Leveraging meta-regression to test if medication effects on cue-induced craving are associated with clinical efficacy.

RATIONALE: The alcohol cue exposure paradigm is a common method for evaluating new treatments for alcohol use disorder (AUD); however, it is unclear if medication-related reductions in cue-induced craving in the human laboratory can predict the clinical success of those medications in reducing alcohol consumption during clinical trials. OBJECTIVES: To use a novel meta-analytic approach to test whether medication effect sizes on cue-induced alcohol craving are associated with clinical efficacy in clinical trials. METHOD: We searched the literature for medications tested for AUD treatment using both the alcohol cue-reactivity paradigm and randomized clinical trials (RCTs). For alcohol cue-reactivity studies, we computed medication effect sizes for cue-induced alcohol craving (k = 36 studies, 15 medications). For RCTs, we calculated medication effect sizes for heavy drinking and abstinence (k = 139 studies, 19 medications). Using medication as the unit of analysis, we applied the Williamson-York bivariate weighted least squares estimation to account for errors in both independent and dependent variables. We also conducted leave-one-out cross validation simulations to examine the predictive utility of cue-craving medication effect sizes on RCT heavy drinking and abstinence endpoints. RESULTS: There was no significant relationship between medication effects on cue-induced alcohol craving in the human laboratory and medication effects on heavy drinking ( ß ^ = 0.253, SE = 0.189, p = 0.090) and abstinence ( ß ^ = 0.829, SE = 0.747, p = 0.133) in RCTs. CONCLUSIONS: The preliminary results of the current study challenge the assumption that alcohol cue-reactivity alone can be used as an early efficacy indicator for AUD pharmacotherapy development. These findings suggest that a wider range of early efficacy indicators and experimental paradigms be considered for Phase II testing of novel compounds.

Neurobiology and the Treatment of Alcohol Use Disorder: A Review of the Evidence Base.

Alcohol use disorder (AUD) is a significant public health concern, accounting for a majority of substance use disorder cases in the United States. Treatment for AUD is complex, with multiple intervention points that may be further complicated by genotype and phenotype, resulting in diverse outcomes. In order to better understand the current landscape of AUD treatment, the present review considers different etiological models of AUD and assesses the evidence base of current treatment options. The first section of this review summarizes various etiological models of AUD and presents different approaches to classifying the disorder. Various theories, including neurobiological models, are discussed. The second section presents a comprehensive analysis of available treatment options for AUD, encompassing behavioral and pharmacological interventions and their current evidence base. Finally, this review discusses the ongoing treatment gap and significant factors contributing to low treatment utilization. Together, this review provides an overview of different etiological processes and mechanisms of AUD, as well as summarizes the literature on key treatment approaches. By integrating historical, theoretical, and empirical data, this review aims to inform both researchers and providers with valuable insights to advance AUD treatment approaches and narrow the treatment gap.

Testing pharmacotherapies for alcohol use disorder with cue exposure paradigms: A systematic review and quantitative synthesis of human laboratory trial methodology.

Alcohol cue exposure is a widely used experimental paradigm for screening pharmacotherapies for alcohol use disorder (AUD). Medication-related reductions in cue-reactivity signal early efficacy and inform medications development. Yet, across trials, the design of cue exposure, parameter testing, and outcome reporting is heterogeneous. This systematic review is a quantitative synthesis of trial methodologies and effect size estimation for AUD medication-related craving and psychophysiological outcomes under the cue exposure paradigm. A PubMed search was conducted on January 3, 2022 based on identified pharmacotherapies for peer-reviewed articles reported in English. Study-level characteristics, including sample descriptors, paradigm design, analytic approach, and Cochrane Risk of Bias, along with descriptive statistics for cue-exposure outcomes, were coded by two independent raters. Study-level effect sizes were estimated for craving and psychophysiological outcomes separately and sample-level effect sizes were calculated for each medication. Thirty-six trials, comprising 1640 participants and testing 19 different medications satisfied eligibility criteria. All studies reported on biological sex (71% male participants on average). The exposure paradigms implemented used in vivo (n = 26), visual (n = 8), and audio script (n = 2) cues. Some trials included means for craving by medication condition in text (k = 7) or figures (k = 18). The quantitative synthesis included 63 effect sizes (craving kes = 47; psychophysiological kes = 16) from 28 unique randomized trials testing 15 medications for effects on cue reactivity. For cue-induced craving, eight medications (kes range: 1-12) demonstrated small-to-medium effects (Cohen's d range: |0.24-0.64|) compared to placebo, with individuals randomized to receive medication reporting lower craving following cue exposure. Recommendations are provided to promote further consilience, so that the utility of cue exposure paradigms can be maximized in the development of effective AUD pharmacotherapies. Future work should explore the predictive utility of medication-related reductions in cue-reactivity on clinical outcomes.

Are medication effects on subjective response to alcohol and cue-induced craving associated? A meta regression study.

RATIONALE: Alcohol administration and cue-reactivity paradigms are frequently used to screen for the initial efficacy of medications for alcohol use disorder (AUD). While medication effects on the primary outcomes for these paradigms are assumed to be qualitatively related, there is a critical lack of quantitative evidence to support this hypothesis. OBJECTIVES: The study aims to test the relationship between medication effect sizes on subjective response to alcohol administration and medication effect sizes for cue-induced craving to cue exposure, using meta-analysis. METHODS: Systematic literature searches were conducted to identify randomized trials, wherein AUD medications were tested using the alcohol administration and/or cue-reactivity paradigms. From these studies, descriptive statistics were collected to compute medication effect sizes on the primary outcomes for each respective paradigm. With medication as the unit of analysis, medication effect sizes in alcohol administration studies were compared with medication effect sizes in cue-reactivity studies using the Williamson-York regression which allows for meta-regression across independent samples. RESULTS: Medication effect sizes on alcohol-induced stimulation and alcohol-induced craving were not significantly associated with medication effect sizes on cue-induced alcohol craving (k stimulation = 10 medications, [Formula: see text] and k craving = 11 medications, [Formula: see text] (SE = 0.237), [Formula: see text]), respectively. Medication effect sizes on alcohol-induced sedation were significantly associated with medication effects on cue-induced craving (k = 10 medications, [Formula: see text] (SE = 0.258), [Formula: see text]), such that medications that increased alcohol-induced sedation were more likely to reduce cue-induced alcohol craving. CONCLUSIONS: With the exception of alcohol-induced sedation, there is little quantitative evidence of medication effects on subjective response domains measured during alcohol administration parallel medication effects on cue-induced alcohol craving. To provide additional context to the current study, future work should examine whether cue-reactivity findings predict clinical trial outcomes.

The Brief Alcohol Use Disorder Severity Scale: An Initial Validation Evaluation.

AIMS: The goal of this study was to develop a standard measure of AUD severity that includes multiple dimensions and can be used in clinical settings to inform treatment selection. METHODS: A large sample (n = 1939) of moderate to heavy drinkers was amassed from six psychopharmacology studies. The severity factor was comprised of four dimensions: withdrawal, craving, AUD symptoms and alcohol-related consequences. First, a confirmatory factor analysis (CFA) was conducted to examine model fit. Next, a comprehensive item list from the four measures (i.e. CIWA, DrinC, PACs and SCID-5 AUD criteria) was reduced through exploratory factor analysis (EFA). Once the final items were merged into a preliminary assessment, an EFA was run to observe the factor structure. Initial validation of the measure was obtained via associations with clinical endpoints. RESULTS: The chi-square test statistic (${\chi}^2(2)=2.432\ P=0.297$) for a single-factor model of severity demonstrated good fit. Additional goodness-of-fit indices from the CFA revealed similar support for the single-factor model of severity (i.e. SRMSR = 0.011; RMSEA = 0.011; CFI = 0.999). Next, nine items from the individual EFAs were selected based on factor loading. The final EFA conducted on the 9-item scale demonstrated that a single factor model of severity best fit the data. Analysis of the psychometric properties revealed good internal consistency ($\alpha$= 0.79). CONCLUSIONS: The current study extends upon the measurement of severity and supports a brief severity measure. This brief 9-item scale can be leveraged in future studies as a screening instrument and as a tool for personalized medicine.

A Meta-Regression of Trial Features Predicting the Effects of Alcohol Use Disorder Pharmacotherapies on Drinking Outcomes in Randomized Clinical Trials: A Secondary Data Analysis.

AIMS: To test whether two critical design features, inclusion criteria of required pre-trial abstinence and pre-trial alcohol use disorder (AUD) diagnosis, predict the likelihood of detecting treatment effects in AUD pharmacotherapy trials. METHODS: This secondary data analysis used data collected from a literature review to identify randomized controlled pharmacotherapy trials for AUD. Treatment outcomes were selected into abstinence and no heavy drinking. Target effect sizes were calculated for each outcome and a meta-regression was conducted to test the effects of required pre-trial abstinence, required pre-trial AUD diagnosis, and their interaction on effect sizes. A sub-analysis was conducted on trials, which included FDA-approved medications for AUD. RESULTS: In total, 118 studies testing 19 medications representing 21,032 treated participants were included in the meta-regression analysis. There was no significant effect of either predictor on abstinence or no heavy drinking outcomes in the full analysis or in the sub-study of FDA-approved medications. CONCLUSION: By examining these design features in a quantitative, rather than qualitative, fashion the present study advances the literature and shows that requiring AUD diagnosis or requiring pre-trial abstinence do not impact the likelihood of a significant medication effect in the trial.

Alcohol use disorder severity moderates clinical response to varenicline.

BACKGROUND: In a multisite clinical trial, varenicline was effective in reducing drinking in both smoking and non-smoking patients with alcohol dependence. Because alcohol use disorder (AUD) is heterogeneous, research aimed at characterizing features associated with treatment response could advance personalized pharmacotherapy. The current study examined the utility of a multidimensional assessment of AUD severity to identify responders to varenicline treatment. METHODS: The study utilized data from a 13-week, Phase 2, randomized, double-blind, placebo-controlled, multisite trial of varenicline in 200 alcohol-dependent patients. Four hypothesized measures of AUD severity (i.e., DSM-IV criterion count, withdrawal, craving, and alcohol-related consequences) were combined into a single severity factor. A series of multilevel models that included the severity factor were conducted to examine its effects on treatment outcomes. RESULTS: All hypothesized indices of AUD severity loaded significantly onto a singular severity factor. Among low-severity groups, varenicline treatment significantly reduced drinking (i.e., percent heavy drinking days, drinks per day, and drinks per drinking day) and, in the lowest severity group, it improved the mental health component of quality of life more than placebo. The most severe group showed no differences between the varenicline and placebo groups on drinking or quality of life measures. CONCLUSIONS: Treatment response to varenicline may be greater among individuals with less-severe AUD, as evidenced by both reductions in drinking outcomes and improvements in psychosocial functioning.

Understanding low treatment seeking rates for alcohol use disorder: A narrative review of the literature and opportunities for improvement.

Despite a well-documented global burden of disease attributable to alcohol use disorder (AUD), treatment seeking rates remain low. In this qualitative literature review, we address treatment seeking for AUD from a host of perspectives and summarize the literature on key factors. First, we summarize the rates of alcohol treatment seeking across various epidemiological surveys, spanning decades. Second, we discuss the definition of treatment seeking and 'what' is typically considered formal treatment. Third, we consider timing and discuss 'when' individuals are most likely to seek treatment. Fourth, we review the literature on 'who' is most likely to seek treatment, including demographic and clinical correlates. Fifth, we address the critical question of 'why' so few people receive clinical services for AUD, relative to the number of individuals affected by the disorder, and review barriers to treatment seeking at the treatment- and person-levels of analysis. Finally, we identify opportunities to improve treatment seeking rates by focusing on tangible points of intervention. Specifically, we recommend a host of adaptations to models of care including efforts to make treatment more appealing across stages of AUD severity, accept a range of health-enhancing drinking goals as opposed to an abstinence-only model, educate providers and consumers about evidence-based behavioral and pharmacological treatments, and incentivize the delivery of evidence-based services.

Lifetime heavy drinking years predict alcohol use disorder severity over and above current alcohol use.

Background: Preclinical studies demonstrate that chronic and heavy alcohol use facilitates neuroadaptations that perpetuate addiction-like behaviors. In clinical studies, it is unclear whether the extent of heavy alcohol use over the lifetime contributes to alcohol use disorder (AUD) severity over and above current alcohol use patterns (i.e. last 30 days to 3-months). Such information may improve our understanding of the phenomenology of AUD.Objectives: The purpose of this study was to examine lifetime heavy drinking years in relation to a clinical assessment of AUD.Methods: Participants, who were non-treatment-seeking and engaged in heavy drinking (n = 140; 50% male), completed an interview-based assessment of lifetime regular and heavy drinking years along with a battery of measures indexing alcohol use and problems, drinking motives, and depression and anxiety symptomatology.Results: Lifetime heavy drinking years was positively associated with lifetime regular drinking years, current alcohol use, alcohol problems, tonic alcohol craving, drinking for the enhancing effects of alcohol, and drinking to cope (r's = .21-.58). Adjusting for lifetime regular drinking years and current alcohol use, lifetime heavy drinking years predicted higher scores on the Alcohol Use Disorder Identification Test (AUDIT; B = .382; SE = .123). A multivariate logistic regression found that lifetime heavy drinking years predicted greater odds of more severe AUD over and above current alcohol use (OR = 1.147).Conclusion: Our findings suggest that lifetime heavy drinking years are a clinically meaningful indicator of AUD severity that is not redundant with current alcohol use measures.

Baseline Drinking Patterns in Non-Treatment Seeking Problem Drinkers.

AIMS: Natural processes of change have been documented in treatment-seekers who begin to reduce their drinking in anticipation of treatment. The study examined whether non-treatment-seeking problem drinkers would engage in drinking reduction in anticipation of participating in a research study. METHODS: Non-treatment-seeking problem drinkers (n = 935) were culled from five behavioral pharmacology studies. Participants reported on their alcohol use during the past 30 days using the Timeline Followback. Cluster analysis identified distinct groups/clusters based on drinking patterns over the 30-day pre-visit period. The identified clusters were compared on demographic and clinical measures. RESULTS: Three distinct clusters were identified (a) heavy-decreasing drinking group (n = 255, 27.27%); (b) a moderate-stable drinking group (n = 353, 37.75%) and (c) low-stable drinking group (n = 327, 34.97%). The three clusters differed significantly on a host of measures including pre-visit drinking (age at first drink, drinking days, drinks per week, drinks per drinking day), alcohol use severity, alcohol craving, readiness for change, depression and anxiety levels. These differences were alcohol dose-dependent such that the heavier drinking group reported the highest levels on all constructs, followed by the moderate group, and the low drinking group last. CONCLUSIONS: Baseline drinking patterns of non-treatment-seekers were generally stable and pre-visit reductions were only observed among the heavy drinking group. This generally stable pattern stands in contrast to previous reports for treatment-seeking samples. Nevertheless, the heavier drinking group, which is most similar to treatment-seekers, displayed pre-study drinking reduction. Overall, naturalistic processes of change may pose less of a threat to randomization and testing in this population.

Alcohol Cue-Induced Ventral Striatum Activity Predicts Subsequent Alcohol Self-Administration.

BACKGROUND: Human laboratory paradigms are a pillar in medication development for alcohol use disorders (AUD). Neuroimaging paradigms, in which individuals are exposed to cues that elicit neural correlates of alcohol craving (e.g., mesocorticolimbic activation), are increasingly utilized to test the effects of AUD medications. Elucidation of the translational effects of these neuroimaging paradigms on human laboratory paradigms, such as self-administration, is warranted. The current study is a secondary analysis examining whether alcohol cue-induced activation in the ventral striatum is predictive of subsequent alcohol self-administration in the laboratory. METHODS: Non-treatment-seeking heavy drinkers of East Asian descent (n = 41) completed a randomized, placebo-controlled, double-blind, crossover experiment on the effects of naltrexone on neuroimaging and human laboratory paradigms. Participants completed 5 days of study medication (or placebo); on day 4, they completed a neuroimaging alcohol taste cue-reactivity task. On the following day (day 5), participants completed a 60-minute alcohol self-administration paradigm. RESULTS: Multilevel Cox regressions indicated a significant effect of taste cue-elicited ventral striatum activation on latency to first drink, Wald χ2  = 2.88, p = 0.05, such that those with higher ventral striatum activation exhibited shorter latencies to consume their first drink. Similarly, ventral striatum activation was positively associated with total number of drinks consumed, F(1, 38) = 5.90, p = 0.02. These effects were significant after controlling for alcohol use severity, OPRM1 genotype, and medication. Other potential regions of interest (anterior cingulate, thalamus) were not predictive of self-administration outcomes. CONCLUSIONS: Neuroimaging alcohol taste cue paradigms may be predictive of laboratory paradigms such as self-administration. Elucidation of the relationships among different paradigms will inform how these paradigms may be used synergistically in experimental medicine and medication development.