Codeine and Metabolite Concentrations in the Breastfed Neonate

Analgesic effect from codeine is from its metabolite, morphine. Morphine is formed by the O-demethylation of codeine and that enzyme is controlled by the cytochrome P450 2D6. More than 60 alleles in the CYP2D6 gene have been identified. This spectrum of polymorphism can be categorized into four groups: poor (PM), intermediate (IM), normal (NM), and ultra-rapid (UR) metabolizers. Codeine is rarely used in children because of fears that those with the UR genotype may suffer respiratory depression from increased morphine production. There is also concern that postpartum women medicated with codeine and who are UR metabolizers may have enough morphine in breastmilk to cause respiratory depression in a breastfed neonate. A pharmacokinetic compartment model was used to explore this assumption. There are five issues to consider in the pharmacological pathway from maternal ingestion of codeine to neonatal morphine plasma concentration: maternal morphine concentration that is dependent on genotype, milk to plasma concentration ratio, neonatal codeine and morphine exposure from breastmilk, codeine metabolism to morphine in the neonate, and morphine clearance in the neonate. The compartment model confirmed the implausibility of neonatal opioid toxicity from breastfeeding. Currently, short-term maternal use of prescription opioids (other than codeine) is considered safe and infrequently presents a hazard to the newborn. Postpartum women are denied codeine for analgesia and yet predicted neonatal morphine concentrations are lower than 1 μg/L, regardless of genotype. Maternal opioids are used with caution, especially after multiple doses, and neonates younger than 46 weeks postmenstrual age are observed for drowsiness and respiratory depression. The maternal use of codeine requires similar considerations and the current ban on codeine use in postpartum women who are breastfeeding requires review.