(R)‐ and (S)‐methadone and buprenorphine concentration ratios in maternal and umbilical cord plasma following chronic maintenance dosing in pregnancy

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Both methadone and buprenorphine cross the placenta during pregnancy which can result in neonatal abstinence syndrome (NAS). Reduced NAS in buprenorphine‐exposed infants may be as a result of relatively less buprenorphine reaching the foetal circulation compared with methadone. WHAT THIS STUDY ADDS Under chronic dosing conditions in humans, the transfer of methadone and buprenorphine appears greater than previously found in human placental tissue in vitro models. Infants born to buprenorphine maintained women may be exposed to relatively less of the maternal dose compared with infants born to women maintained on methadone during pregnancy. There is stereoselectivity in the transfer of the individual enantiomers of methadone across the placenta to the foetal circulation. AIMS The aim of this study was to compare the transfer of buprenorphine and methadone between maternal and cord blood in women under chronic dosing conditions and to determine if differences exist in the transfer of the two methadone enantiomers. METHODS Maternal and cord blood samples were collected at delivery from women maintained on methadone (35, 25–140 mg day −1 ) (median; range) or buprenorphine (6.00, 2–20 mg day −1 ) during pregnancy. Plasma concentration ratios are presented as an indicator of foetal exposure relative to the mother. RESULTS Methadone was quantified in all samples, with cord : maternal plasma methadone concentration ratios ( n = 15 mother‐infant pairs) being significantly higher ( P < 0.0001; mean difference (MD) 0.07; 95% confidence interval (CI) 0.048, 0.092) for the active (R)‐methadone enantiomer (0.41; 0.19, 0.56) (median; range) compared with (S)‐methadone (0.36; 0.15, 0.53). (R)‐ : (S)‐methadone concentration ratios were also significantly higher ( P < 0.0001; MD 0.24 95% CI 0.300, 0.180) for cord (1.40; 0.95, 1.67) compared with maternal plasma (1.16; 0.81, 1.38). Half the infant buprenorphine samples were below the assay lower limit of quantification (LLOQ) (0.125 ng ml −1 ). The latter was four‐fold lower than the LLOQ for methadone (0.50 ng ml −1 ). The cord : maternal plasma buprenorphine concentration ratio ( n = 9 mother‐infant pairs) was 0.35; 0.14, 0.47 and for norbuprenorphine 0.49; 0.24, 0.91. CONCLUSIONS The transfer of the individual methadone enantiomers to the foetal circulation is stereoselective. Infants born to buprenorphine maintained women are not exposed to a greater proportion of the maternal dose compared with methadone and may be exposed to relatively less of the maternal dose compared with infants born to women maintained on methadone during pregnancy.