![Page 1: E Wachman , M Hayes, M Brown, J Paul, K Harvey-Wilkes,](https://reader036.vdocuments.mx/reader036/viewer/2022062310/5681663d550346895dd9a8a7/html5/thumbnails/1.jpg)
“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 Davis
JAMA Media BriefingApril 30, 2013
![Page 2: E Wachman , M Hayes, M Brown, J Paul, K Harvey-Wilkes,](https://reader036.vdocuments.mx/reader036/viewer/2022062310/5681663d550346895dd9a8a7/html5/thumbnails/2.jpg)
Disclosures
No Conflicts of Interest
This study was supported in part by NIH funding: DA024806-01A2 to Dr. Marie Hayes
and R01DA032889-01A1 to Dr. Jonathan Davis
![Page 3: E Wachman , M Hayes, M Brown, J Paul, K Harvey-Wilkes,](https://reader036.vdocuments.mx/reader036/viewer/2022062310/5681663d550346895dd9a8a7/html5/thumbnails/3.jpg)
Neonatal Abstinence Syndrome
• Opioid exposure in pregnancy - 5.6 infants/1,000 births
• Incidence has tripled in the past decade• The mother may also be smoking or taking
other medications • Signs of withdrawal in 60-80% of infants
exposed to opioids• Dysfunction of the central nervous system,
gastrointestinal tract, and/or respiratory system
![Page 4: E Wachman , M Hayes, M Brown, J Paul, K Harvey-Wilkes,](https://reader036.vdocuments.mx/reader036/viewer/2022062310/5681663d550346895dd9a8a7/html5/thumbnails/4.jpg)
Neonatal Abstinence Syndrome
• Prolonged treatment in hospital, high healthcare costs
• Safety and efficacy of agents not well established
• Significant variability in the incidence and severity
• Factors influencing this variability are unknown
![Page 5: E Wachman , M Hayes, M Brown, J Paul, K Harvey-Wilkes,](https://reader036.vdocuments.mx/reader036/viewer/2022062310/5681663d550346895dd9a8a7/html5/thumbnails/5.jpg)
Neonatal Abstinence Syndrome
• Genetic factors may be important
• Single nucleotide polymorphisms (SNPs): Single base pair changes that can alter protein’s function
• SNPs influence opioid dosing, metabolism, and addiction in adults
• No prior studies of genetic links to NAS
![Page 6: E Wachman , M Hayes, M Brown, J Paul, K Harvey-Wilkes,](https://reader036.vdocuments.mx/reader036/viewer/2022062310/5681663d550346895dd9a8a7/html5/thumbnails/6.jpg)
Candidate Genes for NAS• SNPs present in 40-50% of the population have been
studied in adults• Mu Opioid Receptor (OPRM1) = Site of Action
• 118A>G SNP• Multi-Drug Resistance Gene (ABCB1) = Transporter
• 1236C>T SNP• 3435C>T SNP• 2677G/T/A SNP
• Catechol-O-methyltransferase (COMT) = Modulator• 158A>G SNP
![Page 7: E Wachman , M Hayes, M Brown, J Paul, K Harvey-Wilkes,](https://reader036.vdocuments.mx/reader036/viewer/2022062310/5681663d550346895dd9a8a7/html5/thumbnails/7.jpg)
Objective• Do 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 pregnancy
• Outcome Measures: • Primary: Length of hospital stay• Secondary: Treatment for NAS, need for
multiple medications
![Page 8: E Wachman , M Hayes, M Brown, J Paul, K Harvey-Wilkes,](https://reader036.vdocuments.mx/reader036/viewer/2022062310/5681663d550346895dd9a8a7/html5/thumbnails/8.jpg)
Methods• 86 opioid exposed term infants• Mothers receiving methadone or buprenorphine• Infants treated with morphine or methadone• If severe - additional medications given• A sample of blood or saliva collected from
each infant • Incidence and severity correlated with changes
in genetic profiles
![Page 9: E Wachman , M Hayes, M Brown, J Paul, K Harvey-Wilkes,](https://reader036.vdocuments.mx/reader036/viewer/2022062310/5681663d550346895dd9a8a7/html5/thumbnails/9.jpg)
ResultsDEMOGRAPHICSWhite 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%
![Page 10: E Wachman , M Hayes, M Brown, J Paul, K Harvey-Wilkes,](https://reader036.vdocuments.mx/reader036/viewer/2022062310/5681663d550346895dd9a8a7/html5/thumbnails/10.jpg)
OPRM1 118A>G Results • AA vs AG/GG infants compared in models that
adjust for breastfeeding and study site• Those with the AG/GG genotype - treated less
frequently and had shorter LOS
OUTCOME UNADJUSTEDRESULTS
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
![Page 11: E Wachman , M Hayes, M Brown, J Paul, K Harvey-Wilkes,](https://reader036.vdocuments.mx/reader036/viewer/2022062310/5681663d550346895dd9a8a7/html5/thumbnails/11.jpg)
COMT 158A>G Results• AA infants vs AG/GG infants in models that
adjusted for breastfeeding and site• AG/GG infants were treated less frequently and
had shorter LOS than AA infants
OUTCOME 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
![Page 12: E Wachman , M Hayes, M Brown, J Paul, K Harvey-Wilkes,](https://reader036.vdocuments.mx/reader036/viewer/2022062310/5681663d550346895dd9a8a7/html5/thumbnails/12.jpg)
Conclusions• NAS is a complex disorder with many factors
contributing to the incidence and severity• SNPs in the OPRM1 and COMT genes - reduced
treatment and LOS• No associations found with ABCB1 SNPs• Combining clinical risk factors with genetic
profiling would permit personalized genetic medicine and targeted treatment regimens
![Page 13: E Wachman , M Hayes, M Brown, J Paul, K Harvey-Wilkes,](https://reader036.vdocuments.mx/reader036/viewer/2022062310/5681663d550346895dd9a8a7/html5/thumbnails/13.jpg)
Challenges in Neonatal Drug Development
• Most drugs used in newborn infants not FDA approved - safety and efficacy not established
• Small market, high liability, ethical concerns• Significant variability in NAS treatment protocols• Many NAS medications include alcohol or
propylene glycol • Concern for adverse long-term developmental
outcomes
![Page 14: E Wachman , M Hayes, M Brown, J Paul, K Harvey-Wilkes,](https://reader036.vdocuments.mx/reader036/viewer/2022062310/5681663d550346895dd9a8a7/html5/thumbnails/14.jpg)
Future Directions
• NIH 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 NAS
• Establish other genetic factors - Addiction Array (1350 SNPs for addiction disorders)
![Page 15: E Wachman , M Hayes, M Brown, J Paul, K Harvey-Wilkes,](https://reader036.vdocuments.mx/reader036/viewer/2022062310/5681663d550346895dd9a8a7/html5/thumbnails/15.jpg)
Acknowledgements• The Floating Hospital at Tufts Medical Center:
• Tufts Medical Center, Melrose Wakefield Hospital, Brockton Hospital, and Lowell General Hospital
• Ozlem Kasaroglu, Teresa Marino, Mario Cordova• CTRC Genomics Laboratory
• Eastern Maine Medical Center:• Staff at the EMMC • Hira Shrestha; Nicole Heller, Beth Logan, Deborah
Morrison
![Page 16: E Wachman , M Hayes, M Brown, J Paul, K Harvey-Wilkes,](https://reader036.vdocuments.mx/reader036/viewer/2022062310/5681663d550346895dd9a8a7/html5/thumbnails/16.jpg)
That’s All Folks!