Drug and Alcohol Deptz&n.ce, 29 (1991) 195 - 204 Elsevier Scientific Publishers Ireland Ltd.
Benzodiazepine dependence: detoxification standardized conditions P.M. Brenner,
Department
B. Wolf, Th. Rechlin”, G. Kauertb, E. Riither’
of Psychiatry, University of Munich, ‘Department Medicine, University of Munich and ‘Department
under
and H. Hippius
of Neurology, Erlungen University, “Department of Psychiatry, GBttingrn University (Grrmrtny/
(Accepted September
of Forrn,sic
7th, 1991)
In an analysis of the withdrawal syndrome of 12 patients dependent on benzodiazepines (BZD), important factors such as underlying psychiatric disease, precipitating life events, complaints leading to BZD use, and also positive and negative psychological and social consequences, duration of intake, dose and type of BZD dependence are discussed. Withdrawal was completed under standardized inpatient conditions reducing the BZD dose to 50% of the previous dose once every 5 days and maintaining control through regular measurements of the BZD urine concentrations. The course of the somatic, psychological and perceptual withdrawal phenomena was documented according to Lader’s BZD withdrawal symptom checklist (Lader, M. (1983) J. Clin. Psychiatry 44, 121- 127). The reduction scheme proved to be safe and efficient; no major withdrawal syndromes developed. Abstinence phenomena largely disappeared within 10 days of discontinuation. Key words: benzodiazepines;
dependence;
withdrawal
syndrome; withdrawal
Introduction BZD are by far the most frequently prescribed psychotropic drugs. Data are available about the frequency of BZD use in the general population [2]. However, it is hardly possible to estimate the incidence of physical BZD dependence on the basis of scanty epidemiological investigations [3]. Boning [4] points out that although the risk of dependence may be relatively low in terms of extensive worldwide use, BZD dependence nevertheless represents a considerable problem in daily clinical practice. Several authors make a distinction between minor and major withdrawal symptoms [5-g]. Major events, such as withdrawal psychosis, delirium and convulsions were mainly observed afComespondvnce to: P.M. Brenner, Abt. fur Neurologie, Universitat Erlangen, Schwabachanlage 6, DW-8520 Erlangen, Germany. 0376~8716/91/$03.50 01991 Elsevier Scientific Publishers Printed and Published in Ireland
schedule; time course
ter sudden or too fast withdrawal of high doses taken over a long period of time [lo - 131. As with barbiturate dependence, gradual dose reduction is generally recommended in cases of long-term BZD intake [14 - 171, although there are only few detailed suggestions as to the course of reduction. Cone11 [18] and Harrison [19] favoured a daily reduction of lo%, which represents a linear drop in dose. Other authors [20 - 221 propose a weekly reduction of between 0.5 and 2.5 mg diazepam or an equivalent BZD dose. Some investigators suggest a minimum reduction time of 4 weeks [23,24], others regard an even slower procedure of up to 4 months as appropriate [25]. In addition, there were trials of BZD withdrawal aided by neuroleptics, anbetablockers, tidepressants, barbiturates, clonidine and baclofen, in which efficiency was judged to be divergent [26-361. The aim of this investigation was to work out a reduction schedule which is practicable in the Ireland Ltd.
196
clinical routine and clear to the patients, avoiding major withdrawal symptoms and making the withdrawal tolerable without unnecessarily lengthy inpatient treatment. Method Twelve patients, 10 women and 2 men, were admitted for detoxification to the ward for alcohol and drug addicts of the Department of Psychiatry of the University of Munich. Standardized withdrawal was carried out with all patients, the dose being reduced by 50% of the preceding dose every 5 days. This reduction procedure was used for both high- and low-dose dependence, merely requiring an extension of the withdrawal for high-dose dependence. At the beginning there was a rapid exponential decline in dosage, whereas towards the end of withdrawal only small reduction steps were taken. Withdrawal was carried out with the BZD derivative solely or mainly used by the patient in the previous 6 weeks. In order to verify the reliability of the patients’ statements with regard to dosage, to find out the starting dose, and to ascertain the current psychopathological status, a preceding observation period of several days continuing the stated dosage was schedul-
ed. On admission urine was screened for addicquantitative Further substances. tive assessments of BZD urine concentrations were carried out at 5-day intervals, each time prior to a reduction step (Fig. 1).Withdrawal symptoms were recorded daily according to Lader’s withdrawal symptom check-list [l].Calculation of the absolute values for the different categories of withdrawal symptoms, that is somatic, psychological and perceptual symptoms, took into account both the number and intensity (severity l-3) of the single symptoms. Patients rated their condition at 5-day intervals using the Befindlichkeitsskala (Bf-S) according to Von Zerssen. Results The 12 patients investigated (10 women and 2 men) were aged between 27 and 53 years old (average 45 years). The underlying psychiatric or neurological disorder was anxiety neurosis in 2 patients; depressive neuroses in 3; reactive depression in 2; and 1 case each of schizophrenia, dependent personality and nocturnal myoclonus syndrome (International Classificatoin of Diseases 9). For 2 patients the diagnosis was solely addiction. The following events were cited
100” 90
10 0. 100%
56%
12.;x
25%
6%
04:
Dose Fig. 1.
Percentage
of urine BZD-concentrations
during withdrawal courses of 12 patients.
as trigger factors for using substances with dependence liability (3 patients gave two factors): in 3 cases death of a relative, separation from a partner, chronic marital problems, birth (and in one patient also death) of a child, difficulties at work in 2 cases, divorce of parents and physical illness in 2 other cases. Two patients mentioned no precipitating life-event. Reasons for intake (6 patients gave several reasons) were given as: nervousness and tension by 7 patients; hyposomnia by 5; anxiety by 3; depression and pain by 2; weakness in the legs by one and difficulties in making contacts by one further patient, 1 patient began to use BZD following an alcohol withdrawal seizure. All patients - at least initially - experienced positive psychological effects. In 6 cases sedation and relaxation; in 5 anxiolysis; in 3 an improvement in sociability; and a temporary improvement of sleep or euphoric effect in one case each were mentioned. Gradually increasing negative effects were reported by all patients. The long-term BZD intake was regarded as, at least partly, responsible for concentration disturbances by 8 patients; memory impairment and lessened initiative by 5; deteriorating performance and efficiency by 4; rapid mood swings, depression and aggressive outbursts by 2 patients. In 7 cases there were negative social consequences such as divorce, difficulties at work, and job-loss. Primary BZD dependence was assumed only in 2 cases, secondary in 8 patients and classification remained indeterminate in 2. Alcohol was abused as the first addictive substance by 4 patients, barbiturates by 3 and an analgesic by 1. At time of admission 6 cases were classified as suffering from isolated BZD dependence, while in 2 cases the BZD dependence was connected with polytoxicomania and in 4 with alcoholism. Before starting BZD withdrawal, alcohol or other drugs had been discontinued. Five patients were assumed to have high-dose, and 7 low-dose dependence. The upper therapeutic limit representing the low-dose category was settled by 30 mglday diazepam or an equivalent dose of another BZD derivate. Increase in dosage occurred in 10 cases, but
the dose still remained within therapeutic limits in 5. The average daily equivalent dose was 41 mg diazepam. With regard to BZD derivatives, bromazepam was the most common, recently taken substance in 8 cases. The average duration of BZD intake, including time of use, abuse and dependence, was 13.7 years varying between 3.5 and 24 years. Use was defined as either sporadic or regular without increase of dose and the possibility of abstinence. Abuse was assumed when there was an increase of dose beyond the therapeutically indicated limit or a simultaneous intake of several different BZD derivatives. Physical dependence was evidenced by withdrawal symptoms occurring on reduction or discontinuation. In most cases psychological dependence preceded the physical one; as the addictive development was a gradual process the beginning of psychological dependence was difficult to define. An average duration of physical dependence of 4.6 years, varying between 1 and 10 years, was determined with reasonable certainty, judged by the first occurrence of abstion previous withdrawal nence symptoms attempts by the patient. Withdrawal
symptoms
All 12 patients suffered at some time during withdrawal both from physical and psychological withdrawal symptoms and 11 patients reported perceptual disturbances (Table I). The intensity and duration of the withdrawal symptoms and also the number of symptoms were subject to great intra- and interindividual variation. The following physical symptoms occurred in decreasing order of frequency (Table I): insomnia, sweating, tremor, headache, palpitafasciculations, nightmares, loss of tions, appetite, dizziness and blurred vision. Eleven patients suffered from slight to severe headache, which in one patient had led to inmeasures including vasive diagnostic angiography and lumbar puncture. Fasciculations predominantly of the lower extremities, were observed in 9 patients; 8 patients complained of nightmares, 5 patients developed gastro-intestinal symptoms, some with the se-
198
Table I.
Most frequent withdrawal
Perceptual
Psychological
Somatic Insomnia Tremor Headache Palpitations Loss of appetite Fasciculations Nightmares Dizziness Blurred vision Nausea Abdominal cramps
symptoms.
12 12 11 11 9 9 8 7 7 6 5
Inner restlessness Depression Concentration disturbance Anxiety Motor restlessness Loss of drive Dysphoria Irritability Impaired memory Affective instability Euphoria (intermittent) Suicidal ideas Depersonalisation
verity of an acute abdomen, leading to extensive diagnostic measures. The major psychological withdrawal symptoms were inner and motor restlessness, depression, diffuse anxiety, affective instability with fluctuations between dysphoria and irritability on the one hand and euphoria on the other. Three patients developed suicidal ideas in the withdrawal situation, two of them for the first time. Three patients experienced frightening depersonalisation phenomena. Perceptual disturbances such as change of taste, hypersensitivity to noise and paraesthesias were recorded in 11 cases according to Lader’s scale [l]. Time course of withdrawal syndrome (Figs. 2 and 3)
The physical withdrawal symptoms ascertained with the Lader’s BZD withdrawal symptom checklist reached their maximum between 12.5 and 25% of the initial dose. The psychological symptoms (Fig. 4) and perceptual changes (Fig. 5) reached peak intensity at a dose reduction to 25%. Ten days after complete discontinuation the physical and psychological symptoms had already dropped below the basal value at the full dose (100%). Perceptual disturbances persisted longest in largely diminished intensity. The self-assessment according to the Bf-S
12 11 8 8 8 8 6 6 6 5 4 3 3
Changed/diminished taste Paraesthesias Hypersensitivity of noise Feeling of motion/swaying
8 5 7 5
(Fig. 6) corresponded well with the objective rating, The patients’ condition was estimated to be worst at a BZD reduction to 25 and 12.5% and almost regained the starting level at complete discontinuation. Surprisingly the severity of withdrawal symptoms was experienced as being relatively mild in contrast to the objective rating. Discussion In line with published reports [3,37], our patients were mainly middle-aged women. As found by other authors [4,8,21], BZD dependence mostly developed on the basis of an underlying psychiatric disorder, above all depressive neuroses and anxiety disorders. Personalities with depressive, anxious or asthenic traits seemed to be predisposed [22] to abuse. The abuse usually began in connection with particular life-events [11,38,39,40]. All of our patients experienced negative psychological and/or social consequences. Almost without exception an organic brain syndrome caused by chronic intoxication, with lack of initiative, loss of interest, depressivedysphoric mood, poor concentration and forgetfulness could been demonstrated. Such negative effects summarized by Radmayer [41] under the
0%
1215% Dose Fig.
2.
Time course
of withdrawal
symptomatology
during
tapering
in 1‘2 BZD dependent
patients.
60 70 60
30 20 10 0 100%
50%
25%
12.5%
0%
5days after
Dose Fig.
3.
Time course
of somatic
withdrawal
symptoms.
10 days after
200
80
10 0 100%
12.5%
25%
50%
0%
5doys after
10 days after
Dose Fig. 4. Time course of psychological withdrawal
symptoms.
20
15 6 :: 10
5
0 100%
50%
25%
12.5%
0%
Dose Fig. 5. Time course of perceptual
disturbances
5 days after
‘OZ
after 15daF
201
30 1
25-
20-
h $15ul
lo-
5-
07 25%
12.5%
0%
Dose Fig.
6.
Time course
of self-rating
(Bf-S [0 - 561 according
term ‘intoxication psycho-syndrome’, have only rarely been described so far [27,37,42,43]. After initial positive social effects such as improvement of sociability and loss of inhibitions, social problems such as difficulties at work or divorce arose with some of the patients later in the course. The detrimental effects in our patients are probably connected with the long duration of intake, averaging 14 years. Long-term abuse rarely exceeded a decade [8,17,31]. Five of our patients increased their dose, but still remained within the therapeutic limits. This agreed with other observations that an excess in dose was not necessarily a criterion for diagnosis of BZD dependence [38,44]. Half of our patients were classified as suffering from primary, half from secondary BZD dependence. Two patients took BZD exclusively; the remaining 10 at times used alcohol or other potentially addictive drugs in addition. However, at least ultimately, BZD represented the main addictive substance for all patients. During
to von Zerssen).
the first days symptoms typical of alcohol withdrawal were observed in the 4 patients with combined BZD-alcohol dependence. Initial continuation of the patients’ usual BZD dose probably mitigated these symptoms, however. BZD tapering started after an interval of several days. This two-step withdrawal procedure allowed a fairly certain differentiation of symptoms caused by withdrawal of BZD, e.g. the relatively BZD-specific perceptual disturbances and those of the alcohol withdrawal syndrome [24,45,46]. The long duration of intake probably explained the occurrence of withdrawal symptoms in all patients. Several investigators [6,37,38] found a correlation between length of intake and severity of the withdrawal syndrome. There was no appreciable difference in the severity of withdrawal symptoms between patients with highor low-dose dependence, which is also confirmed by other authors [1,24,45]. This may be partly explained by the fact that the reduction phase was longer for patients with high-dose dependence. With regard to frequency of the different
202
withdrawal symptoms, the results we obtained from the Lader withdrawal check-list correspond to Lader’s own study on 24 patients [l]. Eleven of the 12 patients reported perceptual disturbances, including transitory symptoms. Mellor [47] also found high percentages for patients with high-dose dependence, e.g. hyperacusis, in 80% of the cases, while Schopf [8] reported a frequency of 50% during withdrawal from therapeutic doses. In contrast to most investigators, we recorded findings daily and so also included symptoms, even those which occurred only briefly for 1 or 2 days. This frequent assessment seemed essential to establish a clear-cut picture of the withdrawal syndrome, particularly as it is well known that the course of withdrawal symptoms may fluctuate 19,471. Similar to Lader [l], we found disturbed gustation such as changed or lessened tastesensitivity in two-thirds of the patients. The high incidence (92%) of headache was remarkable, as also pointed out by other authors, although with lower frequency [1,7,17]. Whereas abdominal symptoms have been largely associated with withdrawal of opioids, gastrointestinal symptoms such as nausea and abdominal pain in half of our patients showed that such symptoms were also rather frequent during BZD withdrawal. Next to restlessness and tension, insomnia was the common reason for BZD intake; anxiety as the main symptom leading to BZD use was mentioned somewhat less often, in contrast to other reports [1,8,47-491. Whereas three patients experienced anxiety as a new phenomenon during withdrawal, five patients exhibited a temporary increase in pre-existing anxiety, gradually returning to its pre-withdrawal level, representing rebound anxiety, as described by Scharf 1501. Five patients experienced very distressing mood swings. Depression clearly predominated in our study, in 4 cases alternating intermittently with euphoric states [27,31,51,52]. Several investigators have drawn attention to possible suicidal tendencies in connection with withdrawal [29,34,46]. Three of our patients suffered suicidal ideas during withdrawal, two of them for the first time, a remin-
der that during withdrawal the suicide risk is not to be underestimated. We tried to elaborate a clearly defined reduction schedule appropriate for inpatient BZD withdrawal. The recommendations of Rickels [21] and Lader [53], who suggested reduction steps of between 0.5 and 2.5 mg diazepam per week, were more suitable for outpatient rather than for inpatient withdrawal, as they were obviously time consuming. The suggestion of other authors concerning inpatient withdrawal [18,19] at a daily reduction rate of 10% is too fast in our experience. Whereas these methods represent a linear decline in dosage, our concern was to investigate the efficiency of reducing the dose in an exponential fashion which has the advantage of progressively smaller reduction steps. The withdrawal syndrome reached its peak at the reduction to 25% and 12.5% of the initial dose whereas Smith [9] considered the final reduction step the most difficult. This difference may be explained by the exponential course of our tapering schedule resulting in a very small last reduction step. The length of time until complete withdrawal of BZD was relatively short, between 3 and 5 weeks, depending on the starting dose. The patients remained in hospital for about another 2 weeks for further stabilisation. Whereas in Lader’s investigation [l], the psychological withdrawal symptoms were more persistent, our results agree with those of Mellor [47] and Schijpf [54] who observed that the physical and in particular the perceptual withdrawal symptoms lasted longer. In contrast to the reports of Boning [29] and Schijpf [54] who described withdrawal symptoms persisting for months, the abstinence phenomena in our study had largely disappeared 10 days after complete discontinuation. Three months after symptoms were discharge no withdrawal present. No major withdrawal symptoms such as delirium, psychosis or seizures occurred under this scheme and the EEGs carried out at 5-day intervals gave no indication of a decreased seizure threshold. The intensity of the withdrawal syndrome appeared tolerable for all patients. It never reached a stage at which supplementary
medication, such as antidepressants, neuroleptics or clomethiazole was necessary. In our opinion it is important to explain the planned withdrawal scheme and the symptoms which may emerge to the patients, in order that they be clear on the expected treatment. However, particularly with suggestible and hypochondriac patients, there is the risk of inducing pseudo-withdrawal symptoms [6,55], especially if possible withdrawal phenomena are rated daily. Differentiation between true and pseudo-withdrawal symptoms would only be possible by means of a placebo-controlled study. However, a pseudo-withdrawal syndrome seems unlikely in the patients examined, since the intensity of the withdrawal symptoms did not reach its peak at complete discontinuation but at an earlier reduction phase. After detoxification the treatment of the underlying psychiatric disorder was not to be ignored. In respect of the common underlying anxiety neuroses or depressive neuroses a therapy with antidepressants and/or betablockers was to be considered in addition to psychotherapeutic measures, as otherwise the danger of relapse to BZD dependence appeared relatively high [56]. With pre-existent chronic hyposomnia, prescription of a sedative antidepressant could be considered [57,58]. If treatment of the withdrawal syndrome was required, temporary medication with sedative antidepressants such as doxepin or amitryptiline could be useful in individual cases with pronounced anxiety, agitation, affective instability, depression and suicidal impulses [29,51].
of the initial dose, which may be explained by the exponential course of our reduction schedule, resulting in very small last reduction steps. We regarded the withdrawal schedule under investigation with a 50% reduction of the preceding dose every 5 days as practicable and safe, since no complications such as withdrawal psychosis, delirium, seizures or suicide attempts occurred. Furthermore no other psychotropic medication was necessary during withdrawal, and detoxification could be carried out within a reasonable time between 3 and 5 weeks. In the outpatient situation more gradual withdrawal over some months seemed advisable when dependence had lasted several years. However, we preferred withdrawal under stationary conditions. Since all patients suffered from negative psychological and/or social consequences such as concentration and memory disturbances, lessened initiative, irritability and also social problems such as dosage and abuse duration increased, and since no effective treatment of the underlying psychiatric disorder was carried out during BZD intake, we regarded long-term BZD medication as inadequate treatment in cases such as those examined here. If the underlying psychiatric illness still persisted, detoxification and subsequent participation in a self-help group seemed to be sufficient only for relatively stable individuals, whereas psychotherapeutic measures and/or treatment with antidepressants or betablockers were to be considered for more severely disturbed patients.
Conclusions
References
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Benzodiazepine dependence: detoxification standardized conditions P.M. Brenner,
Department
B. Wolf, Th. Rechlin”, G. Kauertb, E. Riither’
of Psychiatry, University of Munich, ‘Department Medicine, University of Munich and ‘Department
under
and H. Hippius
of Neurology, Erlungen University, “Department of Psychiatry, GBttingrn University (Grrmrtny/
(Accepted September
of Forrn,sic
7th, 1991)
In an analysis of the withdrawal syndrome of 12 patients dependent on benzodiazepines (BZD), important factors such as underlying psychiatric disease, precipitating life events, complaints leading to BZD use, and also positive and negative psychological and social consequences, duration of intake, dose and type of BZD dependence are discussed. Withdrawal was completed under standardized inpatient conditions reducing the BZD dose to 50% of the previous dose once every 5 days and maintaining control through regular measurements of the BZD urine concentrations. The course of the somatic, psychological and perceptual withdrawal phenomena was documented according to Lader’s BZD withdrawal symptom checklist (Lader, M. (1983) J. Clin. Psychiatry 44, 121- 127). The reduction scheme proved to be safe and efficient; no major withdrawal syndromes developed. Abstinence phenomena largely disappeared within 10 days of discontinuation. Key words: benzodiazepines;
dependence;
withdrawal
syndrome; withdrawal
Introduction BZD are by far the most frequently prescribed psychotropic drugs. Data are available about the frequency of BZD use in the general population [2]. However, it is hardly possible to estimate the incidence of physical BZD dependence on the basis of scanty epidemiological investigations [3]. Boning [4] points out that although the risk of dependence may be relatively low in terms of extensive worldwide use, BZD dependence nevertheless represents a considerable problem in daily clinical practice. Several authors make a distinction between minor and major withdrawal symptoms [5-g]. Major events, such as withdrawal psychosis, delirium and convulsions were mainly observed afComespondvnce to: P.M. Brenner, Abt. fur Neurologie, Universitat Erlangen, Schwabachanlage 6, DW-8520 Erlangen, Germany. 0376~8716/91/$03.50 01991 Elsevier Scientific Publishers Printed and Published in Ireland
schedule; time course
ter sudden or too fast withdrawal of high doses taken over a long period of time [lo - 131. As with barbiturate dependence, gradual dose reduction is generally recommended in cases of long-term BZD intake [14 - 171, although there are only few detailed suggestions as to the course of reduction. Cone11 [18] and Harrison [19] favoured a daily reduction of lo%, which represents a linear drop in dose. Other authors [20 - 221 propose a weekly reduction of between 0.5 and 2.5 mg diazepam or an equivalent BZD dose. Some investigators suggest a minimum reduction time of 4 weeks [23,24], others regard an even slower procedure of up to 4 months as appropriate [25]. In addition, there were trials of BZD withdrawal aided by neuroleptics, anbetablockers, tidepressants, barbiturates, clonidine and baclofen, in which efficiency was judged to be divergent [26-361. The aim of this investigation was to work out a reduction schedule which is practicable in the Ireland Ltd.
196
clinical routine and clear to the patients, avoiding major withdrawal symptoms and making the withdrawal tolerable without unnecessarily lengthy inpatient treatment. Method Twelve patients, 10 women and 2 men, were admitted for detoxification to the ward for alcohol and drug addicts of the Department of Psychiatry of the University of Munich. Standardized withdrawal was carried out with all patients, the dose being reduced by 50% of the preceding dose every 5 days. This reduction procedure was used for both high- and low-dose dependence, merely requiring an extension of the withdrawal for high-dose dependence. At the beginning there was a rapid exponential decline in dosage, whereas towards the end of withdrawal only small reduction steps were taken. Withdrawal was carried out with the BZD derivative solely or mainly used by the patient in the previous 6 weeks. In order to verify the reliability of the patients’ statements with regard to dosage, to find out the starting dose, and to ascertain the current psychopathological status, a preceding observation period of several days continuing the stated dosage was schedul-
ed. On admission urine was screened for addicquantitative Further substances. tive assessments of BZD urine concentrations were carried out at 5-day intervals, each time prior to a reduction step (Fig. 1).Withdrawal symptoms were recorded daily according to Lader’s withdrawal symptom check-list [l].Calculation of the absolute values for the different categories of withdrawal symptoms, that is somatic, psychological and perceptual symptoms, took into account both the number and intensity (severity l-3) of the single symptoms. Patients rated their condition at 5-day intervals using the Befindlichkeitsskala (Bf-S) according to Von Zerssen. Results The 12 patients investigated (10 women and 2 men) were aged between 27 and 53 years old (average 45 years). The underlying psychiatric or neurological disorder was anxiety neurosis in 2 patients; depressive neuroses in 3; reactive depression in 2; and 1 case each of schizophrenia, dependent personality and nocturnal myoclonus syndrome (International Classificatoin of Diseases 9). For 2 patients the diagnosis was solely addiction. The following events were cited
100” 90
10 0. 100%
56%
12.;x
25%
6%
04:
Dose Fig. 1.
Percentage
of urine BZD-concentrations
during withdrawal courses of 12 patients.
as trigger factors for using substances with dependence liability (3 patients gave two factors): in 3 cases death of a relative, separation from a partner, chronic marital problems, birth (and in one patient also death) of a child, difficulties at work in 2 cases, divorce of parents and physical illness in 2 other cases. Two patients mentioned no precipitating life-event. Reasons for intake (6 patients gave several reasons) were given as: nervousness and tension by 7 patients; hyposomnia by 5; anxiety by 3; depression and pain by 2; weakness in the legs by one and difficulties in making contacts by one further patient, 1 patient began to use BZD following an alcohol withdrawal seizure. All patients - at least initially - experienced positive psychological effects. In 6 cases sedation and relaxation; in 5 anxiolysis; in 3 an improvement in sociability; and a temporary improvement of sleep or euphoric effect in one case each were mentioned. Gradually increasing negative effects were reported by all patients. The long-term BZD intake was regarded as, at least partly, responsible for concentration disturbances by 8 patients; memory impairment and lessened initiative by 5; deteriorating performance and efficiency by 4; rapid mood swings, depression and aggressive outbursts by 2 patients. In 7 cases there were negative social consequences such as divorce, difficulties at work, and job-loss. Primary BZD dependence was assumed only in 2 cases, secondary in 8 patients and classification remained indeterminate in 2. Alcohol was abused as the first addictive substance by 4 patients, barbiturates by 3 and an analgesic by 1. At time of admission 6 cases were classified as suffering from isolated BZD dependence, while in 2 cases the BZD dependence was connected with polytoxicomania and in 4 with alcoholism. Before starting BZD withdrawal, alcohol or other drugs had been discontinued. Five patients were assumed to have high-dose, and 7 low-dose dependence. The upper therapeutic limit representing the low-dose category was settled by 30 mglday diazepam or an equivalent dose of another BZD derivate. Increase in dosage occurred in 10 cases, but
the dose still remained within therapeutic limits in 5. The average daily equivalent dose was 41 mg diazepam. With regard to BZD derivatives, bromazepam was the most common, recently taken substance in 8 cases. The average duration of BZD intake, including time of use, abuse and dependence, was 13.7 years varying between 3.5 and 24 years. Use was defined as either sporadic or regular without increase of dose and the possibility of abstinence. Abuse was assumed when there was an increase of dose beyond the therapeutically indicated limit or a simultaneous intake of several different BZD derivatives. Physical dependence was evidenced by withdrawal symptoms occurring on reduction or discontinuation. In most cases psychological dependence preceded the physical one; as the addictive development was a gradual process the beginning of psychological dependence was difficult to define. An average duration of physical dependence of 4.6 years, varying between 1 and 10 years, was determined with reasonable certainty, judged by the first occurrence of abstion previous withdrawal nence symptoms attempts by the patient. Withdrawal
symptoms
All 12 patients suffered at some time during withdrawal both from physical and psychological withdrawal symptoms and 11 patients reported perceptual disturbances (Table I). The intensity and duration of the withdrawal symptoms and also the number of symptoms were subject to great intra- and interindividual variation. The following physical symptoms occurred in decreasing order of frequency (Table I): insomnia, sweating, tremor, headache, palpitafasciculations, nightmares, loss of tions, appetite, dizziness and blurred vision. Eleven patients suffered from slight to severe headache, which in one patient had led to inmeasures including vasive diagnostic angiography and lumbar puncture. Fasciculations predominantly of the lower extremities, were observed in 9 patients; 8 patients complained of nightmares, 5 patients developed gastro-intestinal symptoms, some with the se-
198
Table I.
Most frequent withdrawal
Perceptual
Psychological
Somatic Insomnia Tremor Headache Palpitations Loss of appetite Fasciculations Nightmares Dizziness Blurred vision Nausea Abdominal cramps
symptoms.
12 12 11 11 9 9 8 7 7 6 5
Inner restlessness Depression Concentration disturbance Anxiety Motor restlessness Loss of drive Dysphoria Irritability Impaired memory Affective instability Euphoria (intermittent) Suicidal ideas Depersonalisation
verity of an acute abdomen, leading to extensive diagnostic measures. The major psychological withdrawal symptoms were inner and motor restlessness, depression, diffuse anxiety, affective instability with fluctuations between dysphoria and irritability on the one hand and euphoria on the other. Three patients developed suicidal ideas in the withdrawal situation, two of them for the first time. Three patients experienced frightening depersonalisation phenomena. Perceptual disturbances such as change of taste, hypersensitivity to noise and paraesthesias were recorded in 11 cases according to Lader’s scale [l]. Time course of withdrawal syndrome (Figs. 2 and 3)
The physical withdrawal symptoms ascertained with the Lader’s BZD withdrawal symptom checklist reached their maximum between 12.5 and 25% of the initial dose. The psychological symptoms (Fig. 4) and perceptual changes (Fig. 5) reached peak intensity at a dose reduction to 25%. Ten days after complete discontinuation the physical and psychological symptoms had already dropped below the basal value at the full dose (100%). Perceptual disturbances persisted longest in largely diminished intensity. The self-assessment according to the Bf-S
12 11 8 8 8 8 6 6 6 5 4 3 3
Changed/diminished taste Paraesthesias Hypersensitivity of noise Feeling of motion/swaying
8 5 7 5
(Fig. 6) corresponded well with the objective rating, The patients’ condition was estimated to be worst at a BZD reduction to 25 and 12.5% and almost regained the starting level at complete discontinuation. Surprisingly the severity of withdrawal symptoms was experienced as being relatively mild in contrast to the objective rating. Discussion In line with published reports [3,37], our patients were mainly middle-aged women. As found by other authors [4,8,21], BZD dependence mostly developed on the basis of an underlying psychiatric disorder, above all depressive neuroses and anxiety disorders. Personalities with depressive, anxious or asthenic traits seemed to be predisposed [22] to abuse. The abuse usually began in connection with particular life-events [11,38,39,40]. All of our patients experienced negative psychological and/or social consequences. Almost without exception an organic brain syndrome caused by chronic intoxication, with lack of initiative, loss of interest, depressivedysphoric mood, poor concentration and forgetfulness could been demonstrated. Such negative effects summarized by Radmayer [41] under the
0%
1215% Dose Fig.
2.
Time course
of withdrawal
symptomatology
during
tapering
in 1‘2 BZD dependent
patients.
60 70 60
30 20 10 0 100%
50%
25%
12.5%
0%
5days after
Dose Fig.
3.
Time course
of somatic
withdrawal
symptoms.
10 days after
200
80
10 0 100%
12.5%
25%
50%
0%
5doys after
10 days after
Dose Fig. 4. Time course of psychological withdrawal
symptoms.
20
15 6 :: 10
5
0 100%
50%
25%
12.5%
0%
Dose Fig. 5. Time course of perceptual
disturbances
5 days after
‘OZ
after 15daF
201
30 1
25-
20-
h $15ul
lo-
5-
07 25%
12.5%
0%
Dose Fig.
6.
Time course
of self-rating
(Bf-S [0 - 561 according
term ‘intoxication psycho-syndrome’, have only rarely been described so far [27,37,42,43]. After initial positive social effects such as improvement of sociability and loss of inhibitions, social problems such as difficulties at work or divorce arose with some of the patients later in the course. The detrimental effects in our patients are probably connected with the long duration of intake, averaging 14 years. Long-term abuse rarely exceeded a decade [8,17,31]. Five of our patients increased their dose, but still remained within the therapeutic limits. This agreed with other observations that an excess in dose was not necessarily a criterion for diagnosis of BZD dependence [38,44]. Half of our patients were classified as suffering from primary, half from secondary BZD dependence. Two patients took BZD exclusively; the remaining 10 at times used alcohol or other potentially addictive drugs in addition. However, at least ultimately, BZD represented the main addictive substance for all patients. During
to von Zerssen).
the first days symptoms typical of alcohol withdrawal were observed in the 4 patients with combined BZD-alcohol dependence. Initial continuation of the patients’ usual BZD dose probably mitigated these symptoms, however. BZD tapering started after an interval of several days. This two-step withdrawal procedure allowed a fairly certain differentiation of symptoms caused by withdrawal of BZD, e.g. the relatively BZD-specific perceptual disturbances and those of the alcohol withdrawal syndrome [24,45,46]. The long duration of intake probably explained the occurrence of withdrawal symptoms in all patients. Several investigators [6,37,38] found a correlation between length of intake and severity of the withdrawal syndrome. There was no appreciable difference in the severity of withdrawal symptoms between patients with highor low-dose dependence, which is also confirmed by other authors [1,24,45]. This may be partly explained by the fact that the reduction phase was longer for patients with high-dose dependence. With regard to frequency of the different
202
withdrawal symptoms, the results we obtained from the Lader withdrawal check-list correspond to Lader’s own study on 24 patients [l]. Eleven of the 12 patients reported perceptual disturbances, including transitory symptoms. Mellor [47] also found high percentages for patients with high-dose dependence, e.g. hyperacusis, in 80% of the cases, while Schopf [8] reported a frequency of 50% during withdrawal from therapeutic doses. In contrast to most investigators, we recorded findings daily and so also included symptoms, even those which occurred only briefly for 1 or 2 days. This frequent assessment seemed essential to establish a clear-cut picture of the withdrawal syndrome, particularly as it is well known that the course of withdrawal symptoms may fluctuate 19,471. Similar to Lader [l], we found disturbed gustation such as changed or lessened tastesensitivity in two-thirds of the patients. The high incidence (92%) of headache was remarkable, as also pointed out by other authors, although with lower frequency [1,7,17]. Whereas abdominal symptoms have been largely associated with withdrawal of opioids, gastrointestinal symptoms such as nausea and abdominal pain in half of our patients showed that such symptoms were also rather frequent during BZD withdrawal. Next to restlessness and tension, insomnia was the common reason for BZD intake; anxiety as the main symptom leading to BZD use was mentioned somewhat less often, in contrast to other reports [1,8,47-491. Whereas three patients experienced anxiety as a new phenomenon during withdrawal, five patients exhibited a temporary increase in pre-existing anxiety, gradually returning to its pre-withdrawal level, representing rebound anxiety, as described by Scharf 1501. Five patients experienced very distressing mood swings. Depression clearly predominated in our study, in 4 cases alternating intermittently with euphoric states [27,31,51,52]. Several investigators have drawn attention to possible suicidal tendencies in connection with withdrawal [29,34,46]. Three of our patients suffered suicidal ideas during withdrawal, two of them for the first time, a remin-
der that during withdrawal the suicide risk is not to be underestimated. We tried to elaborate a clearly defined reduction schedule appropriate for inpatient BZD withdrawal. The recommendations of Rickels [21] and Lader [53], who suggested reduction steps of between 0.5 and 2.5 mg diazepam per week, were more suitable for outpatient rather than for inpatient withdrawal, as they were obviously time consuming. The suggestion of other authors concerning inpatient withdrawal [18,19] at a daily reduction rate of 10% is too fast in our experience. Whereas these methods represent a linear decline in dosage, our concern was to investigate the efficiency of reducing the dose in an exponential fashion which has the advantage of progressively smaller reduction steps. The withdrawal syndrome reached its peak at the reduction to 25% and 12.5% of the initial dose whereas Smith [9] considered the final reduction step the most difficult. This difference may be explained by the exponential course of our tapering schedule resulting in a very small last reduction step. The length of time until complete withdrawal of BZD was relatively short, between 3 and 5 weeks, depending on the starting dose. The patients remained in hospital for about another 2 weeks for further stabilisation. Whereas in Lader’s investigation [l], the psychological withdrawal symptoms were more persistent, our results agree with those of Mellor [47] and Schijpf [54] who observed that the physical and in particular the perceptual withdrawal symptoms lasted longer. In contrast to the reports of Boning [29] and Schijpf [54] who described withdrawal symptoms persisting for months, the abstinence phenomena in our study had largely disappeared 10 days after complete discontinuation. Three months after symptoms were discharge no withdrawal present. No major withdrawal symptoms such as delirium, psychosis or seizures occurred under this scheme and the EEGs carried out at 5-day intervals gave no indication of a decreased seizure threshold. The intensity of the withdrawal syndrome appeared tolerable for all patients. It never reached a stage at which supplementary
medication, such as antidepressants, neuroleptics or clomethiazole was necessary. In our opinion it is important to explain the planned withdrawal scheme and the symptoms which may emerge to the patients, in order that they be clear on the expected treatment. However, particularly with suggestible and hypochondriac patients, there is the risk of inducing pseudo-withdrawal symptoms [6,55], especially if possible withdrawal phenomena are rated daily. Differentiation between true and pseudo-withdrawal symptoms would only be possible by means of a placebo-controlled study. However, a pseudo-withdrawal syndrome seems unlikely in the patients examined, since the intensity of the withdrawal symptoms did not reach its peak at complete discontinuation but at an earlier reduction phase. After detoxification the treatment of the underlying psychiatric disorder was not to be ignored. In respect of the common underlying anxiety neuroses or depressive neuroses a therapy with antidepressants and/or betablockers was to be considered in addition to psychotherapeutic measures, as otherwise the danger of relapse to BZD dependence appeared relatively high [56]. With pre-existent chronic hyposomnia, prescription of a sedative antidepressant could be considered [57,58]. If treatment of the withdrawal syndrome was required, temporary medication with sedative antidepressants such as doxepin or amitryptiline could be useful in individual cases with pronounced anxiety, agitation, affective instability, depression and suicidal impulses [29,51].
of the initial dose, which may be explained by the exponential course of our reduction schedule, resulting in very small last reduction steps. We regarded the withdrawal schedule under investigation with a 50% reduction of the preceding dose every 5 days as practicable and safe, since no complications such as withdrawal psychosis, delirium, seizures or suicide attempts occurred. Furthermore no other psychotropic medication was necessary during withdrawal, and detoxification could be carried out within a reasonable time between 3 and 5 weeks. In the outpatient situation more gradual withdrawal over some months seemed advisable when dependence had lasted several years. However, we preferred withdrawal under stationary conditions. Since all patients suffered from negative psychological and/or social consequences such as concentration and memory disturbances, lessened initiative, irritability and also social problems such as dosage and abuse duration increased, and since no effective treatment of the underlying psychiatric disorder was carried out during BZD intake, we regarded long-term BZD medication as inadequate treatment in cases such as those examined here. If the underlying psychiatric illness still persisted, detoxification and subsequent participation in a self-help group seemed to be sufficient only for relatively stable individuals, whereas psychotherapeutic measures and/or treatment with antidepressants or betablockers were to be considered for more severely disturbed patients.
Conclusions
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