A Comparison of Buprenorphine Versus Morphine in the Treatment of the Neonatal Ab

描述（由申请人提供）：新生儿戒断综合征（NAS）是与母体转移阿片类药物突然戒断相关的产后体征和症状的复合体。NAS的最佳治疗方法尚未建立，在过去的25年里，治疗方法只有适度的变化。尽管在脆弱的新生儿人群中进行研究存在困难，但不言而喻的是，成人成瘾的成功进展将被测试、验证并转移到患有NAS的婴儿身上。口服吗啡在医院的治疗时间为8-79天。我们进行了唯一一项使用舌下丁丙诺啡治疗NAS的临床试验，并证明与标准护理吗啡治疗相比，治疗时间从33天减少到22天。然而，我们最初的调查是第一阶段，非盲法设计。为了达到1a级证据标准，采用主观测量驱动主要终点和次要终点的随机对照试验必须采用双盲。本研究的目的是验证舌下丁丙诺啡比口服吗啡溶液治疗NAS更有效的中心假设。我们特别旨在证明舌下丁丙诺啡在治疗时间和住院时间的临床终点方面比吗啡具有疗效优势。根据我们的初步研究，我们建立了药代动力学/药效学（PK/PD）模型。我们将建立在这个模型上，确定影响药物处置的协变量，并优化丁丙诺啡的剂量和给药间隔。我们还计划建立口服吗啡在NAS中的药物计量学模型。我们的第三个主要目的是使用药物遗传学来阐明NAS中药物治疗需求的变异性来源，以及该人群对阿片类药物替代治疗的差异反应。为了达到这些目标，我们提出了一项为期四年、随机、盲法、双假人、单地点、平行组临床试验，其中80名需要NAS药物治疗的足月婴儿将按1:1的比例随机分配到每个治疗组。PK样品的稀疏采样将使用质谱分析。所有有NAS风险的婴儿都将有药理学样本，以便在接受治疗和未接受治疗的婴儿之间进行比较，并区分对药物治疗的反应。患者将主要从一个完善的综合治疗方案，以美沙酮治疗成瘾的孕妇。为进行试验而组建的研究小组仍然存在。开展调查的综合专业知识从父母摄入、出生、新生儿医疗问题管理、临床试验管理、分析化学、遗传分析、生物统计学和药物计量学分析等方面垂直存在。正是通过这些研究，我们希望更好地了解成瘾的生物学，并最终改善有NAS风险的婴儿的治疗选择。

DESCRIPTION (provided by applicant): The Neonatal abstinence Syndrome (NAS) is a complex of signs and symptoms in the postnatal period associated with the sudden withdrawal of maternally transferred opioids. Optimal treatment for NAS has not been established, with only modest changes in treatment approaches over the past ~25 years. Despite the difficulties in conducting research in a vulnerable neonatal population, it is self-evident that successful advances in adult addiction be tested, validated, and transferred to infants with NAS. Administration of oral morphine is associated with lengths of treatment of 8-79 days in the hospital setting. We have performed the only clinical trial employing sublingual buprenorphine to treat NAS and have demonstrated a reduction in length of treatment from 33 to 22 days relative to standard of care morphine treatment. Our initial investigation, however, was a phase one, unblinded design. To meet level 1a evidence standards, a randomized controlled trial employing a subjective measurement driving the primary and secondary endpoints must have double blinding. The purpose of the current investigation is to test the central hypothesis that sublingual buprenorphine is more efficacious than oral morphine solution in the treatment of NAS. We specifically aim to demonstrate that sublingual buprenorphine has an efficacy advantage over morphine for the clinical endpoints of length of treatment and duration of hospitalization. From our initial investigations we have built a pharmacokinetic/pharmacodynamic (PK/PD) model. We will build upon this model, identify covariates that influence drug disposition, and optimize buprenorphine dose and interval of administration. We plan to also build a pharmacometric model of oral morphine in NAS. Our third major aim is to use pharmacogenetics to elucidate sources of variability in the need for pharmacologic treatment in NAS, and the differential response to opioid replacement therapy in this population. To reach achieve these aims, we propose a four year, randomized, blinded, double dummy, single site, parallel group clinical trial in which eighty term infants who require pharmacologic treatment for NAS will be randomized in a 1:1 ratio to each treatment arm. Sparse sampling for PK samples will be analyzed by use of mass spectroscopy. All infants at risk for NAS will have pharmacogenetic samples to allow for comparisons between treated and non-treated infants, as well as a discrimination of response to drug therapy. Patients will be drawn primarily from a well-established comprehensive treatment program for pregnant women treated with methadone for addiction. The research team assembled to perform the trial is extant. Comprehensive expertise to conduct the investigation exists vertically from parent intake, through birth, management of neonatal medical issues, clinical trial administration, analytic chemistry, genetic analysis, biostatistics, and pharmacometric analysis. It is through these investigations that we hope to better understand the biology of addiction, and ultimately improve the treatment options for infants at risk for NAS. PUBLIC HEALTH RELEVANCE: Newborns exposed to opioids prior to birth can show withdrawal symptoms that cause difficulty feeding, irritability, diarrhea, and tremors. This disease, called the Neonatal Abstinence Syndrome, is generally treated in the hospital with morphine for 4-6 weeks. Buprenorphine is a medication that is used to treat adults with addiction to opioids. We propose to see if buprenorphine is more effective than the standard treatment of morphine. Another goal is to investigate if there are inherited factors which make some babies react to treatment differently than others. Finally, we will measure levels of buprenorphine and morphine to see differences between adults and children, and to be able to pick the best dose of medication to use in treating this disease.