Guanfacine to reduce relapse risk in women with alcohol use disorder (AUD)

 描述(由申请人提供)：美国约有570万女性符合酒精使用障碍(AUD)标准。虽然这一数字仍然明显低于男性，但由于女性饮酒模式的急剧上升，传统的性别差距正在迅速缩小，部分原因是劳动力中的社会经济收益。由于AUD的性别风险因素使妇女在临床健康结果方面处于相当不利的地位，酒精消费的急剧增加迫切需要制定专门针对妇女的干预措施。有鉴于此，来自 我们的实验室已经证明，α2肾上腺素能激动剂Ganfacine可以减弱酒精的负面强化效应，并在面对压力时增强认知调节，与男性相比，早期戒酒的女性优先使用这种药物。我们认为这可能是由于不同性别的交感敏感度不同造成的。因此，我们提出了一项双盲、安慰剂对照、为期10周的随机临床试验，以检查60名患有AUD的女性服用金刚烷缓释剂(GXR，每天3毫克)的初步效果。在4周的治疗(全量)后，还将进行一项平行的为期两天的实验研究，使用应激和中性图像暴露范式，以检查支持胍法辛疗效的与应激相关的主观和生物标记物的变化。60名患有AUD的女性将被招募参加为期10周的门诊试验，分别服用GXR(每天3毫克)和安慰剂(解放军)。这将包括每周两次的预约，包括医疗管理和应急管理方案、尿液收集、呼气分析筛查和生命体征。此外，还将评估对欲望和情绪的测量。保持禁欲4周的参与者将参加两次实验室挑战会议，在那里他们将以随机顺序每天暴露在个人压力和放松的想象条件下。渴望、焦虑、情绪、认知控制、心率血压和生物应激系统标记物将在基线、成像后和不同的恢复时间点进行评估。门诊结束后30天内将进行后续访谈。根据先前的研究，我们预计GXR对患有AUD的女性(H1)将是安全和耐受性良好的；与解放军组相比(主要结果指标)(H2A)，GXR导致更多的戒断和治疗依从性，以及在门诊治疗(H2B)期间和在实验室应激暴露后(H3a)，更大程度地缓解戒断症状和改善调节功能(次要结果指标)。我们还预计，实验室中与GXR相关的应激反应变化将预测初次饮酒结果的改善(H3B)。这些发现将有助于阐明支持AUD女性饮酒减少的独特压力系统机制，然后在更大规模的随机临床试验中进行进一步评估。这对于开发对日益脆弱的饮酒者亚群体的健康和福祉不可或缺的药物至关重要。

 DESCRIPTION (provided by applicant): Approximately 5.7 million women in the US meet criteria alcohol use disorder (AUD). While this figure remains significantly lower than men, the traditional gender gap is rapidly converging as a result of sharp elevations in women drinking patterns due, in part, to socioeconomic gains within the labor force. As gender- specific risk factors for AUD place women at a considerable disadvantage in terms of clinical health outcomes, this sharp increase in alcohol consumption urgently necessitates the development of interventions that have been specifically tailored to women. In view of this, preliminary data from our laboratory has shown that the alpha2 adrenergic agonist, guanfacine, attenuates the negative reinforcing effects of alcohol and enhances cognitive regulation in the face of stress, preferentially in early abstinent women compared with men. We suggest that this may be due to gender-specific variation in sympathetic sensitivity. Thus, we propose a double blind, placebo-controlled, 10-week randomized clinical trial to examine the preliminary effects of guanfacine extended release (GXR, 3mgs/daily) in 60 women with AUD. A parallel 2-day experimental study using a stress versus neutral imagery exposure paradigm will also be conducted following 4 weeks of treatment (when at full dose), to examine the stress-related subjective and biological markers of change underpinning guanfacine's efficacy. Sixty women with AUD will be recruited to take part in the 10-week outpatient trial for GXR (3mgs/daily) versus placebo (PLA). This will include twice weekly appointments comprising medical management and contingency management protocols, collection of urine, breathalyzer screens, and vitals. Measures of craving and mood will also be assessed. Participants who maintain abstinence for 4 weeks will take part in 2 laboratory challenge sessions, where they will be exposed to a personal stress versus relaxing imagery condition, 1 condition per day, in a randomized order. Craving, anxiety, mood, cognitive control, HRBP, and biological stress system markers will be assessed at baseline, following imagery and at various recovery time- points. A follow-up interview will be conducted 30 days following outpatient completion. In view of prior research, we anticipate that GXR will be safe and well tolerated in women with AUD (H1); lead to greater abstinence and treatment adherence compared with the PLA group (primary outcome measures) (H2a) as well as greater attenuation of withdrawal symptoms and improved regulatory function (secondary outcome measures) both during outpatient treatment (H2b) and following stress exposure in the laboratory (H3a). We also anticipate that GXR-related changes to stress response in the laboratory will predict improved primary alcohol use outcomes (H3b). Findings will help to elucidate unique stress-system mechanisms which support attenuation of drinking in women with AUD prior to further assessment in larger randomized clinical trials. This is of paramount importance to developing medications that are integral to the health and well-being of an increasingly vulnerable sub-population of drinkers.