Improving Outcome in Neonatal Abstinence Syndrome

描述（由申请人提供）：在美国，怀孕期间滥用阿片类药物和其他精神药物是一个严重的问题。新生儿戒断综合征（NAS）影响大多数在子宫内暴露于阿片类药物的婴儿，尽管其表达是可变的。NAS的最佳治疗方法尚未确定，研究仅限于短期结果，长期安全性和有效性尚未确定。此外，可能导致新生儿NAS严重程度的遗传因素尚未得到研究。该提案的目标是：1)证明新生儿期NAS药物治疗的短期和长期益处（导致FDA批准）；2)探讨麻醉代谢和药效学的遗传变异在NAS发病机制中的作用。结果将显著提高我们对NAS的理解，并阐明不同的治疗方案如何影响近期和长期的神经发育结果。首先，184名需要NAS治疗的足月婴儿将在双盲、双假人设计中随机接受吗啡或美沙酮治疗。据推测，与美沙酮治疗的婴儿相比，吗啡治疗的婴儿需要的住院天数要少得多。接下来，NAS治疗对18月龄婴儿神经发育的影响将使用Bayley III婴儿发育量表进行评估。假设吗啡治疗的婴儿在18个月时比美沙酮治疗的婴儿有更好的神经发育结果。最后，将分析多药耐药（MDR1）、阿片受体（OPRM1）和/或儿茶酚- o -甲基转移酶（COMT）基因（阿片作用的药物遗传调节剂）的单核苷酸多态性（snp），并将其与短期预后和神经发育评估相关联，以确定遗传变异在NAS发病机制中是否重要。初步数据确实表明遗传变异确实影响NAS的发病率和严重程度。这些研究的结果将增强我们对NAS发病机制的理解，确定最佳治疗方法，促进早期识别神经发育障碍高危人群，并促进有针对性的干预，以改善这些高危婴儿的预后。

DESCRIPTION (provided by applicant): Misuse of opioids and other psychoactive drugs during pregnancy is a significant problem in the US. Neonatal abstinence syndrome (NAS) affects most infants exposed to opioids in utero, although its expression is variable. Optimal treatment of NAS has not been established, with studies limited to short term outcomes, with longer term safety and efficacy undefined. In addition, genetic factors that may contribute to the severity of NAS have not been studied in newborns. The goals of this proposal are: 1) to demonstrate short and long term benefits of pharmacotherapy of NAS in the newborn period (leading to FDA approval) and; 2) to explore how genetic variations in narcotic metabolism and pharmacodynamics contribute to the pathogenesis of NAS. Results should significantly improve our understanding of NAS and elucidate how different therapeutic regimens can influence immediate and long term neurodevelopmental outcome. First, 184 term infants needing treatment for NAS will be randomized to receive either morphine or methadone in a double blind, double dummy design. It is hypothesized that morphine treated infants will require significantly fewer days in the hospital compared to methadone treated infants. Next, the effects of NAS treatment on infant neurodevelopment at 18 months of age will be assessed using the Bayley III Scales of Infant Development. It is hypothesized that morphine treated infants will have better neurodevelopmental outcome at 18 months compared to methadone treated infants. Finally, single nucleotide polymorphisms (SNPs) in the multi-drug resistance (MDR1), mu opioid receptor (OPRM1), and/or catechol-O-methyltransferase (COMT) genes (pharmacogenetic modulators of opioid action) will be analyzed and correlated with short term outcomes and neurodevelopment assessments to determine if genetic variation is important in the pathogenesis of NAS. Preliminary data does suggest that genetic variation does influence the incidence and severity of NAS. The results of these studies will enhance our understanding of the pathogenesis of NAS, define best treatment practices, promote early identification of those at highest risk for neurodevelopmental impairment, and facilitate targeted interventions to improve outcome in these high risk infants.