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.

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.

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.

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.

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.

Screening and Counseling for Unhealthy Alcohol Use in Primary Care Settings.

Unhealthy alcohol use is a leading causes of preventable death in the United States. Reducing unhealthy alcohol use should be a high priority for health care providers. Well-validated screening instruments are available, and behavioral counseling interventions delivered in primary care can reduce risky drinking. For people with alcohol use disorder, treatment programs with or without medication can reduce consumption and promote abstinence. To overcome barriers to implementation of screening for alcohol use and subsequent delivery of appropriate interventions in primary care settings, support systems, changes in staffing or roles, formal protocols, and additional provider and staff training may be required.

Association of the Sweet-Liking Phenotype and Craving for Alcohol With the Response to Naltrexone Treatment in Alcohol Dependence: A Randomized Clinical Trial.

IMPORTANCE: Identification of moderators of the response to naltrexone hydrochloride treatment for alcohol dependence could improve clinical care for patients with alcohol use disorders. OBJECTIVE: To investigate the preliminary finding that the sweet-liking (SL) phenotype interacts with a high level of craving for alcohol and is associated with an improved response to naltrexone in alcohol dependence. DESIGN, SETTING, AND PARTICIPANTS: This 12-week double-blind, randomized, placebo-controlled clinical trial was conducted from February 1, 2010, to April 30, 2012, in an academic outpatient medical center. Eighty actively drinking patients were randomized by the SL (n = 22) or the sweet-disliking (SDL) (n = 58) phenotype and by pretreatment high (n = 40) or low (n = 40) craving for alcohol, with high craving defined as greater than the median. Patients and staff were blinded to categorization. Patients were excluded for unstable medical or psychiatric illness, including dependence on drugs other than nicotine. Four patients (2 in the placebo arm and 2 in the naltrexone arm) stopped medication therapy because of adverse effects. Data were analyzed from January 15, 2013, to May 15, 2016, based on intention to treat. INTERVENTIONS: Oral naltrexone hydrochloride, 50 mg/d, or daily placebo with weekly to biweekly brief counseling. MAIN OUTCOMES AND MEASURES: The a priori hypothesis tested SL/SDL phenotype, pretreatment craving, and their interaction as moderators of frequency of abstinent and heavy drinking days during treatment, assessed with the timeline follow-back method. RESULTS: Eighty patients were randomized (57 men [71%]; 23 women [29%]; mean [SD] age, 47.0 [8.6] years). A nonsignificant effect of naltrexone on heavy drinking was noted (4.8 fewer heavy drinking days; Cohen d = 0.45; 95% CI, -0.01 to 0.90; F1,67 = 3.52; P = .07). The SL phenotype moderated the effect of naltrexone on heavy drinking (6.1 fewer heavy drinking days; Cohen d = 0.58; 95% CI, 0.12-1.03; F1,67 = 5.65; P = .02) and abstinence (10.0 more abstinent days; Cohen d = 0.57; 95% CI, 0.11-1.02; F1,67 = 5.36; P = .02), and high craving moderated heavy drinking (7.1 fewer heavy drinking days; Cohen d = 0.66; 95% CI, 0.20-1.11; F1,67 = 7.37; P = .008). The combination of the SL phenotype and high craving was associated with a strong response to naltrexone, with 17.1 fewer heavy drinking days (Cohen d = 1.07; 95% CI, 0.58-1.54; F1,67 = 19.33; P < .001) and 28.8 more abstinent days (Cohen d = 0.72; 95% CI, 0.25-1.17; F1,67 = 8.73; P = .004) compared with placebo. CONCLUSIONS AND RELEVANCE: The SL phenotype and a high craving for alcohol independently and particularly in combination are associated with a positive response to naltrexone. The SL/SDL phenotype and a high craving for alcohol merit further investigation as factors to identify patients with alcohol dependence who are responsive to naltrexone. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01296646.

Alcohol Use Disorder Treatment: The Association of Pretreatment Use and the Role of Drinking Goal.

BACKGROUND: In a recent study conducted in a family medicine setting, the medication acamprosate was found not to be efficacious in the treatment of alcohol dependence, but a drinking goal of abstinence was found to have positive effects on alcohol use outcomes. The purpose of this secondary analysis was to further understand which patients with an alcohol use disorder may be most successfully treated in a primary care setting. METHODS: The study was exploratory and used a trajectory-based approach based on data from the acamprosate treatment trial of 100 participants (recruited mostly by advertisement) who were randomly assigned to receive either acamprosate or a matching placebo. Post hoc trajectories of alcohol use before treatment were identified to examine whether trajectory classes and their interactions with treatment arm (acamprosate or placebo), pretreatment drinking goal (abstinence or a reduction), and time predicted alcohol use outcomes. RESULTS: Three distinct trajectory classes were identified: frequent drinkers, nearly daily drinkers, and consistent daily drinkers. Consistent daily drinkers with a goal of abstinence significantly improved over time on the primary outcome measure of percent days abstinent when compared with frequent and nearly daily drinkers. In addition, all participants with a goal of abstinence, regardless of trajectory class, significantly reduced their percentage of heavy drinking days over time. CONCLUSIONS: Patients with an alcohol use disorder who have a drinking goal of abstinence, in particular consistent daily drinkers, may maximally benefit from alcohol use disorder treatment, including the use of medication, in a primary care setting.

Genetic polymorphisms and response to medications for alcohol use disorders: a systematic review and meta-analysis.

AIM: To assess whether response to medications for alcohol use disorders varies by genotype. METHODS: Systematic review and meta-analysis. RESULTS: We found no studies that assessed the clinical utility of genotype-guided dosing strategies or genotype-guided medication selection, and none randomized by genotype. All included studies assessed the association between genotype and response to medication. Of 15 included studies, eight (n = 1365 participants) assessed variation in naltrexone response and polymorphisms of OPRM1. Our meta-analyses for return to heavy drinking found no significant difference between A allele homozygotes and those with at least one G allele, both without (risk difference: 0.26; 95% CI: -0.01-0.53; n = 174) and with inclusion of studies rated as high or unclear risk of bias (risk difference: 0.14; 95% CI: -0.03-0.3; n = 382). For all other polymorphism-medication pairs, we found just one eligible study. CONCLUSION: Estimates of effect for return to heavy drinking suggest it is possible that patients with at least one G allele of A118G polymorphism of OPRM1 might be more likely to respond to naltrexone, but confidence intervals were wide; additional studies are needed to improve confidence in the estimates.

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.

Clinical and biological moderators of response to naltrexone in alcohol dependence: a systematic review of the evidence.

AIM: The goal of this systematic review was to identify moderators of naltrexone efficacy in the treatment of alcohol dependence. METHODS: We searched Pubmed, CINHAL, Embase, PsycINFO and the Cochrane Library from 1990 to April 2012 and reference lists of pertinent review articles, which yielded 622 trial, pooled analysis and review articles. Using pre-established eligibility criteria, two reviewers independently determined whether abstracts contained evidence of demographic or biological characteristics, i.e. moderators, influencing naltrexone response in alcohol dependence. We assessed each publication for risk of bias and evaluated the strength of the body of evidence for each moderator. RESULTS: Twenty-eight publications (on 20 studies) met criteria for data synthesis. These included 26 publications from 12 randomized, placebo-controlled trials, three non-randomized, non-placebo studies and one randomized, non-placebo study. In addition, there were two publications from pooled analyses of four randomized, placebo-controlled trials. Family history of alcohol problems and the Asn40Asp polymorphism of the µ-opioid receptor gene showed a positive association with efficacy in four of five and three of five studies, respectively. Other moderators reported to be associated with efficacy included male sex (two of five studies), pre-treatment drinking (two of two studies) and high craving (two of five studies). However, the overall risk of bias in the published literature is high. CONCLUSIONS: The identification of naltrexone-responsive alcohol-dependent patients is still in development. Studies to date point to two potential moderators-family history and presence of the OPRM1 Asn40Asp polymorphism-as having the strongest evidence. However, the data to date is still insufficient to recommend that any moderator be used in determining clinical treatment.

Intact Hedonic Responses to Sweet Tastes in Autism Spectrum Disorder.

The Sweet Taste Test (STT) is a standardized measure designed to index the ability to detect differences in sweet tastes (sweet taste sensitivity) and hedonic responses to sweet tastes (sweet taste liking). Profiles of response on the STT suggest enhanced hedonic responses to sweet tastes in psychiatric disorders characterized by dysfunctional reward processing systems, including binge-eating disorders and substance use disorders, and a putative mechanism governing STT responses is the brain opioid system. The present study examined STT responses in 20 adults with autism spectrum disorder (ASD) and 38 healthy control adults. There were no differences in sweet taste sensitivity or hedonic response to sweet tastes between the ASD and control groups. Within the ASD sample, ASD symptom severity was associated with sweet taste sensitivity, but not hedonic response to sweet taste. Results may ultimately shed light on brain opioid system functioning in ASD.