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.

Maintenance of World Health Organization Risk Drinking Level Reductions and Posttreatment Functioning Following a Large Alcohol Use Disorder Clinical Trial.

BACKGROUND: Reductions in the World Health Organization (WHO) risk drinking levels have been proposed as an alternative primary outcome for alcohol clinical trials. Yet, little is known about whether reductions in WHO risk drinking levels can be maintained over time. The current study examined whether reductions in WHO risk drinking levels were maintained for up to 1 year following treatment, and whether reductions over time were associated with improvements in functioning. METHODS: Secondary data analysis of individuals with alcohol dependence (n = 1,226) enrolled in the COMBINE study, a multisite, randomized, placebo-controlled clinical trial. Logistic regression was used to examine the maintenance of end-of-treatment WHO risk level reductions and WHO risk level reductions at the 1-year follow-up. Repeated-measures mixed models were used to examine the association between WHO risk level reductions and functional outcomes over time. RESULTS: Achieving at least a 1- or 2-level reduction in risk by the end of treatment was significantly associated with WHO risk level reductions at the 1-year follow-up assessment (p < 0.001). Among individuals who achieved at least a 1-level reduction by the end of treatment, 85.5% reported at least a 1-level reduction at the 1-year follow-up. Among individuals who achieved at least a 2-level reduction by the end of treatment, 77.8% reported at least a 2-level reduction at the 1-year follow-up. WHO risk level reductions were associated with significantly lower alcohol consumption, better physical health (p < 0.01), and fewer alcohol-related consequences (p < 0.001) up to 1 year following treatment. CONCLUSIONS: One- and 2-level reductions in WHO risk levels during alcohol treatment were maintained after treatment and associated with better functioning over time. These findings support the use of the WHO risk level reductions as an outcome measure that reflects clinically significant improvement in how individuals seeking treatment for alcohol use disorder feel and function.

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.

Drinking Risk Level Reductions Associated with Improvements in Physical Health and Quality of Life Among Individuals with Alcohol Use Disorder.

BACKGROUND: Abstinence and no heavy drinking days are currently the only Food and Drug Administration-approved end points in clinical trials for alcohol use disorder (AUD). Many individuals who fail to meet these criteria may substantially reduce their drinking during treatment, and most individuals with AUD prefer drinking reduction goals. One- and two-level reductions in World Health Organization (WHO) drinking risk levels have been proposed as alternative end points that reflect reduced drinking and are associated with reductions in drinking consequences, improvements in mental health, and reduced risk of developing alcohol dependence. The current study examined the association between WHO drinking risk level reductions and improvements in physical health and quality of life in a sample of individuals with alcohol dependence. METHODS: Secondary data analysis of individuals with alcohol dependence (n = 1,142) enrolled in the longitudinal, prospective COMBINE study, a multi site randomized placebo-controlled clinical trial, examining the association between reductions in WHO drinking risk levels and change in blood pressure, liver enzyme levels, and self-reported quality of life following treatment for alcohol dependence. RESULTS: One- and two-level reductions in WHO drinking risk level during treatment were associated with significant reductions in systolic blood pressure (p < 0.001), improvements in liver enzyme levels (all p < 0.01), and significantly better quality of life (p < 0.001). CONCLUSIONS: One- and two-level reductions in WHO drinking risk levels predicted significant improvements in markers of physical health and quality of life, suggesting that the WHO drinking risk level reduction could be a meaningful surrogate marker of improvements in how a person "feels and functions" following treatment for alcohol dependence. The WHO drinking risk levels could be useful in medical practice for identifying drinking reduction targets that correspond with clinically significant improvements in health and quality of life.

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.

Posttreatment Low-Risk Drinking as a Predictor of Future Drinking and Problem Outcomes Among Individuals with Alcohol Use Disorders: A 9-Year Follow-Up.

BACKGROUND: Treatment for alcohol use disorders (AUDs) has traditionally been abstinence oriented, but new research and regulatory guidelines suggest that low-risk drinking may also be an acceptable treatment outcome. However, little is known about long-term outcomes for patients who become low-risk drinkers posttreatment. This study explores a posttreatment low-risk drinking outcome as a predictor of future drinking and psychosocial outcomes over 9 years. METHODS: Study participants were adults with AUDs at treatment entry who received follow-up interviews 6 months posttreatment intake (N = 1,061) in 2 large randomized studies conducted at Kaiser Permanente Northern California, a large private, nonprofit, integrated health system. Six-month drinking status was defined as abstinent, low-risk (nonabstinent, no 5+ drinking days), or heavy drinking (1 or more days of 5+ drinks). Using logistic regression models, we explored the relationship between past 30-day drinking status at 6 months and odds of being abstinent or a low-risk drinker (compared to heavy drinking), and positive Addiction Severity Index psychosocial outcomes over 9 years (9-year follow-up rate of 73%). RESULTS: Abstainers and low-risk drinkers at 6 months had higher odds of recent abstinence/low-risk drinking over 9 years than heavy drinkers; abstainers had better drinking outcomes than low-risk drinkers. Additionally, among those with interview data, 95% of abstainers and 94% of low-risk drinkers at 6 months were abstinent/low-risk drinkers at 9 years; surprisingly, 89% of heavy drinkers at 6 months were also abstinent/low-risk drinkers although still significantly fewer than the other groups. Abstainers and low-risk drinkers at 6 months had better psychiatric outcomes, and abstainers had better family/social outcomes than heavy drinkers; medical outcomes did not differ. Low-risk drinkers and abstainers showed no reliable differences across psychosocial measures. CONCLUSIONS: The findings suggest that a low-risk drinking outcome may be reasonable over the long-term for some alcohol-dependent individuals receiving addiction treatment.

Differences Between Treatment-Seeking and Nontreatment-Seeking Alcohol-Dependent Research Participants: An Exploratory Analysis.

BACKGROUND: Alcoholism is a chronic relapsing disorder with complex behavioral and functional heterogeneity. To date, attempts to characterize subgroups of alcohol-dependent (AD) individuals have largely been focused on categorical distinctions based on behaviors such as ability to abstain, age of onset, and drinking motives, but these have failed to yield predictors of treatment response and disease course. The distinction between AD individuals who are or are not interested in treatment holds significant implications for interpreting results of human laboratory studies with nontreatment seekers and clinical trials with treatment-seeking AD patients. However, despite their crucial role in alcohol-related research, these 2 groups are poorly defined. In this exploratory analysis, we attempt to better define the phenotypic differences between these 2 experimentally relevant populations. METHODS: We analyzed data from AD individuals who participated in screening protocols to evaluate their suitability for participation in either treatment or nontreatment research studies at NIAAA. Scores on individual measures from a battery of behavioral, neuropsychological, and blood laboratory measures were compared between those who presented seeking treatment for AD and those who were not seeking treatment. Differences in each measure were assessed between the 2 groups. In addition, we explored whether significant differences were apparent when drinking behavior was used as a covariate. RESULTS: Treatment seekers manifested more impairment compared to nontreatment seekers on a wide variety of measures in the following categories: alcohol drinking, personality, impulsivity, trauma/stress, cognition, aggression, mood, and liver enzyme tests. Treatment seekers endorsed a greater number of AD criteria. Several measures including elevations in liver enzyme tests remained significantly different between the 2 groups when average daily alcohol consumption per drinking day was used as a covariate. CONCLUSIONS: Treatment-seeking, compared to nontreatment-seeking AD subjects who present for alcohol-related research studies, differ in characteristics beyond the quantity of alcohol consumption. Implications of these differences with respect to clinical research for treatments of AD are discussed.

Clinical Validation of Reduced Alcohol Consumption After Treatment for Alcohol Dependence Using the World Health Organization Risk Drinking Levels.

BACKGROUND: Alcohol use disorder (AUD) is a highly prevalent public health problem associated with considerable individual and societal costs. Abstinence from alcohol is the most widely accepted target of treatment for AUD, but it severely limits treatment options and could deter individuals who prefer to reduce their drinking from seeking treatment. Clinical validation of reduced alcohol consumption as the primary outcome of alcohol clinical trials is critical for expanding treatment options. One potentially useful measure of alcohol treatment outcome is a reduction in the World Health Organization (WHO, International Guide for Monitoring Alcohol Consumption and Related Harm. Geneva, Switzerland, 2000) risk levels of alcohol use (very high risk, high risk, moderate risk, and low risk). For example, a 2-shift reduction in WHO risk levels (e.g., high risk to low risk) has been used by the European Medicines Agency (2010, Guideline on the Development of Medicinal Products for the Treatment of Alcohol Dependence. UK) to evaluate nalmefene as a treatment for alcohol dependence (AD; Mann et al. 2013, Biol Psychiatry 73, 706-13). METHODS: The current study was a secondary data analysis of the COMBINE study (n = 1,383; Anton et al., ) to examine the association between reductions in WHO risk levels and reductions in alcohol-related consequences and mental health symptoms during and following treatment in patients with AD. RESULTS: Any reduction in WHO risk drinking level during treatment was associated with significantly fewer alcohol-related consequences and improved mental health at the end of treatment and for up to 1 year posttreatment. A greater reduction in WHO risk drinking level predicted a greater reduction in consequences and greater improvements in mental health. CONCLUSIONS: Changes in WHO risk levels appear to be a valid end point for alcohol clinical trials. Based on the current findings, reductions in WHO risk drinking levels during treatment reflect meaningful reductions in alcohol-related consequences and improved functioning.

Temporal Stability of Heavy Drinking Days and Drinking Reductions Among Heavy Drinkers in the COMBINE Study.

BACKGROUND: Recently, the Food and Drug Administration (FDA) proposed to expand the options for primary end points in the development of medications for alcohol use disorder to include either abstinence from alcohol or a nonabstinent outcome: no heavy drinking days (with a heavy drinking day defined as more than 3 drinks per day for women and more than 4 drinks per day for men [>3/>4 cutoff]). The FDA also suggested that 6 months would be the most appropriate length for a clinical trial to demonstrate the stability of this nonabstinent drinking outcome. However, few alcohol clinical trials have examined the stability of nonheavy drinking during and after treatment. METHODS: In a secondary analysis of the COMBINE study data (n = 1,383), we examined transitions in heavy drinking days during the course of treatment (months 1 through 4), during the transition out of treatment (months 4 through 7), and up to 12 months afterward (months 13 through 16) using latent variable mixture models. RESULTS: Heavy drinking and nonheavy drinking were relatively stable in consecutive months (minimum agreement [kappa] = 0.64 for months 1 to 2). Most individuals were stable low-risk drinkers/abstainers or heavy drinkers by the end of treatment, as characterized by a 10% probability (or less) of transitioning out of either a no heavy drinking state or a heavy drinking state. More than two-thirds of the heavy drinkers who exceeded the heavy drinking threshold during treatment reported, on average, a 64% reduction in drinking frequency and a 38% reduction in drinking intensity from pretreatment drinking levels. CONCLUSIONS: The results show stability of no heavy drinking as an outcome within the first 4 months of treatment and that the >3/>4 drink cutoff may mask substantial reductions in alcohol consumption among some patients. Future studies should explore the clinical utility of reduction end points.

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.

Missing Data in Alcohol Clinical Trials with Binary Outcomes.

BACKGROUND: Missing data are common in alcohol clinical trials for both continuous and binary end points. Approaches to handle missing data have been explored for continuous outcomes, yet no studies have compared missing data approaches for binary outcomes (e.g., abstinence, no heavy drinking days). This study compares approaches to modeling binary outcomes with missing data in the COMBINE study. METHODS: We included participants in the COMBINE study who had complete drinking data during treatment and who were assigned to active medication or placebo conditions (N = 1,146). Using simulation methods, missing data were introduced under common scenarios with varying sample sizes and amounts of missing data. Logistic regression was used to estimate the effect of naltrexone (vs. placebo) in predicting any drinking and any heavy drinking outcomes at the end of treatment using 4 analytic approaches: complete case analysis (CCA), last observation carried forward (LOCF), the worst case scenario (WCS) of missing equals any drinking or heavy drinking, and multiple imputation (MI). In separate analyses, these approaches were compared when drinking data were manually deleted for those participants who discontinued treatment but continued to provide drinking data. RESULTS: WCS produced the greatest amount of bias in treatment effect estimates. MI usually yielded less biased estimates than WCS and CCA in the simulated data and performed considerably better than LOCF when estimating treatment effects among individuals who discontinued treatment. CONCLUSIONS: Missing data can introduce bias in treatment effect estimates in alcohol clinical trials. Researchers should utilize modern missing data methods, including MI, and avoid WCS and CCA when analyzing binary alcohol clinical trial outcomes.

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.

Methods to analyze treatment effects in the presence of missing data for a continuous heavy drinking outcome measure when participants drop out from treatment in alcohol clinical trials.

BACKGROUND: Attrition is common in alcohol clinical trials and the resultant loss of data represents an important methodological problem. In the absence of a simulation study, the drinking outcomes among those who are lost to follow-up are not known. Individuals who drop out of treatment and continue to provide drinking data, however, may be a reasonable proxy group for making inferences about the drinking outcomes of those lost to follow-up. METHODS: We used data from the COMBINE study, a multisite, randomized clinical trial, to examine drinking during the 4 months of treatment among individuals who dropped out of treatment but continued to provide drinking data (i.e., "treatment dropouts;" n = 185). First, we estimated the observed treatment effect size for naltrexone versus placebo in a sample that included both treatment completers (n = 961) and treatment dropouts (n = 185; total N = 1,146), as well as the observed treatment effect size among just those who dropped out of treatment (n = 185). In both the total sample (N = 1,146) and the dropout sample (n = 185), we then deleted the drinking data after treatment dropout from those 185 individuals to simulate missing data. Using the deleted data sets, we then estimated the effect of naltrexone on the continuous outcome percent heavy drinking days using 6 methods to handle missing data (last observation carried forward, baseline observation carried forward, placebo mean imputation, missing = heavy drinking days, multiple imputation (MI), and full information maximum likelihood [FIML]). RESULTS: MI and FIML produced effect size estimates that were most similar to the true effects observed in the full data set in all analyses, while missing = heavy drinking days performed the worst. CONCLUSIONS: Although missing drinking data should be avoided whenever possible, MI and FIML yield the best estimates of the treatment effect for a continuous outcome measure of heavy drinking when there is dropout in an alcohol clinical trial.

Five-year healthcare utilization and costs among lower-risk drinkers following alcohol treatment.

BACKGROUND: Lower-risk drinking is increasingly being examined as a treatment outcome for some patients following addiction treatment. However, few studies have examined the relationship between drinking status (lower-risk drinking in particular) and healthcare utilization and cost, which has important policy implications. METHODS: Participants were adults with alcohol dependence and/or abuse diagnoses who received outpatient alcohol and other drug treatment in a private, nonprofit integrated healthcare delivery system and had a follow-up interview 6 months after treatment entry (N = 995). Associations between past 30-day drinking status at 6 months (abstinence, lower-risk drinking defined as nonabstinence and no days of 5+ drinking, and heavy drinking defined as 1 or more days of 5+ drinking) and repeated measures of at least 1 emergency department (ED), inpatient or primary care visit, and their costs over 5 years were examined using mixed-effects models. We modeled an interaction between time and drinking status to examine trends in utilization and costs over time by drinking group. RESULTS: Heavy drinkers and lower-risk drinkers were not significantly different from the abstainers in their cost or utilization at time 0 (i.e., 6 months postintake). Heavy drinkers had increasing odds of inpatient (p < 0.01) and ED (p < 0.05) utilization over 5 years compared with abstainers. Lower-risk drinkers and abstainers did not significantly differ in their service use in any category over time. No differences were found in changes in primary care use among the 3 groups over time. The cost analyses paralleled the utilization results. Heavy drinkers had increasing ED (p < 0.05) and inpatient (p < 0.001) costs compared with the abstainers; primary care costs did not significantly differ. Lower-risk drinkers did not have significantly different medical costs compared with those who were abstinent over 5 years. However, post hoc analyses found lower-risk drinkers and heavy drinkers to not significantly differ in their ED use or costs over time. CONCLUSIONS: Performance measures for treatment settings that consider treatment outcomes may need to take into account both abstinence and reduction to nonheavy drinking. Future research should examine whether results are replicated in harm reduction treatment, or whether such outcomes are found only in abstinence-based treatment.

Designing clinical trials to address alcohol use and alcohol-associated liver disease: an expert panel Consensus Statement.

Most patients with alcohol-associated liver disease (ALD) engage in heavy drinking defined as 4 or more drinks per day (56 g) or 8 (112 g) or more drinks per week for women and 5 or more drinks per day (70 g) or 15 (210 g) or more drinks per week for men. Although abstinence from alcohol after diagnosis of ALD improves life expectancy and reduces the risk of decompensation of liver disease, few studies have evaluated whether treatment of alcohol use disorders will reduce progression of liver disease and improve liver-related outcomes. In November 2021, the National Institute of Alcohol Abuse and Alcoholism commissioned a task force that included hepatologists, addiction medicine specialists, statisticians, clinical trialists and members of regulatory agencies to develop recommendations for the design and conduct of clinical trials to evaluate the effect of alcohol use, particularly treatment to reduce or eliminate alcohol use in patients with ALD. The task force conducted extensive reviews of relevant literature on alcohol use disorders and ALD. Findings were presented at one in-person meeting and discussed over the next 16 months to develop the final recommendations. As few clinical trials directly address this topic, the 28 recommendations approved by all members of the task force represent a consensus of expert opinions.

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.

A double-blind, placebo-controlled trial to assess the efficacy of quetiapine fumarate XR in very heavy-drinking alcohol-dependent patients.

BACKGROUND: Despite advances in developing medications to treat alcohol dependence, few such medications have been approved by the Food and Drug Administration. Identified molecular targets are encouraging and can lead to the development and testing of new compounds. Atypical antipsychotic medications have been explored with varying results. Prior research suggests that the antipsychotic quetiapine may be beneficial in an alcohol-dependent population of very heavy drinkers. METHODS: In this double-blind, placebo-controlled trial, 224 alcohol-dependent patients who reported very heavy drinking were recruited across 5 clinical sites. Patients received either quetiapine or placebo and Medical Management behavioral intervention. Patients were stratified on gender, clinical site, and reduction in drinking prior to randomization. RESULTS: No differences between the quetiapine and placebo groups were detected in the primary outcome, percentage heavy-drinking days, or other drinking outcomes. Quetiapine significantly reduced depressive symptoms and improved sleep but had no effect on other nondrinking outcomes. Results from a subgroup analysis suggest that patients who reduced their drinking prior to randomization had significantly better drinking outcomes during the maintenance phase (p < 0.0001). No significant interactions, however, were observed between reducer status and treatment group. Finally, quetiapine was generally well tolerated. Statistically significant adverse events that were more common with quetiapine versus placebo include dizziness (14 vs. 4%), dry mouth (32 vs. 9%), dyspepsia (13 vs. 2%), increased appetite (11 vs. 1%), sedation (15 vs. 3%), and somnolence (34 vs. 9%). CONCLUSIONS: This multisite clinical trial showed no efficacy for quetiapine compared with placebo at reducing alcohol consumption in heavy-drinking alcohol-dependent patients.