Safety of codeine during breastfeeding

Discussion

The clinical and toxicologic pictures in this case are consistent with opioid toxicity leading to neonatal death. Codeine itself has only mild opioid properties, while most of its analgesia and central nervous system–depressant effects are secondary to its biotransformation to morphine, a reaction catalyzed by CYP 2D6.5 While most people are extensive metabolizers of codeine to morphine, CYP 2D6 gene duplication results in an ultrarapid metabolizer phenotype (in an estimated 1% of people in Finland and Denmark, 10% of people in Greece and Portugal, and 29% of people in Ethiopia) and, thus, the potential for substantially increased production of morphine from codeine.8 In adults, this has been shown to result in serious opioid toxicity even with small doses of codeine,6 an observation consistent with the symptoms of opiate excess experienced by the mother in this case. Furthermore, the high levels of morphine in the breast milk in this case (86 ng/mL) corroborate the clinical picture observed in the infant. Breastfed infants of mothers prescribed 60 mg of codeine for postnatal pain achieved maximum plasma morphine concentrations of only 2.2 ng/mL.7 In our case, a milk sample was available only for a period when the mother halved her dose. Hence, assuming linear kinetics, it is likely that peak levels of morphine in the milk were approximately 100 ng/mL.

The predominant routes of morphine elimination include biotransformation to M3G and M6G. The production of the active metabolite M6G is almost exclusively catalyzed by UGT 2B7.9 Sawyer et al10 reported increased M6G:morphine in individuals homozygous for the single nucleotide polymorphisms constituting the UGT 2B7*2 allele. Since the mother’s genotype was UGT 2B7*2/*2, it is possible that the infant might have also been exposed to higher than anticipated concentrations of the pharmacologically active M6G metabolite, and not just of morphine itself.

There are several previous reports of somnolence11 and neonatal apnea12 in babies exposed to codeine through breast milk, suggesting that varying degrees of opioid toxicity are more prevalent than commonly assumed. Codeine is widely perceived to be compatible with breastfeeding, owing to previously measured low levels of morphine in milk.1,2 Our case reveals that polymorphism in CYP 2D6 and possibly UGT 2B7 can be life threatening for some breastfed babies. Given that a CYP 2D6 ultrarapid metabolizer genotype occurs at a frequency of 1% to 29%, genetic combination would be expected to occur quite commonly among breastfeeding mothers.

As demonstrated by this case, the common practice of prescribing codeine in the postpartum period cannot be regarded as safe for all breastfed infants. Therefore, we propose several clinical approaches that can be considered to prevent life-threatening neonatal toxicity, each with its benefits and disadvantages (see box). Whatever clinical approach is taken, codeine cannot be considered safe during breastfeeding.