“Association of OPRM1 and COMT Single Nucleotide Polymorphisms with Hospital Length of Hospital...
-
Upload
norman-hensley -
Category
Documents
-
view
214 -
download
0
Transcript of “Association of OPRM1 and COMT Single Nucleotide Polymorphisms with Hospital Length of Hospital...
“Association of OPRM1 and COMT Single Nucleotide Polymorphisms with Hospital Length
of Hospital Stay and Treatment of Neonatal Abstinence Syndrome”
“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
DisclosuresDisclosures
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
Neonatal Abstinence SyndromeNeonatal 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
Neonatal Abstinence Syndrome 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
Neonatal Abstinence SyndromeNeonatal 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
Candidate Genes for NASCandidate 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
ObjectiveObjective
• 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
MethodsMethods
• 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
ResultsResultsDEMOGRAPHICSWhite 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 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
COMT 158A>G ResultsCOMT 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
ConclusionsConclusions
• 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
Challenges in Neonatal Drug Development 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
Future DirectionsFuture 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)
AcknowledgementsAcknowledgements• 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
That’s All Folks!