Prevention of neonatal opioid withdrawal syndrome

摘要 美国阿片类药物滥用引发的公共健康问题对孕妇和 他们的孩子。新生儿禁欲综合征(NAS)的发生率，这是一种麻醉剂 依赖毒品的母亲所生婴儿出现的戒毒症状急剧上升。 治疗患有NAS的婴儿通常需要延长住院时间和长期服用阿片类药物 含有可能影响婴儿发育的药物。尽管它作为一个非常昂贵的公众出现了 健康问题，NAS没有预防性的治疗方法。以前和当前的NAS研究计划 一般情况下，探索用于治疗已确诊的NAS婴儿的麻醉药物剂量或类型的变化。 这项研究的第一个目标是完成一项临床试验，测试一种预防NAS的新方法。基座 在基因发现的基础上，我们证明了5-HT3拮抗剂(恩丹西酮)的使用可以预防 在小鼠和成人身上进行的实验研究中的麻醉药物戒断症状。从这一点上，我们 假设恩丹西酮对患有阿片类药物使用障碍(OUD)的孕妇在 分娩后给新生儿短暂服用恩丹西酮可以降低发病率或 NAS的严重性。恩丹西酮是一种广泛使用的药物，在孕妇和 婴儿。因此，我们将完成一项多中心、随机、双盲和安慰剂对照试验，以 确定昂丹西酮治疗是否会降低发病率(婴儿需要 NAS的药物治疗)或严重程度(使用阿片类药物的总量、住院时间、NAS OUD母亲所生婴儿的NAS症状严重程度评分)。这是唯一一项测试小说的研究 而且通常是无害的治疗，可以预防NAS。如果恩丹西酮的短暂任期能够 阻止重大NAS的发展，这将提供一种迫切需要的预防性治疗， 这将减少人类的痛苦和与阿片剂滥用相关的日益增长的社会成本。 这项研究的第二个目的是开发一种创新的新方法[毛细管微采样，(CMS)]，它 使用非常小的血量(8微升)来准确测量新生儿的药物水平。我们已经修改了这个 方法，使其能够在新生儿护理环境中使用。用优化的CMS方法得到的结果 (ISO-CMS)将在临床环境中通过确定ISO-CMS结果是否准确地反映 同时测定成人受试者的恩丹西酮血药浓度。然后我们将使用iso- CMS测量研究新生儿的恩丹西酮水平。我们还将演示iso-CMS可以 可靠地测量至少5种其他药物的浓度。这一创新的新方法将使 治疗指数较窄的新生儿需调整给药方案。

Abstract The public health problem caused by opiate abuse in the US has had consequences for pregnant women and their babies. The incidence of the neonatal abstinence syndrome (NAS), which is a constellation of narcotic drug withdrawal symptoms that develops in infants born to narcotic dependent mothers, has risen dramatically. Treatment of infants with NAS often requires a prolonged hospitalization and lengthy administration of opioid containing medications, which can affect infant development. Despite its emergence as a very costly public health problem, there are no preventative treatments for NAS. Previous and current NAS research programs generally explore alterations in the dose or type of narcotic drug used to treat an infant with established NAS. The first aim of this study is to complete a clinical trial that tests a novel approach for preventing NAS. Based upon a genetic discovery, we demonstrated that administration of a 5-HT3 antagonist (ondansetron) prevented the symptoms of narcotic drug withdrawal in experimental studies in mice and in adult humans. From this, we hypothesize that ondansetron administration to pregnant mothers with opiate use disorder (OUD) just prior to delivery, followed by a brief period of ondansetron administration to the neonate, could reduce the incidence or severity of NAS. Ondansetron is a broadly utilized drug with a substantial safety record in pregnant women and infants. Therefore, we will complete a multi-center, randomized, double blind, and placebo-controlled trial to determine whether ondansetron treatment will reduce the incidence (percentage of infants requiring pharmacotherapy for NAS) or severity (total amount of opiate drug administered, length of hospitalization, NAS symptom severity scores) of NAS in babies born to mothers with OUD. This is the only study that tests a novel and generally innocuous treatment that will prevent NAS. If a brief period of ondansetron administration can prevent the development of significant NAS, this would provide a desperately needed preventative therapy, which would reduce human suffering and the growing societal costs associated with opiate abuse. The second aim of this study is to develop an innovative new method [Capillary microsampling, (CMS)], which uses a very small volume of blood (8 ul) to accurately measure drug levels in neonates. We have modified this method to enable its use in a neonatal care setting. The results obtained using the optimized CMS method (iso-CMS) will be validated in a clinical setting by determining whether iso-CMS results accurately reflect simultaneously measured plasma ondansetron concentrations in adult human subjects. We will then use iso- CMS to measure ondansetron levels in study neonates. We will also demonstrate that that iso-CMS can reliably measure the concentrations of at least 5 other drugs. This innovative new method will enable the dosing regimens for drugs with a narrow therapeutic index to be adjusted in neonates.