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Codeine and breastfeeding
Codeine and breastfeeding In 2006, Gideon Koren and colleagues1 published a Case Report in The Lancet on the death of a neonate whose mother was taking codeine and who was genetically an ultrarapid metaboliser of codeine to morphine. Koren and colleagues suggested that the baby died from morphine transferred during breastfeeding—a conclusion that led to widespread concerns in obstetric and paediatric circles. We have doubts about this conclusion. Furthermore another publication on the same case reveals data not presented in The Lancet,2 and we have subsequently become aware of other unpublished information. The original Case Report stated that the mother breastfed while taking paracetamol/codeine (500 mg/30 mg), initially two tablets twice daily (ie, 120 mg codeine daily). This dose would maximally provide 120 mg morphine if all the codeine was converted (usually only 10–20% is converted). The mother became drowsy but recovered after halving her dose on the second day (to 60 mg codeine daily). The baby died 11 days later, having reduced its milk intake at least 24 h before death. The second paper2 reported a high blood paracetamol concentration in the baby at post mortem (5·9 mg/L). In correspondence, Koren and colleagues stated that the stomach had “high levels of morphine and very low levels of acetaminophen” (paracetamol). Our concerns are: (1) whether quantities of morphine in breastmilk at this codeine dose could be fatal, and (2) the source of paracetamol in blood and of morphine in the stomach found post mortem. With regard to the first concern, Koren and colleagues have previously reported the case of a mother who received 10 mg morphine daily and who had a breastmilk morphine concentration of 10–100 μg/L; her neonate had a blood concentration of 4 μg/L.3 Koren and colleagues concluded that maternal doses of www.thelancet.com Vol 372 August 23, 2008
100 mg morphine daily would result in a therapeutic neonatal morphine concentration. We and others4 agree with this assessment. On this basis, total conversion of the codeine in the present case would have produced only 60 mg morphine daily and neonatal blood morphine concentration well within the therapeutic range.5,6 Breastmilk morphine was 87 μg/L when retrospectively measured in this case, but post-mortem morphine in the baby was disproportionately high (70 μg/L).2 Therapeutic doses of morphine in neonates are 40–100 μg/L/kg intravenously. The baby’s oral dose of morphine was the concentration in milk (87 μg/L) multiplied by volume ingested (normally 30 mL/kg per feed7)—ie, about 8 μg per feed in a 3 kg child. Therefore morphine blood concentrations in this baby who had not been feeding well for more than 24 h should have been well below therapeutic levels. In view of the relations between neonatal morphine kinetics,8 plasma concentrations, and respiratory function, we do not believe that maternal ingestion of codeine can explain the baby’s death. A baby, symptomatic from ingestion of morphine in breastmilk, would reduce breastfeeding due to drowsiness before it could ingest a lethal dose. Furthermore, as opioidnaive individuals, the mother and infant would be expected to have similar features. Although this occurred within the first 2 days, it did not occur around the time of the baby’s death. With regard to our second concern, given that breastmilk typically provides less than 5% of a neonatal therapeutic dose of paracetamol and less than 5% of a weight-corrected maternal dose,6,9 we believe that the baby’s post-mortem paracetamol concentration in blood is far too high to be derived from breastmilk. Paracetamol has a similar half-life in neonates and adults.6 A blood concentration of 5·9 mg/L occurs in adults soon after a therapeutic dose; more than 24 h after
dosing, it suggests a life-threatening overdose.10 In addition, we believe that the presence of “high” amounts of morphine in the stomach post mortem should have been highlighted in the original Case Report. Although we acknowledge the complexities of codeine metabolism and the resultant difficulties in using this drug, we believe that this Case Report does not justify the author’s conclusions as to the cause of this child’s death.
Science Photo Library
Correspondence
See Comment page 606
Nearly 1 year after first contacting The Lancet about this issue, we were informed that the original product involved was made by a subsidiary of Johnson & Johnson. DNB was named on an unrestricted educational grant awarded to the University of Edinburgh from a different Johnson & Johnson subsidiary in 2001. We declare that we have no conflict of interest.
*D Nicholas Bateman, Michael Eddleston, Euan Sandilands [email protected] Scottish Poisons Information Bureau, New Royal Infirmary, 51 Little France, Edinburgh EH16 4SA, UK 1
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Koren G, Cairns J, Chitayat G, Leeder SJ. Pharmacogenetics of morphine poisoning in a breast fed neonate of a codeine-prescribed mother. Lancet 2006; 368: 704. Madadi P, Koren G, Cairns J, et al. Safety of codeine during breast feeding. Can Fam Physician 2007; 53: 33–35. Robieux I, Koren G, Vandenbergh H, Schneiderman J. Morphine excretion in breast milk and resultant exposure. J Toxicol Clin Toxicol 1990; 28: 365–70. Baka NE, Bavoumeu F, Boutrov MJ, Laxenaire MC. Colostrum morphine concentrations during postcesarean intravenous patient-controlled analgesia. Anesth Analg 2002; 94: 184–87. Wittels B, Scott DT, Sinatra RS. Exogenous opioids in human breast milk and acute neonatal neurobehavior: a preliminary study. Anesthesiology 1990; 73: 864–69. Spigset O, Hägg S. Analgesics and breastfeeding: safety considerations. Paediatr Drugs 2000; 2: 223–38. Bennett PN. Drugs and human lactation, 2nd edn. Amsterdam: Elsevier, 1996. Barrett DA, Barker DP, Rutter N, Pawula M, Shaw PN. Morphine, morphine-6-glucuronide and morphine-3-glucuronide pharmacokinetics in newborn infants receiving diamorphine infusions. Br J Clin Pharm 1996; 41: 531–37. Bitzen PO, Gustafsson B, Jostell KG, Melander A, Wahlin-Boll E. Excretion of paracetamol in human breast milk. Eur J Clin Pharmacol 1981; 20: 123–25. Anon. British national formulary 55. London: BMJ Publishing Group and RPS Publishing, 2008.
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
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100 mg morphine daily would result in a therapeutic neonatal morphine concentration. We and others4 agree with this assessment. On this basis, total conversion of the codeine in the present case would have produced only 60 mg morphine daily and neonatal blood morphine concentration well within the therapeutic range.5,6 Breastmilk morphine was 87 μg/L when retrospectively measured in this case, but post-mortem morphine in the baby was disproportionately high (70 μg/L).2 Therapeutic doses of morphine in neonates are 40–100 μg/L/kg intravenously. The baby’s oral dose of morphine was the concentration in milk (87 μg/L) multiplied by volume ingested (normally 30 mL/kg per feed7)—ie, about 8 μg per feed in a 3 kg child. Therefore morphine blood concentrations in this baby who had not been feeding well for more than 24 h should have been well below therapeutic levels. In view of the relations between neonatal morphine kinetics,8 plasma concentrations, and respiratory function, we do not believe that maternal ingestion of codeine can explain the baby’s death. A baby, symptomatic from ingestion of morphine in breastmilk, would reduce breastfeeding due to drowsiness before it could ingest a lethal dose. Furthermore, as opioidnaive individuals, the mother and infant would be expected to have similar features. Although this occurred within the first 2 days, it did not occur around the time of the baby’s death. With regard to our second concern, given that breastmilk typically provides less than 5% of a neonatal therapeutic dose of paracetamol and less than 5% of a weight-corrected maternal dose,6,9 we believe that the baby’s post-mortem paracetamol concentration in blood is far too high to be derived from breastmilk. Paracetamol has a similar half-life in neonates and adults.6 A blood concentration of 5·9 mg/L occurs in adults soon after a therapeutic dose; more than 24 h after
dosing, it suggests a life-threatening overdose.10 In addition, we believe that the presence of “high” amounts of morphine in the stomach post mortem should have been highlighted in the original Case Report. Although we acknowledge the complexities of codeine metabolism and the resultant difficulties in using this drug, we believe that this Case Report does not justify the author’s conclusions as to the cause of this child’s death.
Science Photo Library
Correspondence
See Comment page 606
Nearly 1 year after first contacting The Lancet about this issue, we were informed that the original product involved was made by a subsidiary of Johnson & Johnson. DNB was named on an unrestricted educational grant awarded to the University of Edinburgh from a different Johnson & Johnson subsidiary in 2001. We declare that we have no conflict of interest.
*D Nicholas Bateman, Michael Eddleston, Euan Sandilands [email protected] Scottish Poisons Information Bureau, New Royal Infirmary, 51 Little France, Edinburgh EH16 4SA, UK 1
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Koren G, Cairns J, Chitayat G, Leeder SJ. Pharmacogenetics of morphine poisoning in a breast fed neonate of a codeine-prescribed mother. Lancet 2006; 368: 704. Madadi P, Koren G, Cairns J, et al. Safety of codeine during breast feeding. Can Fam Physician 2007; 53: 33–35. Robieux I, Koren G, Vandenbergh H, Schneiderman J. Morphine excretion in breast milk and resultant exposure. J Toxicol Clin Toxicol 1990; 28: 365–70. Baka NE, Bavoumeu F, Boutrov MJ, Laxenaire MC. Colostrum morphine concentrations during postcesarean intravenous patient-controlled analgesia. Anesth Analg 2002; 94: 184–87. Wittels B, Scott DT, Sinatra RS. Exogenous opioids in human breast milk and acute neonatal neurobehavior: a preliminary study. Anesthesiology 1990; 73: 864–69. Spigset O, Hägg S. Analgesics and breastfeeding: safety considerations. Paediatr Drugs 2000; 2: 223–38. Bennett PN. Drugs and human lactation, 2nd edn. Amsterdam: Elsevier, 1996. Barrett DA, Barker DP, Rutter N, Pawula M, Shaw PN. Morphine, morphine-6-glucuronide and morphine-3-glucuronide pharmacokinetics in newborn infants receiving diamorphine infusions. Br J Clin Pharm 1996; 41: 531–37. Bitzen PO, Gustafsson B, Jostell KG, Melander A, Wahlin-Boll E. Excretion of paracetamol in human breast milk. Eur J Clin Pharmacol 1981; 20: 123–25. Anon. British national formulary 55. London: BMJ Publishing Group and RPS Publishing, 2008.
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
625