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Drug and Alcohol Dependence 133 (2013) 15– 29

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Drug and Alcohol Dependence

jo ur nal homep ag e: www.elsev ier .com/ locate /drugalcdep

eview

merging pharmacotherapies for alcohol dependence: A systematiceview focusing on reduction in consumption�

enri-Jean Aubina,∗, Jean-Bernard Daeppenb,1

Hôpital Paul Brousse, INSERM 669, Université Paris-Sud, Villejuif, FranceAlcohol Treatment Center, Lausanne University Hospital, Lausanne, Switzerland

r t i c l e i n f o

rticle history:eceived 7 November 2012eceived in revised form 15 March 2013ccepted 22 April 2013vailable online 6 June 2013

eywords:bstinencelcohol dependenceurdenystematic reviewreatmenteduction in consumption

a b s t r a c t

Background: European Medicines Agency guidelines recognize two different treatment goals for alco-hol dependence: abstinence and reduction in alcohol consumption. All currently approved agents areindicated for abstinence. This systematic review aimed to identify drugs in development for alcoholdependence treatment and to establish, based upon trial design, if any are seeking market authorizationfor reduction in consumption.Methods: We searched PubMed and Embase (December 2001–November 2011) to identify agents indevelopment for alcohol dependence treatment. Additional studies were identified by searching Clini-calTrials.gov and the R&D Insight and Clinical Trials Insight databases. Studies in which the primary focuswas treatment of comorbidity, or n ≤ 20, were excluded. Studies were then classified as ‘abstinence’ ifthey: described a detoxification/alcohol withdrawal period; enrolled patients who had undergone detox-ification previously; or presented relapse/abstinence rates as the primary outcome. Studies in patientsactively drinking at baseline were classified as ‘reduction in consumption’.Results: Of 602 abstracts identified, 45 full-text articles were eligible. Five monotherapies were in devel-opment for alcohol dependence treatment: topiramate, fluvoxamine, aripiprazole, flupenthixol andnalmefene. Nalmefene was the only agent whose sponsor was clearly seeking definitive approval for
reduction in consumption. Development status was unclear for topiramate, fluvoxamine, aripiprazoleand flupenthixol. Fifteen agents were examined in published exploratory investigator-initiated trials;the majority focused on abstinence. Ongoing (unpublished) trials tended to focus on reduction in con-sumption.Conclusions: While published studies generally focused on abstinence, ongoing trials focused on reductionin consumption, suggesting a change in emphasis in the approach to treating alcohol dependence.
© 2013 Elsevier Ireland Ltd. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

2.1. Published literature search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162.2. Proprietary database search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173.1. Published literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

3.1.1. Sponsored agents in development for alcohol dependence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183.1.2. Agents explored in investigator-initiated trials for alcohol dependence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

3.2. Proprietary databases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.2.1. Additional trials in ClinicalTrials.gov and CTI without pu3.2.2. Additional agents identified via R&D Insight . . . . . . . . . . . . .

� Supplementary material can be found by accessing the online version of this paper at ht∗ Corresponding author at: Addictologie, Hôpital Paul Brousse, 12, avenue Paul-Vaillan

ax: +33 145 59 38 63.E-mail addresses: [email protected], [email protected] (H.-J. Aubin).

1 Service d’alcoologie, Avenue de Beaumont 21bis, CHUV 1011 Lausanne, Switzerland.

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16 H.-J. Aubin, J.-B. Daeppen / Drug and Alcohol Dependence 133 (2013) 15– 29

4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Appendix A. Supplementary data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. Introduction

Despite the high prevalence of alcohol dependence (Departmentf Health, 2004; World Health Organization, 2004) and theigh burden it poses to society (Rehm et al., 2009; Worldealth Organization, 2004, 2007), effective management remains ahallenge for several reasons. Firstly, alcohol dependence is under-ecognized and undertreated. A trial assessing the use of healthervices for mental disorders in Europe reported that only 8% ofatients with alcohol abuse/dependence attend treatment (Alonsot al., 2004). Similar values were reported in the USA; data from aelephone survey and medical record assessment showed that only0.5% of participants received the recommended care for alcoholependence (McGlynn et al., 2003). In a review of community-ased epidemiology studies, alcohol abuse/dependence had theighest median untreated rate (78%) of the eight psychiatric disor-ers examined (Kohn et al., 2004). Reasons for these poor treatmentates may include the stigmatization of being labeled an alco-olic and individuals’ resistance to stop drinking when treatmentrograms have traditionally focused on abstinence. Often patientsnter treatment under duress from employers or family membersDiClemente et al., 1999; Parhar et al., 2008) and, when treatments initiated, patient readiness to stop drinking is relatively low,

ith most patients being ambivalent (DiClemente et al., 1999).urthermore, both clinicians and patients have little faith in theuccess of abstinence-focused treatment programs, meaning thatlinicians may be reluctant to refer patients with alcohol depend-nce (Department of Health, 2004). The timing of treatment forlcohol dependence represents another challenge to effective man-gement. Prompt intervention is essential; alcohol use disorder haseen shown to have a poor outcome when treatment is delayedMoos and Moos, 2006).

The existing landscape of pharmacological treatments for alco-ol dependence is limited. At present, oral naltrexone (approved inhe USA and Europe), injectable naltrexone (USA), oral acamprosateUSA and Europe), disulfiram (USA and Europe) and sodium oxy-ate (the sodium salt of gamma-hydroxybutyric acid; marketed in

taly and Austria) are indicated for treatment of alcohol depend-nce. Off-label use is common; for example, in France, there haseen a large increase in the off-label use of baclofen for the treat-ent of alcohol dependence. As originally proposed by Ameisen

2005), proponents of baclofen claim that the drug facilitates low-isk drinking and there has been substantial pressure from patientssociations for the acceptance of this off-label use for reductionn alcohol consumption (Rolland et al., 2012). Other agents thatre widely used off label in this setting include ondansetron andopiramate (Collins et al., 2006).

All of the agents currently approved for alcohol dependenceave market authorization for achieving and maintaining completebstinence from alcohol. None are indicated for reduction of alcoholonsumption, although some are used in this setting. For instance,
altrexone has been investigated for delaying first “heavy drink-
ng day” (HDD) as opposed to “first drink” (Garbutt et al., 1999;osner et al., 2008, 2010), and for preventing relapse to heavy drink-

ng (Rosner et al., 2008). These studies suggested that the major

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benefits of naltrexone are in reducing relapse to heavy drinkingand thus number of HDDs, and to a lesser extent increase in absti-nence, even in studies where the psychotherapeutic focus was onabstinence (Anton et al., 2006; Volpicelli et al., 1992).

There is, therefore, a need for agents aimed at reducing alcoholconsumption. Such agents would be suitable for individuals whowould otherwise be deterred from abstinence-based treatmentstrategies (Ambrogne, 2002). Drugs facilitating a reduction in alco-hol use for patients who are not ready to stop drinking altogetherwould change the attitudes of patients and general practitioners(GPs) to alcohol problems. In the USA, 42% of patients who neededtreatment for alcohol problems reported that they had not soughttreatment because they were not ready to stop alcohol intake(Substance Abuse and Mental Health Services Administration,2009); the availability of drugs for reducing alcohol consumptionwould make it much easier for patients to request help to reducetheir alcohol use (Marlatt and Witkiewitz, 2002) and, similarly, itwould be much easier for GPs to have available an effective tool tohelp their heavy drinking patients without having to insist on absti-nence. What is more, alcohol use reduction in alcohol-dependentpatients might be an intermediary aim to prepare individualsfor complete abstinence or a long-term controlled drinking goal(Hodgins et al., 1997). In addition, reduction in alcohol use hasbeen associated with a reduction in alcohol-related morbidity andmortality (reviewed in (Gastfriend et al., 2007)). The reduction inconsumption treatment strategy can be used at an early stage ofalcohol dependence in primary care and at later stages in specialistcare. The validity of the reduction in consumption approach is rec-ognized in the European Medicines Agency (EMA) guidelines on thedevelopment of products for alcohol dependence; these guidelinesrecognize two different treatment goals in alcohol dependence: fullabstinence and harm reduction, i.e., reduction in alcohol consump-tion (EMA, 2010).

The aim of this systematic review was to (a) research the scien-tific literature, trial registries and proprietary databases to identifydrugs in development for the treatment of alcohol dependence and(b) to identify how many, if any, are seeking to establish a specificindication for the reduction in alcohol consumption, by examiningthe design of the studies identified in the literature search.

2. Methods

2.1. Published literature search strategy

Published abstracts examining pharmacotherapy for the treatment of alcoholdependence were identified by searching PubMed and Embase using the followingMeSH terms: “Alcoholism/drug therapy”[Majr] AND (“humans”[MeSH Terms] ANDEnglish[lang] AND “adult”[MeSH Terms]). In the hierarchy of MeSH terms, alco-holism captures the desired area of interest, excluding conditions such as acutealcohol intoxication, alcohol withdrawal syndrome, and alcohol-induced physi-cal and mental disorders. Results were limited to the last 10 years (December2001–November 2011). Additional abstracts were identified by searching the refer-ence lists of full-text articles identified in the literature search.

Abstracts and/or full text-articles were excluded if they were: examining prod-
ucts already marketed for alcohol dependence; conducted in patients with alcoholdependence but the primary focus was treatment of a comorbid disease; con-ducted in patients with alcohol dependence plus drug dependence; reviews, casestudies, letters and commentaries; pilot studies with ≤20 patients in total; con-ducted in adolescents; focusing on alcohol withdrawal (AW) syndrome (including
l - JCon January 08, 2017.017. Elsevier Inc. All rights reserved.

H.-J. Aubin, J.-B. Daeppen / Drug and Alcohol Dependence 133 (2013) 15– 29 17

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Fig. 1. Process for identifying papers eligible for inclusion i

aboratory studies in which drinking was assessed at the end of withdrawal treat-ent); assessing outcomes other than alcohol consumption (e.g., cue reactivity

tudies); laboratory studies; examining non-pharmacological therapy; or exam-ning agents for which development for alcohol dependence treatment had beeniscontinued.

From information obtained from the included full-text articles, agents were thenlassified according to whether they were ‘in development’ for alcohol dependencei.e., being examined in a pharmaceutical company-sponsored trial and aiming for

licensed indication) or if they were examined in investigator-initiated trials (IITs).harmaceutical company-driven trials were identified by examining the authorffiliations and acknowledgments sections of each full-text article. A trial was con-idered to be an IIT if no pharmaceutical company sponsorship was evident. If a trialas led by an investigator group but sponsored by a pharmaceutical company (i.e.,

trictly an IIT, but with pharmaceutical company financial support), this distinctionas noted in the trial summary in the results.

The design of each trial was then examined to classify each trial into eithern ‘abstinence’ or a ‘reduction in consumption’ trial. As outlined above, the EMAuidelines recognize a full abstinence goal, i.e., relapse prevention after detoxifica-ion, and an intermediate harm reduction goal, i.e., significant moderation withoutrior detoxification (EMA, 2010). With this in mind, studies were considered toocus on ‘abstinence’ if they: (a) included a detoxification or alcohol withdrawaleriod; (b) enrolled patients who had undergone detoxification previously; or (c)

ncluded abstinence rates as the primary outcome. Several studies assessed included detoxification or alcohol withdrawal period but assessed reduction in consumptionutcomes (e.g., number of HDDs or relapse to heavy drinking); they were neverthe-ess classified as ‘abstinence’ studies. Studies in patients who were actively drinkingt baseline and who had not undergone detoxification were classified as focusing on

reduction in consumption’. According to the EMA guidelines, the primary efficacyariable in such studies should be change from baseline in total alcohol consump-ion (TAC; per month, in grams of pure alcohol per day) and reduction in number ofDDs (defined as >60 g of pure alcohol in men and 40 g in women).

.2. Proprietary database search strategy

To supplement the published literature search, we also searched the proprietary
atabases R&D Insight (RDI) and Clinical Trials Insight (CTI), together with Clinical-rials.gov, using ‘alcoholism’ as an indication. We used CTI and ClinicalTrials.govo find studies (Phase II and above) without published data for each of the agentsdentified in the literature search. We also searched RDI, CTI and ClinicalTrials.govo identify agents in early-stage (i.e., preclinical or Phase I) development. Finally,

eview. a≤20 patients in total. bCovering a total of 38 trials.

we searched RDI to identify agents for which development appears to have beendiscontinued.

3. Results

3.1. Published literature

Overall, 599 abstracts were identified from the literature search.During the initial eligibility screening process, 518 abstracts wereexcluded; almost half (n = 251) because they examined agents thatwere already marketed for alcohol dependence, and the remainder(n = 267) for a variety of reasons listed in Fig. 1. Full-text articleswere then retrieved for the 81 abstracts that met the inclusioncriteria. After examining the reference lists of the retrieved full-textarticles a further four abstracts were identified. Following removalof two duplicates, a total of 83 full-text articles were assessed foreligibility. A further 38 were excluded for reasons listed in Fig. 1.

Forty-five full-text articles were identified as examining phar-macotherapy for the treatment of alcohol dependence. Thesearticles covered a total of 38 trials, which were therefore includedin the current review. Overall, 19 monotherapies (covered in 42articles) and three combination therapies (four articles, of whichone had already been counted as monotherapy (Stella et al., 2008))were identified.

While there were some differences in patient inclusion crite-ria between studies, in general, exclusion criteria were fairlyconsistent and included the following: substance abuse; use ofpsychotropic medication; presence of clinically significant disease;suicide ideation; and liver function values three times the upper
limit of normal.
In many of the studies, pharmacological therapy was admin-istered together with psychosocial intervention, for example thelow-intensity intervention BRENDA (Biopsychosocial evaluation,


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eport of findings to patient, Empathetic understanding of patient’situation, Needs to be addressed, Direct advice to patient on how toeet these needs [designed for use alongside pharmacotherapy];olpicelli et al., 2001), or cognitive-behavioral coping skills ther-py from Project MATCH (National Institute on Alcohol Abuse andlcoholism, 2006).

.1.1. Sponsored agents in development for alcohol dependence. Fiveonotherapies were identified as being in development for alcohol

ependence; topiramate, fluvoxamine, aripiprazole, flupenthixolnd nalmefene; main efficacy outcomes are shown in Table 1 andetailed results are shown in Supplementary Table 1. These fiveonotherapies were being examined in a total of five studies (and

total of eight publications). All five of the studies identified wereonsidered to be Phase III, based on the sample size, the random-zed, double-blind, placebo-controlled trial design, and the lengthf the trial (see further details below).

.1.1.1. Topiramate. Topiramate is an anticonvulsant that is widelysed off-label in alcohol dependence. One relatively large, random-

zed, placebo-controlled trial was identified (Johnson et al., 2007).his trial was conducted in actively drinking patients, indicating

focus on reduction in consumption as opposed to abstinence.t week 14, the percentage of HDDs was 43.8% with topiramatend 51.8% with placebo (mean difference: 8.4; p = 0.002; Table 1nd Supplementary Table 1). It is of note that the dose-escalationchedule for topiramate in this study was somewhat complicated,omprising up-titration from 25 to 200 mg/day from weeks 0 to 5nd maintenance dosing at 300 mg/day from weeks 5 to 14. Dur-ng weeks 0–5, dosing varied in terms of morning and/or afternoonosing and number of tablets.

Based on the size and design of the trials identified, topiramateould appear to be in Phase III development for alcohol depend-

nce. The sponsor of this agent is Ortho-McNeil Pharmaceuticals;here are no details in the public domain on its development stage.

.1.1.2. Fluvoxamine. Fluvoxamine is a selective serotonin reup-ake inhibitor (SSRI). A large, placebo-controlled trial assessingelapse rates was undertaken with fluvoxamine, in which this agentailed to show a benefit over placebo in terms of the proportion ofatients who remained abstinent at week 52 (29% in both groups;able 1 and Supplementary Table 1; Chick et al., 2004). Accordingo ClinicalTrials.gov and the RDI and CTI databases, no ongoing tri-ls were identified for fluvoxamine. The development status of thisgent for alcohol dependence is, therefore, unclear.

.1.1.3. Aripiprazole. Aripiprazole is a second-generation antipsy-hotic. It is considered to be a partial dopaminergic agonist with

low rate of extrapyramidal symptoms (EPS). It is approved inhe USA and Europe for schizophrenia, bipolar disorder and, in theSA, as adjunctive treatment for major depression. One large, ran-omized double-blind abstinence trial has been published (Antont al., 2008). In this trial, no significant differences were observedetween aripiprazole and placebo with respect to the percentagef days abstinent (58.7% vs. 63.3%; p = 0.227 [Table 1 and Supple-entary Table 1]; Anton et al., 2008). While several studies (all ofhich are IITs) are listed as ongoing in ClinicalTrials.gov, a lower-ose trial does not appear to have been published to date, and it isnclear whether development is ongoing for aripiprazole.

.1.1.4. Flupenthixol. Flupenthixol, an antipsychotic, is a non-
elective dopamine D1, D2, D3 and (less so) D4 antagonist. It alsoffects serotonin and noradrenaline binding. One trial investi-ating the efficacy of flupenthixol for promoting abstinence wasdentified, which reported higher relapse rates at 6 months with

hol Dependence 133 (2013) 15– 29

flupenthixol (85.2%) than with placebo (65.5%; Table 1 and Sup-plementary Table 1; Wiesbeck et al., 2001). No ongoing trials arelisted on ClinicalTrials.gov for flupenthixol in alcohol dependence.It is unclear whether this agent is still in active development foralcohol dependence.

3.1.1.5. Nalmefene. Nalmefene is a specific opioid antagonist. It hasaffinity for the three opioid receptor subtypes �, к and �. One trialinvestigating the efficacy of nalmefene for reducing consumptionof alcohol in heavy drinkers was identified by the literature search(Karhuvaara et al., 2007).

Three Phase III reduction in consumption trials have alsobeen completed with nalmefene in alcohol-dependent patients(two 6-month trials [ESENSE 1, n = 604, ClinicalTrials.gov identifierNCT00811720 (Mann et al., 2012) and ESENSE 2, n = 718, Clini-calTrials.gov identifier NCT00812461 (Gual et al., 2012)] and onelong-term [SENSE, 1-year] trial, n = 675, ClinicalTrials.gov identifierNCT00811941 (van den Brink et al., 2012)). To date, these stud-ies have only been published as abstracts; therefore, they werenot identified by our literature search. All three studies assessedthe efficacy of nalmefene 18 mg/day (base), administered on anas-needed basis, on monthly HDDs and monthly total alcohol con-sumption. Daily drinking estimates were made using the TimelineFollowback Method. This tool is used to assess recent drinkingbehavior by asking patients to estimate daily alcohol consump-tion over a designated period of time (Sobell and Sobell, 1992).The Timeline Followback Method has been employed previouslyin large trials in patients with alcohol dependence (Johnson et al.,2007; Karhuvaara et al., 2007).

In both 6-month studies, the reduction in monthly HDDs at6 months was significantly greater with nalmefene than withplacebo in the overall population (ESENSE 1: −2.3 [95% confi-dence interval [CI], −3.8; 0.8], p = 0.002; ESENSE 2: −1.7 [95% CI,−3.1; −0.4], p = 0.012) (Gual et al., 2012; Mann et al., 2012). Reduc-tions in TAC were significantly greater with nalmefene than withplacebo in ESENSE 1 (p < 0.001) and numerically greater in ESENSE2 (p = 0.088). The long-term (1-year) study showed similar trends inthe overall population; significantly greater reductions in monthlynumber of HDDs and TAC were observed with nalmefene (n = 509)than with placebo (n = 166) after 1 year’s treatment (both p < 0.05)(van den Brink et al., 2012). Subgroup analyses in patients witha high drinking risk level (>60 g/day for men and >40 g/day forwomen) at screening and randomization showed a significantlygreater reduction in the number of HDDs and TAC with nalmefenethan with placebo (p < 0.05) in all three studies; for HDDs, the treat-ment difference for nalmefene vs. placebo was −3.7 (95% CI, −5.9;−1.5; p = 0.001) for ESENSE 1, −2.7 (95% CI, −5.0; −0.3; p = 0.0253)in ESENSE 2, and −3.6 (95% CI: 6.5; −0.7; p = 0.016) in the long-termSENSE study. For TAC, the treatment difference was −18.3 (−26.9;−9.7; p < 0.0001), −10.3 (−20.2; −0.5; p = 0.040) and −17.3 (−30.9;−3.8; p = 0.013) for ESENSE 1, ESENSE 2 and SENSE, respectively(van den Brink et al., 2013a,b,c).

In February 2013, nalmefene received marketing authorizationfor the reduction of alcohol consumption in adults with alcoholdependence who have a high drinking risk level (>60 g/day formen and >40 g/day for women, as outlined above), do not havephysical withdrawal symptoms, do not require immediate detoxi-fication and continue to have a high drinking risk level two weeksafter an initial assessment. This indication is in line with the sub-group analysis performed on patients with a high drinking risk levelat screening and randomization, and with the patient population
included in the trials. Nalmefene should be prescribed in conjunc-tion with continuous psychosocial support focused on treatmentadherence and the reduction of alcohol consumption. Nalmefene isto be taken on an as-needed basis, i.e., on each day that the patient


Table 1Overview of monotherapies currently in development for alcohol dependence (published data).

Drug Trial design Patients Intervention, n Outcomes

Anti-epileptics/anticonvulsantsTopiramateJohnson et al. (2007)

(primary analysis)Johnson et al. (2008)

(quality of life secondaryanalysis)

• Randomized• Double-blind• 14-week treatmentperiod

• 18–65 years• Diagnosis of alcoholdependence according to DSM-IV(American PsychiatricAssociation, 1994)• ≥35 drinks/week (men) or ≥28drinks/week (women) during 28days before enrolment• AUDIT score ≥8 (Saunders et al.,1993)

• Topiramate25–300 mg/day, n = 183• Placebo, n = 188

Primary analysis

• Percentage of HDDs was significantlylower with topiramate than placebo(mean difference, 8.4%; p = 0.002)

Quality of life secondary analysis

• Topiramate was significantly moreeffective than placebo for reducing bodymass index, liver enzymes, plasmacholesterol and systolic and diastolicblood pressure (p < 0.01)

Antidepressants/antipsychoticsFluvoxamineChick et al. (2004) • Randomized

• Double-blind• 52-week treatmentperiod

• ≥21 years• Diagnosis of current alcoholdependence according toDSM-III-TR (AmericanPsychiatric Association, 1987)• Undergone detoxification andbeen abstinent for 10–30 days

• Fluvoxamine100–300 mg/day, n = 261• Placebo, n = 260

• Abstinence rates and the proportion ofpatients who had not relapsed sincebaseline were similar between groups atboth week 12 and week 52 (p = NS)• Mean dependence severity and days notdrinking since last assessment favoredplacebo at week 12 but werenon-significant by week 52

AripiprazoleAnton et al. (2008) • Randomized

• Double-blind• 12-week treatmentperiod

• 21–65 years• Diagnosis of current alcoholdependence according toDSM-IV-TR (AmericanPsychiatric Association, 2000)• Drinking on ≥70% of days in 60days before enrolment

• Aripiprazole 2–30 mg/dayat escalating doses, n = 149• Placebo, n = 146

• Abstinence rates were not significantlydifferent between aripiprazole andplacebo (58.7% vs. 63.3%)

FlupenthixolWiesbeck et al. (2001)

(primary analysis)Wiesbeck et al. (2003)

(gender sub-analysis)

• Randomized• Double-blind• 6-month treatmentperiod and 6-monthfollow-up period

• 22–55 years• Diagnosis of current alcoholdependence according toDSM-III-TR (AmericanPsychiatric Association, 1987)• Munich Alcoholism Test Score≥11 (Feuerlein et al., 1980)

• Flupenthixol 10 mgintramuscularinjection/fortnight, n = 142• Placebo, n = 139

Primary analysis

• Relapse rates were significantly higherwith flupenthixol than placebo, both at 6months (85.2% vs. 65.5%) and 12 months(91.5% vs. 74.8%; both p < 0.001)

Gender sub-analysis

• In men, risk of relapse was 4 timeshigher with flupenthixol than withplacebo (odds ratio, 3.95)• In women, flupenthixol did not have anegative effect on relapse rates (oddsratio, 1.51)

Opioid receptor antagonistsNalmefeneKarhuvaara et al. (2007)

(primary analysis)Arias et al. (2008)

(pharmacogeneticsub-analysis)

• Randomized• Double-blind• 28-week treatmentperiod followed by24-week randomizedfollow-up period(patients who hadresponded to nalmefenewere re-randomized tonalmefene or placebo)

• ≥18 years• Heavy drinkers• Difficulty in controllingdrinking• ≥18 HDDs and ≤14 consecutiveabstinence days during 12-weekrun-in period• Sober at inclusion visit andwithout severe withdrawalsymptoms

Treatment period

• Nalmefene 20 mg/day(dose could be increased to40 mg/day or reduced to10 mg/day if required),n = 242• Placebo, n = 161• Patients instructed to taketreatment when theybelieved drinking may beimminent

Withdrawal period

• Nalmefene, n = 30• Placebo, n = 27

Pharmacogeneticsub-analysis

• Nalmefene, n = 166• Placebo, n = 106

Treatment period

• Mean number of HDDs/month reducedfrom 15.5 at baseline to 8.8 at the end oftreatment with nalmefene, and from 16.2to 10.6 with placebo (p = 0.0065 fornalmefene vs. placebo)

Follow-up period

• Return to more frequent heavy drinkingwas more common among placeborecipients; in the nalmefene group,patients generally continued at level ofdrinking achieved during treatment

Pharmacogenetic sub-analysis

• No difference in response to nalmefenetreatment for the 5 SNPs examined (twoSNPs in OPRM1, two in OPRD1, and one inOPRK1)

Trials classified as ‘reduction in consumption’ are shaded. Those classified as ‘abstinence’ are not shaded. Studies were considered ‘abstinence’ studies if they: (a) included adetoxification period; (b) enrolled patients who had undergone detoxification previously; or (c) included abstinence rates as the primary outcome. Studies assessing outcomesin drinking patients, such as number of HDDs or relapse to heavy drinking, were classified as focusing on ‘reduction in consumption’.

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erceives a risk of drinking alcohol, one tablet should be taken,deally 1–2 h prior to the anticipated time of drinking (EMA, 2013).

.1.2. Agents explored in investigator-initiated trials for alcoholependence. Fifteen monotherapies were examined in pub-ished IITs (including topiramate, for which both pharmaceuticalompany-sponsored trials and IITs were identified). Thirtyonotherapy trials (34 publications) and four combination trials

4 publications, one of which also included a monotherapy armnd is discussed above (Stella et al., 2008)) were identified via theiterature search. The main efficacy data are presented in Table 2;lease refer to Supplementary Table 2 for detailed results).

.1.2.1. Monotherapies examined in both reduction in consump-ion and abstinence IITs. Two monotherapies were assessed inoth reduction in consumption and abstinence IITs. The first ofhese was topiramate, an anticonvulsant, as described above.ive of the IITs identified were active comparator trials, all ofhich focused on abstinence outcomes (Baltieri et al., 2008; De

ousa et al., 2008; Florez et al., 2008, 2011; Narayana et al.,008). One placebo-controlled abstinence IIT was identified (Rubiot al., 2009). One placebo-controlled trial (Johnson et al., 2003)nd one non-comparative trial (Fernandez Miranda et al., 2007)ssessed reduction in consumption outcomes. Studies in abstinencessessing topiramate versus an active comparator yielded mixedesults (Table 2 and Supplementary Table 2). As noted above, theosing schedule employed for topiramate in many of these studiesas complex, comprising up-titration and maintenance doses.

The second agent was sertraline, an SSRI. One reduction inonsumption trial (Pettinati et al., 2001) and one abstinence trialKranzler et al., 2011) were identified. These studies yielded mixedesults (Table 2 and Supplementary Table 2), reinforcing the impor-ance of subtyping when prescribing sertraline to patients withlcohol dependence.

.1.2.2. Monotherapies examined in reduction in consumption onlyITs. One monotherapy was assessed in reduction in consumptionITs only; ondansetron, an anti-emetic drug that is primarily usedn chemotherapy. Three reduction IITs have been conducted withhis agent (Johnson et al., 2011; Kranzler et al., 2003; Roache et al.,008). Ondansetron does not interfere with the breakdown of alco-ol, and can therefore be taken while drinking. Its mechanism ofction in alcohol dependence is due to its effects on serotonin recep-ors. This agent may show promise in patients with early-onsetlcoholism and those with the LL polymorphism in the serotoninransporter gene (Table 2 and Supplementary Table 2).

.1.2.3. Monotherapies examined in abstinence only IITs. The major-ty of monotherapies studied in IITs were examining abstinenceutcomes only. Baclofen, a gamma-aminobutyric receptor ago-ist, is primarily used as a muscle relaxant but is also widelysed off-label for the treatment of alcohol dependence. All ofhe IITs identified for baclofen were classed as abstinence studiesAddolorato et al., 2002, 2007, 2011; Garbutt et al., 2010). It is ofote that one of the abstinence studies was performed in patientsith alcohol dependence and liver cirrhosis, in whom total absti-ence is the goal of treatment, in order to avoid further liver damagend its associated consequences (Addolorato et al., 2007). Baclofenmproved some drinking outcomes in these abstinence studies, butesults were mixed (Table 2 and Supplementary Table 2).

Gabapentin is an anticonvulsant agent primarily used in theetting of alcohol withdrawal. Two gabapentin studies were iden-
ified, both of which were classified as abstinence studies (Antont al., 2009; Furieri and Nakamura-Palacios, 2007). In one trial,he gabapentin treatment period was preceded by a 2-day AWeriod comprising intravenous flumazenil for 2 days followed by


gabapentin for 39 days (Anton et al., 2009). The second trial didnot include an AW period (Furieri and Nakamura-Palacios, 2007).Mixed results were reported for gabapentin in these two studies(Table 2 and Supplementary Table 2).

Zonisamide is an anticonvulsant agent that bears some struc-tural resemblance to topiramate. Both trials identified were classedas abstinence studies (Arias et al., 2010; Rubio et al., 2010). In theplacebo-controlled study, no significant difference in abstinencerates was observed between zonisamide and placebo (p = 0.94;Table 2 and Supplementary Table 2; Arias et al., 2010).

One abstinence publication was identified for each of the fol-lowing agents: oxcarbazepine, a sodium channel blocker and aderivative of carbamazepine primarily used as an anti-epileptic(Croissant et al., 2006); tiagabine, a gamma-aminobutyric acidtransporter 1 reuptake inhibitor used in the treatment of epilepsy(Paparrigopoulos et al., 2010); escitalopram, an SSRI (Stella et al.,2008); olanzapine, an atypical antipsychotic whose effects areattributed to antagonism of the serotonergic and dopaminergic sys-tems (Guardia et al., 2004); tiapride, a selective dopamine D2/D3antagonist (Bender et al., 2007); lisuride, a dopamine D2 receptoragonist that has primarily been used in the treatment of Parkinson’sdisease (Schmidt et al., 2002); amisulpride, a dopamine D2 and D3receptor antagonist that displays both antidepressant and antipsy-chotic activity (Marra et al., 2002); galantamine, a cholinesteraseinhibitor used in the treatment of Alzheimer’s disease (Mann et al.,2006); and metadoxine, an ion pair (pyridoxine–pyrrolidone car-boxylate) that has been used to treat acute AW with some success(Addolorato et al., 2003 reviewed in Guerrini et al., 2006). Withthe exception of metadoxine, all of these agents failed to show sta-tistical superiority over the comparator for the primary endpoint(Table 2 and Supplementary Table 2). Metadoxine was associatedwith significantly higher abstinence rates than placebo at 6 months(44.8% vs. 21.6%; p = 0.0037), however, the authors noted that ran-domized controlled trials were necessary to confirm these findings(Guerrini et al., 2006). Escitalopram was not effective for preventingrelapse when administered as a monotherapy, however, combi-nation therapy did appear to be effective (see below, Table 2 andSupplementary Table 2).

3.1.2.4. Combination therapies. As outlined above, four combina-tion therapy IITs were identified across four publications. Eachof these trials investigated naltrexone together with an agent ofa different class. The combination of naltrexone + sertraline wasassessed in two studies, both of which assessed were classified asabstinence studies (Farren et al., 2009; O’Malley et al., 2008). Inthe first trial, a detoxification period was not required (O’Malleyet al., 2008), but in the second trial it was mandatory (Farren et al.,2009). Combination therapy did not improve outcomes comparedwith naltrexone alone. The combination of naltrexone + gabapentinwas shown to be effective in one abstinence trial (Anton et al.,2011). A further trial examined the efficacy of triple ther-apy with naltrexone + hydroxybutyric acid + escitalopram (Stellaet al., 2008). Abstinence outcomes were assessed. Triple therapywas associated with higher abstinence rates than escitaloprammonotherapy or dual therapy with escitalopram + naltrexone orescitalopram + gabapentin.

3.2. Proprietary databases

3.2.1. Additional trials in ClinicalTrials.gov and CTI without publisheddata. In order to supplement the literature search, we also searchedClinicalTrials.gov and CTI to identify additional studies (Phase II and
above) that do not yet have published data. While many of the olderpublished trials focused on abstinence outcomes, newer ongoingtrials tended to be focused on reduction in consumption. All ofthe additional trials identified in this search appeared to be IITs


Table 2Overview of monotherapies examined in exploratory investigator-initiated trials (published data).


Anti-epileptics/anticonvulsantsTopiramateDe Sousa et al. (2008) • Randomized

• Open-label• 9-monthtreatment period

• 18–65 years• Male• Diagnosis of alcoholdependence according toDSM-IV (American PsychiatricAssociation, 1994)

• Topiramate 150 mg/day,n = 50• Disulfiram 250 mg/day, n = 50

• Abstinence rates were significantly higherwith disulfiram than topiramate (90% vs. 56%;p = 0.0002)

Narayana et al. (2008) • Randomized• Blinding notspecified• 1-year treatmentperiod

• Age not specified• Uniformed personnel fromArmy/DSC, Air Force, Navy andCoast Guard• Diagnosis of alcoholdependence according toICD-10 (World HealthOrganization, 1992)

• Topiramate 100–125 mg/dayin escalating doses, n = 38• Naltrexone 50 mg/day, n = 26• Acamprosate 333 mg/day(2-1-1 or 2-2-2 dosageaccording to whetherbodyweight was above orbelow 60 kg), n = 28

• Abstinence rates were higher withtopiramate (76.3%) than naltrexone (57.7%) oracamprosate (60.7%)

Baltieri et al. (2008) • Randomized• Double-blind• 12-weektreatment period

• 18–60 years• Diagnosis of alcoholdependence according toICD-10 (World HealthOrganization, 1992)

• Topiramate 25–300 mg/dayin escalating doses, n = 52• Naltrexone 50 mg/day, n = 49• Placebo, n = 54

• Topiramate was significantly more effectivethan placebo for: time to first relapse; CAD;weeks of heavy drinking (all p < 0.05)• Abstinence rates were significantly higherwith topiramate than placebo at 4 weeks(67.3% vs. 42.6%; p = 0.01) and 8 weeks (61.5%vs. 31.5%; p = 0.01) but not 12 weeks (46.2% vs.27.8%; p = NS)• Differences in drinking outcomes were notsignificant between naltrexone and placebo ortopiramate and naltrexone

Florez et al. (2008) • Randomized• Open-label• 6-monthtreatment period


• Topiramate 50–400 mg/dayin escalating doses (Volpicelliet al., 2001) n = 51• Naltrexone 50 mg/day(Volpicelli et al., 2001) n = 51

• Drinking outcomes were similar betweentopiramate and naltrexone (abstinence;moderate drinking without problems;moderate drinking with problems; heavydrinking without problems; heavy drinkingwithout problems)

Florez et al. (2011) • Randomized• Open-label• 6-monthtreatment period


• Topiramate 50–200 mg/dayin escalating doses (Volpicelliet al., 2001) n = 91• Naltrexone (mean dose50 mg/day) (Volpicelli et al.,2001) n = 91

• Proportion of patients who remainedabstinent at 6 months was 47.3% and 41.8% fortopiramate and naltrexone, respectively• Moderate drinking without problems wasmore frequent with topiramate (27.5%) thannaltrexone (9.9%)• Topiramate and naltrexone were similar forother drinking outcomes (moderate drinkingwith problems; heavy drinking withoutproblems; heavy drinking with problems)

Rubio et al. (2009) • Randomized• Double-blind• 12-weektreatment period

• 18–50 years• Diagnosis of alcoholdependence according toDSM-IV (American PsychiatricAssociation, 1994)

• Topiramate 250 mg/day,n = 31• Placebo, n = 32

• All drinking parameters (both reduction inconsumption and abstinence outcomes) weresignificantly improved with topiramate vs.placebo (all p < 0.05)

Johnson et al. (2003)(primary analysis)a

Johnson et al. (2004)(quality of lifesecondary analysis)

Ma et al. (2006) (‘safe’drinking secondaryanalysis)

• Randomized• Double-blind• 12-weektreatment period

• 21–65 years• Diagnosis of alcoholdependence according toDSM-IV (American PsychiatricAssociation, 1994)• AUDIT score ≥8 (Saunderset al., 1993)• ≥35 drinks/week (men) or≥21 drinks/week (women)during 90 days beforeenrolment

• Topiramate 25–300 mg/day,n = 75• Placebo, n = 75

Primary analysis

• Topiramate was significantly more effectivethan placebo for improving all drinkingoutcomes: self-reported drinks/day,drinks/drinking day, HDDs and abstinent days(all p < 0.05)• Trend towards increasing efficacy as thestudy progressed

Quality of life secondary analysis

• Compared with placebo, topiramatesignificantly improved overall well-being,reported abstinence and not seeking alcohol,overall life satisfaction, and reduced harmfuldrinking consequences (all p < 0.05)

‘Safe’ drinking secondary analysis

• Longest ‘safe’ drinking period was 16.7 daysfor topiramate and 8.9 days for placebo• Percentage of ‘safe’ drinking days was 52.2%for topiramate vs. 42.6% for placebo (p = 0.049)



Table 2 (Continued)


Fernandez Mirandaet al. (2007)

• Non-randomized• Open-label• 12-monthfollow-up trial

• Age range not given (meanage, 38.6 years)• Diagnosis of alcoholdependence according toICD-10 (World HealthOrganization, 1992)• Receiving dehabituationtreatment during previous 3months

• Topiramate (mean doses,87.1 mg/day at baseline and195.8 mg/day at 12 months),n = 64

• Significant improvements were observedfor all drinking outcomes from baseline toend of study: craving scale; priming scale;Alcohol Dependence Intensity Scale;number of drinking days/month; drinkingvolume/drinking day; MCV; and GGT (allp < 0.001)

Anti-spasticity agentsBaclofenAddolorato et al. (2007) • Randomized

• Double-blind• 12-weektreatment period

• 18–75 years• Diagnosis of alcoholdependence according toDSM-IV (American PsychiatricAssociation, 1994)• Diagnosis of liver cirrhosis• ≥2 HDDs/week on average(men, ≥5 drinks/day; women,≥4 drinks/day) and averageconsumption ≥21 drinks/week(men) or ≥14 drinks/week(women) during 4 weeksbefore enrolment

• Baclofen 15 mg/day for 3 daysfollowed by 30 mg/day for theremainder of the treatmentperiod, n = 42• Placebo, n = 42

• Abstinence rates were significantlyhigher with baclofen (71%) than placebo(29%; p = 0.0001)

Garbutt et al. (2010) • Randomized• Double-blind• 12-weektreatment period

• 18–60 years• Diagnosis of current alcoholdependence according toDSM-IV (American PsychiatricAssociation, 1994)• ≥2 HDDs/week (men as ≥5standard drinks/day and forwomen as ≥4 standarddrinks/day) on average during4 weeks prior to screening• Ability to refrain from alcoholfor 3 days prior to therandomization

• Baclofen 30 mg/day(Volpicelli et al., 2001) n = 40• Placebo (Volpicelli et al.,2001) n = 40

• Percentage of HDDs was similar betweenbaclofen (25.5%) and placebo (25.9%,p = NS)• Proportion of patients who remainedabstinent were similar between treatments(baclofen, 50.6%; placebo, 27.9%, p = NS)

Addolorato et al. (2002) • Randomized• Double-blind• 30-day treatmentperiod

• 18–70 years• Diagnosis of current alcoholdependence according toDSM-IV (American PsychiatricAssociation, 1994)

• Baclofen 45 mg/day for first 3days followed by 90 mg/day for27 days, n = 20• Placebo, n = 19

• Abstinence rates were significantlyhigher with baclofen than placebo (70.0%vs. 21.1%; p < 0.005)• CAD was significantly higher withbaclofen (19.6 days) than placebo (6.3days; p < 0.005)

Addolorato et al. (2011) • Randomized• Double-blind• 12-weektreatment period

• 18–60 years• Diagnosis of alcoholdependence according toDSM-IV-TR (AmericanPsychiatric Association, 2000)• ≥2 HDDs/week (men: ≥5standard drinks/day; women:≥4 standard drinks/day) onaverage during 4 weeks andaverage consumption ≥21drinks/week (men) or ≥14drinks/week (women) during 4weeks before enrolment priorto screening• Ability to refrain from alcoholfor 3 days prior to therandomization

• Baclofen 30 mg/day, n = 14• Baclofen 60 mg/day, n = 14• Placebo, n = 14

• Significant reduction in number ofdrinks/day was observed with baclofen30 mg/day (53%; p < 0.0001) and baclofen60 mg/day (68%; p < 0.0001); differencebetween baclofen doses was significant(p = 0.0214)

GabapentinFurieri and

Nakamura-Palacios(2007)

• Randomized• Double-blind• 4-weektreatment period

• 18–65 years• Male• Diagnosis of current alcoholdependence according toDSM-IV (American PsychiatricAssociation, 1994)• ≥35 drinks/week during lastyear and during 90 days beforeenrolment

• Gabapentin up to600 mg/day, n = 30• Placebo, n = 30

• Number of drinks/day, mean percentageof HDDs, and mean percentage of days ofabstinence were significantly lower withgabapentin than placebo (all p < 0.05)• Number of drinks/drinking day was lowerwith gabapentin than placebo (p = NS)



Table 2 (Continued)


Anton et al. (2009) • Randomized• Double-blind• 39-day treatmentperiod and 8-weekfollow-up period

• 18–70 years• Diagnosis of current alcoholdependence according toDSM-IV (American PsychiatricAssociation, 1994)• ≥5 drinks/day on 70% of daysin 1 month before screening• Drinking within 72 h ofscreening

• Gabapentin up to1200 mg/day, n = 33• Placebo, n = 27

• In the overall population, gabapentin wasnot significantly more effective thanplacebo for percentage of days abstinent(p = NS)• Gabapentin was not significantly moreeffective than placebo for time to first HDD

ZonisamideRubio et al. (2010) • Non-randomized

• Open-label• 12-weektreatment period

• 18–65 years• Diagnosis of current alcoholdependence according toDSM-IV (American PsychiatricAssociation, 1994) within 6months

• Zonisamide 50–300 mg/day,n = 22

• Significant improvements were observedin craving scores (from 7.4 at baseline to2.4 at week 12), number of drinks/week(37.4–4.0) and GGT (79.7–62.4; all p < 0.05)

Arias et al. (2010) • Randomized• Double-blind• 12-weektreatment period

• Age range not specified;mean age, 47.8 years inzonisamide group and 50.4years in placebo group

• Zonisamide 100–500 mg/day,n = 20• Placebo, n = 20

• No significant differences betweengroups in abstinence rates and HDDs/week

OxcarbazepineCroissant et al. (2006) • Randomized

• Open-label• 12-weektreatment periodfollowed by12-weektreatment-freefollow-up period

• 18–65 years• Diagnosis of alcoholdependence according toICD-10 (World HealthOrganization, 1992) andDSM-IV (American PsychiatricAssociation, 1994)

• Oxcarbazepine150–1200 mg/day, n = 15• Acamprosate 1998 mg/day,n = 15

• Time to severe relapse was notsignificantly different between treatments

TiagabinePaparrigopoulos et al.

(2010)• Randomized• Open-label• 6-monthtreatment period

• 18–70 years• Diagnosis of alcoholdependence according toDSM-IV-TR (AmericanPsychiatric Association, 2000)

• Tiagabine 15–20 mg/day,n = 60• Placebo, n = 60

• Hepatic abstinence measures decreasedsignificantly with both tiagabine andplacebo (p < 0.001)• No significant differences betweentreatments• Abstinence rates were 7.0% for tiagabineand 14.3% for placebo

Antidepressants/antipsychoticsSertralinePettinati et al. (2001)

(primary analysis)Dundon et al. (2004)

(long-term outcomesanalysis)

Pettinati et al. (2004)(exploratory genderanalysis)

• Randomized• Double-blind• 14-weektreatment periodfollowed by6-monthtreatment-freefollow-up period

• ≥18 years• Diagnosis of current alcoholdependence according toDSM-III-TR (AmericanPsychiatric Association, 1987)• Actively drinking in previous30 days• Patients classified accordingto lifetime DSM-III-TR(American PsychiatricAssociation, 1987) diagnosis ofmajor depression or dysthymia(data are shown for patientsclassified as ‘Never depression’for the primary analysis, butfor all patients [n = 100] for thelong-term outcomes analysisand the exploratory genderanalysis)

• Sertraline 200 mg/day, n = 24• Placebo, n = 23

Primary analysis in the ‘Never depression’group

• Percentage of drinking days was 17.6with sertraline and 25.4 with placebo(p = NS)• Time to relapse was longer withsertraline than placebo (11.0 vs. 7.2 weeks;p = 0.05)• Percentage of patients remainingabstinent was 50.0% vs. 21.7% (p = 0.03)

Long-term outcomes analysis

• Type A alcoholics who had receivedsertraline maintained good treatmentoutcomes in the 6 months followingtreatment discontinuation• Type B alcoholics who had receivedsertraline continued to show no benefit6 months after treatment discontinuation

• Number of HDDs increased during the6-month follow-up period among Type Bsertraline recipients

Gender analysis

• Type A alcoholic men had consistentlybetter outcomes than Type A alcoholicwomen on drinking outcomes• In Type B alcoholics, no differencesbetween sertraline and placebo wereobserved for men or women



Table 2 (Continued)


Kranzler et al. (2011) • Randomized• Double-blind• 12-weektreatment period

• 18–65 years• Diagnosis of current alcoholdependence according toDSM-IV (American PsychiatricAssociation, 1994)• Self-reported abstinencefrom alcohol for ≥3 days beforebaseline

• Sertraline 50–200 mg/day• LOA, n = 42• EOA, n = 21

• Placebo• LOA, n = 46• EOA, n = 25

• Among L’L’ homozygotes in serotonintransporter gene:

• LOA patients receiving sertraline hadfewer DDs than those receiving placebo(mean difference, 3.01 days; p = 0.009)

• EOAs receiving sertraline had more DDsthan those receiving placebo (meandifference, 5.28 days; p < 0.001)

• Similar trends for HDDs (p = 0.051and p < 0.001, respectively)• Among S’ carriers in the serotonintransporter gene:

• Time × medication × age of onset was notsignificant in terms of either DDs or HDDs

EscitalopramStella et al. (2008) • Randomized

• Blinding notspecified• 6-monthtreatment period

• 21–66 years• Diagnosis of current alcoholdependence according toDSM-IV (American PsychiatricAssociation, 1994) and AUDIT(Saunders et al., 1993)

• Escitalopram 20 mg/day,n = 11• Three combination therapyarms also included (see text inResults–Combinationtherapies)

• Abstinence rates were highest in the tripletherapy group (83.3%)• Alcohol consumption and OCDS scoreswere significantly lower in triple therapygroup than in all other groups (p < 0.05)• HAM-D scores reduced significantly frombaseline in all treatment groups (p < 0.05)

OlanzapineGuardia et al. (2004) • Randomized


• 18–60 years• Diagnosis of current alcoholdependence according toDSM-IV (American PsychiatricAssociation, 1994)

• Olanzapine 5–15 mg/day,n = 29• Placebo, n = 31

• Relapse rates were 37.9% with olanzapineand 29.0% with placebo (p = NS)

TiaprideBender et al. (2007) • Randomized



• Tiapride 300 mg/day, n = 149• Placebo, n = 150

• Median time to first relapse was 71 and 92days in the tiapride and placebo groups,respectively (p = NS)

LisurideSchmidt et al. (2002) • Randomized

• Double-blind• 6-monthtreatment periodand 6-monthfollow-up period

• Diagnosis of alcoholdependence according toICD-10 (World HealthOrganization, 1992)

• Lisuride 1.0 mg/day orlisuride 1.8 mg/day, n = 57b

• Placebo, n = 63

• Relapse rates at 6 months weresignificantly higher with lisuride (77.2%) vs.placebo (58.7%; p < 0.05)• Similar trends at 12 months (86.0% vs.69.8%; p < 0.03)• Time to first drink was significantly shorterwith lisuride (107.5 days) than placebo(159.7 days; p < 0.05)

AmisulprideMarra et al. (2002) • Randomized

• Double-blind• 6-monthtreatment period

• 18–65 years• Diagnosis of alcoholdependence according toDSM-IV-TR (AmericanPsychiatric Association, 2000)

• Amisulpride 50 mg/day, n = 37• Placebo, n = 34

• Trend towards fewer DDs with placebothan amisulpride (66.9 vs. 80.8; p = 0.098)

OtherOndansetron (AD04)Kranzler et al. (2003) • Non-randomized

• Open-label• 8-weektreatment period

• 18–65 years• Diagnosis of alcoholdependence according toDSM-IV (American PsychiatricAssociation, 1994)

• Ondansetron oral solution 4�g/kg/mL/day + psychotherapy

• EOA, n = 20• LOA, n = 20

• Reductions in drinks/day, drinks/drinkingday and alcohol-related problems weresignificantly greater among EOAs thanamong LOAs (p < 0.05)

Johnson et al. (2011) • Randomized• Double-blind• 11-weektreatment period

• 20–78 years• Diagnosis of alcoholdependence according toDSM-IV (American PsychiatricAssociation, 1994)• AUDIT score > 8 (Saunderset al., 1993)• Breath alcohol concentrationlimit of < 0.02% in order tocomplete the rating scales

• Ondansetron 8 �g/kg/day,n = 49 for LL genotype andn = 91 for S genotype• Placebo, n = 44 for LLgenotype and n = 99 for Sgenotype

• Among patients with LL genotype,percentage of days abstinent wassignificantly higher (difference, 11.3%;p = 0.023) and mean number ofdrinks/drinking day was significantly lower(–1.62; p = 0.007) with ondansetron thanplacebo• Among ondansetron recipients, drinkingoutcomes were more favorable among thosewith the LL genotype than those with theLS/SS genotype (mean drinks/drinking daydifference,–1.53; p = 0.005 and percentage ofdays abstinent difference, 9.7%; p = 0.03)• Ondansetron LL group had more favorableoutcomes than all other genotype andtreatment groups combined (p < 0.05)



Table 2 (Continued)


Roache et al. (2008)c • Randomized• Double-blind• 11-weektreatment period

• 25–65 years• Diagnosis of alcoholdependence according toDSM-III-TR (AmericanPsychiatric Association, 1987)• Michigan AlcoholismScreening Test score > 5(Selzer, 1971)• ≥3 drinks/day

• Ondansetron 2, 8 or32 �g/kg/dayd

• Type A alcoholism, n = 180• EOA, n = 59• LOA, n = 121

• Type B alcoholism, n = 141• EOA, n = 102• LOA, n = 39

• 72% of patients with Type B alcoholismhad EOA; 67% of patients with Type Aalcoholism had LOA• Among EOA patients, ondansetronsignificantly reduced drinks/day anddrinks/drinking day vs. placebo (p < 0.05)• Percentage of days abstinent was alsosignificantly higher with ondansetron8 �g/kg/day and 32 �g/kg/day thanplacebo (p < 0.05)• Among LOA patients, ondansetron didnot improve drinking outcomes vs. placeboat any dose• Ondansetron 8 �g/kg/day significantlyreduced drinks/day and drinks/drinkingday among Type B patients (p < 0.05)

GalantamineMann et al. (2006) • Randomized

• Double-blind• 12-weektreatment periodand 12-weekfollow-up period

• 18–65 years• Diagnosis of alcoholdependence according toICD-10 (World HealthOrganization, 1992) andDSM-IV (American PsychiatricAssociation, 1994)

• Galantamine transdermaltherapeutic system/daycontaining 25 mg, of whichapproximately 44% isdelivered/day, n = 74• Placebo transdermaltherapeutic system, n = 75

• Galantamine did not prolong time to firstsevere relapse vs. placebo (60.2 days vs.65.3 days)

MetadoxineGuerrini et al. (2006) • Non-randomized

• Blinding notreported• 3-monthtreatment period

• Age range not specified(mean age, 44 years)• Diagnosis of current alcoholdependence according toDSM-III-TR (AmericanPsychiatric Association, 1987)

• Metadoxine3000 mg/day + rehabilitativeinterventions, n = 58• Rehabilitative interventionsonly, n = 102

• Abstinence rates at 3 months were 44.8%in metadoxine group vs. 21.6% in untreatedgroup (p = 0.0037)

Trials classified as ‘reduction in consumption’ are shaded. Those classified as ‘abstinence’ are not shaded. Studies were considered ‘abstinence’ studies if they: (a) included adetoxification period; (b) enrolled patients who had undergone detoxification previously; or (c) included abstinence rates as the primary outcome. Studies assessing outcomesin drinking patients, such as number of heavy drinking days or relapse to heavy drinking, were classified as focusing on ‘reduction in consumption’.

a Classified as a pharmaceutical company-sponsored trial because funding was provided, however, could also be considered an investigator-initiated trial as the trial designwas conceived by the investigator group (as declared in the Acknowledgments).

b n numbers not given for doses separately. for o

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c Secondary analysis from a paper published in 2000, i.e., outside the timeframeJohnson et al., 2000).

d n numbers not given for doses and alcoholism types separately.

ather than pharmaceutical company-sponsored trials; approxi-ately half of them were supported by the National Institute onlcohol Abuse and Alcoholism. The majority of the remaining tri-ls were managed by leading investigators in the field of alcoholependence.

.2.2. Additional agents identified via R&D Insight. Agents in theipeline at early-stage development were identified by the RDIearch. These agents are detailed in Table 3.

Several other monotherapies for which development appears toave been discontinued for alcohol dependence were also identi-ed via RDI. These agents are listed in Supplementary Table 3.

. Discussion

Fifteen agents (including topiramate) were investigated in smallITs. The majority of IITs identified were with topiramate oraclofen. It is unlikely that many of the agents investigated in IITsill ever undergo regulatory approval owing to the fact that reg-latory bodies demand large randomized controlled trials. Thesendings, together with the high proportion of agents that have beeniscontinued, suggest that the pipeline for alcohol dependence isery limited and that very few agents are likely to be approved forhis indication in the next 5–10 years.

In contrast to the published studies, which often focused onbstinence outcomes, the unpublished studies tended to focus oneduction in consumption. Many of these trials were supported byhe NIAAA and/or led by key investigators in the field of alcohol


ur literature search. Inclusion/exclusion criteria are taken from the original paper

dependence. This suggests a change in emphasis in the treatmentof alcohol dependence, and reinforces the fact that the reduction inconsumption approach is becoming recognized as a valid alterna-tive to complete abstinence in patients with alcohol dependence.Indeed, for many patients, abstinence from alcohol is not a real-istic goal; changing emphasis towards reduction in consumptionas opposed to abstinence could help to fulfill the unmet need inalcohol dependence. This strategy could help to alleviate the wide-ranging consequences (medical, psychiatric, social, occupationaland legal) that characterize alcohol dependence (World HealthOrganization, 2007). Our search suggests that nalmefene (recom-mended for use on an as-needed basis) and topiramate (complexdose escalation schedule followed by maintenance dosing) are theonly agents targeting a reduction in consumption indication (asopposed to abstinence), based on the primary outcome and absenceof a detoxification period in the identified studies. It should be high-lighted that the shift towards a reduction in consumption focus isaccompanied by developments in the psychotherapeutic compo-nent of alcohol dependence management. Recent years have seena change in emphasis from cognitive therapy towards complianceenhancement and combined behavioral intervention, such as thatseen in the COMBINE trial with naltrexone (Anton et al., 2006).

It is of note that the EMA guidelines on the development ofproducts for the treatment of alcohol dependence (published in
February 2010) include recommendations on adequate trial length,which will have implications for the design of new trials in the alco-hol dependence setting. For a new compound aiming to promotestable clinically significant moderation of drinking for the longer


Table 3Early-stage agents in the pipeline for alcohol dependence, based on R&D Insight, Clinical Trials Insight and ClinicalTrials.gov.a

Compound name Mechanism of action Reduction in consumption/abstinence trialb

Phase II–IIILevetiracetamc,d Synaptic vesicle protein SV2A modulator • 4 reduction in consumption and 1 abstinence

Phase IIChlorzoxazoned Muscle relaxant • 1 reduction in consumptionCitalopramc Selective serotonin reuptake inhibitor • 1 abstinenceDuloxetine Serotonin-norepinephrine reuptake inhibitor • 1 reduction in consumptionDutasterided 5-� reductase inhibitor • 1 reduction in consumptionMecamylamine �4�2 nicotinic receptor antagonist • 1 reduction in consumptionMemantinec NMDA receptor antagonist • 1 reduction in consumptionMirtazapinec Noradrenergic and specific serotonergic antidepressant • 2 reduction in consumptionOdelepran (LY2196044) Opioid receptor antagoniste • 1 reduction in consumptionORG 25935 Glycine transporter 1 inhibitor • 1 abstinencePrazosinc,d �-adrenergic antagonist • 2 reduction in consumptionQuetiapine Atypical antipsychotic (�2 adrenergic receptor antagonist,

dopamine D2 receptor antagonist, serotonin1A receptoragonist, serotonin2A receptor antagonist)

• 1 reduction in consumption and 2 abstinence

Samidorphan (ALKS 33/RDC-0313) Opioid receptor antagonist (�) • 1 abstinenceVareniclinec �4�2 nicotinic receptor antagonist • 2 reduction in consumption and 2 abstinence

Phase IGSK1144814 Neurokinin-1 receptor antagonist; neurokinin-3 receptor

antagonist• N/A

GSK1521498 Opioid receptor inverse agonist (�) • N/AGSK598809 Dopamine D3 receptor antagonist • N/AGSK618334 Dopamine D3 receptor antagonist • N/AMT-7716 Nociceptin receptor agonist • N/AMTIP Corticotropin-releasing factor receptor 1 antagonist • N/APasireotide Corticotropin-releasing factor receptor antagonist, growth

hormone-releasing factor antagonist, insulin-like growthfactor 1 inhibitor, vascular endothelial growth factor inhibitor

• N/A

PreclinicalJMV 2959 Ghrelin receptor antagonists • N/ASoRI-9409 Opioid receptor antagonist (�) • N/AVMD C620 Protein kinase modulator • N/A

UnclearKRL 901 Aldehyde dehydrogenase inhibitor • N/A

a ‘Early stage’ was defined as: preclinical; Phase I; or Phase II but without any publication of Phase II data.b Studies were considered ‘abstinence’ studies if they: (a) included a detoxification period; (b) enrolled patients who had undergone detoxification previously; or

(c) included abstinence rates as the primary outcome. Studies assessing outcomes in drinking patients, such as number of heavy drinking days or relapse to heavy drinking,were classified as focusing on ‘reduction in consumption’.

c These agents had also been identified in the literature search, however, the papers did not meet the criteria for inclusion in the review.d Classified as being in Phase IV development on ClinicalTrials.gov due to agent already being marketed in another indication. These agents were assumed to be in

P hase I

trTbtfiwtat

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hase II development for alcohol dependence (except levetiracetam; classified as Pe Receptor not specified.

erm (harm reduction), a 12–15-month active treatment period isecommended in initial responders at 3–6 months (EMA, 2010).he majority of studies identified in this review were initiatedefore the release of these guidelines. Nevertheless, it is interestingo note that, among the reduction in consumption trials identi-ed, none (either pharmaceutical company-sponsored trials or IITs)ere of adequate study length according to the EMA recommenda-

ions. One of the nalmefene studies (currently only published as anbstract and therefore not identified by the literature search) methese criteria (van den Brink et al., 2012).

The lack of agents in development for alcohol dependence mayo be due to the fact that to date, very few agents have beenhown to be effective in this setting. Indeed, a broad range of druglasses have been investigated in alcohol dependence, and treat-ent success appears to differ not only within classes but alsoithin agents (Tables 1 and 2, Supplementary Table 1 and Supple-entary Table 2). For example, manipulation of the dopaminergic

nd serotonergic systems has failed to show promise in the setting
f alcohol dependence, and response to treatment has been showno be highly variable. In the case of sertraline, response has beenhown to differ according to the presence or absence of depres-ion (Pettinati et al., 2001), Type A or Type B alcoholism (Dundon

I–III due to the presence of one Phase III trial on ClinicalTrials.gov).

et al., 2004), gender (Pettinati et al., 2004), and polymorphismsin the serotonin transporter gene (Kranzler et al., 2011). Indeed,development has been discontinued for a number of agents act-ing on these neurotransmitter systems (Supplementary Table 3).The other agents that have been discontinued for alcohol depend-ence are somewhat varied, and include aldehyde dehydrogenaseinhibitors, opioid receptor antagonists and adrenergic receptoragonists. Our literature search, together with our assessment ofearly-stage agents, shows that there is still some interest in thesedrug classes in alcohol dependence as development continues forseveral agents in these classes. These observations suggest that theneuropsychiatric mechanisms for alcohol dependence are poorlyunderstood, and further research is warranted. Furthermore, agreat deal of the existing evidence comes from exploratory pilotstudies, some of which are non-comparative or included very fewpatients. It is clear that there is a significant unmet need in thetreatment of alcohol dependence.

Our systematic review was subject to some limitations. The
classification of agents into those in development and those inves-tigated in IITs was, to some degree, subjective, and relied on overtdeclaration of trial sponsorship. Where the classification may havebeen ambiguous, a note has been added to Table 1. This applied to

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ne trial in our review (Johnson et al., 2003). It should also be bornen mind that ‘reduction in consumption’ is a more difficult out-ome to characterize than ‘abstinence’ and therefore some papersere difficult to classify. Our classification was based on the patientopulation and outcome requirements outlined in the EMA recom-endations alcohol dependence trials (EMA, 2010); in line with

hese recommendations, psychotherapy was not considered as partf our classification. Indeed, patient population and outcomes wereeemed more important than the nature of psychotherapy whenlassifying trials as either ‘abstinence’ or ‘reduction in consump-ion’.

As with most literature reviews, ours was based largely on aublished literature search, and supplemented by searching RDI,TI and ClinicalTrials.gov. For the additional trials identified inlinicalTrials.gov/CTI, one should consider that the classificationreduction in consumption/abstinence, as well as trial phase) wasased on information given in the trial profile, and may be subject tohange upon trial publication. For example, inclusion criteria wereinimal in some cases, and a detoxification period may not have

een declared. In addition, for agents already approved for anotherndication, trials were sometimes classed as Phase IV for alcoholependence in ClinicalTrials.gov. In these cases, we reclassified therial according to the most likely trial phase for alcohol dependence.

Finally, one should bear in mind that the development status ofach agent (both those in active development and those for whichevelopment has been discontinued) depended on the accuracynd timeliness of information provided by the drug manufacturer.

. Conclusions

Our searches identified five monotherapies in developmentor alcohol dependence treatment; topiramate, fluvoxamine,ripiprazole, flupenthixol and nalmefene. The pharmaceuticalompany-sponsored trials with topiramate were conducted inctively drinking patients, suggesting that the sponsors of topira-ate may pursue a reduction in consumption indication. However,

here is no information on the status of this agent in the publicomain and therefore its development status is unclear. In addition,

t is of note that the dosing schedule with topiramate may renderhis therapy difficult to use in real-life clinical practice. Currently,almefene is the only agent whose sponsors are clearly seekingpproval for a reduction in consumption indication. Developmenttatus was unclear for the remaining three agents identified: flu-oxamine, aripiprazole and flupenthixol.

Many of the published trials identified in our search focusedn abstinence outcomes. In contrast, ongoing unpublished trialsended to focus on reduction in consumption. This suggests ahange in emphasis in the approach to treating alcohol dependencend a move towards reduction in consumption as a more realisticoal for patients with alcohol dependence.

Agents targeting reduction in consumption of alcohol aspposed to abstinence (e.g., nalmefene and topiramate), may helpo remove barriers to treatment and improve drinking outcomesn patients with alcohol dependence and reduce the substantialconomic burden associated with alcohol dependence.

ole of funding source

Financial support for preparation of the manuscript was pro-ided by Lundbeck.

ontributors

Both authors were involved in manuscript preparation. Bothuthors have contributed to and approved the final manuscript.


hol Dependence 133 (2013) 15– 29 27

Conflict of interest

Dr Aubin has received sponsorship to attend scientific meet-ings, speaker honoraria and consultancy fees from Pfizer, McNeil,GlaxoSmithKline, Sanofi-Aventis, Lundbeck and Merck-Sereno.

Professor Daeppen has received speaker honoraria and consul-tancy fees from Lundbeck.

Acknowledgments

Medical writing assistance was provided by Claire Byrne ofinScience Communications, Springer Healthcare, and funded byLundbeck.

Appendix A. Supplementary data

Supplementary data associated with this article can be found,in the online version, at http://dx.doi.org/10.1016/j.drugalcdep.2013.04.025.

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