Effect of Baclofen on Alcohol Cue-Elicited Urges to Drink and Smoke

描述（由申请人提供）：酒精和尼古丁依赖之间存在较高的共病率。酒精依赖性吸烟者与烟草相关的死亡率和发病率风险增加，而与吸烟相关的疾病是酗酒者死亡的主要原因。因此，我们在治疗酗酒者时，非常需要考虑吸烟。目前，没有批准的药物能够减少酒精和尼古丁共同依赖者的饮酒和吸烟。因此，该领域迫切需要确定可能有效治疗两种依赖性的药物。 最近的研究证据表明GABAB受体参与成瘾的神经生物学。人类研究表明，选择性GABAB受体激动剂巴氯芬可以减少酒精渴望和摄入量。有趣的是，巴氯芬显示出有效性和安全性，即使在严重患病人群-酒精依赖性肝硬化患者中也是如此。此外，最近在非酗酒者中进行的双盲安慰剂对照试验也表明，巴氯芬减少了每天吸烟的数量和对香烟的渴望，表明巴氯芬在戒烟中的效用。这些结果使人得出结论，巴氯芬有可能成为一种新的药物治疗干预治疗酒精依赖患者吸烟，虽然这方面从来没有正式调查。 基于这一背景，Leggio博士获得了“ABMRF/酒精研究基金会”的资助，进行了一项为期12周的双盲、安慰剂对照受试者间治疗研究，以研究巴氯芬（80 mg/d）在减少酒精依赖、重度饮酒个体（也符合DSM-IV当前尼古丁依赖标准）的酒精和香烟消费方面的双重作用。该研究的主要目的是调查巴氯芬与安慰剂相比是否减少了大量饮酒天数的百分比并增加了戒酒（累积戒酒持续时间）;以及巴氯芬与安慰剂相比是否减少了每天吸烟的数量并增加了戒烟（累积戒烟持续时间）。 本提案与当前RFA SOAR-R 03的目标一致，以补充新的研究者/早期研究者，他们承诺支持从NIH以外的资金来源（例如私人基金会）开展临床酒精研究。当前R 03 SOAR由一项子研究组成，该子研究将允许在ABMRF资助的母研究中添加实验室生物行为部分。虽然父母资助的研究将在12周的自然时期内比较巴氯芬与安慰剂对酒精和香烟消费的疗效，但本R 03 SOAR的目标是提供关于巴氯芬如何影响暴露于非酒精（中性）与酒精线索后饮酒和吸烟欲望的生物行为机制的信息。具体而言，本R 03 SOAR子研究项目将是一项在母研究的酒精依赖尼古丁依赖受试者中进行的巴氯芬（80 mg/d）1天双盲、安慰剂对照、受试者间随机线索反应性（CR）实验。在实验过程中，饮酒和吸烟的冲动将在暴露于非酒精和酒精线索后进行评估。在CR实验期间，还将评估对线索的视觉和嗅觉的注意力以及心理生理反应（心率、平均动脉压和唾液分泌变化）。本实验的总体目标是探索巴氯芬如何影响酒精刺激后饮酒和吸烟的生物行为机制。 公共卫生相关性：酒精使用障碍每年造成10万人死亡。依赖酒精的吸烟者与烟草有关的死亡率和发病率风险增加，与吸烟有关的疾病是酗酒者死亡的主要原因。减少酒精和尼古丁依赖的干预措施可能会对公共卫生产生重要影响。本研究的目的是探讨巴氯芬如何影响酒精吸烟者饮酒和吸烟冲动的生物行为机制。这种知识的获得可能会导致对酒精吸烟者更有效的药物治疗。

DESCRIPTION (provided by applicant): There is a high co-morbidity between alcohol and nicotine dependence. Alcohol-dependent smokers show an increased risk of tobacco-related mortality and morbidity, and smoking-related illnesses are the leading cause of death among alcoholics. Therefore, there is a crucial need to consider smoking when we treat alcoholics. Currently, there are no approved medications able to reduce both alcohol drinking and smoking in individuals with alcohol and nicotine co-dependencies. Therefore, there is a critical need in the field to identify medications that may be effective in treating both dependencies. Recent research evidence suggests the involvement of the GABAB receptor in the neurobiology of addictions. Human studies have shown that the selective GABAB receptor agonist baclofen reduces alcohol craving and intake. Interestingly, baclofen showed efficacy and a safe profile even when administered to a severely ill population - alcohol dependent patients with cirrhosis. Moreover, a recent double-blind placebo- controlled trial in non-alcoholics also indicated that baclofen reduced the number of cigarettes smoked per day and cigarette craving, suggesting the utility of baclofen in smoking cessation. These results lead one to conclude that baclofen has the potential to be a new pharmacotherapy intervention for the treatment of alcohol dependent patients who smoke, though this aspect has never been formally investigated. Based on this background, Dr. Leggio received a grant from the 'ABMRF/The Foundation for Alcohol Research' to perform a 12-week double-blind, placebo-controlled between-subject treatment study to investigate the dual roles of baclofen (80mg/d) in reducing alcohol and cigarette consumption in alcohol- dependent, heavy-drinking individuals who also satisfy DSM-IV criteria for current nicotine dependence. The primary aims of that study are to investigate whether baclofen, as compared to placebo, reduces the percentage of heavy drinking days and increases alcohol abstinence (cumulative alcohol abstinence duration); and whether baclofen, as compared to placebo, reduces the number of cigarettes per day and increases smoking abstinence (cumulative smoking abstinence duration). The present proposal is consistent with the goals of the present RFA SOAR-R03 to supplement new investigators/early stage investigators who have a commitment of support to conduct research in clinical alcohol research from funding sources other than NIH (e.g. private foundation). The present R03 SOAR consists of a sub-study, which will allow adding a laboratory biobehavioral component to the parent ABMRF- funded study. While the parent funded study will compare the efficacy of baclofen to placebo on alcohol and cigarette consumption during a 12-week naturalistic period, the goal of the present R03 SOAR is to provide information on the biobehavioral mechanisms of how baclofen affects urges to drink and smoke after exposure to nonalcoholic (neutral) vs. alcoholic cues. Specifically, this R03 SOAR sub-study project will be a 1-day double-blind, placebo-controlled, between-subject randomized cue-reactivity (CR) experiment with baclofen (80mg/d) conducted in those alcohol-dependent nicotine-dependent participants of the parent study. During the experiment, urges to drink and to smoke will be assessed after exposure to nonalcoholic and alcoholic cues. Attention to the sight and smell of cues and psychophysiological responses (heart rate, mean arterial pressure and salivation changes) will also be assessed during the CR experiment. The overall goal of this experiment is to explore the biobehavioral mechanisms how baclofen affects urges to drink and smoke after the exposure to alcoholic cues. PUBLIC HEALTH RELEVANCE: Alcohol use disorders account for 100,000 excess deaths per year. Alcohol-dependent smokers show an increased risk of tobacco-related mortality and morbidity, and smoking-related illnesses represent the leading cause of death among alcoholics. Interventions that reduce both alcohol and nicotine dependence may have important public health implications. The goal of this research is to explore the biobehavioral mechanisms of how baclofen affects urges to drink and smoke in alcoholic smokers. This gain in knowledge may lead to more effective pharmacological treatments for alcoholic smokers.