Toxicity and Adverse Consequences
of Benzodiazepine Use
Professor C Heather Ashton, DM, FRCP
First published in:
Psychiatric Annals Volume 25: pp158-165
March 1995
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
In short-term, occasional, or intermittent use, benzodiazepines are remarkably useful drugs. Efficacious in a wide range of conditions (Table 1), they are singularly free from serious toxic effects. Adverse consequences of such use are usually dose related and predictable. More serious adverse effects can result from long-term regular use in therapeutic dosage and from self prescription or recreational use in excessive doses.
Adverse consequences can be minimised by rational prescribing, which requires consideration of a number of factors, including (1) the wide variation in potency and rates of elimination between different benzodiazepines (Table 2); (2) the risks of dependence associated with long-term use; and (3) careful selection of patients, taking into account those at special risk of toxicity (Table 3).
ADVERSE EFFECTS OF BENZODIAZEPINES
Toxicity in Overdose
The acute toxicity of benzodiazepines is extremely low; even large overdoses taken alone rarely cause death, although risks are increased in the presence of obstructive pulmonary disease. However, benzodiazepines, usually in combination with other drugs, are involved in 30% to 40% of self poisoning incidents. Under these circumstances. additive effects of benzodiazepines with other CNS depressants can aggravate or precipitate respiratory failure, particularly in the elderly and those with respiratory disease. Similarly, hypotensive effects of benzodiazepines may augment adverse cardiovascular effects of cardiodepressant drugs. Reversal of benzodiazepine effects with the antagonist flumazenil is now possible, although caution is needed in benzodiazepine-dependent patients because flumazenil can precipitate acute withdrawal reactions, including convulsions.
Oversedation
Oversedation is a dose-related extension of the sedative-hypnotic effects of benzodiazepines. Symptoms include drowsiness, poor concentration and vigilance, ataxia, dysarthria, motor inco-ordination, diplopia, muscle weakness, vertigo, and mental confusion. When benzodiazepines are taken at night as hypnotics, sedation may persist the next day as "hangover" effects, particularly with slowly eliminated preparations (Table 2). However, tolerance to the sedative effects usually develops over 1 or 2 weeks, and anxious patients taking benzodiazepines as daytime anxiolytics rarely complain of sleepiness, although psychomotor performance, including fine judgment and memory functions, may still be impaired (see below).
Oversedation persists longer and is more marked in the elderly, partly due to decreased rates of metabolism and partly due to greater susceptibility to CNS depression. In these patients, benzodiazepines contribute to falls and fractures, and acute confusional states may result even from small doses. Oversedation from benzodiazepines contributes to accidents at home and at work, and studies from many countries have shown a highly significant association between the use of benzodiazepines and the risk of serious traffic accidents. Patients prescribed benzodiazepines should be warned of the risks of driving and of operating machinery when taking these drugs.
Drug Interactions
Benzodiazepines have additive effects with other CNS depressants, including other hypnotics, sedative antidepressants, neuroleptics, anticonvulsants, sedative antihistamines, and alcohol. The combined disinhibitory effects of alcohol and benzodiazepines (see below) may also be additive and contribute to aggressive behaviour. Patients prescribed benzodiazepines should be warned of these interactions.
Impairment of Memory
Benzodiazepines have long been known to induce anterograde amnesia. This action is utilised when the drugs are administered as premedication before major surgery and for minor surgical procedures. Loss of memory for unpleasant events is here a welcome therapeutic effect. For this purpose, fairly large single doses are employed and the drugs are often given intravenously (e.g., midazolam).
Oral doses of benzodiazepines, in the range used for hypnotic and anxiolytic effects, can also cause memory impairment. Acquisition of new information is deficient, an effect that may be partly due to the sedative actions. However, some specific amnesic effects appear to be separate from sedation.[1] Episodic memory (the remembering of recent events, the circumstances in which they occurred, and their sequence in time) is particularly impaired. By contrast, semantic memory (memory for words) and immediate memory (ability to recall a series of digits over a few seconds) are unaffected, as is retrieval of memory from long-term stores. These effects have been demonstrated in normal subjects, anxious patients, and chronic long-term benzodiazepine users. The effects of benzodiazepines on memory are more marked in heavy alcohol drinkers,[2] and the memory impairment is similar to that seen in alcoholic Korsakoff's syndrome. Specific defects in visuospatial ability and sustained attention have also been described in patients who had taken therapeutic doses of benzodiazepines regularly for at least a year.[3]
The impairment of event memory by benzodiazepines may lead to memory lapses (transient global amnesia) many hours after the drug has been taken. Several instances of such lapses have been reported after triazolam, taken as a hypnotic in doses of 0.125 mg to 0.5 mg.[4] During these "blackouts," patients performed complex daily activities, behaved normally, and yet had no recollection of events for periods of time up to 11 hours - much longer than the half life of triazolam (2 to 3 hours). Similar memory lapses have occurred with other benzodiazepines, and have led to patients being charged with shoplifting. Rarely, other antisocial acts, including homicide, seem to have occurred during an amnesic episode. Memory lapses can occur both in patients unaccustomed to taking benzodiazepines and in chronic users.
The elderly appear to be particularly vulnerable to the amnesic effects of benzodiazepines, and Lader[5] cautions that "forgetfulness, amnesic episodes, or confusion should not be ascribed facilely to 'old age' or 'dementia'" in older patients taking benzodiazepines.
Benzodiazepines are often prescribed for acute stress-related anxieties and, at the time, may afford relief from the distress of catastrophic events such as accidents and bereavement. However, some authorities warn against prescribing benzodiazepines in these circumstances "as the amnesic property of these compounds may not allow patients to make an optimum response to the situation... In cases of loss or bereavement, the psychological adjustment to this trauma may be severely inhibited..."[6] In other anxiety states, including panic disorder and agoraphobia, benzodiazepines may inhibit the learning of alternative stress-coping strategies, including behavioural treatment.
Paradoxical Stimulant Effects
Benzodiazepines occasionally cause paradoxical excitement with increased anxiety, insomnia, nightmares, hypnogogic hallucinations at sleep onset, irritability, hyperactive or aggressive behaviour, and exacerbation of seizures in epileptics. Increased aggression, hostility, and impulsivity occur in some subjects and may result in attacks of rage and violent behaviour. Such effects are most likely to occur within the first few days of benzodiazepine administration or soon after an increase in dosage, and have also been noted after intravenous administration. The incidence of this reaction, which appears to be rare, is not known, as the evidence consists mostly of single case reports. Nevertheless, antisocial acts, including sexual offences and acts of violence (both homicide and suicide), have been attributed to benzodiazepines and have led to medicolegal complications. [7]
Less dramatic increases in irritability and argumentativeness are much more common and often remarked on both by patients on long-term benzodiazepines and by their families.[8.9] Such reactions appear to be most frequent in anxious and aggressive individuals, in children. and in the elderly, and may be due to disinhibition of behavioural tendencies[9] normally suppressed by social restraints, and also to impaired benzodiazepine metabolism at the extremes of age.
Triazolam, especially in high doses (0.5 mg to 1 mg), can produce a syndrome of severe anxiety, paranoia, hyperacusis. altered smell and taste, and paraesthesiae.[10] Increased daytime anxiety commonly occurs with this drug when used regularly as a hypnotic.[11] These symptoms may largely represent withdrawal effects occurring between doses of this rapidly eliminated drug. Similar symptoms, although usually less marked, also occur as part of the withdrawal syndrome from other benzodiazepines.
Depression, Emotional Blunting
Long-term benzodiazepine users, like alcoholics and barbiturate-dependent patients, are often depressed, and the depression may first appear during prolonged benzodiazepine use.[12] It is possible that benzodiazepines cause or aggravate depression, perhaps by reducing central monoamine activity.[13] However, anxiety and depression often coexist, and benzodiazepines are often prescribed for mixed anxiety/depression. Sometimes, the drugs seem to precipitate suicidal tendencies in such patients.[6,14] It has been suggested that this effect is due to disinhibition of aggressive tendencies (paradoxical stimulation), which are then turned toward the self.[14] For this reason, the Committee on Safety of Medicines[14] recommends that "benzodiazepines should not be used alone to treat depression or anxiety associated with depression. Suicide may be precipitated in such patients."
"Emotional anaesthesia," the inability to feel pleasure or pain, is a common complaint of long-term benzodiazepine users. Such emotional blunting has similarities to the anhedonia seen in anergic depression and is probably related to the inhibitory effect of benzodiazepines on activity in emotional centres in the limbic system. Former long-term benzodiazepine users often bitterly regret their lack of emotional response to family events during the period that they were taking the drugs.
Adverse Effects in Pregnancy
Benzodiazepines cross the placenta, and if taken regularly by the mother in late pregnancy, even in therapeutic doses, can cause neonatal complications. The foetus and neonate metabolise benzodiazepines slowly, and appreciable concentrations may persist in the infant up to 2 weeks after birth, resulting in the "floppy infant syndrome" of hypotonia, CNS depression, and failure to suck. Infants regularly exposed to benzodiazepines in utero may also develop delayed withdrawal symptoms with hyperreflexia, irritability, crying, and feeding difficulties. Benzodiazepines are also secreted in breast milk.
Benzodiazepines in therapeutic doses appear to carry very little, if any, teratogenic risk. However, some reports suggest that chronic maternal use in therapeutic doses may impair intrauterine growth and increase the incidence of perinatal complications.[15] High-dose benzodiazepine abusers who also take other drugs and alcohol are at increased risk of teratogenesis and other complications.[16]
Tolerance
Tolerance can develop to all the actions of benzodiazepines, although at variable rates and to different degrees. Tolerance to hypnotic effects develops rapidly: sleep latency, Stage 2 sleep, slow wave sleep, dreaming, and intrasleep awakenings all tend to return to pretreatment levels after a few weeks of regular hypnotic use,[17] and daytime anxiolytic users no longer feel sleepy after a few days. Unusually large doses of intravenous benzodiazepines are sometimes required to obtain adequate preoperative sedation in chronic benzodiazepine users. Tolerance to anticonvulsant effects makes benzodiazepines generally unsuitable for long-term control of epilepsy.
Tolerance to anxiolytic effects seems to develop more slowly, but there is little evidence that benzodiazepines retain their effectiveness after 4 months of regular treatment[14,18.19] and clinical observations suggest that long-term benzodiazepine use over the years does little to control, and may even aggravate, anxiety states.[12] Tolerance may not be complete and chronic users may report continued efficacy, which may be partly due to the suppression of withdrawal effects. On the other hand, high-dose users and recreational abusers develop remarkable degrees of tolerance and may continue to carry out normal activities while taking 500mg to 1000mg diazepam or equivalent daily, although still complaining of anxiety and insomnia. Complete tolerance to the amnesic effects does not seem to occur and memory remains impaired in long-term users (see above).[20]
Dependence
Benzodiazepines are potentially addictive drugs. They can provide positive reinforcement in some individuals[4] and negative reinforcement in many. They can give rise to both psychological and pharmacological dependence, and dependent individuals show varying degrees of drug-seeking behaviour, develop tolerance, and suffer withdrawal effects on drug cessation or dosage reduction. Dependence can develop within a few weeks or months of regular use, and chronic users are at increased risk of all of the adverse effects of benzodiazepines mentioned above.
Therapeutic Dose Dependence
Prevalence of benzodiazepine use remains enormous worldwide. In the US, 10.9% of a large population surveyed in 1990 reported some benzodiazepine use the previous year. About 2% of the adult population of the US (4 million people) and of the UK (1 million people) appear to have used prescribed benzodiazepine hypnotics or tranquillisers regularly for 12 months or more, almost 50% of these for 5 to 10 years or more.[4] A high proportion of these users must be assumed to be, at least to some degree, dependent on benzodiazepines.
These patients use the drugs initially for their anxiolytic or hypnotic properties and later to prevent perceived or anticipated withdrawal effects. Drug-seeking behaviour is shown by regular visits to doctors to obtain repeat prescriptions, often for years after the original indication for the drug has disappeared.[12,21] There is a slight tendency to escalate dosage over the years, but prescriptions usually remain within therapeutically recommended limits. Psychological dependence is evident: patients become anxious if the next prescription is not readily available; they often carry their tablets around with them and not uncommonly take an extra dose before an anticipated stressful event or a night in a strange bed. Many of these patients are reluctant to stop their drugs because of anticipated or previously experienced withdrawal effects, and 50% to 100% of eligible patients declined to participate in various reported withdrawal studies.[4]
Among this population of chronic benzodiazepine users, females outnumber males by 2:1. Prevalence of anxiolytic use increases with age up to 50 to 65 years, while hypnotic use is maximal at 65 years of age and over. Such use may reflect the higher prevalence of anxiety disorders in younger age groups and of insomnia in the elderly, but it should be noted that the pharmacological actions, dependence potential, incidence and type of withdrawal symptoms are similar for all benzodiazepines whether marketed as hypnotics or anxiolytics (Table 2). Prevalence of physical and psychological ill health and scores for trait and state anxiety are significantly higher among chronic benzodiazepine users than in the general population.[22] The extent to which ill health is the cause or result of long-term benzodiazepine prescriptions is arguable.[12,21] Such patients do not use illicit drugs and only a minority overindulge in alcohol.
Prescribed High-Dose Dependence
A minority of patients who start on prescribed benzodiazepines begin to "require" larger and larger doses. (This statement is based on the author's clinical experience with approximately 20 of 200 patients [unpublished observations].) At first, they may persuade their doctors to escalate the size of prescriptions, but on reaching the prescriber's limits, may visit several doctors or hospital emergency departments with ingeniously concocted stories designed to obtain further supplies, which they self prescribe. Sometimes, although not always, this group combines benzodiazepine misuse with excessive alcohol consumption. Patients in this group tend to be highly anxious, depressed, and may have "passive dependent" or other personality difficulties. They may have a history of other sedative or alcohol misuse, but do not typically use illicit drugs.
Recreational Benzodiazepine Abuse
Recreational abuse of benzodiazepines is a growing problem. Although benzodiazepines are at present rarely used as primary recreational drugs,[4] a large proportion (30% to 90%) of polydrug abusers worldwide also abuse benzodiazepines, and polydrug abuse has become the norm among illicit drug abusers. Benzodiazepines are used in this context to increase the euphoriant effects of illicit drugs particularly opiates, and to alleviate the abstinence syndromes of other drugs of abuse (opiates, barbiturates, cocaine, amphetamines).[23] In addition, some subjects use high doses of benzodiazepines as euphoriants in their own right.[23]
For oral use, drugs such as diazepam, which penetrate the brain rapidly, are used in preference to oxazepam, which enters the brain more slowly. Doses 10 or more times greater than therapeutically recommended doses (up to 1000mg diazepam daily) are taken by recreational users who build up a high degree of tolerance to the CNS depressant effects. Recreational use of diazepam, alprazolam, lorazepam, temazepam, triazolam, midazolam, and flunitrazepam has been reported in various countries. The drugs are obtained by prescription forgeries, theft, or purchase from illegal sources.
In the UK, abuse of temazepam, often by intravenous injection, has been increasing rapidly in recent years. Over 50 cases of intravenous temazepam abuse were reported between 1988 and 1992. Most of these reached the medical literature because they developed complications; the numbers must represent only a small minority of actual users. Complications have included death, withdrawal convulsions, deep vein thrombosis, and gangrene from accidental intra-arterial injection. One intravenous drug abuser, following a leg amputation after ischemic damage from intra-arterial injections, became bilaterally blind following self injection of temazepam gel into the inner canthus of the eye.[24] Doses for intravenous injection are high: one patient injected the contents of 30 to 90 temazepam capsules daily[25]; in another survey of 23 temazepam injectors, the mean dose was 609.5 mg daily (maximum 3600 mg daily).[23] Both the contents of gel-filled capsules and solutions of crushed temazepam tablets have been used for injection. This practice carries all the risks of intravenous drug abuse in general, including that of HIV infection.
Woods et al[26] note that recreational benzodiazepine abuse is virtually nonexistent among prescribed therapeutic dose users and, on these grounds, claim that benzodiazepine abuse "is not characteristically an iatrogenic condition and should not be regarded as a substantial risk of benzodiazepine therapy." This statement seems unduly complacent since medical prescriptions constitute the initial source of supply for benzodiazepine abusers. Many high-dose abusers originally received benzodiazepines on medical prescription[4] and many, especially opiate abusers and those maintained on methadone, continue to receive them. The population of prescribed high-dose users also started on medical prescriptions and continue to receive them from multiple medical sources. Thirdly, many years of overprescription of long-term benzodiazepine therapeutic dose users resulted in the presence of these drugs in the majority of households; their easy availability undoubtedly aided their entry into the illicit drug scene. Many "bona fide" patients (in the UK at least) sell part of their prescriptions, and temazepam capsules are readily available in a large number of English and Scottish pubs for £2-3 per capsule. The prevalence of temazepam abuse has paralleled the increasing popularity of temazepam as a prescribed hypnotic.
The present population of nonmedical users may be relatively small, perhaps one tenth of that of long-term therapeutic dose prescribed users, but probably amounts to some hundreds of thousands in the US and Western Europe, and may be increasing in many countries. More rational medical use of benzodiazepines, especially a decrease in regular long-term prescribing and careful selection of patients, would result in decreased exposure of individuals vulnerable to high-dose abuse.
Withdrawal Symptoms
Benzodiazepine withdrawal symptoms have been fully described and discussed by many authors.[27-30] Abrupt withdrawal from high doses can cause a severe reaction, including convulsions and psychotic episodes. Withdrawal symptoms from therapeutic doses are mainly those of anxiety, both psychological and somatic, but certain symptoms such as sensory hypersensitivity and perceptual distortion may be especially prominent, and depression may sometimes be a prominent feature.[12,30]
The incidence of the withdrawal syndrome is not clear; it depends on factors such as definition and measures of withdrawal symptoms, selection of patients, and rate of withdrawal. In general, a withdrawal syndrome is believed to occur in 30% to 45% of patients who have used regular therapeutic doses of benzodiazepines for more than a few months, but the incidence varies between less than 20% to 100% in different studies. High-dose benzodiazepine abusers are at almost certain risk of withdrawal symptoms unless dosage tapering is extremely slow. Certain potent, rapidly metabolised benzodiazepines (alprazolam, triazolam, lorazepam; Table 2) have been associated with more severe and acute withdrawal symptoms. Dosage (within the therapeutic range) and duration of benzodiazepine use (above 6 to 12 months) do not appear to affect the incidence or severity of withdrawal, but anxious and passive-dependent personality types[28] and alcohol-dependent subjects may be especially vulnerable.
The duration of the withdrawal syndrome is variable. Many symptoms subside to prewithdrawal levels within 4 to 6 weeks, but some symptoms may decline more slowly, merging into a period of increased vulnerability to stress, which may last for many months. Protracted symptoms have been described by Ashton[30] and include prolonged anxiety and depression, as well as physical symptoms including gastrointestinal disturbances, and neurological symptoms such as tinnitus, neuromuscular abnormalities, and paraesthesiae.
Structural Brain Damage
The question of whether prolonged benzodiazepine use can cause structural brain damage remains unanswered. A computer tomography (CT) study[31] suggesting that some long-term users had enlarged cerebral ventricles, indicative of brain atrophy, was not confirmed in other studies in which concomitant alcohol abuse was rigidly excluded.[32] However Schmauss and Krieg[33] found a significant increase in cerebral ventricular size in 17 long-term benzodiazepine users who had never abused alcohol compared with control subjects. The degree of ventricular enlargement was related to drug dosage. Uhde and Kellner[34] also found an association between ventricular brain ratio and duration of benzodiazepine use in panic disorder patients, although mean ventricular size in these patients was within normal limits. The use of more sophisticated techniques such as magnetic resonance imaging might help to elucidate this question. It remains possible that subtle, perhaps reversible, structural changes may underlie the neuropsychological impairments shown in long-term benzodiazepine users.
Socio-economic Costs of Long-Term Use
The socio-economic costs of long-term benzodiazepine use are unquantified and perhaps unquantifiable. Most of these have been mentioned above and are summarized in Table 4. Each of the risks may be individually slight, but together they add up to a considerable burden for many individuals and for the state. The costs could be minimised by careful prescribing.
RATIONAL USE OF BENZODIAZEPINES
Although benzodiazepines are highly effective as short-term treatments for disorders such as anxiety and insomnia, in long-term use, the risks of dependence and other adverse effects outweigh the benefits. Rational use of these drugs has recently been reviewed.[35] It is recommended that prescriptions should be limited, when possible, to short-term (maximum 4 weeks) or intermittent courses, in minimal effective doses, and prescribed only when symptoms are severe.[6,14,36] Psychological treatments, sometimes combined with antidepressant drugs, are more appropriate in the long term for most patients with anxiety disorders.[36] Benzodiazepines should be avoided altogether or used in minimal dosage in patients who are at increased risk of adverse effects (Table 3).
For patients who have already taken benzodiazepines for long periods, withdrawal is possible. Management of withdrawal ideally consists of slow dosage tapering, often over many months, at an individually tailored pace controlled by the patient, combined with appropriate, but often essential, psychological support. Adjuvant drugs have not been found to be generally helpful, but antidepressant drugs may be indicated for depression. The outcome of withdrawal is good and most patients feel better and less anxious after withdrawal than while they were taking benzodiazepines and remain well for prolonged periods.[12,36] Intermittent courses of benzodiazepines can be repeated if anxiety recurs, but can usually be avoided by skilled psychological support. Continuation of long-term benzodiazepines is appropriate only in dependent patients unwilling to withdraw and in a minority of patients with chronic anxiety.
The Future
With rational prescribing, benzodiazepines will remain useful drugs for short-term use. Prevalence of use should decline as the number of chronic users decreases and fewer new patients become dependent. Caution should be exercised in prescribing new non-benzodiazepine hypnotics and anxiolytics now appearing on the market; such drugs, if effective (and despite claims to the contrary), may also induce dependence if used long-term.
SUMMARY AND CONCLUSIONS
Acute adverse effects of benzodiazepines are few and consist mainly of dose-related oversedation, additive effects with other CNS depressants, and occasional paradoxical reactions. Long-term benzodiazepine use is associated with more severe adverse effects, including memory impairment, depression, tolerance, and dependence. The population of chronic, prescribed-dose benzodiazepine users in the US is estimated at about 4 million individuals, and adverse effects in these users lead to a considerable socio-economic cost. In addition, recreational abuse of benzodiazepines is increasing and has become a regular feature of polydrug abuse. Certain patient groups, including the elderly, those with a history of alcohol or sedative drug abuse, and those with personality disorders, are particularly vulnerable to adverse effects from benzodiazepines. More rational prescribing of benzodiazepines, especially limitation to occasional, short-term, or intermittent use, would maximise their therapeutic benefits and minimise their disadvantages.
of some anxiety disorders. Short-term aid to alcohol/other CNS depressant drug withdrawal. |
|
Drug-induced convulsions. Short-term or adjuvant treatment of some types of epilepsy. |
|
Minor surgical procedures. |
|
dystonias and involuntary movements. |
(active metabolite) |
Equivalent to 10 mg Diazepam |
|
Note: The pharmacological actions of all benzodiazepines are similar; the distinction between
tranquillisers and hypnotic preparations is based on commercial, not pharmacological grounds.
*Withdrawn in UK in 1991.
falls, and fractures. |
|
withdrawal reactions. |
|
precipitation of suicide. |
|
sedative abuse |
|
|
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