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

描述(由申请人提供)：新生儿戒断综合症(NAS)是一种与母亲转运的阿片类药物突然停用有关的出生后时期的复杂体征和症状。NAS的最佳治疗方法尚未确定，在过去的25年里，治疗方法只有轻微的变化。尽管在脆弱的新生儿群体中进行研究存在困难，但不言而喻的是，成人成瘾方面的成功进展需要进行测试、验证并转移到患有NAS的婴儿身上。口服吗啡与在医院治疗8-79天的时间有关。我们已经进行了使用丁丙诺啡舌下注射治疗NAS的唯一临床试验，并证明与标准的吗啡治疗相比，治疗时间从33天缩短到22天。然而，我们最初的调查是第一阶段的非盲目设计。为了达到1a级证据标准，采用主观测量驱动主要和次要终点的随机对照试验必须具有双盲。本研究的目的是验证舌下含服丁丙诺啡在治疗NAS中比口服吗啡溶液更有效的中心假设。我们的具体目的是证明舌下含服丁丙诺啡在临床终点、治疗时间和住院时间方面比吗啡有疗效优势。通过我们的初步研究，我们已经建立了一个药代动力学/药效学(PK/PD)模型。我们将在这个模型的基础上，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。我们还计划在NAS中建立口服吗啡的药物计量模型。我们的第三个主要目标是利用药物遗传学来阐明NAS药物治疗需求的变异性来源，以及这一人群对阿片类药物替代治疗的不同反应。为了达到这些目标，我们提出了一项为期四年的随机、双盲、双模拟、单部位、平行组临床试验，将80名需要药物治疗的足月新生儿按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学进行分析。所有有NAS风险的婴儿都将拥有药物遗传样本，以便对接受治疗和未接受治疗的婴儿进行比较，并区分对药物治疗的反应。患者将主要来自一项完善的全面治疗计划，该计划针对接受美沙酮成瘾治疗的孕妇。为进行这项试验而组建的研究团队仍然存在。进行这项调查的全面专业知识从父母的摄取到出生、新生儿医学问题的管理、临床试验管理、分析化学、遗传分析、生物统计和药物计量分析，都是垂直的。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NAS风险婴儿的治疗选择。 与公共卫生相关：新生儿在出生前接触阿片类药物可表现出戒断症状，导致喂养困难、易怒、腹泻和震颤。这种疾病被称为新生儿禁欲综合征，通常在医院用吗啡治疗4-6周。丁丙诺啡是一种用于治疗成人阿片成瘾的药物。我们建议看看丁丙诺啡是否比标准的吗啡治疗更有效。另一个目标是调查是否存在遗传因素，使一些婴儿对治疗的反应与其他婴儿不同。最后，我们将测量丁丙诺啡和吗啡的水平，以了解成人和儿童之间的差异，并能够选择最佳剂量的药物用于治疗这种疾病。

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.