Buprenorphine pharmacotherapy during pregnancy: Characterization of excretion in maternal and neonatal biological specimens and dose-concentration-effect relationships.

Abstract

A collaborative study between the Johns Hopkins Bayview Medical Center, Center for Addiction and Pregnancy and the National Institute on Drug Abuse was designed to compare methadone and buprenorphine for the treatment of opioid dependent pregnant women. Women were admitted to the study at 18-26 weeks gestation and provided written informed consent to participate in the Institutional Review Board-approved study. Biological specimens collected from women treated with buprenorphine during this study provided the first opportunity to study the excretion of buprenorphine and metabolites in meconium and urine during pregnancy. Additionally, the relationships between maternal buprenorphine dose, meconium concentrations and neonatal outcomes such as neonatal abstinence syndrome (NAS) were evaluated. The first analytical method for the quantification of buprenorphine, norbuprenorphine, and glucuronide conjugates in meconium was developed and validated. The method was sensitive and specific for buprenorphine and norbuprenorphine and analysis of specimens with and without enzymatic hydrolysis allowed for an estimation of glucuronide concentrations. Norbuprenorphine was the primary metabolite excreted in meconium, with most drug in the free form. No relationship was found between maternal buprenorphine dose and meconium concentrations or neonatal outcomes. Total buprenorphine meconium concentrations and buprenorphine to norbuprenorphine ratios were significantly related to neonatal abstinence syndrome scores greater than 4. A urine quantification method for buprenorphine and three metabolites was developed and fully validated. This assay was applied to the quantification of buprenorphine analytes in 515 urine specimens from buprenorphine-maintained pregnant women. The urinary excretion of buprenorphine and metabolites provided insight on metabolic changes during pregnancy. Among all participants, mean BUP-Gluc to NBUPGluc ratio was significantly higher in the second trimester as compared to third trimester and there were significant intra-subject differences between trimesters in 71% of participants. Percent of dose excreted during pregnancy was higher than post-pregnancy results, consistent with other data indicating increase in renal clearance of drug during pregnancy. This research confirms the safety and efficacy of buprenorphine pharmacotherapy during pregnancy and offers women an alternative to methadone treatment. These buprenorphine pharmacokinetic data in pregnant women provide clinicians with valuable information on successfully treating this vulnerable population and their neonates.