Human laboratory paradigms in alcohol research.

BACKGROUND: Human laboratory studies have a long and rich history in the field of alcoholism. Human laboratory studies have allowed for advances in alcohol research in a variety of ways, including elucidating neurobehavioral mechanisms of risk, identifying phenotypically distinct subtypes of alcohol users, investigating the candidate genes underlying experimental phenotypes for alcoholism, and testing mechanisms of action of alcoholism pharmacotherapies on clinically relevant translational phenotypes, such as persons exhibiting positive-like alcohol effects or alcohol craving. Importantly, the field of human laboratory studies in addiction has progressed rapidly over the past decade and has built upon earlier findings of alcohol's neuropharmacological effects to advancing translational research on alcoholism etiology and treatment. METHODS AND RESULTS: To that end, the new generation of human laboratory studies has focused on applying new methodologies, further refining alcoholism phenotypes, and translating these findings to studies of alcoholism genetics, medication development, and pharmacogenetics. The combination of experimental laboratory approaches with the recent developments in neuroscience and pharmacology has been particularly fruitful in furthering our understanding of the impact of individual differences in alcoholism risk and in treatment response. CONCLUSIONS: This review of the literature focuses on human laboratory studies of subjective intoxication, alcohol craving, anxiety, and behavioral economics. Each section discusses opportunities for phenotype refinement under laboratory conditions, as well as its application to translational science of alcoholism. A summary and recommendations for future research are also provided.

Examining naltrexone and alcohol effects in a minority population: results from an initial human laboratory study.

Prior clinical findings have indicated a potential lack of naltrexone efficacy among African Americans with alcohol dependence. However, no definitive conclusions have been drawn due to the relatively small numbers of African Americans in most alcohol treatment trials. The purpose of this study was to examine alcohol and naltrexone effects on healthy African-American individuals in a laboratory environment. Nonalcohol-dependent social drinking adults of African descent (n = 43) were recruited for participation. After consenting and completing the baseline assessment, they participated in four separate alcohol challenge sessions each separated by at least 10 days. During each of the sessions, subjects were administered alcohol or sham drinks, after pretreatment with either naltrexone (50 mg/day) or placebo in a double-blind fashion. The order of the four sessions was randomly assigned. During each session, breath alcohol levels and subjective responses were measured. Results indicate an alcohol effect among these subjects for subjective responses, but no naltrexone effect. Similar to the apparent lack of clinical efficacy findings, naltrexone does not appear to impact alcohol effects in African-American social drinkers. Future studies should investigate African-American populations with heavy drinking as well as alcohol-dependent subjects in order to strengthen the parallels to clinical findings.

Study blinding and correlations between perceived group assignment and outcome in a cocaine pharmacotherapy trial.

While much research has suggested that the integrity of the blind is compromised in psychotropic drug trials, little research has been conducted on blinding in substance abuse trials. The current study examines the integrity of the blind in an outpatient pharmacotherapy trial investigating the effectiveness of amantadine and propranolol in treating cocaine addiction. Results suggest that neither nurses (N = 174, kappa = 0.08, p = 0.22) nor participants (N = 163, kappa = 0.09, p = 0.26) could accurately predict treatment assignment. Furthermore, nurses' perceptions of treatment assignment were significantly related to trial completion, medication compliance, and cocaine use--results that may have training implications for medical personnel.

Behavioral risk assessment for infectious diseases (BRAID): Self-report instrument to assess injection and noninjection risk behaviors in substance users.

BACKGROUND: Infectious diseases such as Human Immunodeficiency Virus and Hepatitis C are a significant problem among substance abusers. Current risk behavior measures [e.g., HIV Risk Taking Behaviour Scale (HRBS) and Risk Assessment Battery (RAB)] were developed for injection drug users and do not include newly identified risks or noninjection drug use behaviors. This study developed and provided initial, internal validation of the Behavioral Risk Assessment for Infectious Diseases (BRAID) to assess infectious disease risk behaviors among alcohol and other drug users. METHODS: A self-report measure was developed from literature regarding risk behaviors. Participants (total N=998) with alcohol/substance use disorder completed the measure in 2 phases to establish initial psychometric validity. RESULTS: Phase 1 (N=270) completed 65 self-report questions; factor analysis revealed a 12-item solution with 5 factors (Unprotected Sex with Risky Partners, Injection Use, Sex on Cocaine/Crack, Condom Availability, and Intranasal Drug Use). Infectious disease history was positively associated with Injection Use (Sample 1) and Unprotected Sex with Risky Partners (Sample 2) and negatively associated with Intranasal Drug Use (Samples 1 and 2). Phase 2 (N=728) added additional injection-related items and confirmed the factor structure of the existing BRAID. CONCLUSIONS: The BRAID is a 5-factor, 14-item self-report measure of past 6 month risk behaviors that is composed of noninjection and injection risk behaviors and was psychometrically confirmed. Though additional external (convergent/divergent) validation is needed, this report provides preliminary support for the use of the BRAID to assess infectious disease risk in substance users.

Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence.

BACKGROUND: Alcohol use, abuse and dependence remain a pressing public health problem. Based on its mechanism of action, varenicline seemed to be a likely candidate for treating alcohol dependence. METHODS: Alcohol dependent subjects (n=40) were enrolled in a 13-week double-blind placebo controlled clinical trial. Subject visits were once per week. At each visit, subjects were tested for breath alcohol levels, provided self-report data on alcohol and nicotine use, and on mood and craving. In addition, subjects received once a week medical management (MM). RESULTS: There was no difference between varenicline and placebo treated groups on any of the drinking outcomes. Compared to placebo-treated subjects, varenicline treated subjects had decreased rates of alcohol craving and cigarette smoking, as well as greater mood improvements during the later part of the study (weeks 6-13). In addition, among subjects who were cigarette smokers, those treated with varenicline were significantly less likely to report heavy drinking during the trial. CONCLUSIONS: Although varenicline was not significantly more effective than placebo at reducing drinking during the trial, its effects on alcohol craving and mood suggest that future investigation of the mechanism of action of varenicline, as well as additional clinical studies may be warranted. In particular, the findings regarding the influence of smoking status on heavy drinking among varenicline-treated subjects should be investigated in future studies.

An adaptive approach for identifying cocaine dependent patients who benefit from extended continuing care.

OBJECTIVE: Study tested whether cocaine dependent patients using cocaine or alcohol at intake or in the first few weeks of intensive outpatient treatment would benefit more from extended continuing care than patients abstinent during this period. The effect of incentives for continuing care attendance was also examined. METHOD: Participants (N = 321) were randomized to treatment as usual (TAU), TAU and telephone monitoring and counseling (TMC), or TAU and TMC plus incentives (TMC+). The primary outcomes were (a) abstinence from all drugs and heavy alcohol use and (b) cocaine urine toxicology. Follow-ups were at 3, 6, 9, 12, 18, and 24 months. RESULTS: Cocaine and alcohol use at intake or early in treatment predicted worse outcomes on both measures (ps ≤ .0002). Significant effects favoring TMC over TAU on the abstinence composite were obtained in participants who used cocaine (odds ratio [OR] = 1.95 [1.02, 3.73]) or alcohol (OR = 2.47 [1.28, 4.78]) at intake or early in treatment. A significant effect favoring TMC+ over TAU on cocaine urine toxicology was obtained in those using cocaine during that period (OR = 0.55 [0.31, 0.95]). Conversely, there were no treatment effects in participants abstinent at baseline and no overall treatment main effects. Incentives almost doubled the number of continuing care sessions received but did not further improve outcomes. CONCLUSION: An adaptive approach for cocaine dependence in which extended continuing care is provided only to patients who are using cocaine or alcohol at intake or early in treatment improves outcomes in this group while reducing burden and costs in lower risk patients.

Results of an initial clinical trial of varenicline for the treatment of cocaine dependence.

BACKGROUND: Cocaine use, abuse and dependence remains a pressing public health problem. Based on its mechanism of action, varenicline, an alpha4beta2 partial agonist seemed to be a likely candidate for treating cocaine dependence. METHODS: Cocaine dependent participants (n=37) were enrolled in a 9-week double-blind placebo controlled clinical trial. Varenicline was titrated up to a target dose of 1mg BID during the first week of medication. RESULTS: Varenicline was associated with lower odds of cocaine use than placebo (OR=2.02, p=0.08), as measured by thrice-weekly urinalysis results. Compared to placebo-treated participants, varenicline treated participants had significantly decreased rates of cocaine reward, as measured by the Multiple Choice Procedure (MCP) (p=0.02). CONCLUSIONS: Varenicline appears to decrease cocaine use and reward, suggesting that further investigation of varenicline may be warranted.

A double-blind, placebo-controlled trial of modafinil for cocaine dependence.

This is a randomized, double-blind, placebo-controlled study of modafinil treatment for cocaine dependence. Patients (N = 210) who were actively using cocaine at baseline were randomized to 8 weeks of modafinil (0 mg/day, 200 mg/day, or 400 mg/day) combined with once-weekly cognitive-behavioral therapy. Our primary efficacy measure was cocaine abstinence, based on urine benzoylecgonine (BE) levels, with secondary measures of craving, cocaine withdrawal, retention, and tolerability. We found no significant differences between modafinil and placebo patients on any of these measures. However, there was a significant gender difference in that male patients treated with 400 mg/day tended to be more abstinent than their placebo-treated counterparts (p = .06). Our negative findings might be explained by gender differences and/or inadequate psychosocial treatment intensity in patients with severe cocaine dependence.

Combined effects of alcohol and hepatitis C: a secondary analysis of alcohol use biomarkers and high-risk behaviors from two medication trials for alcohol dependence.

OBJECTIVES: The goal of this secondary analysis was to examine the combined effects of HCV infection and recent alcohol use on baseline biologic markers of alcohol consumption in two outpatient medication trials for alcohol dependence. In addition, the relationship between Hepatitis C virus (HCV) infection and behavioral risk factors for HCV infection in these clinical populations were examined. METHODS: Data (n=345) from two randomized, placebo-controlled trials of naltrexone and psychosocial treatment for alcohol dependence (Study I, n=212) and comorbid alcohol and cocaine dependence (Study II, n=133) were used to examine baseline measures of HCV risk behaviors (injection drug use, needle sharing), and biomarkers of alcohol use (AST, ALT, GGT and CDT) were compared by HCV serostatus first within each study and then across studies. RESULTS: Although groups had differing sociodemographic profiles (as indicated by race, marital status, level of education) subjects in Study I exhibited no statistically significant differences from the Study II cohort in HCV prevalence (12.7 vs. 20.0%, p=0.07), lifetime history of injection drug use (13.8 vs. 22.0%, p=0.74), lifetime history of needle sharing (9.1 vs. 18.0%, p=0.62). As such, the data from both studies were analyzed together. Regardless of drinking status, HCV infection was significantly associated with an upward shift in the baseline level of ALT, AST, and GGT (p<0.006 for all measures) and a downward shift in baseline CDT (p=0.002). When using standard laboratory cutoff values to determine clinically significant elevations, HCV seropositivity was significantly associated with elevations in ALT, AST, GGT (p<0.001), and with decreases in CDT (p=.002). CONCLUSIONS: These data emphasize the importance of evaluating HCV infection and HCV risk behaviors at intake in medication trials for alcohol dependence and also raise questions regarding the use of cutoff scores for ALT, AST, GGT and CDT levels as biologic markers of alcohol use in subjects when HCV status is unknown.

Early abstinence in cocaine pharmacotherapy trials predicts successful treatment outcomes.

There is a robust relationship between early and later abstinence in smoking cessation, but that relationship has not been explored among other substances of abuse. To assess whether early abstinence during treatment, as opposed to baseline abstinence, predicted later abstinence among cocaine-dependent patients, data from two randomized double-blind controlled clinical pharmacotherapy trials were analyzed. Similar to the findings in the smoking cessation literature, results indicate that abstinence in the first 2 weeks of pharmacotherapy predicted later in-trial abstinence. This finding has implications both for treatment research and for clinical practice, suggesting that patients who do not respond early in treatment may need a more intensive intervention.