Exploration of the Impact of Combining Risk Phenotypes on the Likelihood of Alcohol Problems in Young Adults.

AIMS: We tested the hypothesis that high novelty seeking (NS-an externalizing trait), sweet-liking (SL-a phenotype that may reflect processing of hedonic stimuli) and initial insensitivity to the impairing effects of alcohol (SRE-A) act independently and synergistically to increase the likelihood of having alcohol-related problems in young adults. METHODS: A sample of 145 young adults, ages 18-26, balanced for gender and alcohol use disorders identification test (AUDIT) scores <8 or ≥8 were selected from a prior sample. NS, SL and SRE-A were assessed along with AUDIT score and family history of alcoholism (FH). The effect of phenotypes and their interaction on the likelihood of alcohol problems was assessed. RESULTS: All three phenotypes contribute to the total AUDIT score. The best-fitting model explaining 35.8% of AUDIT variance includes all three phenotypes and an interaction between NS and SL/sweet-disliking (SDL) status. The addition of FH to the model explains an additional 4% of variance in both models. Classification and regression tree analysis showed that the main phenotype influencing AUDIT score is NS. The SL/SDL phenotype is a strong modifying factor for high NS. SRE-A was shown to be a weak modifier for individuals with low NS. CONCLUSION: The evidence supports the hypothesis that the presence of multiple alcohol use disorders (AUD) risk phenotypes with different underlying neurobiological mechanisms within an individual (SL, NS and SRE-A) represents a higher likelihood for developing alcohol-related problems and may allow for a graded assessment of risk for AUD and offer the possibility for early intervention strategies.

A Randomized Controlled Trial of an Integrated Alcohol Reduction Intervention in Patients With Hepatitis C Infection.

BACKGROUND AND AIMS: Hepatitis C virus (HCV) and alcohol use are patient risk factors for accelerated fibrosis progression, yet few randomized controlled trials have tested clinic-based alcohol interventions. APPROACH AND RESULTS: A total of 181 patients with HCV and qualifying alcohol screener scores at three liver center settings were randomly assigned to the following: (1) medical provider-delivered Screening, Brief Intervention, and Referral to Treatment (SBIRT), including motivational interviewing counseling and referral out for alcohol treatment (SBIRT-only), or (2) SBIRT plus 6 months of integrated colocated alcohol therapy (SBIRT + Alcohol Treatment). The timeline followback method was used to assess alcohol use at baseline and 3, 6, and 12 months. Coprimary outcomes were alcohol abstinence at 6 months and heavy drinking days between 6 and 12 months. Secondary outcomes included grams of alcohol consumed per week at 6 months. Mean therapy hours across 6 months were 8.8 for SBIRT-only and 10.1 for SBIRT + Alcohol Treatment participants. The proportion of participants exhibiting full alcohol abstinence increased from baseline to 3, 6, and 12 months in both treatment arms, but no significant differences were found between arms (baseline to 6 months, 7.1% to 20.5% for SBIRT-only; 4.2% to 23.3% for SBIRT + Alcohol Treatment; P = 0.70). Proportions of participants with any heavy drinking days decreased in both groups at 6 months but did not significantly differ between the SBIRT-only (87.5% to 26.7%) and SBIRT + Alcohol Treatment (85.7% to 42.1%) arms (P = 0.30). Although both arms reduced average grams of alcohol consumed per week from baseline to 6 and 12 months, between-treatment effects were not significant. CONCLUSIONS: Patients with current or prior HCV infection will engage in alcohol treatment when encouraged by liver medical providers. Liver clinics should consider implementing provider-delivered SBIRT and tailored alcohol treatment referrals as part of the standard of care.

Bupropion, Alone and in Combination with Naltrexone, Blunts Binge-Like Ethanol Drinking and Intake Following Chronic Intermittent Access to Ethanol in Male C57BL/6J Mice.

BACKGROUND: Regular binge drinking is associated with numerous adverse consequences, yet the U.S. Food and Drug Administration (FDA) has approved only 4 medications for the treatment of alcohol use disorders, and none have been specifically targeted for treating binge drinking. Here, we assessed the effectiveness of the dopamine/norepinephrine re-uptake inhibitor, bupropion (BUP), alone and in combination with naltrexone (NAL), to reduce binge-like and chronic ethanol (EtOH) intake in mice. While BUP is an FDA-approved drug that is currently used to treat depression and nicotine dependence, there has been only limited investigation to assess the ability of BUP to reduce EtOH intake. METHODS: Male C57BL/6J mice were tested with 20% (v/v) EtOH using "drinking in the dark" (DID) procedures to model binge-like EtOH intake and following intermittent access to EtOH (IAE). In Experiment 1, mice were given intraperitoneal (i.p.) injection of 0, 20, or 40 mg/kg BUP 30 minutes before DID testing; in Experiment 2, mice were given i.p. injection of vehicle, BUP (20 mg/kg), NAL (3 mg/kg), or BUP + NAL (20 and 3 mg/kg, respectively) 30 minutes before DID testing; and in Experiment 3, mice were given i.p. injection of 0, 20, 40, or 60 mg/kg BUP 30 minutes before EtOH access after mice had 16 weeks of IAE. RESULTS: BUP dose dependently blunted EtOH intake with DID procedures and after 16 weeks of IAE. Administration of subthreshold doses of BUP + NAL also reduced binge-like EtOH intake. Finally, BUP failed to reduce consumption of a 3% (w/v) sucrose solution. CONCLUSIONS: BUP, alone and in combination with NAL, may represent a novel approach to treating binge EtOH intake. We are currently assessing the efficacy of BUP to curb binge drinking in a phase II clinical trial experiment.

Sweet-liking is associated with transformation of heavy drinking into alcohol-related problems in young adults with high novelty seeking.

BACKGROUND: We tested the hypothesis that high novelty seeking (NS) (a trait that promotes experimentation) and sweet-liking (SL) (a phenotype that may reflect processing of hedonic stimuli) act independently and synergistically to increase the risk of having alcohol-related problems in young adults. METHODS: A sample of 163 young adults, ages 18 to 26, was recruited and balanced for gender and evidence for presence of alcohol problems to yield 150 evaluable participants. NS was evaluated using the Tridimensional Personality Questionnaire. Pleasurable response to sweet taste was tested to identify sweet-likers and sweet-dislikers. Alcohol use and problems were assessed by the Alcohol Use Disorders Identification Test and the Rutgers Alcohol Problem Index. RESULTS: NS, but not SL, was positively and significantly associated with alcohol consumption and alcohol problems; however, the effect of NS on alcohol problems was significantly enhanced in the presence of the SL phenotype, thus showing a strong synergistic interaction. The combination of SL and high NS was associated with increased odds of having alcohol problems -20.64 (95% CI: -89.98, 4.74) compared to those with low NS and sweet-disliking. Other combinations did not produce such odds ratios. SL and low NS showed OR = 1.88 (95% CI 0.44, 7.99), and sweet-dislikers and high novelty seekers had OR = 4.07 (95%, CI 1.01, 16.46). CONCLUSIONS: These results support and extend our hypothesis that as clinically distinct phenotypes, high NS and the SL phenotype are associated with risk of alcohol-related problems. High NS is associated with the use of alcohol, and the presence of the SL phenotype appears to bias an individual to alcohol problems once alcohol use is initiated. Understanding the biology and phenomenology of these phenotypes will allow a more complete picture of the processes that lead to alcohol problems.

Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis.

IMPORTANCE: Alcohol use disorders cause substantial morbidity and early mortality yet remain greatly undertreated. Medications are considerably underused. OBJECTIVE: To conduct a systematic review and meta-analysis of the benefits and harms of medications (US FDA-approved and others) for adults with alcohol use disorders. DATA SOURCES: PubMed, Cochrane Library, PsycINFO, CINAHL, EMBASE, FDA website, and clinical trials registries (January 1, 1970, to March 1, 2014). STUDY SELECTION: Two reviewers selected randomized clinical trials (RCTs) with at least 12 weeks' duration that reported eligible outcomes and head-to-head prospective cohort studies reporting health outcomes or harms. DATA EXTRACTION AND SYNTHESIS: We conducted meta-analyses using random-effects models and calculated numbers needed to treat for benefit (NNTs) or harm (NNHs). MAIN OUTCOMES AND MEASURES: Alcohol consumption, motor vehicle crashes, injuries, quality of life, function, mortality, and harms. RESULTS: We included 122 RCTs and 1 cohort study (total 22,803 participants). Most assessed acamprosate (27 studies, n = 7519), naltrexone (53 studies, n = 9140), or both. The NNT to prevent return to any drinking for acamprosate was 12 (95% CI, 8 to 26; risk difference [RD], -0.09; 95% CI, -0.14 to -0.04) and was 20 (95% CI, 11 to 500; RD, -0.05; 95% CI, -0.10 to -0.002) for oral naltrexone (50 mg/d). The NNT to prevent return to heavy drinking was 12 (95% CI, 8 to 26; RD -0.09; 95% CI, -0.13 to -0.04) for oral naltrexone (50 mg/d). Meta-analyses of trials comparing acamprosate to naltrexone found no statistically significant difference between them for return to any drinking (RD, 0.02; 95% CI, -0.03 to 0.08) or heavy drinking (RD, 0.01; 95% CI, -0.05 to 0.06). For injectable naltrexone, meta-analyses found no association with return to any drinking (RD, -0.04; 95% CI, -0.10 to 0.03) or heavy drinking (RD, -0.01; 95% CI, -0.14 to 0.13) but found an association with reduction in heavy drinking days (weighted mean difference [WMD], -4.6%; 95% CI, -8.5% to -0.56%). Among medications used off-label, moderate evidence supports an association with improvement in some consumption outcomes for nalmefene (heavy drinking days per month: WMD, -2.0; 95% CI, -3.0 to -1.0; drinks per drinking day: WMD, -1.02; 95% CI, -1.77 to -0.28) and topiramate (% heavy drinking days: WMD, -9.0%; 95% CI, -15.3% to -2.7%; drinks per drinking day: WMD, -1.0; 95% CI, -1.6 to -0.48). For naltrexone and nalmefene, NNHs for withdrawal from trials due to adverse events were 48 (95% CI, 30 to 112) and 12 (95% CI, 7 to 50), respectively; risk was not significantly increased for acamprosate or topiramate. CONCLUSIONS AND RELEVANCE: Both acamprosate and oral naltrexone were associated with reduction in return to drinking. When directly compared with one another, no significant differences were found between acamprosate and naltrexone for controlling alcohol consumption. Factors such as dosing frequency, potential adverse events, and availability of treatments may guide medication choice.

Efficacy of acamprosate for alcohol dependence in a family medicine setting in the United States: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Acamprosate has been found to enhance rates of complete abstinence and to increase percent days abstinent (PDA) from alcohol relative to placebo treatment. As most U.S. clinical trials of acamprosate have been conducted in alcohol and other drug specialty clinics, there is a need to examine the efficacy of acamprosate in generalist settings. This study tested the efficacy of acamprosate versus placebo on the primary study outcome of PDA in the treatment of alcohol-dependent patients in a family medicine setting. Secondary study outcomes included percent heavy drinking days (%HDD) and gamma glutamyltransferase level (normal or high). METHODS: A randomized, double-blind, placebo-controlled, parallel group design of acamprosate was conducted in 2 family medicine settings (North Carolina and Wisconsin). One hundred volunteers were recruited primarily by advertisement, and participants were assigned to 666 mg (2 pills) oral acamprosate 3 times daily (1,998 mg/d) or matching placebo over a 12-week period. All participants concomitantly received 5 sessions of a brief behavioral intervention from a family/primary care physician. RESULTS: No significant treatment effect of acamprosate was found on PDA or the secondary outcomes. Significant treatment goal by time interaction effects was found on PDA and %HDD. Participants who had an initial goal of abstinence versus a reduction in alcohol use improved on average over time in PDA and had less %HDD from baseline to the end of treatment. CONCLUSIONS: This clinical trial did not find evidence of efficacy for acamprosate compared to placebo among alcohol-dependent individuals recruited primarily by advertisement as studied in a primary care setting. Drinking outcomes significantly improved regardless of medication condition. A goal of abstinence was significantly associated with improved drinking outcomes, suggesting that alcohol-dependent patients with such a goal may do particularly well with counseling in a family medicine setting.

Intranasal oxytocin blocks alcohol withdrawal in human subjects.

BACKGROUND: The neuropeptide, oxytocin (OT), has been reported to block tolerance formation to alcohol and decrease withdrawal symptoms in alcohol-dependent rodents. Numerous recent studies in human subjects indicate that OT administered by the intranasal route penetrates into and exerts effects within the brain. METHODS: In a randomized, double-blind clinical trial, intranasal OT (24 IU/dose, N = 7) or placebo (N = 4) was given twice daily for 3 days in alcohol-dependent subjects admitted to a research unit for medical detoxification using Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score-driven PRN administration of lorazepam. Subjects rated themselves on the Alcohol Withdrawal Symptom Checklist (AWSC) each time CIWA scores were obtained. Subjects also completed the Penn Alcohol Craving Scale, an Alcohol Craving Visual Analog Scale (ACVAS) and the Profile of Mood States (POMS) on inpatient days 2 and 3. RESULTS: All subjects had drunk heavily each day for at least 2 weeks prior to study and had previously experienced withdrawal upon stopping/decreasing alcohol consumption. OT was superior to placebo in reducing alcohol withdrawal as evidenced by: less total lorazepam required to complete detoxification (3.4 mg [4.7, SD] vs. 16.5 [4.4], p = 0.0015), lower mean CIWA scores on admission day 1 (4.3 [2.3] vs. 11.8 [0.4], p < 0.0001) and day 2 (3.4 [2.2] vs. 11.1 [3.6], p < 0.002), lower AWSC scores on days 1 and 2 (p < 0.02; p = 0.07), and lower ACVAS ratings (p = 0.01) and lower POMS Tension/Anxiety subscale scores on day 2 (p < 0.01). CONCLUSIONS: This is the first demonstration that OT treatment may block alcohol withdrawal in human subjects. Our results are consistent with previous findings in rodents that OT inhibits neuroadaptation to and withdrawal from alcohol. OT could have advantages over benzodiazepines in managing alcohol withdrawal because it may reverse rather than maintain sedative-hypnotic tolerance. It will be important to test whether OT treatment is effective in reducing drinking in alcohol-dependent outpatients.

Behavioral counseling after screening for alcohol misuse in primary care: a systematic review and meta-analysis for the U.S. Preventive Services Task Force.

BACKGROUND: Alcohol misuse, which includes the full spectrum from risky drinking to alcohol dependence, is a leading cause of preventable death in the United States. PURPOSE: To evaluate the benefits and harms of behavioral counseling interventions for adolescents and adults who misuse alcohol. DATA SOURCES: MEDLINE, EMBASE, the Cochrane Library, CINAHL, PsycINFO, International Pharmaceutical Abstracts, and reference lists of published literature (January 1985 through January 2012, limited to English-language articles). STUDY SELECTION: Controlled trials at least 6 months' duration that enrolled persons with alcohol misuse identified by screening in primary care settings and evaluated behavioral counseling interventions. DATA EXTRACTION: One reviewer extracted data and a second checked accuracy. Two independent reviewers assigned quality ratings and graded the strength of the evidence. DATA SYNTHESIS: The 23 included trials generally excluded persons with alcohol dependence. The best evidence was for brief (10- to 15-minute) multicontact interventions. Among adults receiving behavioral interventions, consumption decreased by 3.6 drinks per week from baseline (weighted mean difference, 3.6 drinks/wk [95% CI, 2.4 to 4.8 drinks/wk]; 10 trials; 4332 participants), 12% fewer adults reported heavy drinking episodes (risk difference, 0.12 [CI, 0.07 to 0.16]; 7 trials; 2737 participants), and 11% more adults reported drinking less than the recommended limits (risk difference, 0.11 [CI, 0.08 to 0.13]; 9 trials; 5973 participants) over 12 months compared with control participants (moderate strength of evidence). Evidence was insufficient to draw conclusions about accidents, injuries, or alcohol-related liver problems. Trials enrolling young adults or college students showed reduced consumption and fewer heavy drinking episodes (moderate strength of evidence). Little or no evidence of harms was found. LIMITATIONS: Results may be biased to the null because the behavior of control participants could have been affected by alcohol misuse assessments. In addition, evidence is probably inapplicable to persons with alcohol dependence and selective reporting may have occurred. CONCLUSION: Behavioral counseling interventions improve behavioral outcomes for adults with risky drinking. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Risk and resilience for alcohol use disorder revealed in brain functional connectivity.

A family history of alcoholism (FH) increases risk for alcohol use disorder (AUD), yet many at-risk individuals never develop alcohol use problems. FH is associated with intermediate levels of risk phenotypes, whereas distinct, compensatory brain changes likely promote resilience. Although several cognitive, behavioral, and personality factors have been associated with AUD, the relative contributions of these processes and their neural underpinnings to risk or resilience processes remains less clear. We examined whole-brain resting-state functional connectivity (FC) and behavioral metrics from 841 young adults from the Human Connectome Project, including healthy controls, individuals with AUD, and their unaffected siblings. First, we identified functional connections in which unaffected siblings were intermediate between controls and AUD, indicating AUD risk, and those in which siblings diverged, indicating resilience. Canonical correlations relating brain risk and resilience FC to behavioral patterns revealed AUD risk and resilience phenotypes. Risk phenotypes primarily implicated frontal-parietal networks corresponding with executive function, impulsivity, externalizing behaviors, and social-emotional intelligence. Conversely, resilience-related phenotypes were underpinned by networks of medial prefrontal, striatal, temporal, brainstem and cerebellar connectivity, which associated with high trait attention and low antisocial behavior. Additionally, we calculated "polyphenotypic" risk and resilience scores, to investigate how the relative load of risk and resilience phenotypes influenced the probability of an AUD diagnosis. Polyphenotypic scores predicted AUD in a dose-dependent manner. Moreover, resilience phenotypes interacted with risk phenotypes, reducing their effects. The hypothesis-generating results revealed interpretable AUD-related phenotypes and offer brain-informed targets for developing more effective interventions.

Efficacy and tolerability of baclofen in a U.S. community population with alcohol use disorder: a dose-response, randomized, controlled trial.

Identification of new medications for alcohol use disorder (AUD) is important for improving treatment options. Baclofen, a GABAB agonist, has been identified as a potential pharmacotherapy for AUD. In a 16-week double-blind, randomized, placebo-controlled trial, we investigated 30 and 90 mg/day of baclofen compared to placebo and examined effects of dose, sex, and level of pretreatment drinking. One hundred and twenty participants with DSM-IV alcohol dependence (age 46.1 (sd = 10.1) years, 51.7% male) were randomized after exclusion for unstable medical/psychiatric illness and/or dependence on drugs other than nicotine. Seventy-three participants completed the trial. A main effect of baclofen was found [%HDD (F(2,112) = 4.16, p = 0.018, d = 0.51 95%CI (0.06-0.95), 13.6 fewer HDD) and %ABST (F(2,112) = 3.68, p = 0.028, d = 0.49 95%CI (0.04-0.93), 12.9 more abstinent days)] and was driven by the 90 mg/day dose. A sex × dose interaction effect was present for both %HDD (F(2,110) = 5.48, p = 0.005) and %ABST (F(2,110) = 3.19, p = 0.045). Men showed a marginally positive effect for 90 mg/day compared to PBO (%HDD t(110) = 1.88, p = 0.063, d = 0.36 95%CI (-0.09-0.80), 15.8 fewer HDD days; %ABST t(110) = 1.68 (p = 0.096, d = 0.32 95%CI (-0.12-0.76), 15.7 more ABST)) with no effect for 30 mg/day. Women showed a positive effect for 30 mg/day (%HDD, t(110) = 3.19, p = 0.002, d = 0.61 95%CI (0.16-1.05), 26.3 fewer HDD days; %ABST t(110) = 2.73, p = 0.007, d = 0.52 95%CI (0.07-0.96), 25.4 more ABST days) with marginal effects for 90 mg/day on %ABST (p = 0.06) with drop-outs/dose reduction from sedative side-effects of 59% in women at 90 mg/day compared to 5% for men. These findings support the hypothesis that baclofen has efficacy in AUD and suggest that dose and sex be further explored as potential moderators of baclofen response and tolerability.

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.

Unipolar depression does not moderate responses to the Sweet Taste Test.

BACKGROUND: The Sweet Taste Test (STT) measures hedonic responses to sweet tastes and has been linked to both alcoholism and to a family history of alcoholism. However, STT response profiles in unipolar major depressive disorder (MDD), a disorder characterized by anhedonia, have been minimally investigated. METHODS: Twelve adults with and 15 adults without MDD participated in two identical STT assessments separated by approximately 12 weeks. Between assessments, MDD outpatients received Behavioral Activation Therapy for Depression, a psychotherapy modality designed to increase engagement with rewarding stimuli and reduce avoidance behaviors. Primary-dependent measures included sensitivity to sucrose, hedonic response to sucrose, and designation as a Sweet-Liker or Sweet-Disliker. RESULTS: A total of 75% of adults with MDD were treatment responders. There were no significant differences in STT response profiles between groups overall or at either timepoint. Furthermore, STT profiles of MDD participants did not differ after psychotherapy, relative to baseline. CONCLUSIONS: Findings suggest that although anhedonia is a symptom of MDD, the disorder is not characterized by altered responses to sweet tastes. Implications and future directions are discussed.

Sweet liking and high novelty seeking: independent phenotypes associated with alcohol-related problems.

AIM: We tested the hypothesis that high novelty seeking (NS; a trait that promotes experimentation) and hedonic response to sweet taste (a trait that may reflect processing of hedonic stimuli) act independently to increase the risk for having alcohol-related problems in young adults. METHODS: The study was conducted in 158 healthy subjects (age 20-25 years) with no lifetime history of alcohol and/or drug abuse/dependence. NS was evaluated using the Tridimensional Personality Questionnaire. Pleasurable response to sweet taste was tested, using a sweet taste test to identify sweet likers (SL; those preferring the strongest offered sucrose solution) and sweet dislikers (SDL; those preferring weaker sucrose solutions). RESULTS: NS score, but not SL/SDL status, was positively correlated with drinks per month (P = 0.0054) and drinks per drinking day (P = 0.021). When tested individually, both NS and SL/SDL status predict having alcohol-related problems (NS: odds ratio [OR] = 5.3, P = 0.0016 and SL/SDL: OR = 5.8, P = 0.0001) with an OR similar to positive family history of alcoholism status (OR = 5.7, P = 0.0007). The combination of SL status and high NS score (greater than gender-specific 70th percentile) greatly increased the estimated odds of having alcohol-related problems (OR 27.5, P < 0.0001). CONCLUSIONS: These results support the hypothesis that high NS and SL phenotypes are independently associated with risk of alcohol-related problems. The combination of both phenotypes greatly increases the likelihood of alcohol-related problems. Although confirmation is necessary, this suggests that these phenotypes could contribute to improved methods to assess risk for alcohol-related problems and provide additional insight into processes underlying progression to alcohol-related problems.

The melanocortin system as a potential target for treating alcohol use disorders: A review of pre-clinical data.

The melanocortin (MC) system consists of neuropeptides that are cleaved from the polypeptide precursor proopiomelanocortin (POMC). In the brain, MC neuropeptides signal primarily through the MC-3 and MC-4 receptors, which are widely expressed throughout the brain. While the MC system has been largely studied for its role in food intake and body weight regulation, converging evidence has emerged over approximately the last 20-years showing that alcohol (ethanol), and other drugs of abuse influence the central MC system, and that manipulating MC receptor signalling modulates ethanol intake. Although there is divergent evidence, the wealth of data appears to suggest that activating MC signalling, primarily through the MC-4 receptor, is protective against excessive ethanol consumption. In the present review, we first describe the MC system and then detail how ethanol exposure and consumption alters central MC and MC-receptor expression and levels. This is followed by a review of the data, from pharmacological and genetic studies, which show that manipulations of MC receptor activity alter ethanol intake. We then briefly highlight studies implicating a role for the MC system in modulating neurobiological responses and intake of other drugs of abuse, including amphetamine, cocaine and opioids. Finally, we introduce relatively new observations that the drug, bupropion (BUP), a drug that activates central MC activity, significantly reduces ethanol intake in rodent models when administered alone and in combination with the non-selective opioid receptor antagonist, naltrexone. Phase II clinical trials are currently underway to assess the efficacy of BUP as a treatment for alcohol use disorders.

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.

Implementation of a Process for Initiating Naltrexone in Patients Hospitalized for Alcohol Detoxification or Withdrawal.

BACKGROUND: Naltrexone trials have demonstrated improved outcomes for patients with alcohol use disorders. Hospital initiation of naltrexone has had limited study. OBJECTIVE: To describe the implementation and impact of a process for counseling hospitalized patients with alcohol withdrawal about naltrexone. DESIGN: A pre-post study analysis. SETTING: A tertiary academic center. PATIENTS: Patients hospitalized for alcohol withdrawal. INTERVENTION: (1) Provider education about the efficacy and contraindications of naltrexone and (2) algorithms for evaluating patients for naltrexone. MEASUREMENTS: The percentages of patients counseled about and prescribed naltrexone before discharge and the percentages of pre- and postintervention patients with 30-day emergency department (ED) revisits and rehospitalizations. RESULTS: We identified 128 patient encounters before and 114 after implementation. The percentage of patients counseled about naltrexone rose from 1.6% preimplementation to 63.2% postimplementation (P<.001); the percentage of patients prescribed naltrexone rose from 1.6% to 28.1% (P<.001). Comparing preintervention versus postintervention groups, there were no unadjusted differences in 30-day ED revisits (25.8% vs 19.3%; P=.23) or rehospitalizations (10.2% vs 11.4%; P=.75). When adjusted for demographics and comorbidities, postintervention patients had lower odds of 30-day ED revisits (odds ratio [OR]=0.47; 95% confidence interval [CI], 0.24-0.94) but no significant difference in rehospitalizations (OR=0.76; 95% CI, 0.30-1.92). In subgroup analysis, postintervention patients counseled versus those not counseled about naltrexone were less likely to have 30-day ED revisits (9.7% vs 35.7%; P=.001) and rehospitalizations (2.8% vs 26.2%; P<.001). CONCLUSIONS: The implementation of a process for counseling patients hospitalized for alcohol withdrawal about using naltrexone for the maintenance of sobriety was associated with lower 30-day ED revisits but no statistically significant difference in rehospitalizations.

The Use of Baclofen as a Treatment for Alcohol Use Disorder: A Clinical Practice Perspective.

Alcohol use disorder (AUD) is a brain disorder associated with high rates of mortality and morbidity worldwide. Baclofen, a selective gamma-aminobutyric acid-B (GABA-B) receptor agonist, has emerged as a promising drug for AUD. The use of this drug remains controversial, in part due to uncertainty regarding dosing and efficacy, alongside concerns about safety. To date there have been 15 randomized controlled trials (RCTs) investigating the use of baclofen in AUD; three using doses over 100 mg/day. Two additional RCTs have been completed but have not yet been published. Most trials used fixed dosing of 30-80 mg/day. The other approach involved titration until the desired clinical effect was achieved, or unwanted effects emerged. The maintenance dose varies widely from 30 to more than 300 mg/day. Baclofen may be particularly advantageous in those with liver disease, due to its limited hepatic metabolism and safe profile in this population. Patients should be informed that the use of baclofen for AUD is as an "off-label" prescription, that no optimal fixed dose has been established, and that existing clinical evidence on efficacy is inconsistent. Baclofen therapy requires careful medical monitoring due to safety considerations, particularly at higher doses and in those with comorbid physical and/or psychiatric conditions. Baclofen is mostly used in some European countries and Australia, and in particular, for patients who have not benefitted from the currently used and approved medications for AUD.

Reduction in heavy drinking as a treatment outcome in alcohol dependence.

In the field of clinical alcohol disorders treatment in North America, abstinence continues to be largely viewed as the optimal treatment goal; however, there is a growing awareness of limitations when abstinence is considered the only successful outcome. Although this issue has been discussed in research settings, new studies on the public health significance of heavy drinking (defined as five or more standard drinks per drinking day in men, and four or more standard drinks per drinking day in women) in the past 10 years suggest that clinical providers should consider the value of alternative outcomes besides abstinence. A focus on abstinence as the primary outcome fails to capture the impact of treatment on reduction in the pattern and in the frequency of alcohol consumption. In addition, evaluating reduction in drinking as "positive" has value for patients as an indicator of clinical progress. Measurement of continuous variables, such as the quantity and the frequency of alcohol consumption, has provided a clearer understanding of the scope of alcohol-related morbidity and mortality at the societal level, and of the relationship between individual patient characteristics and the naturalistic course of alcohol use, abuse, and dependence. A review of these characteristics suggests that there are clinical benefits associated with reducing heavy drinking in alcohol-dependent patients. Given the significant public health consequences associated with heavy drinking and the benefits associated with its reduction, it is proposed that researchers, public health professionals, and clinicians consider using reduction in heavy drinking as a meaningful clinical indicator of treatment response, and that outcomes be individualized to patients' goals and readiness to change.