Recently, the FDA issued a warning concerning the use of codeine in breastfeeding mothers (http://www.fda.gov/cder/drug/advisory/codeine.htm).  This late response is due to a case which occurred in April, 2005, and reported in 2006.

Case Report

In April, 2005,  a full term healthy infant showed intermittent periods of poor feeding and lethargy starting on day 7¹.   During a well-baby visit to the pediatrician, the infant was noted to have regained his birth weight.   The pediatrician apparently did not connect the maternal use of codeine with symptoms in the infant.  On day 12, the infant had grey skin and milk intake had fallen.  On day 13, the infant was found dead.

Postmortem analysis showed blood concentrations of morphine were 70 ng/mL.   Typically, infants exposed to codeine-containing products have morphine serum concentrations of 0.5-2.2 μg/L².

The dose consumed by the mother contained 30 mg codeine.  On day 1, she took 2 tablets every 12 hours.  On day 2, she started taking 1 tablet every 12 hours because of maternal side effects (somnolence and constipation).   She continued this dosing for two weeks postpartum.  Because of side effects in the infant, she stored some of her milk on day 10 in the freezer.  A morphine concentration of 87 ng/mL was present in this milk sample, corresponding to a relative infant dose of only 1.5%.   The typical morphine concentration in milk is reported to range from 1.9 to 20.5 ng/mL at doses of 60 mg every 6 hours.

Codeine is a prodrug that requires metabolism to the active metabolite, morphine.  Approximately 5-10% of codeine will be converted to morphine in most individuals by Cytochrome P450 2D6 .  As in this mother above, we now know of certain individuals who convert codeine to morphine much more efficiently due to hyperactivity of this enzyme.  This genotype leads to much higher plasma levels of morphine, and in this case, apparently in the breastfed infant as well.  The frequency of CYP2D6 ultra-rapid metabolizer genotypes ranges with 1% in Caucasians, 10% in Greeks and Portuguese, and 29% in Ethiopians³.  Interestingly, at least 7-10% of Caucasians lack this enzyme altogether and cannot metabolize codeine to morphine.  Thus, codeine is ineffective in these individuals.

While codeine has been used safely in perhaps millions of breastfeeding mothers, 

because of relatively high rates of ultra-rapid metabolizers in certain populations, codeine may not necessarily be the best choice analgesic to use in breastfeeding mothers. 

Regardless of the opiate chosen, mothers should be individually warned to not use this product more than a few days postpartum and to closely observe their infant for fatigue, apnea, poor feeding, constipation, bluish discoloration of the lips, and other signs of opiate intoxication.  In most cases, codeine taken at low doses and for brief periods should be safe for most breastfed infants.

Suggestions by the FDA:

• When prescribing codeine for a nursing mother, doctors should prescribe the lowest dose for the shortest amount of time to relieve pain or cough.  Doctors need to tell their nursing patients how to recognize signs of high morphine levels in themselves and their babies.
• If you are a nursing mother taking codeine, call your doctor if you become extremely sleepy and have trouble caring for your baby.
• Breastfed babies usually nurse every two to three hours and should not sleep more than four hours at a time.  If your baby shows signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness, talk to the baby’s doctor immediately.  If you cannot reach the doctor right away, take the baby to an emergency room or call 911 (or local emergency services). 
• Nursing mothers should talk to their doctors if they have any questions about taking codeine. 

Author’s Suggestions:

1)  The suggestions by the FDA are good and should be followed.

2)  If you need a strong opiate, hydrocodone (Vicodin®) or perhaps oxycodone are probably preferred, as we do not think their metabolism is subject to polymorphism of CYP2D6⁴ .  Thus, levels of active opiates in most mothers will be unaffected by their genotype.  Levels transferred to the infant should be relatively safe for a breastfed infant.

3)  Again, never use opiates more than a few days for typical postpartum complications unless under the direct and immediate supervision of a healthcare professional.  Mothers should only use the medication when they actually need it, not routinely every few hours.  There are numerous situations when opiates may be necessary for prolonged periods while a mother breastfeeds (such as addicted individuals consuming methadone or individuals with chronic and severe pain syndromes).  In these situations, the infant may indeed become moderately “tolerant” to rather large maternal doses and be unaffected by opiate consumption.  This, however, requires close and consistent observation by trained healthcare professionals.  The point here is that if the mother requires prolonged exposure to strong opiates, she can still breastfeed as long as the infant does not show symptoms of opiate overdose.

4)  Most importantly, use NSAIDs whenever possible.  These include :  acetaminophen, ibuprofen, naproxen, celecoxib, or ketorolac.

Reference List

  (1)   Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet. 2006; 368(9536):704.

  (2)   Meny RG, Naumburg EG, Alger LS, Brill-Miller JL, Brown S. Codeine and the breastfed neonate. J Hum Lact. 1993; 9(4):237-40.

  (3)   Cascorbi I. Pharmacogenetics of cytochrome p4502D6: genetic background and clinical implication. Eur J Clin Invest. 2003; 33 Suppl 2:17-22.

  (4)   Lalovic B, Phillips B, Risler LL, Howald W, Shen DD. Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos. 2004; 32(4):447-54.