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

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


both dopamine agonists. all of whom gave a history of drinking alcohol in excess of 80 g/day for five or more years. Recently bromocriptine and apomorphine. 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. have been used successfully to treat alcohol withdrawal without undue drowsiness or sedation (Borg and Weinholdt. No placebo group was included.5 7. The drugs were masked in the same size at Washington University at St Louis on April 24..5 7. is altered and in whom cerebral sensitivity to sedative drugs is increased (Hoyumpa and Schenker. These drugs have not been compared with either chlordiazepoxide or chlormethiazole for the treatment of alcohol withdrawal. Downloaded from http://alcalc. Patients in the 'minor withdrawal group' were randomised to treatment with either bromocriptine. Chlormethiazole is the drug favoured in Europe. 1974).5 5 2.5 Placebo (lactose) 1 2 3 4 5 . 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. chlordiazepoxide or chlormethiazole in reducing doses over seven days (Table 1). patients were assessed and then allocated to one of two study groups. together with patients with minor withdrawal symptoms on admission to hospital. Placebo capsules containing lactose were used to make up the requisite number of capsules in the dosage schedule. Patients who had taken psychotropic drugs within 48 hr of hospital admission were omitted from the study. severe). chlordiazepoxide.. whereas chlordiazepoxide is commonly used in North America where chlormethiazole is not available (Gross et al. K.264 A. This is particularly likely to occur in patients with liver disease in whom metabolism of benzodiazepines (Wilkinson. with a blocked design. 1978) and chlormethiazole (Pentikainen et al. The first group ('minor withdrawal group') included patients with a history of previous alcohol withdrawal who were admitted for 'drying out'. 1980). 1982).5 Chlordiazepoxide (mg) 125 100 75 50 25 Chlormethiazole (g) 4 3 2 1 0. 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. 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. to ensure roughly equal numbers in the different treatment groups. 1980). Patients in the 'major withdrawal group' were randomised to treatment with either bromocriptine. 2013 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. 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. 35 maximum. usual to use minor tranquillisers. BURROUGHS et al. On admission to hospital. chlormethiazole or placebo all given in reducing doses over five days (Table 1). Both drugs are given in reducing daily dose to avoid undue accumulation leading to over-sedation. 1978). 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).

5 7. serum aspartate transaminase. on an open basis but were still assessed using the original schedule. mean corpuscular volume. and at 48 hr or at the time of failure in the two study groups were examined using a one-way analysis of variance. recent mean alcohol intake. 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'.. They were nursed on an open ward whenever possible.5 2 1. 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). both taking placebo were withdrawn. The study was approved by the Royal Free Hospital Ethics Committee and consent was obtained from the patients studied.5 Chlordiazepoxide (mg) 200 150 125 100 75 50 25 Chlormethiazole (g) 6 4 at Washington University at St Louis on April 24. Treatment was considered to have failed if the rating score on two consecutive assessments was higher than the initial assessment on either rating score. RESULTS No statistically significant differences were observed in the age. and in the 'major withdrawal group' 14 of 26 (54%) responded successfully to treatment. In the 'minor withdrawal group' 26 of 42 (62%). serum bilirubin. . were given a well-balanced diet and received highdose parenteral B and C vitamins.5 1 0. Treatment failure invariably occurred within 48 hr of starting treatment. responded to chlormethiazole orally (20 patients) or intravenously (8 patients). Two patients in the 'minor withdrawal group'. and the rating scale of Borg and Weinholdt (1980). 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. oral folic acid and potassium supplements as required.DOUBLE-BUND CONTROLLED TRIAL (b) Major withdrawal group Day 265 Bromocriptine (mg) 7. and degree of histological liver damage between treatment groups (Table 2a and b). All patients were adequately hydrated. The 28 patients who were treatment failures. or if patients developed hallucinations or seizures. one because of continued alcohol abuse and one because of the development of spontaneous bacterial peritonitis within 24 hr of admission.oxfordjournals. both improved symptomatically without further treatment. sex distribution. Liver biopsy was performed in the majority of patients using a Menghini needle. 2013 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. 1973) (scale score 7-68).5 7. 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. The remaining 68 patients continued in the trial. Differences in biochemical or haematological parameters were analysed similarly.5 7. Differences between assessment scores at the start of treatment.5 7. The severity of withdrawal symptoms was assessed using the selective severity assessment scale (Gross et al.5 1 2 3 4 5 6 7 Downloaded from http://alcalc.5 5 2. Routine haematological and biochemical values were estimated using standard laboratory methods. Patients in whom treatment failed were given chlormethiazole orally 8 g/day initially or intravenously (10-15 mg/min for 24 hr reducing).

7±2.2±25. In the 'major withdrawal group' treatment was effective in none of the nine patients treated with bromocriptine.95. (1973) rating scales (F=7. BURROUGHS et al. Gross rating scale 7=4.7 101.mol/1). />< P<0.4 (8-72) 25 7(58%) 2 2 3 1 2 1 2 1 1 2 * MCV — mean corpuscular volume (reference range 80-95 fl). 36% (4 of 11) taking bromocriptine.28. yr (mean and range Male : female ratio Mean daily alcohol intake (g) Mean MCV* (0) Mean ASTt (U/l) Bilirubin } (n.9 155. Table 2. P<0. Student's r-test of treatments vs placebo showed chlormethiazole and chlordiazepoxide to be statistically significantly better (7=2.6±2. 90% (9 of 10) taking chlordiazepoxide and 80% (10 of 12) taking chlormethiazole. 2013 8:4 ± S.26).33) using the Borg and Weinholdt (1980) rating scale and similarly with that of Gross et al. X Bilirubin (reference range 5-17 n.06. chlordiazepoxide 7=2.3 12 49.01). (1973) (chlormethiazole 7=2.6.5. bromocriptine 7=0.5 74 3±5 (12-^54) 22 6(55%) 2 180+21 103. P<0.5 and 7=2.5+84.5 (38-65) Downloaded from http://alcalc. (1973) rating scales (F=2.3.1 +1.4±40.6 1O5±3 1 181. In the 'minor withdrawal group' treatment was successful in 27% (3 of 11) taking placebo.8 177. Analysis of variance showed significant differences between treatments using both Borg and Weinholdt's (1980) (F= 10. Analysis of variance of the scores showed significant variance ratios for both the Borg and Weinholdt (1980) (F=5. P<0. in 70% (7 of 10) taking chlordiazepoxide.001 but no difference could be demon- .39.9+11 (5-131) 24 5(50%) 2 236±29.5 respectively) but no difference was noted with bromocriptine (7=0.266 A.I5 (31-55) 5:4 11 49.01) and Gross et al.oxfordjournals.1+2.4 104. Chlormethiazole was significantly more effective than bromocriptine (Borg rating scale 7=5.4 157.001. t AST — aspartate transaminase (reference range 5-40 U/l).5.3 (11-150) 40 5(45%) 190.4±25.1 + 3 51. K. patients randomised at Washington University at St Louis on April 24. f<0. and in 87% (7 of 8) taking chlormethiazole.EM.6+1.7±4. Details of patients randomised to treatment (a) Minor withdrawal symptoms Placebo Total No.mol/1) Range Median Fatty liver + fibrosis Alcoholic hepatitis Cirrhosis ± alcoholic hepatitis Biopsy not performed Bromocnptine Chlordiazepoxide Chlormethiazole 11 44±2. P<0.05). P<0.2 (30-53) 7. P<0.5.8 28.9+16.9 7. P<0.) 182±22.3(±3 8) (31-65) 4:6 10 41.001) and Gross et al.

1 + 1.7±3.8+5. 2013 MCV (1) 98.1+50.9 103.4 103+2. of patients Borg and Weinholdt (1980) Gross (1973) (SSA) "Two withdrawn (see text).4 6:3 50. of patients Borg and Weinholdt (1980) Gross (1973) (SSA) Bromocriptine 22 7.91+26.6±4 4:4 243.M. of patients Borg and Weinholdt (1980) Gross (1973) (SSA) Score at time of failure* (between 0 and 48 hr) No.7±3.7 11 10.3 Chlormethiazole 12 11.8+2 9 7.5 Chlordiazepoxide 10 11. t AST — aspartate transaminase (reference range 5-40 U/1).oxfordjournals.5 4 2.1±46. Table 3.8±1 10.1 173.3+1.4 22.1±1.2 17.7 177.6±2.4±1 16.8 13.1+5.9±1.6±57 4 108. Mean scores ( ± S.5±60. yr (mean ± S.9 6 18.5±1.4+3.3 at Washington University at St Louis on April 24.5 16.DOUBLE-BLIND CONTROLLED TRIAL (b) Major withdrawal symptoms Bromocriptine Patients randomised Age.E. 3 3.3±2.3±2.31 11.9±.E.1 6:3 41.9 Downloaded from http://alcalc.7±1 9.3±1.7 42±10.1 1 21 34 12 7.6±16 (8-136) 20.4 22.) and range Male : female ratio Mean daily alcohol (g) 267 Chlordiazepoxide Chlormethiazole 9 10 8 42±6. $ Bilirubin (reference range 5-17 jimol/l).4 (15-183) 20 325±48.6±1.5 2 25 and 22 38 and 29 .3 (9-545) 28.1 7 17.3+1.3 48 hr score in study successes No.5 5(63%) 2 1 ASTt (U/1) Bilirubint (M.4 12.2+5.5 5(56%) 2 2 326±62.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).1 33.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.7+1.

or result in receptor changes. of patients Borg and Weinholdt (1980) Gross (1973) (SSA) Score at time of failure* (between 0 and 48 hr) No. BURROUGHS et al. dopamine turnover is reduced (Hunt and Majchrowicz. 1977).org/ at Washington University at St Louis on April 24. 2013 9 26. of patients Borg and Weinholdt (1980) Gross (1973) (SSA) 'One withdrawn (see text)..4±. No side-effects were seen with bromocriptine. One patient taking chlormethiazole developed an erythematous rash on the third day of treatment which faded rapidly when the drug was stopped. A standard rating scale (SSA) (Gross et al. 1973). Gross rating scale 7=4.. remaining low for at least three days and returning to baseline values by seven days (Darden and Hunt.oxfordjournals.2 8 22. Chlordiazepoxide Chlormethiazole 9 21.3 10.6 0 10 21.8±1.7±.. Dopamine release falls quickly to below control values during withdrawal. 1973) and the rating scale used in the original bromocriptine study for assessment of alcohol withdrawal symptoms (Borg and Weinholdt. (b) Patients with major withdrawal symptoms Bromocriptine Initial score No.3 2 27 and 24 38 and 29 1 28 37 strated vs chlordiazepoxide (Borg rating scale 7=0. Whitfield et al. 1978). DISCUSSION Difficulties arise in evaluating drug treatment for alcohol withdrawal because of the great variability in the severity of the withdrawal syndrome. 1979.268 A. Chlordiazepoxide was significantly more effective than bromocriptine (Borg rating scale 7=3. 1974) both during acute intoxication and withdrawal.6±2.911. In ethanol dependent rats. One patient with cirrhosis became severely drowsy whilst taking chlordiazepoxide but rapidly improved once the drug was withdrawn. 1979).5 7 6.6 Downloaded from http://alcalc. K.. At the same time there is increased activity of the cholinergic system (Hunt et al. 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. P<0.005).31. The dopaminergic system has been implicated in the mechanism of alcohol withdrawal.9±2.02).27.5±1. 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. 1979.8±5.3±1.4±8.7 28. of patients Borg and Weinholdt (1980) Gross (1973) (SSA) 48 hr score m study successes No. with patients stratified for severity of withdrawal symptoms.2 37. 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. 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.01.84. These changes do not appear to be induced by.4 7 10. Gross rating scale T=0. 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. 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. 1979). 1980) were included. P<0. This has been attributed to chronic deprivation of dopamine transmitter . Whitfield et al.2 22.5 14.31.7±3.7 21.

chlordiazepoxide and chlormethiazole were equally effective in preventing and treating alcohol withdrawal symptoms. 1977). 2013 . Moreover. Thus. 1976. patients with liver disease tend to show increased sensitivity to sedatives (Hoyumpa and Schenker.. These observations are supported by the results of the present study. 1974). Tiapride is a dopamine receptor blocking agent. However.. it is of interest that recently tiapride. However. dopamine receptor function appeared less responsive to dopamine agonists (piribedil) (Hoffman and Tabakoff. drowsiness and excess sedation were not observed. This subpopulation could be that involved with changes in post-synaptic dopamine receptor function found in ethanoldependent mice (Tabakoff and Hoffman.. it is without sedative effect and can be used with safety in patients with chronic liver disease (Morgan etal. In ethanoldependent mice changes were found in dopamine-sensitive adenylate cyclase activity in striatal tissue during withdrawal (Tabakoff and Hoffman.DOUBLE-BLIND CONTROLLED TRIAL 269 which was found to accumulate in the limbic forebrain. 1979). 1978). Blacker al. and abnormal locomotion (as a sign of withdrawal) was less responsive to apomorphine (Tabakoff et al. The sensitivity of noradrenergic and cholinergic receptor mechanisms appears unchanged in this model (Liljequist and Engel.. the changes in dopamine sensitivity did not correlate with signs of alcohol withdrawal (Tabakoff and Hoffman.oxfordjournals... 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. 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. For these reasons sedative drugs must be used with caution in alcoholic patients. 1980). Editorial. Results from this mouse model suggest that despite the presence of changes in dopamine sensitivity.. no placebo group was included and the patients were not stratified according to the severity of their withdrawal symptoms. 1979). if at Washington University at St Louis on April 24.. KochWeser et al. although little. 1980). In man a single preliminary double-blind study has suggested that bromocriptine (7. 1979. and some clinical evidence suggesting dopaminergic drugs may be of benefit.. a dopamine antagonist. 1979). has been found to be equally as effective as chlormethiazole in treating alcohol withdrawal symptoms (Murphy et al. Although sedative drugs were given concomitantly to 9 of the 24 patients studied. Wilkinson. Additionally. 1979. Gessner. attention is ever drawn to this point in major reviews and editorials on treatment of alcohol withdrawal (Gross et al. 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. Furthermore. symptoms of alcohol withdrawal might not be improved by dopamine agonists. 1978). overdosage can be minimised by reducing the standard dosage in susceptible patients. As dopaminergic agonists decrease the activity of both dopaminergic and cholinergic neurons (Westerink and Kork. Sedative drugs are generally effective in treating alcohol withdrawal symptoms. a substituted benzamide. It was for this reason that treatment with bromocriptine appeared so attractive. 1980). 1982). A reducing daily dosage schedule was used for both drugs. 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. However. 1978). which reversed to normal when alcohol was re-introduced. 1978). 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. 191 A. as in this study. 1983). Although there is theoretical evidence to suggest that the dopaminergic system might be involved in the pathogenesis of alcohol withdrawal. contrary evidence also exists. 1981). 1979). In addition these patients show increased Downloaded from http://alcalc. In the present study. 1978).5 mg daily) and apomorphine (30 mg daily) were equally effective in the treatment of alcohol withdrawal (Borg and Weinholdt. and possibly acts selectively on a subpopulation of these receptors (Jenner and Marsden. 1978. they might on theoretical grounds be of use in the treatment of alcohol withdrawal in man.

In addition.. though none had liver disease (McGrath. Hunt. (1979) Drug therapy of the alcohol withdrawal syndrome. F. M. Liljequist. (1974) Acute alcohol withdrawal syndrome. Koch-Weser. 191-263. Hoffman. C. P. K. A. M. (1982) Major drug interactions: effect of liver disease. The intravenous dosage can be titrated to control symptoms without undue sedation.. at Washington University at St Louis on April 24. Although chlordiazepoxide and chlormethiazole are equally effective in treating alcohol withdrawal symptoms. Hoyumpa.. S. Taylor. Ten patients treated with chlordiazepoxide. R. H. and Kersten.. M (1973) An improved quantitative system for assessing the acute alcoholic psychosis and related states (TSA and SSA). Dallon. (1974) Alterations in the turnover of brain norepinephrine and dopamine in alcohol dependent rats. alcohol and malnutrition. Editorial (1981) Management of alcohol withdrawal symptoms. and Mareden C. E. Both chlordiazepoxide and chlormethiazole were equally effective. 3. Chlordiazepoxide was successful in preventing delirium tremens in 90% (39 of 41) of treated patients while chlormethiazole was succesful in 100% (46 of 46).375-435. 1143—1145. 33.. E. E.. E. Stewart. and Kalant.. Plenum Press. B. (1980) Alcohol and the emergency service patient. H. chlormethiazole is the more flexible drug. Sellers. 549-552. S. eds. J. New England Journal of Medicine 294. (1980) A preliminary doubleblind study of two dopaminergic drugs. 1982). Gower. In The Biology of Alcoholism. Life Sciences 25. pp. and Nagarajan. E M. B. and Schenker. Broschek EG Fieberbrunn for supplying the drugs. and Tabakoff. Plenum Press. and Wixon. Hoffman.. and seven treated with chlormethiazole were withdrawn because their symptoms were inadequately controlled. C. Alcoholism: Clinical and Experimental Research 4. pp. 502 Gessner. 365-377. 757-762. Surgery. (1977) Reduction of striatal dopamine release during ethanol withdrawal syndrome. H. H. P. Dixon. J. 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. New York. K. Lewis. eds. In Annual Review of Medicine. S. Palo Alto. H.270 A. Acknowledgement — We would like to thank Dr R. and Weinholdt. Acta Pharmacologica el Toxicologica 43. eds.113-149. V. L. Holt. Kissin. British Medical Journal 1. J. British Medical Journal 280.. (1979) Alcoholism in the general hospital. and Hancock. P. J. London for their help in organising the trial drug formulations and Dr E. D. Harper of Advisory Services (Clinical & General) Ltd. Fay of Gebro-G. withdrawal. apomorphine and bromocriptine (Pardolel) in the treatment of the alcohol withdrawal syndrome. V. P. Advances in Experimental Medicine and Biology 35. Journal of Neurochemistry 29. 294-297. E. (1980) Prevention of alcohol withdrawal symptoms in surgical patients. pp. (1977) Alterations in dopamine receptor sensitivity by chronic ethanol treatment. C . T. M M. Lewis. M. Parenteral administration of chlordizepoxide is impractical. and Kellett. Only one study is available comparing the efficacy of chlordiazepoxide and chlormethiazole in the treatment of alcohol withdrawal in patients. 382-384. and Begleiter. A. no intravenous preparation exists and intramuscular absorption is very slow (Robinson etal. 2. Gynecology and Obstetrics 151. H. A. and Majchrowicz. Chlormethiazole has the shorter half-life so that over-sedation is less of a problem than with chlordiazepoxide. Hunt. Vol. Vol. 469-472. M. and Little. Borg. 551-553. Current Therapeutic Research 27. Annual Review Inc. (1979) The substituted benzamides — a novel class of dopamine antagonists.. cerebral sensitivity to this class of drug (Hoyumpa and Schenker. W. I.oxfordjournals. K. 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