Benzodiazepine overdose: are
specific antagonists useful?
Dr C Heather Ashton, DM, FRCP
University of Newcastle upon Tyne,
Newcastle upon Tyne NE2 4HH
First published in the British Medical Journal
16th March 1985, 290, 805-806
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[Key words: Benzodiazepine antagonists; Ro 15-1788; flumazenil; Romazicon ®; Anexate ®]
Benzodiazepines are remarkably non-toxic. Taken alone, even large doses rarely produce serious effects. Self poisoners commonly take mixtures of drugs, however, and benzodiazepines are included in 40% of drug overdoses in Britain.(1) Because of additive effects large doses of benzodiazepines taken with other depressants may aggravate or precipitate respiratory failure, especially in the elderly or patients with pulmonary disease; they may also add to hypotension and occasionally lead to fatal hypothermia in myxoedema.(2)
A patient suspected of having taken benzodiazepines with other drugs producing coma may present diagnostic difficulties. Furthermore, since most benzodiazepines or their metabolites are slowly eliminated, their use may considerably prolong the hospital stay of patients who have taken an overdose. Performance in skilled tasks (including car driving) may be impaired for weeks after apparent recovery from benzodiazepine overdose,(1) and withdrawal effects such as anxiety, insomnia, and rebound rapid eye movement sleep may be similarly prolonged.(3) All these factors increase the burden imposed on health services. Hence an antagonist which rapidly reverses benzodiazepine effects is an interesting prospect.
Many of the effects of benzodiazepines are thought to result from interaction with specific receptors forming part of the postsynaptic gamma-aminobutyric acid (GABA) receptor complex. Occupation of these sites by benzodiazepines enhances the inhibitory (hyperpolarising) effects of GABA, resulting in sedative, anxiolytic, muscular relaxant, and anticonvulsant actions.(4-6) Different subtypes, or states, of the GABA-benzodiazepine receptor may be concerned in the different effects.(7)
Endogenous benzodiazepine receptor ligands, which perhaps physiologically modulate anxiety, have to be discovered,(8) but several synthetic compounds are known to bind selectively to central high affinity benzodiazepine receptors.(9,10) Some are agonists: non-benzodiazepines such as Zopiclone and some triazopyridazines produce classical benzodiazepine like effects. Others, including some imidazodiazepines, pyrazoloquinolines, and ß carbolines, make up a range of panial agonists and competitive antagonists. These have some but not all of the benzodiazepine like actions, antagonise one or more benzodiazepine effects, or combine agonist and antagonist properties. Yet others are termed "inverse agonists": they bind to benzodiazepine receptors but produce opposite, anxiogenic, stimulant, and convulsant effects.(9) The range of activity exerted by this series of benzodiazepine ligands suggests that the physiological control of mood may be mediated by endogenous anxiogenic as well as (or instead of) anxiolytic substances and that the various actions of benzodiazepines may be separable.
Of the benzodiazepine agonist-antagonists, the most studied is Ro 15-1788, a synthetic imidazodiazepine which has little agonist activity and is even less toxic than benzodiazepines.(11) Ro 15-1788 is not yet generally available for clinical use. In animals it reverses the behavioural, biochemical, and electrophysiological effects of benzodiazepines, and it precipitates withdrawal signs in benzodiazepine dependent animals.(12) In man oral Ro 15-1788 (200 mg) antagonises the effects of diazepam on psychomotor performance without decreasing its bio-availability(13,14) and reverses the benzodiazepine effects on rapid eye movement sleep.(15) Given intravenously (10 mg) it immediately reverses the deep sedation induced by intravenous flunitrazepam (2 mg) and the impaired performance caused by intravenous midazolam.(16) Ro 15-1788 is almost devoid of intrinsic effects in oral doses of 600 mg,(13) though it may depress stage 4 sleep.(15) Electroencephalographic frequency analysis and evoked potentials both show a stimulant effect after intravenous Ro 15-1788 (5 mg); some people report mild anxiety and "pressure to move,"(17) suggesting slight inverse agonist activity.
A few clinical trials of Ro 15-1788 in benzodiazepine overdose have been reported. In one open study nine patients (aged 22-74) in deep coma due to benzodiazepines responded within one to two minutes to intravenous Ro 15-1788 (2.5-10 mg).(18) They opened their eyes and responded to pain; the electroencephalogram changed from a pattern of coma to one of waking; respiratory rate and blood pressure temporarily increased. The duration of benzodiazepine antagonists was three to five hours and repeated administration of Ro15-1788 was necessary to maintain the effects. Convulsions were precipitated in one epileptic patient who had been treated for status epilepticus with diazepam, phenobarbitone, and phenytoin. No other adverse effects were noted.
In two patients with coma due to diazepam overdosage for sedation being treated on a ventilator the coma was reversed by Ro 15-1788.(19) The authors comment that slowly eliminated benzodiazepines such as diazepam may often be responsible for delay in extubation. In a patient in coma due to liver disease and benzodiazepine overdose intravenous Ro 15-1788 facilitated diagnosis by removing the drug induced components.(18) The use of Ro 15-1788 for immediately reversing sedation induced by midazolam for minor operations has been described in 17 patients.(20)
These sparse clinical data make it difficult to draw conclusions about the therapeutic value of Ro 15-1788. It appears to be safe and effective in reversing benzodiazepine effects. Although active treatment is rarely required for straightforward benzodiazepine overdose, Ro 15-1788 may speed recovery, reduce after effects, and shorten hospital stay. In coma due to multiple drug overdose Ro 15-1788 may avoid the necessity for artificial ventilation by removing the benzodiazepine component of central depression and for the same reason facilitate diagnosis. Drawbacks include the precipitation of convulsions in epileptics and possibly in the presence of convulsant drugs such as tricyclic antidepressants (which are commonly taken with benzodiazepines in suicidal patients). Withdrawal symptoms may be precipitated in patients dependent on benzodiazepines - and many who take overdoses of these drugs are likely to fall into this category. The short elimination half life of Ro 15-1788 (one to two hours) is an inconvenience; patients need to be monitored and the drug given repeatedly, but slow release preparations may become available.
Another potential use of Ro 15-1788 is reversal of sedation for minor surgery with short acting benzodiazepines. It may also be of value in hypersomnolent states such as narcolepsy. The development of an array of benzodiazepine agonist-antagonists with selective benzodiazepine like or antibenzodiazepine actions may open a wider range of possibilities, including perhaps a use in benzodiazepine dependence and withdrawal.(21) At present, however, the greatest need is for more careful prescribing of benzodiazepines.
Dr C Heather Ashton
Senior Lecturer in Clinical Psychopharmacology,
University of Newcastle upon Tyne,
Newcastle upon Tyne NE2 4HH
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