Association of OPRM1 and COMT Single-Nucleotide Polymorphisms With Hospital Length of Stay and Treatment of Neonatal Abstinence Syndrome

Department of Pediatrics, The Floating Hospital for Children, Tufts Medical Center, 800 Washington St, Boston, MA 02111, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 05/2013; 309(17):1821-7. DOI: 10.1001/jama.2013.3411
Source: PubMed


Neonatal abstinence syndrome (NAS) caused by in utero opioid exposure is a growing problem; genetic factors influencing the incidence and severity have not been previously examined. Single-nucleotide polymorphisms (SNPs) in the μ-opioid receptor (OPRM1), multidrug resistance (ABCB1), and catechol-o-methyltransferase (COMT) genes are associated with risk for opioid addiction in adults.
To determine whether SNPs in the OPRM1, ABCB1, and COMT genes are associated with length of hospital stay and the need for treatment of NAS.
Prospective multicenter cohort study conducted at 5 tertiary care centers and community hospitals in Massachusetts and Maine between July 2011 and July 2012. DNA samples were genotyped for SNPs, and then NAS outcomes were correlated with genotype. Eighty-six of 140 eligible mother-infant dyads were enrolled. Infants were eligible if they were 36 weeks' gestational age or older and exposed to methadone or buprenorphine in utero . MAIN OUTCOMES AND MEASURES: Primary outcome measure was length of hospital stay, with between-group differences expressed as β and calculated with linear regression models. Secondary outcome measures included need for any medical treatment for NAS and treatment with 2 or more medications.
Infants with the OPRM1 118A>G AG/GG genotype had shortened length of stay (β = -8.5 days; 95% CI, -14.9 to -2.1 days; P = .009) and were less likely to receive any treatment than AA infants (48% vs 72%; adjusted odds ratio, 0.76; 95% CI, 0.63-0.96; P = .006). The COMT 158A>G AG/GG genotype was associated with shortened length of stay (β = -10.8 days; 95% CI, -18.2 to -3.4 days; P = .005) and less treatment with 2 or more medications (18% vs 56%; adjusted odds ratio, 0.68; 95% CI, 0.55-0.86; P = .001) than the AA genotype. Associations with the ABCB1 SNPs were not significant.
Among infants with NAS, variants in the OPRM1 and COMT genes were associated with a shorter length of hospital stay and less need for treatment. These preliminary findings may provide insight into the mechanisms underlying NAS.

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    • "This SNP has previously been associated with an increased risk of depression in adults as well as nicotine dependence (Beuten et al., 2006; Pap et al., 2012) In addition, rs740603 has been associated with impulsivity, depression, and cocaine-associated paranoia (Ittiwut et al., 2011; Pap et al., 2012). Similarly, our previous study in the same 86 mother–infant dyads found an association within another SNP in COMT (rs4680) with NAS severity under a dominant model (Wachman et al., 2013). The minor G allele of this SNP leads to a decrease in COMT enzyme activity suggesting that an increase in circulating catecholamines would lead to improved stress tolerance in infants with NAS (Rakvag et al., 2005). "
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    ABSTRACT: There is significant variability in the severity of neonatal abstinence syndrome (NAS) due to in-utero opioid exposure. We wanted to determine if single nucleotide polymorphisms (SNPs) in key candidate genes contribute to this variability. Full-term opioid-exposed newborns and their mothers (n=86 pairs) were studied. DNA was genotyped for 80 SNPs from 14 genes utilizing a custom designed microarray. The association of each SNP with NAS outcomes was evaluated. SNPs in two opioid receptor genes in the infants were associated with worse NAS severity: (1) The PNOC rs732636 A allele (OR=3.8, p=0.004) for treatment with 2 medications and a longer hospital stay (LOS) of 5.8 days (p=0.01), and (2) The OPRK1 rs702764 C allele (OR=4.1, p=0.003) for treatment with 2 medications. The OPRM1 rs1799971 G allele (β=-6.9 days, p=0.02) and COMT rs740603 A allele (β=-5.3 days, p=0.01) were associated with shorter LOS. The OPRD1 rs204076 A allele in the mothers was associated with a longer LOS by 6.6 days (p=0.008). Results were significant point-wise but did not meet the experiment-wide significance level. These findings suggest that SNPs in opioid receptor and the PNOC genes are associated with NAS severity. However, further testing in a large sample is warranted. This has important implications for prenatal prediction and personalized treatment regimens for infants at highest risk for severe NAS. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Drug and alcohol dependence 07/2015; 155. DOI:10.1016/j.drugalcdep.2015.07.001 · 3.42 Impact Factor
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    • "Seven studies were identified that examined the role of infant feeding method on NAS outcomes [9,38-43]. All studies were retrospective cohorts of primarily full-term infants exposed to methadone, heroin, and buprenorphine and were determined to have NAS symptoms. "
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    ABSTRACT: Neonatal abstinence syndrome (NAS) secondary to in-utero opioid exposure is an increasing problem. Variability in assessment and treatment of NAS has been attributed to the lack of high-quality evidence to guide management of exposed neonates. This systematic review examines available evidence for NAS assessment tools, nonpharmacologic interventions, and pharmacologic management of opioid-exposed infants. There is limited data on the inter-observer reliability of NAS assessment tools due to lack of a standardized approach. In addition, most scales were developed prior to the prevalent use of prescribed prenatal concomitant medications, which can complicate NAS assessment. Nonpharmacologic interventions, particularly breastfeeding, may decrease NAS severity. Opioid medications such as morphine or methadone are recommended as first-line therapy, with phenobarbital or clonidine as second-line adjunctive therapy. Further research is needed to determine best practices for assessment, nonpharmacologic intervention, and pharmacologic management of infants with NAS in order to improve outcomes.
    Addiction science & clinical practice 09/2014; 9(1):19. DOI:10.1186/1940-0640-9-19
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    • "Recently, a link between neonatal pharmacogenetics (i.c. í µí¼‡-opioid receptor and catechol-Omethyltransferase single-nucleotide polymorphisms) and the presence and extent of neonatal abstinence syndrome following maternal opioid exposure has been documented [8]. "
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    ABSTRACT: Karel Allegaert was supported by the Fund for Scientific Research, Flanders (Fundamental Clinical Investigatorship 1800214N). Johannes N. van den Anker is supported by NIH Grants (R01HD048689, K24DA027992, and U54HD071601) and FP7 Grants TINN (223614), TINN2 (260908), and GRIP (261060).
    04/2014; 2014:101620. DOI:10.1155/2014/101620
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