Improving Outcome in Neonatal Abstinence Syndrome

改善新生儿戒断综合症的治疗效果

• 批准号: 8690003
• 负责人: Jonathan M. Davis
• 金额: $ 69.3万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690003
• 关键词: ABCB1 gene; Adult; Affect; Age; Age-Months; Agonist; Best Pharmaceuticals for Children Act; Candidate Disease Gene; Catechol O-Methyltransferase; Cells; Consensus; DNA; Data; Development; Diagnosis; Double-Blind Method; Early identification; Fetus; Functional disorder; Genes; Genetic; Genetic Variation; Genotype; Goals; Growth; Heritability; Hospitals; Incidence; Infant; Infant Development; Intervention; Length; Length of Stay; Long-Term Effects; Medical; Metabolism; Methadone; Methyltransferase Gene; Morphine; Mothers; Multi-Drug Resistance; Narcotics; National Institute of Drug Abuse; Neonatal Abstinence Syndrome; Neuraxis; Neurodevelopmental Impairment; Newborn Infant; Opiate Addiction; Opiates; Opioid; Outcome; Pathogenesis; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacotherapy; Play; Pregnancy; Pregnant Women; Prenatal care; Psychotropic Drugs; Public Health; Randomized; Randomized Controlled Trials; Regimen; Resources; Role; Safety; Saliva; Severities; Single Nucleotide Polymorphism; Substance-Related Disorders; Symptoms; Therapeutic; Therapeutic Intervention; Twin Studies; Umbilical Cord Blood; United States National Institutes of Health; common treatment; design; high risk; high risk infant; improved; in utero; indexing; infant outcome; mu opioid receptors; neonate; neurobehavioral; neurodevelopment; opioid misuse; pregnant; primary outcome; prospective; public health relevance; secondary outcome; therapy development

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.

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活性药物是一个严重问题。新生儿戒断综合征 (NAS) 影响大多数在子宫内接触阿片类药物的婴儿，尽管其表达情况各不相同。 NAS 的最佳治疗方案尚未确定，研究仅限于短期结果，长期安全性和疗效尚不清楚。此外，尚未在新生儿中研究可能导致 NAS 严重程度的遗传因素。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）探索麻醉代谢和药效学的遗传变异如何影响NAS的发病机制。结果应显着提高我们对 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、双模拟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住院的天数明显减少。接下来，将使用贝利 III 婴儿发育量表评估 NAS 治疗对 18 个月大婴儿神经发育的影响。据推测，与美沙酮治疗的婴儿相比，吗啡治疗的婴儿在 18 个月时的神经发育结果会更好。最后，将分析多药耐药性 (MDR1)、mu 阿片受体 (OPRM1) 和/或儿茶酚-O-甲基转移酶 (COMT) 基因（阿片类药物作用的药物遗传学调节剂）中的单核苷酸多态性 (SNP)，并将其与短期结果和神经发育评估，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，确定最佳治疗实践，促进早期识别神经发育障碍风险最高的人群，并促进有针对性的干预措施以改善这些高风险婴儿的预后。