European Neuropsychopharmacology 9 Suppl. 6 (1999) S399–S405 www.elsevier.

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Limitations on the use of benzodiazepines in anxiety and insomnia: are they justified?
Malcolm H. Lader O.B.E, D.Sc., Ph.D., M.D., F.R.C.Psych.*
Institute of Psychiatry, University of London, London SE5 8 AF, UK

Abstract The benzodiazepines are still extensively used in psychiatry, neurology and medicine in general. Anxiety disorder and severe insomnia are important syndromal indications, but these drugs are widely prescribed at the symptomatic level, resulting in potential overuse. The official data sheets recommend short durations of usage and conservative dosage. Although short-term efficacy is established, long-term efficacy remains controversial, as relevant data are scanty and relapse, rebound and dependence on withdrawal not clearly distinguished. The risks of the benzodiazepines are well-documented and comprise psychological and physical effects. Among the former are subjective sedation, paradoxical release of anxiety and / or hostility, psychomotor impairment, memory disruption, and risks of accidents. Physical effects include vertigo, dysarthria, ataxia with falls, especially in the elderly. Dependence can supervene on long-term use, occasionally with dose escalation. The benzodiazepines are now recognised as major drugs of abuse and addiction. Other drug and non-drug therapies are available and have a superior risk benefit ratio in long-term use. It is concluded that benzodiazepines should be reserved for short-term use — up to 4 weeks — and in conservative dosage. © 1999 Elsevier Science B.V. All rights reserved.
Keywords: Benzodiazepines; Anxiolytics; Hypnotics; Psychological impairment; Dependence; Abuse

1. Introduction The benzodiazepines comprise a large group of drugs which are used extensively 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 to induce anaesthesia. Although generally regarded as safe and effective drugs, their risk / benefit profile is becoming increasingly questioned (Rosenbaum, 1982; Maczaj, 1993; Lader, 1994). The benzodiazepines were originally marketed as improvements on the barbiturates and on meprobamate. They seemed much safer in overdose, had fewer drug interactions and probably a low liability for both dependence in licit medical use and illicit abuse ‘on the street’. Over the years the unwanted effects of the benzodiazepines have become more obvious: psychomotor / cognitive impairment is common and more serious neuropsychiatric reactions such as amnesic and aggressive episodes may occur. With long-term use dependence is now a recognised risk, and abuse, orally, intravenously and by ‘snorting’ (Sheehan et
*Tel.: 144-171-919-3372; fax: 144-171-252-5437. E-mail address: spklmhl@iop.Kol.ac.uk (M.H. Lader)

al., 1991) is a burgeoning worldwide concern. Despite these misgivings, the benzodiazepines are still regarded in many European countries as useful drugs providing they are prescribed appropriately. I will concentrate on two indications, anxiety and insomnia. Both tend to be chronic conditions.

2. Indications, dosage and duration of treatment Figs. 1 and 2 show the recommendations in the UK data sheets for diazepam and temazepam, respectively. Both refer to ‘short-term management’ when the disorder is ‘‘severe, disabling or subjecting the individual to extreme distress’’. There are also similar definitions of ‘short-term’: 2–4 weeks which includes a tapering-off period in the case of temazepam. Extension beyond this time is acknowledged to be necessary sometimes but only with re-evaluation of the patient’s status. Dosage recommendations are also conservative. For diazepam the statement is: ‘‘The lowest dose which can control symptoms should be used’’. The maximum is 30 mg daily in divided doses. Temazepam should be started ‘‘with the lowest recommended dose (10 mg)’’. The usual dosage range is 10–20 mg with the proviso, ‘‘In

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Fig. 2. UK datasheet for temazepam. Fig. 1. UK datasheet for diazepam.

exceptional circumstances, the dose may be increased to 30–40 mg’’. Half doses are indicated in the elderly. Such statements reflect the Licensing Authority’s concerns about using benzodiazepines beyond a few weeks and at high dose. Are these concerns justified? In this overview, various issues will be explored briefly to establish some estimates of the risk / benefit ratios of these drugs as anxiolytics and hypnotics in short- and longer-term treatment. Short-term is defined as up to 4 weeks, longterm as over 6 months, with a period in between which poses the major questions.

3. The benefits

3.1. Short-term
Anxiety disorders are found commonly in the general population. Estimates range from 5 to 20% depending on the severity criteria for ‘caseness’ and the mode of detection. Generalised 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. Despite the frequency of these conditions, anxiety is often overlooked. A study in a Health Maintenance Organisation (HMO) setting screened 6370 patients for anxiety symptoms or disorders (Fifer et al., 1994). About a third had some symptoms of anxiety, but only a half had their symptoms recognised. Patients with untreated anxiety had substantially reduced functioning and wellbeing as compared with non-anxious patients. Patients with anxiety disorders also tend to have multiple physical symptoms (Kroenke et al., 1994). The benzodiazepines are generally accepted to be useful and powerful anxiolytic agents, at least in short-term usage. Nevertheless, close evaluation of the available data shows even this efficacy to be surprisingly limited. One early meta-analysis from Australia evaluated 81 studies mainly of benzodiazepines in anxiety, that compared them to a placebo, and in some studies, to no treatment at all (Quality Assurance Project, 1985). Useful therapeutic effects were apparent in the meta-analysis but about 50%

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of this improvement was placebo-related, i.e. non-specific. Similarly, many short-term trials (up to 28 nights) show benzodiazepines to be effective treatments for insomnia (Nicholson, 1986). These hypnotics shorten time to sleep onset, usually prolong sleep time (mainly longer-acting ones, and reduce the number of arousals in the night. Such effects can be quantified both with objective EEG and other recordings in the sleep laboratory (polysomnogram) and subjectively with rating scales completed by the patient each morning. Although these two sets of data correlate at a disappointingly weak 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.

3.2. Long-term effects
Controversy surrounds the issue of whether these unequivocal short-term benefits as anxiolytic and hypnotic agents continue beyond a few weeks. A further complication is the problem of relapse on discontinuation, which can be misread as continued efficacy. This must also be differentiated from rebound or withdrawal, evidence that the benzodiazepines were acting merely to suppress discontinuation effects (Task Force Report of the American Psychiatric Association, 1990). Of course, apparent long-term efficacy might be, and in many cases probably is, a combination of them both. But the implication is that the frequent observation that many long-term benzodiazepine users claim continuing benefit cannot be taken at its face value. One important study invoked chronically anxious patients being treated with benzodiazepines for 6, 14 or 22 weeks. They were then transferred to placebo for 18, 10 and 2 weeks, respectively (Rickels et al., 1983). 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 as low as 5% in the short-term users. Even in those patients who did not develop withdrawal reactions, the switch to placebo was usually followed 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 a definite risk of inducing dependence. Another study from this group evaluated the long-term treatment of chronic anxiety with the benzodiazepine clorazepate as compared with the effects of the nonbenzodiazepine, buspirone (Rickels et al., 1988). After double-blind placebo substitution, the clorazepate-treated patients developed increased anxiety levels and some had typical withdrawal syndromes: no such phenomena were detected in the buspirone-treated group. In a more complex study (Tyrer et al., 1988), 210 psychiatric outpatients (71 GAD; 74 PD; 65 dysthymic

disorder) were treated with either diazepam, dothiepin (a sedative 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 more symptomatic than those on placebo and the other treatments. Benzodiazepines are used, often at higher dose ranges and for months at a time, in the management of panic patients. The panics may be spontaneous (PD) or occur in agoraphobic or social phobic situations. The drug quickly 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 again placebo responses can be appreciable (Ballenger et al., 1988). As with GAD, discontinuation of the benzodiazepine can be complicated by the panics recrudescing often with rebound to higher levels than experienced before, and / or with withdrawal phenomena (Pecknold et al., 1988; Dager et al., 1992). Direct comparisons with other effective anti-panic agents such as imipramine, or an SSRI, indicates that such withdrawal after several months is often an important problem requiring clinical resources for its management. Studying the long-term efficacy of the hypnotic benzodiazepines is objectified because of the availability of the polysomnogram, PSG. Fairly consistently, sleep EEG measures of hypnotic effect revert to pre-treatment values after 1–4 weeks (Kales and Kales, 1983). Despite this, most patients claim that some benefit remains and may insist on continuing medication. This demonstrates the mismatch between subjective and objective measures. In one study, patients given a benzodiazepine overestimated their sleep duration by an average of 72 min as compared with the EEG recordings (Schneider-Helmert, 1988). The benzodiazepine was then abruptly withdrawn, and patients slept poorly but underestimated their duration of sleep by about 1 h. Thus, the symptomatic improvement on a hypnotic and worsening on withdrawal are magnified in opposite directions by these subjective discrepancies. To summarise the benefits, benzodiazepine anxiolytic, antipanic and hypnotic effects are certainly useful, indeed often invaluable, in the short-term, say up to 2 weeks for hypnotic use, 4 for anxiolytic use, and 12 for antipanic effects. But placebo effects and general measures of support and reassurance are important elements in those responses. Beyond these periods, efficacy wanes but to a variable extent, both patient-to-patient, and probably among the individual benzodiazepines. Some patients develop tolerance with the possibility of rebound or a full withdrawal syndrome on discontinuation. The efficacy of the benzodiazepine as a symptomatic remedy then becomes tangled up with its effectiveness in suppressing possible withdrawal reactions on discontinuation. The

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contribution of these constituents to the apparent therapeutic actions of the benzodiazepine varies among patients, and at different phases in the course of treatment. Careful clinical questioning and observation is needed to distinguish the beneficial elements of benzodiazepine treatment from the potential problems of rebound and withdrawal.

4. Risks These will be reviewed under several headings.

4.1. Psychological effects
The psychological effects of the benzodiazepines can be divided 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 as a hypnotic in a single dose at night to induce sleep but is an unwanted side-effect when administered during the day for generalised or panic anxiety. Sedation occurs in about a third of people given an anxiolytic benzodiazepine (Salzman, 1992), and euphoria may be induced in some. These effects are most noticeable during the first week but lessen until the patient can detect no sedation at all. The severity of the sedation depends on dose, individual susceptibility and also on the particular benzodiazepine: diazepam, for example, is more sedative than lorazepam or oxazepam. Long-acting hypnotics are likely to produce residual sedative effects for much of the next day. Although uncommon, paradoxical effects can present a major management problem (Dietch and Jennings, 1988). The patient may become more anxious, panicky 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 dangerous. Uncharacteristic acts such as petty theft or sexual improprieties may occur, or the patient break down into uncontrollable weeping. Reduction in dosage or total discontinuation of the benzodiazepine is usually needed to remove the reaction. 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.

pine. Tasks that are ‘overlearned’ such as mental arithmetic are less affected, if at all. Effects are strongly dose-related and also vary from drug to drug. On repeated dosing, normal subjects show the wellknown 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 disorders themselves: anxiety and sleeplessness interfere with attention, concentration and motivation (Bond et al., 1974). Consequently, by reducing anxiety and insomnia the anxiolytic drug tends to improve psychological performance. This improvement outweighs any drugrelated 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 detectable and persistent. Thus, withdrawal from long-term benzodiazepine use may be followed by some improvements.

4.3. 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 (Curran, 1991). Thus, an individual given a benzodiazepine can remember immediate information and that remembered before the benzodiazepine was initiated but may have difficulty recalling material given after taking the benzodiazepine was given (see Table 1). As with psychomotor tests, single-dose studies in normals detect these effects much more readily than repeated dose studies in patients. Moreover, tolerance to these effects may be incomplete so that memory difficulties can persist. Periods of total amnesia may follow the use of a benzodiazepine, particularly when taken in high dose and / or in combination with alcohol. This type of problem with triazolam forced a reevaluation 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 (Ancill et al., 1987).
Table 1 Effects of benzodiazepines on memory Type of memory Working Episodic Semantic Function Short-term: Hold Autobiographical: Remember Shared knowledge: Know Skills: Know how Representational: Identity BZD effect Nil Impairment Nil Nil Depends on BZ

4.2. Psychomotor effects
Benzodiazepines can impair psychomotor functions such as those involving speed and accuracy (Koelega, 1989). Tasks requiring sustained attention and concentration can be markedly disrupted by administration of a benzodiaze-

Procedural PRS

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4.4. Real-life effects
Automobile driving 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 (Ray et al., 1992). A study by Neutel (1995) in Canada showed a several-fold excess risk for hospitalisation for accident injury after benzodiazepine use, particularly during the first 2 weeks of usage (Table 2).

4.5. Physical effects
These include vertigo, dizziness, dysarthria and ataxia. In the elderly, incoordination may lead to falls (MacDonald, 1985). Other adverse effects include rash, gain in body weight, impairment of sexual function, menstrual irregularities and, occasionally, blood dyscrasias. The progress of childbirth can be impeded by excessive benzodiazepine administration and the baby when born may be floppy or even suffer a withdrawal reaction. Small amounts of benzodiazepines are secreted in the breast-milk so the mother should not suckle. Although some drug interactions do occur (e.g. with cimetidine), they are not usually clinically significant. However, potentiation of sedative CNS depressants especially alcohol is the main problem. Deliberate overdose is quite frequent but usually the patient recovers within 48 h. However, benzodiazepines can be dangerous in the young, the old and the physically ill, particularly those with respiratory insufficiency. Indeed, the safety of flurazepam and temazepam, in particular, has been challenged (Serfaty and Masterton, 1993).

4.6. Dependence and abuse
Both the therapeutic and unwanted effects of the benzodiazepines show tolerance (see earlier). This does not usually develop into full-blown tolerance with escalation of dose to several times the therapeutic levels, as with some other drugs. Patients on such high doses are physically dependent and may suffer severe, even life-threatenTable 2 Risk [odds ratio (confidence limits)] of hospitalisation for accident injury after BZD use Risk of traffic accident injury Within 2 weeks of index (n554) Potential risk factor BZD anxiolytic BZD hypnotic Antidepressants Antipsychotics 5.6 6.5 1.0 0.7 (1.7–18.4) (1.9–22.4) (0.4–2.6) (0.2–2.9) Within 4 weeks prescription (n589) 2.5 3.9 1.0 0.6 (1.2–5.2) (1.9–8.3) (0.5–2.1) (0.2–1.9)

ing, withdrawal reactions, including fits or a psychotic disorder if the medication is stopped abruptly. These patients also show drug-seeking behaviour, so they are psychologically dependent as well. It is now generally accepted that some, perhaps as many as 10–30% of long-term users, develop a state of physical dependence despite remaining on therapeutic doses ¨ (Hallstrom, 1993). 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 doses of short-acting compounds (Lader, 1992). Its clinical significance, however, remains unclear, particularly in terms of resumption of medication. Withdrawal reactions 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 3), and include almost pathognomic perceptual symptoms such as photophobia, hyperacusis and a feeling of incessant movement. The symptoms come on within 48 h of stopping a mediumacting benzodiazepine such as lorazepam or temazepam, and 5–10 days of stopping long-acting drugs like diazepam and clorazepate. Symptoms usually disappear over a few weeks but occasional patients complain of problems persisting over months or even years. Withdrawal from lorazepam is more difficult to accomplish than from diazepam and withdrawal from hypnotics is easier than from those given by day. This whole topic of normal-dose dependence remains under debate (Woods et al., 1987), 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 might be. The prognosis is not good: 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 worldwide. 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
Table 3 Symptoms associated with benzodiazepine withdrawal Anxiety Insomnia Shakiness Impaired concentration Lethargy Dysphoria Nausea Loss of appetite Headaches Dizziness Photophobia Hyperacusis

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mouth, sniffed or sometimes intravenously. Injection may be followed by thrombophlebitis and even gangrene (Strang et al., 1992). Worldwide, flunitrazepam is believed to be the greatest problem and its abuse occurs even in countries where it is not licensed (Calhoun et al., 1996).

5. Other therapies A range of 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 non-selective and irreversible, like phenelzine, and selective and 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. A meta-analysis concluded that SSRIs are superior to imipramine and alprazolam in alleviating panic attacks (Boyer, 1995). Buspirone, a nonbenzodiazepine, acts on serotonin mechanisms and has some efficacy in GAD. Cautious initial dosage is essential to minimise 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. For insomniac patients, alternatives include, 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. Many non-pharmacological treatments are available to help anxiety and insomnia (Durham and Allan, 1993). Those for anxiety are listed in Table 4 and for insomnia in Table 5. These interventions are quite effective (Morin et al., 1994). 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
Table 4 Non-drug management of anxiety and panic Non-directive counselling Directive counselling Cognitive therapy Psychotherapy (various types) Applied relaxation Assertiveness training Exposure

evidence is accruing that some forms of such combined therapy produce responses distinctly superior to either treatment alone.

6. Conclusions A wide spectrum of opinions is expressed concerning the benzodiazepines. As this symposium shows this ranges from protestations that they are valuable drugs grossly underused and therefore depriving suffering patients of effective symptomatic relief to judgements that their risk benefit ratios as anxiolytics and hypnotics is adverse under all circumstances. The middle ground, held by most prescribers is that short-term use is acceptable but that questions hang over long-term use. Thus:

‘‘ even if BZs still represent a powerful treatment for several psychopathological conditions accompaniedby acute anxiety and agitation, doubts about their longterm use in chronic and recurrent mental disorders have arisen. In addition to dependence and withdrawal phenomena, the presence of chronic subtle toxicity and interference with underlying psychopathology appears to suggest that a more careful evaluation of the risk / benefit ratio in the long-term administration of BZs is needed’’ ( Michelini et al., 1996).
Until these questions are satisfactorily addressed, the wise prescriber will limit his prescriptions in number to those patients who are severely anxious or insomniac; in dosage to the lowest effective; and in duration to a few weeks rather than months or years.

7. 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 (Ashton, 1994; Lader, 1994). A comprehensive treatment strategy is necessary to

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manage patients suffering from anxiety, panics or insomnia.

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