« back · www.benzo.org.uk »
ADVERSE EFFECTS OF PROLONGED
ADVERSE DRUG REACTION BULLETIN
JUNE 1986 · No 118
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
Benzodiazepines are safe and effective drugs for short-term administration. Their therapeutic uses as sedative/hypnotics, anxiolytics, anticonvulsants, muscle relaxants, and amnesic agents for minor surgery result from enhancement of the actions of the central neurotransmitter gamma-aminobutyric acid (GABA) by a specific receptor interaction.(1) When taken chronically, however, they not only lose much of their therapeutic efficacy but may also produce a large range of adverse effects. Symptoms appearing after long-term benzodiazepine use include (a) dose-related extensions of the initial pharmacological actions, and (b) withdrawal symptoms resulting from the development of tolerance and drug dependence. Perhaps because of uneven development of tolerance to different benzodiazepine actions, patients continuing to take therapeutic doses may exhibit both types of symptoms simultaneously. Withdrawal symptoms also commonly occur when dosage is reduced or medication stopped. Since benzodiazepines are the most commonly prescribed drugs in the western world,(2) and as there are probably over 3 million chronic users in this country,(3) these long-term effects are a matter of concern.
Because of the slow elimination of many of the benzodiazepines, cumulation may occur on repeated dosage and may lead to excessive sedation with impaired psychomotor performance, ataxia, dysarthria, motor inco-ordination, diplopia, muscle weakness, vertigo, poor memory and concentration, and mental confusion. When the drugs are used as hypnotics these effects may not be noticed, but many benzodiazepines give rise to subjective 'hangover' on the following day, and after most of them, even those with short elimination half-lives, psychomotor performance may still be impaired the next day.(4) Several authors(4,5) have drawn attention to the probable contribution of benzodiazepines to traffic accidents. Over-sedation from benzodiazepines is most marked in the elderly in whom drowsiness, inco-ordination and ataxia leading to falls and fractures, poor memory, and acute confusional states may result even from small doses.(6) The greater vulnerability of the elderly is partly due to decreased rates of metabolism, particularly of benzodiazepines that undergo hepatic oxidation,(7) and partly due to greater susceptibility to central nervous system depression.(8) In the presence of organic brain disease, benzodiazepines can cause tremulousness, crying, poor concentration, nocturnal confusion, and agitation.(9)
Benzodiazepines potentiate the actions of other central depressant drugs. The effects are mainly additive, although some authors suggest that synergistic effects may occur, especially with alcohol(10-13) – a further contributor to traffic accidents.
Chronic benzodiazepine usage can cause both depression and 'emotional anaesthesia', an apathetic state with dulling of all emotions.(9) In patients with depressive illness, benzodiazepines can aggravate the depression and provoke suicide.(6) On the other hand, some individuals experience euphoria, and benzodiazepines have abuse liability when used intravenously.(14,15)
Occasionally, benzodiazepines produce apparently paradoxical stimulant effects. Clonazepam, given as an anticonvulsant, can provoke aggressive and hyperactive behaviour and exacerbation of seizures.(16) Patients on low chronic doses of benzodiazepines sometimes commit uncharacteristic antisocial acts such as shoplifting or sexual offences, while higher doses may produce outbursts of rage and violent behaviour, especially in anxious patients.(9) Chronic benzodiazepine use has been suggested to be a contributory cause of 'baby-battering' and 'grandma-bashing': these paradoxical effects have been attributed to disinhibition of behaviour previously suppressed by social restraints, fear, or anxiety, and are most likely to occur in aggressive or anxious individuals.(11)
Some anxious patients treated with benzodiazepines report an increase in anxiety, insomnia, hypnogogic hallucinations on sleep induction, nightmares, and irritability.(6) Triazolam, used regularly in high doses (0.5-1mg), can produce a syndrome of severe anxiety, paranoia, hyperacusis, altered smell and taste, and paraesthesiae;(17) this syndrome can also occur with smaller doses (0.25mg) taken nightly.
Benzodiazepines may affect the central control of endocrine function by an action on the hypothalamus or anterior pituitary.(18) Temazepam and oxazepam have been shown to increase plasma cortisol and prolactin concentrations,(19) and diazepam to raise growth hormone secretion(20) in normal subjects. Endocrine symptoms occurring in long-term benzodiazepine users include menstrual irregularities, pre-menstrual tension, breast engorgement, gynaecomastia, and galactorrhoea,(21) but the mechanisms are not understood.
Possible neurotoxic effects
Some long-term benzodiazepine users have been noted in preliminary study to have abnormal CAT scans.(22) A group of 20 patients who had taken benzodiazepines for 2-20 years had significantly higher ventricle/brain ratios than controls, though lower ratios than alcoholics. There was no relation between CAT scan appearances and duration of drug use, and some of the patients had abstained for 3 months. However, the possibility that prolonged benzodiazepine treatment is associated with structural brain damage requires further investigation.
Adverse effects in pregnancy
Adverse effects on the foetus and neonate of maternally administered benzodiazepines have been reviewed previously.(23) The drugs readily cross the placenta and reach high concentrations in foetal tissues since metabolism in the foetal liver is minimal. If taken regularly in normal hypnotic doses during late pregnancy, they can cause neonatal depression. Infants chronically exposed in utero may develop benzodiazepine withdrawal symptoms 2-3 weeks after birth. The drugs also appear in breast milk.
Early experience with benzodiazepines suggested that drug dependence was rare.(24) It has since become clear, however, that dependence occurs readily and quickly in some patients and is not uncommon. Such patients develop a reliance on the drug to maintain psychological comfort, and experience withdrawal symptoms if the drug is stopped or the dosage reduced. It has been estimated that about one-third of patients taking benzodiazepines for 6 months become dependent,(25) and some do so after a few weeks of treatment,(26) while withdrawal symptoms in the form of rebound insomnia can occur after administration of low doses of triazolam or flurazepam for only a week.(27) Some patients gradually increase their dosage, but others become dependent while maintaining their original therapeutic dosage.(25) Present estimates suggest that perhaps half a million people in the United Kingdom and 2-3 million in the world are now dependent on benzodiazepines.(25,28) It is not possible to predict which patients are likely to become dependent, although a history of dependence on other drugs,(24) and 'passive dependent'(25) or neurotic(21) personality types appear to be partially predictive. Previous psychiatric history is not necessarily related to the development of dependence.(21)
The benzodiazepine withdrawal syndrome has been described by many authors.(2,9,21,25) The syndrome can be of considerable severity and has similarities to abstinence syndromes associated with alcohol, opiates, and barbiturates. The symptoms may develop insidiously while the patient continues to take therapeutic doses or may occur on dosage reduction or drug withdrawal. In the latter case, the onset of the syndrome is related to the pharmacokinetic properties of the benzodiazepine involved, appearing sooner with rapidly eliminated drugs. The time course is often characterised by the early appearance of acute anxiety and psychotic symptoms (1-2 weeks after withdrawal),(26) followed by a prolonged period (many months)(21) of gradually diminishing mixed psychological and somatic symptoms.
Symptoms described during benzodiazepine withdrawal are very numerous, and most patients experience many of them.(21) Psychological symptoms are predominantly those of acute anxiety, with insomnia, hyperactivity and panic attacks. Agoraphobia, other phobias, and depression are common during withdrawal, disappearing as the syndrome subsides. Perceptual distortions (sometimes hallucinations) and feelings of depersonalisation and unreality are characteristic. Acute psychotic episodes occur occasionally, but obsessions, intrusive thoughts and memories, and paranoid feelings are not uncommon. Irritability, rage, and aggression are also frequent and it is possible that some of the apparently paradoxical stimulant effects of chronic benzodiazepine use are, in fact, withdrawal symptoms.
Neurological symptoms include episodes of paraesthesiae and numbness, tremor, muscle pains, stiffness, weakness and fasciculation, ataxia, and blurred or double vision – a symptom cluster which occasionally leads to the mistaken diagnosis of multiple sclerosis. Hypersensitivity especially to sound but also to light, taste, and smell; headache; and tinnitus are common; and formication and itching are not infrequent. Major convulsions or temporal lobe seizures sometimes occur on abrupt withdrawal.
Gastrointestinal symptoms are very common and include nausea, vomiting, constipation, diarrhoea, abdominal pain, gaseous distension, and dysphagia. Many patients on long-term benzodiazepines have undergone extensive gastrointestinal investigations for 'irritable bowel syndrome'. However, the symptoms usually subside some months after withdrawal.
Cardiovascular symptoms (palpitations, flushing, chest pain), hyperventilation, urinary symptoms (frequency, urgency, incontinence), and loss of libido are similar to those seen in anxiety states. An influenza-like syndrome with prostration and increased upper respiratory tract secretion may occur and resembles that seen after narcotic withdrawal, although it is more protracted.
Although many of the withdrawal symptoms are similar to those seen in spontaneously occurring anxiety states, the benzodiazepine withdrawal syndrome is unlikely to represent a recurrence of an original anxiety state.(25) Many of the symptoms are qualitatively different from those present before benzodiazepines were prescribed; the same range of symptoms are experienced by normal subjects prescribed benzodiazepines experimentally or for reasons unrelated to anxiety; the symptoms reach a peak after withdrawal and then subside gradually; and the syndrome is similar to other well recognised abstinence syndromes.
The exact mechanism of the benzodiazepine withdrawal syndrome is not clear. It seems likely that many of the symptoms result from underactivity of GABA-ergic systems in the brain (particularly in the limbic system), due to the development of drug tolerance. Tolerance appears to occur unevenly to different benzodiazepine effects; it occurs rapidly to the hypnotic(20,27) and anticonvulsant(11,16) effects, but more slowly to the anxiolytic effects.(11)
However, it has been claimed that benzodiazepines are no longer effective in the treatment of anxiety after 1-4 months of continuous treatment(29,30) and in minor affective disorders presenting to general practitioners, chronic benzodiazepine therapy was found to be no more affective than brief counselling.(31) There is some evidence that tolerance is due to down-regulation of GABA receptors: decreased GABA receptor density, diminished response to GABA agonists, and decreased density of benzodiazepine binding sites have been observed in animals after chronic benzodiazepine treatment.(32,33) Such down-regulation would expose the body, on benzodiazepine withdrawal, to a decrease in the usual inhibitory effects of GABA, with a consequent inappropriate surge in the output of excitatory transmitters normally controlled by GABA,(21) and perhaps a decrease in endogenous opioid activity.(34,35)
Since dependence takes time to develop, it is best prevented by limiting the duration of benzodiazepine use. Severe withdrawal effects are uncommon if the drugs have been used for less than two weeks,(25) and it would seem advisable to restrict regular benzodiazepine administration to periods of 7-14 days. The optimal method of withdrawing benzodiazepines in patients who have become dependent has not yet been determined. Various methods of slow dosage reduction combined with symptomatic treatment are described,(21,28) but even with these methods the syndrome may be protracted and the illness more severe than that for which the benzodiazepines were originally prescribed.(21)
Braestrup C, Nielson M, Honore T, Jensen LH, Petersen EN. benzodiazepine receptor Ligands with positive and negative efficacy, Neuropharmacol 1983;22:1451-8.
Petursson H, Lader MH. benzodiazepine dependence. Br J Addict 1981;76: 133-45.
National Tranquilliser Advisory Council. Annual Report 1985.
Beets TA, Birtle J. Effect of two hypnotic drugs on actual driving performance next morning. Br Med J 1982; 285:852.
Skegg DCG, Richards SM, Doll R. Minor tranquillisers and road accidents. Br Med J 1979; 1: 917-19.
Baldessarini RJ. Drugs and the treatment of psychiatric disorders in: Gilman AG, Goodman LS, Gilman A, eds. The pharmacological basis of therapeutics. New York: MacMillan Publishing Co Ltd, 1980; 391-447.
Cook P. How drug activity is altered in the elderly. Geriat Med 1979; &: 45-6.
Castleden CM, George CF, Marcer D, Hallett C. Increased sensitivity to nitrazepam in old age. Br Med J 1977; 1:10-12.
Lader MH, Petursson H. Benzodiazepine derivatives – side-effects and dangers. Biol Psychiatry 1981; 16:1195-21.
Ticku MK. Benzodiazepine – GABA receptor – ionophoric complex: current concepts. Neuropharmacol 1983; 22: 1459-70.
Speth RC, Giudotti A, Yamamura H. The pharmacology of the benzodiazepines. In: Palmer CG, ed. Neuropharmacology of central nervous system and behavioural disorders. New York:Academic Press, 1980; 243-83.
Paul GH, Whitehouse LW. Metabolic basis for the supra-additive effect of the ethanol-diazepam combination in mice. Br J Pharmacol 1977; 60:83-90.
Hockings N, Ballinger BR. Hypnotics and anxiolytics. Br Med J 1983:286:1949-51.
Strang J. Intravenous benzodiazepine abuse. Br Med J 1984; 289:964.
Griffiths RR, McLeod DR, Bigelow GE, Liebson, Roache JD. Relative abuse liability of diazepam and oxazepam: behavioural and subjective dose effects. Psychopharmacology 1984; 84:141-54.
Rall TW, Schleifer S. Drugs effective in the therapy of the epilepsies. In: Gilman AG, Goodman LS, Gilman A, eds. The pharmacological basis of therapeutics. New York: MacMillan Publishing Co Ltd, 1980; 592-607.
Drug and Therapeutics Bulletin. Triazolam (Halcion): psychological disturbances. Drug Ther Bull 1979; 17:76.
Grandison L. Actions of benzodiazepines in the neuroendocrine system. Neuropharmacol 1983; 22: 1505-10.
Beary MD, Lacey JH, Bhat AV. The neuroendocrine impact of 3-hydroxy-diazepam (temazepam) in women. Psychopharmacology 1983; 79: 295-7.
Petursson H, Shar E, Checkley S, Slade A, Lader MH. A neuroendocrine approach to benzodiazepine tolerance and dependence. Br J Clin Pharmacol 1981; 11: 526-8.
Ashton H. Benzodiazepine withdrawal: an unfinished story. Br Med J 1984; 288: 1135-40.
Lader MH, Ron M, Petursson H. Computed axial brain tomography in long-term benzodiazepine users. Psychol Med 1984; 14: 203-6.
Ashton H. Disorders of the foetus and infant. In: Davies DM, ed. Textbook of adverse drug reactions. 3rd ed. Oxford: Oxford University Press, 1985; 77-127.
Marks J. The benzodiazepines: use, overuse, misuse, abuse. Lancaster: MTP Press, 1978.
Owen RT, Tyrer P. Benzodiazepine dependence: a review of the evidence. Drugs 1983; 25: 385-98.
Murphy SM, Owen RT, Tyrer PJ. Withdrawal symptoms after six weeks' treatment with diazepam. Lancet 1984; ii: 1389.
Kales A, Scharf MB, Kales JD. Rebound insomnia: a new clinical syndrome. Science 1978; 201: 1039-41.
Salkind M. Topics in drug therapy, Module 2. Milton Keynes: Open University Press, 1982.
Drug and Therapeutics Bulletin. The CRM on benzodiazepines. Drug Ther Bull 1980; 18: 97-8.
Burrows GD, Davies B. Recognition and management of anxiety. In: Burrows GD, Norman TR, Davies B. Antianxiety agents. Amsterdam: Elsevier Science Publishers BV, 1984; 1-11.
Catalan J. Gath DH. Benzodiazepines in general practice: time for decision. Br Med J 1985; 198: 1374-6.
Cowen PJ, Nutt DJ. Abstinence symptoms after withdrawal from tranquillising drugs; is there a common neurochemical mechanism? Lancet 1982; ii: 360-2.
Crawley JN. Marangos PJ, Stivers J, Goodwin FK. Chronic clonazepam administration induces benzodiazepine receptor subsensitivity. Neuropharmacol 1982; 21: 85-9.
Millan MJ, Duka TH. Anxiolytic properties of opiates and endogenous opioid peptides and their relationship to the actions of benzodiazepines. Mod Probl Pharmacopsychiat 1981; 17: 123-41.
Cooper SJ. Benzodiazepine-opiate antagonist interactions in relation to anxiety and appetite. Trends Pharmacol Sci 1983; 4: 456-8.
The Ashton Manual · Professor Ashton's Main Page« back · top · www.benzo.org.uk »