BRITISH MEDICAL JOURNAL VOLUME 290 16 MARCH 1985 805 Br Med J (Clin Res Ed): first published as 10.1136/bmj.290.6471.805 on 16 March 1985. Downloaded from benzodiazepine dependent animals.'2 In man oral Ro 15- Benzodiazepine overdose: 1788 (200 mg) antagonises the effects of diazepam on are antagonists psychomotor performance without decreasing its bio- specific availability'3"' and reverses the benzodiazepine effects on useful? rapid eye movement sleep.'5 Given intravenously (10 mg) it immediately reverses the deep sedation induced by intravenous flunitrazepam (2 mg) and the impaired per- Benzodiazepines are remarkably non-toxic. Taken alone, formance caused by intravenous midazolam.'6 Ro 15-1788 is even large doses rarely produce serious effects. Self almost devoid of intrinsic effects in oral doses of 600 mg,'3 poisoners commonly take mixtures of drugs, however, and though it may depress stage 4 sleep.'5 Electroencephalo- benzodiazepines are included in 40% of drug overdoses in graphic frequency analysis and evoked potentials both show Britain.' Because of additive effects large doses of benzo- a stimulant effect after intravenous Ro 15-1788 (5 mg); diazepines taken with other depressants may aggravate or some people report mild anxiety and "pressure to move,"'7 precipitate respiratory failure, especially in the elderly or suggesting slight inverse agonist activity. patients with pulmonary disease; they may also add to A few clinical trials of Ro 15-1788 in benzodiazepine hypotension and occasionally lead to fatal hypothermia in overdose have been reported. In one open study nine myxoedema.2 patients (aged 22-74) in deep coma due to benzodiazepines A patient suspected of having taken benzodiazepines with responded within one to two minutes to intravenous Ro 15- other drugs producing coma may present diagnostic 1788 (2-5-10 mg).'8 They opened their eyes and responded difficulties. Furthermore, since most benzodiazepines or to pain; the electroencephalogram changed from a pattern of their metabolites are slowly eliminated, their use may coma to one of waking; respiratory rate and blood pressure considerably prolong the hospital stay of patients who have temporarily increased. The duration of benzodiazepine taken an overdose. Performance in skilled tasks (including antagonism was three to five hours and repeated administra- car driving) may be impaired for weeks after apparent tion of Ro 15-1788 was necessary to maintain the effects. recovery from benzodiazepine overdose,' and withdrawal Convulsions were precipitated in one epileptic patient who effects such as anxiety, insomnia, and rebound rapid eye had been treated for status epilepticus with diazepam, movement sleep may be similarly prolonged.3 All these phenobarbitone, and phenytoin. No other adverse effects factors increase the burden imposed on health services. were noted. Hence an antagonist which rapidly reverses benzodiazepine In two patients with coma due to diazepam overdosage effects is an interesting prospect. for sedation being treated on a ventilator the coma was Many of the effects of benzodiazepines are thought to reversed by Ro 15-1788."' The authors comment that slowly result from interaction with specific receptors forming part eliminated benzodiazepines such as diazepam may often be of the postsynaptic y-aminobutyric acid (GABA) receptor responsible for delay in extubation. In a patient in coma due complex. Occupation of these sites by benzodiazepines to liver disease and benzodiazepine overdose intravenous Ro enhances the inhibitory (hyperpolarising) effects of GABA, 15-1788 facilitated diagnosis by removing the drug induced resulting in sedative, anxiolytic, muscular relaxant, and component.'8 The use of Ro 15-1788 for immediately anticonvulsant actions.i6 Different subtypes, or states, of reversing sedation induced by midazolam for minor the GABA-benzodiazepine receptor may be concerned in operations has been described in 17 patients.20 the different effects. These sparse clinical data make it difficult to draw http://www.bmj.com/ Endogenous benzodiazepine receptor ligands, which conclusions about the therapeutic value of Ro 15-1788. It perhaps physiologically modulate anxiety, have to be appears to be safe and effective in reversing benzodiazepine discovered,8 but several synthetic compounds are known to effects. Although active treatment is rarely required for bind selectively to central high affinity benzodiazepine straightforward benzodiazepine overdose, Ro 15-1788 may receptors.90 Some are agonists: non-benzodiazepines such speed recovery, reduce after effects, and shorten hospital as zopiclone and some triazopyridazines produce classical stay. In coma due to multiple drug overdose Ro 15-1788 benzodiazepine like effects. Others, including some may avoid the necessity for artificial ventilation by removing on 30 September 2021 by guest. Protected copyright. imidazodiazepines, pyrazoloquinolines, and Pi carbolines, the benzodiazepine component of central depression-and make up a range of partial agonists and competitive for the same reason facilitate diagnosis. Drawbacks include antagonists. These have some but not all of the benzo- the precipitation of convulsions in epileptics and possibly in diazepine like actions, antagonise one or more benzodiaze- the presence of convulsant drugs such as tricyclic pine effects, or combine agonist and antagonist properties. antidepressants (which are commonly taken with benzo- Yet others are termed "inverse agonists": they bind to diazepines in suicidal patients). Withdrawal symptoms may benzodiazepine receptors but produce opposite, anxiogenic, be precipitated in patients dependent on benzodiazepines- stimulant, and convulsant effects.9 The range of activity and many who take overdoses of these drugs are likely to fall exerted by this series of benzodiazepine ligands suggests into this category. The short elimination half life of Ro 15- that the physiological control of mood may be mediated by 1788 (one to two hours) is an inconvenience; patients need endogenous anxiogenic as well as (or instead of) anxiolytic to be monitored and the drug given repeatedly, but slow substances and that the various actions of benzodiazepines release preparations may become available. may be separable. Another potential use of Ro 15-1788 is reversal Of the benzodiazepine agonist-antagonists, the most of sedation for minor surgery with short acting benzo- studied is Ro 15-1788, a synthetic imidazodiazepine which diazepines. It may also be of value in hypersomnolent states has little agonist activity and is even less toxic than such as narcolepsy. The development of an array of benzodiazepines." Ro 15-1788 is not yet generally available benzodiazepine agonist-antagonists with selective benzo- for clinical use. In animals it reverses the behavioural, diazepine like or antibenzodiazepine actions may open a biochemical, and electrophysiological effects of benzo- wider range of possibilities, including perhaps a use in diazepines, and it precipitates withdrawal signs in benzodiazepine dependence and withdrawal.2' At present, 806 BRITISH MEDICAL JOURNAL VOLUME 290 16 MARCH 1985 Br Med J (Clin Res Ed): first published as 10.1136/bmj.290.6471.805 on 16 March 1985. Downloaded from however, the greatest need is for more careful prescribing of the community and that transfer ofpatients from hospitals to benzodiazepines. hostels, sheltered housing, or care by their own families C HEATHER ASHTON would save money. Senior Lecturer in Clinical Psychopharmacology, The committee's comments on this belief are crucial to an University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH understanding of the failure of the policy. "Savings do not accrue," the report explains, "when a hospital transfers patients elsewhere.... If the more able patients leave staff I Proudfoot A. Diagnosis and management of acute poisoning. Oxford: Blackwell Scientific Publications, 1982. levels may have to rise to compensate for the unrecorded care 2 Rogers HO, Spector RG, Trounce JR. A textbook ofclinical pharmacology. London: Hodder and Stoughton, 198 1. service these former patients provided. .. . The scale of 3 Haider I, Oswald I. Late brain recovery processes after drug overdose. BrMed3r 1970;ii:318-22. reduction required is wards rather than individuals.... In 4 Sepinwall J, Cook L. Mechanism of action of the benzodiazepines: behavioral aspect. Fed Proc 1979;39:3024-31. simple terms until you have got the capital from selling all or S Braestrup C, Neilsen M. Benzodiazepine receptors. Arzneimittelforsch 1980;30:852-7. part ofa hospital site you do not have the capital for its whole 6 Toffano G, Leon A, Massotti M, Guidotti A, Costa E. GABA-modulin, a regulatory protein for GABA receptors. In: Pepeu G, Kuhar MJ, Enna SJ, eds. Receptors for neurotransmitters and or partial replacement in terms ofhostels or homes within the peptide hormones. New York: Raven Press, 1980:133-42. community." And the staff who used to work in the hospital 7 Squires RF. Benzodiazepine receptor multiplicity. Neuropharmacology 1983;22:1443-7. 8 Costa E, Corda MG, Guidotti A. On a brain polypeptide functioning as a putative effector for the should be redeployed within the community-again with no recognition sites of benzodiazepine and beta-carboline derivatives. Neuropharmacology 1983;22: 1481-92. financial saving. 9 Braestrup C, Nielsen M, Honore T, Jensen LH, Petersen EN. Benzodiazepine receptor ligands The results of closing hospitals ahead of the establishment with positive and negative efficacy. Neuropharmacology 1983;22:1451-7. 10 Pellow S, File SE. Multiple sites of action for anxiogenic drugs: behavioural, electrophysio- of equivalent community resources may be seen most clearly logical and biochemical correlations. Psychopharmacology 1984;83:304-15. in the United States and Italy, the two countries which have 11 Hunkeler W, Mohler H, Pieri L, et al. Selective antagonists of benzodiazepines. Nature 1981;290:514-6. moved furthest and fastest in the move towards community 12 Cumin R, Bonetti EP, Scherschlict R, Haefely WE. Use of the specific benzodiazepine care. There the homeless mentally ill have congregated in antagonist, Ro 15-1788, in studies of physiological dependence on benzodiazepines. Experientia 1982;38:833-4. large cities, sleeping in night shelters, destitute and 13 Darragh A, Lambe R, O'Boyle C, Kenny M, Brick I. Absence of central effects in man of the benzodiazepine antagonist Ro 15-1788. Psychopharmacology 1983;80:192-5. abandoned. As yet the scale of that problem is smaller in 14 Darragh A, Lambe R, Kenny M, Brick I, Taaffe W, O'Boyle C. Ro 15-1788 antagonises the Britain-but the committee found that "there are hundreds central effects of diazepam in man without altering diazepam bioavailability. Br J7 Clin Pharmacol 1982;14:677-82. if not thousands of mentally ill people living unsupported in 15 Gaillard JM, Blois R. Effect of the benzodiazepine antagonist Ro 15-1788 on flunitrazepam- the community .. . large numbers are sleeping rough in induced sleep changes. Brj Clin Pharmacol 1983;15:529-36. 16 Ziegler WH, Schalch E. Antagonism of benzodiazepine-induced sedation in man. In: Borbely A, archways and under railway bridges, some within hailing ed. Sixth European congress of sleep research abstracts. Zurich: Pharmakologisches Institut der distance of the Palace of Westminster." Universitat Zurich, 1982:128. 17 Schopf J, Laurian S, Gaillard Le J-M. Intrinsic activity of the benzodiazepine antagonist Ro 15- The BMJ gets little satisfaction from saying that "we told 1788 in man: an electrophysiological investigation. Pharmacopsychiatry 1984;17:79-83. 18 Scollo-Lavizzari G. First clinical investigation of the benzodiazepine antagonist Ro 15-1788 in you so"-but we have argued consistently and repeatedly comatose patients. Eur Neurol 1983;22:7-1 1. since 1966 that community care had to be shown to be more 19 Rapold HJ, Follath F, Scollo G, Ritz R. Diazepam: hazardous sedation of ventilated patients. Intensive Care Med 1983;9:218. than a politician's catch phrase.2 So too has the BMA. In 1973 20 Martinez-Aguirre E, Navarro T. Ro 15-1788, a highly specific benzodiazepine antagonist: we warned that it was difficult to believe that an existence preliminary clinical experience. In: Boulton TB, ed. Sixth European congress ofanaesthesiology abstracts. London: Academic Press, 1982:422. of aimless destitution is preferable to the organised and 21 Ashton H. Benzodiazepine withdrawal: an unfinished story. Br MedJ 1984;288:1135-40. structured life in a well run mental hosD)ital.3 To its credit, the Social Services Committee makes clear its conviction that there are many patients who still need asylum-in the best sense of that word. Of the 70000 resident patients in mental illness hospitals 48 000 are over http://www.bmj.com/ Community care the age of 65; and many such hospitals have hundreds of patients who have been there for more than 10 years. Many other patients living in the community are being cared for by For more than 20 years the agreed policy of successive their aging parents, but they may eventually need long stay governments has been that mentally ill and mentally handi- hospital care. Certainly there can be no justification for capped persons should, wherever possible, be cared for in the discharging more patients into communities neither willing community-rather than in the large hospitals described in nor equipped to accept responsibility for them. on 30 September 2021 by guest. Protected copyright. vivid terms by Mr Enoch Powell: "isolated, majestic, The message for the government from the all party imperious, brooded over by the gigantic water tower and committee is plain-and no doubt unwelcome. Mental chimney combined, rising unmistakably and daunting out of illness and handicap will not go away; nor can the care of the countryside-the asylums which our forefathers built patients with these disorders be privatised. Community care with such solidity." is the ideal solution for some (but not all) patients-but only The current results of that policy have now been assessed if adequate resources are provided-and that will cost more in a detailed report by the House ofCommons Social Services in the short term than keeping patients in long stay hospitals. Committee (with its majority of Conservative MPs).' While Doctors have an ethical obligation to speak out on this confirming the desirability of the policy the report has an issue and remind politicians that the care of its weakest unequivocal message for the government. Community care is members is the measure by which our society will be judged not-and never will be-a cheap solution. Indeed ifit is to be by future generations. effective investment will have to be made in buildings, staff, and back up facilities. 1 Social Services Commsittee. Second report. Community care with special reference to adult mentally ill and mentally handicapped people. London: HMSO, 1985. (Chairman Renee Short.) Politicians and policy makers have been seduced by the 2 Anonymous. Does the community care? [Editorial]. BrMedJ 1966;ii:655-6. belief that institutional care is more expensive than care in 3 Anonymous. Rootless wanderers [Editorial]. BrMed7 1973;iii: 1-2.