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J Pediatr. 2014 Sep;165(3):472-8. doi: 10.1016/j.jpeds.2014.05.040. Epub 2014 Jul 1.

Epigenetic variation in the mu-opioid receptor gene in infants with neonatal abstinence syndrome.

Author information

  • 1Pediatrics, Boston Medical Center, Boston, MA. Electronic address:
  • 2Psychology, Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME.
  • 3Center for the Study of Children at Risk, Alpert Medical School of Brown University and Women and Infant's Hospital, Providence, RI.
  • 4Tufts Clinical and Translational Science Institute, Tufts University, Boston, MA; Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA.
  • 5Pediatrics, Eastern Maine Medical Center, Bangor, ME.
  • 6Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX.
  • 7Tufts Clinical and Translational Science Institute, Tufts University, Boston, MA; Pediatrics, The Floating Hospital for Children at Tufts Medical Center, Boston, MA.



Neonatal abstinence syndrome (NAS) from in utero opioid exposure is highly variable with genetic factors appearing to play an important role. Epigenetic changes in cytosine:guanine (CpG) dinucleotide methylation can occur after drug exposure and may help to explain NAS variability. We correlated DNA methylation levels in the mu-opioid receptor (OPRM1) promoter in opioid-exposed infants with NAS outcomes.


DNA samples from cord blood or saliva were analyzed for 86 infants who were being treated for NAS according to institutional protocol. Methylation levels at 16 OPRM1 CpG sites were determined and correlated with NAS outcome measures, including need for treatment, treatment with ≥ 2 medications, and length of hospital stay. We adjusted for covariates and multiple genetic testing.


Sixty-five percent of infants required treatment for NAS, and 24% required ≥ 2 medications. Hypermethylation of the OPRM1 promoter was measured at the -10 CpG in treated vs nontreated infants (adjusted difference δ = 3.2% [95% CI, 0.3-6.0%], P = .03; nonsignificant after multiple testing correction). There was hypermethylation at the -14 (δ = 4.9% [95% CI, 1.8%-8.1%], P = .003), -10 (δ = 5.0% [95% CI, 2.3-7.7%], P = .0005), and +84 (δ = 3.5% [95% CI, 0.6-6.4], P = .02) CpG sites in infants requiring ≥ 2 medications, which remained significant for -14 and -10 after multiple testing correction.


Increased methylation within the OPRM1 promoter is associated with worse NAS outcomes, consistent with gene silencing.

Copyright © 2014 Elsevier Inc. All rights reserved.

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