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Northern Regional Health Authority
DRUG NEWSLETTER
Dr C Heather Ashton

Wolfson Unit of Clinical Pharmacology
Royal Victoria Infirmary
Newcastle upon Tyne
NE1 4LP

No 31 · April 1985

The Ashton Manual · Professor Ashton's Main Page

BENZODIAZEPINE DEPENDENCE AND
WITHDRAWAL: AN UPDATE

Since we first reviewed benzodiazepine dependence in 1983 [1], awareness has grown that these drugs are associated with a protracted and sometimes severe withdrawal syndrome. The news media have publicised this problem, leading many people to seek advice from lay support groups. Recent experience [2] has clarified the nature and duration of withdrawal symptoms, and we therefore update our earlier Newsletter.

Withdrawal Symptoms

It is estimated that a withdrawal syndrome is experienced by 30-50% of people stopping chronic treatment with benzodiazepines [3,4], but dependence has also been reported after only 6 weeks of treatment with diazepam [5]. A very wide range of symptoms has been reported, some of which may resemble anxiety states and imply a recurrence of the original problem. However, these symptoms are reported by people irrespective of a history of psychiatric disorders, and by those who were originally prescribed benzodiazepines for conditions unrelated to anxiety, such as backache.

Symptoms may also arise during treatment or following spontaneous attempts at dose reduction by the patient; people may therefore present with unusual symptoms before the doctor is aware of any change in drug therapy. When benzodiazepines are eventually stopped, these effects become worse and new symptoms may develop. The time taken for this to occur depends on the half-life of the drug; for diazepam [half-life up to 200 hours], the delay is between 5 and 7 days, but this will be much less for a shorter-acting benzodiazepine such as ketazolam. Thereafter, their severity fluctuates and tends to diminish over 4-6 months [2]. Most people, however, continue to experience unpleasant symptoms after this period. Some still taking benzodiazepines, especially lorazepam and others with a short half-life, report a craving for their drug, but this diminishes rapidly over the first 2 weeks of withdrawal. Although symptoms may be persistent, eventual recovery appears to be the rule.

Frequent reassurance may be necessary, and many patients find lay counselling centres helpful. A number of counselling centres are now operating in the North East; their addresses may be obtained from the numbers given below:

The Tranquilliser Withdrawal Centre
[ Address Removed ]
Northern MIND
[ Address Removed ]

Common symptoms include:
Psychological Disturbances

anxiety, insomnia, nightmares	panic attacks, with hyperventilation, flushing, sweating, palpitations
dimensional distortions of rooms and television pictures	visual and auditory hallucinations
paranoid thoughts and feelings of persecution	delusions
depersonalisation and feelings of unreality, leading to fears of 'going mad'; these symptoms may improve intermittently to give 'windows' of well-being	heightened perception of taste, smell, sound, and light; photophobia agoraphobia
depression, occurring in some, in episodes several times daily	poor memory and concentration
aggression, excitability	acute psychotic episodes

Somatic Symptoms

numbness or altered sensations in the skin, varying in severity and distribution but often occurring in the arms, legs, mouth, jaw, and tongue	pain, stiffness, and weakness in the neck, head, jaw, and limbs, which may be severe; toothache may result in unnecessary extraction
muscle fasciculation, ranging from twitches to jerks affecting the legs, shoulders, or back ataxia	paraesthesiae [in the absence of overt hyperventilation]
influenza-like symptoms: appearing within the first fortnight of withdrawal and lasting up to four weeks [without fever]; some people seek treatment [including alternative medical treatments] for chronic sinusitis	visual disturbances: blurred double vision [which has led some people to replace their spectacles]
metabolic and endocrine symptoms: menorrhagia, breast pain; mammary pain in men; loss of or dramatic gain in appetite, thirst with polyuria, occasional urinary incontinence	gastrointestinal symptoms: dysphagia, nausea, vomiting, abdominal pain, diarrhoea, constipation; these may lead to a substantial loss in weight

Less frequently, fits may occur after rapid dose reduction.

Benzodiazepines and the Limited List

Of the many benzodiazepine preparations currently on the market, seven generic forms are included in the Limited List: chlordiazepoxide, clobazam [for the treatment of epilepsy], diazepam, lorazepam, oxazepam, temazepam and triazolam. Each may be prescribed on the NHS only by generic name and, with drugs for which different brands or generic equivalents are available, pharmacists may substitute alternative products.

For the majority of patients taking other benzodiazepines, changing over to one of these drugs should present little difficulty, providing that the substitution is carried out gradually and that the relative potencies and elimination half-lives of different benzodiazepines are taken into account. Care must be taken in ensuring that a short-acting benzodiazepine is not substituted for a long-acting one; conversely, although substitution of a long- for a short-acting drug will overcome potential problems of withdrawal, more daytime sedation may occur. The table below gives the elimination half-lives of a number of benzodiazepines and their approximate potencies relative to diazepam.

In view of the disadvantages of long-term benzodiazepine therapy [1], many doctors may wish to take this opportunity of helping chronic users to withdraw from these drugs. Present experience suggests that benzodiazepine withdrawal is most conveniently accomplished in two stages: substitution with diazepam, followed by a gradual reduction of diazepam dosage. Diazepam is particularly useful for slow withdrawal because of its long elimination half-life and its availability in low dosage forms: 2 mg tablets [which can be halved] and elixir containing 2 mg in 5 ml [which can be diluted].

Diazepam Substitution

The benzodiazepine in use should be replaced in increments of one dose per day by the equivalent dose of diazepam [see table]. This substitution can usually be accomplished within a week, although the duration of this period should be varied to suit individual patients. For example, a regime for a patient taking lorazepam 1mg morning, midday and evening is to replace the evening dose with 10mg diazepam for two days, then add replacement of the midday dose for two days, and finally replace the morning dose. The patient is then taking a daily dose of 30mg diazepam, which is approximately equivalent to 3mg lorazepam. Some patients feel better when lorazepam or other relatively short-acting benzodiazepines are replaced by diazepam in this manner. Some, however, require slightly more than the approximately equivalent doses of diazepam given in the table to replace the benzodiazepine they are used to. A minority of patients experience real difficulties in changing from one benzodiazepine to another. In these cases, the changeover needs to be carried out more gradually.

Reduction of Diazepam Dosage

The rate at which dosage reduction of diazepam is pursued can vary greatly depending on the circumstances of individual patients. A stepwise reduction by 2mg in the daily dose can usually be tolerated by patients on daily doses above 15-20mg. Reduction by steps of 1mg is advisable when patients start from or reach a daily dose of 10-15mg, and 1/2mg reductions may be preferred when dosage is down to 5mg a day. The stepwise reductions can be made weekly, fortnightly, or even monthly.

Benzodiazepine withdrawal requires active participation by the patient who, because of the wide variation in individual responses, is usually in the best position to choose the optimum rate. It is therefore essential that an adequate number of tablets is available to allow changes to be made to the scheduled withdrawal regime. Strict calculation of the number of tablets required in a particular period will not allow a temporary increase in dose to be made when needed.

Symptomatic treatment with non-benzodiazepine hypnotics may be required occasionally, but care must be taken in not substituting one drug dependence for another. Alternatives include the phenothiazines and dichloralphenazone, but it is not yet clear whether the counter-prescribing of such drugs [eg promethazine] by community pharmacists is appropriate in this context. A very few patients may require hospital admission, when supervised withdrawal is of necessity carried out more rapidly.

Benzodiazepines not available on the NHS¹
after April 1^st, 1985

Approved name	BNF *	Brand name	Half life [hrs]**	dose[mg]equivalent to 10mg diazepam
Alprazolam	a	Xanax	6-12	0.5
Bromazepam	a	Lexotan	10-20	6
Clorazepate	a	Tranxene	[36-200]	15
Flunitrazepam	h	Rohypnol	20-30 [36-200]	1
Flurazepam	h	Dalmane	[40-250]	15-30
Ketazolam	a	Anxon	2	15-30
Lormetazepam	h	Noctamid	10-12	1-2
Loprazolam	h	Dormonoct	6-12	1-2
Medazepam	a	Nobrium	[36-200]	10
Prazepam	a	Centrax	[36-200]	10-20

Benzodiazepines which remain available on the NHS¹

Chlordiaz- epoxide	a	Librium	5-30 [36-200]	25
Clobazam ***	a	Frisium	12-60	20
Diazepam	a	Valium and others	20-100 [36-200]	10
Lorazepam	a	Ativan	10-20	1-2
Nitrazepam	h	Mogadon and others	15-38	10
Oxazepam	a	Serenid	4-15	20
Temazepam	h	Normison, Euhypnos	8-22	20
Triazolam	h	Halcion	2	0.5

NB. These dose equivalents are only approximate and adjustment
to patients' individual requirements may be needed.

*BNF classification: a=anxiolytic, h=hypnotic.
**Where there is an active metabolite its half-life is shown in brackets.
***Clobazam may be prescribed on the NHS for epilepsy only.

NHS¹ = National Health Service in the UK.

References

1. Drug Newsletter 1983; Suppl April:77-80

2. Ashton H. Br Med J 1984;288:1135-40

3. Tyrer P et al. Lancet 1981;i:520-2

4. Tyrer P et al. Lancet 1983;i:1402-6

5. Murphy SM et al. Lancet 1984;ii:1389

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Please note that most addresses and phone numbers have been
removed from this document which was written in 1985.
They are probably no longer relevant now – benzo.org.uk.

Benzodiazepines: How they Work & How to Withdraw
by Professor C Heather Ashton, DM, FRCP, 2002

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The Ashton Manual · Professor Ashton's Main Page

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