Effects of Alcohol Cue Reactivity on Subsequent Treatment Outcomes Among Treatment-Seeking Individuals with Alcohol Use Disorder: A Multisite Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Varenicline.

BACKGROUND: The alcohol cue reactivity paradigm is increasingly used to screen medications for the treatment of alcohol use disorder (AUD) and other substance use disorders. Yet, its prospective association with craving and naturalistic drinking outcomes in clinical trials remains unknown. This study embedded repeated human laboratory assessments of alcohol cue reactivity within the context of a randomized controlled trial to examine the effects of varenicline tartrate (Chantix® ), a partial agonist of α4ß2 nicotinic acetylcholine receptors, on alcohol craving among treatment-seeking heavy drinkers with AUD. Our main objectives were to test whether varenicline, as compared to placebo, blunts alcohol cue-elicited craving and test whether alcohol cue reactivity observed in the human laboratory predicts subsequent alcohol craving and use during the remainder of the trial. DESIGN AND METHODS: This double-blind, randomized, 2-site study compared the effects of varenicline (up to 2 mg/d) and placebo on responses to in vivo alcohol cue and affective picture cue exposure in the human laboratory. Forty-seven volunteers (18 females, 29 males), ages 23 to 67 years (M = 43.7, SD = 11.5), were recruited from the community via advertisements to participate in a clinical trial designed to study the effects of varenicline on alcohol use. Participants were randomized to either varenicline or placebo for 6 weeks. RESULTS: Varenicline did not attenuate cue-induced alcohol craving relative to placebo, but craving captured during the cue reactivity paradigm significantly predicted subsequent alcohol use in real-world settings during the clinical trial. Higher craving predicted heavier alcohol use. CONCLUSIONS: Our results are among the first to show alcohol cue-induced craving captured during a human laboratory paradigm predicts drinking outcomes in the context of a clinical trial.

Medication Development for Alcohol Use Disorder: A Focus on Clinical Studies.

Compared to other medical disorders, including other brain diseases, the number of medications approved for alcohol use disorder (AUD) is very small. Disulfiram, naltrexone (oral and long-acting), and acamprosate are approved by the US Food and Drug Administration (FDA) to treat patients with AUD. These medications are also approved in other countries, including in Europe, where the European Medicines Agency (EMA) also approved nalmefene for AUD. Furthermore, baclofen was recently approved for AUD in France. These approved medications have small effect sizes, which are probably the consequence of the fact that they only work for some patients, yet a personalized approach to match the right medication with the right patient is still in its infancy. Therefore, research is needed to expand the armamentarium of medications that clinicians can use to treat their patients, as well as to better develop personalized approaches. This book chapter reviews other medications, beyond those approved by the FDA, that have shown efficacy in clinical trials, as well as medications which are still in the early stages of evaluation in human studies.

Evaluation of Drinking Risk Levels as Outcomes in Alcohol Pharmacotherapy Trials: A Secondary Analysis of 3 Randomized Clinical Trials.

Importance: The US Food and Drug Administration recognizes total abstinence and no heavy drinking days as outcomes for pivotal pharmacotherapy trials for alcohol use disorder (AUD). Many patients have difficulty achieving these outcomes, which can discourage seeking treatment and has slowed the development of medications that affect alcohol use. Objective: To compare 2 drinking-reduction outcomes with total abstinence and no heavy drinking outcomes. Design, Setting, and Participants: Data were obtained from 3 multisite, randomized, placebo-controlled clinical trials of medications for treating alcohol dependence (naltrexone, varenicline, and topiramate) in adults with DSM-IV-categorized alcohol dependence. Main Outcomes and Measures: Within each trial, the percentage of participants in active and placebo conditions who met responder definitions of abstinence, no heavy drinking days, a WHO 1-level reduction, and a WHO 2-level reduction was computed by month with corresponding effect sizes (Cohen h). Results: Across the 3 trials (N = 1169; mean [SD] age, 45 [10] years; 824 [70.5%] men), the percentage of participants classified as responders during the last 4 weeks of treatment was lowest for abstinence (naltrexone, 34.7% [100 of 288]; varenicline, 7.3% [7 of 96]; topiramate, 11.7% [21 of 179]) followed by no heavy drinking days (naltrexone, 51.0% [147 of 288]; varenicline, 24.0% [23 of 96]; topiramate, 20.7% [37 of 179]), WHO 2-level reduction (naltrexone, 75.0% [216 of 288]; varenicline, 55.2% [53 of 96]; topiramate, 44.7% [80 of 179]), and WHO 1-level reduction (naltrexone, 83.3% [240 of 288]; varenicline, 69.8 [67 of 96]; topiramate, 54.7% [98 of 179]) outcomes. Standardized treatment effects observed for the WHO 2-level reduction outcomes (naltrexone, Cohen h = 0.214 [95% CI, 0.053 -0.375]; varenicline, 0.273 [95% CI, -0.006 to 0.553]; topiramate, 0.230 [95% CI, 0.024-0.435]) and WHO 1-level reduction (naltrexone, Cohen h = 0.116 [95% CI, -0.046 to 0.277]; varenicline, 0.338 [95% CI, 0.058-0.617]; topiramate, 0.014 [95% CI, -0.192 to 0.219]) were comparable with those obtained using abstinence (naltrexone, Cohen h = 0.142 [95% CI, -0.020 to 0.303]; varenicline, 0.146 [95% CI, -0.133 to 0.426]; topiramate, 0.369 [95% CI, 0.163-0.574]) and no heavy drinking days (naltrexone, Cohen h = 0.140 [95% CI, -0.021 to 0.302]; varenicline, 0.232 [95% CI, -0.048 to 0.511]; topiramate, 0.207 [95% CI, 0.002-0.413]). Conclusions and Relevance: WHO drinking risk level reductions appear to be worthwhile indicators of treatment outcome in AUD pharmacotherapy trials. These outcomes may align with drinking reduction goals of many patients and capture clinically meaningful improvements experienced by more patients than either abstinence or no heavy drinking days. Trial Registration: ClinicalTrials.gov identifiers: NCT00006206; NCT01146613; NCT00210925.

Gabapentin Enacarbil Extended-Release for Alcohol Use Disorder: A Randomized, Double-Blind, Placebo-Controlled, Multisite Trial Assessing Efficacy and Safety.

BACKGROUND: Several single-site alcohol treatment clinical trials have demonstrated efficacy for immediate-release (IR) gabapentin in reducing drinking outcomes among individuals with alcohol dependence. The purpose of this study was to conduct a large, multisite clinical trial of gabapentin enacarbil extended-release (GE-XR) (HORIZANT® ), a gabapentin prodrug formulation, to determine its safety and efficacy in treating alcohol use disorder (AUD). METHODS: Men and women (n = 346) who met DSM-5 criteria for at least moderate AUD were recruited across 10 U.S. clinical sites. Participants received double-blind GE-XR (600 mg twice a day) or placebo and a computerized behavioral intervention (Take Control) for 6 months. Efficacy analyses were prespecified for the last 4 weeks of the treatment period. RESULTS: The GE-XR and placebo groups did not differ significantly on the primary outcome measure, percentage of subjects with no heavy drinking days (28.3 vs. 21.5, respectively, p = 0.157). Similarly, no clinical benefit was found for other drinking measures (percent subjects abstinent, percent days abstinent, percent heavy drinking days, drinks per week, drinks per drinking day), alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms. Common side-effects were fatigue, dizziness, and somnolence. A population pharmacokinetics analysis revealed that patients had lower gabapentin exposure levels compared with those in other studies using a similar dose but for other indications. CONCLUSIONS: Overall, GE-XR at 600 mg twice a day did not reduce alcohol consumption or craving in individuals with AUD. It is possible that, unlike the IR formulation of gabapentin, which showed efficacy in smaller Phase 2 trials at a higher dose, GE-XR is not effective in treating AUD, at least not at doses approved by the U.S. Food and Drug Administration for treating other medical conditions.

Advances in Pharmacotherapy Development: Human Clinical Studies.

For more than 25 years, researchers have made advances in developing medications to treat alcohol use disorder (AUD), highlighted by the US Food and Drug Administration's (FDA's) approval of disulfiram, naltrexone (oral and long-acting), and acamprosate. These medications are also approved in Europe, where the European Medicines Agency (EMA) recently added a fourth medication, nalmefene, for AUD. Despite these advances, today's medications have a small effect size, showing efficacy for only a limited number of individuals with AUD. However, a host of new medications, which act on variety of pharmacologic targets, are in the pipeline and have been evaluated in numerous human studies. This article reviews the efficacy and safety of medications currently being tested in human trials and looks at ongoing efforts to identify candidate compounds in human studies. As mentioned in the National Institute on Alcohol Abuse and Alcoholism's Strategic Plan 2017-2021 ( https://www.niaaa.nih.gov/sites/default/files/StrategicPlan_NIAAA_optimized_2017-2020.pdf ), medications development remains a high priority. By developing more effective and safe medications, and identifying those patients who will benefit the most from these treatments, we can provide clinicians with the tools they need to treat this devastating disorder, providing relief for patients and their families and markedly improving public health and safety.

A Phase 2, Double-Blind, Placebo-Controlled Randomized Trial Assessing the Efficacy of ABT-436, a Novel V1b Receptor Antagonist, for Alcohol Dependence.

Alcohol use disorder has been linked to dysregulation of the brain stress systems, producing a negative emotional state leading to chronic relapsing behavior. Vasopressin receptors appear to have a regulatory role in stress, anxiety, and alcohol. This study evaluated the novel compound, ABT-436, a V1b receptor antagonist, in alcohol-dependent participants in a 12-week clinical trial. Men and women (n=150) who met criteria for DSM-IV alcohol dependence were recruited across four sites. Participants received double-blind ABT-436 or placebo, and a computerized behavioral intervention. ABT-436 was titrated to 800 mg/day during weeks 2-12. Although the primary outcome, percentage of heavy drinking days, was lower in participants receiving ABT-436 compared with placebo, this difference was not statistically significant (31.3 vs 37.6, respectively; p=0.172; d=0.20). However, participants receiving ABT-436 had significantly greater percentage of days abstinent than those receiving placebo (51.2 vs 41.6, respectively; p=0.037; d=0.31). No significant differences were found between treatment groups on any other measures of drinking, alcohol craving, or alcohol-related consequences. Smokers receiving ABT-436 smoked significantly fewer cigarettes per week than those receiving placebo (p=0.046). ABT-436 was well tolerated, with diarrhea (mild-to-moderate severity) being the most common side effect. In subgroup analyses, participants with relatively higher baseline levels of stress responded better to ABT-436 than placebo on select drinking outcomes, suggesting there may be value in testing medications targeting the vasopressin receptor in high stress, alcohol-dependent patients.

An exploratory evaluation of Take Control: A novel computer-delivered behavioral platform for placebo-controlled pharmacotherapy trials for alcohol use disorder.

Placebo-controlled pharmacotherapy trials for alcohol use disorder (AUD) require an active behavioral platform to avoid putting participants at risk for untreated AUD and to better assess the effectiveness of the medication. Therapist-delivered platforms (TDP) can be costly and present a risk to study design because of the variability in therapist fidelity. Take Control is a novel computer-delivered behavioral platform developed for use in pharmacotherapy trials sponsored by the National Institute on Alcohol Abuse and Alcoholism Clinical Investigations Group (NCIG). This behavioral platform was developed with the goal of reducing trial implementation costs and limiting potential bias introduced by therapists providing TDP. This exploratory study is the first to compare Take Control with TDP on measures related to placebo response rate, medication adherence, and participant retention. Data were drawn from the placebo arms of four multisite, double-blind, randomized controlled trials (RCT) for AUD conducted by NCIG from 2007 to 2015. Data were compared from subjects receiving TDP (n=156) in two RCTs and Take Control (n=155) in another two RCTs. Placebo response rate, as represented by weekly percentage of heavy drinking days, was similar between groups. Subjects who received Take Control had a higher rate of medication adherence than those who received TDP. Subject retention was not significantly different between groups. The findings suggest that Take Control is comparable to TDP on measures of retention, medication adherence, and placebo response. Additional research is needed to evaluate Take Control directly against TDPs in a randomized trial.

Discovery, Development, and Adoption of Medications to Treat Alcohol Use Disorder: Goals for the Phases of Medications Development.

For more than 25 years, advances have been made in developing medications to treat alcohol use disorder (AUD), highlighted by the U.S. Food and Drug Administration's approval of naltrexone (oral and long-acting) and acamprosate. Despite this progress, more work remains to be done in this area because these medications, although effective for some people, do not work for everyone. A high priority for the National Institute on Alcohol Abuse and Alcohol is to put into place a solid infrastructure to aid in the development of medications that are more effective than those currently available and with few side effects. Medication development, especially for a disorder as complex as AUD, is challenging and involves multiple phases, including discovery of "druggable" targets, preclinical studies, human clinical trials, and the adoption and implementation of the new medication into mainstream medicine. A successful medications development program requires clearly established goals for each phase to ensure that a candidate compound is not trapped in one particular phase, a condition known as "the valley of death." In this article, the phases of medication development are described as they apply to AUD, and specific goals of each phase are identified for the next decade. In addition, several important crosscutting themes are outlined for each phase, all of which are essential for advancing medications development. These include identifying and validating screening models and druggable targets, making use of precision medicine, and establishing partnerships among key stakeholders. Our goal in writing this article is to provide a guide on medications development that will aid the alcohol research community in planning, testing, and developing medications for AUD.

Potential medications for the treatment of alcohol use disorder: An evaluation of clinical efficacy and safety.

Alcohol use disorder (AUD), as currently defined in the Diagnostic and Statistical Manual, 5th Edition (DSM-5), is a heterogeneous disorder stemming from a complex interaction of neurobiological, genetic, and environmental factors. As a result of this heterogeneity, there is no one treatment for AUD that will work for everyone. During the past 2 decades, efforts have been made to develop a menu of medications to give patients and clinicians more choices when seeking a therapy that is both effective and which has limited side effects. To date, 3 medications have been approved by the US Food and Drug Administration (FDA) to treat alcohol dependence: disulfiram, naltrexone, and acamprosate. In addition to these approved medications, researchers have identified new therapeutic targets and, as a result, a number of alternative medications are now being evaluated for treatment of AUD in human studies. Although not approved by the FDA for the treatment of AUD, in some cases, these alternative medications are being used off-label by clinicians for this purpose. These potential medications are reviewed here. They include nalmefene, varenicline, gabapentin, topiramate, zonisamide, baclofen, ondansetron, levetiracetam, quetiapine, aripiprazole, and serotonin reuptake inhibitors. The effectiveness of these medications has been mixed-some show good efficacy with side effects that are mild to moderate in intensity; others have mixed or promising results but are awaiting findings from ongoing studies; and still others show poor efficacy, despite promising preliminary results. Medications development remains a high priority. Key initiatives for the National Institute on Alcohol Abuse and Alcoholism (NIAAA) include supporting the discovery and development of more effective and safer medications, advancing the field of personalized medicine, and forging public and private partnerships to investigate new and more effective compounds.

Measures of outcome for stimulant trials: ACTTION recommendations and research agenda.

BACKGROUND: The development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success, other than sustained abstinence. METHODS: In March, 2015, a meeting sponsored by Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) was convened to discuss the current state of the evidence regarding meaningful outcome measures in clinical trials for stimulant use disorders. Attendees included members of academia, funding and regulatory agencies, pharmaceutical companies, and healthcare organizations. The goal was to establish a research agenda for the development of a meaningful outcome measure that may be used as an endpoint in clinical trials for stimulant use disorders. RESULTS AND CONCLUSIONS: Based on guidelines for the selection of clinical trial endpoints, the lessons learned from prior addiction clinical trials, and the process that led to identification of a meaningful indicator of treatment success for alcohol use disorders, several recommendations for future research were generated. These include a focus on the validation of patient reported outcome measures of functioning, the exploration of patterns of stimulant abstinence that may be associated with physical and/or psychosocial benefits, the role of urine testing for validating self-reported measures of stimulant abstinence, and the operational definitions for reduction-based measures in terms of frequency rather than quantity of stimulant use. These recommendations may be useful for secondary analyses of clinical trial data, and in the design of future clinical trials that may help establish a meaningful indicator of treatment success.

Moderators of Varenicline Treatment Effects in a Double-Blind, Placebo-Controlled Trial for Alcohol Dependence: An Exploratory Analysis.

OBJECTIVES: To explore whether varenicline (Chantix) showed more efficacy in treating certain subgroups of patients. In a recent multisite trial, varenicline was shown to be effective in reducing drinking in alcohol-dependent patients, both smokers and nonsmokers. Given the heterogeneity among alcohol-dependent patients, secondary analyses were conducted to determine whether certain subgroups responded more favorably than others to treatment with varenicline. METHODS: Data were drawn from a phase 2 randomized, double-blind, placebo-controlled multisite 13-week trial of varenicline in alcohol-dependent patients (Litten et al., 2013). Seventeen moderator variables were selected for exploratory testing on the basis of theoretical and scientific interest. RESULTS: Of the 17 moderator variables assessed, 4 were statistically significant, including cigarettes per day reduction, treatment drinking goal, years drinking regularly, and age of the patient. Two other variables­the type of adverse events experienced by patients and the severity of alcohol-related consequences­seemed to moderate the varenicline treatment effect at borderline statistical significance. Individuals who reduced the number of cigarettes per day experienced a significant effect from varenicline in reducing drinking, whereas those who did not change or who increased their number of cigarettes observed no beneficial effect. Reviewing the moderators related to severity, varenicline seemed to have greater efficacy than placebo among less severely dependent patients. CONCLUSIONS: Varenicline seems to be more efficacious in certain subgroups, particularly in those who reduced their smoking and in the "less severe" patient. Additional studies are warranted to confirm the results of these exploratory analyses.

Alcohol medications development: advantages and caveats of government/academia collaborating with the pharmaceutical industry.

The process of developing pharmacological treatments for alcohol use disorder is notoriously complex and challenging. The path to market is long, costly, and inefficient. One way of expediting and reducing the drug development process is through collaborations-building partnerships among government, academia, pharmaceutical and biotechnology companies, healthcare organizations and advocacy groups, and the patients (end consumers) themselves. By forging collaborations, particularly with pharmaceutical companies, the alcohol treatment field stands to reap benefits in generating new medications for use in mainstream treatment settings. At the same time, there are certain caveats that should be considered, particularly by academic researchers, before entering into such partnerships. This commentary examines the advantages and caveats of government and academia collaborations with pharmaceutical companies.

Research opportunities for medications to treat alcohol dependence: addressing stakeholders' needs.

During the past decade, significant advances have been made in the development of medications to treat alcohol dependence. Four medications have been approved by the U.S. Food and Drug Administration for treating alcohol dependence-naltrexone, injectable naltrexone, acamprosate, and disulfiram-and several others show promise. The fact remains, however, that because of the heterogeneity of alcohol dependence, these medications will not work for all people, in all circumstances. Moreover, clinicians are not routinely prescribing these medications for alcohol treatment. This commentary poses a number of issues that must be addressed in order to advance the alcohol research field and to make medications a mainstream treatment for problematic drinking. These issues are framed from the perspective of the various stakeholders involved, including clinicians, patients, regulatory agencies, the pharmaceutical industry, and third-party payers. Addressing these issues will not only help to improve treatment but, as further described, will also open up many new research opportunities for alcohol investigators in the coming decade.

The placebo effect in clinical trials for alcohol dependence: an exploratory analysis of 51 naltrexone and acamprosate studies.

BACKGROUND: The placebo effect often undermines efforts to determine treatment effectiveness in clinical trials. A significant placebo response occurs in alcohol trials, but it is not well understood. The purpose of this study was to characterize the placebo response across multiple naltrexone and acamprosate studies. METHODS: Fifty-one trials, 3 with a naltrexone and an acamprosate arm, 31 with at least 1 naltrexone arm, and 17 with at least 1 acamprosate arm, were identified from Cochrane reviews and PubMed search. To be included in this study, patients had to be at least 18 years old, abstinent from alcohol before randomization, and meet a diagnosis of alcohol dependence. Pearson correlation coefficients (rp ) and simple linear regression were used to describe the strength of linear relationships between placebo response and treatment effect size. Spearman's rank correlation coefficients (rs ) were used to examine the strength of associations between study characteristics and placebo response. RESULTS: For the end point measures of percent days abstinent and total abstinence, a negative relationship was evident between placebo response and treatment effect size in the naltrexone trials (rp  = -0.55, p < 0.01 and rp  = -0.20, p = 0.35, respectively) as well as in the acamprosate trials (rp  = -0.45, p = 0.09 and rp  = -0.56, p = 0.01, respectively). The placebo response for percent days abstinent was negatively correlated with mean age of participants (rs  = -0.42, p = 0.05) across naltrexone trials and positively correlated with publication year (rs  = 0.57, p = 0.03) across acamprosate trials. However, these 2 study characteristics were not significantly correlated with treatment effect size. CONCLUSIONS: The placebo response varied considerably across trials and was negatively correlated with the treatment effect size. Additional studies are required to fully understand the complex nature of the placebo response and to evaluate approaches to minimize its effects.

A double-blind, placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence.

OBJECTIVES: To assess the efficacy and safety of varenicline (Chantix) for the treatment of alcohol dependence. Varenicline is a partial α4ß2 nicotinic acetylcholine agonist approved by the Food and Drug Administration for smoking cessation. It has reduced drinking in animal studies and in small studies of humans who were both heavy drinkers and smokers. This is the first multisite clinical trial of varenicline in a population of smokers and nonsmokers with alcohol dependence. METHODS: Men and women (n = 200) meeting the criteria for alcohol dependence were recruited across 5 clinical sites. Patients received double-blind varenicline or placebo and a computerized behavioral intervention. Varenicline was titrated during the first week to 2 mg/d, which was maintained during weeks 2 to 13. RESULTS: The varenicline group had significantly lower weekly percent heavy drinking days (primary outcome) (adjusted mean difference = 10.4), drinks per day, drinks per drinking day, and alcohol craving compared with the placebo group (P < 0.05). The average treatment effect on alcohol use was similar for smokers and nonsmokers. Varenicline was well-tolerated; adverse events were expected and mild. CONCLUSIONS: Varenicline significantly reduced alcohol consumption and craving, making it a potentially viable option for the treatment of alcohol dependence.

Posttreatment low-risk drinking as a predictor of future drinking and problem outcomes among individuals with alcohol use disorders.

BACKGROUND: Treatment for alcohol disorders has traditionally been abstinence-oriented, but evaluating the merits of a low-risk drinking outcome as part of a primary treatment endpoint is a timely issue given new pertinent regulatory guidelines. This study explores a posttreatment low-risk drinking outcome as a predictor of future drinking and problem severity outcomes among individuals with alcohol use disorders in a large private, not for profit, integrated care health plan. METHODS: Study participants include adults with alcohol use disorders at 6 months (N = 995) from 2 large randomized studies. Logistic regression models were used to explore the relationship between past 30-day drinker status at 6 months posttreatment (abstinent [66%], low-risk drinking [14%] defined as nonabstinence and no days of 5+ drinking, and heavy drinking [20%] defined as 1 or more days of 5+ drinking) and 12-month outcomes, including drinking status and Addiction Severity Index measures of medical, psychiatric, family/social, and employment severity, controlling for baseline covariates. RESULTS: Compared to heavy drinkers, abstinent individuals and low-risk drinkers at 6 months were more likely to be abstinent or low-risk drinkers at 12 months (adj. ORs = 16.7 and 3.4, respectively; p < 0.0001); though, the benefit of abstinence was much greater than that of low-risk drinking. Compared to heavy drinkers, abstinent and low-risk drinkers were similarly associated with lower 12-month psychiatric severity (adj. ORs = 1.8 and 2.2, respectively, p < 0.01) and family/social problem severity (adj. OR = 2.2; p < 0.01). While abstinent individuals had lower 12-month employment severity than heavy drinkers (adj. OR = 1.9; p < 0.01), low-risk drinkers did not differ from heavy drinkers. The drinking groups did not differ on 12-month medical problem severity. CONCLUSIONS: Compared to heavy drinkers, low-risk drinkers did as well as abstinent individuals for many of the outcomes important to health and addiction policy. Thus, an endpoint that allows low-risk drinking may be tenable for individuals undergoing alcohol specialty treatment.

Medications development to treat alcohol dependence: a vision for the next decade.

More than 76 million people world-wide are estimated to have diagnosable alcohol use disorders (AUDs) (alcohol abuse or dependence), making these disorders a major global health problem. Pharmacotherapy offers promising means for treating AUDs, and significant progress has been made in the past 20 years. The US Food and Drug Administration approved three of the four medications for alcoholism in the last two decades. Unfortunately, these medications do not work for everyone, prompting the need for a personalized approach to optimize clinical benefit or more efficacious medications that can treat a wider range of patients, or both. To promote global health, the potential reorganization of the National Institutes of Health (NIH) must continue to support the National Institute on Alcohol Abuse and Alcoholism's (NIAAA's) vision of ensuring the development and delivery of new and more efficacious medications to treat AUDs in the coming decade. To achieve this objective, the NIAAA Medications Development Team has identified three fundamental long-range goals: (1) to make the drug development process more efficient; (2) to identify more efficacious medications, personalize treatment approaches, or both; and (3) to facilitate the implementation and adaptation of medications in real-world treatment settings. These goals will be carried out through seven key objectives. This paper describes those objectives in terms of rationale and strategy. Successful implementation of these objectives will result in the development of more efficacious and safe medications, provide a greater selection of therapy options and ultimately lessen the impact of this devastating disorder.

A double-blind, placebo-controlled trial assessing the efficacy of levetiracetam extended-release in very heavy drinking alcohol-dependent patients.

BACKGROUND: Despite advances in the development of medications to treat alcohol dependence, few medications have been approved by the U.S. Food and Drug Administration. The use of certain anticonvulsant medications has demonstrated potential efficacy in treating alcohol dependence. Previous research suggests that the anticonvulsant levetiracetam may be beneficial in an alcohol-dependent population of very heavy drinkers. METHODS: In this double-blind, randomized, placebo-controlled clinical trial, 130 alcohol-dependent patients who reported very heavy drinking were recruited across 5 clinical sites. Patients received either levetiracetam extended-release (XR) or placebo and a Brief Behavioral Compliance Enhancement Treatment intervention. Levetiracetam XR was titrated during the first 4 weeks to 2,000 mg/d. This target dose was maintained during weeks 5 through 14 and was tapered during weeks 15 and 16. RESULTS: No significant differences were detected between the levetiracetam XR and placebo groups in either the primary outcomes (percent heavy drinking days and percent subjects with no heavy drinking days) or in other secondary drinking outcomes. Treatment groups did not differ on a number of nondrinking outcomes, including depression, anxiety, mood, and quality of life. The only difference observed was in alcohol-related consequences. The levetiracetam XR treatment group showed significantly fewer consequences than did the placebo group during the maintenance period (p = 0.02). Levetiracetam XR was well tolerated, with fatigue being the only significantly elevated adverse event, compared with placebo (53% vs. 24%, respectively; p = 0.001). CONCLUSIONS: This multisite clinical trial showed no efficacy for levetiracetam XR compared with placebo in reducing alcohol consumption in heavy drinking alcohol-dependent patients.