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New Zealand Medical Journal, 1980; 92: 94-96
A. Khan MB BS, Registrar,
P. Joyce BSc MB ChB, Registrar,
A. V. Jones Dip Psych Med MRANZCP, Consultant Psychiatrist,
Sunnyside Hospital, Christchurch
We report eight cases of benzodiazepine withdrawal syndromes seen in a general psychiatric hospital. These consisted of acute organic brain syndrome, grand mal convulsions and abstinence syndromes. All of the cases were using benzodiazepines in prescribed therapeutic doses. These problems appear to be more common than are generally acknowledged.
Greenblatt and Shader (1974) report the beginning of the era of benzodiazepines with the synthesis of chlordiazepoxide in 1957 and its clinical use since 1960.(1) Since then diazepam, oxazepam, nitrazepam, flurazepam, lorazepam and clorazepate have become readily available. They are used principally as anxiolytics, hypnotics and for the relief of chronic somatic complaints. These drugs are most frequently prescribed by general practitioners.(2) Skegg (1977) found that 6.1 percent of the general population in the UK received a prescription for diazepam over the course of one year.(3) Balter (1974) in his cross-national study of nine countries found that between 10-17 percent of adults between 18 and 74 had used an anti-anxiety/sedative drug in the past year.(4) A similar rate is suspected in New Zealand.
Up to 1966, there were nine reported cases of withdrawal syndromes.(5) Bliding (1977) reports that the abuse of benzodiazepines was generally denied in 1971.(6) Covi and others (1973) demonstrated a minor abstinence syndrome of barbiturate type following abrupt withdrawal of chlordiazepoxide administered in therapeutic doses for periods longer than 16 weeks.(7) Rifkin and others (1976) reported a case of withdrawal convulsions.(8) Preskorn and Denner (1977) reported three cases of withdrawal psychosis.(9) In 1977, Drug and Therapeutics Bulletin(10) found less than 50 reported cases, although Bliding (1977) found 68 papers describing dependence or abuse.(6)
In view of these reports of benzodiazepine dependence, it is surprising that in recent symposia no reference is made to this problem.(11, 12) Similarly, Hollister (1978) in his monograph on clinical psychopharmacology makes no reference to dependence or withdrawal syndromes.(13) Indeed, Greenblatt and Shader (1978) comment that the hazards of benzodiazepine withdrawal have been exaggerated.(5)
In contrast to barbiturates and alcohol, the withdrawal symptoms from benzodiazepines tend to occur later and persist longer.(14) This may be because of their longer half-lives, although these vary from 16 hours with lorazepam and oxazepam to 40 hours with diazepam.
One of the difficulties in establishing the existence of mild abstinence syndromes is that these could be due to resurgence of original symptoms. However, this is not a difficulty with more pronounced syndromes.
Patients and Methods
The setting consisted of a general psychiatric hospital adult inpatient and outpatient services. The acute inpatient facilities of the clinic are for a population of about 150 000 and the annual admission rate is about 500. The reported cases were seen in the latter half of 1979. The limited outpatient facilities must cope with a population of 300 000. The annual rate of referral has been about 250. The reported cases were seen in the last quarter of 1979.
Detailed histories regarding previous drug taking and psychiatric complaints including the reason for the use of benzodiazepines were documented. Detailed mental status and physical examinations were made. Cases with an extensive past history of drug abuse or those with marked addictive personality traits were excluded. Inevitably almost half of the cases had been taking another drug. However, it was only the benzodiazepine which was stopped before the onset of the syndrome.
Patient 1: A 38 year old mate technician was admitted with loss of impulse control, emotional liability and disordered thinking. About a year prior to admission he was started on diazepam 5mg twice a day, nitrazepam 5mg at night and imipramine for anxiety and depression. Later oxazepam and tranylcypromine were substituted. About a month before admission he was changed onto lorazepam 2.5mg three times a day and phenelzine 15mg three times a day. About a week before admission he discontinued the phenelzine, and 48 hours prior to admission he discontinued lorazepam. He was initially diagnosed as having a functional psychosis and was commenced on thioridazine 100mg three times a day. However, his mental status deteriorated over the next three days resulting in a picture of acute organic brain syndrome characterised by marked disorientation, urinary incontinence, visual, tactile and auditory hallucinations. His thioridazine was stopped and he was recommenced on lorazepam. Within 24 hours his mental status improved and within 48 hours he had returned to normal.
He readily agreed to coming off lorazepam, but a drop of 2.5mg over the next day resulted in resurgence of the above symptoms. The drug was then withdrawn slowly at 0.5mg every 10 days. He had no medication in the following four months and has resumed his former activities including work.
Patient 2: A 58 year old housewife was admitted with a one-month history of depression. She had one admission three years previously when she had been started on tranylcypromine. Also, over the past four years she had been taking diazepam and oxazepam in therapeutic doses for chronic shoulder pain. About six months before admission she was started on lorazepam 2.5mg four times a day. One week prior to admission she had discontinued her tranylcypromine. On admission her lorazepam was stopped. On the first night there was a marked disturbance in her sleep pattern. Next day she became extremely agitated with worsening of depressive symptoms. On the fourth day she developed an acute organic brain syndrome with disorientation, vivid visual hallucinations and marked nightmares. She was given a stat dose of lorazepam 5mg and her sleep improved that night. Within 24 hours there was a marked improvement in her mental status. Her later course was more erratic and she was discharged on perphenazine, trimipramine and thioridazine. Later she recommenced lorazepam.
Patient 3: A 61 year old male storekeeper was transferred for psychotic behaviour. He had been detoxified from alcohol elsewhere five weeks before. On admission to the alcohol treatment centre his oxazepam 15mg three times a day had been stopped. About three days later he manifested anxiety, depression and disordered thinking for which he was transferred to hospital next day. On admission he manifested signs of an acute organic brain syndrome with disorientation, urinary and faecal incontinence, visual and tactile hallucinations. He was commenced on diazepam 5mg three times a day and within 12 hours his mental status returned to normal. There was no deterioration and after four stable days he was transferred back to the alcohol treatment centre where he was withdrawn from diazepam slowly.
Patient 4: A 29 year old housewife was admitted for depression. She was on an oral contraceptive and lorazepam, which were withdrawn over ten days. During this time she was agitated, weepy, and had occasional panic attacks. Her sleep was markedly disturbed and she experienced severe headaches. She was prescribed chlorpromazine 100mg as required. On the second day following complete withdrawal she had a grand mal convulsion and two more in the next six days. She was commenced on carbamazepine and diazepam. Two weeks later she had a further grand mal seizure at which point Dilantin was started. She had had febrile convulsions in childhood and one grand mal seizure about two years previously. In the six months following recovery she was well on imipramine and Dilantin.
Patient 5: A 32 year old housewife was referred as an outpatient complaining of an inability to cope with her children, housework, and shopping. She had been prescribed oxazepam 30mg three times a day three years previously for anxiety and nausea. Six months prior to referral this was increased to 30mg four times a day because of insomnia and panic attacks. After discussion, she was withdrawn from oxazepam over two weeks, during which time she received thioridazine 25mg three times a day. During withdrawal she suffered insomnia and panic attacks. On the fifth day her head felt heavy and at times she felt separated from her body. On the sixth day of withdrawal she experienced gastric distress, poor concentration, was unsteady on her feet and developed severe muscle twitches. She had uncontrollable shaking spells which lasted for half an hour but no convulsions. Most of these symptoms persisted over the next ten days. Three weeks later she was much improved and felt better than over the past few years. This improvement continued during a four months follow-up.
Patient 6: A 35 year old housewife was referred as an outpatient with a depression of six months' duration which had failed to respond to two tricyclic antidepressants. She had first been prescribed diazepam 5mg three times a day ten years previously for anxiety. Over the past year she developed headaches, dizziness and muscle cramps if she missed her regular diazepam and she had increased her dose to 5mg four times a day. She was relieved to discuss her benzodiazepine dependence and requested a rapid withdrawal over four days. During the following week she had insomnia, panic attacks, blurred vision, paraesthesiae, headaches, a sense of rocking and periods of uncontrollable shaking. After two weeks her symptoms subsided and she has remained well.
Patient 7: A 39 year old housewife was referred as an outpatient for depression. She had been prescribed diazepam 5mg three times a day ten years before when she feared her husband had been lost at sea. Over the years the dose had increased to 10mg three times a day. During the past year she had twice attempted withdrawal and on both occasions had developed such severe gastric distress, muscle cramps, blurred vision and agitation that she had recommenced by the sixth day. She was withdrawn over a period of two weeks with additional help from thioridazine 25mg three times a day. By the third day she was more tearful, anxious and feeling depersonalised. These symptoms slowly settled, but about the tenth day recurred. She improved dramatically with the reinstitution of diazepam which was eventually withdrawn at an even slower rate. At follow-up she remained well.
Patient 8: A 21 year old female factory worker was referred as an outpatient for depression. She had been prescribed lorazepam 1mg three times a day three years previously for similar complaints. In the past few months she had increased her lorazepam to 1mg four times a day. She was prescribed amitriptyline but made no improvement. Her lorazepam was stopped abruptly and when seen on the eighth day she was ataxic and had paraesthesiae of her limbs and face. She had feelings of unreality and improved over the following weeks. She was later fully discharged on amitriptyline 75mg at night.
All of the reported cases were using benzodiazepines in therapeutic doses and were documented within a short period of time in a relatively small population, alarming us regarding the true incidence of these problems. More cases with withdrawal reactions have been seen over a longer period of time, many of whom were withdrawing from a number of drugs or had marked addictive personality traits.
Contrary to the view that these people are keen to take benzodiazepines, we found that they felt guilty and were eager to stop them. A number of them had in fact attempted withdrawal on their own but without success. Following withdrawal, only one of the cases showed any desire to use these drugs again in the short term (Table 1). Except for the one who experienced withdrawal convulsions, the rest had increased their dosage over a period of time to obtain the same relief.
Amongst the group who manifested the abstinence syndrome certain common features were discerned. These were women who had been prescribed a benzodiazepine in therapeutic doses over a minimum of three years for persisting anxiety and/or depression. On withdrawal they uniformly suffered from insomnia, panic attacks, agitation, depersonalisation and an increase in depression. Their suffering was obvious and they all described it as being the worst experience of their lives. Their feeling of well-being two weeks following complete withdrawal was remarkable except in one case where a second withdrawal seemed to occur and responded dramatically to reinstitution of the benzodiazepine. This drug was then withdrawn more gradually. None of these cases has required a benzodiazepine in the short term. Only in one case was another psychotropic drug required.
In all cases of acute organic brain syndrome a benzodiazepine was substituted resulting in marked improvement in mental status and thus confirming the diagnosis. Two of these three cases had withdrawn from a MAO inhibitor about a week earlier (Table 1). We are unaware of any synergistic effect between these drugs. It is interesting that these cases were withdrawing from benzodiazepines which have shorter half-lives (Table 1). Similarly, it is the barbiturates with shorter half-lives which are prone to cause dependence.(13) One of the hazards of lorazepam may be its relatively greater effectiveness leading onto the use of comparatively higher doses.
In the case of withdrawal convulsions, there were other complicating factors. These were the use of chlorpromazine and the patient's probably low convulsive threshold. However, Einarson (1980) has reported two cases following lorazepam withdrawal.(15)
Our experience suggests that there should be greater awareness regarding the problems of dependence on benzodiazepines and we would recommend that withdrawal be carried out slowly (rate of 5-10 percent per day) under close supervision. We are unable to estimate the true incidence of benzodiazepine dependence and would suggest that more work needs to be done in this area.
Table 1. Summary of patient characteristics, withdrawal symptoms and their management
# Age Sex Presenting
Drug dosage Length of
Tolerance Type of withdrawal reaction Treatment Follow-up drug schedule 1 38 M Psychotic
Lorazepam 2.5mg tds
one week earlier
4 weeks (other benzodiazepines over 12 months) Yes Acute organic brain syndrome Reinstitution of lorazepam Well
2 58 F Recurrent depression Lorazepam 2.5mg qid
stopped one week earlier
6 months (other benzodiazepines
for 4 years)
Yes Acute organic brain syndrome Reinstitution of lorazepam Perphenazine Trimipramine Thioridazine Lorazepam sos 3 61 M Psychotic
Oxazepam 15mg qid (alcohol detoxification 5 weeks earlier) 8 years Yes Acute organic brain syndrome Substitution by diazepam Nil 4 29 F Recurrent depression Lorazepam 2.5mg tds
3 years ? Grand mal convulsions Substitution by diazepam and
5 32 F Recurrent anxiety and depression Oxazepam
3 years Yes Agitation, depression, depersonal-
isation, sleep disturbances, 'shakes'
Thioridazine 25mg tds Well
6 35 F Recurrent depression Diazepam
10 years Yes Above along with headache and paraesthesiae No drugs Well
7 39 F Recurrent depression Diazepam
10 years Yes As above Thioridazine 25mg tds Well
8 21 F Recurrent anxiety and depression Lorazepam
3 years Yes Above and cerebellar signs No drugs Well Amitriptyline
We are grateful to Dr M. Langley and Dr H. R. Hewland who willingly allowed us to report some of their cases. We would like to thank Dr J. W. B. Walshe for help with the manuscript. Finally we would like to thank Mrs P. Mitcalfe and Mrs C. Khan for secretarial assistance.
Reprints: Requests for reprints to Dr A. Khan, Department of Psychological Medicine, Christchurch Hospital, Christchurch.
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