Sweet Preference and Alcohol Craving Predict Naltrexone Response in Alcoholism

甜食偏好和酒精渴望预测酒精中毒中的纳曲酮反应

• 批准号: 7904111
• 负责人: James C. Garbutt
• 金额: $ 21.98万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904111
• 关键词: Alcohol dependence; Alcoholism; Alcohols; Biological; Brain; Clinical; Communities; Data; Equilibrium; Exhibits; Family history of; Genetic Polymorphism; Goals; Health; Heavy Drinking; Individual; Measures; Medicine; Methods; Naltrexone; Narcotic Antagonists; Opioid; Opioid Receptor; Participant; Patients; Pharmacotherapy; Phenotype; Pilot Projects; Placebo Control; Placebos; Predictive Value; Randomized; Receptor Gene; Research; Rewards; Sampling; Severities; Sucrose; System; Testing; Treatment Efficacy; Treatment outcome; United States; alcohol craving; base; clinical care; craving; double-blind placebo controlled trial; endogenous opioids; genetics of alcoholism; hedonic; novel marker; open label; preference; problem drinker; public health relevance; response; secondary outcome; sweet taste perception; trait; treatment effect

DESCRIPTION (provided by applicant): Alcohol dependence (AD) is a common problem with significant health consequences. The discovery that the opioid antagonist naltrexone has efficacy for the treatment of AD was an important breakthrough. However, despite clinical evidence that some patients have an excellent response to naltrexone, the overall treatment effect of naltrexone is moderate and this has discouraged its use. Three markers associated with different aspects of activity of the endogenous opioid system have been identified as having predictive value for naltrexone response: 1) polymorphism of the 5-opioid receptor gene; 2) family history of alcoholism; 3) severity of craving for alcohol. However, the predictive value of these markers is modest pointing out the need to identify new methods to predict naltrexone response. The main goal of the present proposal is to test the hypothesis that the hedonic response to sweet taste is a novel marker that can help to identify which AD patients have robust responses to naltrexone. The hedonic response to sweet taste (HRST) is a heritable trait associated with genetic risk for alcoholism and one that likely reflects an integrative measure of the endogenous opioid system. Two principal HRST phenotypes have been identified-Sweet Liking (SL) associated with a preference for highly concentrated sweets and Sweet Disliking (SDL) associated with a preference for weaker sweet tastes. In a 12-week, open-label, pilot study of naltrexone (50 mg orally) in 40 AD patients (25 SDL, 15 SL) we evaluated the predictive value of HRST regarding treatment outcome and its interaction with craving for alcohol, another marker related to opioid function. Prior to receiving naltrexone, SL participants took 30% longer to achieve three consecutive abstinent days than SDL individuals (p=.02). During treatment, SDL individuals exhibited 48% days abstinent compared to 30% days abstinent for SL participants (p=0.034). Furthermore, SL individuals required a median of 44 days to achieve two consecutive abstinent days compared to 4 days for SDL participants (Chi[1]=6.88, p<0.01). A combination of response to sweet taste and initial alcohol craving as assessed by the Penn Alcohol Craving Scale (Flannery et al, 1999) was significantly associated with the amount of abstinent days attained during treatment (F[1,36]=13.94, p<0.001)-the combination of the two measures predicted 26.2% of the variance for % days abstinent whereas the SL/SDL phenotype alone predicted 7% of the variance. These findings indicate that HRST may help to differentiate response to naltrexone and that the combination of HRST and craving for alcohol may provide additive information to predict naltrexone response. To confirm and extend these preliminary findings it is essential that a placebo-controlled naltrexone trial be completed. The present proposal will test the above hypothesis utilizing a double-blind, placebo-controlled trial in an adequate number of subjects balanced for SL/SDL phenotype and level of craving. Identifying which patients are more likely to respond to naltrexone would be an important advance towards individualized pharmacotherapy for alcohol dependence. PUBLIC HEALTH RELEVANCE: The identification of predictors of naltrexone response in alcohol dependence is an important research objective to advance clinical care. The pleasurable response to sweet taste represents a probe of the brain opioid reward system that we have shown, along with craving for alcohol, to have predictive value for naltrexone response. In the proposed study, we will conduct a double-blind, placebo-controlled trial to assess how sweet preference and craving for alcohol interact to predict naltrexone response.

描述（由申请人提供）：酒精依赖（AD）是一种常见的问题，对健康有重大影响。阿片受体拮抗剂纳洛酮治疗AD的有效性的发现是一个重要的突破。然而，尽管临床证据表明，一些患者对纳洛酮有很好的反应，纳洛酮的总体治疗效果是中等的，这阻碍了其使用。与内源性阿片系统活性的不同方面相关的三种标志物已被鉴定为对纳洛酮反应具有预测价值：1）5-阿片受体基因的多态性; 2）酒精中毒家族史; 3）对酒精的渴望的严重程度。然而，这些标志物的预测价值是适度的，指出需要确定新的方法来预测纳洛酮的反应。本提案的主要目标是检验以下假设：对甜味的享乐反应是一种新的标志物，可以帮助识别哪些AD患者对纳洛酮具有稳健的反应。甜味快感反应（HRST）是一种与酒精中毒遗传风险相关的遗传性状，可能反映了内源性阿片系统的综合指标。两个主要的HRST表型已被确定-甜喜欢（SL）与高度集中的糖果和甜不喜欢（SDL）与偏好较弱的甜味。在40例AD患者（25例SDL，15例SL）中进行的为期12周的开放标签纳洛酮（50 mg口服）初步研究中，我们评估了HRST对治疗结果及其与酒精渴望（另一个与阿片功能相关的标志物）的相互作用的预测价值。在接受纳洛酮之前，SL参与者比SDL个体（p=.02）多花30%的时间来实现连续三天的禁欲。在治疗期间，SDL个体表现出48%的禁欲天数，而SL参与者的禁欲天数为30%（p=0.034）。此外，SL个体需要44天的中位数来实现连续两天的禁欲，而SDL参与者需要4天（Chi[1]=6.88，p<0.01）。根据Penn酒精渴望量表评估的对甜味和初始酒精渴望的反应组合（Flannery et al，1999）与治疗期间达到的禁欲天数显著相关（F[1，36]=13.94，p<0.001）-两种测量的组合预测%戒断天数的方差为26.2%，而SL/SDL表型单独预测7%。方差。这些结果表明，HRST可能有助于区分反应纳洛酮和HRST和酒精的渴望相结合，可以提供额外的信息来预测纳洛酮的反应。为了证实和扩展这些初步发现，必须完成安慰剂对照的纳洛酮试验。本提案将在足够数量的SL/SDL表型和渴望水平平衡的受试者中利用双盲、安慰剂对照试验来检验上述假设。确定哪些患者更有可能对纳洛酮产生反应将是酒精依赖个体化药物治疗的重要进展。 公共卫生相关性：确定酒精依赖患者纳洛酮反应的预测因子是推进临床护理的重要研究目标。对甜味的愉悦反应代表了大脑阿片类物质奖赏系统的一种探索，我们已经证明，沿着对酒精的渴望，对纳洛酮反应具有预测价值。在拟议的研究中，我们将进行一项双盲，安慰剂对照试验，以评估甜食偏好和对酒精的渴望如何相互作用，以预测纳洛酮的反应。