Efficacy and safety of baclofen for alcohol dependence: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Recent clinical trials and case-reports indicate that baclofen, a GABA(B) agonist, may have efficacy for alcohol dependence. Baclofen has been shown to enhance abstinence, to reduce drinking quantity, to reduce craving, and to reduce anxiety in alcohol-dependent individuals in 2 placebo-controlled trials in Italy. However, the clinical trial data with baclofen is limited. The purpose of the present study was to test the efficacy and tolerability of baclofen in alcohol dependence in the United States. METHODS: The study was a double-blind, placebo-controlled, randomized study comparing 30 mg/d of baclofen to placebo over 12 weeks of treatment and utilizing 8 sessions of BRENDA, a low-intensity psychosocial intervention. One hundred and twenty-one subjects were screened to yield 80 randomized subjects (44 men) with randomization balanced for gender. Percent heavy drinking days was the primary outcome measure with other drinking outcomes, anxiety levels, and craving as secondary outcomes. Tolerability was examined. RESULTS: Seventy-six percent of subjects completed the study. No difference by drug condition was seen in percentage of heavy drinking days where on-average rates were 25.5% (±23.6%) for placebo and 25.9% (±23.2%) for baclofen during treatment (t(73)=0.59, p=0.56). Similarly, no differences were seen by drug condition in percentage of days abstinent, time to first drink, or time to relapse to heavy drinking. Baclofen was associated with a significant reduction in state anxiety (F(1,73)= 5.39, p=0.02). Baclofen was well tolerated with only 2 individuals stopping baclofen because of adverse events. There were no serious adverse events. CONCLUSIONS: Baclofen, a GABA(B) agonist, represents a possible new pharmacotherapeutic approach to alcohol dependence. Despite encouraging preclinical data and prior positive clinical trials with baclofen in Italy, the current trial did not find evidence that baclofen is superior to placebo in the treatment of alcohol dependence. Additional clinical trial work is necessary to establish whether baclofen does or does not have therapeutic efficacy in alcohol dependence and, if it does, what factors are predictive of response.

Sweet liking phenotype, alcohol craving and response to naltrexone treatment in alcohol dependence.

AIMS: To investigate the relationship between the sweet liking/sweet disliking phenotype (a putative probe of brain opioid function), craving for alcohol and response to treatment with naltrexone in individuals with alcohol dependence. METHODS: Forty individuals with alcohol dependence were enrolled in a 12-week open-label study of 50 mg of naltrexone with four sessions of motivational enhancement therapy. Prior to treatment, individuals completed a sweet preference test and the Penn Alcohol Craving Scale. Subjects were categorized as sweet liking (SL), n = 15, or sweet disliking (SDL), n = 25, via a standard sweet tasting paradigm. The sweet tasting results were blinded to the subjects and to treatment staff. SL status, pretreatment craving and their interaction were examined as predictors of frequency of abstinent days and heavy drinking days during treatment with naltrexone. RESULTS: SL and SDL subjects achieved similar reductions in percent heavy drinking days with treatment. During treatment, SDL subjects had 48% abstinent days compared to 30% for SL subjects (P = 0.034). Pretreatment craving did not predict % heavy drinking days or % abstinent days. An interaction effect was found between the SL/SDL phenotype and pretreatment craving such that SL subjects with high craving demonstrated higher rates of percent abstinent days whereas SDL subjects with high craving demonstrated lower rates of percent abstinent days, P < 0.001. CONCLUSIONS: These findings indicate that the SL/SDL phenotype may predict variation in response to naltrexone and/or counseling treatment. Furthermore, the SL/SDL phenotype may interact with craving to provide a more robust prediction of outcome with naltrexone or counseling.

Neurocognitive characterizations of Russian heroin addicts without a significant history of other drug use.

Research on the neurocognitive characteristics of heroin addiction is sparse and studies that do exist include polydrug abusers; thus, they are unable to distinguish neurocognitive effects of heroin from those of other drugs. To identify neurocognitive correlates specific to heroin addiction, the present study was conducted in St. Petersburg, Russia where individuals typically abuse and/or become addicted to only one substance, generally alcohol or heroin. Heroin addicts were recruited from an inpatient treatment facility in St. Petersburg. Three comparison groups included alcoholics, addicts who used both alcohol and heroin, and non-abusers. Psychiatric, background, and drug history evaluations were administered after detoxification to screen for exclusion criteria and characterize the sample. Executive Cognitive Functions (ECF) that largely activate areas of the prefrontal cortex and its circuitry measured include complex visual pattern recognition (Paired Associates Learning), working memory (Delayed Matching to Sample), problem solving (Stockings of Cambridge), executive decision making (Cambridge Decision Making Task), cognitive flexibility (Stroop Color-Word Task) and response shifting (Stop Change Task). In many respects, the heroin addicts were similar to alcohol and alcohol+heroin dependent groups in neurocognitive deficits relative to controls. The primary finding was that heroin addicts exhibited significantly more disadvantageous decision making and longer deliberation times while making risky decisions than the other groups. Because the nature and degree of recovery from drug abuse are likely a function of the type or pattern of neurocognitive impairment, differential drug effects must be considered.

Pigeons' choices between fixed-interval and random-interval schedules: utility of variability?

Pigeons' choosing between fixed-interval and random-interval schedules of reinforcement was investigated in three experiments using a discrete-trial procedure. In all three experiments, the random-interval schedule was generated by sampling a probability distribution at an interval (and in multiples of the interval) equal to that of the fixed-interval schedule. Thus the programmed delays to reinforcement on the random alternative were never shorter and were often longer than the fixed interval. Despite this feature, the fixed schedule was not strongly preferred. Increases in the probability used to generate the random interval resulted in decreased preferences for the fixed schedule. In addition, the number of consecutive choices on the preferred alternative varied directly with preference, whereas the consecutive number of choices on the nonpreferred alternative was fairly constant. The probability of choosing the random alternative was unaffected by the immediately prior interval encountered on that schedule, even when it was very long relative to the average value. The results loosely support conceptions of a "preference for variability" from foraging theory and the "utility of behavioral variability" from human decision-making literatures.

Physical pain, common psychiatric and substance use disorders, and the non-medical use of prescription analgesics in the United States.

This study investigated the link between physical pain and non-medical prescription analgesic use (NMPAU), as well as the degree to which this association may vary by the presence of psychiatric and substance use disorders. Data were from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a nationally representative, in-person probability sample of adults (n=43,093) aged 18 or older in the United States (2001-2002). Face-to-face interviews were used to gather information on past-year levels of physical pain (i.e., low, medium, high), in addition to DSM-IV classifications for mood, anxiety, substance use problems (i.e., abuse and/or dependence), and personality disorders. Within the analytic sample of those with valid data (n=42,734), the past-year rate of NMPAU was 1.8%, of which 20% met the DSM-IV criteria for abuse/dependence. Among past-year NMPAUs, 53% was incidental (e.g., less than monthly), but daily use was substantial (13% of NMPAUs). Accounting for our target confounding factors, pain was positively associated (p<0.05) with an increased probability of non-disordered (i.e., no abuse and/or dependence) and disordered (i.e., abuse and/or dependence) NMPAU in the past year. Within each level of pain, the odds of past-year non-disordered and disordered NMPAU were significantly higher (p<0.05) for those with disordered alcohol use compared with non-disordered users. This pattern was similar for illicit drugs, although marginally significant (p=0.060) and specific to disordered NMPAU. In contrast, psychiatric disorders increased the probability of both types of NMPAU, but these associations did not differ by levels of pain. These findings suggest that pain is an independent risk factor for non-disordered and disordered NMPAU, yet its effects are substantially modified by patterns of substance use.

Differential relationships between personal and community stressors and children's neurocognitive functioning.

Early adversity can alter development of neurocognition, including executive cognitive and emotional regulatory functions. This is the first study to explore differential relationships between personal (physical and emotional abuse and neglect, school and parental stressors) and community (neighborhood problems and witnessing neighborhood violence) stressors and neurocognition. Predominantly Latino children (n = 553) aged 10 to 12 years completed tasks measuring intelligence, impulsivity, problem solving, cognitive flexibility, decision making, and emotion attributions. Adjusting for age and parent education, bivariate regression analyses found exposure to personal stressors to be associated with relative deficits in at least one neurocognitive function. Community stressors were related to relative deficits in emotion attributions and problem solving. In multivariate analyses, neglect was related to misattributions of emotion and IQ deficits, and physical abuse was related to problem solving. Community stressors were not correlated with neurocognition when viewed relative to personal stressors. Stressor types were differentially associated with performance on specific neurocognitive tasks.

Multidimensionality of the Alcohol Withdrawal Symptom Checklist: a factor analysis of the Alcohol Withdrawal Symptom Checklist and CIWA-Ar.

BACKGROUND: This study evaluated the factor structure of 2 scales for measuring the severity of the alcohol withdrawal syndrome (AWS): a self-rated scale, the Alcohol Withdrawal Symptoms Checklist (AWSC), and an observer-rated scale, the Clinical Institute Withdrawal Assessment-Alcohol, Revised (CIWA-Ar). METHODS: Alcohol-dependent male inpatients [n=127, age: 43.0+/-9.7 (mean+/-SD) years] were recruited from an inpatient treatment unit. Both measures of AWS were assessed repeatedly during the initial week of sobriety in these patients. An exploratory factor analysis was applied to the data collected on the first study day. RESULTS: Five independent factors accounted for 64% of total variance in the AWSC: autonomic arousal, depression, nausea and vomiting, alcohol craving, and tension/anxiety. Three items (abdominal pain, hallucinations, confusion) could not be included in the analysis due to insufficient variance. Three dimensions identified for the CIWA-Ar (autonomic arousal, nausea and vomiting, tension/anxiety) were also captured by the ASWC. Total AWSC scores correlated well with total CIWA-Ar scores (r=0.72), supporting validity of the AWSC. Lower correlations between total CIWA-Ar and the 5 factors (r=0.32-0.52) suggested that the CIWA-Ar and AWSC factors had discriminative value. CONCLUSIONS: Self-rated measures of AWS could play an important role in complementing observer-rated measures in clinical and research settings. In this sample, the AWSC appeared to identify multiple dimensions of AWS with face validity for clinical relevance.

Gender differences in neurocognitive functioning among alcohol-dependent Russian patients.

BACKGROUND: There are a limited number of studies that have examined gender differences in the neurocognitive test performances of alcohol-dependent individuals. Those that have been conducted reported that compared with men, women's visuospatial skills, psychomotor speed, and working memory are more profoundly affected by chronic alcohol abuse despite a shorter duration of drinking and a lesser quantity of alcohol consumed. METHODS: The performances of Russian male and female alcoholic and nonalcoholic control subjects were compared on a series of neurocognitive tasks that assess motor speed, visuoperceptual processing, visuospatial processing, decision making, and cognitive flexibility. RESULTS: Group and gender differences emerged on specific components of each task administered. Female compared with male alcoholic subjects exhibited poorer performances on tests of visual working memory, spatial planning and problem solving, and cognitive flexibility. CONCLUSION: The data support and extend prior research demonstrating a more deleterious impact of alcohol dependence on female alcoholic subjects' cognitive functioning compared with male alcoholic subjects. Several theories are offered to account for gender differences in neurocognitive performance.

Alcohol use among out-of-treatment crack using African-American women.

OBJECTIVE: The purpose of this study was to categorize the quantity and frequency of alcohol use among African-American women who were abusing crack cocaine and to explore relationships between categories of alcohol use and demographic variables, cocaine use, comorbidity, and risky sexual behaviors. METHOD: Data were collected from 635 out-of-treatment crack cocaine-abusing African-American women in the Raleigh/Durham area of North Carolina. The women were categorized as light (n = 272), moderate (n = 216), or heavy drinkers (n = 147). RESULTS: Women classified as heavy drinkers were demographically similar to light and moderate drinkers. Heavy drinkers used more crack cocaine and were more likely to engage in sexual risk behaviors than were the other two drinking groups. The heavy drinkers also reported greater psychological distress, and they were more likely to report histories of physical, sexual, and emotional abuse. CONCLUSIONS: Heavy alcohol use among crack-abusing African-American women may be a marker for a host of underlying problems that require special attention. The HIV prevention programs and substance abuse treatment programs that provide services to crack-abusing women should screen for heavy drinking. Women identified as heavy drinkers should undergo more in-depth assessments and receive additional referrals as appropriate.

Using acquired knowledge and new technologies in alcoholism treatment trials.

This article represents the proceedings of a symposium held at the 2001 RSA meeting in Montreal, Canada. The organizer and chair was Barbara A. Flannery and the discussant was Raye Z. Litten. The presentations were (1) The use of biomarkers in alcohol-dependence treatment trials, by John P. Allen; (2) Strategies for enhancing patient compliance in clinical treatment trials, by Helen M. Pettinati; (3) The predictive utility of an alcohol-craving measure, by Barbara A. Flannery; (4) What should be the primary outcome measures in a clinical trial, by Damaris J. Rohsenow; (5) Innovative strategies for assessing functional outcomes in alcoholism treatment clinical trials, by Ron A. Cisler.

Baclofen for alcohol dependence: a preliminary open-label study.

BACKGROUND: Recent preclinical and clinical studies have shown that the gamma-aminobutyric acid-B agonist baclofen may be an effective treatment for reducing alcohol consumption. This preliminary open-label investigation examined the tolerability and effect of a 30-mg daily baclofen dose for reducing drinking, subclinical anxiety and depressive symptoms, and craving in alcohol-dependent subjects. METHODS: Nine men and three women participated in a 12-week trial during which they took baclofen on a 10 mg thrice-daily regimen and received four sessions of motivational enhancement therapy. Each participant received a comprehensive physical and psychiatric screening before being enrolled. At each visit, side effects were monitored with a revised version of the Systematic Assessment of Treatment Emergent Events-General Inquiry, and drinking data were collected via the timeline follow-back interview. Participants also completed the Beck Depression Inventory, the Beck Anxiety Inventory, and the Penn Alcohol Craving Scale at each visit. RESULTS: Baclofen was reasonably tolerated. Two participants discontinued because of side effects. No serious adverse events were noted. Six other individuals did not complete the trial. Overall, there were statistically significant reductions in the number of drinks per drinking day and the number of heavy-drinking days, and there was an increase in the number of abstinent days. Significant decreases in anxiety and craving were also shown. CONCLUSIONS: These findings suggest that baclofen is reasonably tolerated in an alcohol-dependent population, although the high dropout rate in the study is of concern. Baclofen may be effective for the reduction of drinking, anxiety, and craving for some alcohol-dependent individuals. A larger-scale placebo-controlled study is needed to further explore these effects and to determine the characteristics of those who respond to this medication.