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.

Public Health Relevance

Optimal treatment of neonatal abstinence syndrome (NAS) has not been established, with studies limited to short term outcomes (e.g. length of hospital stay), with longer term safety and efficacy undefined. The goals of this proposal are: 1) to examine short and long term effects of methadone compared to morphine in 184 newborn infants with NAS and;2) to explore how genetic variations in narcotic metabolism and pharmacodynamics contribute to the pathogenesis 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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA032889-01A1
Application #
8372286
Study Section
Special Emphasis Panel (ZDA1-GXM-A (08))
Program Officer
Biswas, Jamie
Project Start
2012-09-01
Project End
2016-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$783,536
Indirect Cost
$196,038
Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111
Wachman, Elisha M; Hayes, Marie J; Lester, Barry M et al. (2014) Epigenetic variation in the mu-opioid receptor gene in infants with neonatal abstinence syndrome. J Pediatr 165:472-8
Wachman, Elisha M; Hayes, Marie J; Brown, Mark S et al. (2013) Association of OPRM1 and COMT single-nucleotide polymorphisms with hospital length of stay and treatment of neonatal abstinence syndrome. JAMA 309:1821-7