E Wachman M Hayes M Brown J Paul K HarveyWilkes N Terrin G Huggins JV Aranda and JM Davis JAMA Media Briefing April 30 2013 Disclosures No C onflicts of Interest This study was supported in part by NIH funding DA02480601A2 to Dr Marie Hayes and R01DA03288901A1 to ID: 911421
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Slide1
“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
Slide2DisclosuresNo
Conflicts of InterestThis study was supported in part by NIH funding: DA024806-01A2 to Dr. Marie Hayes and R01DA032889-01A1 to Dr. Jonathan Davis
Slide3Neonatal 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
Slide4Neonatal 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
Slide5Neonatal 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
Slide6Candidate 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
Slide7ObjectiveDo 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
Slide8Methods86 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
Slide9Results
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%
Slide10OPRM1 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
Slide11COMT 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
Slide12ConclusionsNAS 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
Slide13Challenges 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
Slide14Future 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)
Slide15AcknowledgementsThe 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
Slide16That’s All Folks!