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The Role of Norbuprenorphine in Buprenorphine‐Induced Neonatal Abstinence Syndrome: A Pilot Study

Opioid abuse during pregnancy may cause drug dependence in the fetus, and the abrupt discontinuation of opioid exposure at birth may induce neonatal abstinence syndrome (NAS) during the first week of life. NAS is characterized by inconsolable high‐pitched crying, tremor, vomiting, diarrhea, hypersensitivity, and sleep disturbances. Buprenorphine (BUP), a mu‐opioid receptor partial agonist, is administered as a substitution therapy to treat opioid use disorder during pregnancy. BUP improves neonatal outcome compared with methadone or no treatment, but BUP exposure often leads to NAS. Furthermore, NAS severity is independent of maternal BUP dose throughout pregnancy, suggesting that individual differences in maternal‐fetal BUP pharmacology may increase NAS susceptibility in some newborns. One possible explanation is that fetal exposure to norbuprenorphine (NorBUP), a metabolite of BUP that has high affinity and efficacy at the mu‐opioid receptor, differs across the BUP‐treated population and drives individual differences in the development of opioid dependence. This study tested the hypothesis that NorBUP can induce NAS. To test this hypothesis, we developed a novel model of NAS in which exposure to opioids occurs continuously across fetal development. Pregnant rats were implanted with subcutaneous minipumps containing NorBUP (0.1 or 0.3 mg/kg*day) or vehicle (5 % Emulphor) on gestation day (GD) 9. Treatment continued until delivery. Upon delivery, half of the pups were observed and scored for signs of precipitated withdrawal for 10 minutes after administration of the mu‐opioid receptor antagonist naltrexone (1 or 10 mg/kg, i.p.) or saline (10 ml/kg). Because of the CNS immaturity of the neonatal rat pup relative to the human newborn, this group models opioid dependence in preterm newborns. To model NAS at term, the other half of each litter was fostered to an untreated dam and received subcutaneous injections of NorBUP (0.05 mg/kg or 1.5 mg/kg) every 12 hours (BID) until they were tested for precipitated opioid withdrawal on postnatal day (PD) 7. Few withdrawal signs were observed in the pups tested within 24 hours of delivery, but PD7 pups exposed to the high dose of NorBUP in utero and after birth exhibited significantly more “wall climbing” and less “quiet” signs when challenged with naltrexone, indicating opioid withdrawal. The results of these preliminary studies suggest that NorBUP can induce opioid dependence in the neonatal pup. Ongoing experiments will determine fetal brain concentrations of NorBUP after maternal exposure to NorBUP (GD 9‐ GD20). Results of this experiment will be used to determine additional doses of NorBUP to be tested in the novel rat model of NAS.