Gillian Jolly

Introduction: Neonatal opioid withdrawal syndrome (NOWS) is caused by chronic exposure to opioids in-utero, which causes a physiologic dependence on the opioids, and when exposure is abruptly stopped after birth, the neonate experiences withdrawal symptoms such as hyperthermia, tachycardia, tremors, vomiting, sleep deprivation, and hyperirritability^1,2. NOWS prevalence has increased following the increase in opioid use disorder, which has increased 47% worldwide from 1990-2016 and has 333% in pregnancy from 1999-2014^1,3. Despite increasing prevalence of NOWS, it has been difficult to predict long-term effects, and more research is needed to be done to better understand the multifactorial mechanisms and the best course of action for treatment for short-term relief and long-term health. Methods: Wachman et. al collected saliva and purified DNA samples from two groups of mother-infant dyads, those with NOWS who required pharmacological treatment and those who did not require pharmacological treatment; they then used bisulfite conversion and PCR-based assay for DNA methylation to analyze the methylation, and were then genotyped for OPRM1 118A>G by microarray⁴. Viet et. al quantified OPRM1 methylation for patients taking opioids for cancer pain, and then findings were reverse translated onto head and neck squamous cell carcinoma mouse models with re-expressed opioid receptors using an adenovirus (Ad-OPRM1) or a control (Ad-GFP), and pain reactions in mice were measured⁵. Results: Wachman et. al showed that there was hypermethylation on CpG sites -18, -14, and +23 on the OPRM1 promoter region in NOWS infants who required pharmacologic treatment and on sites -169 in mothers of those infants; this maternal hypermethylation was also positively correlated with infant hospital length of stay⁴. Viet et. al showed that mice who had re-expressed OPRM1 genes had less thermal and mechanical pain than the controls⁵. Conclusions: Wachman et. al showed there was statistically significantly more DNA methylation on the promoter region of OPRM1 in infants with more serious NOWS symptoms as well more methylation for the mothers of these infants, showing that DNA methylation of this site downregulates the mu opioid receptor, which then leads to worsened symptoms, showing that this one possible mechanism leading to NOWS⁴. Viet et. all showed that in mice models, re-expressing OPRM1 helped alleviate pain in mice with cancer and resensitized the receptors to opioids, showing a decreased tolerance once opioids were used. This could have implications for possible treatments for pain patients, including NOWS patients, with further research⁵.

1. Anbalagan S. Neonatal Abstinence Syndrome. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK551498/. Published December 10, 2019. Accessed February 27, 2020.
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4. Wachman EM, Hayes MJ, Shrestha H, et al. Epigenetic variation in OPRM1 gene in opioid-exposed mother-infant dyads. Genes, Brain and Behavior. 2018;17(7). doi:10.1111/gbb.12476
5. Viet CT, Dang D, Aouizerat BE, et al. OPRM1 Methylation Contributes to Opioid Tolerance in Cancer Patients. The Journal of Pain. 2017;18(9):1046-1059. doi:10.1016/j.jpain.2017.04.001