Is codeine treatment compatible with breast feeding?/nThis is a general question.

Fråga: Is codeine treatment compatible with breast feeding?

This is a general question.

Sammanfattning: Codeine could be used in single doses in lactating mothers. If codeine is used for long term treatment accumulation in the child, of its active metabolite morphine, could occur. If codeine is used the child should be observed for signs of opioid adverse effects.

Svar: Codeine is a prodrug which is metabolised by cytochrome P-450 CYP2D6 to morphine which probably is responsible for the analgesic effect (1). About 7-10% of the Caucasian population are slow metabolisers of CYP2D6 and receive no analgesic effect of codeine (2). On the other hand about 1% of the Caucasian and for example up to 29% of the Ethiopian population are ultra rapid metabolisers (2) of CYP2D6 and risk side effects due to high morphine concentrations (3). Morphine is then further metabolised by glucoronidation (4).

Codeine has previously been considered safe for occasional use during lactation (5). Codeine passes into breast milk and since it is a weak base and highly lipophilic the concentration in milk is 1.3-2.5 times higher than in the plasma of the mother (6). The maximum milk codeine concentration in two mothers, 455ng/ml, was reached one hour after a single dose of 60mg codeine (6). Calculating with this level would give a worst case weight adjusted infant dose of 6.8%. Morphine is also passing into breast milk and has an apparent half life of 6 hours and is detectable for 24, but not 48 hours (6).

In another study, free codeine and morphine levels in breast milk from seven mothers and plasma levels from eleven healthy term neonates were studied (7). The milk codeine levels ranged from 33.8 to 314ng/ml and the morphine levels ranged from 1.9 to 20.5ng/ml. Infant plasma had codeine levels ranging from <0.8 to 4.5ng/ml and morphine ranged from <0.5 to 2.2ng/ml. None of the infants showed any opioid side effects.

However, recently a case report of suspected fatal opioid toxicity in a breastfed infant of a codeine using mother has been published (8). The mother received high doses of codeine due to epiphysiotomy pain. At seven days the infant became somnolent and not to feed well, at 14 days the infant died. Postmortem morphine levels were toxic (70ng/ml) ten times higher than those seen in infats treated with morphine. The milk levels were also ten times higher than usually seen. The mother was shown to be an ultra rapid metaboliser of CYP2D6.

The CYP2D6 metabolising capacity of the newborn is maturing after parturition and is only about 9% of the adult capacity during the first week of life and up to 24% during the second week. The fetal microsomes catalyses morphine glucoronidation at 10-20% the efficiency of the adult microsomes. Morphine therefore has a half life of 3-4 times longer in neonates than in adults. Parturition triggers an increase in enzymactivity and at by three months of age the glucoronidation capacity has reached 30% of the adult (9,10).