Association of OPRM1 and COMT Single Nucleotide Polymorphisms with Hospital Length of Hospital Stay and Treatment of Neonatal Abstinence Syndrome E Wachman M Hayes M Brown J Paul K HarveyWilkes ID: 769335
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“Association of OPRM1 and COMT Single Nucleotide Polymorphisms with Hospital Length of Hospital Stay and Treatment of Neonatal Abstinence Syndrome” E Wachman, M Hayes, M Brown, J Paul, K Harvey-Wilkes, N Terrin, G Huggins, JV Aranda, and JM DavisJAMA Media BriefingApril 30, 2013
DisclosuresNo Conflicts of InterestThis study was supported in part by NIH funding: DA024806-01A2 to Dr. Marie Hayes and R01DA032889-01A1 to Dr. Jonathan Davis
Neonatal Abstinence Syndrome Opioid exposure in pregnancy - 5.6 infants/1,000 births Incidence has tripled in the past decadeThe mother may also be smoking or taking other medications Signs of withdrawal in 60-80% of infants exposed to opioidsDysfunction of the central nervous system, gastrointestinal tract , and/or respiratory system
Neonatal Abstinence Syndrome Prolonged treatment in hospital, high healthcare costsSafety and efficacy of agents not well establishedSignificant variability in the incidence and severity Factors influencing this variability are unknown
Neonatal Abstinence SyndromeGenetic factors may be important Single nucleotide polymorphisms (SNPs): Single base pair changes that can alter protein’s functionSNPs influence opioid dosing, metabolism, and addiction in adultsNo prior studies of genetic links to NAS
Candidate Genes for NASSNPs present in 40-50% of the population have been studied in adults Mu Opioid Receptor (OPRM1) = Site of Action118A>G SNPMulti-Drug Resistance Gene (ABCB1) = Transporter1236C>T SNP 3435C>T SNP 2677G/T/A SNPCatechol-O-methyltransferase (COMT) = Modulator 158 A>G SNP
ObjectiveDo SNPs in the OPRM1, ABCB1, and/or COMT genes influence length of hospital stay (LOS) and need for treatment in infants exposed to opioids during pregnancyOutcome Measures: Primary: Length of hospital staySecondary: Treatment for NAS, need for multiple medications
Methods86 opioid exposed term infants Mothers receiving methadone or buprenorphineInfants treated with morphine or methadoneIf severe - additional medications givenA sample of blood or saliva collected from each infant Incidence and severity correlated with changes in genetic profiles
Results DEMOGRAPHICS White 98% Maternal Methadone 64% Maternal Buprenorphine 36% Maternal Smoking 78% Maternal Benzodiazepines 12% LOS All Infants Mean 22.3 days LOS Treated Infants Mean 31.6 days Treatment for NAS 65% Treated with > 2 medications 24%
OPRM1 118A>G Results AA vs AG/GG infants compared in models that adjust for breastfeeding and study siteThose with the AG/GG genotype - treated less frequently and had shorter LOS OUTCOME UNADJUSTED RESULTS ADJUSTED RESULTS P-VALUE Infant Treated 72% vs 48% OR = 0.76 (CI 0.63, 0.96) 0.006 Mean LOS 24.1 vs 17.6 days - 8.5 days 0.009
COMT 158A>G ResultsAA infants vs AG/GG infants in models that adjusted for breastfeeding and siteAG/GG infants were treated less frequently and had shorter LOS than AA infantsOUTCOME UNADJUSTED RESULTS ADJUSTED RESULTS P-VALUE Infant Treated 88% vs 60% OR = 0.79 (CI 0.61, 0.99) 0.02 Mean LOS 31.1 vs 20.4 days - 10.8 days 0.005
ConclusionsNAS is a complex disorder with many factors contributing to the incidence and severitySNPs in the OPRM1 and COMT genes - reduced treatment and LOSNo associations found with ABCB1 SNPsCombining clinical risk factors with genetic profiling would permit personalized genetic medicine and targeted treatment regimens
Challenges in Neonatal Drug Development Most drugs used in newborn infants not FDA approved - safety and efficacy not established Small market, high liability, ethical concernsSignificant variability in NAS treatment protocolsMany NAS medications include alcohol or propylene glycol Concern for adverse long-term developmental outcomes
Future DirectionsNIH Grant – “Improving Outcomes in Neonatal Abstinence Syndrome”Randomize infants to receive morphine or methadone (determine best practice) Evaluate long-term neurodevelopmental outcomes of infants treated for NASEstablish other genetic factors - Addiction Array (1350 SNPs for addiction disorders)
AcknowledgementsThe Floating Hospital at Tufts Medical Center: Tufts Medical Center, Melrose Wakefield Hospital, Brockton Hospital, and Lowell General Hospital Ozlem Kasaroglu, Teresa Marino, Mario CordovaCTRC Genomics Laboratory Eastern Maine Medical Center:Staff at the EMMC Hira Shrestha; Nicole Heller, Beth Logan, Deborah Morrison
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