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Expert Opinion on Pharmacotherapy

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Current pharmacological treatment approachesfor alcohol dependence

Christian A Müller MD, Olga Geisel MD, Roman Banas & Andreas Heinz MD

To cite this article: Christian A Müller MD, Olga Geisel MD, Roman Banas & Andreas Heinz MD(2014) Current pharmacological treatment approaches for alcohol dependence, Expert Opinionon Pharmacotherapy, 15:4, 471-481, DOI: 10.1517/14656566.2014.876008

To link to this article: http://dx.doi.org/10.1517/14656566.2014.876008

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1. Introduction

2. New pharmacological

treatment approaches

3. Expert opinion

Review

Current pharmacologicaltreatment approaches for alcoholdependenceChristian A Muller†, Olga Geisel, Roman Banas & Andreas Heinz†Charite -- Universitatsmedizin Berlin, Department of Psychiatry, Campus Charite Mitte, Berlin,

Germany

Introduction: At present, the substances acamprosate, naltrexone and

disulfiram are available for pharmacotherapy in alcohol dependence, but

clinical studies found only modest effect sizes of these treatment options.

Areas covered: This article focuses on current pharmacological treatment

approaches for alcohol dependence, which have been evaluated in random-

ized, placebo-controlled trials (RCTs).

Expert opinion: Besides the opioid system modulator nalmefene, which has

recently been approved as a medication for the reduction of alcohol

consumption, several compounds have been investigated in patients with

alcohol dependence using a randomized, placebo-controlled design. In these

studies, the antiepileptic drugs topiramate and gabapentin were found to be

effective in improving several drinking-related outcomes, whereas levetirace-

tam failed to show efficacy in the treatment of alcohol dependence. Clinical

studies using (low-dose) baclofen, a selective GABA-B receptor agonist,

produced conflicting results, so that results of further trials are needed.

Varenicline has also shown mixed results in two RCTs, but might possibly be

useful in patients with comorbid nicotine dependence. The a1 adrenergic

antagonist prazosin is currently under investigation in alcohol dependence

with and without comorbid posttraumatic stress disorder (PTSD). Finally, first

clinical evidence suggests that the 5-HT3 antagonist ondansetron might possi-

bly be used in future within a pharmacogenetic treatment approach in

alcohol dependence.

Keywords: alcohol dependence, pharmacotherapy, reduced drinking, relapse prevention

Expert Opin. Pharmacother. (2014) 15(4):471-481

1. Introduction

Alcohol use disorders (AUDs) represent common and serious diseases, which in mostcases require intensive medical treatment; up to 40% of hospitalized patients sufferfrom AUDs [1]. An alcohol detoxification is often the first step in the treatment ofalcohol dependence and mainly addresses the complications of the underlyingdisease. After detoxification, the vast majority of alcohol-dependent patients (up to85%) suffer from relapses [2]. Improvement of the treatment outcome can beachieved by combining psychosocial with pharmacological interventions. However,since alcohol dependence represents a heterogeneous disorder that results fromgene � environment interactions, which differ from patient to patient, it seemsunlikely that one single medication will show efficacy in all alcohol-dependentpatients [3]. Currently, the anti-craving substances acamprosate and naltrexone aswell as the aversion therapeutic agent disulfiram are available for pharmacotherapyof alcohol dependence. Acamprosate was thought to modulate glutamatergic trans-mission by inhibition of N-methyl-D-aspartate (NMDA) and metabotropic gluta-mate (mGluR5) receptors [4]. However, a recent study suggests that acamprosate

10.1517/14656566.2014.876008 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 471All rights reserved: reproduction in whole or in part not permitted

might act through calcium [5]. In a meta-analysis including24 clinical trials [6], acamprosate has been shown to signifi-cantly reduce the risk of relapse to 86% of the risk of the pla-cebo group and to increase cumulative abstinence duration by11% compared to placebo. In terms of tolerability, diarrheawas the only side effect that occurred more frequently inpatients treated by acamprosate than placebo. With regard tothe opioid antagonist naltrexone, a meta-analysis including47 clinical trials [7] found a significant risk reduction for relapseto heavy drinking (defined as ‡ 5 standard drinks/day formen; ‡ 4 standard drinks/day for women, 1 standarddrink = 12 g of alcohol) to 83% of the risk of the placebogroup and a reduction of drinking days by 4% compared toplacebo. Gastrointestinal and sedative effects were the mostcommon side effects of naltrexone. However, these meta-analyses found only modest effect sizes of these treatmentapproaches, with a number needed to treat (NNT) of 9 forboth acamprosate and naltrexone. Moreover, some large trialsfailed to replicate the positive effects of acamprosate [8,9].The aldehyde dehydrogenase inhibitor disulfiram has been

evaluated in numerous trials in alcohol dependence showinginconsistent results [10,11]. Most of these studies possessedrelevant methodological limitations [10]; only three trialsinvestigated (unsupervised) disulfiram using a randomized,double-blind, placebo-controlled design. One study in a smallsample of adolescent patients reported a higher abstinence rate(54 vs 15%) and a higher cumulative abstinence duration(69 vs 30 days) for disulfiram [12]. In contrast, two large stud-ies could not show unsupervised disulfiram to be superiorwith regard to total abstinence compared to placebo [13,14].Interestingly, disulfiram has shown preliminary efficacy inreducing craving and relapse rates in cocaine dependence [15].

These effects might possibly be related to the ability ofdisulfiram to inhibit the dopamine beta-hydroxylase (DBH),leading to an increase in dopamine concentrations whiledecreasing the concentrations of norepinephrine in thebrain [16-18].

In summary, given the high relapse rates and the sufferingof dependent patients, further research is urgently needed todevelop more effective pharmacotherapies for the treatmentof alcohol dependence.

2. New pharmacological treatmentapproaches

2.1 Approved medications

2.1.1 NalmefeneNalmefene, an opioid system modulator structurally related tonaltrexone, possesses antagonistic properties at the µ- andd-receptor and partial agonistic properties at the k-receptor[19]. It has already been evaluated in several randomized,placebo-controlled trials (RCTs) in alcohol dependence [20-22].With the exception of one study [23], all trials reported areduction of heavy drinking during the treatment withnalmefene. Recently, the results of two large multicenterRCTs have been published [24,25]; in both studies, alcohol-dependent patients received an ‘as-needed’ treatment withnalmefene (-18 mg/day) or placebo over 24 weeks.

The first study in a sample of 604 patients reported agreater reduction of heavy-drinking days (-2.3 days/month)and total alcohol consumption (-11.0 g/day) in the nalmefenegroup compared to placebo [24]. Side effects were more com-mon in the nalmefene group and included nausea, dizziness,fatigue, sleep disorder, insomnia, hyperhidrosis and vomiting.Thirty-eight serious adverse events (AEs) were reported(18 nalmefene vs 20 placebo). The authors reported moredropouts due to side effects in the nalmefene group(23 vs 7%).

The second study in 718 patients found a significant reduc-tion in heavy-drinking days (group diff.: -1.7 days/month),but no significant reduction in total alcohol consumption(group diff.: -5.0 g/day, p = 0.088) [25]. The most commonside effects were dizziness, nausea and insomnia, with an inci-dence two times higher in the nalmefene group compared toplacebo. The rate of dropouts due to side effects did not differbetween the groups (6.7 nalmefene vs 5.9% placebo). SeriousAEs occurred in 25 patients (8 nalmefene vs 17 placebo).

In February 2013, nalmefene has been approved by the Euro-pean Medicines Agency (EMA) for the reduction of alcoholconsumption in alcohol-dependent patients who have a highdrinking-risk level without physical withdrawal symptomsand who do not require immediate detoxification [26].

2.2 Off-label medications (Table 1)2.2.1 LevetiracetamLevetiracetam is a second-generation antiepileptic drug thathas recently been investigated in several preclinical and

Article highlights.

. The efficacy of topiramate has repeatedly been reportedby well-designed randomized, placebo-controlled trials(RCTs), but its use might be limited by its side effects.

. The anticonvulsant gabapentin has been found to beeffective and well tolerated in two independent clinicaltrials, but further studies are needed to define its futurerole in the treatment of alcohol dependence.

. RCTs using low-dose baclofen produced conflictingresults in terms of efficacy. The efficacy and tolerabilityof high-dose baclofen are currently under investigation.

. Varenicline has shown mixed results in two RCTs, butmight possibly be useful in patients with comorbidnicotine dependence.

. Based on the findings from one pilot trial usingprazosin, further studies investigating its effects inalcohol dependence with and without comorbid PTSDare currently ongoing.

. First clinical evidence suggests that ondansetron mightpossibly be used in future within a pharmacogenetictreatment approach in alcohol dependence.

This box summarizes key points contained in the article.

C. A. Muller et al.

472 Expert Opin. Pharmacother. (2014) 15(4)

Table

1.Studych

aracteristicsandoutcomesofrandomized,placebo-controlledtrials

investigatingoff-labelmedicationsin

alcoholdependence.

Study

NDuration

Dose

Efficacy

Tolerabilty

Levetiracetam

Richteretal.[39]

201

16weeks

Targetdose:

2000mg/day

Levetiracetam

=placebo:rate

ofsevere

relapse,timeto

severe

relapse,abstinence

rate

Nodifferencesin

AEsandSAEs

Fertig

etal.[40]

130

16weeks

Targetdose:

2000mg/day

extended-release

Levetiracetam

=placebo:percentof

heavy-drinkingdays,percentofsubjectswith

noheavy-drinkingdays

Levetiracetam:fatigue,nodifferences

inSAEs

Topiramate

Johnsonetal.[46]

150

12weeks

25--300mg/day

Topiramate

>placebo:drinksperday,

drinks

perdrinkingday,

fewerheavy-drinkingdays,

days

abstinent

Topiramate:dizziness,paraesthesia,

psychomotorslowing,memory

or

concentrationim

pairment,weightloss,

noSAEs

Johnsonetal.[47]

371

14weeks

upto

300mg/day

Topiramate

>placebo:percentageof

heavy-drinkingdays

Topiramate:paraesthesia,taste

perversion,anorexia,difficultywith

concentration/attention,pruritus;

no

differencesin

SAEs

Baltierietal.[48]

155

12weeks

Targetdose:

300mg/day

Topiramate

=naltrexon>placebo:timeto

firstrelapse,cumulative

abstinence

duration,

weeksofheavy

drinking

Nodifferencesin

AEs,noSAEs

Rubio

etal.[49]

76

12weeks

upto

250mg/day

Topiramate

>placebo:drinksperdrinking

day,

percentageofheavy-drinkingdays,

percentageofabstinentdays

Nodetailedreport

Gabapentin

Furierietal.[50]

60

4weeks

600mg/day

Gabapentin>placebo:drinksperday,

percentageofheavy-drinkingdays,

percentageofabstinentdays

Nodifferencesin

AEs,noSAEs

Masonetal.[51]

150

12weeks

900and

1800mg/day

Gabapentin1800mg/day>gabapentin

900mg/day>placebo:rate

ofabstinence,

rate

ofnoheavy

drinking

Nodifferencesin

AEs,

nodrug-relatedSAEs

Baclofen

Addolorato

etal.[61]

39

4weeks

30mg/day

Baclofen>placebo:abstinence

rate,

cumulative

abstinence

duration

Nodifferencesin

AEs,noSAEs

Addolorato

etal.[62]

84

12weeks

30mg/day

Baclofen>placebo:abstinence

rate,

cumulative

abstinence

duration

Nodifferencesin

AEs,noSAEs

AEs:Adverseevents;SAEs:

Seriousadverseevents.

Current pharmacological treatment approaches for alcohol dependence

Expert Opin. Pharmacother. (2014) 15(4) 473

Table

1.Studych

aracteristicsandoutcomesofrandomized,placebo-controlledtrials

investigatingoff-labelmedicationsin

alcoholdependence

(continued).

Study

NDuration

Dose

Efficacy

Tolerabilty

Garbutt

etal.[63]

80

12weeks

30mg/day

Baclofen=placebo:percentageof

heavy-drinkingdays,percentageabstinent

days

Nodifferencesin

AEs,

noSAEs

Addolorato

etal.[64]

42

12weeks

30and

60mg/day

Baclofen=placebo:heavy-drinkingdays,

abstinent.days,timeto

firstlapse,timeto

firstrelapse.Secondary

analysis:

baclofen

60mg/day>baclofen

30mg/day>placebo:number

ofdrinksperday

Nodifferencesin

AEs,

noSAEs

Varenicline

Plebanietal.[69]

40

13weeks

2mg/day

Varenicline=placebo:alcoholuse

Varenicline>placebo:rate

ofcigarette

smoking

Nodifferencesin

AEs,

noSAEs

Littenetal.[70]

200

13weeks

2mg/day

Varenicline>placebo:percentheavy-drinking

days,drinksperday,

drinksperdrinkingday,

numberofcigarettessm

oked

Varenicline:nausea,abnorm

aldreams,

constipation;nodifferencesin

SAEs

Prazo

sin

Sim

psonetal.[72]

24

6weeks

16mg/day

Prazosin>placebo:numberofdrinkingdays,

numberofdrinks

Nodifferencesin

AEs,

noSAEs

Ondansetron

Johnsonetal.[74]

271

11weeks

2,8or

32µg

/kgperday

Ondansetron(alldosages)

>placeboin

early-onsetAD:numberofdrinksperday,

drinksperdrinkingday

Nodifferencesin

AEs,

noSAEs

Johnsonetal.[75,76]

283

11weeks

8µg

/kgperday

Ondansetron=placebo;

withsubgroupsaccordingto

genotype:ondansetron>placebo:

drinksperdrinkingday,

percentageofdays

abstinent,percentageofheavy-drinking

days

[76]

Ondansetron:fatigue,nomedication-

relatedSAEs

CorreaFilhoand

Baltieri

[77]

102

12weeks

16mg/day

Ondansetron=placebo:percentageof

abstinentdays,percentageofheavy-drinking

days

Nodifferencesin

AEs,

noSAEs

AEs:Adverseevents;SAEs:

Seriousadverseevents.

C. A. Muller et al.

474 Expert Opin. Pharmacother. (2014) 15(4)

clinical studies in alcohol dependence [27,28]. The precisemechanism of action of levetiracetam is still unclear. It hasno significant affinity to gamma-aminobutyric acid (GABA)or glutamate receptors and does not directly interact withthe benzodiazepine binding site [29-31]. Levetiracetam wasreported to bind to the synaptic vesicle protein 2A, which isinvolved in synaptic vesicle function and calcium-dependentregulation of neurotransmitter release during repetitivestimulation [30,32-35]. In alcohol-dependent mice, levetirace-tam has been shown to reduce the alcohol withdrawalsyndrome [36]. Two open-label trials provided some evidencethat levetiracetam might also be safe and efficacious in thein- and outpatient treatment of alcohol withdrawalsyndrome [28,37], whereas one RCT failed to show superiorityof levetiracetam in the treatment of alcohol withdrawalsyndrome compared to placebo [38]. With regard to relapseprevention in alcohol-dependent patients, two RCTs havebeen conducted to date. In a multicenter, 16-week RCT,the efficacy and safety of levetiracetam have been investigatedin a sample of 201 recently detoxified alcohol-dependentpatients using target dosages of 2000 mg per day [39]. At studyend, no significant differences between the levetiracetam andthe placebo group were observed for the endpoints ‘rate ofsevere relapse’ (defined as any alcohol consumptionof > 60 g/day for men and > 48 g/day for women; 45 vs40%), ‘time to severe relapse’ (77.4 vs 76.4 days) and‘abstinence rate’ (35 vs 34%). The overall incidence of AEsdid not differ between the levetiracetam and the placebogroup (73 vs 71%); also, no differences in serious AEsbetween both groups were found (2 vs 3%). The study reten-tion rate was similar in the levetiracetam and the placebogroup (82 vs 75%). In a further multisite, 16-week RCT,levetiracetam XR (extended-release) has been evaluated in130 very heavy drinking alcohol-dependent patients (definedas 10 or more drinks/drinking day for men, 8 or moredrinks/drinking day for women at least 40% of the days dur-ing the last month) with a target dose of 2000 mg/day [40]. Nosignificant differences between the levetiracetam XR and theplacebo group were found in terms of percent of heavy-drinking days (LSMEAN 45.8 vs 41.2), percent of subjectswith no heavy-drinking days (14 vs 18%) or in other second-ary drinking outcomes. Except for fatigue (with a prevalencerate in the levetiracetam XR group of 53 vs 24% in theplacebo group), the number of AEs did not differ betweenboth groups. A total of 13 serious AEs occurred duringthe study period (3 in the levetiracetam XR group, 10 in theplacebo group). The study retention rate was similar in thelevetiracetam and the placebo group (78 vs 85%).

2.2.2 TopiramateThe anticonvulsant topiramate has been hypothesized toantagonize the rewarding effects of alcohol by inhibition ofmesolimbic dopamine release, mediated through the facilita-tion of GABAergic function via a non-benzodiazepine siteon the GABA-A receptor and antagonism of a-Amino-3-

hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) andkainate glutamate receptors [41-43]. In preclinical studies, top-iramate has been shown to suppress ethanol drinking and toreduce stress-induced increases in alcohol consumption inmice [44,45]. Until now, four RCTs have been conducted inpatients with alcohol dependence. In a first 12-week RCT[46], 150 patients received either topiramate in escalatingdosages of 25 -- 300 mg per day or placebo; both groupsalso received a standardized medication compliance manage-ment program. At study end, topiramate was significantlymore effective than placebo in improving several drinkingoutcomes: patients receiving topiramate had 2.9 fewer drinksper day, 3.1 fewer drinks per drinking day, 28% fewer heavy-drinking days and 26% more days abstinent in comparison topatients who received placebo. AEs that were reported morefrequently in the topiramate than in the placebo group weredizziness (28 vs 10%), paraesthesia (57 vs 19%), psychomotorslowing (27 vs 12%), memory or concentration impairment(19 vs 5%) and weight loss (55 vs 27%). The study comple-tion rate did not differ between both groups. No seriousAEs have been reported.

In a second, 14-week, multicenter RCT [47], topiramate hasbeen evaluated in 371 alcohol-dependent patients withdosages up to 300 mg per day. In this trial, topiramate wasmore effective in reducing the percentage of heavy-drinkingdays from baseline to week 14 than placebo (mean difference8.4%). Furthermore, topiramate significantly decreased thepercentage of heavy-drinking days compared to placebo(mean difference: 16.2%). AEs that occurred more frequentlyin the topiramate group were paraesthesia (51 vs 11%), tasteperversion (23 vs 5%), anorexia (20 vs 7%), difficulty withconcentration/attention (15 vs 3%) and pruritus (10 vs 1%).Four participants of both treatment groups experienced aserious adverse event. At study end, the retention rates inboth groups differed significantly (topiramate 61 vs placebo77%), and the attrition rates due to AEs were 19% for thetopiramate group and 4% for the placebo group.

In a third 12-week RCT, the efficacy and safety of topira-mate (target dose 300 mg/day) have been compared with nal-trexone (50 mg/day) and placebo in 155 alcohol-dependentpatients who had received a 1-week detoxification prior tothe initiation of the relapse prevention treatment [48]. Topira-mate was superior to placebo in terms of ‘time to first relapse’(7.8 vs 5.0 weeks), ‘cumulative abstinence duration’ (8.2 vs5.6 weeks) and ‘weeks of heavy drinking’ (3.4 vs 5.9). No sig-nificant differences between topiramate and naltrexone werefound. The overall incidence of AEs did not differ betweenthe groups, and no serious AEs were reported. Dropout rateswere significantly lower in the topiramate group compared toplacebo (36 vs 57%).

Rubio and colleagues conducted a fourth RCT using topir-amate for 12 weeks with a daily dose of 250 mg/day in asample of 76 alcohol-dependent patients [49]. Patients of thetopiramate group consumed fewer drinks per drinking day(6.5 vs 8.8), had a lower percentage of heavy-drinking days

Current pharmacological treatment approaches for alcohol dependence

Expert Opin. Pharmacother. (2014) 15(4) 475

(33 vs 51%) and a higher percentage of abstinent days (52 vs37%). No detailed information on occurrence of AEs or seri-ous AEs was given. Three patients of the topiramate groupand one patient of the placebo group withdrew because ofside effects.

2.2.3 GabapentinGabapentin, a non-benzodiazepine anticonvulsant GABAanalog, has been evaluated in two clinical trials in alcoholdependence. A 4-week RCT in 60 patients investigated thecompound using dosages of 300 mg twice per day [50]. Com-pared to placebo, patients receiving gabapentin showed a sig-nificant reduction in number of drinks per day and percentageof heavy-drinking days. Also, the percentage of abstinent dayswas significantly increased in this group. Side effects occurredin the form of insomnia, sleepiness and headache withno differences between the groups. No serious AEs werereported. The retention rate was higher in the gabapentingroup compared to placebo.In a recent 12-week RCT, gabapentin was administered in

150 alcohol-dependent patients with dosages of 900 and1800 mg per day, respectively [51]. Patients receiving gabapen-tin showed a significantly higher rate of abstinence in compar-ison to placebo (17% in the 1800 mg/day group vs 11% inthe 900 mg/day group vs 4% in the placebo group) with anNNT of 8 for 1800 mg/day. With regard to the co-primaryendpoint ‘no heavy drinking’ rate, gabapentin was also supe-rior compared to placebo (48% in the 1800 mg/day groupvs 30% in the 900 mg/day group vs 23% in the placebogroup; NNT = 5 for 1800 mg/day). Side effects such as head-ache, fatigue and insomnia were reported, but no significantdifferences between the treatment groups were found. Also,no serious drug-related AEs occurred during the study. Theretention rates were similar in all groups.

2.2.4 BaclofenBaclofen, a selective GABA-B receptor agonist, is approvedfor the treatment of spasticity resulting from various neuro-logical conditions [52]. In the past years, several lines of exper-imental evidence have demonstrated a role of GABA-Breceptors and baclofen in affecting different alcohol-relatedbehaviors in rodents. The GABA-B receptor is located withinthe mesolimbic reward system of the brain and has beenhypothesized to modulate dopaminergic neurotransmis-sion [53,54], which plays a crucial role in the development ofalcohol dependence [55]. In preclinical studies, baclofen wasfound to suppress acquisition and maintenance of alcohol-drinking behavior in rats [56,57], the increase in alcohol intakeafter a period of alcohol abstinence in rats [58], and oral self-administration of alcohol in rats and mice trained to lever-press for alcohol [59,60]. In alcohol-dependent patients, fourRCTs using baclofen have been published until now. In a firstclinical trial, 39 alcohol-dependent patients received 30 mg ofbaclofen per day or placebo for 4 weeks [61]. Compared toplacebo, there was a higher proportion of patients who

achieved and maintained alcohol abstinence during the studyin the baclofen group (70 vs 21%). Furthermore, the cumula-tive abstinence duration was significantly higher in the baclo-fen group (19.6 vs 6.3 days). The occurrence of AEs did notdiffer between both groups, and also, no serious AEs werereported. The study retention rate was similar in both groups.

A second RCT assessed the efficacy and safety of 30 mg ofbaclofen per day in 84 patients with alcohol dependence andcomorbid liver cirrhosis during a 12-week study period [62]. Inthis trial, a significantly higher number of patients achievedand maintained abstinence in the baclofen group in compari-son to the placebo group (71 vs 29%). The cumulative absti-nence duration was significantly higher in the group ofpatients who received baclofen (62.8 vs 30.8 days). Tolerabil-ity of the study medication was similar in both groups, and noserious AEs were reported. The study retention rate did notdiffer between the baclofen and the placebo groups.

A third RCT has been conducted in 80 alcohol-dependentpatients using 30 mg of baclofen per day or placebo for12 weeks [63]. With regard to the endpoints ‘percentage ofheavy-drinking days’ and ‘percentage abstinent days,’ no dif-ferences between the baclofen and the placebo group werefound (26 vs 26%; 50 vs 51%). The rates of reported AEsand the study completion rate did not differ between bothtreatment groups. No serious AEs occurred during the studyperiod.

In a fourth 12-week RCT, baclofen has been investigated in42 alcohol-dependent patients using target dosages of 30 and60 mg per day in comparison to placebo [64]. Regarding theendpoints ‘heavy-drinking days,’ ‘abstinent days,’ ‘time tofirst lapse’ and ‘time to first relapse,’ no significant differencesbetween the groups were found. In a secondary analysis,patients receiving 30 mg of baclofen per day had a 53%reduction in the number of drinks per day and patients receiv-ing 60 mg of baclofen had a 68% reduction in the number ofdrinks per day compared to placebo. Occurrence of AEs andstudy completion rates were similar in all treatment groups,and no serious AEs have been reported.

In line with a recent review of baclofen for the treatment ofsubstance use disorders [65], final conclusions regarding itsefficacy and safety for the treatment of alcohol dependencecan currently not be drawn due to the divergent results frompast RCTs.

2.2.5 VareniclineVarenicline is a partial agonist at the a4b2 nicotinic acetylcho-line receptor subtype and is approved for smoking cessation.Based on the positive results from preclinical studies [66] aswell as clinical trials in heavy-drinking smokers [67,68], vareni-cline has been evaluated in alcohol dependence in two RCTs.In a pilot study [69], 40 alcohol-dependent patients received2 mg/day of varenicline/placebo for a 13-week treatmentperiod. At study completion, no significant difference betweentreatment groups for the primary endpoint ‘alcohol use’ wasfound. With regard to nicotine consumption, a significantly

C. A. Muller et al.

476 Expert Opin. Pharmacother. (2014) 15(4)

lower rate of cigarette smoking was detected for the vareniclinegroup compared to placebo. Common side effects were head-ache, sleep disturbances, nausea and diarrhea, with nosignificant differences between the groups. No serious AEswere reported.

In a recent multicenter RCT, varenicline has been investi-gated in a sample of 200 alcohol-dependent patients [70].Patients received 2 mg/day of varenicline or placebo for13 weeks in combination with a computerized behavioralintervention. Compared to placebo, the varenicline grouphad lower weekly percent heavy-drinking days (adjustedmean diff.: 10.4), less drinks per day (4.4 vs 5.3) and drinksper drinking day (5.8 vs 6.8). Moreover, a lower number ofcigarettes smoked per day was found for the varenicline group(7.4 vs 11.7). Side effects like nausea, abnormal dreams andconstipation occurred with significantly higher rates in thevarenicline group compared to the placebo group. Fourserious AEs were reported (two in the varenicline, two in theplacebo group). The retention rates were similar in bothtreatment groups (88% varenicline vs 84% placebo).

2.2.6 PrazosinBased on the findings from preclinical studies showing that thea1 adrenergic antagonist prazosin reduces self-administrationof ethanol in rats [71], the substance has been evaluated in a6-week RCT in a small sample of 24 alcohol-dependentpatients using a target dose of 16 mg/day. [72]. Patients whoreceived prazosin reported fewer drinking days per week andfewer drinks per week during the final 3 weeks of the study.The average total number of drinking days was 0.9 for theprazosin group and 5.7 for the placebo group, and average totalnumber of drinks was 2.6 for the prazosin group and 20.8 forthe placebo group. Side effects were dizziness, lack of energyand drowsiness, with no differences between the groups. Noserious AEs occurred during the treatment period. The reten-tion rates were similar in both groups. Currently, severalRCTs investigate the efficacy and safety of prazosin in alcoholdependence with and without comorbid PTSD.

2.2.7 OndansetronThe selective 5-hydroxytryptamine 3 (5-HT3) receptor antago-nist ondansetron is an antiemetic drug that has been shown toreduce ethanol consumption in rodents [73]. In a first RCT,271 patients received ondansetron in dosages of 1, 4 or16 µg/kg twice per day for 11 weeks [74]. Compared to placebo,ondansetron decreased the number of drinks per day (1.9,1.6 and 1.9 vs 3.3) and drinks per drinking day (4.8, 4.3 and5.2 vs 6.9) in early-onset (< 25 years of age) but not in late-onset alcohol-dependent patients. Common side effects wereheadache, constipation, tachycardia and pruritus; no differen-ces between the treatment groups were observed, and also, noserious AEs were reported. The dropout rates did not differbetween the treatment groups.

A pharmacogenetic RCT investigated the efficacy of ondan-setron (4 µg/kg twice per day) versus placebo in 283 alcohol-

dependent patients over 11 weeks [75]. In this study, patientswere subgrouped based on their 5¢-HTTLPR and rs1042173genotypes in the serotonin transporter (5-HTT) geneSLC6A4. The authors reported that carriers of SLC6A4-LL/TT who were treated with ondansetron had fewer standarddrinks per drinking day (-2.6) and a percentage of daysabstinent 17% higher in comparison to noncarriers of thatgenotype. However, no significant effect of ondansetroncompared to placebo was found when patients were notsubgrouped according to these genotypes. With regard toside effects, only fatigue occurred more frequently in theondansetron group compared to placebo. Further side effectsincluded insomnia, headache, appetite disturbances and diar-rhea, with no significant differences between the groups. Nomedication-related serious AEs were reported. The retentionrate did not differ among the treatment groups.

A further analysis within the same trial found that also poly-morphisms of the HTR3A and HTR3B genes (which encodethe 5-HT3 receptor subunits A and B) predicted treatmentresponse to ondansetron [76]. For patients carrying one ormore of the genotypes rs1150226-AG and rs1176713-GG inHTR3A and rs17614942-AC in HTR3B, a mean differencein drinks per drinking day (2.5), percentage of heavy-drinkingdays (20.6%) and percentage of days abstinent (18.2%) forondansetron versus placebo was found.

A recent 12-week RCT assessed the efficacy and safety ofondansetron in 102 alcohol-dependent patients using dosagesof 16 mg/day [77]. No significant difference between the groupsregarding the percentage of abstinent days (76 placebo vs 89%ondansetron) was found. Also, there was no significant differ-ence regarding percentage of heavy-drinking days (10 placebovs 6% ondansetron). Side effects occurred in the form of head-ache, dyspepsia and constipation, with no differences betweenthe groups. No serious AEs were reported. The dropout ratesdid not differ significantly between the groups.

Table 1 shows the study characteristics and outcomesof RCTs investigating off-label medications in alcoholdependence.

3. Expert opinion

Based on the findings from two meta-analyses [6,7], theanti-craving substances acamprosate and naltrexone seem torepresent efficacious and safe treatment options for alcoholdependence, but the reported effect sizes are only moderate.

Although disulfiram has been evaluated in several clinicalstudies, no clear conclusions can currently be drawn due tomethodological limitations of these studies.

As a further treatment option, the opioid system modulatornalmefene has shown efficacy in several RCTs [22,24,25] andhas recently been approved by the EMA for the reduction ofalcohol consumption in alcohol-dependent patients. Thus,patients who are not able or willing to abstain from alcoholcan be included in treatment programs aimed to reduce

Current pharmacological treatment approaches for alcohol dependence

Expert Opin. Pharmacother. (2014) 15(4) 477

alcohol intake and dosing as needed, thereby offering a way toreduce harm in those patients.RCTs (single- and multisite) using levetiracetam with

dosages up to 2000 mg per day for the treatment of alcoholwithdrawal syndrome or for the prevention of alcohol relapsecould not show its efficacy in comparison to placebo [38-40].Thus, there is currently no good evidence for its use as anoff-label medication in the treatment of alcohol dependence.In contrast, topiramate has repeatedly been shown to be

effective in improving several drinking outcomes in fourwell-designed RCTs using dosages of up to 300 mg perday [46-49]. However, its widespread use in alcohol-dependentpatients might be limited by the reported, frequently occur-ring side effects such as weight loss and cognitive impair-ments. Another disadvantage of topiramate in a clinicalsetting might be the long titration phase (up to 8 weeks fora dose of 300 mg/day). On the other hand, an improvementof physical and psychosocial well-being in alcohol-dependentpatients receiving topiramate has been reported [78]. Takentogether, the off-label use of topiramate can be considered asevidence based, but its future role in the treatment of alcoholdependence needs to be determined.The anticonvulsant gabapentin has been evaluated posi-

tively in two independent RCTs using dosages up to1800 mg/day [50,51]. Both trials also reported a high tolerabilityof gabapentin in alcohol-dependent patients. Thus, this com-pound possibly represents a further pharmacological treatmentoption in alcohol dependence, but these findings have to bereplicated in future studies to draw final conclusions.With regard to baclofen, four RCTs have reported a high

tolerability in alcohol-dependent patients (also in patientswith comorbid liver cirrhosis [62] -- the EASL clinical practicalguidelines recommend its use in patients with advanced alco-holic liver disease [79]) but conflicting results in terms ofefficacy [61-64]. These inconsistent findings might possibly berelated to the rather low dosages of baclofen used in these tri-als (30 -- 60 mg/day). Based on the preclinical observations ofa dose-dependent effect of baclofen on alcohol consumption

in rats treated with dosages up to 3 mg/kg [80] as well as twocase reports in alcohol-dependent patients receiving high-dose baclofen with up to 270 mg/day [81,82], three ongoingRCTs investigate the efficacy and safety of high-dose baclofen(up to 300 mg/day) in alcohol-dependent patients (Cinical-trials.gov: NCT01266655; NCT01738282; NCT01604330).Since the evidence for baclofen in the treatment of alcoholdependence is low and its risk profile (high-dose baclofen)has not been extensively studied until now, the broadeneduse of baclofen can, currently, not be recommended.

Varenicline, a substance approved for smoking cessation,has shown mixed results in two recent RCTs in alcoholdependence [69,70]. If varenicline were to be found to be effec-tive in future trials, this approach might be a useful extensionof the currently available medications, given that nicotinedependence represents one of the most common comorbiditesin alcohol-dependent patients [83].

Prazosin has shown efficacy in a pilot trial within a smallsample of patients with alcohol dependence [72]. Currently,several clinical trials are ongoing to investigate its efficacy inpatients with and without comorbid PTSD.

The antiemetic drug ondansetron has been assessed in threeRCTs [74-77], showing efficacy in patients with early-onsetalcohol dependence in one trial [74] and in two pharmacoge-netic studies within one trial, when patients were subgroupedaccording to their genotypes of the serotonin transporter(5-HTT) gene and the 5-HT3 receptor subunits A and B genes[75,76]. Without subgrouping, no differences between the treat-ment groups were found. A further trial investigating ondanse-tron in alcohol dependence reported negative results [77]. Thus,first clinical evidence suggests that ondansetron might be afurther pharmacological strategy for alcohol dependencewhen used within a pharmacogenetic treatment approach.

Declaration of interest

The authors state no conflict of interest and have received nopayment in preparation of this manuscript.

C. A. Muller et al.

478 Expert Opin. Pharmacother. (2014) 15(4)

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AffiliationChristian A Muller† MD, Olga Geisel MD,

Roman Banas & Andreas Heinz MD†Author for correspondence

Charite -- Universitatsmedizin Berlin,

Department of Psychiatry, Campus Charite

Mitte, Chariteplatz 1, 10117 Berlin, Germany

E-mail: ch.mueller@charite.de

Current pharmacological treatment approaches for alcohol dependence

Expert Opin. Pharmacother. (2014) 15(4) 481