de Bejczy Andrea, Löf Elin, Walther Lisa, Guterstam Joar, Hammarberg Anders, Asanovska Gulber, Franck Johan, Isaksson Anders, Söderpalm Bo
Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Beroendekliniken, Sahlgrenska University Hospital, Gothenburg, Sweden.
Alcohol Clin Exp Res. 2015 Nov;39(11):2189-99. doi: 10.1111/acer.12854. Epub 2015 Sep 28.
Alcohol dependence is a devastating illness affecting a large population, and new pharmacological treatments with good efficacy are greatly needed. One potential candidate is varenicline, a smoking cessation agent with partial agonist action at α4 β2 nicotinic acetylcholine receptors.
A total of 160 subjects, 30 to 70 years of age, fulfilling DSM-IV criteria for alcohol dependence without any serious physical or mental disorders, were recruited through advertisement at 3 university clinics in Sweden during March 2009 to January 2011. After a 2-week placebo run-in period, subjects received 2 mg varenicline daily (titrated from 0.5 mg during first week) or placebo for 12 weeks in a double-blind manner.
The primary outcome was the proportion of heavy drinking days, measured by self-reported alcohol consumption. Primary and secondary outcomes were calculated as a mean over the 10-week steady-state active treatment period. In the primary outcome analysis, no effect of varenicline over placebo was found (p = 0.73 for the intention to treat [ITT] and 0.92 for per protocol [PP]). Secondary outcome analysis found a significant reduction of specific alcohol marker phosphatidylethanol (PEth) in the blood in the varenicline group compared to placebo (p = 0.02 ITT). Craving (p = 0.048 PP) and Alcohol Use Disorders Identification Test (AUDIT) scores (p = 0.015 ITT) were also reduced in the active treatment group. PEth more strongly correlated with self-reported alcohol consumption than carbohydrate-deficient ttransferrin and γ-glutamyl transferase, and correlation coefficients were higher in the varenicline group than in the placebo group for all markers.
Although the results of the main outcome of this study did not support an effect of varenicline in alcohol-dependent individuals, the secondary analyses of PEth, craving and AUDIT score support an effect of varenicline on alcohol consumption. The disclosure of a treatment effect and the lack of a clear placebo effect when using PEth as outcome variable, together with a nonsymmetric bias associated with self-reported data, strongly argue for using the specific biomarker PEth in studies of treatments of alcohol dependence.
酒精依赖是一种影响大量人群的毁灭性疾病，非常需要疗效良好的新药物治疗方法。一种潜在的候选药物是伐尼克兰，它是一种戒烟药物，对α4β2烟碱型乙酰胆碱受体具有部分激动作用。
2009年3月至2011年1月期间，通过在瑞典3所大学诊所发布广告，招募了160名年龄在30至70岁之间、符合DSM-IV酒精依赖标准且无任何严重身心障碍的受试者。经过2周的安慰剂导入期后，受试者以双盲方式接受每日2毫克伐尼克兰（第一周从0.5毫克滴定）或安慰剂治疗12周。
主要结局是通过自我报告的酒精摄入量来衡量的重度饮酒天数比例。主要和次要结局计算为10周稳态积极治疗期的平均值。在主要结局分析中，未发现伐尼克兰相对于安慰剂有效果（意向性分析[ITT]的p值为0.73，符合方案分析[PP]的p值为0.92）。次要结局分析发现，与安慰剂相比，伐尼克兰组血液中特定酒精标志物磷脂酰乙醇（PEth）显著降低（ITT的p值为0.02）。积极治疗组的渴望程度（PP的p值为0.048）和酒精使用障碍识别测试（AUDIT）得分（ITT的p值为0.015）也有所降低。与缺糖转铁蛋白和γ-谷氨酰转移酶相比，PEth与自我报告的酒精摄入量的相关性更强，并且所有标志物在伐尼克兰组中的相关系数均高于安慰剂组。
尽管本研究的主要结局结果不支持伐尼克兰对酒精依赖个体有效果，但对PEth、渴望程度和AUDIT得分的次要分析支持伐尼克兰对酒精消费有效果。当将PEth作为结局变量时，治疗效果的显现以及缺乏明确的安慰剂效应，再加上与自我报告数据相关的不对称偏差，有力地支持在酒精依赖治疗研究中使用特定生物标志物PEth。
