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
3.5.1.1 Infrared spectroscopy
3.5.1.2 Ultraviolet absorption
3.5.1.3 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
3.8.2.1 Absorption
3.8.2.2 Distribution
3.8.2.3 Elimination
3.8.3. Toxicology
3.8.3.1 Acute toxicity
3.8.3.2 Subacute toxicity
3.8.3.3 Chronic toxicity
3.8.3.4 Embryotoxicity
3.8.3.5 Mutagenicity
3.9. Volunteer studies
3.9.1. Pharmacodynamics
3.9.1.1 BZD antagonist effect
3.9.1.2 Intrinsic effects
3.9.2. Pharmacokinetics
3.9.2.1 Absorption
3.9.2.2 Distribution
3.9.2.3 Elimination
3.9.3. Tolerance of flumazenil
3.9.4. Other studies
3.10. Clinical studies - clinical trials
3.10.1. Anaesthesiology
3.10.1.1 General anaesthesia
3.10.1.2 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
3.13.3.1 Pharmaceutical precautions
3.13.3.2 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
4.5.2.1 Spectrofluorimetry
4.5.2.2 High-performance liquid chromatography
4.6. Shelf life
4.7. General properties
4.8. Animal studies
4.8.1. Pharmacodynamics
4.8.1.1 Effect on skeletal muscle
4.8.1.2 Effects on other tissues
4.8.1.3 Studies in malignant hyperthermia-
susceptible pigs
4.8.2. Pharmacokinetics
4.8.3. Toxicology
4.8.3.1 Acute toxicity
4.8.3.2 Subacute toxicity
4.8.3.3 Chronic toxicity
4.8.3.4 Teratogenicity
4.9. Volunteer studies
4.9.1. Administration and plasma concentrations
4.9.2. Distribution
4.9.2.1 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
4.11.1.1 Prophylaxis of malignant hyperthermia
4.11.1.2 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
4.12.1.1 Treatment of malignant hyperthermia
4.12.1.2 Treatment of neuroleptic malignant
syndrome
4.12.1.3 Treatment of hyperthermia induced by
muscle rigidity in poisoning
4.12.2. Advised routes and doses
4.12.2.1 Treatment of severe drug-induced
hyperthermia, including malignant
hyperthermia
4.12.2.2 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
4.12.6.1 Hepatoxicity
4.12.6.2 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. Naloxone treatment does not appear to be a
contraindication to breast feeding, although the opiate poisoning
being treated may itself be a contraindication.
2.13.6 Storage
Naloxone for injection should be stored protected from light.
Its shelf-life is 3 years.
2.14 References
Aitkenhead AR, Derbyshire DR, Pinnock CA, Achola K, & Smith G (1984)
Pharmacokinetics of intravenous naloxone in healthy volunteers.
Anaesthesiology, 61: A381.
Asali LA (1983) Determination of naloxone in blood by high
performance liquid chromatography. J Chromatogr, 278: 329-335.
Asali LA & Brown KF (1984) Naloxone protein binding in adult and
fetal plasma. Eur J Clin Pharmacol, 27: 459-464.
Badawy AA-R, Evans M, Punjani NF, & Morgan CJ (1983) Does naloxone
always act as an opiate antagonist? Life Sci, 33(Suppl 1): 739-742.
Banner W, Lund ME, & Clawson L (1983) Failure of naloxone to reverse
clonidine toxic effect. Am J Dis Child, 137: 1170-1171.
Barraclough CJ & Lowe RA (1982) Failure of naloxone to reverse the
cardiotoxicity of Distalgesic overdose. Postgrad Med J, 58: 667-668.
Bell EF (1975) The use of naloxone in the treatment of diazepam
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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).
3.5.1.1 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.
3.5.1.2 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.
3.5.1.3 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
3.8.2.1 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.
3.8.2.2 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.
3.8.2.3 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
3.8.3.1 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
3.8.3.2 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.
3.8.3.3 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.
3.8.3.4 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.
3.8.3.5 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
3.9.1.1 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).
3.9.1.2 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
3.9.2.1 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).
3.9.2.2 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.
3.9.2.3 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
3.10.1.1 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).
3.10.1.2Conscious 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
3.13.3.1 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.
3.13.3.2 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).