Combined Pharmacotherapies And Behavioral Interventions For Alcohol Dependence Research Articles

Trajectories of change in subclinical anxiety and alcohol use during alcohol treatment: A parallel process growth model

BackgroundAnxiety is implicated in the course and prognosis of alcohol use disorder (AUD); however, it is unclear how current AUD treatments affect the joint trajectories of anxiety and alcohol use. We used data from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study to examine the longitudinal relationship between subclinical anxiety symptoms and alcohol use during and following AUD treatment in adults with AUD and no comorbid anxiety disorders. MethodsUnivariate and parallel process growth models using five waves of COMBINE study data were analyzed from 865 adults randomized to medication (n = 429) or medication plus psychotherapy (n = 436). Weekly drinking quantity and average weekly anxiety symptoms were measured at baseline, mid-treatment, end-of-treatment, and three follow-up periods. ResultsSignificant positive associations of anxiety symptoms and drinking were found at mid-treatment and over time. Temporal associations revealed that higher mid-treatment anxiety predicted decreases in drinking over time. Baseline anxiety and drinking predicted mid-treatment anxiety and drinking. Only baseline anxiety predicted increases in drinking over time. Group differences revealed mid-treatment drinking predicted decreases in anxiety over time in the medication group. ConclusionsFindings demonstrate the influence of subclinical anxiety on alcohol use during and up to one year after AUD treatment. Baseline anxiety symptoms may influence drinking behavior over the course of treatment. Findings suggest that greater attention to negative affect in AUD treatment is warranted even for those individuals who do have a comorbid anxiety disorder.

COMBINE follow‐up: Some heavy use of alcohol compatible with recovery

Newly published research casts serious doubt on whether the path to a successful long‐term recovery from alcohol use disorder (AUD) must always embrace abstinence. The follow‐up analysis of individuals who participated in the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study found that a group that engaged in frequent drinking and occasional heavy drinking after treatment had above‐average health outcomes and showed overall results comparable to those who were mostly abstinent.

World Health Organization risk drinking level reductions are associated with improved functioning and are sustained among patients with mild, moderate and severe alcohol dependence in clinical trials in the United States and United Kingdom

To examine whether World Health Organization (WHO) risk-level reductions in drinking were achievable, associated with improved functioning and maintained over time among patients at varying initial alcohol dependence severity levels. Design and setting Secondary data analysis of multi-site randomized clinical trials: the US Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study and the UK Alcohol Treatment Trial (UKATT). Individuals with alcohol dependence enrolled in COMBINE (n=1383; 68.8% male) and seeking treatment for alcohol problems in UKATT (n=742; 74.1% male). Interventions Naltrexone, acamprosate or placebo, and combined behavioral intervention or medication management in COMBINE. Social behavior network therapy or motivational enhancement therapy in UKATT. WHO risk-level reductions were assessed via the calendar method. Alcohol dependence was measured by the Alcohol Dependence Scale, the Leeds Dependence Questionnaire and the Diagnostic and Statistical Manual of Mental Disorders. Measures of functioning included alcohol-related consequences (Drinker Inventory of Consequences and Alcohol Problems Questionnaire), mental health (Short Form Health Survey) and liver enzyme tests. One- and two-level reductions in WHO risk levels in the last month of treatment were maintained at the 1-year follow-up [adjusted odds ratio (OR), 95% confidence interval (CI)= one-level reduction in COMBINE: 3.51 (2.73, 4.29) and UKATT: 2.65 (2.32, 2.98)] and associated with fewer alcohol-related consequences [e.g. B, 95% CI=one-level reduction COMBINE: -26.22 (-30.62, -21.82)], better mental health [e.g. B, 95% CI=one-level reduction UKATT: 9.53 (7.36, 11.73)] and improvements in γ-glutamyltransferase [e.g. B, 95% CI=one-level reduction UKATT: -89.77 (-122.50, -57.04)] at the end of treatment, even among patients with severe alcohol dependence. Results were similar when abstainers were excluded. Conclusions Reductions in World Health Organization risk levels for alcohol consumption appear to be achievable, associated with better functioning and maintained over time in both the United States and the United Kingdom.

Predictive value of non-consumption outcome measures in alcohol use disorder treatment.

For decades, researchers have called for the systematic inclusion of non-consumption outcomes, such as alcohol-related consequences and temptation/craving, in addition to consumption outcomes (e.g. percentage of days abstinent) to evaluate alcohol use disorder (AUD) treatment efficacy. However, Food and Drug Administration (FDA) guidelines for alcohol medications development suggest that non-consumption outcomes may be insensitive to changes that occur within AUD treatment trial assessment windows, although this has never been directly tested. We aimed to measure the predictive value of diagnostically related, non-consumption measures of AUD treatment effects. Pre- to post-treatment effect sizes were examined. Logistic regression analyses were used to test the predictive value of non-consumption outcome measures that were administered in the COMBINE (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence) Study and Project MATCH (Matching Alcoholism Treatment to Client Heterogeneity) in detecting 12-month outcomes following treatment. Pre- to post-treatment effect sizes suggested that non-consumption measures changed during the course of treatment; effect sizes for temptation/craving, self-efficacy, consequences and consumption variables were mostly medium to large (medium effect sizes were 0.2<dz<0.8, large effect sizes were dz>0.8). The regression results indicated temptation/craving and self-efficacy predicted 12-month drinking outcomes in COMBINE and MATCH, and drinking consequences predicted 12-month drinking outcomes in COMBINE. Self-report measures of temptation and alcohol craving can change as a result of alcohol dependence treatment and can predict drinking outcomes.

Short- and Long-Term Effects of Within-Session Client Speech on Drinking Outcomes in the COMBINE Study.

There is evidence of a causal chain in motivational interviewing (MI) involving counselor MI-consistent skills, client change language, and outcomes. MI was a key component of the combined behavioral intervention in the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) Study. Participants in COMBINE were treatment-seeking and medication-seeking, and were required to maintain a period of abstinence before enrollment. Counselors were closely monitored and were temporarily removed from the study for remediation and supervision if their performance fell below threshold. The purpose of this study was to evaluate the MI causal chain among initial-session combined behavioral intervention audio recordings in this unique sample of highly motivated clients and highly monitored counselors. Session 1 audio recordings (N = 254, 73.5% men) were evaluated using the Motivational Interviewing Skill Code Version 2.0 with good interrater reliability. Counselor speech was measured using a summary measure of MI-consistent behavior. Client change language was assessed, using change talk and sustain talk. The outcome measure of drinks per week was computed using the COMBINE data set. Higher sustain talk was significantly associated with increased drinking during treatment, whereas higher change talk was significantly associated with decreased drinking at the 1-year follow-up. In addition, there were significant indirect effects linking counselor behavior, client speech, and drinking both during treatment and at 1 year. Results supported the posited causal chain for MI. Despite somewhat lower variability of counselor behavior and use of a coding instrument that did not capture directional counselor behaviors, counselor behavior, client speech, and drinking outcomes were clearly linked in this unique sample.

Broad Coping Repertoire Mediates the Effect of the Combined Behavioral Intervention on Alcohol Outcomes in the COMBINE Study: An Application of Latent Class Mediation.

Few studies have found support for coping as a mechanism of behavior change (MOBC) following coping skills training interventions for alcohol use disorder (AUD). One potential reason for null findings is heterogeneity in the patterns of coping skills acquired during treatment. This study sought to identify latent classes of coping and to test the latent class variable as a mediator of the effect of a combined behavioral intervention for AUD. Secondary analyses of data from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) Study (N = 1,124; mean age = 44.4 years; 69.1% male; 23.2% non-White), a multisite study of medication and behavioral treatments for individuals with AUD. Latent class mediation models were estimated to test whether patterns of alcohol-specific coping mediated the effect of combined behavioral intervention with medication management, as compared with medication management only, on drinking outcomes 12 months following treatment. Three classes were identified, which differed in repertoire broadness, or the degree in which a wide range of different skills were used. Coping repertoire class was a significant mediator of the effect of the combined behavioral intervention on drinking outcomes. Receiving the combined behavioral intervention, in addition to medication management, predicted a greater likelihood of expected classification in the broad coping repertoire class, which in turn was associated with significant improvements in drinking outcomes. Using the novel methodological approach of latent class mediation, this study identified coping repertoire as a significant mediator of behavioral intervention efficacy for AUD. Future work examining heterogeneity in mediators and outcomes may help refine AUD treatment to be maximally effective.

Efficacy of Naltrexone for the Treatment of Alcohol Dependence in Latino Populations.

Naltrexone has been identified as a promising psychopharmacological treatment for alcohol dependence. Previous studies have suggested that its efficacy may vary based on ethnic background. The current study examined the efficacy of naltrexone in the treatment of alcohol dependence in Latino adults, a previously unexplored population. This was a secondary analysis of the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) Study. The overall COMBINE sample consisted of 1,383 adult participants who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for alcohol dependence, including 155 Latinos, who are the focus of this report. Consistent with the main trial, primary drinking outcomes, including percentage of days abstinent (PDA) and time to first heavy drinking day (TTHD), were examined. In addition, we examined the effects of naltrexone on a clinically relevant secondary outcome measure, global clinical outcome of alcohol consumption and alcohol-related problems. As seen with the subsample of African Americans from the COMBINE Study, results of the present analysis indicated that there were no significant effects of naltrexone on PDA and TTHD despite these significant effects in the original study. However, contrary to findings in the African American subsample, for Latino participants naltrexone was a significant predictor of a good global clinical outcome (i.e., abstinence or moderate drinking without problems). Naltrexone was not significantly associated with improvements in the primary drinking outcomes of PDA or TTHD at the end of treatment or at follow-up. However, Latinos appeared to benefit from naltrexone as demonstrated by improved ratings of global clinical outcome. These results indicate mixed findings for the efficacy of naltrexone among Latinos in the COMBINE Study.

Predictors of Abstinence From Heavy Drinking During Follow-Up in COMBINE.

Although the primary focus of clinical trials is on between-group comparisons during treatment, these studies can also yield insights into which patient characteristics predict longer term outcomes. Our goal was to identify predictors of good outcome during the 1-year follow-up in the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) Study. We constructed classification trees and a deterministic forest to predict no heavy drinking days during the last 8 weeks of the 1-year follow-up in COMBINE, based on more than 100 baseline predictors and drinking outcomes during the treatment phase of the study. The COMBINE sample was randomly split into a training and a validation data set. Logistic regression models were fit to compare the predictive performance of tree-based methods and classical methods. A small tree with only two splits and four nodes based on abstinence and good clinical outcome during treatment had fair classification accuracy in the training and the validation samples: area under the curve (AUC) of 71% and 70%, respectively. Drinking outcomes during treatment were the strongest predictors in the deterministic forest. Logistic regression analyses based on four main effects (good clinical outcome, level of drinking during treatment, age at onset of alcohol dependence, and feeling more energetic) had slightly better classification accuracy (AUC = 74%). End-of-treatment outcomes were the strongest predictors of long-term outcome in all analyses. The results emphasize the importance of optimizing outcomes during treatment and identify potential subgroups of individuals who require additional or alternative interventions to achieve good long-term outcome.

Zero-inflated count models for longitudinal measurements with heterogeneous random effects.

Longitudinal zero-inflated count data arise frequently in substance use research when assessing the effects of behavioral and pharmacological interventions. Zero-inflated count models (e.g. zero-inflated Poisson or zero-inflated negative binomial) with random effects have been developed to analyze this type of data. In random effects zero-inflated count models, the random effects covariance matrix is typically assumed to be homogeneous (constant across subjects). However, in many situations this matrix may be heterogeneous (differ by measured covariates). In this paper, we extend zero-inflated count models to account for random effects heterogeneity by modeling their variance as a function of covariates. We show via simulation that ignoring intervention and covariate-specific heterogeneity can produce biased estimates of covariate and random effect estimates. Moreover, those biased estimates can be rectified by correctly modeling the random effects covariance structure. The methodological development is motivated by and applied to the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study, the largest clinical trial of alcohol dependence performed in United States with 1383 individuals.

Toward Personalized Medicine in the Pharmacotherapy of Alcohol Use Disorder: Targeting Patient Genes and Patient Goals

Toward Personalized Medicine in the Pharmacotherapy of Alcohol Use Disorder: Targeting Patient Genes and Patient Goals

Cumulative Proportion of Responders Analysis (CPRA) as a Tool to Assess Treatment Outcome in Alcohol Clinical Trials

Several definitions of treatment response have been proposed for alcohol clinical trials (e.g., abstinence and no heavy drinking). However, each of these outcomes allows only one definition of successful response. In contrast, the cumulative proportion of responders analysis (CPRA) includes all of the possible drinking response cutoff points, providing a more complete picture of the therapeutic effects of a treatment. CPRA has been used to examine the efficacy of analgesics but not alcohol pharmacotherapy. To demonstrate its potential utility, we conducted CPRA in two large alcohol treatment trials: the COMBINE (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence) trial (naltrexone) and a multisite topiramate trial. CPRA was used to demonstrate the efficacy of naltrexone and topiramate on continuous measures of in-treatment drinking-heavy drinking days and drinks per day-and their reductions from pretreatment. All possible cutoff points were portrayed for each measure. We provide graphs to illustrate the effects of the active medications compared with placebo and examined them statistically over a number of salient drinking outcomes to evaluate their efficacy. Treatment group responder curves were not parallel across the entire range of cutoff points; rather, they separated only at lower levels of drinking. In general, effect sizes increased by 0.10-0.15 when going from the lowest drinking level cutoff (i.e., abstinence and no heavy drinking) to the cutoff associated with the maximal treatment effect. CPRA may be useful in designing subsequent trials and helping to illustrate for treatment providers the likelihood of treatment success given various definitions of a positive response.

Simultaneous Modeling of the Impact of Treatments on Alcohol Consumption and Quality of Life in the COMBINE Study: A Coupled Hidden Markov Analysis

Clinical trials for alcoholism have historically regarded alcohol consumption as the primary outcome. In a subset of trials, quality of life (QOL) has been considered as a secondary outcome. Joint latent-variable modeling techniques may provide a more accurate and powerful simultaneous analysis of primary and secondary outcomes in clinical trials. The goal of this study was to evaluate longitudinal associations between treatment status, alcohol consumption, and QOL in the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. A total of 1,383 alcohol-dependent patients were randomized to 9 treatment groups. Percent heavy drinking days (PHDD) and health-related QOL from the 30days preceding baseline, week 16, and week 52 were calculated using the Form 90 and the Medical Outcomes Study Health Survey Short Form-12 (SF-12), respectively. Latent profile analysis (LPA) was conducted to determine an appropriate number of latent states to represent PHDD and QOL. Subsequently, univariate and coupled hidden Markov models (for PHDD and SF-12 mental health, and PHDD and SF-12 physical) were fit to the data. LPA suggested that PHDD should be represented by 3 latent states and that each SF-12 scale should be represented by 2 states. Joint modeling results suggested that (i) naltrexone significantly predicted decreased PHDD (p<0.05), and marginally predicted improved mental health QOL via decreased PHDD (p<0.10), and (ii) that the combinations of naltrexone and combined behavioral intervention (CBI), and acamprosate and CBI, each predicted significantly improved physical QOL (p<0.05), and marginally predicted decreased PHDD via improved physical QOL (p<0.10). This study illustrates a powerful and novel statistical approach for simultaneously evaluating the impact of treatments on primary and secondary outcomes in clinical trials. This study also suggests that behavioral interventions may impact drinking behavior through their ameliorative effects on QOL.

Cigarette Smoking Predicts Differential Benefit from Naltrexone for Alcohol Dependence

Identifying factors that modify responsiveness to pharmacotherapies for alcohol dependence is important for treatment planning. Cigarette smoking predicts more severe alcohol dependence and poorer treatment response in general. Nevertheless, there is limited research on cigarette smoking as a potential predictor of differential response to pharmacological treatment of alcoholism. We examined the association between cigarette smoking and drinking outcomes in the COMBINE (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence) study, a randomized, double-blind placebo-controlled 16-week trial comparing combinations of medications (i.e., acamprosate and naltrexone) and behavioral interventions (i.e., medical management, combined behavioral therapy) in 1383 alcohol-dependent individuals. Smokers (i.e., more than one half the sample) significantly differed from nonsmokers on several demographic and drinking-related variables at baseline and generally had poorer treatment outcomes than nonsmokers. However, smokers who received naltrexone had better drinking outcomes than smokers who received placebo, whereas alcohol use among nonsmokers did not vary by naltrexone assignment. This pattern of findings occurred independent of whether patients received combined behavioral intervention or medical management and remained after controlling for alcoholism typology and baseline demographic differences. Approximately 9% of smokers quit smoking, and an additional 10% reduced their cigarette intake during treatment. Reductions in smoking did not vary by treatment assignment. These results suggest that naltrexone might be particularly beneficial for improving alcohol use outcomes in alcohol-dependent smokers.

Treatments for Alcohol Dependence: Rethinking the Role of Comorbidity and Clinical Subtypes

Treatments for Alcohol Dependence: Rethinking the Role of Comorbidity and Clinical Subtypes

Blood Glucose Level, Alcohol Heavy Drinking, and Alcohol Craving During Treatment for Alcohol Dependence: Results From the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) Study

Heavy drinking may increase blood glucose levels. Moreover, in alcohol-dependent subjects, glucose may play a putative role in alcohol preference. This study investigated the relationship between blood glucose levels and both alcohol heavy drinking and craving in alcohol-dependent subjects participating in the COMBINE Study. The primary objective was to evaluate the relationship between baseline (pretreatment) glucose levels and percentage of heavy drinking day (PHDD) during treatment. The secondary objective was to evaluate the relationship between glucose levels, baseline PHDD, and craving measured by the Obsessive Compulsive Drinking Scale (OCDS). This analysis consisted of 1,324 participants. Baseline glucose levels were significantly and positively associated with PHDD during treatment [F(1, 1225) = 5.21, p = 0.023], after controlling for baseline PHDD [F(1, 1225) = 36.25, p < 0.0001], gender [F (1, 1225) = 3.33, p = 0.07], and body mass index (BMI) [F(1, 1225) = 0.31, p = 0.58]. Higher glucose levels at baseline were associated with a higher percentage of PHDD at pretreatment [F(1, 1304) = 5.96, p = 0.015], after controlling for gender [F(1, 1304) = 0.29, p = 0.59] and BMI [F(1, 1304) = 0.90, p = 0.34]. Glucose was not significantly associated with the OCDS total score [F(1, 1304) = 0.12, p = 0.73], the OCDS Obsessive subscale [F(1, 1304) = 0.35, p = 0.56], or the OCDS Compulsive subscale [F(1, 1304) = 1.19, p = 0.28] scores, after controlling for gender and BMI. A link between pretreatment glucose levels and heavy drinking during treatment was found, suggesting a role of glucose in predicting heavy alcohol consumption. Although caution is needed in the interpretation of these results, elevated glucose and heavy drinking may be affected by a common mechanism and manipulations affecting glucose regulation may influence alcohol consumption.