Sweet Preference and Alcohol Craving Predict Naltrexone Response in Alcoholism

描述(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。阿片类拮抗剂纳曲酮治疗阿尔茨海默病的发现是一项重要的突破。然而，尽管临床证据表明一些患者对纳曲酮有很好的反应，但纳曲酮的总体治疗效果是中等的，这阻碍了它的使用。与内源性阿片系统活动的不同方面相关的三个标志物已被确定为具有预测纳曲酮反应的价值：1)5-阿片受体基因的多态性；2)酒精中毒的家族史；3)对酒精的严重渴望。然而，这些标记物的预测价值不大，表明有必要确定新的方法来预测纳曲酮的疗效。本提案的主要目的是检验这样一种假设，即对甜味的享乐反应是一种新的标记物，可以帮助识别哪些AD患者对纳曲酮有强大的反应。对甜味的享乐反应(HRST)是一种与酒精中毒遗传风险相关的可遗传特征，可能反映了内源性阿片系统的综合衡量标准。已确定了两种主要的HRST表型--喜欢甜味(SL)与偏爱高浓度甜食有关，以及不喜欢甜味(SDL)与偏爱较弱的甜味有关。在一项为期12周的开放标签初步研究中，40名AD患者(25名SDL，15名SL)口服纳曲酮(50 Mg)，我们评估了HRST对治疗结果的预测价值及其与酒精渴求的相互作用，酒精渴求是另一个与阿片类药物功能相关的标记物。在服用纳曲酮之前，SL参与者实现连续三天戒酒所需的时间比SDL参与者多30%(p=0.02)。在治疗期间，SDL人禁欲天数为48%，而SL参与者的禁欲天数为30%(p=0.034)。此外，SL参与者实现连续两天禁欲所需的中位数为44天，而SDL参与者为4天(CHI[1]=6.88，p&lt；0.01)。由宾夕法尼亚大学酒精渴望量表(弗兰纳里等人，1999年)评估的对甜味和最初酒精渴望的反应与治疗期间获得的戒酒天数显著相关(F[1，36]=13.94p&lt；0.001)--这两项测量的组合预测了戒酒百分比天数的26.2%的变异，而SL/sdl表型单独预测了7%的变异。这些发现表明，HRST可能有助于区分纳曲酮的反应，HRST和酒精渴求的结合可能为预测纳曲酮的反应提供补充信息。为了证实和推广这些初步发现，必须完成一项安慰剂对照的纳曲酮试验。目前的建议将利用一项双盲、安慰剂对照试验，在足够数量的受试者中，平衡SL/SDL的表型和渴望程度，来检验上述假设。确定哪些患者更有可能对纳曲酮有反应，将是实现酒精依赖个体化药物治疗的重要进展。 公共卫生相关性：确定酒精依赖纳曲酮反应的预测因素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对大脑阿片类药物奖励系统的探测，我们已经证明，与对酒精的渴望一起，对纳曲酮反应具有预测价值。在这项拟议的研究中，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来预测纳曲酮的反应。

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.