Dangers and medico-legal aspects
of benzodiazepines
First published:
Journal of the Medical Defence Union 3, pp. 6-8
[IATROGENIC INJURIES]
Summer 1987
Professor C Heather Ashton DM, FRCP
School of Neurosciences
Division of Psychiatry
The Royal Victoria Infirmary
Queen Victoria Road
Newcastle upon Tyne NE1 4LP
The Ashton Manual · Professor Ashton's Main Page
The benzodiazepines appeared 30 years ago in the vanguard of the permissive society. Efficacious for all forms of insomnia and anxiety, muscle relaxant, anticonvulsant, safe, and apparently non-addictive, they rapidly became (and still are) the most commonly prescribed of all drugs in the western world. (1) In their hey-day, due to a blend of patient demand and medical compliance (perhaps complacency), they were sometimes given as premedication before visiting the dentist, taking a driving test, or, by university health services, for 'exam nerves'. They were the ideal replacement for barbiturates, whose prescription was later curbed (2), and they became, like cannabis, alcohol, and tobacco, a sociological as well as a pharmacological phenomenon (3).
Experience has confirmed the short-term efficacy and safety of benzodiazepines for administration. Long-term use, however, carries definite disadvantages and dangers (4, 5) many of which have medico-legal implications.
Over-sedation
Because of the slow elimination of many benzodiazepines, repeated dosage can result in cumulation, leading to excessive sedation. Impaired psychomotor performance, motor inco-ordination, ataxia, diplopia, muscle weakness, vertigo, poor memory and concentration, and mental confusion may occur (5) not only when the drugs are used as daytime anxiolytics, but also as 'hangover' effects from use as night-time hypnotics (6). These effects may increase the risk of accidents at home, at work, and when driving (7). Additive effects with alcohol (8) may contribute further to traffic accidents and doctors should warn patients of these risks. Benzodiazepines may also increase mortality in drug overdose: additive effects of large doses taken with other central depressants can aggravate or precipitate respiratory failure, especially in the elderly or patients with pulmonary disease, can add to hypotension, and occasionally can lead to fatal hypothermia or myxoedema. (8)
The elderly are particularly vulnerable to over-sedation from benzodiazepines (9) and in such patients even small doses may produce drowsiness, inco-ordination and ataxia (resulting in falls and fractures) and acute confusional states. (10) Patients who have tolerated a fixed dose of a benzodiazepine for many years may begin to show adverse effects with advancing age when drug metabolism becomes slower and the brain becomes more sensitive to depressant drugs.
There is a suggestion from one CAT scan study (11) that prolonged benzodiazepine treatment is associated with structural brain damage, but this possibility requires further investigation.
Affective reactions
Chronic benzodiazepine usage can cause both depression and 'emotional anaesthesia', an apathetic state with emotional dulling. (5) Benzodiazepines can also aggravate depression in patients with depressive disorders and provoke suicide. (10)
Occasionally benzodiazepines produce apparently paradoxical stimulant effects manifested as hyperactivity, aggression, and outbursts of rage and violence (12, 13) These effects have been attributed to disinhibition of behaviour normally suppressed by social restraints, fear, or anxiety, and are most likely to occur in aggressive or anxious individuals. (13, 14) They may be a contributory cause of wifebeating, baby-battering, and grandma-bashing, especially when combined with alcohol.
Disinhibition, combined with memory loss and confusion, may lead patients on low doses of benzodiazepines to commit a variety of antisocial acts, from shoplifting to sexual offences. Doctors may be called to give evidence when such acts lead to legal prosecution and patients claim diminished responsibility due to prescribed drugs.
Prolonged continuous treatment with benzodiazepines appears to be associated with a considerable morbidity. In a series of 50 patients on chronic medication for 1-22 years, (15) ten had taken drug overdoses requiring hospital admission, ten had developed incapacitating agoraphobia, nine underwent gastroenterological investigations for irritable bowel, and three had been investigated neurologically and had been told they had multiple sclerosis (not subsequently confirmed). In addition, 31 of the patients had received other psychotropic drugs (usually antidepressants) while on benzodiazepines. None of these symptoms were the original indication for starting on benzodiazepines, but developed during chronic use and largely disappeared when the drugs were stopped. The extent to which benzodiazepines may actually cause or aggravate psychological or psychosomatic problems is arguable, but the patients attributed their symptoms to drug use and many felt resentful towards their doctors for assuring them that the drugs were harmless and for continuing their prescriptions.
Pregnancy
Until recently the benzodiazepines were thought to be relatively free of teratogenic effects, (16) though there have been sporadic reports of cleft palate associated with diazepam. (17-19) A report from Sweden now suggests a possible specific benzodiazepine teratogenicity. (20) In prospective studies, seven cases of a characteristic dysmorphism, similar to but not identical with the foetal alcohol syndrome, occurred in the infants of 36 mothers who regularly took relatively large doses of benzodiazepines (oxazepam 75mg daily or diazepam 30-50mg daily) throughout pregnancy. Two of the infants died within two months of birth. The data do not allow a definite calculation of the risk of benzodiazepine teratogenicity, nor was alcohol abuse strictly excluded (although denied by the mothers), but the spectre of thalidomide and Debendox, and the accompanying litigation, is raised by these observations. Benzodiazepines taken in moderate doses in late pregnancy are well known to cause neonatal depression, and infants may also develop benzodiazepine withdrawal symptoms 2-3 weeks after birth. (21-23)
Abuse
Benzodiazepines are increasingly becoming drugs of abuse. Intravenous diazepam abuse for 'kicks' has been reported in the United Kingdom, (24) and some patients pleading iatrogenic dependence on prescribed benzodiazepines have been selling prescriptions obtained at psychiatric clinics (Charlton, personal communication). Surveys in Sweden, Iceland and the United States have shown significant numbers of prescription forgeries and mentions in theft and loss reports both for diazepam and oxazepam (diazepam being the preferred drug). (25) The abuse of benzodiazepines appears to depend on the availability of other drugs of abuse.
Dependence and withdrawal effects
There is now little doubt that regular use of benzodiazepines in prescribed doses can lead to drug dependence in patients who are not drug abusers. (1, 5, 26) Such patients come to rely on the drugs for psychological comfort and suffer withdrawal symptoms if the drug is stopped or dosage reduced. It is estimated that about one-third of patients taking benzodiazepines for six months become dependent, (26) and some do so after only a few weeks of treatment, (27) while mild withdrawal symptoms such as rebound insomnia can occur after taking some benzodiazepine hypnotics for only one week. (28) Possibly due to the development of tolerance, some patients experience withdrawal symptoms while continuing to take 'therapeutic' doses. (4, 15) Present estimates suggest that perhaps 500,000 people in the UK and 2-3,000,000 in the world are now dependent on benzodiazepines. (29-31)
The benzodiazepine withdrawal syndrome (1, 5, 26, 32) has similarities to the abstinence syndromes associated with alcohol, narcotics, and barbiturates. Abrupt or rapid withdrawal of benzodiazepines can result in major convulsions, which can be life-threatening. (1) This complication is mainly associated with withdrawal from large doses, and is less common than in barbiturate withdrawal, but doctors should be aware of the dangers of abrupt cessation in patients who have taken benzodiazepines for more than a few weeks. Other severe withdrawal effects, which can occur on withdrawal from moderate or even small doses, include acute psychotic reactions with hallucinations, delusions, paranoia and acute confusional states. (1) Major depressive disorders and even suicide may follow withdrawal after an interval, even in patients without previous psychiatric history. (15) More commonly, the symptoms of withdrawal are those of an anxiety state, with panic attacks, insomnia, tremor, hyperventilation, increased muscle tension, and cardiovascular symptoms. Perceptual distortions and depersonalisation are frequent and particularly distressing to patients who may fear they are going mad. There is evidence from placebo controlled studies that these symptoms are related to benzodiazepine withdrawal and do not represent merely the return of a pre-existing anxiety state. (26) The syndrome may be severe, worse than the condition for which benzodiazepines were originally prescribed, and may be prolonged for many months. (32) However, an unknown proportion of patients are apparently able to stop taking their drugs without difficulty.
A groundswell of litigation
In view of the considerable morbidity associated with prolonged benzodiazepine use and the sometimes severe and prolonged withdrawal syndrome, it is not surprising that many patients are now questioning the wisdom of their doctors in initiating benzodiazepine use without warning of the possible dangers, and in acquiescing to requests for repeat prescriptions over many years. Some patients feel themselves to be innocent victims of avoidable medical ignorance, complaining of the irretrievable loss of years of normal life while on benzodiazepines, and (rightly or wrongly) attributing job losses and break-up of marriage and family relationships to the drugs.
There may be some justification for these claims, but the wide publicity recently devoted to benzodiazepine dependence has probably caused some to use benzodiazepines as a scapegoat for problems which may not be drug-related. A groundswell of litigation concerning benzodiazepines is beginning to make itself felt as increasing numbers of patients apply for legal aid to take proceedings against drug companies marketing benzodiazepines and doctors prescribing them long-term.
Doctors who become involved in such claims may reasonably argue that the danger of benzodiazepine dependence and the adverse effects of long-term use were not widely recognised until the early 1980s (1, 5, 26, 30) (though some predicted them long before that). Furthermore, there is still no consensus of medical opinion on the incidence and severity of benzodiazepine dependence or withdrawal symptoms; some leading authorities claim that these are minor problems and that the long-term use of benzodiazepines for chronic anxiety may be appropriate. (33)
Nevertheless, the weight of evidence is such that doctors should now hesitate before instituting benzodiazepine use for more than a week or two in newly presenting patients. Benzodiazepines lose their efficacy as anxiolytics after 1-4 months of continuous treatment, (34) and for minor affective disorders they are no more effective than brief counselling. (35) Particular caution should be exercised in prescribing benzodiazepines for the elderly or in pregnancy, and patients should be warned about possible effects on car-driving and interactions with alcohol and other central depressants. When medical opinion is sought concerning legal offences, such as shoplifting or violence, each case must clearly be considered on its merits, but it should be remembered that benzodiazepines can cause memory impairment and aggressive outbursts in susceptible individuals.
Finally, the adverse effects described above are common to all benzodiazepines, not only those used as anxiolytics and hypnotics but also anticonvulsants such as clonazepam. (12) It is possible that lorazepam (36) and triazolam pose particular problems because of their greater potency and short half-lives compared with diazepam. Alprazolam has additional antidepressant activity (37), but it is potent, has a half-life similar to that of lorazepam and probably, like other benzodiazepines, induces dependence (38).
References
Petursson, H. and Lader, M.H. Benzodiazepine dependence. Brit J Addict. 1981; 76 133-145.
British Medical Journal. Barbiturates on the way out. Brit Med J 1975; 3 725-726.
Ed. J. Gabe and P. Williams. Tranquillisers - Social, Psychological and Clinical Perspectives. Tavistock Publications, London and New York, 1986.
Ashton. H. Adverse effects of prolonged benzodiazepine use. Adv. Drug Reaction Bull. 1986; 118: 440-443.
Lader, M.H. and Petursson. H. Benzodiazepine derivatives - side effects and dangers. Biol. Psychiatry 1981; 16: 1195-1121.
Betts, T.A. and Birtle, J. Effect of two hypnotic drugs on actual driving performance next morning. Brit Med J 1982; 285: 852.
Skegg. D.C.G., Richards, S.M. and Doll, R. Minor tranquillisers and road accidents. Brit Med J 1979; 2: 917-919.
Rogers, H.O., Spector, R.G. and Trounce, J.R. A Textbook of Clinical Pharmacology. Hodder and Stoughton, London, 1981.
Castleden, C.M., George, C.F., Marcer, D. and Hallett, C. Increased sensitivity to nitrazepam in old age. Brit Med J 1977; 1: 10-12.
Baldessarini, R.J. Drugs and the treatment of psychiatric disorders. In: Eds. Gilman, A.G., Goodman, L.S. and Gilman, A. The Pharmacological. Basis of Therapeutics. MacMillan Publishing Co. Ltd., New York, 1980: 391-447.
Lader, M.H., Ron, M. and Petursson, H. Computed axial brain tomography in long-term benzodiazepine users. Psychol Med 1984: 14: 203-206.
Rall, T.W. and Schleifer, S. Drugs effective in the therapy of the epilepsies. In: Eds. Gilman, A.G.. Goodman. L.S. and Gilman, A. The Pharmacological Basis of Therapeutics. MacMillan Publishing Co. Ltd., New York.1980; 592-607.
Hall, R.C.W. and Zisook, S. Paradoxical reactions to benzodiazepines. Brit J Clin Pharmac 1981; 11: 995-104S.
Speth, R.C.. Guidotti, A. and Yamamura, H. The pharmacology of the benzodiazepines. ln: Ed. C.G. Palmer. Neuropharmacology of Central Nervous System and Behavioural Disorders. Academic Press, New York. 1980: 243-283.
Ashton, H. Benzodiazepine withdrawal: outcome in 50 patients. Brit J Addict 1987; (at press).
Schardein, J.L. Drugs as Teratogens CRC Press, Cleveland, Ohio, 1976.
Saxen, I. and Saxen, L. Association between maternal intake of diazepam and oral clefts. Lancet 1975; ii: 489.
Safra, M.J. and Oakley, G.P. Association between cleft lip with or without cleft palate and prenatal exposure to diazepam. Lancet 1975; ii: 478-480.
Aarskog, D. Association between maternal intake of diazepam and oral clefts. Lancet 1975; ii: 921.
Laegreid, L., Olegard, R., Wahlstrom, J. and Conradi, N. Abnormalities in children exposed to benzodiazepines in utero. Lancet 1987; 1:108-109.
Speight, A.N.P. Floppy infant syndrome and maternal diazepam and/or nitrazepam. Lancet 1977; ii: 878.
Gillberg, C. 'Floppy infant syndrome' and maternal diazepam. Lancet 1977; ii: 244.
Rowlatt, R.J. Effect of maternal diazepam on the newborn. Brit Med J 1978; i: 985.
Strang. J. Intravenous benzodiazepine abuse. Brit Med J 1984; 289: 964.
Bergman, U. and Griffiths, R.R. Relative abuse of diazepam and oxazepam: prescription forgeries and theft/loss reports in Sweden. Drug and Alcohol Dependence 1986; 16: 293-301.
Owen, R.T. and Tyrer, P. Benzodiazepine dependence: a review of the evidence. Drugs 1983: 25: 385-398.
Murphy. S.M., Owen, R.T. and Tyrer, P.J. Withdrawal symptoms after six weeks' treatment with diazepam. Lancet 1984; ii: 1389.
Kales, A., Scharf, M.B. and Kales, J.D. Rebound insomnia: a new clinical syndrome. Science 1978; 201: 1039-1041.
National Tranquilliser Advisory Council. Annual Report 1985.
Hallström, C. and Lader, M.H. The incidence of benzodiazepine dependence in long-term users. Journal of Psychiatric Treatment and Evaluation. 1982; 4: 293-296.
Balter, M.B., Manheimer, D.I., Melinger, G.D. and Uhlenuth, E.H. A cross-national comparison of antianxiety/sedative drug use. Current Medical Research Opinion 1984; 8 (Suppl. 4): 5-20.
Ashton, H. Benzodiazepine withdrawal: an unfinished story. Brit Med J 1984; 288: 1135-1140.
Rickels, K. Are benzodiazepines overused and abused? Brit J Clin Pharmac 1981; 11 (Suppl. 1): 71S-83S.
Drug and Therapeutics Bulletin. The CRM on benzodiazepines. Drug Therap Bull 1980; 18: 97-98.
Catalan, J. and Gath, D.H. Benzodiazepines in general practice: time for decision. Brit Med J 1985; 1374-1376.
Tyrer, P., Owen, R. and Dawling, S. Gradual withdrawal of diazepam after long-term therapy. Lancet 1983; i: 1402-1406.
Feighner, J.P. Benzodiazepines as antidepressants. In: Ed. T.A. Ban, Modern Problems of Pharmacopsychiatry S. Karger, Basel, 1982: 196-212.
Smith, D.E. Benzodiazepine dependence potential: current studies and trends. J Substance Abuse Treatment 1984; 1: 163-167.
The Ashton Manual · Professor Ashton's Main Page
« back · top · www.benzo.org.uk »