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有很高的共同发病率。酒精依赖吸烟者表现出与烟草相关的死亡和发病率增加的风险，与吸烟相关的疾病是酗酒者死亡的主要原因。因此，当我们治疗酗酒者时，有必要考虑吸烟。目前，还没有批准的药物能够减少酒精和尼古丁共同依赖的个人饮酒和吸烟。因此，该领域迫切需要确定可能有效治疗这两种依赖的药物。最近的研究证据表明，GABAB受体参与了成瘾的神经生物学。人体研究表明，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，巴氯芬显示了有效性和安全性，即使在严重患病的人群中使用巴氯芬时也是如此。此外，最近在非酒精者中进行的一项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，这表明巴氯芬在戒烟方面是有用的。这些结果使人们得出结论，巴氯芬有可能成为治疗吸烟的酒精依赖患者的一种新的药物治疗干预措施，尽管这方面从未得到正式调查。基于这一背景，莱吉奥博士获得了“ABMRF/酒精研究基金会”的资助，进行了一项为期12周的双盲、安慰剂对照的受试者间治疗研究，以调查巴氯芬(80 mg/d)在减少酒精依赖、重度饮酒者的酒精和香烟消费方面的双重作用，这些人目前也符合DSM-IV的尼古丁依赖标准。该研究的主要目的是调查与安慰剂相比，巴氯芬是否减少了酗酒天数的百分比，并增加了酒精戒断(累积戒酒持续时间)；与安慰剂相比，巴氯芬是否减少了每天的香烟数量，增加了戒烟(累积戒烟持续时间)。目前的建议与现行RFA SOAR-R03的目标一致，目的是补充新的调查人员/早期调查人员，这些调查人员承诺支持从NIH以外的资金来源(例如私人基金会)进行临床酒精研究。目前的R03 SOAR包括一个子研究，它将允许在ABMRF资助的母公司研究中增加实验室生物行为成分。虽然家长资助的研究将在12周的自然主义时期比较巴氯芬和安慰剂对酒精和香烟消费的有效性，但目前R03飙升的目标是提供有关巴氯芬在接触非酒精(中性)和酒精暗示后如何影响饮酒和吸烟冲动的生物行为机制的信息。具体地说，R03 SOAR子研究项目将是一项为期1天的双盲、安慰剂对照、受试者之间的随机线索反应性(CR)实验，使用巴氯芬(80 mg/d)，在父研究中那些酒精依赖尼古丁依赖的参与者中进行。在实验中，饮酒和吸烟的冲动将在接触到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气味以及心理生理反应(心率、平均动脉压和唾液变化)的注意力。本实验的总体目标是探索巴氯芬在暴露于酒精线索后如何影响饮酒和吸烟冲动的生物行为机制。 与公共卫生相关：酒精使用障碍每年造成10万人额外死亡。酒精依赖吸烟者表现出与烟草相关的死亡和发病率增加的风险，与吸烟相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。这项研究的目的是探索巴氯芬如何影响酗酒吸烟者饮酒和吸烟冲动的生物行为机制。这种知识的增长可能会导致对酗酒吸烟者进行更有效的药物治疗。

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.