Alcohol A Alcoholism, Vo\ 20, No 3,pp 263-271,1985 Printed in Great Britain

0309-1635/85 $3 00 + 0 00 Pcrgamon Press Ltd 1985 Medical Council on Alcoholism

DOUBLE-BLIND CONTROLLED TRIAL OF BROMOCRIPTINE, CHLORDIAZEPOXIDE AND CHLORMETHIAZOLE FOR ALCOHOL WITHDRAWAL SYMPTOMS
A. K. BURROUGHS, MARSHA Y. MORGAN and SHEILA SHERLOCK
The Royal Free Hospital School of Medicine (University of London), Rowland Hill Street, Hampstead, London, NW3 2PF, U.K. {Received 11 January 1985) Abstract Seventy-one patients undergoing withdrawal from alcohol were randomly assigned to treatment with oral bromocriptine, chlormethiazole or chlordiazepoxide. Forty-one percent had alcoholic hepatitis and/or cirrhosis Patients were stratified into two groups, major and minor withdrawal symptoms. The latter group included a placebo tratment. Bromocriptine was ineffective in treating withdrawal symptoms, whilst chlormethiazole and chlordiazepoxide were equally effective. These findings do not support the evidence from animal and clinical studies suggesting that the disturbances in the dopaminergic system found in alcohol dependence and withdrawal can be reversed by dopamine agonists.
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INTRODUCTION Approximately 40% of alcoholics develop a withdrawal syndrome when they stop or substantially reduce their alcohol intake. As 2030% of patients admitted to hospital drink alcohol to excess (Jarman and Kellett, 1979; Holt et al., 1980), alcohol withdrawal is commonly encountered in clinical practice. Most patients manifest a 'minor symptom complex or syndrome' which usually starts 6-8 hr from abrupt reduction of alcohol intake (Wolfe and Victor, 1972). It may include any combination of generalised hyperactivity, anxiety, tremor, sweating, nausea, retching, tachycardia, raised blood pressure, mild fever and agitation. Less frequently hallucinations and convulsions occur. This symptom complex usually attains its peak between 10 and 30 hr and, subsides by 40-50 hr (Wolfe and Victor, 1972). The more severe syndrome of delerium tremens occurs in about 5% of patients withdrawing from alcohol (Editorial, 1981) starting 60-80 hr from cessation of drinking. Convulsions may precede the onset of the syndrome (Wolfe and Victor,
Correspondence to: Dr A. K. Burroughs, Academic Department of Medicine, Royal Free Hospital, Pond Street, London, NW3 2QG, U.K.

1972); orientation and perception are usually profoundly disturbed (Wolfe and Victor, 1972). Patients with severe delirium tremens may die if inadequately treated. The diagnosis of alcohol withdrawal syndrome is not usually difficult once a history of excess alcohol intake has been obtained. However, there is great variability in the severity of symptoms and thus rating scales based on psychological, physical and behavioural characteristics have been devised to provide a basis for more accurate description, and for therapeutic trials. The best validated are those by Gross (Gross et al., 1973; 1974). The pathogenesis of alcohol withdrawal is not well understood. Ethanol probably does not interact directly with neurotransmitter receptors but does alter neurotransmitter synthesis, release and catabolism and affects neurotransmitter-receptor interactions (Tabakoff, 1979). Changes of neuronal membranes have been found in animals after chronic treatment with ethanol. Brain calcium metabolism is affected and may be thefinalcommon pathway for changes in neurotransmitter systems (Tabakoff, 1979). While alcohol in small doses has been used to treat withdrawal symptoms (Gower and Kersten, 1980; Editorial, 1981), it is more

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A. K. BURROUGHS et al.

usual to use minor tranquillisers. Chlormethiazole is the drug favoured in Europe, whereas chlordiazepoxide is commonly used in North America where chlormethiazole is not available (Gross et al., 1974). Both drugs are given in reducing daily dose to avoid undue accumulation leading to over-sedation. This is particularly likely to occur in patients with liver disease in whom metabolism of benzodiazepines (Wilkinson, 1978) and chlormethiazole (Pentikainen et al., 1978), is altered and in whom cerebral sensitivity to sedative drugs is increased (Hoyumpa and Schenker, 1982). Recently bromocriptine and apomorphine, both dopamine agonists, have been used successfully to treat alcohol withdrawal without undue drowsiness or sedation (Borg and Weinholdt, 1980). These drugs have not been compared with either chlordiazepoxide or chlormethiazole for the treatment of alcohol withdrawal. The aim of the present study was to observe the effect of treatment with bromocriptine in a controlled phase II clinical trial (initial clinical investigation for treatment effect), comparing it with chlormethiazole and chlordiazepoxide on alcohol withdrawal symptoms in patients with liver disease of varying severity. METHODS AND PATIENTS Seventy-one patients were entered into the study, all of whom gave a history of drinking alcohol in excess of 80 g/day for five or more years. On admission to hospital, patients were assessed and then allocated to one of two study groups. The first group ('minor withdrawal group') included patients with a history of previous

alcohol withdrawal who were admitted for 'drying out', together with patients with minor withdrawal symptoms on admission to hospital. The latter were defined arbitrarily by a score of 17 or less on the rating scale of Borg and Weinholdt (1980) (scale score: 0 absent, 35 maximum, severe). The second group included patients with established withdrawal symptoms of moderate to major severity defined arbitrarily by a score of 18 or more on the same rating scale (Borg and Weinholdt, 1980). Patients who had taken psychotropic drugs within 48 hr of hospital admission were omitted from the study. The patients in each group then were randomised to treatment in doubleblind fashion using a pre-fixed code devised by the hospital pharmacy from a random number table, with a blocked design, to ensure roughly equal numbers in the different treatment groups. Patients in the 'minor withdrawal group' were randomised to treatment with either bromocriptine, chlordiazepoxide, chlormethiazole or placebo all given in reducing doses over five days (Table 1). Patients in the 'major withdrawal group' were randomised to treatment with either bromocriptine, chlordiazepoxide or chlormethiazole in reducing doses over seven days (Table 1). No placebo group was included. The drugs were masked in the same size capsule, and were pre-packaged into daily dosage containers. The timing and number of capsules per administration were the same within each of the study groups. Placebo capsules containing lactose were used to make up the requisite number of capsules in the dosage schedule.

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Table 1. Daily dosage schedules of trial drugs for patients with minor or major symptoms of alcohol withdrawal (a) Minor withdrawal group
Day

Bromocriptine (mg)
7.5 7.5 7.5 5 2.5

Chlordiazepoxide (mg)
125 100 75 50 25

Chlormethiazole
(g) 4 3 2 1 0.5

Placebo (lactose)

1 2 3 4 5

DOUBLE-BUND CONTROLLED TRIAL (b) Major withdrawal group

Day

265

Bromocriptine (mg)
7.5 7.5 7.5 7.5 7.5 5 2.5

Chlordiazepoxide (mg)
200 150 125 100 75 50 25

Chlormethiazole
(g) 6 4 2.5 2 1.5 1 0.5

1 2 3 4 5 6 7

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All patients were assessed 6-8 hourly for the first 48 hr and thereafter twice a day for the next 48 hr and then once daily. The severity of withdrawal symptoms was assessed using the selective severity assessment scale (Gross et al., 1973) (scale score 7-68), and the rating scale of Borg and Weinholdt (1980). Treatment was considered to have failed if the rating score on two consecutive assessments was higher than the initial assessment on either rating score, or if patients developed hallucinations or seizures. Patients in whom treatment failed were given chlormethiazole orally 8 g/day initially or intravenously (10-15 mg/min for 24 hr reducing), on an open basis but were still assessed using the original schedule. All patients were adequately hydrated, were given a well-balanced diet and received highdose parenteral B and C vitamins, oral folic acid and potassium supplements as required. They were nursed on an open ward whenever possible. Routine haematological and biochemical values were estimated using standard laboratory methods. Liver biopsy was performed in the majority of patients using a Menghini needle. Analysis of differences between groups was based on intent of treatment regardless of subsequent withdrawal from the study or continuation of alcohol consumption in hospital. Differences between assessment scores at the start of treatment, and at 48 hr or at the time of failure in the two study groups were examined using a one-way analysis of variance. Student's Mest (modified for multiple comparisons) was then used to test differences vs placebo in the 'minor withdrawal group' and between all three treatments in the 'major withdrawal

group'. Differences in biochemical or haematological parameters were analysed similarly. The study was approved by the Royal Free Hospital Ethics Committee and consent was obtained from the patients studied. RESULTS No statistically significant differences were observed in the age, sex distribution, recent mean alcohol intake, mean corpuscular volume, serum aspartate transaminase, serum bilirubin, and degree of histological liver damage between treatment groups (Table 2a and b). Mean initial scores for withdrawal symptoms were not statistically different which ever rating scale was used although patients taking bromocriptine in the 'minor withdrawal group' tended to be less symptomatic (Table 3a). Two patients in the 'minor withdrawal group', both taking placebo were withdrawn, one because of continued alcohol abuse and one because of the development of spontaneous bacterial peritonitis within 24 hr of admission; both improved symptomatically without further treatment. One patient in the 'major withdrawal group' taking chlordiazepoxide was withdrawn following severe gastrointestinal bleeding, but his alcohol withdrawal symptoms already had subsided before the onset of bleeding. The remaining 68 patients continued in the trial. In the 'minor withdrawal group' 26 of 42 (62%), and in the 'major withdrawal group' 14 of 26 (54%) responded successfully to treatment. Treatment failure invariably occurred within 48 hr of starting treatment. The 28 patients who were treatment failures, responded to chlormethiazole orally (20 patients) or intravenously (8 patients).

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A. K. BURROUGHS et al. Table 2. Details of patients randomised to treatment (a) Minor withdrawal symptoms Placebo Total No. patients randomised Age, yr (mean and range Male : female ratio Mean daily alcohol intake (g) Mean MCV* (0) Mean ASTt (U/l) Bilirubin } (n.mol/1) Range Median Fatty liver + fibrosis Alcoholic hepatitis Cirrhosis alcoholic hepatitis Biopsy not performed Bromocnptine Chlordiazepoxide Chlormethiazole

11 442.I5 (31-55) 5:4

11 49.3(3 8) (31-65) 4:6

10 41.1+2.2 (30-53) 7.3

12 49.62.5 (38-65) Downloaded from http://alcalc.oxfordjournals.org/ at Washington University at St Louis on April 24, 2013 8:4

S.EM.)

18222.6 1O53 1 181.1 + 3 51.9+16.3 (11-150) 40 5(45%)

190.225.4 104.72.8 177.5+84.5 74 35 (12-^54) 22 6(55%) 2

180+21 103.6+1.9 155.425.8 28.9+11 (5-131) 24 5(50%) 2

23629.7 101.1 +1.4 157.440.9 7.74.4 (8-72) 25 7(58%) 2

2 3
1

2 1

2 1

1 2

* MCV mean corpuscular volume (reference range 80-95 fl). t AST aspartate transaminase (reference range 5-40 U/l). X Bilirubin (reference range 5-17 n.mol/1).

In the 'minor withdrawal group' treatment was successful in 27% (3 of 11) taking placebo, 36% (4 of 11) taking bromocriptine, 90% (9 of 10) taking chlordiazepoxide and 80% (10 of 12) taking chlormethiazole. Analysis of variance of the scores showed significant variance ratios for both the Borg and Weinholdt (1980) (F=5.3; P<0.01) and Gross et al. (1973) rating scales (F=2.95; P<0.05). Student's r-test of treatments vs placebo showed chlormethiazole and chlordiazepoxide to be statistically significantly better (7=2.9; P<0.5 and 7=2.6; P<0.5 respectively) but no difference was noted with bromocriptine (7=0.33) using the Borg and Weinholdt (1980) rating scale and similarly

with that of Gross et al. (1973) (chlormethiazole 7=2.6; P<0.5, chlordiazepoxide 7=2.5, P<0.5, bromocriptine 7=0.26). In the 'major withdrawal group' treatment was effective in none of the nine patients treated with bromocriptine, in 70% (7 of 10) taking chlordiazepoxide, and in 87% (7 of 8) taking chlormethiazole. Analysis of variance showed significant differences between treatments using both Borg and Weinholdt's (1980) (F= 10.09; P<0.001) and Gross et al. (1973) rating scales (F=7.39; P<0.01). Chlormethiazole was significantly more effective than bromocriptine (Borg rating scale 7=5.28; /><0.001; Gross rating scale 7=4.06; f<0.001 but no difference could be demon-

DOUBLE-BLIND CONTROLLED TRIAL (b) Major withdrawal symptoms Bromocriptine Patients randomised Age, yr (mean S.E.M.) and range Male : female ratio Mean daily alcohol
(g)

267

Chlordiazepoxide

Chlormethiazole

10

426.1
6:3

41.73.4
6:3

50.64
4:4

243.146.4 103+2.1 173.657 4 108.560.3 (9-545) 28.5 5(56%)

2 2

32662.9 103.1 + 1.7 177.1+50.7 4210.4 (15-183)

20

32548.9
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MCV
(1)

98.73.3 131.91+26.1 33.616 (8-136) 20.5 5(63%)

2 1

ASTt (U/1) Bilirubint (M.mol/1) Range Median Fatty liver fibrosis Alcoholic hepatitis Cirrhosis alcoholic hepatitis

4(40%)
2 4

MCV mean corpuscular volume (reference range 80-95 fl). t AST aspartate transaminase (reference range 5-40 U/1). $ Bilirubin (reference range 5-17 jimol/l).

Table 3. Mean scores ( S.E.M) on the Gross (1973) selective severity assessment (SSA) and the Borg and Weinholdt (1980) scale for alcohol withdrawal (a) Patients with minor withdrawal symptoms Placebo Initial score No. of patients Borg and Weinholdt (1980)
Gross (1973) (SSA)

Bromocriptine 22 7.9.31
11.1+5.5

Chlordiazepoxide 10 11.11.5
16.4+3.3

Chlormethiazole 12 11.41
16.8+5.7

11 10.3+1.2
17.32.3

48 hr score in study successes No. of patients Borg and Weinholdt (1980) Gross (1973) (SSA) Score at time of failure* (between 0 and 48 hr) No. of patients Borg and Weinholdt (1980) Gross (1973) (SSA) "Two withdrawn (see text).

3 3.71 9.31.9 6 18.62.4 22.32.5

4 2.81 10.3+1.1 7 17.7+1.4 22.8+2

9 7.61.4 12.51.1 1 21 34

12 7.91.8 13.2+5.5 2 25 and 22 38 and 29

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A. K. BURROUGHS et al. (b) Patients with major withdrawal symptoms Bromocriptine Initial score No. of patients Borg and Weinholdt (1980) Gross (1973) (SSA) 48 hr score m study successes No. of patients Borg and Weinholdt (1980) Gross (1973) (SSA) Score at time of failure* (between 0 and 48 hr) No. of patients Borg and Weinholdt (1980) Gross (1973) (SSA) 'One withdrawn (see text). Chlordiazepoxide Chlormethiazole

9 21.4.2 22.31.6 0

10 21.62.7 21.92.5 7 6.911.3 10.51.2

8 22.7.7 28.73.4 7 10.85.5 14.48.6

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9 26.31.2 37.81.3

2 27 and 24 38 and 29

1 28 37

strated vs chlordiazepoxide (Borg rating scale 7=0.27; Gross rating scale T=0.02). Chlordiazepoxide was significantly more effective than bromocriptine (Borg rating scale 7=3.31; P<0.01; Gross rating scale 7=4.84; P<0.005). One patient taking chlormethiazole developed an erythematous rash on the third day of treatment which faded rapidly when the drug was stopped. One patient with cirrhosis became severely drowsy whilst taking chlordiazepoxide but rapidly improved once the drug was withdrawn. No side-effects were seen with bromocriptine. DISCUSSION Difficulties arise in evaluating drug treatment for alcohol withdrawal because of the great variability in the severity of the withdrawal syndrome, the often subjective nature of the methods used to assess and measure responses to treatment and the fact that some patients do not require drug treatment at all (Olbrich, 1979; Whitfield et al., 1979). For this reason any preliminary (phase II) or fully fledged (phase III) clinical trial to evaluate proposed new treatment should be conducted double-blind against standard treatment, with patients stratified for severity of withdrawal symptoms. In the present study patients were stratified according to the severity of their symptoms and a placebo group was included in the minor withdrawal group. Previous clinical experience had suggested that this group would

require less sedation and would include more patients who would withdraw without need for drug therapy (Olbrich, 1979; Whitfield et al., 1973). A standard rating scale (SSA) (Gross et al., 1973) and the rating scale used in the original bromocriptine study for assessment of alcohol withdrawal symptoms (Borg and Weinholdt, 1980) were included. The results of the present study show that bromocriptine was less effective than either chlordiazepoxide or chlormethiazole in treating minor withdrawal and was ineffective in treatment of major withdrawal symptoms. The dopaminergic system has been implicated in the mechanism of alcohol withdrawal. In ethanol dependent rats, dopamine turnover is reduced (Hunt and Majchrowicz, 1974) both during acute intoxication and withdrawal. Dopamine release falls quickly to below control values during withdrawal, remaining low for at least three days and returning to baseline values by seven days (Darden and Hunt, 1977). At the same time there is increased activity of the cholinergic system (Hunt et al., 1979). These changes do not appear to be induced by, or result in receptor changes. Chronic administration of ethanol in rats for five or more months results in long-lasting increases in receptor sensitivity to dopamine (a postsynaptic effect) with markedly increased responses to apomorphine or dopamine (Liljequist, 1978). This has been attributed to chronic deprivation of dopamine transmitter

DOUBLE-BLIND CONTROLLED TRIAL

269

which was found to accumulate in the limbic forebrain. The sensitivity of noradrenergic and cholinergic receptor mechanisms appears unchanged in this model (Liljequist and Engel, 1979). As dopaminergic agonists decrease the activity of both dopaminergic and cholinergic neurons (Westerink and Kork, 1974), they might on theoretical grounds be of use in the treatment of alcohol withdrawal in man. In man a single preliminary double-blind study has suggested that bromocriptine (7.5 mg daily) and apomorphine (30 mg daily) were equally effective in the treatment of alcohol withdrawal (Borg and Weinholdt, 1980). Although sedative drugs were given concomitantly to 9 of the 24 patients studied, drowsiness and excess sedation were not observed. However, no placebo group was included and the patients were not stratified according to the severity of their withdrawal symptoms. Although there is theoretical evidence to suggest that the dopaminergic system might be involved in the pathogenesis of alcohol withdrawal, and some clinical evidence suggesting dopaminergic drugs may be of benefit, contrary evidence also exists. In ethanoldependent mice changes were found in dopamine-sensitive adenylate cyclase activity in striatal tissue during withdrawal (Tabakoff and Hoffman, 1979), which reversed to normal when alcohol was re-introduced. However, the changes in dopamine sensitivity did not correlate with signs of alcohol withdrawal (Tabakoff and Hoffman, 1979). Moreover, dopamine receptor function appeared less responsive to dopamine agonists (piribedil) (Hoffman and Tabakoff, 1977), and abnormal locomotion (as a sign of withdrawal) was less responsive to apomorphine (Tabakoff et al., 1978). Results from this mouse model suggest that despite the presence of changes in dopamine sensitivity, symptoms of alcohol withdrawal might not be improved by dopamine agonists. These observations are supported by the results of the present study. Furthermore, it is of interest that recently tiapride, a substituted benzamide, a dopamine antagonist, has been found to be equally as effective as chlormethiazole in treating alcohol withdrawal symptoms (Murphy et al., 1983). Tiapride is a dopamine receptor blocking agent, and possibly acts selectively on

a subpopulation of these receptors (Jenner and Marsden, 1979). This subpopulation could be that involved with changes in post-synaptic dopamine receptor function found in ethanoldependent mice (Tabakoff and Hoffman, 1979; Blacker al., 1980). Sedative drugs are generally effective in treating alcohol withdrawal symptoms. However, alcoholic patients often show impaired drug metabolism because of induction of drug metabolising enzymes on the one hand and impaired hepatic function on the other (Pentikainen et al., 1978; Wilkinson, 1978). Additionally, patients with liver disease tend to show increased sensitivity to sedatives (Hoyumpa and Schenker, 1982). For these reasons sedative drugs must be used with caution in alcoholic patients, although little, if any, attention is ever drawn to this point in major reviews and editorials on treatment of alcohol withdrawal (Gross et al., 191 A; KochWeser et al., 1976; Gessner, 1979; Editorial, 1981). It was for this reason that treatment with bromocriptine appeared so attractive; it is without sedative effect and can be used with safety in patients with chronic liver disease (Morgan etal., 1980). In the present study, chlordiazepoxide and chlormethiazole were equally effective in preventing and treating alcohol withdrawal symptoms. A reducing daily dosage schedule was used for both drugs, thus the incidence of over-sedation was extremely low despite the fact that 41% of the patients treated had significant liver disease with alcoholic hepatitis and/or cirrhosis. The bioavailability of chlormethiazole is increased in patients with cirrhosis because it has a high first pass metabolism but its elimination rate is unchanged (Pentikainen et al., 1978). Thus, overdosage can be minimised by reducing the standard dosage in susceptible patients, as in this study. Intravenous administration eliminates the variability of oral bioavailability so that this might be the optimal route of administration in patients with cirrhosis (Pentikainen et al., 1978). Chlordiazepoxide is metabolised in the liver to a number of active metabolites which have long half-lives and accumulate more in patients with liver disease (Wilkinson, 1978). In addition these patients show increased

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270

A. K. BURROUGHS el al. withdrawal. Alcoholism: Clinical and Experimental Research 4, 294-297. Borg, V. and Weinholdt, T. (1980) A preliminary doubleblind study of two dopaminergic drugs, apomorphine and bromocriptine (Pardolel) in the treatment of the alcohol withdrawal syndrome. Current Therapeutic Research 27, 170-177. Darden, J. H. and Hunt, W. A. (1977) Reduction of striatal dopamine release during ethanol withdrawal syndrome. Journal of Neurochemistry 29, 11431145. Editorial (1981) Management of alcohol withdrawal symptoms. British Medical Journal 1, 502 Gessner, P. K. (1979) Drug therapy of the alcohol withdrawal syndrome. In Biochemistry and Pharmacology of Alcohol, Vol. 2, Noble, E. P. and Majchrowicz, E. eds, pp.375-435. Plenum Press, New York. Gower, W. E. and Kersten, H. (1980) Prevention of alcohol withdrawal symptoms in surgical patients.
Surgery, Gynecology and Obstetrics 151, 382-384.

cerebral sensitivity to this class of drug (Hoyumpa and Schenker, 1982). Overdosage may occur more readily with this drug than with chlormethiazole in alcoholics with liver disease and was indeed observed in one patient in the present trial. Parenteral administration of chlordizepoxide is impractical; no intravenous preparation exists and intramuscular absorption is very slow (Robinson etal., 1983). Only one study is available comparing the efficacy of chlordiazepoxide and chlormethiazole in the treatment of alcohol withdrawal in patients, though none had liver disease (McGrath, 1975). Chlordiazepoxide was successful in preventing delirium tremens in 90% (39 of 41) of treated patients while chlormethiazole was succesful in 100% (46 of 46). Ten patients treated with chlordiazepoxide, and seven treated with chlormethiazole were withdrawn because their symptoms were inadequately controlled. No side-effects were seen with either drug. In the present preliminary study bromocriptine proved ineffective in the treatment of alcohol withdrawal which suggests that fullscale clinical investigation for this indication (phase III clinical trial) is unwarranted. Both chlordiazepoxide and chlormethiazole were equally effective. Chlormethiazole has the shorter half-life so that over-sedation is less of a problem than with chlordiazepoxide. In addition, chlormethiazole can be given intravenously which is invaluable for treating patients with significant liver disease or for treating patients too restless or too uncooperative to take oral medication. The intravenous dosage can be titrated to control symptoms without undue sedation. Although chlordiazepoxide and chlormethiazole are equally effective in treating alcohol withdrawal symptoms, chlormethiazole is the more flexible drug.
Acknowledgement We would like to thank Dr R. Kohn and Dr J. F. Harper of Advisory Services (Clinical & General) Ltd., London for their help in organising the trial drug formulations and Dr E. Fay of Gebro-G. Broschek EG Fieberbrunn for supplying the drugs.

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