European Neuropsychopharmacology 9 Suppl.

6 (1999) S399–S405
www.elsevier.com / locate / euroneuro

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 al., 1991) is a burgeoning worldwide concern. Despite

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 im-
provements on the barbiturates and on meprobamate. They
seemed much safer in overdose, had fewer drug interac-
tions 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)
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 acknowl-
edged to be necessary sometimes but only with re-evalua-
tion 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

0924-977X / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved.
PII: S0924-977X( 99 )00051-6
S400 M.H. Lader / European Neuropsychopharmacology 9 Suppl. 6 (1999) S399 –S405
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 con-
cerns 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 estab-
lish 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, long-
term 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
Fig. 2. UK datasheet for temazepam.
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 com-
monly encountered. Despite the frequency of these con-
ditions, 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%
 M.H. Lader / European Neuropsychopharmacology 9 Suppl. 6 (1999) S399 –S405
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 un-
equivocal short-term benefits as anxiolytic and hypnotic
agents continue beyond a few weeks. A further complica-
tion 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 dis-
continuation 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 pa-
tients 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 proba-
bly 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 non-
benzodiazepine, 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
S401
disorder) were treated with either diazepam, dothiepin (a
sedative tricyclic antidepressant), placebo, cognitive / be-
haviour 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 benzodiaze-
pine 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 effec-
tive 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 benzo-
diazepines 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 be-
comes tangled up with its effectiveness in suppressing
possible withdrawal reactions on discontinuation. The
S402 M.H. Lader / European Neuropsychopharmacology 9 Suppl. 6 (1999) S399 –S405
contribution of these constituents to the apparent therapeu-
tic actions of the benzodiazepine varies among patients,
and at different phases in the course of treatment. Careful
clinical questioning and observation is needed to dis-
tinguish the beneficial elements of benzodiazepine treat-
ment from the potential problems of rebound and with-
drawal.
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 anxie-
ty 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 general-
ised 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 sleep-
less rather than less. Abnormal affects may develop such
as hostility or depression; antisocial behaviour may super-
vene with rare cases of violence to persons or property.
The interaction with alcohol is particularly dangerous.
Uncharacteristic acts such as petty theft or sexual im-
proprieties 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.
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-
pine. Tasks that are ‘overlearned’ such as mental arith-
metic 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 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 im-
paired 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 psychologi-
cal performance. This improvement outweighs 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 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 consolida-
tion process in semantic (verbal) memory whereby materi-
al in short-term stores is transferred to long-term stores
(Curran, 1991). Thus, an individual given a benzodiaze-
pine can remember immediate information and that re-
membered before the benzodiazepine was initiated but may
have difficulty recalling material given after taking the
benzodiazepine was given (see Table 1). As with psycho-
motor 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 Function BZD effect
Working Short-term: Hold Nil
Episodic Autobiographical: Impairment
Remember
Semantic Shared knowledge: Nil
Know
Procedural Skills: Know how Nil
PRS Representational: Depends on
Identity BZ
 M.H. Lader / European Neuropsychopharmacology 9 Suppl. 6 (1999) S399 –S405
4.4. Real-life effects
Automobile driving is the real-life ability par excellence
and impairments are often substantial after a benzodiaze-
pine. Again these are dose-related and particularly notice-
able if alcohol is also taken. Epidemiological data indicate
that benzodiazepines contribute to road traffic (and domes-
tic) 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 hospitalisa-
tion for accident injury after benzodiazepine use, par-
ticularly 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 (Mac-
Donald, 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 benzo-
diazepine 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 espe-
cially 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 benzo-
diazepines 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 phys-
ically dependent and may suffer severe, even life-threaten-
Table 2
Risk [odds ratio (confidence limits)] of hospitalisation for accident injury
after BZD use
Risk of traffic accident injury
Within 2 weeks Within 4 weeks
of index (n554) prescription (n589)
Potential risk factor
BZD anxiolytic 5.6 (1.7–18.4) 2.5 (1.2–5.2)
BZD hypnotic 6.5 (1.9–22.4) 3.9 (1.9–8.3)
Antidepressants 1.0 (0.4–2.6) 1.0 (0.5–2.1)
Antipsychotics 0.7 (0.2–2.9) 0.6 (0.2–1.9)
S403
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 sys-
tematically studied following the stopping of hypnotic
medication, and is common after doses of short-acting
compounds (Lader, 1992). Its clinical significance, how-
ever, 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 pathog-
nomic perceptual symptoms such as photophobia, hy-
peracusis and a feeling of incessant movement. The
symptoms come on within 48 h of stopping a medium-
acting 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, benzo-
diazepines 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 Nausea
Insomnia Loss of appetite
Shakiness Headaches
Impaired concentration Dizziness
Lethargy Photophobia
Dysphoria Hyperacusis
S404 M.H. Lader / European Neuropsychopharmacology 9 Suppl. 6 (1999) S399 –S405
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 in-
hibitors (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 com-
promise compliance. A meta-analysis concluded that
SSRIs are superior to imipramine and alprazolam in
alleviating panic attacks (Boyer, 1995). Buspirone, a non-
benzodiazepine, 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 depen-
dence 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
Table 5
Non-drug management of insomnia
Progressive relaxation
Autogenic training
Feedback techniques
Cognitive-behavioural therapy
Counter-conditioning
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 long-
term 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
 M.H. Lader / European Neuropsychopharmacology 9 Suppl. 6 (1999) S399 –S405 S405

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