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Benefits and risks of benzodiazepines
in anxiety and insomnia
Professor Malcolm Lader
OBE, LLB, DSc, PhD, MD, FRC Psych, FMedSci
Professor of Clinical Psychopharmacology,
Institute of Psychiatry, University of London,
Curriculum Vitae & Quotations
The benzodiazepines are a large group of drugs which are widely used in psychiatry, neurology and other branches of medicine. They were first introduced over 30 years ago, and have been extensively prescribed to treat anxiety, insomnia, muscle spasm, and epilepsy. They have also been used as induction agents in anaesthetic practice. Generally regarded as safe and effective drugs, their safety profile is becoming increasingly questioned.(1,2)
The benzodiazepines were originally marketed as improvements on the barbiturates but it became evident that they were much safer in overdose, had fewer drug interactions and probably a low propensity for both dependence in licit medical use and illicit abuse "on the street". More recently, the unwanted effects of the benzodiazepines have become more obvious. They comprise psychomotor/cognitive impairment and more serious neuropsychiatric reactions such as amnesic and aggressive episodes. On long-term use, dependence is now a recognized risk, and abuse, orally, intravenously and by "snorting" is a burgeoning world-wide concern. Nonetheless, the benzodiazepines are still regarded as useful drugs providing they are prescribed appropriately in the various indications, such as anxiety and insomnia, which tend to be chronic conditions.
This review will first list the benefits and risks of these drugs and then outline their uses. Finally, such usage will be set into treatment algorithms for anxiety and insomnia which also incorporate other forms of treatment. It must be pointed out from the onset that perceptions of the risk/benefit ratio of the benzodiazepines vary substantially from country to country. Thus, medical opinion in the U.K. is more unfavourable than that in the U.S.A. and many European countries.
These will be divided into those with short-term and those with long-term usage, the dividing line being roughly 6 months.Short-term
Anxiety disorders are commonly found in the general population. Estimates range from 5-20% depending on the severity criteria for "caseness" and the mode of detection. Generalized anxiety disorder is probably the commonest of these conditions, followed by panic disorder (with or without agoraphobia), and social phobia. Acute stress reactions and anxiety symptoms as part of other psychiatric disorders or physical disorders are very commonly encountered.
The benzodiazepines seem to be useful and powerful anxiolytic agents and are generally accepted as such, at least in short-term usage. Unfortunately, close evaluation of the available data shows even this efficacy to be surprisingly limited. One meta-analysis from Australia examined 81 studies mainly of benzodiazepines in anxiety, as compared to a placebo, and in some studies, to no treatment at all.(3) Useful therapeutic effects were apparent in the meta-analysis but half of this improvement was placebo-related, i.e. non-specific. A large number of short-term trials (up to 28 nights) attest to the effectiveness of benzodiazepines in the treatment of insomnia.(4) Thus, they shorten time to sleep onset, usually prolong sleep time, and reduce the number of arousals in the night. These effects can be seen both with objective EEG recordings in the sleep laboratory and subjectively with rating scales completed each morning. Although these two sets of data correlate at a notoriously low level, the rating of "a good night's sleep" usually reflects infrequent nocturnal arousals. The effects generally wane beyond 28 nights and even before that time.Long-term effects
Whether these unequivocal short-term benefits as anxiolytic and hypnotic agents continue into the long-term remains a subject of controversy. A further complication is the problem of relapse on discontinuation, which could be interpreted as continued efficacy. This must be distinguished from rebound or withdrawal, evidence that the benzodiazepines were acting merely to suppress discontinuation effects.(5) Of course, apparent long-term efficacy might be, and in many cases probably is, a combination of them both. Thus, the frequent observation that many long-term benzodiazepine users claim continuing benefit cannot be taken at its face value.
One important study involved chronically anxious patients who were being treated with benzodiazepines for 6, 14 or 22 weeks. They were then transferred to placebo for 18, 10 and 2 weeks respectively.(6) In some patients, the switch to placebo was accompanied by withdrawal reactions. The incidence ranged from 43% in patients who had been taking a benzodiazepine for more than a year before entering the study to only 5% in the short-term users. Furthermore, in those patients who did not develop withdrawal reactions, the switch to placebo was usually attended by a worsening of anxiety symptoms. The variability between patients is high but these data can be interpreted as showing that long-term use, although probably maintaining some efficacy, also involves an appreciable risk of inducing dependence.
In another study from this group the long-term treatment of chronic anxiety with the benzodiazepine clorazepate was compared with the effects of the non-benzodiazepine, buspirone.(7) After double-blind placebo substitution, the clorazepate-treated patients showed increased anxiety levels and some developed typical withdrawal syndromes: no such phenomena were seen in the buspirone-treated group. In a more complex study,(8) 210 psychiatric outpatients (71 GAD; 74 PD; 65 dysthymic disorder) were treated with either diazepam, dothiepin (a tricyclic antidepressant), placebo, cognitive/behaviour therapy, or a self-help procedure. All treatments were given for 6 weeks and withdrawn by week 10. By 6 weeks, the initial efficacy of diazepam had waned and by the end of the study period, patients treated with diazepam were actually worse off than those on placebo and the other treatments.
The benzodiazepines are used, often at high dose and for months at a time in the management of panic patients. The panics may be spontaneous (PD) or occur in agoraphobic situations. The drug promptly suppresses the panics and anxiety and facilitates the application of non-drug measures such as psychotherapy and cognitive behavioural therapy (CBT). Efficacy can usually be established in the short-term, although placebo responses can be appreciable. As with GAD, discontinuation of the benzodiazepine can be stormy with the panics reappearing often with rebound to higher levels than experienced before, and/or with withdrawal phenomena. Direct comparisons with other effective anti-panic agents such as imipramine, an SSRI, indicates that such withdrawal after months is often an important problem requiring clinical resources for its management.
Some elucidation of these issues is afforded by study of the long-term efficacy of the hypnotic benzodiazepines because of the availability of objective sleep recordings (polysomnogram, PSG). Fairly consistently, sleep EEG measures of hypnotic effect revert to pre-treatment values after 1-4 weeks.(11) Despite this, most patients claim that some benefit remains and many wish to continue medication. This demonstrates the mis-match between subjective and objective measures. In fact, patients given a benzodiazepine overestimate their sleep duration by an average of 72 minutes as compared with the EEG recordings.(12) The benzodiazepine was then abruptly withdrawn, and patients slept poorly but underestimated their duration of sleep by about an hour. Thus, the symptomatic improvement on an hypnotic and worsening on withdrawal are exaggerated in opposite directions by these subjective discrepancies.
To summarise the benefits, benzodiazepine anxiolytic, antipanic and hypnotic effects are certainly useful, indeed, often invaluable in short-term prescription, say up to 2 weeks for hypnotic use, 4 for anxiolytic use, and 12 for antipanic effects. The placebo effects and general measures of support and reassurance are important elements in the responses. Beyond these watersheds, efficacy wanes but to a variable extent, patient-to-patient, and probably among the individual benzodiazepines. In some patients, tolerance develops with the possibility of rebound or a full withdrawal syndrome on discontinuation. The efficacy of the benzodiazepine as a symptomatic remedy then becomes conflated with its efficacy in suppressing possible withdrawal reactions on discontinuation. The contribution of these constituents to the apparent therapeutic actions of the benzodiazepine varies from patient-to-patient, and at different phases in the course of treatment. Only by careful clinical questioning and observation can the beneficial elements of benzodiazepine treatment be distinguished from the potential problems of rebound and withdrawal.Risks These will be reviewed under a variety of headings. Psychological effects
The psychological effects of the benzodiazepines are divisible into the subjective, behavioural, psychomotor and cognitive. Subjectively, the benzodiazepines reduce anxiety and induce sleepiness, torpor and relaxation. This is the wanted effect when the medication is taken in a single dose at night to induce sleep but is an unwanted side-effect when administered during the day for generalized or panic anxiety. Sedation occurs in about a third of people given an anxiolytic benzodiazepine,(13) and euphoria may be induced in some. These effects are most noticeable the first week but wane steadily until the patient can detect no sedation at all. The severity of the sedation depends on dose, individual susceptibility and also on the specific benzodiazepine: diazepam, for example, is more sedative than lorazepam or clobazam. Long-acting hypnotics are likely to produce residual sedative effects much into the next day.
Paradoxical effects, although uncommon, can be a major management problem.(14) The patient may become more anxious or sleepless rather than less. Abnormal affects may develop such as hostility or depression; antisocial behaviour may supervene with rare cases of violence to persons or property. The interaction with alcohol is particularly hazardous, uncharacteristic acts such as petty theft or sexual improprieties may occur or the patient may break down into uncontrollable weeping. The impulses and acts may perplex the patient who fails to relate them to his medication. In fact he or she may fear the onset of madness. Reduction in dosage or total discontinuation of the benzodiazepine is usually necessary.
Benzodiazepines neither induce nor lessen depression. The euphoriant effects of a benzodiazepine may appear to ameliorate depression. Also, many depressed patients are anxious so that decreasing the anxiety may allow the depressive features greater expression.Psychomotor effects
Benzodiazepines can impair psychomotor functions such as those involving speed and accuracy.(15) Tasks that are "overlearned" such as mental arithmetic are less affected, if at all. Tasks requiring sustained attention and concentration can be markedly disrupted by administration of a benzodiazepine. Effects are strongly dose-related and also vary from drug to drug.
Normal subjects given repeated dosing show the well-known phenomena of tolerance so that impairments wane over a week or so. The situation in patients is more complex. Anxious or insomniac patients are already impaired in psychological performance because of the effects of the conditions themselves: anxiety and sleeplessness interfere with attention, concentration and motivation.(16) Consequently, the anxiolytic drug by reducing anxiety and insomnia tends to improve psychological performance. This improvement swamps any drug-related impairment except when high doses are given. Exceptions to this include the elderly who are typically sensitive to psychomotor-impairing drugs and some tests of very skilled performance where impairments tend to be both detectible and persistent. Thus, withdrawal from long-term benzodiazepine use may be followed by some improvements.Cognitive effects
In memory tasks, benzodiazepines disrupt the consolidation process in semantic (verbal) memory whereby material in short-term stores is transferred to long-term stores.(17) Thus, someone taking a benzodiazepine can remember immediate information and that remembered before the benzodiazepine was initiated but may have difficulty recalling material given while taking the benzodiazepine.
As with psychomotor tests, single-dose studies in normals detect these effects much more reliably than repeated dose studies in patients. Moreover, tolerance to these effects may be incomplete so that memory difficulties can persist.
Episodes of global amnesia may follow the use of a benzodiazepine, particularly in high dose and/or in combination with alcohol. Such problems with triazolam forced a re-evaluation of its risk/benefit ratio and strong recommendations towards conservative dosage. Memory problems in the elderly taking a benzodiazepine may lead to a mis-diagnosis of dementia.(18)Real-life effects
Driving a motor-car is the real-life ability par excellence and impairments are often substantial after a benzodiazepine. Again these are dose-related and particularly noticeable if alcohol is also taken. Epidemiological data indicate that benzodiazepines contribute to road traffic (and domestic) accidents, although to a much lesser extent than alcohol.(19)Physical effects
These include vertigo, dizziness, dysarthria and ataxia. In the elderly, incoordination may lead to falls.(20) Other adverse effects include rash, gain in body weight, impairment of sexual function, menstrual irregularities, and, occasionally, blood dyscrasias. The progress of child-birth can be impeded by excessive benzodiazepine administration and the baby may be floppy or even undergo a withdrawal reaction. Small amounts of benzodiazepines are secreted in the breast-milk so the mother should not breast feed.
Although some drug interactions do occur (e.g. with cimetidine), they are not usually significant. Potentiation of sedative CNS depressants especially alcohol is the main problem. Overdose is quite frequent but usually the patient recovers within 48 hours. However, benzodiazepines can be dangerous in the young, the old and the physically ill, particularly those with respiratory insufficiency.Dependence and abuse
Tolerance to both the therapeutic and unwanted effects of the benzodiazepines has been mentioned earlier. This uncommonly develops into full-blown tolerance with escalation of dose to several times the therapeutic levels. Patients on such high doses are physically dependent and may suffer severe withdrawal including fits or a psychotic disorder if the medication is stopped abruptly. These people also show drug-seeking behaviour so they are psychologically dependent as well.
However, it is now generally accepted that some, perhaps 10-30% of long-term users develop a state of physical dependence despite remaining on therapeutic dosages.(21) Even after short courses of treatment, rebound - a marked worsening of symptoms beyond pre-treatment levels - can follow discontinuation, but can be minimised by tapering. This has been most systematically studied following the stopping of hypnotic medication, and is common after high doses of short-acting compounds.(22) Its clinical significance, however, remains unclear.
|Table 1|| Symptoms associated with
|Insomnia||Loss of appetite|
A withdrawal syndrome may ensue after long-term use at therapeutic dosage, even after tapering. The symptoms are typical of the withdrawal from sedative/hypnotic/alcohol group of drugs (see table 1). They include almost pathognomic perceptual symptoms such as photophobia, hyperacusis and a feeling of incessant movement. The symptoms come on within 48 hours of stopping a medium-acting benzodiazepine such as lorazepam or temazepam, and 5-10 days of stopping long-acting drugs like diazepam and clorazepate. The symptoms usually subside over a few weeks but occasional patients complain of persisting problems. Withdrawal from lorazepam is more difficult to accomplish than from diazepam and withdrawal from hypnotics is easier than from those given by day. It is fair to say that the topic of normal-dose dependence remains under debate,(23) but it is generally agreed that it is a relevant factor to consider when starting a patient on a benzodiazepine anxiolytic or hypnotic. It is difficult to predict who will progress to long-term use and become dependent, and how severe any subsequent withdrawal will be. Less than half of long-term users achieve sustained abstinence, and some become clinically depressed after withdrawal.
Finally, the benzodiazepines pose a major addiction problem world-wide. As part of polydrug abuse, benzodiazepines are used to intensify euphoria with opioids, ease the "crash" down from stimulants like amphetamine and cocaine, and provide enough disinhibition to engage in the criminal activities needed to sustain the polydrug habit. Benzodiazepines are also used by themselves, taken by mouth, sniffed or sometimes intravenously. Injection may be followed by thrombophlebitis and even gangrene.(24)Other therapies
Many other treatments are available, some being appropriate for long-term treatment. For GAD and PD, these alternatives include tricyclic antidepressants (TCAs) such as imipramine and clomipramine, selective serotonin reuptake inhibitors (SSRIs) like citalopram, fluoxetine, sertraline, and paroxetine, and monoamine oxidase inhibitors (MAOIs) both unselective and irreversible like phenelzine, and selective, reversible (moclobemide). Such use of antidepressants is formally approved by the regulatory authorities for panic and phobia indications for some SSRIs. The advantages of antidepressants are definite efficacy and easy withdrawal, and the disadvantages are the various types of side-effect profiles which may compromise compliance. Buspirone, a non-benzodiazepine, acts on serotonin mechanisms and has some efficacy in GAD. Cautious initial dosage is essential to minimize side-effects such as dizziness; withdrawal is almost always uneventful suggesting little or no dependence potential. Beta-blockers can help patients with performance anxiety with tremor and palpitations.
The alternatives for insomnia are, again, the antidepressants, with a preference for sedative agents such as amitriptyline and trazodone. Nefazodone is believed to have beneficial effects on sleep patterns and may prove to be particularly useful to help manage insomnia associated with depression. Alcohol is a poor hypnotic as it causes rebound insomnia later in the night.
A wide range of non-pharmacological treatments are available to aid in the management of anxiety and insomnia.(25) Those for anxiety are listed in table 2 and for insomnia in table 3. It is particularly important to appreciate that drug and non-drug treatments can be given in combination as well as in succession. Care is needed with this strategy but evidence is accruing that some forms of such combined therapy produce responses distinctly superior to either treatment alone.
|Table 2|| Non-drug management of
anxiety and panic
|Psychotherapy (various types)|
|Table 3|| Non-drug management of
An algorithm for the management of the commoner condition, GAD, is set out in figure 1. The plan relates to the primary care context where much of the treatment of this condition takes place.(26)
Physical causes for the anxiety should be excluded at the initial assessment. Thyrotoxicosis is the main differential diagnosis, with phaeochromocytoma a rare one. Caffeine overuse should be enquired for, as should alcohol and substance abuse. An underlying depressive disorder should be sought and excluded. The diagnosis of anxiety disorder is usually easier if the patient presents with psychological rather than physical symptoms. Much time and money can be wasted overinvestigating the latter, for example, a full cardiac work-up for stress-related palpitations in a young person.
Attainable goals must be agreed with the patient. It may only be feasible, at least in the short-term, to understand and control symptoms rather than to abolish them. The attitudes of the patient to taking medication should also be established.
Fig 1. Algorithm for the treatment of anxiety
Simple brief psychotherapy such as counselling is usually sufficient to help most mildly ill patients. Appropriate management involves a clear definition of the problem, information about anxiety and its psychological and physical symptoms, and attempts to encourage patients to adopt an active problem-solving role rather than to remain passive. Bland reassurance is unhelpful. Counselling should also include the provision of books, tapes or leaflets, which help reinforce the direct information.
More structured psychological techniques may be needed for the more severely ill patient. The general term is "anxiety management" which is a "menu" of the techniques listed in table 2. The appropriate techniques and time-points for their application to the individual patient are selected by the clinical psychologist, with the active cooperation of the patient.
When anxiety levels are very high, counselling and more complex psychological techniques may fail. If depressive symptoms emerge, an antidepressant is the treatment of choice and the anxiety should then improve roughly in line with the elevation of mood. An SSRI or buspirone is suitable for the management of both acute and chronic anxiety when a rapid onset of action is not essential and for the treatment of non-depressed patients with histories of abuse of alcohol or sedative hypnotics. Nevertheless, benzodiazepines are still many doctors' first choice when a rapid anxiolytic effect is needed. The doctor must counsel the patient as to the need for, and the risks and benefits of such medication. He should emphasise that the supply will be restricted to only a few prescriptions; that the benzodiazepine is only part of the management plan; that the drug is an aid but not a solution to the problem of anxiety; that performance of skilled tasks such as driving may be impaired; and that interactions with other psychotropic drugs and alcohol may be dangerous. The minimum effective dose of benzodiazepine and the shortest possible duration of use should be chosen. Regular supervision by the prescribing physician is essential.
Patients may need referral to a psychiatrist if the anxiety is severe, chronic, intractable or complicated by personality problems, another condition such as major depressive disorder, or by alcohol or substance abuse. The psychiatrist will probably use more intensive drug and non-drug treatments but only after a careful re-assessment of the various factors in the case. Collaboration between the professional personnel eventually involved - physician, practice nurse, psychiatrist, clinical psychologist, - is essential to avoid conflicting aims and treatments.
Panic and phobic disorders can be managed with a similar plan but with different emphases. In the U.S.A., benzodiazepines are used in quite high doses to suppress panics. Alprazolam is the most popular medication, in doses of 3-6 mg/day or even more, but lorazepam, diazepam and clonazepam have also been widely used. In panic disorder and phobic conditions, the benzodiazepines have a rapid onset of action but their efficacy is somewhat less than that of the antidepressants on longer-term use. The disadvantages of such benzodiazepine use is that dependence may develop, making withdrawal a protracted and often difficult procedure. Because of this, antidepressants are usually the treatment of choice in Europe, although a benzodiazepine may be used for a week or two until the onset of action of the antidepressant.
The effect of either the benzodiazepine or the antidepressant is to lessen both anticipatory and panic anxiety. The patient regains confidence and feels in control again. This provides a "window of opportunity" for non-pharmacological treatments such as exposure therapy, cognitive/behavioural therapy or psychotherapy. When phobic avoidance is treated and the patient has learned ways of coping with minor anxiety (this can take several months), the benzodiazepine (or antidepressant) can be cautiously withdrawn by lowering the dose over a few weeks.How to manage patients with insomnia
Patients complaining of insomnia can be managed using a similar treatment algorithm (Figure 2).(27) At the initial interview the doctor should exclude physical causes for insomnia such as cardiovascular disease, asthma, pain, tinnitus, and nocturnal obstructive apnoea. Drug-related causes include excessive caffeine ingestion, especially in the late evening, alcohol taken to injudicious excess, nicotine (chain-smoking), beta-blockers and stimulants. Physiological causes comprise eating and exercise late at night and disturbing sleep conditions such as a noisy environment.
Fig 2. Algorithm for the treatment of insomnia.
Next, psychiatric causes should be excluded. Anxiety disorders are the commonest, closely followed by depressive disorders and substance and alcohol abuse. Causes of short-term insomnia include stress and tension, grief, and abnormal concern about sleeping ("insomnophobia"). If any of the above factors are detected, the appropriate management is to treat the primary condition appropriately and vigorously.
All insomniac patients should be given advice about sleeping practices (so-called "sleep hygiene" - Table 4). More complex sleep disturbances with abnormal rhythms or habits may need assessment and treatment from one of the increasing number of clinical psychologists who are specialising in sleep disorders. They often use cognitive-behavioural techniques.
|Table 4|| General advice to the patient concerning sleep
hygiene (from ref. no. 27)
| 1) Reinforce the natural rhythm of
alertness during the day
and sleepiness at night: do not go to bed until you feel sleepy,
and rise at the same time every morning.
| 2) Provide a proper sleep environment
appropriate to your
needs - dark and quiet, not too hot, not too cold, not too humid.
|3) Set the mood for sleep - establish a regular bedtime routine.|
| 4) Reserve the bedroom primarily for
sleep. Do not use it for eating,
working or watching television.
| 5) Avoid substances that interfere
with sleep close to
bedtime - caffeine, nicotine or alcohol.
| 6) Avoid strenuous exercise late in the evening;
only exercise gently at this time.
| 7) If you are pre-occupied with
anxieties, try and take time to solve
them before going to bed. If you cannot solve them, try and leave
them until the next day. Relaxation or distraction techniques outside
the bedroom may take your mind off your worries.
|8) Avoid naps during the day; they make insomnia worse.|
Drug treatment usually comprises a benzodiazepine such as triazolam or temazepam or the non-benzodiazepines, zopiclone or zolpidem. As with anxiety, benzodiazepines should be reserved for the severely insomniac patient, with much distress. Treatment should be short-term with the same precautions as with anxiolytic use. Particular care is needed with elderly patients who comprise most of the more chronic patients.
Transient and short-term insomnia such as those related to jet-lag or a sudden distressing bereavement is best treated for a few nights of a short-acting hypnotic drug. Long-term (chronic) insomnia is much more difficult to manage. Hypnotic drugs are only justifiable as a short-term stop-gap while any underlying physical or mental disorder is treated or while non-drug measures are initiated. Hypnotic medication is not indicated for the life-long poor sleeper, as initial therapeutic effects may wane, leaving the patient both insomniac and dependent on the hypnotic. In the elderly, some accumulation may occur with day-time drowsiness, psychomotor and cognitive impairment, and occasionally confusion.(28) Intermittent use may be helpful, the patient taking the medication only on nights when he or she feels particularly over-alert and unlikely to fall or remain asleep.
Referral to a sleep clinic is not useful as a routine but should be reserved for patients with especially chronic or intractable insomnia. In particular, paroxysmal nocturnal obstructive apnoea, a potentially lethal condition, may need exclusion or specialist management.Summary
Benzodiazepines, despite their vicissitudes, are seen as effective treatments, at least in the short-term. The risk/benefit ratio of these drugs becomes less favourable or even adverse as treatment becomes prolonged: efficacy wanes and risks accumulate. Patients with severe anxiety, panic and insomnia disorders can be greatly helped by short-term intervention with a benzodiazepine but the benefits long-term remain debatable.(29,30)
A comprehensive treatment strategy is necessary to manage patients suffering from anxiety, panic or insomnia.References
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Professor Malcolm Lader OBE, LLB, DSc, PhD, MD, FRC Psych, FMedSci
Emeritus Professor of Clinical Psychopharmacology,
Institute of Psychiatry, University of London, England
Professor M H Lader,
Institute of Psychiatry,
London SE5 8AF, England
Tel: 0207 848 0372
Fax: 0207 252 5437
More Prof Lader