Oxytocin Treatment of Alcohol Dependence: A Randomized, Placebo-Controlled Trial

描述(申请人提供)：酒精依赖(AD)是世界范围内导致残疾、发病率和死亡率的主要原因。目前的治疗包括各种形式的心理社会治疗，以及最近的药物干预。然而，大多数AD患者不接受治疗，很少接受药物治疗，部分原因是FDA批准的药物疗效不高。人们普遍认为，治疗AD的新药需要开发出更有效的和/或具有新的活性谱的药物，例如抗焦虑特性。最近的许多人类研究发现，鼻腔给药催产素(OT)具有许多亲社会效应，并可减少焦虑。高剂量鼻腔注射催产素的临床试验长达8周，没有发现任何不良反应。多项研究表明，OT可能是治疗AD的有效方法。动物实验表明，OT阻止了对酒精的耐受形成，并显著减少了戒断症状。我们最近公布了一项随机、双盲试点研究的结果，这些受试者正在接受药物戒毒治疗，接受CIWA评分驱动的PRN劳拉西潘治疗。BID鼻腔注射OT在降低CIWA评分、完成戒毒所需的劳拉西潘总量和焦虑措施方面明显比安慰剂有效。我们的发现是OT治疗阻止人类戒酒的第一个证据。这一点具有临床重要性，因为苯二氮卓类药物对酒精戒断的标准治疗是有效的，但与催眠药不同的是，它可能保持高水平的镇静-催眠耐受性，通过维持酒精渴望、焦虑加剧、应对压力的能力减弱以及使人能够在复发时大量饮酒来增加复发的易感性。我们还发现，OT给药显著减少了反复酒精剥夺合并应激的P(酒精偏好)大鼠的酒精消耗量和焦虑，这是一种复发的动物模型。其他动物研究表明，OT具有很强的抗焦虑作用。这一证据表明，OT治疗可能通过减少焦虑、对压力的脆弱性以及可能的酒精耐受性来减少酒精依赖患者的饮酒。这项拟议的研究代表了一位在OT方面具有专业知识的基础行为神经学家(Cort Pedersen博士)和一位在进行临床试验方面具有丰富经验的AD治疗专家(JC Garbut博士)之间独特的翻译合作。我们提出了一项随机、双盲、安慰剂对照的试验，对50名酒精依赖患者进行鼻腔催产素治疗，从住院药物戒毒的早期开始，一直持续到出院后12周，期间将定期评估受试者的饮酒情况。该项目的总体目标是确定在酗酒者(在精神健康中心寻求药物戒毒的患者)的真实样本中进行OT治疗是否真正有效地减少戒断症状，并在门诊环境中减少饮酒。该项目有可能极大地促进AD的药物治疗。此外，证实OT可阻止酒精戒断，并证明OT可减少门诊环境中的饮酒、焦虑和渴望，这将是翻译研究的胜利，将使CNS OT成为AD病理生理学研究的重要新战线。

DESCRIPTION (provided by applicant): Alcohol dependence (AD) is a major cause of disability, morbidity and mortality world-wide. Current treatment involves various forms of psychosocial treatment and, more recently, pharmacological interventions. However, most patients with AD do not receive treatment and few receive medication, in part because of the modest efficacy of FDA- approved drugs. There is a general consensus that new medications for AD need to be developed that have greater effectiveness and/or new spectrums of activity, e.g. anxiolytic properties. Many recent human studies have found that intranasal administration of oxytocin (OT) has numerous prosocial effects and reduces anxiety. Clinical trials testing high dose intranasal OT for up to 8 weeks found no adverse effects. Several studies indicate that OT may be an effective treatment for AD. Animal experiments have shown that OT blocks tolerance formation to alcohol and markedly decreases withdrawal symptoms. We recently published the results of a randomized, double-blind pilot study in alcohol-dependent subjects undergoing medical detoxification with CIWA score-driven PRN lorazepam treatment. BID intranasal OT was dramatically more effective than placebo in decreasing CIWA scores, the total amount of lorazepam required to complete detoxification, and anxiety measures. Our findings are the first evidence that OT treatment blocks alcohol withdrawal in humans. This is of clinical importance as standard treatment of alcohol withdrawal with benzodiazepines is effective but, unlike OT, may maintain high levels of sedative- hypnotic tolerance that could increase vulnerability to relapse by sustaining alcohol craving, heightened anxiety and diminished ability to cope with stress as well as enabling consumption of large quantities of alcohol upon relapse. We also found that OT administration significantly decreased alcohol consumption and anxiety in P (alcohol-preferring) rats subjected to repeated alcohol deprivation combined with stress, an animal model of relapse. Other animal studies have shown that OT is potently anxiolytic. This evidence suggests that OT treatment may decrease drinking in alcohol- dependent patients by reducing anxiety, vulnerability to stress and perhaps alcohol tolerance. The proposed research represents a unique, translational collaboration between a basic behavioral neuroscientist with expertise in OT (Dr. Cort Pedersen) and an expert in the treatment of AD with extensive experience in conducting clinical trials (Dr. JC Garbutt). We propose a randomized, double-blind, placebo-controlled trial of intranasal OT treatment in 50 alcohol-dependent patients starting early during inpatient medical detoxification and extending for 12 weeks after discharge during which subjects' drinking will be assessed at regular intervals. The overall goal of the project is to determine whether OT treatment in a real world sample of heavy drinkers (patients seeking medical detoxification at a mental health center) is truly effective in decreasing withdrawal symptoms and, in the outpatient setting, reducing drinking. This project has potential to significantly advance the pharmacological treatment of AD. Also, confirming that OT blocks alcohol withdrawal and demonstrating that OT decreases drinking, anxiety, and craving in the outpatient setting would be a triumph of translational research that would establish CNS OT as an important new front for research on the pathophysiology of AD.