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）是一个常见问题，会对健康造成严重后果。阿片类拮抗剂纳曲酮对治疗AD有效的发现是一个重要突破。然而，尽管临床证据表明一些患者对纳曲酮有良好的反应，但纳曲酮的总体治疗效果中等，这阻碍了其使用。与内源性阿片类药物系统不同方面的活性相关的三种标记物已被鉴定为对纳曲酮反应具有预测价值：1）5-阿片类受体基因的多态性； 2）有酗酒家族史； 3）对酒精的渴望的严重程度。然而，这些标记物的预测价值不大，表明需要确定新的方法来预测纳曲酮反应。本提案的主要目标是检验这样的假设：对甜味的享乐反应是一种新的标记，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）是一种与酗酒遗传风险相关的遗传特征，并且可能反映了内源性阿片类药物系统的综合测量。已鉴定出两种主要的 HRST 表型：喜欢甜食 (SL) 与偏爱高浓度甜食相关，以及不喜欢甜食 (SDL) 与偏爱较弱的甜味相关。在对 40 名 AD 患者（25 SDL、15 SL）进行的为期 12 周的开放标签试点研究中，我们评估了 HRST 对治疗结果的预测价值及其与对酒精的渴望（另一个标志物）的相互作用。与阿片类药物的功能有关。在接受纳曲酮之前，SL 参与者实现连续三天禁欲的时间比 SDL 个体长 30% (p=.02)。在治疗期间，SDL 个体的禁欲天数为 48%，而 SL 参与者的禁欲天数为 30% (p=0.034)。此外，SL 个体平均需要 44 天才能实现连续两天的禁欲，而 SDL 参与者则需要 4 天（Chi[1]=6.88，p<0.01）。通过 Penn 酒精渴望量表（Flannery 等，1999）评估，对甜味的反应和最初的酒精渴望的组合与治疗期间达到的戒酒天数显着相关（F[1,36]=13.94，p< 0.001) - 两种测量的组合预测禁欲天数的 26.2% 方差，而 SL/SDL 表型单独预测禁欲天数的 7%方差。这些发现表明，HRST 可能有助于区分对纳曲酮的反应，并且 HRST 和对酒精的渴望的结合可能提供附加信息来预测纳曲酮反应。为了确认和扩展这些初步发现，必须完成安慰剂对照纳曲酮试验。本提案将利用双盲、安慰剂对照试验，在足够数量的受试者中测试上述假设，平衡 SL/SDL 表型和渴望水平。确定哪些患者更有可能对纳曲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：确定酒精依赖纳曲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对大脑阿片类奖励系统的探索，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，以评估甜味偏好和对酒精的渴望如何相互作用以预测纳曲酮反应。