Guidelines for the Rational Use of Benzodiazepines

Guidelines for the Rational
Use of Benzodiazepines
When and What to Use
Professor C Heather Ashton, DM, FRCP
Clinical Psychopharmacology Unit,
Department of Psychiatry
The Royal Victoria Infirmary
Queen Victoria Road
Newcastle upon Tyne NE1 4LP
The Ashton Manual · Professor Ashton's Main Page
Review Article from: Drugs 48 (1):25-40. 1994
Contents
Summary
1. Differences Between Benzodiazepines
2. Rational Use of Benzodiazepines for Insomnia
2.1 Prevalence of Insomnia
2.2 Causes and Types of Insomnia
2.3 General Indications for Drug Treatment of Insomnia
2.4 Effects of Benzodiazepines on Sleep
2.5 Disadvantages of Benzodiazepine Hypnotics
2.5.1 Tolerance
2.5.2 Rebound Insomnia
2.5.3 Hangover Effects
2.5.4 Dependence
2.5.5 Respiratory Depression
2.6 Choice of Benzodiazepine Hypnotic
2.6.1 The Elderly
2.6.2 The Young
2.6.3 Pregnancy and Lactation
2.6.4 Disease States
2.6.5 Withdrawal of Benzodiazepine Hypnotics
2.6.6 Alternatives to Benzodiazepines
3. Rational Use of Benzodiazepines for Anxiety
3.1 Prevalence of Anxiety
3.2 Classification of Anxiety
3.3 Effects of Benzodiazepines on Anxiety
3.4 Disadvantages of Benzodiazepine Anxiolytics
3.4.1 Tolerance
3.4.2 Psychomotor impairment
3.4.3 Disinhibition, Paradoxical Effects
3.4.4 Affective Reactions
3.4.5 Dependence
3.5 Choice and Use of Benzodiazepines in Anxiety

Summary
3.5.1 Panic Disorder and Phobias
3.5.2 Withdrawal of Benzodiazepines
3.5.3 Prevention of Benzodiazepine Dependence
4. Benzodiazepines as Anticonvulsants
4.1 Status Epilepticus
4.2 Prophylaxis in Epilepsy
4.3 Adverse Effects
5. Other Uses of Benzodiazepines
5.1 Anaesthesia
5.2 Motor Disorders
5.3 Acute Psychoses
6. The Future
References
Table I
Table II
Table III
Table IV
The main actions of benzodiazepines (hypnotic, anxiolytic, anticonvulsant, myorelaxant
and amnesic) confer a therapeutic value in a wide range of conditions. Rational use
requires consideration of the large differences in potency and elimination rates between
different benzodiazepines, as well as the requirements of individual patients.
As hypnotics, benzodiazepines are mainly indicated for transient or short term insomnia,
for which prescriptions should if possible be limited to a few days, occasional or
intermittent use, or courses not exceeding 2 weeks. Temazepam, loprazolam and
lormetazepam, which have a medium duration of action are suitable. Diazepam is also
effective in single or intermittent dosage. Potent, short-acting benzodiazepines such as
triazolam appear to carry greater risks of adverse effects.
As anxiolytics, benzodiazepines should generally be used in conjunction with other
measures (psychological treatments, antidepressants, other drugs) although such
measures have a slower onset of action. Indications for benzodiazepines include acute
stress reactions, episodic anxiety, fluctuations in generalised anxiety and as initial
treatment for severe panic and agoraphobia. Diazepam is usually the drug of choice,
Given in single doses, very short (1 to 7 days) or short (2 to 4 weeks) courses, and only
rarely for longer term treatment. Alprazolam has been widely used, particularly in the
US, but is not recommended in the UK, especially for long term use.
Benzodiazepines also have uses in epilepsy (diazepam, clonazepam, clobazam),
anaesthesia (midazolam), some motor disorders and occasionally in acute psychoses.
The major clinical advantages of benzodiazepines are high efficacy, rapid onset of action
and low toxicity. Adverse effects include psychomotor impairment, especially in the
elderly, and occasionally paradoxical excitement. With long term use, tolerance,
dependence and withdrawal effects can become major disadvantages. Unwanted effects
can largely be prevented by keeping dosages minimal and courses short (ideally 4 weeks
maximum, and by careful patient selection. Long term prescription is occasionally
required for certain patients.
All benzodiazepines exert, in slightly varying degrees, 5 major actions: hypnotic,
anxiolytic, anticonvulsant, muscular relaxant and amnesic. Their main advantages are
their high efficacy, rapid onset of action and low toxicity. Few, if any, other drugs can
compete with them in all these respects.

In short term use, benzodiazepines can be valuable, and sometimes lifesaving, across a
wide range of clinical conditions. Nearly all the disadvantages of benzodiazepines result
from long term use, and it is such use, involving some millions of people worldwide,
which has earned them a poor reputation, particularly as drugs of dependence. This
article suggests how benzodiazepines can best be used rationally, to maximise their
advantages and minimise their disadvantages. As with all therapies, the balance
between benefits and risks may vary between individual patients.
1. Differences Between Benzodiazepines
Some properties of benzodiazepines are shown in Table I. There are large differences in
potency between different benzodiazepines, so that equivalent doses vary as much as
20-fold. This factor must be taken into account when changing a patient from one
benzodiazepine to another, and special care must be taken in prescribing minimal
effective doses of potent benzodiazepines such as alprazolam, triazolam and lorazepam.
There are slight differences in the potency of separate effects, possibly due to
differences in affinity for various receptor subtypes. Thus, some benzodiazepines are
more effective than others as anticonvulsants and some may differ in the ratio between
anxiolytic and hypnotic actions, although the marketing of different benzodiazepines as
hypnotics or anxiolytics is governed more by commercial than by pharmacological
factors. Rates of penetration into the brain also differ: oxazepam penetrates relatively
slowly and therefore has a slower onset of action than, for example. diazepam.
Oxazepam is, thus, less suitable as an hypnotic, but also has a lower abuse potential.
Benzodiazepines also differ markedly in their rates of elimination (elimination half-lives
vary from 2 to 100 hours) and some have pharmacologically active metabolites. The
possibility of residual effects after single doses and cumulative effects with multiple-dose
administration must be kept in mind, especially in elderly patients. Potent
benzodiazepines with relatively short elimination half-lives (triazolam, alprazolam,
lorazepam) appear to carry the highest risk of causing problems with dependence.[1]
Indications for benzodiazepines and the optimal choice of different benzodiazepines are
discussed below in order of the conditions for which they are most commonly prescribed.
2. Rational Use of Benzodiazepines for Insomnia
The UK Committee on Safety of Medicines[2] and the Royal College of Psychiatrists[3]
both recommended that benzodiazepines be prescribed for insomnia 'only when it is
severe, disabling, or subjecting the individual to extreme distress'. The Drug and
Therapeutics Bulletin[4] was scarcely less stringent in its view that they 'should only be
used when sleep disturbance markedly affects the life of an individual or his family, and
when other approaches have failed'. Yet nearly 14 million prescriptions for
benzodiazepine hypnotics are dispensed annually in the UK. Prescribing levels have
remained steady despite a decline in the prescription of benzodiazepine anxiolytics.[5]
TABLE I. Indications and characteristics of benzodiazepines
Drug
t1/2 (h)
[metabolite] [c]
Approximately
equivalent
oral dosages (mg)

Hypnotics
Loprazolam 6-12 1
Lormetazepam 10-12 1
Nitrazepam 15-38 10
Temazepam 8-15 20
Triazolam [a] 2-5 0.5
Anxiolytics
Alprazolam 6-12 0.5
Chlordiazepoxide 5-30 [36-200] 25
Diazepam [b] 20-100 [36-200] 10
Lorazepam 10-18 1
Oxazepam 4-15 10
Anticonvulsants
Clobazam 12-60 20
Clonazepam 24-48 1
Premedication, anaesthesia induction; sedation in intensive care
Midazolam[d] 2
Not available for
oral administration.
Usual dosage range
IV or IM 2-7.5mg
a Withdrawn from the UK market in 1991.
b Although classed as an anxiolytic, diazepam is a useful
hypnotic in single or intermittent dosage and is used im as
an anticonvulsant (see table IV).
c Half-life of pharmacologically active metabolite.
d Oral dosage not available.
Abbreviations: IM = intramuscular; IV = intravenous;
t1/2 = elimination half-life.
Such widespread prescribing may be considered casual,[6] but there is no doubt that in
short term use benzodiazepines are effective sleep inducers and sleep promotors. Their
use before an individual has reached a state of 'extreme distress' may sometimes be
appropriate. Although the drugs provide only symptomatic relief and do not affect the
underlying cause, they can, if prescribed judiciously, improve the quality of life for many
patients with insomnia.
2.1 Prevalence of Insomnia

Insomnia is common, particularly in the elderly and especially in women. Thus, up to
40% of individuals over 65 years of age complain of disturbed sleep[7] and 'the five
million British women over 65 probably consume around 40% of all benzodiazepine
hypnotics supplied by the FPS'[5] (FPS = Family Practitioner Service, i.e. general
practitioners). However, insomnia is by no means confined to the elderly[6] and rational
use of benzodiazepines or other hypnotics for this symptom requires consideration of the
causes and types of insomnia, the pharmacological effects of the drugs, and the needs of
the individual patient.
2.2 Causes and Types of Insomnia
The many causes of insomnia can be broadly categorised as physical, physiological,
psychological, psychiatric and pharmacological - the '5P's'.[8] The sleep disturbance
itself may consist mainly of difficulty in falling asleep, frequent nocturnal arousals, early
morning wakening or a general dissatisfaction with the quality of sleep that is perceived
as unrefreshing. The insomnia may be transient, short term or chronic. Pharmacological
treatment is not always, or perhaps rarely, indicated. Explanation of sleep requirements,
instruction in sleep hygiene, reduction in alcohol (ethanol) and [7,9] need to be
considered before the decision is made to prescribe hypnotics.
2.3 General Indications for Drug Treatment of Insomnia
An international conference (National Institute of Mental Health Consensus Conference)
on drugs and insomnia[10] made reasonable general recommendations for appropriate
use of hypnotic drugs, based on the cause and duration of insomnia. For transient
insomnia caused by disruption of circadian rhythms such as in overnight travel, rapid
transit over time zones, alteration of shift work or temporary admission to hospital, an
hypnotic drug with a short or moderate duration of action and few residual effects would
be appropriate to use on 1 or 2 occasions. For short term insomnia resulting from
temporary environmental stress, hypnotics may occasionally be indicated, but should be
prescribed in low dosages for 1 or 2 weeks only, or intermittently. Chronic insomnia,
which is usually secondary to other conditions (physical, psychiatric or psychological),
presents a much greater problem. In selected cases an hypnotic may be helpful, but it
should be used in minimal effective dosage, intermittently, or in short courses.
2.4 Effects of Benzodiazepines on Sleep
Benzodiazepines and related drugs are probably the best (as well as the most widely
used) hypnotics at present available. However, in prescribing them it is necessary to
bear in mind that the sleep they induce differs from natural sleep.
Benzodiazepines in general hasten sleep onset, decrease nocturnal awakenings, increase
total sleeping time and often impart a sense of deep, refreshing sleep. However, they
alter the normal sleep pattern: Stage 2 (light sleep) is prolonged and mainly accounts
for the increased sleeping time, while the duration of slow wave sleep (SWS) and rapid
eye movement sleep (REMS) may be considerably reduced. The onset of the first REMS
episode is delayed and dreaming is diminished. These effects of benzodiazepines have
been well studied.[11-13] The abnormal sleep profile probably results from unselective
depression of both arousal and sleep mechanisms in the brainstem. The suppression of
REMS may initially be helpful in decreasing nightmares, but may also be an important
factor in determining rebound insomnia in drug withdrawal (see section 2.5.2).
The typical changes in sleep stages occur with most benzodiazepines in most patients,
but individual variations in response are considerable and are influenced by dosage,
duration of treatment, type of benzodiazepine, age and clinical state. The increase in
total sleeping time appears to be greatest in patients who complain of insomnia and in

those with short baseline sleep duration. However, patients with insomnia tend to
overestimate both their baseline degree of sleep disturbance and the efficacy of hypnotic
drugs.[14]
2.5 Disadvantages of Benzodiazepine Hypnotics
2.5.1 Tolerance
Benzodiazepines are initially very, efficacious in inducing and prolonging sleep. However,
tolerance to the hypnotic effects develops rapidly, sometimes after only a few days of
regular use.[15,16] Sleep latency, Stage 2 sleep, SWS, REMS and intrasleep awakenings
all tend to return to pretreatment levels after a few weeks.[11,12,16-18] Nevertheless,
poor sleepers may report continued efficacy without escalation of dosage[19] and the
drugs are often used long term, possibly because of difficulties in withdrawal.
Tolerance to other effects of benzodiazepines does not necessarily develop at the same
rate as to the hypnotic actions. Thus, tolerance to the anxiolytic effects appears to
develop more slowly (see section 3.4.1), while complete tolerance to some psychomotor
and cognitive functions may never develop. [20,21]
2.5.2 Rebound Insomnia
Rebound insomnia, in which sleep is poorer than before drug treatment, is common on
withdrawal of benzodiazepines. It is most marked when the drugs have been taken
regularly for long periods, but can occur after only 1 week of low dose
administration.[l6,l8,22,23] Sleep latency is prolonged, intrasleep wakenings become
more frequent, REMS duration and intensity is increased with vivid dreams or
nightmares that may add to frequent awakenings.
Rebound insomnia is conspicuous with moderately rapidly eliminated benzodiazepines
(lorazepam, temazepam) and may last for weeks in some patients.[24] With rapidly
eliminated benzodiazepines (triazolam), rebound effects may occur in the latter part of
the night and cause early morning waking and daytime anxiety.[25] With slowly
eliminated benzodiazepines (nitrazepam, diazepam), SWS and REMS may remain
depressed for some weeks and then slowly return to baseline, sometimes without a
rebound. Rebound effects, when they occur, encourage continued hypnotic usage and
contribute to the development of hypnotic dependence.
2.5.3 Hangover Effects
Benzodiazepine hypnotics often give rise to subjective hangover. After most of them,
even those that are rapidly eliminated (eg triazolam), psychomotor performance and
memory may be impaired the next day.[26] However, there is considerable
interindividual variation.[27] The effects also differ between different benzodiazepines,
and with dosage and duration of administration.[28]
Residual effects are most likely to occur with slowly eliminated benzodiazepines,
especially if used long term, and are most marked in the elderly. Thus, nitrazepam
commonly produces a subjective feeling of hangover and impairs performance the next
day in single or repeated doses[28,29] although subjective effects may decrease as
tolerance develops. Diazepam (5 and 10mg) was shown to produce few residual effects
when used in single doses or intermittently,[27] although long term use impairs daytime
performance.

It is probably an individual matter whether performance the next morning is likely to be
more impaired by lack of sleep or by an hypnotic agent. For transient or short term
insomnia. many patients prefer to use an hypnotic rather than to have a sleepless night.
Daytime sleepiness resulting from chronic insomnia can itself have adverse effects,[30]
but regular hypnotic use does not usually provide a satisfactory long term solution.
Treatment is better directed, where possible, towards its underlying cause.
Table II. Rational use of benzodiazepines in insomnia. Recommended drugs include
temazepam, lormetazepam, loprazolam and diazepam (occasionally in single doses). It is
important to warn patients of possible residual effects, risks associated with driving,
interactions with alcohol (ethanol) and other depressants, danger of dependence with
regular use and possible withdrawal effects.
Type of insomnia
Dosage and administration
General cases
Transient insomnia (e.g. disruption of
circadian rhythm)
Short term insomnia (e.g. temporary
environmental stress)
Chronic insomnia (e.g. secondary to
physical, psychological or psychiatric
causes)
1-2 nights only. Minimal dosage (usually not more than diazepam 2-5mg or
equivalent)
Not for more than 2 weeks. Intermittent if possible (1 night in 2 or 3 nights).
Minimal effective dosage (start with small dose; increase if needed, usually not
more than diazepam 10mg or equivalent.
Treat primary cause first. Intermittent treatment if possible. Not more than 2
weeks (course may be repeated after an interval). Minimal effective dosage (as
above).
Special cases
Elderly patients[a]
Children
Pregnancy and lactation
Disease states
Benzodiazepine dependent patients[a]
Use half adult doses
Generally contraindicated, but single dose may be effective.
Avoid regular use in pregnancy, occasional use safe during lactation.
Avoid in chronic respiratory disease. May occasionally be indicated in other
disease states is if insomnia distressing.
Gradual withdrawal possible and may improve sleep but withdrawal should not be
forced.
2.5.4 Dependence
[a] Continued long term use may sometimes be necessary.
Dependence on benzodiazepine hypnotics can develop if the drugs are taken regularly
for several weeks.[4] Many long term users are reluctant to withdraw the drugs because
of rebound insomnia. Withdrawal from benzodiazepine hypnotics in dependent users may
also give rise to anxiety and other typical withdrawal symptoms.[31-35]
2.5.5 Respiratory Depression

Benzodiazepines can cause respiratory depression and decrease the ventilatory response
to hypercapnia[34] and increase hypopnoeic episodes during; sleep.[35] Like other
drugs which depress respiration they should be avoided in patients with severe chronic
obstructive airways disease.
2.6 Choice of Benzodiazepine Hypnotic
For an hypnotic drug, a rapid onset combined with a medium duration of action is usually
desirable. Temazepam, loprazolam and lormetazepam meet these criteria (Table II).
Temazepam tablets act as rapidly as when the drug is administered in soft gelatine
capsules. The tablets also have less abuse potential and can be cut in half to minimise
dosage.
Rapidly eliminated benzodiazepines, such as triazolam, can impair memory the next
day,[26,28] give rise to daytime anxiety,[25] and probably carry a greater dependence
risk.[1] Oxazepam is not recommended as it has a relatively slow onset of action.
Nitrazepam is only slowly eliminated. Diazepam acts rapidly and, although slowly
eliminated, does not have a prolonged action when used in single doses.
Doses should be minimised to avoid residual effects (especially important for drivers,
airline pilots, and machinery operators) and the patient should be warned about additive
effects with alcohol and other depressants. Recommended dosage schedules are shown
in Table II.
2.6.1 The Elderly
The elderly are especially vulnerable to adverse effects of hypnotic drugs. Rates of
metabolism of benzodiazepines that are oxidised (diazepam, nitrazepam) decline with
age.[35,36] Elderly patients are also more susceptible to CNS depression and may
develop confusional states and ataxia, leading to falls and fractures.[37] They are
sensitive to respiratory depression and prone to sleep apnoea and other sleep
disorders.[38]
However, insomnia is particularly common in this age group and regular hypnotics may
sometimes be indicated if sleep disturbance is distressing. Temazepam, lormetazepam
and loprazolam (which do not have pharmacologically active metabolites) remain
suitable choices. but dosage should be adjusted, usually to half the recommended adult
dose.
2.6.2 The Young
Hypnotics are generally contraindicated for children. Sedative antihistamines are
commonly used if sedation is required, but a single dose of a benzodiazepine, with
suitable dosage reduction, may be more effective.
2.6.3 Pregnancy and Lactation
Regular use of hypnotics in pregnancy is contraindicated as the drugs readily traverse
the placenta. Intermittent doses of relatively rapidly eliminated benzodiazepines have
been shown to be safe during breastfeeding.
2.6.4 Disease States
Benzodiazepines are rarely helpful in insomnia due to organic disease and may depress
respiration in chronic pulmonary disease. However, in terminal conditions, the possibility

of drug dependence becomes less important and regular use of hypnotics should not be
denied if they provide symptomatic relief.
2.6.5 Withdrawal of Benzodiazepine Hypnotics
Many patients who have taken benzodiazepine hypnotics nightly for years can have the
drugs withdrawn successfully (see section 3.5.2). Often there is surprisingly little sleep
disturbance if withdrawal is carried out sufficiently slowly. Many patients find they
actually sleep better without the drugs. The use of liquid preparations of temazepam,
nitrazepam or diazepam facilitates small dosage reductions. However, unmotivated
patients (often elderly patients who have taken hypnotics for years) should not be forced
to withdraw these agents against their will simply because they are dependent. Long
term prescriptions (in minimal dosage) are sometimes necessary.
2.6.6 Alternatives to Benzodiazepines
Benzodiazepines compare favourably with other hypnotics in efficacy and safety. They
have fewer adverse effects than chlormethiazole and chloral derivatives and are more
efficacious than sedative antihistamines.[4] Zopiclone, which has a similar mechanism of
action, is expensive and is not free of dependence liability and other adverse
effects.[39,40] Although antidepressants and antipsychotics may improve sleep in
patients with depression or psychosis, they are more toxic than benzodiazepines and
should not be used as general hypnotics, but reserved for patients with disorders for
which these drugs are specifically indicated.
3. Rational Use of Benzodiazepines for Anxiety
Official recommendations on the use of benzodiazepines in anxiety are similar to those
for insomnia. The UK Committee on Safety of Medicines[2] advised that they 'are
indicated for the short term relief (2-4 weeks only) of anxiety that is severe, disabling or
causing unacceptable distress'. To a considerable extent this advice appears to have
been heeded and yearly prescriptions for benzodiazepine anxiolytics have decreased in
the UK from a peak of 18 million in 1978 to less than 10 million at present. There is no
doubt that benzodiazepines can be highly efficacious in anxiety. The indications for their
rational use in different types of anxiety disorders have become clearer in recent years.
[41,42]
3.1 Prevalence of Anxiety
Anxiety symptoms are common in the general population. Uhlenuth et al.[43] estimated
the prevalence of generalised anxiety disorder among US adults to be 6.4%, while
another 3.5% experienced panic, agoraphobia and other phobias. Prevalence (often
elderly patients who have taken hypnotics for years) should not be forced to withdraw
these agents against their will simply because they are dependent. Long term
prescriptions (in minimal dosage) are sometimes necessary.
3.2 Classification of Anxiety
There is still some controversy about how anxiety states should be classified. Anxiety
disorders recognised on the DSM-III-R criteria [45] include generalised anxiety disorder,
panic disorder, agoraphobic disorder, social phobia, simple phobia and post-traumatic
stress disorder. Generalised anxiety is the most common of the disorders, but Tyrer
[46,47] stresses the considerable overlap of symptoms between different anxiety
disorders, as well as the co-occurrence of depressive symptoms. He argues for a simple
descriptive term, the generalised neurotic syndrome, to encompass most categories.

Acute stress reactions and post-traumatic stress disorder, which may persist as
adjustment disorders, are clearly precipitated by major life events, but the reasons for
anxiety in generalised anxiety disorder, panic and phobias is usually not known.[47]
Vulnerability to stress may be linked with genetic factors[48] and environmental
influences. Most patients with anxiety symptoms have a long history of high anxiety
levels going back to childhood.
Management of anxiety conditions, however classified or caused, usually calls for
nondrug measures that may range from simple counselling to specific psychological
techniques. The latter may include anxiety management training, behaviour or cognitive
therapy. Drug treatment may also be indicated and the range of effective drugs includes
benzodiazepines, antidepressants, antipsychotics and (฿-blockers, each with its own
advantages, disadvantages and specific indications.[47] Possible alternatives include
buspirone and some newer anxiolytics likely to be introduced soon (alpidem, suriclone
and others).[49,50]
3.3 Effects of Benzodiazepines on Anxiety
Benzodiazepines are potent anxiolytic agents and are effective both in otherwise-healthy
patients undergoing stress and in anxious patients. Anxiolytic effects are exerted in
doses that cause minimal sedation, although the hypnotic, muscular relaxant and
perhaps amnesic actions may all contribute to relief of associated tension and insomnia.
The relatively selective effect on anxiety is probably related to the fact that
benzodiazepines suppress activity in many limbic and other brain areas involved in
anxiogenesis, including the septal area, amygdala, hippocampus, hypothalamus, locus
coeruleus and raph◌้ nuclei. They also decrease the turnover of acetylcholine,
norepinephrine (noradrenaline), serotonin (5-hydroxy-tryptamine, 5-HT) and dopamine
in these areas.[51] Suppression of noradrenergic and/or serotonergic pathways appears
to be of particular importance in relation to anxiolytic effects.
The major clinical advantage of benzodiazepines as anxiolytics is the rapid onset of
action, usually apparent after a single dose. This immediate effect contrasts with the
delayed anxiolytic effects of antidepressants, buspirone and psychological treatments. In
addition, benzodiazepines are relatively non-toxic and safer than most of the alternative
drugs. Their immediate efficacy and safety combine to make benzodiazepines the drugs
of first choice for rapid relief of anxiety that is unacceptably distressing, whatever the
cause.
As in insomnia, benzodiazepines provide only symptomatic treatment for anxiety; they
do not cure the underlying disorder. Nevertheless they can provide valuable short term
cover, allowing time for more specific treatments to take effect, and can alleviate
exacerbations of anxiety which are often self-limiting.
3.4 Disadvantages of Benzodiazepine Anxiolytics
3.4.1 Tolerance
Tolerance to the anxiolytic effects of benzodiazepines seems to develop more slowly and
less completely than to the hypnotic effects. There is, however, little evidence that they
retain their effectiveness after 4 months of regular treatment.[52,53] While some
studies indicate that anxiolytic effects are maintained for at least 22 weeks in chronic
anxiety states,[54] clinical observations of long term recipients of these agents suggest
that the prolonged benzodiazepine use over years does little to control and may even
aggravate anxiety states.[55]

The question remains controversial.[44,56] but there is general agreement that
benzodiazepine use in most anxiety states should be limited where possible to short
term (ideally not more than 4 weeks) or intermittent courses.[2,41,42,47]
3.4.2 Psychomotor Impairment
Subjective oversedation is not usually a problem with anxious patients, but the drugs
can impair psychomotor performance, increasing the risk of traffic and other accidents,
especially when combined with alcohol. Memory lapses may lead to uncharacteristic
behaviours such as shoplifting.[57,58] Benzodiazepines, by inhibiting learning, may
decrease the effectiveness of psychological therapies.[59] Although judicious short term
administration of benzodiazepines can improve psychomotor performance by
counteracting the disruptive effects of anxiety, long term users of normal therapeutic
dosages show cognitive deficits, especially in visuospatial and learning ability.[21]
3.4.3 Disinhibition, Paradoxical Effects
Occasionally benzodiazepines produce paradoxical stimulation. This effect is most
marked in anxious patients[60] and in children. Symptoms may include excitement,
increased anxiety, irritability, hostility and outbursts of rage, sometimes leading to
violent behaviour. Although this phenomenon appears to be rare,[61] it is not always
clinically recognised and its true incidence may be underreported. [62]
3.4.4 Affective Reactions
Long term use of benzodiazepines can cause or aggravate depression, a possible risk in
patients with mixed anxiety/depression, and suicidal tendencies may be increased.[60]
Some patients complain of 'emotional anaesthesia', while some obtain a degree of
euphoria. A minority of anxious patients escalate their dosage to the point of abuse, and
benzodiazepines have become popular among illicit drug abusers who take them in
addition to their other drugs of abuse.
3.4.5 Dependence
Long term use of benzodiazepines carries an undisputed risk of inducing dependence.
Approximately 35% of patients taking benzodiazepines for more than 4 weeks develop
dependence as evidenced by the appearance of withdrawal symptoms if dosage is
reduced or the drugs are stopped.[63] Factors increasing the risk of dependence include
high dosage, regular continuous use, dependent personality characteristics and previous
drug dependence. [1,53,64]
3.5 Choice and Use of Benzodiazepines in Anxiety
Despite the drawbacks of long term use, benzodiazepines remain valuable in the short
term management of anxiety, especially where immediate action is required. In most
cases, diazepam is the drug of choice, since onset of action is rapid, while slow
elimination protects against major fluctuations in blood concentration. Potent
benzodiazepines such as lorazepam and alprazolam have been widely used for anxiety,
but are probably inappropriate. These drugs are relatively quickly eliminated and
interdose anxiety frequently occurs.[65] Lack of recognition of the high potency of these
drugs relative to diazepam (Table 1) has often led to excessive dosages, increasing the
risk of adverse effects, dependence and problems in withdrawal.
Guidelines for benzodiazepine use in various types of anxiety are provided by Tyrer,[47]
Consensus Conference,[41] and Russell and Lader[42] among others. Single doses may

e appropriate as prophylaxis against acute stress reactions in predictably stressful
situations (e.g. air travel, dental appointments in phobic patients), although
psychological therapies are preferable in the long run.
Similarly. very short term treatment (1 to 7 days) may be indicated in stress reactions
after catastrophic events (natural disasters, accidents), which have a high rate of
spontaneous resolution. Benzodiazepines are not usually recommended after
bereavement as they may impair the adjustment to grief, but a few days' use may
sometimes be justified. The drugs are probably not suitable for adjustment disorders and
post-traumatic stress disorders that can persist for many months; psychological
treatments are preferable in these cases.
Intermittent treatment in courses of 2 to 4 weeks can be of value in episodic anxiety
often associated with fluctuations in chronic generalised anxiety. Similarly a short course
(2 to 4 weeks) of benzodiazepines may be indicated for the immediate relief of anxiety in
generalised anxiety disorder, but the longer the duration of therapy the less the benefit
and the greater the disadvantages. In these cases benzodiazepines are best combined
with longer term treatments such as antidepressant drugs and/or psychological
therapies.
Long term treatment over months or years has been much used in the past for chronic
generalised anxiety disorder. However, Rickels et al.[54] found that most patients with
chronic anxiety remained symptom-free for at least several months after a course of
diazepam lasting 22 weeks, and in 37% there was no recrudescence of anxiety within a
year. Similar sustained improvement was noted after a shorter 6-week course of
diazepam. The authors concluded that intermittent rather than long term benzodiazepine
therapy is preferable in most cases.
A course of 2 to 4 weeks' medication followed by tapering over 1 to 2 weeks, and
temporary restitution of treatment only if anxiety symptoms recur, is probably rational.
Nondrug therapies should be offered. However, there remains a small core of patients
who fail to benefit from psychological and other therapies and, for these patients,
prolonged treatment, combined with general support, may be the only practical option.
3.5.1 Panic Disorder and Phobias
There is a divergence of opinion over the use of benzodiazepines in panic disorder,
agoraphobia and other phobias. Alprazolam, lorazepam, diazepam and clonazepam have
been widely used for these disorders.[66-72] Some of these studies and others reviewed
by Marks and O'Sullivan[73] and Tyrer[47] have compared the efficacy of
benzodiazepines with that of antidepressants and other treatments.
Most investigations have shown that high doses of benzodiazepines (e.g. as much as 6
to 10mg alprazolam daily) can be effective. They have a rapid onset of action and
improvement with benzodiazepines, compared with antidepressants, is greater in the
first 4 to 5 weeks of treatment, but is not superior after 5 to 6 weeks. Tyrer [47]
concludes from the available evidence that 'monoamine oxidase inhibitors, tricyclic
antidepressants, and benzodiazepines are all effective in the treatment of panic with a
hierarchy of efficacy headed by MAOIs with benzodiazepines as the least effective'.
Since cessation of pharmacological treatment in panic disorders and agoraphobia is
followed by relapse in over 80% of cases, [66] there is a tendency to use the drugs long
term. However, long term use of benzodiazepines, especially in high dosages, carries the
disadvantages of inducing dependence, tolerance withdrawal reactions if the drugs are
stopped,[1] increased anger/hostility,[74] cognitive impairment[21] and other adverse
effects mentioned in section 3.4. There is evidence that psychological treatments, such

as exposure therapy (supervised. gradually increasing exposure to the specific anxiety or
panic-provoking situations), can decrease relapses and improve the long term outcome,
but benzodiazepines appear to interfere with such treatments.[59,73]
For these reasons the consensus of current opinion in much of Europe and Australasia is
that antidepressant drugs combined with psychological therapies are in the long run
superior to benzodiazepines for panic disorder, agoraphobia and other
phobias.[47,53,73,75] In North America, there may be less concern about long term
benzodiazepine use for these conditions. Nevertheless, it would seem more logical to
reserve benzodiazepines for short term initial cover if panic is severe and disabling, while
awaiting the delayed effects of other treatments.
Furthermore, panic and agoraphobia may coexist with generalised anxiety as part of the
general neurotic syndrome. In these cases, intermittent use of benzodiazepines may be
combined with antidepressants and psychological therapies.[47] The observation that
low dose intranasal midazolam taken at the first sign of panic may abort the attack[76]
may offer a further use of benzodiazepines in panic disorder, but confirmation of the
efficacy and safety of this treatment is needed.
Benzodiazepines are not suitable for obsessive-compulsive disorder and should be
avoided where possible in depression, or in the presence of significant depressive
symptoms. Alprazolam is claimed to have antidepressant properties[77]and is effective
in secondary depression associated with anxiety[78] but carries a high risk of
dependence and other adverse effects, especially when used long term.
3.5.2 Withdrawal of Benzodiazepines
There remains a large population of patients, numbering over a million in the UK[5,79]
who have taken benzodiazepines for many months or years. Many of these suffer from
symptoms included in the general neurotic syndrome (chronic anxiety, panic attacks,
agoraphobia, depression). Slow withdrawal of benzodiazepines is a practical option for
motivated patients. Withdrawal symptoms, when they occur, are mainly those of
increased anxiety, although some perceptual and motor disturbances may be especially
prominent.[1]
The management of benzodiazepine withdrawal consists of gradual dosage reduction
combined with appropriate psychological support. The rate of dosage tapering should be
tailored to individual needs, and best results are usually obtained in an outpatient setting
with the patient in control of the rate of withdrawal and proceeding at whatever pace is
found to be tolerable. The process may take 2 to 3 months in some patients or up to a
year in others.
Typical dosage reductions for a patient taking 20mg diazepam (or equivalent) daily
would be 1mg every 1 to 2 weeks initially, followed by decrements of 0.5mg every 1 to 2
weeks when a dosage of 4 to 5mg has been reached. Initial dosage reductions of 2mg
every 1 to 2 weeks may be more appropriate for patients taking over 20mg diazepam
equivalent daily. No adjuvant drugs have been found to be generally helpful in alleviating
withdrawal symptoms, but antidepressants may be indicated for depression and ฿-
blockers are useful for some patients with prominent somatic symptoms.
The degree of psychological support required is also an individual matter and may range
from simple encouragement to formal anxiety management or cognitive and behavioural
therapy. Support should be available not only during dosage reduction, but also for a
prolonged period afterwards. Frequent contact with the physician or other therapist or
counsellor is often desirable throughout withdrawal and post-withdrawal phases.

In the majority of cases, symptoms gradually improve after withdrawal [55,80] although
some patients may need further temporary courses of benzodiazepines.[81] For those
unwilling to withdraw or who find withdrawal symptoms intolerable, and for those in
whom withdrawal is likely to incur more serious problems, such as alcohol
dependence,[1] continued prescribing in minimal doses may be necessary.
Table III. Rational use of benzodiazepines in anxiety. Recommended agent is diazepam
in most cases. Minimal effective dosage may vary from 5 to 30mg daily; usually best
given divided twice daily. Start with a small dose and increase if necessary. It is
important to warn patients of sedative effects, risks associated with driving, interactions
with alcohol and other depressants, danger of dependence with regular use and possible
withdrawal effects
Anxiety state Duration of treatment Other treatments
Mild anxiety
Acute stress reaction prophylaxis (e.g.
dental appointments, aeroplane travel in
patients with phobias)
Benzodiazepines not recommended
Single dose before event
Counselling,
psychological treatment
Psychological treatment
Acute stress reaction
(accidents/disasters)
1-7 days Counselling
Acute stress reaction (bereavement)
Adjustment disorders; post-traumatic
stress
Episodic anxiety
Chronic generalised anxiety[a]
General neurotic syndrome[a]
Panic disorder[a]
Agoraphobia[a]
Other phobias
Benzodiazepine-dependent patients[a]
Single doses or a few days only if distress is severe
Single doses or a few days only initially - not suitable for long term
management
Single or intermittent courses (2-4 weeks followed by 1-2 weeks in
tapering doses). Use in conjunction with other treatments
Initial course 2-4 weeks (if symptoms severe) followed by 1-2 weeks
tapering. Use in conjunction with other treatments as above
(alprazolam not recommended in UK, especially high dose, long
term, though widely used in US)
Gradual withdrawal is possible and may improve anxiety symptoms,
but should not be forced. Longer term prescriptions may sometimes
be necessary
General support,
counselling,
psychological treatment
Psychotherapy
Antidepressants, ฿-
blockers, psychological
treatment
Antidepressants, ฿-
blockers, psychological
treatment
Psychological support,
antidepressants
[a] Occasionally, longer term prescriptions are required for
patients who do not respond to other measures.
3.5.3 Prevention of Benzodiazepine Dependence
Prevention of dependence in new patients depends partly on patient selection, avoiding
prescriptions where possible in patients with dependent-avoidant personalities, identified
clinically as 'timid worriers'.[64] Minimal effective dosage should be used and courses
kept short (4 weeks maximum whenever possible).

The risk of dependence is probably greater with potent, short-acting benzodiazepines
such as lorazepam and alprazolam.[1,64,82] Monitoring of patients before issuing a
repeat prescription is important to ensure that short term treatment does not insidiously
become long term. Practitioners should also be aware that prescriptions (especially of
temazepam capsules) are sometimes diverted to illicit use.
Recommended schedules for benzodiazepine treatment in anxiety are shown in Table III.
4. Benzodiazepines as Anticonvulsants
4.1 Status Epilepticus
Benzodiazepines are drugs of first choice for status epilepticus and convulsions due to
drug poisoning, and are effective in 80% of cases. [83] Diazepam is given intravenously
or as a rectal solution. Clonazepam and lorazepam can also be given intravenously.
4.2 Prophylaxis in Epilepsy
Clonazepam (a 1,4-benzodiazepine) and clobazam (a 1,5-benzodiazepine) are available
as oral anticonvulsant drugs. Clonazepam is effective in myoclonic and generalised
absence seizures but less effective in generalised tonic-clonic seizures.[84] Clobazam is
also effective in these forms of seizures, but is usually reserved as adjunctive therapy in
refractory epilepsy. It can also be valuable when used intermittently in epilepsy related
to menstruation or in patients who have regular clusters of generalised tonic-clonic or
partial seizures,[85] and as cover during changes of anticonvulsant medication. Most
other benzodiazepines have anticonvulsant actions in varying degrees[84] and are useful
in individual cases. Diazepam and chlordiazepoxide are used briefly in alcohol
detoxification to prevent withdrawal seizures, fits and anxiety symptoms (but care is
needed to ensure that alcohol dependence is not followed, after relapse, by alcohol plus
benzodiazepine dependence).
4.3 Adverse Effects
Benzodiazepines are not generally suitable for the long term treatment of epilepsy
because of the development of tolerance in a high proportion of patients[85] However,
tolerance may be partial and some patients may continue to show a reduction in seizure
frequency and/or severity.[86] Both clonazepam and clobazam may cause sedation and
psychomotor impairment, although this is less marked with clobazam. These agents may
also result in irritability, depression, and behaviour disturbance with aggression and
hyperkinesis in children. Exacerbation of seizures may occur on withdrawal which, as
with any anticonvulsant, should always be carried out slowly.[86] Indications and dosage
schedules are shown in Table IV.
5. Other Uses of Benzodiazepines
5.1 Anaesthesia
Benzodiazepines are valuable in anaesthetic practice for their sedative and amnesic
actions.[87] Oral lorazepam and temazepam, or intramuscular midazolam are suitable
for premedication and for brief procedures such as cardioversion. Midazolam can be
combined with a local anaesthetic for surgical procedures, can be used intravenously for
induction of anaesthesia and as an infusion for patients under mechanical ventilation.
Patients who have undergone benzodiazepine withdrawal can be reassured that the use
of a benzodiazepine for anaesthesia will not re-establish dependence.

5.2 Motor Disorders
The muscular relaxant effects of benzodiazepines can sometimes be used in a variety of
motor disorders.[88] These include a range of dystonias and involuntary movements,
myoclonus, akithesia, restless legs syndrome and muscle spasm associated with pain.
However, tolerance develops with long term use and the drugs are not always effective
and may give rise to withdrawal problems. More esoteric uses are to control muscle
spasms in tetanus and rabies.
Table IV. Use of benzodiazepines as anticonvulsants
Indication Drug Dosage
Acute treatment
Status epilepticus Diazepam IV 10-20mg (5 mg/min), repeated if necessary
Convulsions due to poisoning
Prolonged or recurrent febrile convulsions
(children)
Seizure prophylaxis
Myoclonic seizures
Generalised absence seizures
Tonic-clonic seizures
Refractory epilepsy
Cluster or catamenial exacerbations
Detoxification from alcohol (ethanol) and
other CNS depressants
Diazepam Alternatives:
clonazepam or lorazepam
Diazepam
Clonazepam (short term or as
adjunctive therapy)
Clonazepam (short term or as
adjunctive therapy)
Clonazepam (short term or as
adjunctive therapy)
Clonazepam (short term or as
adjunctive therapy)
Clonazepam (short term or as
adjunctive therapy)
Diazepam
IV infusion (max 3 mg/kg/day) PR 10mg (adult), IV
PR 500 ตg/kg (repeated if necessary)
PO 2-8mg
PO 2-8mg
PO 2-8mg
PO 10-40mg
PO 10-40mg
PO - not more than 7 days in declining doses (also
alleviates anxiety symptoms)
Abbreviations: IV = intravenous; PO = oral; PR = rectal.
5.3 Acute Psychoses
In acute psychoses with hyperexcitability and aggressiveness (drug-induced, mania,
schizophrenia), benzodiazepines in single doses or as short term therapy may be an
effective addition to antipsychotic drugs. Their value as adjunctive treatment in chronic
psychosis has not been established.[89]
6. The Future

With rational prescribing, benzodiazepines are likely to remain valuable drugs for many
years. Total numbers of prescriptions should continue to decline as the number of long
term users decreases and fewer new patients become dependent. The development of
partial benzodiazepine agonists/antagonists and of other drugs that act more selectively
on different subtypes of benzodiazepine receptors may overcome some of the
disadvantages of these agents.[90] However, the degree to which such drugs, if
effective, are free of the problems of tolerance and dependence in long term use remains
to be established.
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Correspondence: Professor Heather Ashton, Clinical Psychopharmacology Unit,
Department of Psychiatry, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 1LP,
England