signs and symptoms, e.g., seizures, in (heroin) addicts. Other adverse reactions, as described below, are very rarely seen. Cardiac arrhythmias and, in particular, ventricular fibrillation have resulted from rapid reversal of opiate effects with naloxone. Such events may be a particular problem in patients who have recently undergone surgery or those habituated to opiates (Cuss et al., 1984). These reactions may result from a release of sympathetic transmitters, since a rise in blood pressure and tachycardia have also been demonstrated. Some cases of pulmonary oedema following naloxone use in anaesthetic practice have been reported, but it is unclear in this situation which is the responsible agent: the anaesthetic, the opiate or the antagonist (Partridge & Ward, 1986). 2.12.7 Restrictions of use The fear of provoking withdrawal signs and symptoms should not hinder use of naloxone in those who need it clinically. 2.13 Model Information Sheet 2.13.1 Uses Naloxone is indicated in the management of opiate poisoning, both definite and suspected. Opiate poisoning should be considered in comatose patients with impaired respiration. Miosis is an unreliable sign and is not required for a diagnosis of opioid poisoning. The high wide therapeutic index of naloxone allows its use when a diagnosis of opioid poisoning is uncertain. 2.13.2 Dosage and route Since naloxone is a competitive antagonist of opiate poisoning, there can be no absolute guidelines on dosage. Naloxone should be given intravenously, in successive doses of 0.4 to 2.0 mg, until the desired response has been obtained. It should be noted that to reverse the effects of partial agonists/antagonists, e.g., pentazocine, buprenorphine and dextropropoxyphene, much larger doses may be required, and it may prove impossible to reverse the effects of buprenorphine. Failure to respond to a total dose of 10 mg usually indicates: a) that poisoning is not due to opiates; b) that poisoning is due to a partial agonist/antagonist; or c) that hypoxic brain damage has occurred. It should be noted that dextropropoxyphene has been reported to produce cardiac toxicity that is not reversible by naloxone administration. The duration of action of naloxone is short; careful monitoring is required and repeated doses may be necessary. The alternative is an intravenous infusion of naloxone. The use of an hourly infusion of two-thirds of the dose of naloxone required to resuscitate the patient has been reported to be effective, but dosage should be always titrated to the individual patient. Another alternative, which may be appropriate for opiate addicts, is to give naloxone (0.8-1.2 mg) intramuscularly before waking the patient with an intravenous dose of 0.4-0.8 mg. However, adequate ventilatory support must be given. The patient then has a "depot" of antidote in case he/she departs soon after the initial treatment (as many addicts do). The dose given to children should be reduced according to body weight (0.01 mg/kg initially). 2.13.3 Precautions/contraindications Naloxone may induce symptoms and signs of acute opiate withdrawal in addicts. If seizures occur they are best controlled with diazepam (10-30 mg, intravenously). No dosage alterations seem necessary in the case of changes in renal function. The dose in children should be adjusted on a body-weight basis to that used in adults. Appropriate protective precautions need to be taken by hospital staff in the case of opiate addicts, bearing in mind the risk of infection from blood-borne diseases such as hepatitis B and human immunodeficiency virus (HIV). 2.13.4 Adverse effects Naloxone has a very high therapeutic index and adverse effects are rarely seen. Ventricular arrhythmias including ventricular fibrillation have been reported following rapid reversal of severe opiate intoxication. This may be avoided if oxygen and adequate ventilatory support are also given. The management of withdrawal symptoms in addicts is discussed in section 2.13.3. 2.13.5 Use in pregnancy and lactation Naloxone is not teratogenic in animals, but no relevant human data exist. 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Henry J & Volans G (1984) ABC of Poisoning: Analgesics: Opioids. Br Med J, 289: 990-993. Jasinski DR, Martin WR, & Haertzen CA (1967) The human pharmacology and abuse potential of N-allyl noroxymorphone (naloxone). J Pharm Exp Ther, 157: 420-426. Jeffcoate WJ, Herbert M, Cullen MH, Hastings AG, & Walder CP (1979) Prevention of effects of alcohol intoxication by naloxone. Lancet, 2: 1157-1159. Jefferys DB, Flanagan RJ, & Volans GN (1980) Reversal of ethanol- induced coma with naloxone. Lancet, 1: 308-309. Johnstone RE, Jobes DR, Kennell EM, Behar MG, & Smith TC (1974) Reversal of morphine anaesthesia with naloxone. Anaesthesiology, 41: 361-367. Jordan C (1980) Respiratory depression following diazepam: reversal with high-dose naloxone. Anaesthesiology, 53: 293-298. Kaufman RD, Gabathuler ML, & Bellville JW (1981) Potency, duration of action and pA2 in man of intravenous naloxone measured by reversal of morphine-depressed respiration. J Pharmacol Exp Ther, 219: 156-162. Kaufman JJ, Semo NM, & Koski WS (1975) Microelectrometric titration measurements of the pKa's and partition and drug distribution coefficients of narcotics and narcotic antagonists and their pH and temperature dependence. J Med Chem, 18: 647-655. Kotlinska J & Langwinski R (1990) The lack of effect of opioid agonists and antagonists on some acute effects of ethanol. Pol J Pharmacol Pharm, 42: 129-135. Kulig K, Duffy J, & Rumack BH (1982) Naloxone for treatment of clonidine overdose. J Am Med Assoc, 247: 1697. Longnecker DD, Grazis PA, & Eggors WWN (1973) Naloxone for antagonism of morphine-induced respiratory depression. Anaesth Analg, 53: 447-452. McNicholas LF & Martin WR (1984) New and experimental therapeutic roles for naloxone and related opioid antagonists. Drugs, 27: 98-93. Martin WR (1976) Naloxone. Ann Intern Med, 85: 765-768. Martindale (1982) In: Reznolds JEF ed. The extra pharmacopoeia, 28th ed. London, Pharmaceutical Press. Meffin PF & Smith KJ (1980) Gas chromatographic analysis of naloxone in biological fluids. J Chromatogr, 183: 352-356. Misra AL (1978) Metabolism of opiates. In: Factors affecting the action of narcotics. New York, Raven Press, pp 297-343. Ngai SH, Berkowitz BA, Yang JC, Hampstead J, & Spector S (1976) Pharmacokinetics of naloxone in rats and in man: Basis for its potency and short duration of action. Anaesthesiology, 44: 398-401. North DS, Wieland MJ, & Peterson CD (1981) Naloxone administration in clonidine overdosage. Ann Emergency Med, 10: 397. Nuotto E, Palva ES, & Seppala T (1984) Naloxone-ethanol interaction in experimental and clinical situations. Acta Pharmacol Toxicol, 54: 278-284. Pace NL, Parrish RG, Lieberman MM, Wong KC, & Blatnick RA (1979) Pharmacokinetics of naloxone and naltrexone in the dog. J Pharmacol Exp Ther, 208: 254-256. Partridge BL & Ward CF (1986) Pulmonary edema following low-dose naloxone administration. Anesthesiology, 65: 709-710. Sawynok J, Pinsky C, & Labella FS (1979) Mini review on the specificity of naloxone as an opiate antagonist. Life Sci, 25: 1621-1632. Smits SE & Takemori AE (1970) Quantitative studies on the antagonism by naloxone of some narcotic and narcotic-antagonist analgesics. Br J Pharmacol, 39: 627-638. Social Welfare Board (1976) Nalone (naloxon). Uppsala, Sweden, Social Welfare Board, Pharmaceuticals Department, pp 7-9. Stile IL, Fort M, Marotta F, Wurzburger R, Hiatt IM, & Hegyi T (1984) Pharmacokinetics of naloxone in premature infants. Paediatr Res, 18(392): 161A. Tenenbein M (1984) Continuous naloxone infusion for opiate poisoning in infancy. J Pediatr, 105: 645-647. Terry MD, Hisayasu GH, Kern JW, & Cohen JL (1984) High performance liquid chromatographic analysis of naloxone in human serum. J Chromatogr, 311: 213-217. United States Pharmacopeia (1980) 20th ed. Rockville, Maryland, United States Pharmacopeial Convention, Inc. Weinstein SH, Pfeffer M, & Schor JM (1974) Metabolism and pharmacokinetics of naloxone. Adv Biochem Psychopharmacol, 8: 525-535. Weinstein SH, Pfeffer M, Schor JM, Indindoli L, & Mintz M (1971) Metabolites of naloxone in human urine. J Pharm Sci, 60: 1567-1568. Wiley JF, Wiley CC, Torrey SB, & Henretig FM (1990) Clonidine poisoning in young children. J Pediatr, 116: 654-658. Windholz M ed. (1983) The Merck index: An encyclopedia of chemicals, drugs and biologicals, 10th ed. Rahway, New Jersey, Merck and Co, Inc. 3. FLUMAZENIL 3.1 Introduction Acute poisoning is currently one of the main causes of hospital admission in developed countries. Benzodiazepines (BZDs) are the most commonly used drugs throughout the world and their abuse may be responsible for the impairment of memory and for dependence. An acute overdose can result in long-lasting coma, which is generally treated with supportive measures. Flumazenil, an imidazobenzo-diazepine (AnexateTM), has been shown to reverse the sedative, anti- convulsant, and muscle-relaxant effects of BDZs. It has no convulsive action in itself and its use has therefore been proposed to counteract benzodiazepine action in anaesthetics, clinical toxicology and intensive care. 3.2 Name and Chemical Formula of Antidote * Flumazenil AnexateR (Roche Laboratories) * Ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4] benzo-diazepine-3-carboxylate * Empirical formula: C15H14O3N3F * Relative molecular mass: 303.3 * Therapeutic class : Imidazobenzodiazepine * CAS number: 78 755-81-4 * Conversions:1 mmol = 303.3 mg 1 g = 3.3 mmol µmol/l = 3.3 x µg/ml µg/ml = 0.3 x µmol/l 3.3 Physico-chemical Properties Physico-chemical properties of flumazenil are given in Table 1. Flumazenil remains stable when exposed to light and when stored for 2 years at 35° C. The loss of weight on drying is up to 1%. 3.4 Pharmaceutical Formulation and Synthesis No information is available on the routes of synthesis and manufacture. Flumazenil is supplied for parenteral administration in vials containing 5 or 10 ml aqueous solution (0.1 mg/ml). It is available for oral administration as tablets of 10, 20 or 30 mg. Table 1. Physico-chemical properties of flumazenila Melting point 198-202 °C Solubility in water < 1 g/l Solubility in organic solvents (g/l) chloroform < 250 methanol < 17 ethyl acetate < 3 diethyl ether < 1 Solubility at various pH values (g/l) (in aqueous buffered solution at 37° C) pH 1.2 3 pH 5.3 0.7 pH 7.5 0.6 Acidity (10% aqueous solution) 4.5-7.5 pKa (in weak base) 1.7 a Personal communication from Roche Laboratories (1988) 3.5 Analytical Methods 3.5.1 Identification of the antidote Information on the identification of flumazenil was provided by Roche Laboratories (personal communication, 1988). 220.127.116.11 Infrared spectroscopy The infrared spectrum (625-4000 cm-1) of a sample (a 1:300 solid dispersion in potassium bromide) is compared qualitatively with that of a reference substance. 18.104.22.168 Ultraviolet absorption A portion (85-95 mg) of the sample is dissolved in approximately 100 ml of ethanol and diluted to 150 ml with ethanol (solution 1). This solution is then diluted ten-fold with ethanol to give solution 2, which is further diluted ten-fold with ethanol to give solution 3. The position and absorbance of solution 3 is measured spectrophotometrically at the maximum (245 nm) and minimum (228 nm) wavelengths, against ethanol, in quartz cells. 22.214.171.124 Thin-layer chromatography The TLC details are as follows: * layer: Silica gel 60 F254 * mobile phase: Chloroform/ethanol (90/10 v/v) * sample solution: 10 ml of the ampoule solution is extracted with 1 ml of chloroform * standard solution: 5 mg of flumazenil is dissolved in 5 ml of chloroform saturated with water * front distance: 12 cm * migration time approx: 30 min * detection: the plate is dried in a current of warm air for 5 min, and examined under shortwave light. Decreasing fluorescence due to flumazenil occurs at 254 nm (ultraviolet region). When the plate is sprayed with Dragendorff's reagent, flumazenil appears as an orange spot. The Rf value is approximately 0.5. 3.5.2 Quantification of the antidote in biological samples The determination of flumazenil in plasma by gas-liquid chromatography (GLC) with nitrogen phosphorus detection is a sensitive and specific method, the detection limit being 3 ng/ml (Abernethy et al., 1983). An ethyl acetate extraction (neutral pH) of 0.1-3 ml plasma is used for sample preparation. When methylclonazepam is used as an internal standard, the graph is linear for plasma concentrations up to 200 ng/ml. The retention time for flumazenil is 3.96 min. High-performance liquid chromatography (HPLC) with UV detection at 254 nm is a sensitive method for determination in urine or plasma, the detection limit being about 10 ng/ml (Timm & Zell, 1983; Bun et al., 1989). When the n-propyl ester analogue is used as an internal standard, the graph is linear for plasma concentrations up to 320 ng/ml. 3.5.3 Analysis of the toxic agent in biological samples Three major methods for the quantitative analysis of BZDs in plasma or serum are used: * HPLC with UV detection at 246 nm (detection limits are 5-50 µg/ml of serum) (Rocher, 1984); * immunoenzymology by the EMIT method for a semiquantitative determination (metabolites also measured) of diazepam levels, completed by a chromatographic method (sensitivity from 0.3 to 2 µg/ml) (Rocher, 1984); * gas-liquid chromatography (Pellerin, 1986). 3.6 Shelf-life Vials ready for use are stable at room temperature (15-25° C) for three years. 3.7 General Properties Flumazenil has been shown to block all the typical BZD effects (anticonvulsive, sedative, anxiolytic, muscle relaxant, and amnesic). It acts as a potent BZD-specific antagonist by competing at the central synaptic gamma-aminobutyric acid (GABA) receptor sites in a dose-dependent manner, but does not seem to antagonise BZD effects at peripheral GABA-ergic (renal, cardiac, etc.) receptor sites (Mohler et al., 1981). It possesses agonist properties and has a specific, but discreet, anticonvulsive effect without inducing drowsiness or muscle relaxation (Abernethy et al., 1983; Timm & Zell, 1983; Haaefely, 1983; Rocher, 1984; Scollo-Lavizzari, 1984; personal communication by Roche Laboratories, 1988). In addition, it antagonizes the sedative effects of other compounds that act through GABA receptors, such as zopiclone (Mohler et al., 1981). 3.8 Animal Studiesc 3.8.1 Pharmacodynamics Flumazenil has been tested for its ability to induce withdrawal signs in animals pretreated with benzodiazepine; the signs included emesis, tremors, rigidity and clonic convulsions. c Personal communication by Roche Laboratories to the IPCS, 1988 Rats that had been pretreated with an oral dose (10 or 100 mg/kg) of diazepam for 12 days were administered flumazenil (10 mg/kg) intravenously. Signs were very mild even at 100 mg/kg. Cats were pretreated intraperitoneally for 16 days with either a 10-mg/kg dose of lorazepam twice daily or a 1-mg/kg dose of triazolam once daily. Flumazenil (100 mg/kg) was then administered intraperitoneally either immediately or 1.5, 6, 12, 48, and 60 h after the last dose. Symptoms such as rigidity, vocalization and tachypnoea lasted 30 min, whereas others such as hypersalivation lasted 2 h. Flumazenil (1 to 15 mg/kg) was administered intragastrically to rats that had been pretreated with daily diazepam doses of 113 mg/kg for about 6 months. Abstinence syndromes increased with increasing dose of flumazenil and reached a plateau. The intragastric administration of flumazenil (15 mg/kg per day) to cats pretreated with flurazepam (5 mg/kg per day) for 35 days led to withdrawal symptoms (increasing muscle tone, tremors, piloerection, mydriasis, and hypersalivation) 24 h after the last dose of flurazepam. No convulsions were observed. Intramuscular administration of flumazenil (5 mg/kg) to squirrel monkeys and baboons, pretreated with oral doses of lorazepam, triazolam (3 mg/kg per day), oxazepam (40 or 80 mg/kg per day) or diazepam (8-20 mg/kg per day), produced withdrawal signs. However, no withdrawal signs were precipitated by flumazenil in monkeys treated with oral midazolam (30 mg/kg) or in barbital-dependent rhesus monkeys (the length of pretreatment with BZD was not specified). The severity of withdrawal signs resulting from the blocking of BZD receptors by flumazenil depends on the species tested, the dose of BDZ used to develop physiological dependence, and the duration of treatment. 3.8.2 Pharmacokinetics 126.96.36.199 Absorption A single dose of flumazenil (125 mg/kg) in a carboxymethyl cellulose suspension produced a maximum plasma concentration in rats of 9.9 µg/ml after 20 min. The bioavailability was 0.55. In rabbits, the maximum concentration 90 min after a single dose of flumazenil (150 mg/kg) was 15 µg/ml. The bioavailability was 0.60. 188.8.131.52 Distribution When total radioactivity was measured in rats 0.5, 7, 24, 96, and 192 h after an intravenous dose of 14C-labelled flumazenil (2 mg/kg), the highest level was found at 0.5 h in the kidney, liver and intestine. None was found at 192 h. The volume of distribution ranged from 0.71 to 1.87 l/kg. 184.108.40.206 Elimination Studies on rats given an oral dose (50 mg/kg) of 14C-labelled flumazenil and on dogs given an intravenous dose of 4 mg/kg showed three main inactive metabolites: * Ro 15-3890 acid and major metabolite (72% in the rat, 30-60% in the dog); * Ro 15-4965 hydroxyethyl derivative (3% in the rat); * Ro 15-6877 N-demethyl derivative (1% in the rat, 1-13% in the dog). Table 2 presents elimination data in three different species. In these species, 90% of the intravenously or orally administered flumazenil was eliminated, mainly as metabolites, within 48 h. One third was eliminated in the faeces and two-thirds in the urine. Table 2. Elimination of flumazenil in the rat, rabbit and dog Species Dose Total plasma T´ clearance (min) (ml/min per kg) Rat 2 mg/kg 114 7.4 Rabbit 0.5 mg/kg 24 34 Dog 5 mg 21 48 3.8.3 Toxicology 220.127.116.11 Acute toxicity a) Intravenous administration to rats and mice An aqueous solution of 0.1 mg flumazenil/ml was used and was administered at a dose of 2.5 mg/kg to mice and 1 mg/kg to rats. No abnormal clinical signs and no deaths occurred. LD50 values were not determined; these doses (50 to 250 times higher than the clinical doses) were well tolerated in the two species. A flumazenil solution with a concentration of 50 mg/ml was subsequently used and the LD50 values given in Table 3 were obtained (95% confidence intervals). Deaths occurred 30 min after the injection, preceded by rigidity and clonic convulsions. Table 3. Intravenous LD50 values (mg/kg) for the mouse and rat Species Male Female Mouse 143-198 145-175 Rat 85-167 112-231 b) Intravenous administration to the dog The administration of daily doses of 0.01 to 0.03 mg/kg was well tolerated and no deaths were observed. LD50 values were not determined; the doses (15 to 30 times higher than the clinical doses) were again well tolerated. c) LD50 values (mg/kg) for the rat, mouse and rabbit When flumazenil was administered orally to rats, mice and rabbits (Table 4), deaths were observed within three days, associated with decreased motor activity, catatonic state and tremors. Table 4. LD50 values (mg/kg) for the rat, mouse and rabbit Species Male Female Mouse 2500 1300 Rat 4200 4200 Rabbit 2000 2000 18.104.22.168 Subacute toxicity Systemic tolerance was good in both rats and dogs administered flumazenil intravenously at dosages up to 10 mg/kg per day for 4 weeks. 22.214.171.124 Chronic toxicity In 13-week studies using an oral aqueous solution of flumazenil, very good tolerance was shown by rats at dosages of 0.5, 25 and 125 mg/kg per day and by dogs at 0.5, 20, and 80 mg/kg per day. No haematological, biochemical or gross pathological abnormalities were observed. 126.96.36.199 Embryotoxicity Studies on rats (between the 7th and 16th day of gestation) and rabbits (between the 7th and 19th day of gestation) revealed no signs of embryotoxicity at dosages of 15, 50, and 150 mg/kg per day. 188.8.131.52 Mutagenicity Flumazenil was not mutagenic in the Ames test or micronucleus test, or in tests using Saccharomyces cerevisiae or Chinese hamster V79 cells. 3.9 Volunteer Studies 3.9.1 Pharmacodynamics 184.108.40.206 BZD antagonist effect Efficacy studies were performed on 125 healthy volunteers with oral doses of flumazenil up to 20 mg, the aim being to antagonize the effects of diazepam, flunitrazepam and midazolam on the CNS (Darragh, 1981; Lupolover, 1983). These studies demonstrated the antagonist effect of flumazenil, which rapidly abolished the hypnotic-sedative BZD effects. Other studies used meclonazepam (Darragh et al., 1981), diazepam (Darragh et al., 1982), flunitrazepam (Gaillard & Blois, 1983) and midazolam (Forster et al., 1983). In studies by Ziegler & Schalch (1983) and Lauven et al. (1985), flumazenil was administered to subjects during continuous midazolam infusion after the attainment of a pharmacokinetic and pharmacodynamic steady state, at which point subjects were deeply asleep. The degree and duration of the effect of flumazenil depended on the BZD dose, the antagonist dose and the time that had elapsed since the BZD was given. In the study by Ziegler & Schalch (1983), baseline levels of vigilance and orientation were reached within 1 min. Lauven et al. (1985) used higher midazolam and flumazenil dosages and his patients awoke within 28 to 48 seconds. No signs of BZD withdrawal effects were seen in short-term studies (one single dose) on healthy volunteers given flumazenil to antagonize BZDs (Amrein, 1987). The efficacy of flumazenil in antagonizing the effects of midazolam was also clearly demonstrated in the double-blind placebo- controlled study by Rouiller et al. (1987). 220.127.116.11 Intrinsic effects Most studies on healthy human volunteers have shown little or no intrinsic effect of flumazenil when administered alone. The mild sedation reported by Amrein (1987) occurred after the administration of oral doses greater than 100 mg. Scollo-Lavizzari (1984) observed some anticonvulsant effects in epileptic patients. Decreased amplitude of auditory evoked potentials has also been described (Laurian et al., 1984; Schoepf et al., 1984). Mild, nonspecific effects such as increased alertness may occur after the administration of doses very much higher than those used clinically (Laurian et al., 1987). 3.9.2 Pharmacokinetics 18.104.22.168 Absorption Following oral administration of a 200-mg dose of flumazenil, the highest plasma concentration (Cmax) ranged from 147 to 349 µg/l and was reached within 20 to 45 min. The mean bioavailability of the tablets used was about 17% and the inter-individual variability was 7-29% (Pellerin, 1986). 22.214.171.124 Distribution The proportion of flumazenil bound to plasma proteins is 50% (two-thirds of which is bound to albumin). Values for the mean steady-state volume of distribution of 0.95 l/kg (personal communication by Roche Laboratories, 1988) and 1.23 l/kg (Roncari et al., 1986) have been determined. 126.96.36.199 Elimination Ninety-nine per cent of the flumazenil administered is metabolized by the liver, and 1% is excreted unchanged in the urine. Mean total blood clearance, for which values of 59 l/h (Pellerin, 1986) and 72 l/h (Roncari et al., 1986) have been determined, is essentially due to the hepatic clearance. The apparent plasma half- life in healthy volunteers has been reported to be 53-58 min (Roncari et al., 1986; personal communication by Roche Laboratories, 1988). 3.9.3 Tolerance of flumazenil In the study by Rouiller et al. (1987), no objective agonist effects or biological toxicity of flumazenil could be demonstrated in six healthy volunteers. 3.9.4 Other studies There is evidence that central nervous system effects of ethanol are mediated through the GABA system. For this reason, the effect of flumazenil on psychometric performance was studied in eight healthy volunteers with stable blood ethanol levels of 1.6 g/l (35 mmol/l) under a placebo-controlled double-blind design (Clausen et al., 1990). Flumazenil did not improve psychomotor functions in these ethanol- intoxicated subjects, which is in agreement with experience in clinical toxicology. 3.10 Clinical Studies - Clinical Trials Flumazenil was first used clinically in patients with iatrogenic benzodiazepine overdose due to mechanical ventilation or status epilepticus (Scollo-Lavizzari, 1983). Clinical studies can be grouped under the headings anaesthesiology and toxicology (Amrein, 1986). 3.10.1 Anaesthesiology 188.8.131.52 General anaesthesia Three placebo-controlled studies have been conducted in patients who were given flunitrazepam for general anaesthesia. Jensen et al. (1985) reported that a 0.3-mg to 0.7-mg dose of flumazenil awoke all patients within 5 min, compared with only 35% of the patients in the placebo-treated group (P < 0.001 for sedation, orientation and amnesia). In a study of 60 patients, Tolksdorf et al. (1986) found that patients treated with flumazenil were less sedated than placebo- treated patients (P < 0.05) following flunitrazepam sedation (from 5 min to 1 h after the administration of flumazenil), better orientated at 15 min, and less amnesic. Ellmauer et al. (1986) reported similar results in 57 patients given a 0.1- to 1-mg dose of flunitrazepam (P < 0.005). No significant difference was observed after 2 h between the placebo-treated and flumazenil-treated patients in any of the three studies described in this section. Midazolam effects were reversed by flumazenil in an open study including 18 intracranial surgery patients (Chiolero et al., 1988). 184.108.40.206Conscious sedation In a 74-patient open study (Geller et al., 1986) and a 40-patient placebo-controlled study (Knudsen et al., 1986), in which either midazolam or diazepam was used, there was a significant difference between flumazenil- and placebo-treated patients. In the former study, patients were awakened by a 0.1- to 0.6-mg dose of flumazenil within 1 to 2 min. In the study by Knudsen et al. (1986), 80% of the flumazenil-treated patients were awake 5 min after receiving the dose compared with 50% in the placebo group (P < 0.05). 3.10.2 Benzodiazepine overdose or intoxication Three different studies have indicated that flumazenil may be an effective tool for the management of intoxication (either intentional or iatrogenic) with BZD in the presence or absence of other agents. Owing to its safety and specificity, flumazenil could be used in the initial treatment of poisoning and coma of unknown origin. In a study by Hofer & Scollo-Lavizzari (1985) based on 13 patients, a 1.5-to 10- mg dose of flumazenil administered intravenously at a rate of 1.5 to 2.5 mg/min reversed the CNS depression induced by various BZDs within 1 to 2 min. Geller et al. (1985) treated 34 patients (23 cases of intentional drug intoxication and 11 of iatrogenic BZD overdose) by means of intravenous injections of 0.1 mg flumazenil every 30 seconds until the patient regained consciousness. The treatment proved to be extremely effective, providing reversal effects lasting up to 2 h. Bismuth et al. (1985) treated patients for BZD overdose in a double-blind randomized study, injecting a single dose of either flumazenil or placebo. Two of the 20 placebo patients awoke partially, compared with 17 of the 20 flumazenil-treated patients (one experienced seizures interrupting the study). In a second open study (Bismuth et al., 1986) based on 37 patients, 6 showed no response to doses of flumazenil ranging from 5 to 9.5 mg (mixed intoxication), 11 showed partial awakening (no possible written response) at a dose of 2.1 ± 1.6 mg (mixed intoxication), and 20 were completely awakened by a dose of 1.4 ± 0.7 mg. The awakening was only temporary and return to coma occurred after an interval of 15 min to 5 h. Permanent recovery occurred in a patient suffering intoxication due to triazolam, a BZD with a short half-life, after a single administration of flumazenil. More recent placebo-controlled double-blind studies have confirmed the beneficial effect of flumazenil in cases of BZD poisoning (Aarseth et al., 1988; Ritz et al., 1990). 3.11 Clinical Studies - Case Reports The many controlled clinical studies of the effect of flumazenil limit the need for information from case reports. In the clinical studies reported, there have been few adverse effects associated with the use of flumazenil. There have, however, been case reports of seizures followed by ventricular tachycardia associated with the use of flumazenil in combined poisonings with cyclic antidepressants and BZD (Bismuth et al., 1985). In one report, death was claimed to have been associated with flumazenil administration in an old, obese and anaemic woman who had been sedated with midazolam (4 mg, intravenous) prior to gastroscopy (Lim, 1989). During the investigation she suffered cardiac arrest; flumazenil was given promptly and she recovered temporarily, but then gradually deteriorated and died 16 h later. According to Birch & Miller (1990), the death of this patient was probably not related to flumazenil administration. Recently, successful treatment was achieved by administering flumazenil as an intravenous bolus (0.02 mg/kg) and then as a maintenance dose of 0.05 mg/kg per h to a newborn baby with recurrent apnoea due to BZDs taken by his mother (Richard et al., 1991). The benefit from the diagnostic use of flumazenil in coma of unknown origin has been reported in two recent cases (Burkhart & Kulig, 1990). When flumazenil is used with caution in such situations, time may be saved and further expensive diagnostic procedures, e.g., cerebral computerized tomographic (CT) scan, avoided. 3.12 Summary of Evaluation Flumazenil appears to be a antagonist to BZDs and other GABA- ergic agents. This antagonism, following intravenous injection, has been reported to be sensitive in cases of intoxication resulting solely from BZDs (the reversal of BZD effects being observed with doses of less than 2 mg), rapid in onset (within 2 min), and short- lived (effects last for less than 30 min). 3.12.1 Indications In controlled clinical trials, flumazenil significantly antagonizes BZD-induced coma arising from anaesthesia or acute overdose. However, the use of flumazenil has not been shown to reduce mortality or sequelae in such cases. As the mortality in pure BZD poisoning is extremely low, studies with mortality as end-point are impractical since a reasonable level of statistical significance could probably never be obtained. However, in cases of mixed intoxication, especially with ethanol and triazolam/flunitrazepam, the use of flumazenil may be life-saving due to the poten-tiation of BZD toxicity by ethanol. Given this situation, it is obvious that the routine use of flumazenil in BZD poisoning is not indicated and that recommendations for its use in clinical toxicology must be based on pragmatic considerations made by clinicians experienced in treating these patients. Flumazenil is a relatively expensive drug and this may also influence its use, especially in areas with limited resources. The use of flumazenil in BZD poisoning should, therefore, only be advocated in situations with complications, which are rarely seen except in cases of mixed ingestion. Although not of life-saving significance, it also seems reasonable to advocate the use of flumazenil if intubations (before gastric lavage) and mechanical ventilation can thereby be avoided (see section 3.13.1). The proposed uses of flumazenil within acute medicine and anaesthesia are listed in section 3.13.1. Acute poisoning is always an important differential diagnosis in cases of coma in children and young adults. The diagnostic use of flumazenil in such cases can be justified by its high therapeutic index and the fact that this may limit the use of other diagnostic procedures such as cerebral CT scan, clinical chemistry analyses and even lumbar puncture. 3.12.2 Dosage and route Flumazenil is available for intravenous and oral administration. The need for the latter formulation may be questioned in view of the fact that drugs should generally be given intravenously in the emergency situation and the bioavailability is low and variable. Thus the intravenous route is preferable. Doses need to be adjusted according to individual clinical response, bearing in mind the very high therapeutic index of flumazenil. a) In anaesthetics and in intensive care, doses of 0.2-0.5 mg should be used to reduce sedation and doses of 0.5-1 mg to abolish other BZD effects (Amrein, 1987). b) In cases of BZD overdosage, single doses of 0.3-1 mg can be given and repeated as necessary. If there is no clinical response to 2 mg flumazenil given over a period of 5-10 minutes, diagnoses other than BZD poisoning are likely. It is also possible to administer a continuous infusion (0.3-1 mg/h) of flumazenil (diluted in 0.9% sodium chloride solution or 5% glucose solution) in patients relapsing into a coma and/or respiratory depression following an initial effect of flumazenil injection. c) In children, experience is limited and dosage regimens less well documented (Lheureux & Askenasi, 1988; Wood et al., 1987). It is suggested that intravenous doses of 0.1 mg should be given once per minute until the child is awake. It may be necessary to give a subsequent continuous intravenous infusion at a rate of 0.1 to 0.2 mg/h. 3.12.3 Other consequential or supportive therapy Treatment with flumazenil requires continuous intensive observation. After the administration of a single dose of flumazenil, the patient must be observed for at least 2 h to be certain that BZD- induced complications will not recur. The termination of continuous infusion requires intensive care monitoring. 3.12.4 Areas where there is insufficient information to make recommendations There is insufficient information to make recommendations in the case of hepatic encephalopathy (indication is based on the hypothesis that hepatic encephalopathy is associated with increased GABA-mediated inhibitory neurotransmission). 3.12.5 Proposals for further study The use and dosages of flumazenil in children require further study. Indications for utilization of oral preparations need to be clarified. The use in coma of unknown origin merits further studies. 3.12.6 Adverse effects The most frequent adverse effects have been reviewed by Amrein (1987). When flumazenil is used in anaesthesia, the main adverse effects that have been reported are nausea and vomiting (placebo: 7.5%; < 1 mg flumazenil: 12.1%; 1-10 mg flumazenil: 24.5%). Other adverse effects, which have been reported in less than 5% of cases, are tremor, involuntary movements, dizziness, agitation, discomfort, tears, anxiety, and a sensation of cold. Minor effects occur when flumazenil is used in intensive care, where agitation is the commonest adverse effect (10%). When it is administered to patients showing BZD habituation, the following features occur: anxiety, tenseness, fear, agitation, confusion, convulsions (Marchant & Wray, 1989) and myoclonic seizures. Their frequency and intensity depend on the degree of dependency and they are believed to be related to some sort of BZD abstinence syndrome. When administered rapidly, flumazenil can cause hypertension, tachycardia and acute anxiety. This equivalent of an "exercise test" was observed with the 1 mg/ml solution, which is no longer used. 3.12.7 Restrictions of use In certain circumstances, BZD antagonism by flumazenil may be harmful: a) An acute withdrawal syndrome can occur in patients showing BZD habituation following therapy or abuse. b) Convulsions can occur in cases of mixed drug overdosage where BZD has been taken with a drug liable to cause convulsions (such as a tricyclic antidepressive agent). c) Convulsions can be induced in patients treated with BZD for seizure disorders or in patients who for years have been using BZD for sleep disturbances. There are other limitations to the use of flumazenil. a) It has a short-lived effect and repeated injection or continuous infusion is often necessary unless a short-acting BZD (e.g., triazolam) has been ingested. b) In cases of mixed drug overdosage, the patient may remain unresponsive when other drugs are contributing to the coma. c) The treatment costs are high and supportive treatment may be cheaper. 3.13 Model Information Sheet 3.13.1 Uses Flumazenil is a specific antagonist of the effects of BZD at central GABA-ergic receptors. Within the domains of intensive care and anaesthesia, flumazenil may be valuable in the following circumstances: a) to diagnose BZD-induced unconsciousness in patients presenting coma of unknown origin; b) to terminate long-term BZD-induced sedation in the intensive care unit (e.g., weaning from ventilatory support); c) to reduce BZD-induced sedation or to counteract paradoxical anxiety reactions to BZD in anaesthesia; d) to antagonise BZD-induced sedation after short diagnostic procedures where a long-acting BZD has been used. Flumazenil may be justified in the following situations in cases of BZD poisoning: a) to facilitate gastric lavage and avoid intubation in comatose patients; b) to treat complications in severe cases of mixed poisoning where BZD is thought to be one of the major toxic agents; c) to avoid the need for mechanical ventilation in cases where there is respiratory depression. The routine use of flumazenil for the treatment of BZD overdosage is not recommended. 3.13.2 Dosage and route The intravenous route of administration is recommended when flumazenil is given as a BZD antagonist. Doses need to be adjusted according to individual clinical response and the following are recommended. a) In anaesthetics and in intensive care (adults), doses of 0.2-0.5 mg should be used to reduce sedation and doses of 0.5-1 mg to abolish BZD effects. b) In cases of BZD overdosage (adults), single doses of 0.3-1 mg can be given and repeated as necessary. The absence of clinical response to 2 mg flumazenil within 5-10 min indicates that BZD poisoning is not the major cause of coma and other complications. It is also possible to administer a continuous infusion (0.3 to 1 mg/h) of flumazenil (diluted in 0.9% sodium chloride solution or 5% glucose solution) following an initial response to flumazenil. c) In children, it is suggested that intravenous doses of 0.1 mg should be given once per minute until the child is awake. It may be necessary to give a subsequent continuous intravenous infusion at a rate of 0.1 to 0.2 mg/h. 3.13.3 Precautions/contraindications 220.127.116.11 Pharmaceutical precautions Solutions of flumazenil should be stored at +4 °C. No other drug should be injected or infused with the flumazenil, which should be made up in 0.9% sodium chloride or 5% glucose (dextrose) solution. 18.104.22.168 Other precautions Treatment with flumazenil requires continuous intensive observation. After the administration of a single dose of flumazenil, the patient must be observed for at least 2 h to be certain that BZD-induced complications will not recur. The termination of continuous infusion requires intensive care monitoring. Note that in cases of mixed drug overdosage, the patient may remain unresponsive where other drugs are contributing to the coma. BZD antagonism by flumazenil may in certain circumstances be harmful. a) An acute withdrawal syndrome can occur in patients showing BZD habituation following therapy or abuse. b) Convulsions can occur in cases of mixed drug overdosage where BZD has been taken with a drug liable to cause convulsions (such as a tricyclic antidepressive agent). c) Convulsions can be induced in patients treated with BZD for seizure disorders. The three above-mentioned situations may be considered relative contraindications to its use; flumazenil should only be used when it is strongly indicated. In these situations, it should be given more slowly than usual (e.g., 0.3 mg intravenously over 3 min, a 3-min pause, then a further 0.3 mg at the same rate, and so on).