Correspondence
Codeine, Ultrarapid-Metabolism Genotype, and Postoperative Death
N Engl J Med 2009; 361:827-828August 20, 2009
- Article
To the Editor:
Obstructive sleep apnea is not rare in children with hypertrophic tonsils, and the common curative procedure is adenotonsillectomy.1 Codeine is commonly prescribed for pain after adenotonsillectomy.2 The respiratory depressant effects of opioids may influence the occurrence of respiratory complications.3 An estimated one third of cases of apnea in children are not resolved after adenotonsillectomy.4
We report on the case of a healthy 2-year-old boy weighing 13 kg, with a history of snoring and sleep-study–confirmed sleep apnea, who underwent elective adenotonsillectomy. The outpatient surgery was uncomplicated, and 6 hours after surgery the boy received 10 mg of meperidine and 12.5 mg of dimenhydrinate intramuscularly and was sent home with instructions for 10 to 12.5 mg of codeine and 120 mg of acetaminophen syrup to be administered orally every 4 to 6 hours as needed. On the second evening after surgery, fever and wheezing developed in the child. At 9 a.m. the next day, the child's vital signs were absent, and resuscitation efforts failed.
Postmortem examination showed evidence of chronic tracheitis, aspiration of food particles, and bilateral consolidation in the lungs that was consistent with bronchopneumonia. Codeine (0.70 mg per liter) and morphine (32 ng per milliliter) were detected in the femoral blood by means of gas chromatography–mass spectrometry; there was no evidence of other drugs or metabolites. Cytochrome P-450 2D6 (CYP2D6) genotyping revealed functional duplication of the CYP2D6 allele, resulting in the ultrarapid-metabolizer phenotype.
In this case, the prescribed and administered dose of codeine was within the recommended range of 1 to 3 mg per kilogram of body weight per day.1,2 Increased conversion of codeine to morphine due to ultrarapid metabolism resulted in toxic accumulation of morphine. The concentration of 32 ng per milliliter of morphine at autopsy exceeded therapeutic levels and may have contributed to respiratory depression and death. Respiratory depression has been shown in young children with serum morphine concentrations exceeding 20 ng per milliliter.3
The boy had other contributing factors that should be considered. Autopsy results indicated evidence of bronchopneumonia, further enhancing the risk of hypoxemia. As many as a third of young children with obstructive sleep apnea remain symptomatic after adenotonsillectomy,4 showing decreased responsiveness to increases in the partial pressure of carbon dioxide.5 Recurrent episodes of hypoxemia may lead to alterations in the μ-opioid receptor and increased sensitivity to morphine. A child who has recurrent episodes of hypoxemia and who is also an ultrarapid metabolizer of codeine may have a significantly increased risk of respiratory depression. We are unaware of any other fatalities attributable to the ultrarapid metabolism of CYP2D6 in this susceptible population.
Because of the polymorphic nature of codeine metabolism and the fact that adenotonsillectomy does not reverse all cases of obstructive sleep apnea, codeine cannot be considered a safe outpatient analgesic for young children after adenotonsillectomy.
5 ReferencesCatherine Ciszkowski, B.Sc.
Parvaz Madadi, Ph.D.
University of Western Ontario, London, ON, CanadaMichael S. Phillips, Ph.D.
Montreal Heart Institute, Montreal, QC, CanadaAlbert E. Lauwers, M.D.
Office of the Chief Coroner, Toronto, ON, CanadaGideon Koren, M.D.
University of Toronto, Toronto, ON, Canada
gkoren@sickkids.ca 1
Warwick JP ,Mason DG . Obstructive sleep apnoea syndrome in children. Anaesthesia 1998;53:571-579
CrossRef | Web of Science | Medline2
Lloyd-Thomas AR . Pain management in paediatric patients. Br J Anaesth 1990;64:85-104
CrossRef | Web of Science | Medline3
Lynn AM ,Nespeca MK ,Opheim KE ,Slattery JT . Respiratory effects of intravenous morphine infusions in neonates, infants, and children after cardiac surgery. Anesth Analg 1993;77:695-701
CrossRef | Web of Science | Medline4
Brown KA . What we don't know about childhood obstructive sleep apnoea. Paediatr Anaesth 2001;11:385-389
CrossRef | Web of Science | Medline5
Waters KA ,McBrien F ,Stewart P ,Hinder M ,Wharton S . Effects of OSA, inhalational anesthesia, and fentanyl on the airway and ventilation of children. J Appl Physiol 2002;92:1987-1994
CrossRef | Web of Science | Medline
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R. Landau, L. A. Bollag, J. C. Kraft. (2012) Pharmacogenetics and anaesthesia: the value of genetic profiling. Anaesthesia 67:2, 165-179
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K R Crews, A Gaedigk, H M Dunnenberger, T E Klein, D D Shen, J T Callaghan, E D Kharasch, T C Skaar. (2012) Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Codeine Therapy in the Context of Cytochrome P450 2D6 (CYP2D6) Genotype. Clinical Pharmacology & Therapeutics 91:2, 321-326
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Sudeep P. Pushpakom, Munir Pirmohamed. 2011. Pharmacogenetics of Adverse Drug Reactions. , 121-156.
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Saskia N de Wildt. (2011) Profound changes in drug metabolism enzymes and possible effects on drug therapy in neonates and children. Expert Opinion on Drug Metabolism & Toxicology 7:8, 935-948
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Christopher L Wu, Srinivasa N Raja. (2011) Treatment of acute postoperative pain. The Lancet 377:9784, 2215-2225
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Yijing He, Janelle M. Hoskins, Howard L. McLeod. (2011) Copy number variants in pharmacogenetic genes. Trends in Molecular Medicine 17:5, 244-251
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A.H. Ghodse, S. Galea. 2011. Opioid analgesics and narcotic antagonists. , 205-239.
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Melissa M Statham, Charles M Myer. (2010) Complications of adenotonsillectomy. Current Opinion in Otolaryngology & Head and Neck Surgery 18:6, 539-543
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Geoffrey K Isbister, Felicity Prior, Henry A Kilham. (2010) Restricting cough and cold medicines in children. Journal of Paediatrics and Child Healthno-no
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