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Dependence liability of the benzodiazepines
Drug and Alcohol Dependence, 13 (1984) 139-l Elsevier Scientific Publishers Ireland Ltd.
DEPENDENCE
LIABILITY
49
139
OF THE BENZODIAZEPINES
D. LADEWIG* Department
of Psychiatry, University of Basle (Switzerland)
(Received December 23rd, 1983)
SUMMARY
According to pharmacological data as well as to clinical experience a potential of benzodiazepines for producing dependence is not a matter of doubt. However, when compared to the dependence liability of barbiturates the corresponding effect of benzodiazepines is low. In evaluating the dependence potential of benzediazepines account must be taken of the rareness of psychotropic effects of these substances and of the absence of usual mechanisms of tolerance, as well as the epidemiology of psychosomatic syndromes and their treatment outcome. The paper summarizes different types of clinical approaches to evaluating the abuse and dependence liability. In relation to the high incidence of prescriptions for benzodiazepines, the incidence of dependence syndromes is low, but with a wide range of degrees and patterns of such syndromes, Mostly autonomic and psychic symptoms, occasionally grand mal seizures and sensory disturbances and very rarely psychotic symptoms have been described. While the time course differs there is, in comparison to barbiturates, a shift in onset and duration of symptoms. Key words: Benzodiazepines dromes
- Abuse - Dependence
- Withdrawal
syn-
That benzodiazepines present a potential for dependence is not a matter for doubt. They exhibit partial cross tolerance vis$-vis all the substances belonging to the alcohol-barbiturate type of drug dependence**, This is illustrated clinically by the fact that symptoms of withdrawal from barbiturates such as anxiety, tremor and epileptiform seizures can be aborted by benzodiazepines. It should nevertheless be noted that pentobarbital, for instance, suppresses diazepam withdrawal symptoms but is less effective in *Address for correspondence: Psychiatrische Universitatsklinik, Wilhelm-Klein-Strasse 27, CH-4025, Basel, Switzerland **WHO Expert Committee on Drug Dependence, Technical Report Series, 1969, No. 407. 0376-8716/84/$03.00 o 1984 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
140
doing so than diazepam itself; similarly diazepam suppresses pentobarbitalinduced withdrawal to a lesser degree than does pentobarbital itself [l] . It is also clear that the dependence liability of the benzodiazepines is smaller than that of the substances of the alcohol-barbiturate type and this for two reasons: benzodiazepines have only rarely a psychotropic effect in the sense of mood changes, euphorization or stupor. This is in accordance with clinical and epidemiological experience [ 21 and is corroborated by the few self-administration studies carried out to date. Thus, Johanson and Ulenhuth [ 31 found in a comparison of diazepam and placebo that the placebo preparation was preferred, whereas amphetamine was preferred in a comparison of amphetamine and placebo. Likewise, anxiety-prone subjects tend to prefer a placebo to diazepam: ‘Even in a population of anxious subjects, the anti-anxiety property of the drug does not appear to be a sufficient condition to make it a positive reinforcer. It was algo shown that time of day did not affect the preference of diazepam, even when the drug’s presumed disruptive effects were minimized by giving it late in the day at a time more consistent with recreational drug use’ (de Wit et al. [4] ). In analogous studies with subjects exhibiting sedative abuse, pentobarbital received greater perference over diazepam in comparable doses. Only in non-therapeutic single doses (20-200 mg) did diazepam have a reinforcer effect on consumption behaviour [ 51. A second reason for the comparatively low dependence liability of benzodiazepines is the mechanism of development of tolerance, i.e., tolerance based on enzyme induction appears to be absent. The extent to which central nervous system adaptation at the receptor level can be explained as a tolerance phenomenon is still an open question. Before going into greater detail about the dependence liability and the abstinence syndrome, attention should be drawn to certain psychosocial aspects as regards, their significance for the problem of dependence. The misgivings about benzodiazepines, voiced with increasing frequency at the present time, appear to result primarily from uncertainty about the precise definition of their therapeutic indication and about possible overprescribing. While certain properties of the benzodiazepines with their broad ‘therapeutic spectrum’ and ‘safety’ may possibly result in overprescribing, it must also be noted that the risk of these substances is not a matter merely of their pharmacological properties in the sense of a dependence liability, but is determined also by the medical and socio-cultural setting in which these drugs are demanded and dispensed. In this respect it may be commented in passing that therapists can also become ‘dependent’ and that side effects and secondary effects occur not only in the context of pharmacotherapy but also in that of psychotherapy. The question of dependence liability must therefore be considered in the framework of a benefit/risk analysis. Investigation of the dependence liability must accordingly also imply an investigation of the incidence of the symptomatology in need of treatment, the doctor-patient relationship, and the generally changing attitudes toward certain groups of drugs. Finally, decisive importance also attaches to the
131
clinical situation, in which it must be considered whether the risk of abuse or dependence should be avoided or whether it must be consciously taken into acount as a necessary evil. Two examples are offered as an illustration: In a survey of first-year medical students who were given a list of symptoms, we noted in accordance with expectations a large proportion complaining of psychoautonomic complaints (headache, insomnia, stomach pains, sensitivity to colds, etc.) (Table I). This survey was carried out in 1977 and again in 1982. In 1977 we found not only that a larger proportion claimed to suffer from these complaints but that they also took drugs for them or consulted a physician. It can scarcely be assumed that the 1977 students were sicker. Rather, for whichever reasons, their attitude toward these symptoms or their mode of dealing with them had undergone a change. Would it have been advisable to prescribe a transquillizer for them in 1977? For individual cases in 1977 and also in 1982, undoubtedly yes, but in general rather no, since disorders of subjective well being are referable either TABLE
I
Do you suffer
(1) (2) (3) (4)
(5 ) (6) (7 ) (8) (9) (10)
(11) (12)
(13) (14) (15)
(16) ( 17 ) (18) (19) (20) (21) (22) (23) (24) (25) (26)
from
Headache Sleep disturbance Stomachache Strong sweating Vomiting Nausea Pyrosis Palpitations Oppressions Fatigue Dizziness Feelings of pressure Sensitivity to cold Exhaustion Lack of appetite Heavy legs Diarrhoea Breast tensions Tremor Lightly blushing Cold feet Breathlessness At least one of the disturbances Therefore taking medicaments Therefore having seen a physician Therefore feeling sick
1977
43 20 34 13 2 15 18 15 25 52 28 4 32 43 7 12 10 15 12 30 47 7 88 32 30 28
(N = 190)
1982
(h: = 198)
M
F
M
(%)
(%)
(“/o)
35 22 21 26 6 16 19 13 11 39 16 12 14 53 11 11 17 27 13 29 24 6 89 26 26 38
29 20 10 9 1 12 4 16 6 27 23 7 37 27 9 10
16 11 9 13
4 23 10 26 46 10 93 9 13 16
2 11 9 3 33 2 1 13 35 3 :i 5 3 1 30 1 .i 91 11 23 H
142
to personality characteristics or to expressions of trivial life crises for which drug treatment is rather to be avoided. In addition, drug treatment of this sort also has an effect in breadth and in depth. By natural development, it was seen that in 1982 only one-third of the students took drugs on account of their complaints. Drug therapy thus means not only that the individt1a.l is absolved from accepting discomfort or from working out possible conflicts by himself, but rather that a major group is denied the chance of partaking in a change of attitude. The claim of being unable to sleep cannot be taken to indicate present illness, and by the same token it cannot be regarded as symptomatic of psychiatric disease. One 45-year-old patient who after 2 years of treatment with triazolam (1 mg p.d.) increased the dose to 15 mg p.d. over a period of several weeks suffered from extremely severe insomnia after withdrawal of the drug. Apart from his complaints about inability to sleep, this patient displayed no other symptoms that would have phenomenologically indicated the presence of a depressive syndrome. Only after a maniform clinical picture has developed, in which the patient continued to present sleep disturbances from which however he no longer subjectively suffered, was it possible to establish a diagnosis. In retrospect, the benzodiazepine overdosage could be interpreted as being related to a depressive phase of a manic-depressive illness. The insomnia, primarily interpreted as a withdrawal symptom, was a component of a depressive syndrome that could be diagnosed clinically only after the event. CLINICAL INVESTIGATION DEPENDENCE LIABILITY
AND
EVALUATION
OF
BENZODIAZEPINE
Before discussing clinical observations and systematic investigations, it should be pointed out that using so-called self-administration experiments with various animal species, especially rats and monkeys, there exist methods for the systematic investigation of the dependence liability of a given substance [ 61. Thus Yanagita and Takahashi [7] showed in 19’73 that monkeys consumed benzodiazepines only in doses that caused no central depression and thus no withdrawal symptoms. By contrast, monkeys consumed higher doses of alcohol, phenobarbital and meprobamate, and exhibited withdrawal symptoms when the drug was discontinued. Only when the monkeys received high benzodiazepine dosages in the form of a continuous infusion (up to 115 mg/kg/day) did they display severe withdrawal symptoms, including epileptiform seizures, on the seventh day. The first systematic observations of the benzodiazepine withdrawal syndrome were reported by Hollister [8,9]. In schizophrenic patients treated with chlordiazepoxide (300-600 mg p.d.) for 2-6 months with diazepam (30-120 mg p.d.) for 6 weeks and then suddenly withdrawn the symptoms observed consisted of a deterioration in the clinical picture caused by the illness and - in some of the patients - fresh symptoms which, coinciding with the falling pIasma level of the drug, were to be
143
interpreted as withdrawal symptoms, In particular, in two out of eleven and in one out of thirteen cases, respectively, he observed epileptiform seizures on the eighth day of withdrawal. By comparison with the familiar symptoms following withdrawal of barbiturates or meprobamate, Hollister noted that in the case of the benzodiazepines the onset of the withdrawal symptoms was delayed. Further observations concerning the development of dependence are to be found in reports on clinical investigations of benzodiazepine-dependent patients [ 10-231. From further long-term studies [ 24-321 it can be concluded that after long-term therapy, e.g., longer than 20 weeks [ 261, withdrawal symptoms may occur after sudden discontinuation of the benzodiazepine. There is furthermore a connection between the degree of severity of anxiety depending on the mode of treatment and the intensity of medication. If treatment is carried out in a psychiatric-psychotherapeutic setting, fewer benzodiazepines are needed as time goes on [ 241. Patients receiving high doses of a benzodiazepine (e.g. more than 15 mg/kg/day for diazepam) for a prolonged period (more than 12 months), and who felt that the drug was helping them and who therefore spontaneously increased the dose, had a greater risk of developing severe withdrawal symptoms [ 281. The benzodiazepine withdrawal symptoms reached their peak on the seventh to eighth day [29,30]. Symptoms that first appear after discontinuation of the benzodiazepine treatment but then disappear are part of the withdrawal syndrome. Symptoms that appear and persist or constantly increase indicate a recurrence of the original pathological picture [ 301. An important contribution to the clinical aspects of benzodiazepine dependence is provided by Kemper et al. [ 331. In 26% of their patients an isolated benzodiazepine dependence was present. The authors refer in particular to the occurrence of dependence on lorazepam and bromazepam for which, in their opinion, the development of dependence was especially rapid. In a clinical investigation they noted that patients with primary benzodiazepine dependence had an intensified requirement for the drug even when the withdrawal symptoms were slight. Apart from the usual symptoms the authors also observed a withdrawal delirium; out of eleven cases with delirium, eight were classed as due to lorazepam dependence. Apart from isolated cases of benzodiazepine-dependent patients, the authors found a high percentage (47%) of subjects with multiple dependence, 27% abusing benzodiazepines and/or other habit-forming drugs. In a survey of a representative sample of patients treated by their doctors, we found in 22.7%, abuse of benzodiazepines alone and in 32% combined benzodiazepine abuse following or together with alcohol, other psychotropic drugs, or narcotics [34]. (In 35.6% there was no clear evidence of abuse and in 17.9% of the cases admitted for observation of abuse the therapy was to be considered as correctly indictated.) The groups of patients with an increased risk of benzodiazepine dependence include alcoholics and those dependent on opiates (heroin, methadone, etc.). The doses of a benzodiazepine derivative used by these patients were in some cases exorbitantly high. The question remains open of whether mechanisms
II
Diazepam
Phenobarbital Chlordiazepoxide
oxazepam
Diazepam
Chlordiazepoxide
N = 1 [381
13 [91
rv=
N = 11 [81 300-600 mg 2-6 months
30-l 20 mg 6 weeks
Oxazepam
N = 3 [371
N = 22 [26]
60-250 mg up to 8 years 5-50 mg l-96 months 90 mg/lO weeks 45 mg/lO weeks 45-l 50 mg 23 months to 4 years
Diazepam
N = 1 [361
N = 50 [28]
80 mg 4 years (increased from 20 me) 60-80 mg 8 years
Diazepam
N = 1 [351
SYMPTOMS
Anxious, depressive. reduced performance, rapid fatigability, increased forgetfulness Hypersedation, drowsiness
Anxiety. nervousness, insomnia
Side effects
AND PSYCHIC
Var. benzodiazepines
DOSeI duration
TO AUTONOMIC
N = 43 [331
PRIMARILY
Medicament
REFERRING
NO. patients [Ref.]
REPORTS
TABLE
phase
symptoms. changes
Autonomic symptoms, psychic disturbances, CNS changes (disturbances of attention, comprehension, drive), general EEG changes Clinical signs of withdrawal syndrome in 6 patients, epileptic seizure (1 patient) Autonomic symptoms, psychic symptoms, epileptic seizures, deterioration of psychosis, general EEG changes
Autonomic symptoms, psychic disturbances Autonomic symptoms, psychic changes Autonomic symptoms, psychic changes
psychic
Autonomic
Autonomic symptoms, psychic changes. epileptic seizures, delirious episodes Autonomic symptoms, psychic changes
Withdrawal
day
day
2nd-9th day with maximum 4th-8th day
3rd-10th
on
12th day (significant concentration of serum desmethyldiazepam up to 21st day, traces up to 31st day) Drug resumed after withdrawal trial
After 24 h (psychic withdrawal syndrom)
4th-8th
Appearance of symptoms after withdrawal
g
w
Lorazepam
Lorazepam
Diazepam
Diazepam
Diazepam
N = 1 [39]
N = 1 [40]
1 [20]
N-
N 7 1 [22]
N -- 8 [41]
Depressive symptoms
Insomnia anorexia with loss of weight, depression, dyskinesias
8 mg/6 months 8-16 mg/6 weeks 5 months 12 mglseveral months 5-15 mg 2 years 30 mg 3 months 30 mg 3 years 30-140 mg 1-5 years
SEIZURES
Lorazepam Lorazepam + flurazepam
OF EPILEPTIC
N = 2 [13]
ESPECIALLY Side effects
DESCRIPTIONS Dose/ duration
WITH
Medicament
III
No. patients [Ref.]
REPORTS
TABLE
ma1 seizure
Grand
Grand ma1 seizure, confusion Autonomic symptoms, psychic changes, epileptic seizure, drop in performance, CNS changes, impairment of concentration
ma1 seizure
Grand
48 h
5th day
4th day
72 h
ma1 seizure
Grand
Appearance of symptoms after withdrawal 2nd & 3rd day
phase
Autonomic symptoms, psychic changes, epileptic seizures
Withdrawal
146
T
a 8
2
Diazepam
Diazepam
Diazepam
Diazepam
[ll]
N = 1 [45]
N = 1 [46]
[29J
N ~= 1 [48]
Clorazepate various benrodiatrpines
(Alrohnl) chlordiarepoxide diazepam
N -
1 [47J
Diazepam i fluro.~rpaIr, (1 Pativnc)
1
N = 3 1191
N=
N = 1
to 200
mc
15-40 mg 10 months years
60 mg 80 days For years
60--160 mg F-Z.% months IhOmg
30.-45 mg 20 months
20-240 mg 5 months
IJp
10 mg years .somctimes large doses
Depression
Depressive mood stupor. psychomotor impairment of coordination
Subjectively: energetic, motivated objectively: restlessness, anxiety, tremor. irritability
Autonomic symptoms, psychic changes, grand mal seizure, psychotic symptoms (hallucinations, disorientation), coma (for 6 h, roused with diazepam i.v.) Psychotic symptoms (hallucinations, confusion, disorientation. paranoid) Autonomic symptoms, psychic changes, blurred vision, psychotic symptoms (hallucinations, illusions, paranoid ideas) Autonomic symptoms, psychic changes, sensory disturbances (blurred vision) Autonomic symptoms, psychic changes grand mal seizures. Psychotic symptoms (confusion. diaorientation. hallucinations, delusions). CNS changes (impairmekt of recent memory) Autonomic symptoms, psychic changes PSYchotic changes (disorientation. coniusion, incoherknt speech), delirium (disappeared after diazepam administration) Autonomic symptoms, psychic changes. psychotic sy&toms (disorientation, hallucination?, paranoid?) Autonomic symptoms. psychotic symptoms (hallucinations, disorientation, confusion). CNS changes (forgetfulness) day
day
3rd-6th
8th day
3rd day
8th day
7th day
day
6th--8th
Gradual withdrawal using various drugs disappearance of symptoms within 2-3 weeks
8th day (improvement with haloperidol)
8th day 9thjlOth
K -I
148
of central nervous system adaptation or a seeking after special psychotropic effects resulting from high benzodiazepine dosages are involved. The benzodiazepine withdrawal syndrome is basically similar to that of barbiturate withdrawal. Possible symptoms include insomnia, anxiety, restlessness, excitation or apathy, irritability, mood changes (anxious, dysphoric, depressive), headache, nausea, gastrointestinal disturbances, loss of appetite and weight, tremor, muscular fibrillation, paraesthesias, visual anomalies, sweating, epileptiform seizures, and delirium (Table II-IV). In the survey mentioned [34] of patients receiving medical attention and diagnosed as benzodiazepine abusers, 22% of those designated as abusing only benzodiazepines showed a typical abstinence syndrome and another 5% an atypical syndrome; The data given in the literature regarding the duration of preliminary treatment, dose, occurrence of symptoms, and symptomatology vary according to whether the observations were random or systematic. Tables II-IV give information regarding the more important reports published in the 1970’s and 1980’s. Characteristic for benzodiazepine withdrawal, apart from the symptoms mentioned above, are hypersensitivity and hyposensitivity of all the senses and the long latency period; 2-3 days pass before the appearance of the symptoms, and the peak occurs on the seventh to the eighth day. Also typical is a comparatively long persistence of symptoms for up to several weeks, CONCLUSIONS
In the literature the assessment of the dependence liability of the benzodiazepines is variable.Verdicts range from ‘negligible’ to ‘worse than heroin’. Even if quantitative and qualitative differences vis-a-vis the barbiturate abstinence syndrome are identifiable, there is in principle no difference with regard to the abstinence syndrome that can be observed after discontinuation of barbiturates or non-barbiturate sleep inducing drugs. For the individual benzodiazepine derivatives the course of development of withdrawal symptoms is variable in accordance with the different half-life elimination times. In view of the limited psychotropic potency of benzodiazepines, habituation behaviour typical of the classical psychotropic substances of the morphine or amphetamine type or even of the barbiturates or the nonbarbiturate sleep-inducing drugs is seldom to be observed. Patients predisposed to anxiety or to insomnia who receive benzodiazepines for a prolonged period of time in the course of treatment for a psychosomatic or depressive syndrome may develop - depending on the dose and the duration of treatment - a physical dependence that may manifest itself as a withdrawal syndrome. A distinction must be drawn between such withdrawal symptoms and a recurrence of the original symptoms that form the objective of treatment. In addition, rebound effects are not typical only for the benzodiazepines, but are known for all central nervous system depressant substances.
149
REFERENCES 1 2 3 4 5 6 5 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 12 .43 44 35 36 47 48
W.R. Martin, L.S. MeNicholas and S. Cherian, Life Sci. 31 (1982) 721. D. Ladewig, Med. Welt., 33 (1982) 1306. D.C. Johanson and E.H. UIenhuth Psychopharmacology, 81 (1980) 269. H. de Wit et al., The effect of two non-pharmacological variables on drug preferences in humans, Paper presented at the CPPD-Meeting, Toronto, Canada, June 1982. R.R. Griffiths et al., J. Pharmacol. Exp. Ther., 215 (1980) 649. T. Yanagita, Bull. Narc., XXV (1973) 57. R. Yanagita and S. Takahashi, J. Pharmacol. Exp. Ther., 185 (1973) 307. L.E. Hollister, F.P. Motzenbecker and R.O. Degan, Psychopharmacology, 2 (1961) 63. L.E. Hollister et al., Dis. Nerv. Syst., 24 (1963) 746. L. Darcy, Med. J. Aust., 2 (1972) 450. M.L. De Bard, Am. J. Psychiat., 136 (1) (1979) 104. J.B. Floyd and C.M. Murphy, Kentucky Med. Assoc., 74 (1976) 549. J.R. de la Fuente et al., Mayo Clin. Proc., 55 (1980) 190. S.M. Hanna, Br. J. Psychiat., 120 (1972) 443. D. Haskell, J. Am. Med. Assoc., 233 (1975) 135. K. Kryspin-Exner, Br. J. Addict., 61 (1966) 283. K. Nerenz, Nervenarzt., 45 (1974) 384. H. Petursson and M.H. Lader, Br. J. Addict., 76 (1981) 133. S.H. Preskorn and L.J. Denner, J. Am. Med. Assoc., 237 (1977) 36. A. Rifkin, F. Quitkin and D.F. Klein, J. Am. Med. Assoc., 236 (1976) 2172. J.W. Selig, J. Am. Med. Assoc., 198 (1966) 279. I. Vyas and M.W.P. Carney, Br. Med. J., 4 (1975) 44. H. Watzig and R. Michaels, Nervenarzt., 44 (1973) 499. R. Balmer, R. Battegay and R.v. Marschall, Int. Pharmacopsych., 16 (1981) 221. J. Carranza, Pharmacopsychiatry, 13 (1980) 254. L. Covi et al., Acta Psychiat. Stand., 49 (1973) 51. L.E. Hollister et al., J. Am. Med. Assoc. Schweiz, 1 (1982) 31. B.M. Maletzky and J. Klotter, Int. J. Addict., 11 (1976) 59. J.S. Pevnick, D.R. Jasinski and Ch.A. Haertzen, Arch. Gen. Psychiat., 35 (1978) 995. A. Winokur et al., Arch. Gen. Psychiat., 37 (1980) 101. D.K. Winstead, A. Anderson and M.K. Eilers, Arch. Gen. Psychiat., 30 (1974) 349. C. Moppert, Missbrauch und Abhlngigkeitsentwicklung von Benzodiazepinen, Dissertation, Basel, 1983. N. Kemper, W. Poser and S. Poser, Dtsche. Med. Wsch., 49 (1980) 1707. D. Ladewig, Pharmacopsychiat., 16 (1983) 103. F.S. Tennant, Arch. Int. Med., 139 (1979) 154. F. Miller and J. Nulsen, J. Nerv. Ment. Dis., 167/10 (1979) 637. A. Bliding, Acta Psychiat. Stand., 58/274 (1978) 111. R. Mader and H. Schubert, Wien. Med. Wsch., 14 (1972) 194. Th.R. Einarson, Lancet, 19 (1980) 151. P. Tyrer, Br. J. Psychiat., 137 (1980) 576. H.U. Peters and U. Boeters, Pharmakopsychiatrie., 3 (1970) 339. J. Schopf, Nervenarzt., 52 (1981) 288. J. Boening, Nervenarzt., 52 (1981) 293. M. Le Bellec et al., Therapie, 35 (1980) 113. R. Minter and G. Murray, J. Fam. Pratt., 7 (6) (1978) 1233. P. Agrawal, Can. Psychiat. Assoc., 23 (1978) 35. M.W. Dysken and C.H. Chan, Am. J. Psychiat., 134 (1977) 373. Ch. Allgulander and S. Borg, Br. J. Addict., 73 (2) (1978) 175.
DEPENDENCE
LIABILITY
49
139
OF THE BENZODIAZEPINES
D. LADEWIG* Department
of Psychiatry, University of Basle (Switzerland)
(Received December 23rd, 1983)
SUMMARY
According to pharmacological data as well as to clinical experience a potential of benzodiazepines for producing dependence is not a matter of doubt. However, when compared to the dependence liability of barbiturates the corresponding effect of benzodiazepines is low. In evaluating the dependence potential of benzediazepines account must be taken of the rareness of psychotropic effects of these substances and of the absence of usual mechanisms of tolerance, as well as the epidemiology of psychosomatic syndromes and their treatment outcome. The paper summarizes different types of clinical approaches to evaluating the abuse and dependence liability. In relation to the high incidence of prescriptions for benzodiazepines, the incidence of dependence syndromes is low, but with a wide range of degrees and patterns of such syndromes, Mostly autonomic and psychic symptoms, occasionally grand mal seizures and sensory disturbances and very rarely psychotic symptoms have been described. While the time course differs there is, in comparison to barbiturates, a shift in onset and duration of symptoms. Key words: Benzodiazepines dromes
- Abuse - Dependence
- Withdrawal
syn-
That benzodiazepines present a potential for dependence is not a matter for doubt. They exhibit partial cross tolerance vis$-vis all the substances belonging to the alcohol-barbiturate type of drug dependence**, This is illustrated clinically by the fact that symptoms of withdrawal from barbiturates such as anxiety, tremor and epileptiform seizures can be aborted by benzodiazepines. It should nevertheless be noted that pentobarbital, for instance, suppresses diazepam withdrawal symptoms but is less effective in *Address for correspondence: Psychiatrische Universitatsklinik, Wilhelm-Klein-Strasse 27, CH-4025, Basel, Switzerland **WHO Expert Committee on Drug Dependence, Technical Report Series, 1969, No. 407. 0376-8716/84/$03.00 o 1984 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
140
doing so than diazepam itself; similarly diazepam suppresses pentobarbitalinduced withdrawal to a lesser degree than does pentobarbital itself [l] . It is also clear that the dependence liability of the benzodiazepines is smaller than that of the substances of the alcohol-barbiturate type and this for two reasons: benzodiazepines have only rarely a psychotropic effect in the sense of mood changes, euphorization or stupor. This is in accordance with clinical and epidemiological experience [ 21 and is corroborated by the few self-administration studies carried out to date. Thus, Johanson and Ulenhuth [ 31 found in a comparison of diazepam and placebo that the placebo preparation was preferred, whereas amphetamine was preferred in a comparison of amphetamine and placebo. Likewise, anxiety-prone subjects tend to prefer a placebo to diazepam: ‘Even in a population of anxious subjects, the anti-anxiety property of the drug does not appear to be a sufficient condition to make it a positive reinforcer. It was algo shown that time of day did not affect the preference of diazepam, even when the drug’s presumed disruptive effects were minimized by giving it late in the day at a time more consistent with recreational drug use’ (de Wit et al. [4] ). In analogous studies with subjects exhibiting sedative abuse, pentobarbital received greater perference over diazepam in comparable doses. Only in non-therapeutic single doses (20-200 mg) did diazepam have a reinforcer effect on consumption behaviour [ 51. A second reason for the comparatively low dependence liability of benzodiazepines is the mechanism of development of tolerance, i.e., tolerance based on enzyme induction appears to be absent. The extent to which central nervous system adaptation at the receptor level can be explained as a tolerance phenomenon is still an open question. Before going into greater detail about the dependence liability and the abstinence syndrome, attention should be drawn to certain psychosocial aspects as regards, their significance for the problem of dependence. The misgivings about benzodiazepines, voiced with increasing frequency at the present time, appear to result primarily from uncertainty about the precise definition of their therapeutic indication and about possible overprescribing. While certain properties of the benzodiazepines with their broad ‘therapeutic spectrum’ and ‘safety’ may possibly result in overprescribing, it must also be noted that the risk of these substances is not a matter merely of their pharmacological properties in the sense of a dependence liability, but is determined also by the medical and socio-cultural setting in which these drugs are demanded and dispensed. In this respect it may be commented in passing that therapists can also become ‘dependent’ and that side effects and secondary effects occur not only in the context of pharmacotherapy but also in that of psychotherapy. The question of dependence liability must therefore be considered in the framework of a benefit/risk analysis. Investigation of the dependence liability must accordingly also imply an investigation of the incidence of the symptomatology in need of treatment, the doctor-patient relationship, and the generally changing attitudes toward certain groups of drugs. Finally, decisive importance also attaches to the
131
clinical situation, in which it must be considered whether the risk of abuse or dependence should be avoided or whether it must be consciously taken into acount as a necessary evil. Two examples are offered as an illustration: In a survey of first-year medical students who were given a list of symptoms, we noted in accordance with expectations a large proportion complaining of psychoautonomic complaints (headache, insomnia, stomach pains, sensitivity to colds, etc.) (Table I). This survey was carried out in 1977 and again in 1982. In 1977 we found not only that a larger proportion claimed to suffer from these complaints but that they also took drugs for them or consulted a physician. It can scarcely be assumed that the 1977 students were sicker. Rather, for whichever reasons, their attitude toward these symptoms or their mode of dealing with them had undergone a change. Would it have been advisable to prescribe a transquillizer for them in 1977? For individual cases in 1977 and also in 1982, undoubtedly yes, but in general rather no, since disorders of subjective well being are referable either TABLE
I
Do you suffer
(1) (2) (3) (4)
(5 ) (6) (7 ) (8) (9) (10)
(11) (12)
(13) (14) (15)
(16) ( 17 ) (18) (19) (20) (21) (22) (23) (24) (25) (26)
from
Headache Sleep disturbance Stomachache Strong sweating Vomiting Nausea Pyrosis Palpitations Oppressions Fatigue Dizziness Feelings of pressure Sensitivity to cold Exhaustion Lack of appetite Heavy legs Diarrhoea Breast tensions Tremor Lightly blushing Cold feet Breathlessness At least one of the disturbances Therefore taking medicaments Therefore having seen a physician Therefore feeling sick
1977
43 20 34 13 2 15 18 15 25 52 28 4 32 43 7 12 10 15 12 30 47 7 88 32 30 28
(N = 190)
1982
(h: = 198)
M
F
M
(%)
(%)
(“/o)
35 22 21 26 6 16 19 13 11 39 16 12 14 53 11 11 17 27 13 29 24 6 89 26 26 38
29 20 10 9 1 12 4 16 6 27 23 7 37 27 9 10
16 11 9 13
4 23 10 26 46 10 93 9 13 16
2 11 9 3 33 2 1 13 35 3 :i 5 3 1 30 1 .i 91 11 23 H
142
to personality characteristics or to expressions of trivial life crises for which drug treatment is rather to be avoided. In addition, drug treatment of this sort also has an effect in breadth and in depth. By natural development, it was seen that in 1982 only one-third of the students took drugs on account of their complaints. Drug therapy thus means not only that the individt1a.l is absolved from accepting discomfort or from working out possible conflicts by himself, but rather that a major group is denied the chance of partaking in a change of attitude. The claim of being unable to sleep cannot be taken to indicate present illness, and by the same token it cannot be regarded as symptomatic of psychiatric disease. One 45-year-old patient who after 2 years of treatment with triazolam (1 mg p.d.) increased the dose to 15 mg p.d. over a period of several weeks suffered from extremely severe insomnia after withdrawal of the drug. Apart from his complaints about inability to sleep, this patient displayed no other symptoms that would have phenomenologically indicated the presence of a depressive syndrome. Only after a maniform clinical picture has developed, in which the patient continued to present sleep disturbances from which however he no longer subjectively suffered, was it possible to establish a diagnosis. In retrospect, the benzodiazepine overdosage could be interpreted as being related to a depressive phase of a manic-depressive illness. The insomnia, primarily interpreted as a withdrawal symptom, was a component of a depressive syndrome that could be diagnosed clinically only after the event. CLINICAL INVESTIGATION DEPENDENCE LIABILITY
AND
EVALUATION
OF
BENZODIAZEPINE
Before discussing clinical observations and systematic investigations, it should be pointed out that using so-called self-administration experiments with various animal species, especially rats and monkeys, there exist methods for the systematic investigation of the dependence liability of a given substance [ 61. Thus Yanagita and Takahashi [7] showed in 19’73 that monkeys consumed benzodiazepines only in doses that caused no central depression and thus no withdrawal symptoms. By contrast, monkeys consumed higher doses of alcohol, phenobarbital and meprobamate, and exhibited withdrawal symptoms when the drug was discontinued. Only when the monkeys received high benzodiazepine dosages in the form of a continuous infusion (up to 115 mg/kg/day) did they display severe withdrawal symptoms, including epileptiform seizures, on the seventh day. The first systematic observations of the benzodiazepine withdrawal syndrome were reported by Hollister [8,9]. In schizophrenic patients treated with chlordiazepoxide (300-600 mg p.d.) for 2-6 months with diazepam (30-120 mg p.d.) for 6 weeks and then suddenly withdrawn the symptoms observed consisted of a deterioration in the clinical picture caused by the illness and - in some of the patients - fresh symptoms which, coinciding with the falling pIasma level of the drug, were to be
143
interpreted as withdrawal symptoms, In particular, in two out of eleven and in one out of thirteen cases, respectively, he observed epileptiform seizures on the eighth day of withdrawal. By comparison with the familiar symptoms following withdrawal of barbiturates or meprobamate, Hollister noted that in the case of the benzodiazepines the onset of the withdrawal symptoms was delayed. Further observations concerning the development of dependence are to be found in reports on clinical investigations of benzodiazepine-dependent patients [ 10-231. From further long-term studies [ 24-321 it can be concluded that after long-term therapy, e.g., longer than 20 weeks [ 261, withdrawal symptoms may occur after sudden discontinuation of the benzodiazepine. There is furthermore a connection between the degree of severity of anxiety depending on the mode of treatment and the intensity of medication. If treatment is carried out in a psychiatric-psychotherapeutic setting, fewer benzodiazepines are needed as time goes on [ 241. Patients receiving high doses of a benzodiazepine (e.g. more than 15 mg/kg/day for diazepam) for a prolonged period (more than 12 months), and who felt that the drug was helping them and who therefore spontaneously increased the dose, had a greater risk of developing severe withdrawal symptoms [ 281. The benzodiazepine withdrawal symptoms reached their peak on the seventh to eighth day [29,30]. Symptoms that first appear after discontinuation of the benzodiazepine treatment but then disappear are part of the withdrawal syndrome. Symptoms that appear and persist or constantly increase indicate a recurrence of the original pathological picture [ 301. An important contribution to the clinical aspects of benzodiazepine dependence is provided by Kemper et al. [ 331. In 26% of their patients an isolated benzodiazepine dependence was present. The authors refer in particular to the occurrence of dependence on lorazepam and bromazepam for which, in their opinion, the development of dependence was especially rapid. In a clinical investigation they noted that patients with primary benzodiazepine dependence had an intensified requirement for the drug even when the withdrawal symptoms were slight. Apart from the usual symptoms the authors also observed a withdrawal delirium; out of eleven cases with delirium, eight were classed as due to lorazepam dependence. Apart from isolated cases of benzodiazepine-dependent patients, the authors found a high percentage (47%) of subjects with multiple dependence, 27% abusing benzodiazepines and/or other habit-forming drugs. In a survey of a representative sample of patients treated by their doctors, we found in 22.7%, abuse of benzodiazepines alone and in 32% combined benzodiazepine abuse following or together with alcohol, other psychotropic drugs, or narcotics [34]. (In 35.6% there was no clear evidence of abuse and in 17.9% of the cases admitted for observation of abuse the therapy was to be considered as correctly indictated.) The groups of patients with an increased risk of benzodiazepine dependence include alcoholics and those dependent on opiates (heroin, methadone, etc.). The doses of a benzodiazepine derivative used by these patients were in some cases exorbitantly high. The question remains open of whether mechanisms
II
Diazepam
Phenobarbital Chlordiazepoxide
oxazepam
Diazepam
Chlordiazepoxide
N = 1 [381
13 [91
rv=
N = 11 [81 300-600 mg 2-6 months
30-l 20 mg 6 weeks
Oxazepam
N = 3 [371
N = 22 [26]
60-250 mg up to 8 years 5-50 mg l-96 months 90 mg/lO weeks 45 mg/lO weeks 45-l 50 mg 23 months to 4 years
Diazepam
N = 1 [361
N = 50 [28]
80 mg 4 years (increased from 20 me) 60-80 mg 8 years
Diazepam
N = 1 [351
SYMPTOMS
Anxious, depressive. reduced performance, rapid fatigability, increased forgetfulness Hypersedation, drowsiness
Anxiety. nervousness, insomnia
Side effects
AND PSYCHIC
Var. benzodiazepines
DOSeI duration
TO AUTONOMIC
N = 43 [331
PRIMARILY
Medicament
REFERRING
NO. patients [Ref.]
REPORTS
TABLE
phase
symptoms. changes
Autonomic symptoms, psychic disturbances, CNS changes (disturbances of attention, comprehension, drive), general EEG changes Clinical signs of withdrawal syndrome in 6 patients, epileptic seizure (1 patient) Autonomic symptoms, psychic symptoms, epileptic seizures, deterioration of psychosis, general EEG changes
Autonomic symptoms, psychic disturbances Autonomic symptoms, psychic changes Autonomic symptoms, psychic changes
psychic
Autonomic
Autonomic symptoms, psychic changes. epileptic seizures, delirious episodes Autonomic symptoms, psychic changes
Withdrawal
day
day
2nd-9th day with maximum 4th-8th day
3rd-10th
on
12th day (significant concentration of serum desmethyldiazepam up to 21st day, traces up to 31st day) Drug resumed after withdrawal trial
After 24 h (psychic withdrawal syndrom)
4th-8th
Appearance of symptoms after withdrawal
g
w
Lorazepam
Lorazepam
Diazepam
Diazepam
Diazepam
N = 1 [39]
N = 1 [40]
1 [20]
N-
N 7 1 [22]
N -- 8 [41]
Depressive symptoms
Insomnia anorexia with loss of weight, depression, dyskinesias
8 mg/6 months 8-16 mg/6 weeks 5 months 12 mglseveral months 5-15 mg 2 years 30 mg 3 months 30 mg 3 years 30-140 mg 1-5 years
SEIZURES
Lorazepam Lorazepam + flurazepam
OF EPILEPTIC
N = 2 [13]
ESPECIALLY Side effects
DESCRIPTIONS Dose/ duration
WITH
Medicament
III
No. patients [Ref.]
REPORTS
TABLE
ma1 seizure
Grand
Grand ma1 seizure, confusion Autonomic symptoms, psychic changes, epileptic seizure, drop in performance, CNS changes, impairment of concentration
ma1 seizure
Grand
48 h
5th day
4th day
72 h
ma1 seizure
Grand
Appearance of symptoms after withdrawal 2nd & 3rd day
phase
Autonomic symptoms, psychic changes, epileptic seizures
Withdrawal
146
T
a 8
2
Diazepam
Diazepam
Diazepam
Diazepam
[ll]
N = 1 [45]
N = 1 [46]
[29J
N ~= 1 [48]
Clorazepate various benrodiatrpines
(Alrohnl) chlordiarepoxide diazepam
N -
1 [47J
Diazepam i fluro.~rpaIr, (1 Pativnc)
1
N = 3 1191
N=
N = 1
to 200
mc
15-40 mg 10 months years
60 mg 80 days For years
60--160 mg F-Z.% months IhOmg
30.-45 mg 20 months
20-240 mg 5 months
IJp
10 mg years .somctimes large doses
Depression
Depressive mood stupor. psychomotor impairment of coordination
Subjectively: energetic, motivated objectively: restlessness, anxiety, tremor. irritability
Autonomic symptoms, psychic changes, grand mal seizure, psychotic symptoms (hallucinations, disorientation), coma (for 6 h, roused with diazepam i.v.) Psychotic symptoms (hallucinations, confusion, disorientation. paranoid) Autonomic symptoms, psychic changes, blurred vision, psychotic symptoms (hallucinations, illusions, paranoid ideas) Autonomic symptoms, psychic changes, sensory disturbances (blurred vision) Autonomic symptoms, psychic changes grand mal seizures. Psychotic symptoms (confusion. diaorientation. hallucinations, delusions). CNS changes (impairmekt of recent memory) Autonomic symptoms, psychic changes PSYchotic changes (disorientation. coniusion, incoherknt speech), delirium (disappeared after diazepam administration) Autonomic symptoms, psychic changes. psychotic sy&toms (disorientation, hallucination?, paranoid?) Autonomic symptoms. psychotic symptoms (hallucinations, disorientation, confusion). CNS changes (forgetfulness) day
day
3rd-6th
8th day
3rd day
8th day
7th day
day
6th--8th
Gradual withdrawal using various drugs disappearance of symptoms within 2-3 weeks
8th day (improvement with haloperidol)
8th day 9thjlOth
K -I
148
of central nervous system adaptation or a seeking after special psychotropic effects resulting from high benzodiazepine dosages are involved. The benzodiazepine withdrawal syndrome is basically similar to that of barbiturate withdrawal. Possible symptoms include insomnia, anxiety, restlessness, excitation or apathy, irritability, mood changes (anxious, dysphoric, depressive), headache, nausea, gastrointestinal disturbances, loss of appetite and weight, tremor, muscular fibrillation, paraesthesias, visual anomalies, sweating, epileptiform seizures, and delirium (Table II-IV). In the survey mentioned [34] of patients receiving medical attention and diagnosed as benzodiazepine abusers, 22% of those designated as abusing only benzodiazepines showed a typical abstinence syndrome and another 5% an atypical syndrome; The data given in the literature regarding the duration of preliminary treatment, dose, occurrence of symptoms, and symptomatology vary according to whether the observations were random or systematic. Tables II-IV give information regarding the more important reports published in the 1970’s and 1980’s. Characteristic for benzodiazepine withdrawal, apart from the symptoms mentioned above, are hypersensitivity and hyposensitivity of all the senses and the long latency period; 2-3 days pass before the appearance of the symptoms, and the peak occurs on the seventh to the eighth day. Also typical is a comparatively long persistence of symptoms for up to several weeks, CONCLUSIONS
In the literature the assessment of the dependence liability of the benzodiazepines is variable.Verdicts range from ‘negligible’ to ‘worse than heroin’. Even if quantitative and qualitative differences vis-a-vis the barbiturate abstinence syndrome are identifiable, there is in principle no difference with regard to the abstinence syndrome that can be observed after discontinuation of barbiturates or non-barbiturate sleep inducing drugs. For the individual benzodiazepine derivatives the course of development of withdrawal symptoms is variable in accordance with the different half-life elimination times. In view of the limited psychotropic potency of benzodiazepines, habituation behaviour typical of the classical psychotropic substances of the morphine or amphetamine type or even of the barbiturates or the nonbarbiturate sleep-inducing drugs is seldom to be observed. Patients predisposed to anxiety or to insomnia who receive benzodiazepines for a prolonged period of time in the course of treatment for a psychosomatic or depressive syndrome may develop - depending on the dose and the duration of treatment - a physical dependence that may manifest itself as a withdrawal syndrome. A distinction must be drawn between such withdrawal symptoms and a recurrence of the original symptoms that form the objective of treatment. In addition, rebound effects are not typical only for the benzodiazepines, but are known for all central nervous system depressant substances.
149
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