B4: 2

Benzodiazepines HO1

GP Drug & Alcohol

Supplement No.9
February 1998

Benzodiazepine Dependence & Withdrawal

Martin Evans & Trudy Waghorn

Introduction injecting drug users, 28% had injected BZD at

some time and 13% had injected BZD in the
Benzodiazepines (BZD) have become one of the
last six months. The most commonly injected
most widely prescribed drugs for the
BZD are temazepam, diazepam and
management of anxiety and sleep disturbance.
flunitrazepam.
In recent years there has been a greater
awareness that problems of abuse, dependence  BZD are often used by patients who are
and associated withdrawal can occur with BZD, alcohol-dependent to self-medicate the
even when they are used in recommended effects of hangover or withdrawal symptoms.
therapeutic doses1. General Practitioners play
Pharmacology
an important role in helping patients to withdraw
from BZD and in the prevention of dependence. BZD exert their pharmacological effects
indirectly by occupying specific receptors in the
Prevalence brain; these receptors are in very close proximity
to receptors for the inhibitory neurotransmitter
 BZD are the most widely used psychotropic
gamma amino butryric acid (GABA). The effect
drugs in medical practice and accounted for
of binding BZD to its receptor facilitates the
7.1 million prescriptions (private and NHS) in
effects of GABA. (GABA exerts an inhibitory
19951.
effect on neuro-transmission by promoting the
 20% of patients who are prescribed BZD take uptake of chloride ions across nerve membranes
them for longer than 4 months1. via chloride channels.)
 Although still widespread, there has been a
general decrease in the number of BZD exhibit sedative-hypnotic, anxiolytic,
prescriptions for BZD since 1990. skeletal muscle relaxant, and anti-convulsant
 The most commonly prescribed BZD in properties. BZD decrease the time to sleep
Australia are diazepam, oxazepam, onset, the time spent in deep slow wave sleep
nitrazepam and temazepam, and account for and awakenings, and increase total sleep time.
82% of all BZD use. Differences among members of the
 BZD are used as sleeping pills twice as benzodiazepine class are seen in the time
frequently as they are used as tranquillisers2. course of drug action, which is largely
determined by the lipid solubility of an individual
Who uses benzodiazepines BZD, and the clearance of the drug and its
active metabolites. Lipid solubility may override
 Women are twice as likely as men to report
the effects of a long half-life. A highly lipid-
BZD use, but men who take BZD are just as
soluble BZD such as diazepam will have a rapid
likely to take them long-term 2.
hypnotic and anxiolytic action because of rapid
 Use of BZD increases sharply with age.
absorption and uptake into the central nervous
Nearly one in four people 75 years of age and
system. However, the effect is likely to wear off
over report using BZD 2.
quickly because of extensive distribution into
 45% of all BZD prescriptions are written for adipose tissue. Therefore, despite the long half-
people over 65 years of age3. life of diazepam and its active metabolites, a
 50-70% of patients in nursing homes are t.d.s. dose is often used for effective anxiolytic
prescribed BZD over a long period of time 3. therapy.
 Injection of BZD is a common practice among
opiate users. In a recent study4 of 312

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 GP Drug & Alcohol
Supplement No.9
February 1998
Slow elimination of a BZD which exhibits most common drugs in Australian hospital
significant retention in the central nervous self-poisoning patients6; particularly
system is more likely to be associated with dangerous when taken in combination with
residual sedation the day after a dose, the so- alcohol or opiates
called ‘hangover’ effect. BZD such as  adverse interactions with alcohol and other
temazepam, alprazolam and lorazepam have CNS depressants:
relatively short half-lives and would be expected increased problems with psychomotor and
to be associated with less hangover effect cognitive performance
following a hypnotic dose. However, short half-  potential for abuse:
life BZD may be associated with more acute and BZD use among intravenous drug users
intense withdrawal reactions upon cessation and alcohol users is common and is
because of the relatively rapid decline in central associated with higher rates of HIV risk-
nervous system concentrations5. taking behaviour and psychopathology,
poorer health, poorer social functioning,
Problems associated with BZD use and greater risk of heroin overdose.
 withdrawal syndrome: Injection of BZD has also been associated
psychological and somatic symptoms, with vascular morbidity and mortality.
perceptual disturbances, neurological
complications Assessment steps7
 tolerance: 1. Advise the patient that you wish to review
gradual loss of effectiveness and their benzodiazepine medication with them.
consequent 2. Assess past history of BZD use and initial
dose increase reasons for use.
 side effects: 3. Assess dosage and pattern of use.
drowsiness, lethargy, dizziness, headache, 4. Assess use of alcohol and other psychotropic
gastrointestinal problems, incoordination, drugs.
ataxia, dysarthria, diplopia and paradoxical 5. Assess current and past history of withdrawal
reactions, e.g. stimulation and anger symptoms.
 cognitive impairment: 6. Assess side-effects reported and observed.
subtle psychomotor deficits, memory and 7. Assess history of depression.
concentration difficulties, mental 8. Assess other medical problems.
confusion, pseudo-dementia 9. Discuss the risks of long-term use with the
 increased accident risk: patient.
falls and hip fractures in the elderly,
machine operation and motor vehicle Benzodiazepine tolerance & withdrawal
accidents Tolerance and withdrawal from BZD can occur in
 adverse mood effects: people who have been taking therapeutic or
depression, emotional anaesthesia higher doses of BZD on a regular basis for a
 adverse effects on sleep patterns: duration of two or more weeks. It is estimated
disturbed and broken sleep, nightmares, that tolerance and withdrawal symptoms are
exacerbated hypoxia in respiratory experienced in up to 45% of patients
patients, rebound insomnia in withdrawal discontinuing low therapeutic doses of BZD, and
 risks to the developing embryo, foetus and up to 100% of patients for high doses. There is a
new-born: significant risk of withdrawal if BZD are
possibility of withdrawal symptoms at birth, discontinued abruptly, particularly in the sick and
and transfer of the drug during the elderly.
breastfeeding causing drowsiness and
feeding problems Onset and duration of withdrawal
 potential for overdose: Withdrawal from short-acting BZD generally
occurs earlier than withdrawal from long-acting

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 GP Drug & Alcohol
Supplement No.9
February 1998
BZD. Withdrawal symptoms commence within cessation. Delirium may occur in the absence of
1-2 days after reduction in dose of a short-acting signs of autonomic hyperactivity or withdrawal.
BZD, and between 1-5 days for a long-acting
BZD. The duration of withdrawal is highly Treatment of benzodiazepine withdrawal
variable. Withdrawal symptoms may persist for Outpatient/home detoxification
6-8 weeks after cessation of BZD with a peak in Most patients experiencing uncomplicated
intensity in the second and third weeks. A withdrawal can be effectively managed by their
minority of patients may experience low grade GP in an outpatient setting. Criteria for home
symptoms intermittently for up to six months. detoxification are as follows:
Symptoms of withdrawal  a patient currently using BZD who wishes to
or agrees to withdraw from them
There is a wide range of symptoms that may be
experienced in BZD withdrawal and a  patient is expected to experience only a mild
considerable variation between individuals. The to moderate withdrawal
BZD withdrawal syndrome is usually  a GP is available to provide regular
characterised by some of the signs and monitoring of the patient’s progress
symptoms outlined in the following table:  home supervision (e.g. a reliable relative or
friend) should be available for patients
Table 1. Symptoms of BZD Withdrawal withdrawing from high doses (>dose
equivalent of 60 mg diazepam).
Most Common Medically Other Symptoms
BZD Serious BZD Experienced in Inpatient detoxification
Withdrawal Withdrawal BZD Admission for detoxification is required for a
Symptoms Symptoms Withdrawal minority of patients who:
 insomnia  seizures  muscle twitching  have been repeatedly unsuccessful in
previous attempts at outpatient detoxification
 anxiety  delirium  muscle pains  present already exhibiting severe symptoms
 irritability  anorexia
of withdrawal or have a history of major
withdrawal complications
 restlessness  metallic taste  have been using very high doses for a
significant duration (>dose equivalent of 80
 agitation  fatigue mg diazepam)
 depression  tinnitus  are dependent on other drugs, particularly
alcohol and opiates
 tremor  hyperacusis  have a concurrent psychiatric or serious
medical illness.
 dizziness  photophobia

 headache  perceptual
Pharmacotherapy
disturbances The following are principles of pharmacological
 derealisation therapy in the home setting:
 depersonal-  estimate the average daily intake of BZD
isation  calculate an equivalent dose of diazepam
(Table 2) and substitute diazepam (it has a
 blurred vision
long half-life) for the BZD. In some cases it
 nausea is impossible to ascertain the average daily
intake of BZD. The substitute equivalent
Major manifestations such as seizures and dose of diazepam can then be established by
delirium are rare. However, seizures may occur administering incremental doses of diazepam
from 1-12 days after discontinuing BZD and are to a point where withdrawal symptoms are
usually associated with high doses and abrupt relieved but the patient is not oversedated.

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 GP Drug & Alcohol
Supplement No.9
February 1998
This initial dose is then maintained for a few  sometimes, even when the dose is reduced
days; after that a slow tapering of diazepam by only a small amount, withdrawal
is commenced symptoms re-emerge. In this case, the dose
Table 2. BZD Dose Equivalents8 may be held at a plateau for 1-2 weeks or
even increased for a few days before the
Usual daily oral dose range, dose equivalents and pharmacokinetic reduction regime is resumed.
properties of anxiolytics and hypnotics
Drug Usual daily & Approximate Elimination Supportive Care
dose range equivalent half-lives of
(mg) dose* (mg) to drug and Frequent monitoring, reassurance, provision of
diazepam 5mg active information and a suitable environment are
metabolites ~
+
important to reduce the severity of withdrawal
(hours) symptoms. Advice and written information
alprazolam 1-4 0.5-1 14 should be provided about:
bromazepam 6-9 3-6 16  management of acute stress-related anxiety
clobazam 30-80 10 18, 40  management of insomnia
clonazepam 4-8 0.5 35
 structured problem solving
 diet
diazepam 5-20 5 30, 75
 dealing with cravings
flunitrazepa 0.5-2 1-2 23, 25, 31  relapse prevention.
m
lorazepam 2-4 1# 12 Special cases
nitrazepam 5-20 5-10 25 The reluctant patient
oxazepam 45-90 15-30 10
A number of patients who have been taking BZD
for long periods of time may be reluctant to
temazepam 10-30 10-20 15 consider coming off their drugs or even resistant
triazolam 0.125-0.25 0.25 3 to the idea. This poses a problem for the GP.
Explanation of the drug’s effects and limitations
Others
and encouragement of the patient’s ability to
buspirone 15-30 - 3 cope without them will often be sufficient to
zopiclone 3.75-7.5 - 5 enable the patient to give it a try. Extra resources
may be useful, e.g. counselling, stress
* the widely varying half-lives and receptor binding characteristics of
these agents make exact dose equivalents difficult to establish management. The patient should not feel
pressured but rather supported and encouraged9.
~ the stated half-lives are generally in the middle of the range of
reported values; there is considerable individual variation The habitual drug user (‘Doctor shopping’)
+ where clinically significant Almost all GPs come across habitual drug users
or patients who are obtaining prescriptions from
# lorazepam may be relatively more potent at higher doses
several doctors (‘doctor shopping’). The
Therapeutic Guidelines: Psychotropic Version 4, 2000 following points may assist in dealing more
effectively with these patients1:
 give diazepam in 3-4 divided doses per day
at fixed times  do not prescribe BZD on the first visit
 reduce dose by between 10-20% at weekly  there is rarely a valid indication for BZD in
intervals. Reduction may need to be slower young people
when the dose is down to 15 mg daily  say “no” from the start to the patient’s
 regularly review and titrate dose to the requests for BZD, whilst offering your help as
severity of withdrawal symptoms. In general a doctor
practice a reducing regime will generally take  take the opportunity to discuss risks
6-8 weeks, but may take 3-4 months or even associated with drug use, and refer to a
a year specialist agency.

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 GP Drug & Alcohol
Supplement No.9
February 1998
Prevention of dependence - guidelines  explain the use of the medication and the
for prescribing benzodiazepines context of its use
 use the lowest dose of BZD necessary
Problems of dependence will be minimised if the
following guidelines are followed5:  review regularly
 assess BZD efficacy at one week
 where possible use non-pharmacological  limit prescription of BZD to 2 weeks
alternatives to BZD (e.g. counselling,  discontinue gradually if the patient has been
relaxation techniques) taking BZD for a prolonged period.
 use BZD only for appropriate indications
 warn of possibility of dependency when use General Practitioners who require further
of BZD is prolonged information or assistance regarding patients who
 BZD are contraindicated in patients known to are using or wish to withdraw from
be substance abusers benzodiazepines can contact the GP Drug &
 in chronic conditions, intermittent brief use of Alcohol Local Consultancy Service on
BZD may be appropriate 0413 276 177

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.

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