Sweet Preference and Alcohol Craving Predict Naltrexone Response in Alcoholism

描述（由申请人提供）：酒精依赖（AD）是一种具有重大健康后果的常见问题。阿片拮抗剂纳曲酮治疗阿尔茨海默病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曲酮有很好的反应，但纳曲酮的总体治疗效果一般，这阻碍了它的使用。与内源性阿片系统活性的不同方面相关的三个标记物已被确定为对纳曲酮反应具有预测价值：1)5-阿片受体基因多态性；2)酗酒家族史；3)对酒精的渴望程度。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曲酮的反应。本研究的主要目的是验证一种假设，即甜味的快感反应是一种新的标志物，可以帮助识别哪些AD患者对纳曲酮有强烈的反应。对甜味的享乐反应（HRST）是一种与酒精中毒遗传风险相关的遗传特征，可能反映了内源性阿片系统的综合测量。已经确定了两种主要的HRST表型——喜欢甜味（SL）与对高度浓缩的甜味的偏好有关，不喜欢甜味（SDL）与对较弱甜味的偏好有关。在一项对40例AD患者（25例SDL， 15例SL）口服纳曲酮（50 mg口服）的12周开放试验中，我们评估了HRST对治疗结果的预测价值及其与渴望酒精（另一个与阿片类功能相关的标志物）的相互作用。在接受纳曲酮治疗之前，SL参与者比SDL参与者花了30%的时间来实现连续三天的戒断（p= 0.02）。在治疗期间，SDL个体表现出48%的禁欲天，而SL参与者表现出30%的禁欲天（p=0.034）。此外，与SDL参与者的4天相比，SL个体需要44天才能实现连续两天的戒断（Chi[1]=6.88, p<0.01）。Penn酒精渴望量表（Flannery et al, 1999）评估的甜味反应和最初的酒精渴望的组合与治疗期间获得的戒断天数显著相关(F[1,36]=13.94, p<0.001)-两个测量的组合预测了%戒断天数的26.2%的方差，而SL/SDL表型单独预测了7%的方差。这些发现表明，HRST可能有助于区分对纳曲酮的反应，HRST和对酒精的渴望的结合可能为预测纳曲酮的反应提供附加信息。为了证实和扩展这些初步发现，有必要完成一项安慰剂对照纳曲酮试验。本研究将利用一项双盲、安慰剂对照试验来检验上述假设，在足够数量的受试者中平衡SL/SDL表型和渴望水平。确定哪些患者更可能对纳曲酮有反应，将是酒精依赖个体化药物治疗的重要进展。

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.