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

胍法辛可降低女性酒精使用障碍 (AUD) 复发风险

• 批准号: 9091802
• 负责人: Helen Cecilia Fox
• 金额: $ 18.78万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-14 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9091802
• 关键词: Abstinence; Adherence; Adrenergic Agents; Adrenergic Agonists; Adrenergic Receptor; Adverse effects; Alcohol abuse; Alcohol consumption; Anxiety; Appointment; Arousal; Attenuated; Behavior; Behavior Therapy; Biological; Biological Markers; Breathalyzer Tests; CRH gene; Characteristics; Clinical; Cognitive; Collection; Complex; Data; Development; Diagnosis; Disadvantaged; Disease; Dose; Double-Blind Method; Drug abuse; Effectiveness; Emotional; Exposure to; FDA approved; Gender; Glucuronides; Glutamates; Guanfacine; Health; Imagery; Impulsivity; Interview; Labor Forces; Laboratories; Laboratory Study; Lead; Link; Measures; Medical; Moods; Motivation; Norepinephrine; Outcome; Outcome Measure; Outpatients; Participant; Patient Self-Report; Pattern; Pharmaceutical Preparations; Pharmacology; Phase II Clinical Trials; Placebo Control; Placebos; Population; Process; Protocols documentation; Publishing; Randomized; Randomized Clinical Trials; Recovery; Recruitment Activity; Regulation; Relapse; Research; Rewards; Risk Factors; Safety; Socialization; Specificity; Stress; Symptoms; System; Time; Toxicology; Treatment outcome; Up-Regulation; Urine; Variant; Withdrawal; Withdrawal Symptom; Woman; alcohol abstinence; alcohol craving; alcohol effect; alcohol seeking behavior; alcohol use disorder; attenuation; biological adaptation to stress; cognitive control; cognitive enhancement; cognitive reappraisal; comparative; contingency management; craving; drinking; efficacy study; emotion regulation; experimental study; follow-up; improved; men; negative mood; pilot trial; postsynaptic; presynaptic; prevent; primary outcome; problem drinker; public health relevance; receptor; relapse risk; secondary outcome; sex; socioeconomics; stress reactivity; therapy development; treatment adherence; treatment trial

 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.

 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，但传统的性别差距正在迅速缩小，这是由于女性饮酒模式急剧上升，部分原因是劳动力中的社会经济收益。由于AUD的性别特异性风险因素使女性在临床健康结果方面处于相当不利的地位，这种酒精消费的急剧增加迫切需要制定专门针对女性的干预措施。有鉴于此， 我们的实验室已经表明，α 2肾上腺素能激动剂胍法辛减弱了酒精的负面强化作用，并增强了面对压力时的认知调节，与男性相比，这种作用在早期戒酒的女性中更明显。我们认为，这可能是由于交感神经敏感性的性别特异性变化。因此，我们提出了一个双盲，安慰剂对照，10周的随机临床试验，以检查胍法辛缓释（GXR，3 mg/日）在60名妇女与AUD的初步效果。治疗4周后（全剂量时）还将进行一项平行的2天实验研究，使用压力与中性意象暴露范式，以检查支持胍法辛疗效的压力相关主观和生物学变化标志物。将招募60名患有AUD的女性参加为期10周的GXR（3 mg/天）与安慰剂（PLA）的门诊试验。这将包括每周两次的预约，包括医疗管理和应急管理协议，尿液收集，呼气测醉器屏幕和生命体征。还将评估渴望和情绪的措施。保持禁欲4周的参与者将参加2次实验室挑战会议，在那里他们将暴露于个人压力与放松的图像条件，每天1种条件，以随机顺序。将在基线、成像后和不同恢复时间点评估渴望、焦虑、情绪、认知控制、HRBP和生物应激系统标记物。门诊结束后30天将进行随访。根据先前的研究，我们预计GXR在AUD女性患者中安全且耐受性良好（H1）;与PLA组相比，GXR组的戒断率和治疗依从性更高（主要结局指标）（H2 a），在门诊治疗期间（H2 b）和实验室压力暴露后（H3 a），戒断症状减轻程度更大，调节功能改善（次要结局指标）。我们还预计，实验室中与GXR相关的应激反应变化将预测改善的初级酒精使用结果（H3 b）。研究结果将有助于阐明独特的压力系统机制，支持在更大规模的随机临床试验中进一步评估之前，减少患有AUD的女性的饮酒。这对于开发对日益脆弱的饮酒者亚群的健康和福祉不可或缺的药物至关重要。