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Benzodiazepines HO1
GP Drug & Alcohol
Supplement No.9
February 1998
Benzodiazepine Dependence & Withdrawal
Martin Evans & Trudy Waghorn
Introduction
Benzodiazepines (BZD) have become one of the
most widely prescribed drugs for the
management of anxiety and sleep disturbance.
In recent years there has been a greater
awareness that problems of abuse, dependence
and associated withdrawal can occur with BZD,
even when they are used in recommended
therapeutic doses1. General Practitioners play an
important role in helping patients to withdraw
from BZD and in the prevention of dependence.
Prevalence
 BZD are the most widely used psychotropic
drugs in medical practice and accounted for
7.1 million prescriptions (private and NHS) in
19951.
 20% of patients who are prescribed BZD take
them for longer than 4 months1.
 Although still widespread, there has been a
general decrease in the number of
prescriptions for BZD since 1990.
 The most commonly prescribed BZD in
Australia
are
diazepam,
oxazepam,
nitrazepam and temazepam, and account for
82% of all BZD use.
 BZD are used as sleeping pills twice as
frequently as they are used as tranquillisers2.
Who uses benzodiazepines
 Women are twice as likely as men to report
BZD use, but men who take BZD are just as
likely to take them long-term2.
 Use of BZD increases sharply with age.
Nearly one in four people 75 years of age and
over report using BZD2.
 45% of all BZD prescriptions are written for
people over 65 years of age3.
 50-70% of patients in nursing homes are
prescribed BZD over a long period of time3.
 Injection of BZD is a common practice among
opiate users. In a recent study4 of 312
injecting drug users, 28% had injected BZD at
some time and 13% had injected BZD in the
last six months. The most commonly injected
BZD are temazepam, diazepam and
flunitrazepam.
 BZD are often used by patients who are
alcohol-dependent to self-medicate the effects
of hangover or withdrawal symptoms.
Pharmacology
BZD exert their pharmacological effects indirectly
by occupying specific receptors in the brain;
these receptors are in very close proximity to
receptors for the inhibitory neurotransmitter
gamma amino butryric acid (GABA). The effect
of binding BZD to its receptor facilitates the
effects of GABA. (GABA exerts an inhibitory
effect on neuro-transmission by promoting the
uptake of chloride ions across nerve membranes
via chloride channels.)
BZD exhibit sedative-hypnotic, anxiolytic, skeletal
muscle relaxant, and anti-convulsant properties.
BZD decrease the time to sleep onset, the time
spent in deep slow wave sleep and awakenings,
and increase total sleep time.
Differences
among
members
of
the
benzodiazepine class are seen in the time course
of drug action, which is largely determined by the
lipid solubility of an individual BZD, and the
clearance of the drug and its active metabolites.
Lipid solubility may override the effects of a long
half-life. A highly lipid-soluble BZD such as
diazepam will have a rapid hypnotic and anxiolytic
action because of rapid absorption and uptake
into the central nervous system. However, the
effect is likely to wear off quickly because of
extensive distribution into adipose tissue.
Therefore, despite the long half-life of diazepam
and its active metabolites, a t.d.s. dose is often
used for effective anxiolytic therapy.
Central Coast Area Health Service
GP Drug & Alcohol Supplement No. 9
Slow elimination of a BZD which exhibits
significant retention in the central nervous system
is more likely to be associated with residual
sedation the day after a dose, the so-called
‘hangover’ effect. BZD such as temazepam,
alprazolam and lorazepam have relatively short
half-lives and would be expected to be
associated with less hangover effect following a
hypnotic dose. However, short half-life BZD may
be associated with more acute and intense
withdrawal reactions upon cessation because of
the relatively rapid decline in central nervous
system concentrations5.
Problems associated with BZD use
 withdrawal syndrome:
psychological and somatic symptoms,
perceptual disturbances, neurological
complications
 tolerance:
gradual loss of effectiveness and
consequent
dose increase
 side effects:
drowsiness, lethargy, dizziness, headache,
gastrointestinal problems, incoordination,
ataxia, dysarthria, diplopia and paradoxical
reactions, e.g. stimulation and anger
 cognitive impairment:
subtle psychomotor deficits, memory and
concentration difficulties, mental confusion,
pseudo-dementia
 increased accident risk:
falls and hip fractures in the elderly,
machine operation and motor vehicle
accidents
 adverse mood effects:
depression, emotional anaesthesia
 adverse effects on sleep patterns:
disturbed and broken sleep, nightmares,
exacerbated
hypoxia
in
respiratory
patients, rebound insomnia in withdrawal
 risks to the developing embryo, foetus and
new-born:
possibility of withdrawal symptoms at birth,
and transfer of the drug during
breastfeeding causing drowsiness and
feeding problems
 potential for overdose:
most common drugs in Australian hospital
self-poisoning
patients6;
particularly
dangerous when taken in combination with
alcohol or opiates
 adverse interactions with alcohol and other
CNS depressants:
increased problems with psychomotor and
cognitive performance
 potential for abuse:
February 1998
BZD use among intravenous drug users
and alcohol users is common and is
associated with higher rates of HIV risktaking behaviour and psychopathology,
poorer health, poorer social functioning,
and greater risk of heroin overdose.
Injection of BZD has also been associated
with vascular morbidity and mortality.
Assessment steps7
1. Advise the patient that you wish to review their
benzodiazepine medication with them.
2. Assess past history of BZD use and initial
reasons for use.
3. Assess dosage and pattern of use.
4. Assess use of alcohol and other psychotropic
drugs.
5. Assess current and past history of withdrawal
symptoms.
6. Assess side-effects reported and observed.
7. Assess history of depression.
8. Assess other medical problems.
9. Discuss the risks of long-term use with the
patient.
Benzodiazepine tolerance & withdrawal
Tolerance and withdrawal from BZD can occur in
people who have been taking therapeutic or
higher doses of BZD on a regular basis for a
duration of two or more weeks. It is estimated
that tolerance and withdrawal symptoms are
experienced in up to 45% of patients
discontinuing low therapeutic doses of BZD, and
up to 100% of patients for high doses. There is a
significant risk of withdrawal if BZD are
discontinued abruptly, particularly in the sick and
the elderly.
Onset and duration of withdrawal
Withdrawal from short-acting BZD generally
occurs earlier than withdrawal from long-acting
BZD. Withdrawal symptoms commence within 12 days after reduction in dose of a short-acting
BZD, and between 1-5 days for a long-acting
BZD.
The duration of withdrawal is highly
variable. Withdrawal symptoms may persist for
6-8 weeks after cessation of BZD with a peak in
intensity in the second and third weeks. A
minority of patients may experience low grade
symptoms intermittently for up to six months.
Symptoms of withdrawal
There is a wide range of symptoms that may be
experienced in BZD withdrawal and a
considerable variation between individuals. The
BZD
withdrawal
syndrome
is
usually
characterised by some of the signs and
symptoms outlined in the following table:
Central Coast Area Health Service
GP Drug & Alcohol Supplement No. 9
Table 1. Symptoms of BZD Withdrawal
February 1998
 have been using very high doses for a
significant duration (>dose equivalent of 80
mg diazepam)
 are dependent on other drugs, particularly
alcohol and opiates
 have a concurrent psychiatric or serious
medical illness.
Most Common
BZD
Withdrawal
Symptoms
Medically
Serious BZD
Withdrawal
Symptoms
Other Symptoms
Experienced in
BZD
Withdrawal

insomnia

seizures

muscle twitching

anxiety

delirium

muscle pains
Pharmacotherapy

irritability

anorexia

restlessness

metallic taste
The following are principles of pharmacological
therapy in the home setting:

agitation

fatigue

depression

tinnitus

tremor

hyperacusis

dizziness

photophobia

headache

perceptual
disturbances
derealisation


depersonalisation

blurred vision

nausea
Major manifestations such as seizures and
delirium are rare. However, seizures may occur
from 1-12 days after discontinuing BZD and are
usually associated with high doses and abrupt
cessation. Delirium may occur in the absence of
signs of autonomic hyperactivity or withdrawal.
 estimate the average daily intake of BZD
 calculate an equivalent dose of diazepam
(Table 2) and substitute diazepam (it has a
long half-life) for the BZD. In some cases it is
impossible to ascertain the average daily
intake of BZD. The substitute equivalent dose
of diazepam can then be established by
administering incremental doses of diazepam
to a point where withdrawal symptoms are
relieved but the patient is not oversedated.
This initial dose is then maintained for a few
days; after that a slow tapering of diazepam is
commenced
Table 2. BZD Dose Equivalents8
Usual daily oral dose range, dose equivalents and
pharmacokinetic properties of anxiolytics and hypnotics
Drug
Usual daily
& dose range
(mg)
Approximate
equivalent
dose* (mg) to
diazepam 5mg
alprazolam
1-4
0.5-1
Elimination
half-lives of
drug and
active
metabolites ~
+
(hours)
14
bromazepam
6-9
3-6
16
30-80
10
18, 40
clonazepam
4-8
0.5
35
diazepam
5-20
5
30, 75
flunitrazepa
m
0.5-2
1-2
23, 25, 31
lorazepam
2-4
1#
12
nitrazepam
5-20
5-10
25
oxazepam
45-90
15-30
10
temazepam
10-30
10-20
15
0.125-0.25
0.25
3
buspirone
15-30
-
3
zopiclone
3.75-7.5
-
5
Treatment of benzodiazepine withdrawal
Outpatient/home detoxification
Most patients experiencing uncomplicated
withdrawal can be effectively managed by their
GP in an outpatient setting. Criteria for home
detoxification are as follows:
 a patient currently using BZD who wishes to
or agrees to withdraw from them
 patient is expected to experience only a mild
to moderate withdrawal
 a GP is available to provide regular monitoring
of the patient’s progress
 home supervision (e.g. a reliable relative or
friend) should be available for patients
withdrawing from high doses (>dose
equivalent of 60 mg diazepam).
Inpatient detoxification
Admission for detoxification is required for a
minority of patients who:
 have been repeatedly unsuccessful in
previous attempts at outpatient detoxification
 present already exhibiting severe symptoms
of withdrawal or have a history of major
withdrawal complications
clobazam
triazolam
Others
* the widely varying half-lives and receptor binding characteristics
of these agents make exact dose equivalents difficult to establish
~ the stated half-lives are generally in the middle of the range of
reported values; there is considerable individual variation
Central Coast Area Health Service
GP Drug & Alcohol Supplement No. 9
+ where clinically significant
# lorazepam may be relatively more potent at higher doses
Therapeutic Guidelines: Psychotropic Version 4, 2000
 give diazepam in 3-4 divided doses per day at
fixed times
 reduce dose by between 10-20% at weekly
intervals. Reduction may need to be slower
when the dose is down to 15 mg daily
 regularly review and titrate dose to the severity
of withdrawal symptoms. In general practice a
reducing regime will generally take 6-8 weeks,
but may take 3-4 months or even a year
 sometimes, even when the dose is reduced
by only a small amount, withdrawal symptoms
re-emerge. In this case, the dose may be
held at a plateau for 1-2 weeks or even
increased for a few days before the reduction
regime is resumed.
Supportive Care
Frequent monitoring, reassurance, provision of
information and a suitable environment are
important to reduce the severity of withdrawal
symptoms. Advice and written information should
be provided about:






management of acute stress-related anxiety
management of insomnia
structured problem solving
diet
dealing with cravings
relapse prevention.
Special cases
The reluctant patient
A number of patients who have been taking BZD
for long periods of time may be reluctant to
consider coming off their drugs or even resistant
to the idea. This poses a problem for the GP.
Explanation of the drug’s effects and limitations
and encouragement of the patient’s ability to
cope without them will often be sufficient to
enable the patient to give it a try. Extra resources
may be useful, e.g. counselling, stress
management.
The patient should not feel
pressured but rather supported and encouraged9.
February 1998
Almost all GPs come across habitual drug users
or patients who are obtaining prescriptions from
several doctors (‘doctor shopping’).
The
following points may assist in dealing more
effectively with these patients1:
 do not prescribe BZD on the first visit
 there is rarely a valid indication for BZD in
young people
 say “no” from the start to the patient’s
requests for BZD, whilst offering your help as
a doctor
 take the opportunity to discuss risks
associated with drug use, and refer to a
specialist agency.
Prevention of dependence - guidelines
for prescribing benzodiazepines
Problems of dependence will be minimised if the
following guidelines are followed5:
 where possible use non-pharmacological
alternatives to BZD (e.g. counselling,
relaxation techniques)
 use BZD only for appropriate indications
 warn of possibility of dependency when use of
BZD is prolonged
 BZD are contraindicated in patients known to
be substance abusers
 in chronic conditions, intermittent brief use of
BZD may be appropriate
 explain the use of the medication and the
context of its use
 use the lowest dose of BZD necessary
 review regularly
 assess BZD efficacy at one week
 limit prescription of BZD to 2 weeks
 discontinue gradually if the patient has been
taking BZD for a prolonged period.
General Practitioners who require further
information or assistance regarding patients who
are using or wish to withdraw from
benzodiazepines can contact the GP Drug &
Alcohol Local Consultancy Service on
0413 276 177
The habitual drug user (‘Doctor shopping’)
References:
1. Mant, A., de Burgh, S., Yeo, G., Letton, T. & Shaw, J. (1997) Anxiety & insomnia - think twice before prescribing. The Royal Australian College of General Practitioners.
2. Benzodiazepines: some prescription guidelines (1994) Connexions 14(1): 17.
3. Tranx National Conference on Benzodiazepine Use Proceedings, Melbourne (1991).
4. Ross, J., Darke, S. & Hall, W. (1997) Benzodiazepine injecting among heroin users: why they do it, how they do it and the associated factors. Tenth NDARC Annual
Symposium.
5. Mant, A., Wodak, A. & Day, R. (1987) Benzodiazepine dependence: strategies for prevention and withdrawal. Current Therapeutics February: 59-79.
6. National Drug Abuse Data System (1988).
7. Mant, A. & Walsh, R. (1997) Reducing benzodiazepine use. Drug and Alcohol Review 16: 77-84.
8. Goodman, A. & Gilman, L. (1991) The Pharmacological Basis of Therapeutics. Macmillan, New York. p. 357.
9. Benzodiazepine reduction guidelines for doctors (1990) Tranx Inc.
Central Coast Area Health Service