Risk to the Breast-Fed Neonate From Codeine Treatment to the Mother: A Quantitative Mechanistic Modeling Study

Administering codeine to breast-feeding mothers had been considered safe until the recent death of a breast-fed neonate whose mother had been prescribed codeine. We investigated the risk of opioid poisoning to breast-fed neonates using coupled physiologically based pharmacokinetic models for the mother and child. Neonatal morphine plasma concentrations were simulated for various combinations of cytochrome P450 2D6 (CYP2D6) genotype and morphine clearance, assuming typical breast-feeding schedules and maternal codeine doses of <= 2.5 mg/kg/day. The simulations demonstrated that the mother's codeine and morphine clearances and the neonate's morphine clearance are the most critical determinants of morphine accumulation in the neonate. The cumulative doses ingested by the neonate over 14 days were 0.38 mg/kg codeine and 0.17 mg/kg morphine. Given the added effect of low neonatal elimination capacity for morphine, potentially toxic morphine plasma concentrations can be reached within 4 days in the neonate after repeated codeine dosing to the mother. Importantly, neonates of mothers with the ultrarapid CYP2D6 genotype and neonates of mothers who are extensive metabolizers have comparable risks of opioid poisoning.