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

0309-1635/85 $3 00 + 0 00Pcrgamon 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 SHERLOCKThe 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 totreatment with oral bromocriptine, chlormethiazole or chlordiazepoxide. Forty-one percent hadalcoholic hepatitis and/or cirrhosis Patients were stratified into two groups, major and minorwithdrawal symptoms. The latter group included a placebo tratment. Bromocriptine wasineffective in treating withdrawal symptoms, whilst chlormethiazole and chlordiazepoxide wereequally effective. These findings do not support the evidence from animal and clinical studiessuggesting that the disturbances in the dopaminergic system found in alcohol dependence andwithdrawal can be reversed by dopamine agonists.

INTRODUCTION

Approximately 40% of alcoholics develop awithdrawal syndrome when they stop or sub-stantially reduce their alcohol intake. As 20-30% of patients admitted to hospital drinkalcohol to excess (Jarman and Kellett, 1979;Holt et al., 1980), alcohol withdrawal is com-monly encountered in clinical practice. Mostpatients manifest a 'minor symptom complexor syndrome' which usually starts 6-8 hr fromabrupt reduction of alcohol intake (Wolfe andVictor, 1972). It may include any combinationof generalised hyperactivity, anxiety, tremor,sweating, nausea, retching, tachycardia, raisedblood pressure, mild fever and agitation. Lessfrequently hallucinations and convulsionsoccur. This symptom complex usually attainsits peak between 10 and 30 hr and, subsides by40-50 hr (Wolfe and Victor, 1972). The moresevere syndrome of delerium tremens occurs inabout 5% of patients withdrawing from alcohol(Editorial, 1981) starting 60-80 hr from cessa-tion of drinking. Convulsions may precede theonset of the syndrome (Wolfe and Victor,

Correspondence to: Dr A. K. Burroughs, AcademicDepartment of Medicine, Royal Free Hospital, PondStreet, London, NW3 2QG, U.K.

1972); orientation and perception are usuallyprofoundly disturbed (Wolfe and Victor,1972). Patients with severe delirium tremensmay die if inadequately treated.

The diagnosis of alcohol withdrawal syn-drome is not usually difficult once a history ofexcess alcohol intake has been obtained.However, there is great variability in theseverity of symptoms and thus rating scalesbased on psychological, physical and behaviou-ral characteristics have been devised to providea basis for more accurate description, and fortherapeutic trials. The best validated are thoseby Gross (Gross et al., 1973; 1974).

The pathogenesis of alcohol withdrawal isnot well understood. Ethanol probably doesnot interact directly with neurotransmitterreceptors but does alter neurotransmittersynthesis, release and catabolism and affectsneurotransmitter-receptor interactions (Taba-koff, 1979). Changes of neuronal membraneshave been found in animals after chronictreatment with ethanol. Brain calcium meta-bolism is affected and may be the final com-mon pathway for changes in neurotransmittersystems (Tabakoff, 1979).

While alcohol in small doses has been usedto treat withdrawal symptoms (Gower andKersten, 1980; Editorial, 1981), it is more

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usual to use minor tranquillisers. Chlor-methiazole is the drug favoured in Europe,whereas chlordiazepoxide is commonly used inNorth America where chlormethiazole is notavailable (Gross et al., 1974). Both drugs aregiven in reducing daily dose to avoid undueaccumulation leading to over-sedation. This isparticularly likely to occur in patients with liverdisease in whom metabolism of benzodiaze-pines (Wilkinson, 1978) and chlormethiazole(Pentikainen et al., 1978), is altered and inwhom cerebral sensitivity to sedative drugs isincreased (Hoyumpa and Schenker, 1982).Recently bromocriptine and apomorphine,both dopamine agonists, have been used suc-cessfully to treat alcohol withdrawal withoutundue drowsiness or sedation (Borg andWeinholdt, 1980). These drugs have not beencompared with either chlordiazepoxide orchlormethiazole for the treatment of alcoholwithdrawal.

The aim of the present study was to observethe effect of treatment with bromocriptine in acontrolled phase II clinical trial (initial clinicalinvestigation for treatment effect), comparingit with chlormethiazole and chlordiazepoxideon alcohol withdrawal symptoms in patientswith liver disease of varying severity.

METHODS AND PATIENTSSeventy-one patients were entered into the

study, all of whom gave a history of drinkingalcohol in excess of 80 g/day for five or moreyears. On admission to hospital, patients wereassessed and then allocated to one of two studygroups.

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 minorwithdrawal symptoms on admission to hospit-al. The latter were defined arbitrarily by ascore of 17 or less on the rating scale of Borgand Weinholdt (1980) (scale score: 0 absent, 35maximum, severe). The second group includedpatients with established withdrawal symptomsof moderate to major severity defined arbit-rarily by a score of 18 or more on the samerating scale (Borg and Weinholdt, 1980).Patients who had taken psychotropic drugswithin 48 hr of hospital admission were omittedfrom the study. The patients in each groupthen were randomised to treatment in double-blind fashion using a pre-fixed code devised bythe hospital pharmacy from a random numbertable, with a blocked design, to ensure roughlyequal numbers in the different treatmentgroups.

Patients in the 'minor withdrawal group'were randomised to treatment with eitherbromocriptine, chlordiazepoxide, chlor-methiazole or placebo all given in reducingdoses over five days (Table 1). Patients in the'major withdrawal group' were randomised totreatment with either bromocriptine, chlor-diazepoxide or chlormethiazole in reducingdoses over seven days (Table 1). No placebogroup was included.

The drugs were masked in the same sizecapsule, and were pre-packaged into dailydosage containers. The timing and number ofcapsules per administration were the samewithin each of the study groups. Placebocapsules containing lactose were used to makeup the requisite number of capsules in thedosage schedule.

Table 1. Daily dosage schedules of trial drugs for patients with minor ormajor symptoms of alcohol withdrawal

(a) Minor withdrawal group

Day

12345

Bromocriptine(mg)

7.57.57.552.5

Chlordiazepoxide(mg)

125100755025

Chlormethiazole(g)

4321

0.5

Placebo(lactose)

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(b) Major withdrawal group

265

Day

1234567

Bromocriptine(mg)

7.57.57.57.57.552.5

Chlordiazepoxide(mg)

200150125100755025

Chlormethiazole(g)

642.521.510.5

All patients were assessed 6-8 hourly for thefirst 48 hr and thereafter twice a day for thenext 48 hr and then once daily. The severity ofwithdrawal symptoms was assessed using theselective severity assessment scale (Gross etal., 1973) (scale score 7-68), and the ratingscale of Borg and Weinholdt (1980). Treat-ment was considered to have failed if the ratingscore on two consecutive assessments washigher than the initial assessment on eitherrating score, or if patients developed hallucina-tions or seizures. Patients in whom treatmentfailed were given chlormethiazole orally 8g/day initially or intravenously (10-15 mg/minfor 24 hr reducing), on an open basis but werestill assessed using the original schedule.

All patients were adequately hydrated, weregiven a well-balanced diet and received high-dose parenteral B and C vitamins, oral folicacid and potassium supplements as required.They were nursed on an open ward wheneverpossible.

Routine haematological and biochemicalvalues were estimated using standard labora-tory methods. Liver biopsy was performed inthe majority of patients using a Menghinineedle.

Analysis of differences between groups wasbased on intent of treatment regardless ofsubsequent withdrawal from the study or con-tinuation of alcohol consumption in hospital.Differences between assessment scores at thestart of treatment, and at 48 hr or at the time offailure in the two study groups were examinedusing a one-way analysis of variance. Student'sMest (modified for multiple comparisons) wasthen used to test differences vs placebo in the'minor withdrawal group' and between allthree treatments in the 'major withdrawal

group'. Differences in biochemical or haema-tological parameters were analysed similarly.The study was approved by the Royal FreeHospital Ethics Committee and consent wasobtained from the patients studied.

RESULTS

No statistically significant differences wereobserved in the age, sex distribution, recentmean alcohol intake, mean corpuscularvolume, serum aspartate transaminase, serumbilirubin, and degree of histological liver dam-age between treatment groups (Table 2a and b).Mean initial scores for withdrawal symptomswere not statistically different which everrating scale was used although patients takingbromocriptine in the 'minor withdrawal group'tended to be less symptomatic (Table 3a). Twopatients in the 'minor withdrawal group', bothtaking placebo were withdrawn, one becauseof continued alcohol abuse and one because ofthe development of spontaneous bacterial peri-tonitis within 24 hr of admission; both im-proved symptomatically without further treat-ment. One patient in the 'major withdrawalgroup' taking chlordiazepoxide was withdrawnfollowing severe gastrointestinal bleeding, buthis alcohol withdrawal symptoms already hadsubsided before the onset of bleeding. Theremaining 68 patients continued in the trial.

In the 'minor withdrawal group' 26 of 42(62%), and in the 'major withdrawal group' 14of 26 (54%) responded successfully to treat-ment. Treatment failure invariably occurredwithin 48 hr of starting treatment. The 28patients who were treatment failures, re-sponded to chlormethiazole orally (20 patients)or intravenously (8 patients).

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266 A. K. BURROUGHS et al.

Table 2. Details of patients randomised to treatment

(a) Minor withdrawal symptoms

Total No.patientsrandomised

Age, yr (mean± S.EM.)and range

Male : femaleratio

Mean dailyalcohol intake(g)Mean MCV*(0)Mean ASTt(U/l)

Bilirubin }(n.mol/1)RangeMedian

Fatty liver+ fibrosis

Alcoholichepatitis

Cirrhosis ±alcoholichepatitis

Biopsy notperformed

Placebo

11

44±2.I5(31-55)

5:4

182±22.6

1O5±3 1

181.1 + 3

51.9+16.3(11-150)40

5(45%)

2

3

1

Bromocnptine

11

49.3(±3 8)(31-65)

4:6

190.2±25.4

104.7±2.8

177.5+84.5

74 3±5(12-^54)22

6(55%)

2

2

1

Chlordiazepoxide

10

41.1+2.2(30-53)

7.3

180+21

103.6+1.9

155.4±25.8

28.9+11(5-131)24

5(50%)

2

2

1

Chlormethiazole

12

49.6±2.5(38-65)

8:4

236±29.7

101.1 +1.4

157.4±40.9

7.7±4.4(8-72)25

7(58%)

2

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' treatmentwas successful in 27% (3 of 11) taking placebo,36% (4 of 11) taking bromocriptine, 90% (9 of10) taking chlordiazepoxide and 80% (10 of 12)taking chlormethiazole.

Analysis of variance of the scores showedsignificant variance ratios for both the Borgand Weinholdt (1980) (F=5.3; P<0.01) andGross et al. (1973) rating scales (F=2.95;P<0.05). Student's r-test of treatments vsplacebo showed chlormethiazole and chlordia-zepoxide to be statistically significantly better(7=2.9; P<0.5 and 7=2.6; P<0.5 respect-ively) but no difference was noted with bromo-criptine (7=0.33) using the Borg andWeinholdt (1980) rating scale and similarly

with that of Gross et al. (1973) (chlor-methiazole 7=2.6; P<0.5, chlordiazepoxide7=2.5, P<0.5, bromocriptine 7=0.26).

In the 'major withdrawal group' treatmentwas effective in none of the nine patientstreated with bromocriptine, in 70% (7 of 10)taking chlordiazepoxide, and in 87% (7 of 8)taking chlormethiazole. Analysis of varianceshowed significant differences between treat-ments 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). Chlor-methiazole was significantly more effectivethan bromocriptine (Borg rating scale 7=5.28;/><0.001; Gross rating scale 7=4.06;f<0.001 but no difference could be demon-

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(b) Major withdrawal symptoms

267

PatientsrandomisedAge, yr (mean ± S.E.M.)and rangeMale : female ratioMean daily alcohol(g)M C V(1)ASTt(U/1)Bilirubint(M.mol/1)RangeMedianFatty liver ± fibrosisAlcoholic hepatitisCirrhosis ± alcoholichepatitis

Bromocriptine

9

42±6.16:3

243.1±46.4

103+2.1

173.6±57 4

108.5±60.3(9-545)28.55(56%)2

2

Chlordiazepoxide

10

41.7±3.46:3

326±62.9

103.1 + 1.7

177.1+50.7

42±10.4(15-183)20

4(40%)2

4

Chlormethiazole

8

50.6±44:4

325±48.9

98.7±3.3

131.91+26.1

33.6±16(8-136)20.55(63%)2

1

• 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 andWeinholdt (1980) scale for alcohol withdrawal

(a) Patients with minor withdrawal symptoms

Placebo Bromocriptine Chlordiazepoxide Chlormethiazole

Initial scoreNo. of patients 11 22 10 12Borg and Weinholdt (1980) 10.3+1.2 7.9±.31 11.1±1.5 11.4±1Gross (1973) (SSA) 17.3±2.3 11.1+5.5 16.4+3.3 16.8+5.7

48 hr score in studysuccessesNo. of patients 3 4 9 12Borg and Weinholdt (1980) 3.7±1 2.8±1 7.6±1.4 7.9±1.8Gross (1973) (SSA) 9.3±1.9 10.3+1.1 12.5±1.1 13.2+5.5Score at time of failure*(between 0 and 48 hr)No. of patients 6 7 1 2Borg and Weinholdt (1980) 18.6±2.4 17.7+1.4 21 25 and 22Gross (1973) (SSA) 22.3±2.5 22.8+2 34 38 and 29

"Two withdrawn (see text).

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268 A. K. BURROUGHS et al.

(b) Patients with major withdrawal symptoms

Initial scoreNo. of patientsBorg and Weinholdt (1980)Gross (1973) (SSA)

48 hr score m study successesNo. of patientsBorg and Weinholdt (1980)Gross (1973) (SSA)

Score at time of failure*(between 0 and 48 hr)No. of patientsBorg and Weinholdt (1980)Gross (1973) (SSA)

Bromocriptine

921.4±.222.3±1.6

0

926.31.237.8±1.3

Chlordiazepoxide

1021.6±2.721.9±2.5

76.911.310.5±1.2

227 and 2438 and 29

Chlormethiazole

822.7±.728.7±3.4

710.8±5.514.4±8.6

12837

'One withdrawn (see text).

strated vs chlordiazepoxide (Borg rating scale7=0.27; Gross rating scale T=0.02). Chlor-diazepoxide was significantly more effectivethan bromocriptine (Borg rating scale 7=3.31;P<0.01; Gross rating scale 7=4.84; P<0.005).

One patient taking chlormethiazole de-veloped an erythematous rash on the third dayof treatment which faded rapidly when thedrug was stopped. One patient with cirrhosisbecame severely drowsy whilst taking chlor-diazepoxide but rapidly improved once thedrug was withdrawn. No side-effects were seenwith bromocriptine.

DISCUSSIONDifficulties arise in evaluating drug treat-

ment for alcohol withdrawal because of thegreat variability in the severity of the with-drawal syndrome, the often subjective natureof the methods used to assess and measureresponses to treatment and the fact that somepatients do not require drug treatment at all(Olbrich, 1979; Whitfield et al., 1979). For thisreason any preliminary (phase II) or fullyfledged (phase III) clinical trial to evaluateproposed new treatment should be conducteddouble-blind against standard treatment, withpatients stratified for severity of withdrawalsymptoms. In the present study patients werestratified according to the severity of theirsymptoms and a placebo group was included inthe minor withdrawal group. Previous clinicalexperience had suggested that this group would

require less sedation and would include morepatients who would withdraw without need fordrug therapy (Olbrich, 1979; Whitfield et al.,1973). A standard rating scale (SSA) (Gross etal., 1973) and the rating scale used in theoriginal bromocriptine study for assessment ofalcohol withdrawal symptoms (Borg andWeinholdt, 1980) were included. The results ofthe present study show that bromocriptine wasless effective than either chlordiazepoxide orchlormethiazole in treating minor withdrawaland was ineffective in treatment of majorwithdrawal symptoms.

The dopaminergic system has been impli-cated in the mechanism of alcohol withdrawal.In ethanol dependent rats, dopamine turnoveris reduced (Hunt and Majchrowicz, 1974) bothduring acute intoxication and withdrawal.Dopamine release falls quickly to below con-trol values during withdrawal, remaining lowfor at least three days and returning to baselinevalues by seven days (Darden and Hunt, 1977).At the same time there is increased activity ofthe cholinergic system (Hunt et al., 1979).These changes do not appear to be induced by,or result in receptor changes. Chronic adminis-tration of ethanol in rats for five or moremonths results in long-lasting increases inreceptor sensitivity to dopamine (a post-synaptic effect) with markedly increased re-sponses to apomorphine or dopamine (Lilje-quist, 1978). This has been attributed tochronic deprivation of dopamine transmitter

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DOUBLE-BLIND CONTROLLED TRIAL 269

which was found to accumulate in the limbicforebrain. The sensitivity of noradrenergic andcholinergic receptor mechanisms appears un-changed in this model (Liljequist and Engel,1979). As dopaminergic agonists decrease theactivity of both dopaminergic and cholinergicneurons (Westerink and Kork, 1974), theymight on theoretical grounds be of use in thetreatment of alcohol withdrawal in man.

In man a single preliminary double-blindstudy has suggested that bromocriptine (7.5 mgdaily) and apomorphine (30 mg daily) wereequally effective in the treatment of alcoholwithdrawal (Borg and Weinholdt, 1980).Although sedative drugs were given concom-itantly to 9 of the 24 patients studied, drowsi-ness and excess sedation were not observed.However, no placebo group was included andthe patients were not stratified according to theseverity of their withdrawal symptoms.

Although there is theoretical evidence tosuggest that the dopaminergic system might beinvolved in the pathogenesis of alcohol with-drawal, and some clinical evidence suggestingdopaminergic drugs may be of benefit, con-trary evidence also exists. In ethanol-dependent mice changes were found indopamine-sensitive adenylate cyclase activityin striatal tissue during withdrawal (Tabakoffand Hoffman, 1979), which reversed to normalwhen alcohol was re-introduced. However, thechanges in dopamine sensitivity did not corre-late with signs of alcohol withdrawal (Tabakoffand Hoffman, 1979). Moreover, dopaminereceptor function appeared less responsive todopamine agonists (piribedil) (Hoffman andTabakoff, 1977), and abnormal locomotion (asa sign of withdrawal) was less responsive toapomorphine (Tabakoff et al., 1978). Resultsfrom this mouse model suggest that despite thepresence of changes in dopamine sensitivity,symptoms of alcohol withdrawal might not beimproved by dopamine agonists. Theseobservations are supported by the results of thepresent study. Furthermore, it is of interestthat recently tiapride, a substituted benzamide,a dopamine antagonist, has been found to beequally as effective as chlormethiazole in treat-ing alcohol withdrawal symptoms (Murphy etal., 1983). Tiapride is a dopamine receptorblocking agent, and possibly acts selectively on

a subpopulation of these receptors (Jenner andMarsden, 1979). This subpopulation could bethat involved with changes in post-synapticdopamine receptor function found in ethanol-dependent mice (Tabakoff and Hoffman, 1979;Blacker al., 1980).

Sedative drugs are generally effective intreating alcohol withdrawal symptoms.However, alcoholic patients often show im-paired drug metabolism because of inductionof drug metabolising enzymes on the one handand impaired hepatic function on the other(Pentikainen et al., 1978; Wilkinson, 1978).Additionally, patients with liver disease tendto show increased sensitivity to sedatives(Hoyumpa and Schenker, 1982). For thesereasons sedative drugs must be used withcaution in alcoholic patients, although little, ifany, attention is ever drawn to this point inmajor reviews and editorials on treatment ofalcohol withdrawal (Gross et al., 191 A; Koch-Weser et al., 1976; Gessner, 1979; Editorial,1981). It was for this reason that treatmentwith bromocriptine appeared so attractive; it iswithout sedative effect and can be used withsafety in patients with chronic liver disease(Morgan etal., 1980).

In the present study, chlordiazepoxide andchlormethiazole were equally effective in pre-venting and treating alcohol withdrawal symp-toms. A reducing daily dosage schedule wasused for both drugs, thus the incidence ofover-sedation was extremely low despite thefact that 41% of the patients treated hadsignificant liver disease with alcoholic hepatitisand/or cirrhosis. The bioavailability of chlor-methiazole is increased in patients with cirrh-osis because it has a high first pass metabolismbut its elimination rate is unchanged (Penti-kainen et al., 1978). Thus, overdosage can beminimised by reducing the standard dosage insusceptible patients, as in this study. In-travenous administration eliminates thevariability of oral bioavailability so that thismight be the optimal route of administration inpatients with cirrhosis (Pentikainen et al.,1978). Chlordiazepoxide is metabolised in theliver to a number of active metabolites whichhave long half-lives and accumulate more inpatients with liver disease (Wilkinson, 1978).In addition these patients show increased

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270 A. K. BURROUGHS el al.

cerebral sensitivity to this class of drug(Hoyumpa and Schenker, 1982). Overdosagemay occur more readily with this drug thanwith chlormethiazole in alcoholics with liverdisease and was indeed observed in one patientin the present trial. Parenteral administrationof chlordizepoxide is impractical; no in-travenous preparation exists and intramuscularabsorption is very slow (Robinson etal., 1983).Only one study is available comparing theefficacy of chlordiazepoxide and chlor-methiazole in the treatment of alcohol with-drawal in patients, though none had liverdisease (McGrath, 1975). Chlordiazepoxidewas successful in preventing delirium tremensin 90% (39 of 41) of treated patients whilechlormethiazole was succesful in 100% (46 of46). Ten patients treated with chlordiazepox-ide, and seven treated with chlormethiazolewere withdrawn because their symptoms wereinadequately controlled. No side-effects wereseen with either drug.

In the present preliminary study bromocrip-tine proved ineffective in the treatment ofalcohol withdrawal which suggests that full-scale clinical investigation for this indication(phase III clinical trial) is unwarranted. Bothchlordiazepoxide and chlormethiazole wereequally effective. Chlormethiazole has theshorter half-life so that over-sedation is less ofa problem than with chlordiazepoxide. Inaddition, chlormethiazole can be given in-travenously which is invaluable for treatingpatients with significant liver disease or fortreating patients too restless or too uncoopera-tive to take oral medication. The intravenousdosage can be titrated to control symptomswithout undue sedation. Although chlordiaze-poxide and chlormethiazole are equally effec-tive in treating alcohol withdrawal symptoms,chlormethiazole is the more flexible drug.

Acknowledgement — We would like to thank Dr R. Kohnand Dr J. F. Harper of Advisory Services (Clinical &General) Ltd., London for their help in organising the trialdrug formulations and Dr E. Fay of Gebro-G. BroschekEG Fieberbrunn for supplying the drugs.

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