Use of a GLP-1 Agonist to Treat Opioid Use Disorder in Rats and Man

项目总结： 阿片类药物滥用是一种慢性复发性疾病，是一个重大的、不断升级的公共卫生问题。2017年， 美国有70,237人死于药物过量；其中67.8%涉及阿片类药物。 尽管有批准的药物(美沙酮、丁丙诺啡/纳洛酮、纳曲酮)和前景看好 治疗干预，高复发率(3个月复发率50%，一年复发率65%-70%)表明 需要更好地了解导致阿片类药物复吸的因素，以及发展 新的治疗方法。已知有几个因素导致了这种疾病的复发， 包括(但不限于)渴望、睡眠障碍、降低压力耐受性和负面影响。沉睡 在大多数物质使用障碍综合征中，问题是一种常见且未得到治疗的症状，包括 阿片使用障碍(OUD)。研究表明，睡眠问题在以下人群中普遍存在 患者早期治疗阿片类药物使用障碍(OUD)高于一般人群。然而，标准是 用于治疗睡眠障碍的催眠药物不能用于OUD患者，因为它们会上瘾 属性。事实上，因为他们在阿片受体系统上工作，这两种最常用的 乌德、美沙酮和丁丙诺啡的药物可能会扰乱睡眠。然而，一种新的药物是 正在进行研究，这可能会减少渴望，同时改善OUD患者的睡眠。在一个 正在进行的临床试验中，研究人员正在评估通过以下方式减少人群饥饿感的潜力 刺激高血糖素样多肽-1受体(GLP-1R)的“饱腹感”途径。GLP-1R途径的激活 已被证明不仅能抑制可口糖果的摄取，还能减少对酒精的反应， 尼古丁，可卡因，现在，来自我们实验室的海洛因，在大鼠和小鼠身上。FDA批准的药物， 利拉鲁肽目前被批准用于治疗人类II型糖尿病和肥胖。这样做的目的是 一项补充研究是增加多导睡眠图，这是评估睡眠结构的黄金标准 正在进行的研究。将40名住院治疗的男性和女性随机分成一组， 一项双盲、安慰剂对照研究，以确定每天一次GLP-1R激动剂治疗， 利拉鲁肽可以安全有效地减少渴求和大脑对药物线索的反应，同时改善他们的 总睡眠时间和他们慢波睡眠的百分比。所有患者都将接受程序性治疗 咨询；患者将被允许选择服用丁丙诺啡。将进行多导睡眠图测试 在他们开始服用利拉鲁肽之前，以及在服药30天后，当他们达到全部剂量时再次服用。分析 将评估总睡眠和慢波睡眠的变化，以及睡眠改善是否与 减少渴望和大脑对药物线索的反应。如果我们的假设得到支持，这些数据将显示 GLP-1R激动剂的治疗可以安全有效地减少阿片类药物的渴望，同时也可以改善 睡眠，在人类中，提供了一个全面的多点，第三阶段临床试验的适应症。

Project Summary: Opioid abuse, a disorder of chronic relapse, is a significant and escalating public health concern. In 2017, 70,237 people the United States died from a drug overdose; opioids were involved in 67.8% of these deaths. Despite having approved medications (methadone, buprenorphine/naloxone, naltrexone) and promising therapeutic interventions, the high rates of relapse (50% at 3 months, 65%-70% at one year) indicate a critical need for a better understanding of the factors that contribute to relapse to opioids, and for the development of new approaches to treatment. Several factors are known to contribute to the relapsing nature of this disease, including (but not limited to) craving, sleep disturbances, reduce stress tolerance, and negative affect. Sleep problems are a common – and undertreated – symptom in most substance use disorder syndromes, including opioid use disorders (OUD). Research shows that sleep problems are 8-9 times more prevalent among patients in early treatment for opioid use disorders (OUD) than the general population. However, the standard hypnotic medications used to treat sleep disorders cannot be used in OUD patients because of their addictive properties. Indeed, because they work on the opioid receptor system, the two most commonly used medications for OUD, methadone and buprenorphine, may disrupt sleep. However, a novel medication is being investigated that may allow the reduction of craving while improving sleep in OUD patients. In an ongoing clinical trial, the investigators are evaluating the potential to reduce craving in an OUD population by stimulating a glucagon-like peptide-1 receptor (GLP-1R) ‘satiety’ pathway. Activation of the GLP-1R pathway has been shown to inhibit not only the ingestion of palatable sweets, but also reduce responding for alcohol, nicotine, cocaine, and, now, from our laboratory, heroin, in rats and mice. The FDA-approved medication, liraglutide, is currently approved to treat Type II diabetes milletus and obesity in humans. The purpose of this supplemental study is to add polysomnography, the gold-standard for evaluating sleep architecture, to this ongoing study. Forty men and women in residential treatment for OUD will be recruited into a randomized, double blind, placebo-controlled study to determine whether once daily treatment with the GLP-1R agonist, liraglutide, can safely and effectively reduce craving and brain responses to drug cues, while improving their total sleep time and their percentage of slow wave sleep. All patients will be receiving programmatic counseling; patients will be allowed to elect to be on buprenorphine. Polysomnography tests will be conducted before they begin liraglutide, and again after 30 days of medication, when they are up to full dosage. Analyses will evaluate changes in total sleep and slow wave sleep, and whether improved sleep is associated with reduction of craving and brain responses to drug cues. If our hypotheses are supported, these data will show that treatment with GLP-1R agonists can safely and effectively reduce opioid craving, while also improving sleep, in humans, providing an indication for full multi-site, Phase III clinical trial.