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Drug Res (Stuttg) 2015; 65(12): 640-644
DOI: 10.1055/s-0034-1396885
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Codeine Ultra-rapid Metabolizers: Age Appears to be a Key Factor in Adverse Effects of Codeine

K. Heintze
1   Institute of Pharmacology and Toxicology, RWTH Aachen, Aachen, Germany
,
W. Fuchs
2   Dr. Dr. Fuchs Consulting, Aachen, Germany
› Author Affiliations
Further Information

Publication History

received 18 November 2014

accepted 11 December 2014

Publication Date:
13 January 2015 (online)

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Abstract

Codeine is widely used as an analgesic drug. Taking into account the high consumption of codeine, only few fatal adverse events have been published. A number of reports, where neonates and children showed serious or fatal adverse reactions, led to a restriction of the use of codeine in this patient group. Therefore, we reviewed the safety of codeine in adults. PubMed was systematically searched for clinical studies and case reports, with a special focus on CYP2D6, the enzyme that converts codeine to morphine and exhibits genetic polymorphism.

181 cases were identified in adults in conjunction with serious or lethal effects of codeine. In the vast majority of cases, codeine was used in combination with other drugs by drug-dependent individuals or with a suicidal intent. Only 2 cases were found where ultra-rapid metabolizers experienced severe non-lethal adverse events. This is far less than would be predicted from the number of cases reported in children. The discrepancy may be explained by developmental changes in the disposition of codeine.

The strategy of regulatory authorities to restrict access to codeine for infants and young children, the apparent highest risk group, has a factual and pharmacological rationale. By the same standards, there is no need for restrictions for adult use of codeine.

Key words

codeine - ultra-rapid metabolizers - adults - children - CYP2D6 - CYP3A4
 

  • References

  • 1 FDA Drug Safety Communication. Codeine use in certain children after tonsillectomy and/or adenoidectomy may lead to rare, but life-threatening adverse events or death. 2012 http://www.fda.gov/drugs/drugsafety/ucm313631.htm
    PubMedGoogle Scholar
  • 2 FDA Drug Safety Communication. Safety review update of codeine use in children; new Boxed Warning and Contraindication on use after tonsillectomy and/or adenoidectomy. 2013 http://www.fda.gov/downloads/Drugs/DrugSafety/UCM339116.pdf
    PubMedGoogle Scholar
  • 3 EMA Restrictions on use of codeine for pain relief in children CMDh endorses PRAC recommendation; 28 June 2013; EMA/385716/2013. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/06/WC500144851.pdf
    PubMed
  • 4 Thorn CF, Klein TE, Altman RB. Codeine and morphine pathway. Pharmacogenet Genomics 2009; 19: 556-558
    CrossrefPubMedGoogle Scholar
  • 5 Quiding H, Olsson GL, Boreus LO et al. Infants and young children metabolise codeine to morphine. A study after single and repeated rectal administration. Br J Clin Pharmacol 1992; 33: 45-49
    CrossrefPubMedGoogle Scholar
  • 6 Daly AK, Brockmoller J, Broly F et al. Nomenclature for human CYP2D6 alleles. Pharmacogenetics 1996; 6: 193-202
    CrossrefPubMedGoogle Scholar
  • 7 Marez D, Legrand M, Sabbagh N et al. Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution. Pharmacogenetics 1997; 7: 193-202
    CrossrefPubMedGoogle Scholar
  • 8 Gardiner SJ, Begg EJ. Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice. Pharmacological Reviews 2006; 58: 521-590
    CrossrefPubMedGoogle Scholar
  • 9 Fernandes LC, Kilicarslan T, Kaplan HL et al. Treatment of codeine dependence with inhibitors of cytochrome P450 2D6. J Clin Psychopharmacol 2002; 22: 326-329
    CrossrefPubMedGoogle Scholar
  • 10 Recherche in der Nebenwirkungsdatenbank des BfArM. http://nebenwirkung.bfarm.de/apex/f?p=100:1:0 accessed 03.02.2014
    PubMed
  • 11 MHRA Drug Analysis Print 30-Dec-2013 http://www.mhra.gov.uk/home/groups/public/documents/sentineldocuments/dap_1390480192634.pdf accessed 03.02.2014
    PubMed
  • 12 Search MedWatch Drug Adverse Events (AERS/FAERS). http://www.fdable.com/advanced_aers_query accessed 03.02.2014
    PubMed
  • 13 FDA Drug Safety Communication. Safety review update of codeine use in children. http://www.fda.gov/Drugs/DrugSafety/ucm339112.htm
    PubMedGoogle Scholar
  • 14 Dalén P, Frengell C, Dahl ML et al. Quick onset of severe abdominal pain after codeine in an ultrarapid metabolizer of debrisoquine. Ther Drug Monit 1997; 19: 543-544
    CrossrefPubMedGoogle Scholar
  • 15 Gasche Y, Daali Y, Fathi M et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 2004; 351: 2827-2831
    CrossrefPubMedGoogle Scholar
  • 16 Meny RG, Naumburg EG, Alger LS et al. Codeine and the Breastfed Neonate. Hum Lact 1993; 9: 237
    PubMedGoogle Scholar
  • 17 Ladona MG, Spalding DJ, Persson K et al. Metabolic pathways of ethylmorphine, codeine and dextromethorphan in human fetal liver. Eur J clin Pharmac 1989; 36S: A148
    PubMedGoogle Scholar
  • 18 Stevens JC, Marsh SA, Zaya MJ et al. Developmental Changes in Human Liver CYP2D6 Expression. Drug Metab Dispos 2008; 36: 1587-1593
    CrossrefPubMedGoogle Scholar
  • 19 Williams DG, Hatch DJ, Howard RF. Codeine phosphate in paediatric medicine. British Journal of Anaesthesia 2001; 86: 413-421
    CrossrefPubMedGoogle Scholar
  • 20 Komori M, Nishio K, Kitada M et al. Fetus-specific expression of a form of cytochrome P-450 in human livers. Biochemistry 1990; 29: 4430-4433
    CrossrefPubMedGoogle Scholar
  • 21 Lacroix D, Sonnier M, Moncion A et al. Expression of CYP3A in the human liver – evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. Eur J Biochem 1997; 247: 625-634
    CrossrefPubMedGoogle Scholar
  • 22 Zaya MJ, Hines RN, Stevens JC. Epirubicin Glucuronidation and UGT2B7 Developmental Expression. Drug Metabolism and Disposition 2006; 34: 2097-2101
    CrossrefPubMedGoogle Scholar
  • 23 Choonara IA, McKay P, Hain R et al. Morphine metabolism in children. Br J Clin Pharm 1989; 28: 599-604
    CrossrefPubMedGoogle Scholar
  • 24 de Wildt SN, Kearns GL, Leeder JS et al. Glucuronidation in humans: Pharmacogenetic and developmental Aspects. Clinical Pharmacokinetics 1999; 36: 439-452
    CrossrefPubMedGoogle Scholar
  • 25 Krekels EHJ. Size does matter: drug glucuronidation in children. PhD thesis 2012 Leiden University
    PubMedGoogle Scholar
  • 26 Madadi P, Ross CJD, Hayden MR et al. Pharmacogenetics of Neonatal Opioid Toxicity Following Maternal Use of Codeine During Breastfeeding: A Case-Control Study. Clin Pharmacol Ther 2009; 85: 31-35
    CrossrefPubMedGoogle Scholar
  • 27 Gibbons CA, Blaine SM, Allanson J et al. Genetics: Codeine metabolism. Can Fam Physician 2009; 55: 164
    PubMedGoogle Scholar
  • 28 Kelly LE, Chaudhry SA, Rieder MJ et al. A clinical tool for reducing central nervous system depression among neonates exposed to codeine through breast milk. PLoS One 2013; 8: e70073
    CrossrefPubMedGoogle Scholar
  • 29 Faura CC, Collins SL, Moore RA et al. Systematic review of factors affecting the ratios of morphine and its major metabolites. Pain 1998; 74: 43-53
    CrossrefPubMedGoogle Scholar
  • 30 Ciszkowski C, Madadi P, Philips MS et al. Codeine, ultrarapid-metabolism genotype, and postoperative death. N Engl J Med 2009; 361: 827-828
    CrossrefPubMedGoogle Scholar
  • 31 Brown KA, Laferrière A, Lakheeram I et al. Recurrent hypoxaemia in children is associated with increased analgesic sensitivity in children. Anaesthesiology 2006; 105: 665-669
    CrossrefPubMedGoogle Scholar
  • 32 Lerman J. Unravelling the mysteries of sleep disordered breathing in children. Anesthesiology 2006; 105: 645-647
    CrossrefPubMedGoogle Scholar
  • 33 Bouwmeester NJ, Anderson BJ, Tibboel D et al. Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. British Journal of Anaesthesia 2004; 92: 208-217
    CrossrefPubMedGoogle Scholar
  • 34 Saunders NR, Liddelow SA, Dziegielewska KM. Barrier Mechanisms in the Developing Brain. Front Pharmacol 2012; 3: 46
    PubMedGoogle Scholar
  • 35 Hasselström J, Säwe J. Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active opioid concentrations. Clin Pharmacokinet 1993; 24: 344-354
    CrossrefPubMedGoogle Scholar
  • 36 Vree TB, van Dongen RT, Koopman-Kimenai PM. Codeine analgesia is due to codeine-6-glucuronide, not morphine. Int J Clin Practa 2000; 54: 395-398
    PubMedGoogle Scholar
  • 37 Wilkes TCR, Davies DF, Dar MF. Apnoea in a 3-month-old baby prescribed compound Linctus containing codeine. Lancet 1981; 8230: 1166-1167
    PubMedGoogle Scholar
  • 38 Bass M, Hass R. Near death in twins. JAMA 1992; 268: 1860
    CrossrefPubMedGoogle Scholar
  • 39 Riedler J. Cibalen poisoning in an infant. Padiatr Padol 1988; 23: 343-348
    PubMedGoogle Scholar
  • 40 Magnani B, Evens R. Codeine intoxication in the neonate. Pediatrics 1999; 104: e75
    CrossrefPubMedGoogle Scholar
  • 41 Tong TF, Ng KK. Codeine ingestion and apparent life-threatening event in a neonate. Pediatr Int 2001; 43: 517-518
    CrossrefPubMedGoogle Scholar
  • 42 Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant – an ultra rapid metabolizer. Paediatr Anaesth 2007; 17: 684-687
    CrossrefPubMedGoogle Scholar
  • 43 Ferreirós N, Dresen S, Hermanns-Clausen M et al. Fatal and severe codeine intoxication in 3-year-old twins – interpretation of drug and metabolite concentrations. Int J Legal Med 2009; 123: 387-394
    CrossrefPubMedGoogle Scholar
  • 44 Friedrichsdorf SJ, Nugent AP, Strobl AQ. Codeine-associated pediatric deaths despite using recommended dosing guidelines: three case reports. J Opioid Manag 2013; 9: 151-155
    CrossrefPubMedGoogle Scholar
  • 45 Winek CL, Collom WD, Wecht CH. Codeine fatality from cough syrup. Clin Toxicol 1970; 3: 97-100
    CrossrefPubMedGoogle Scholar
  • 46 Wright JA, Baselt RC, Hine CH. Blood codeine concentrations in fatalities associated with codeine. Clin Toxicol 1975; 8: 457-463
    CrossrefPubMedGoogle Scholar
  • 47 Turner JE, Cravey RH. A fatal case involving propranolol and codeine. Clin Toxicol 1975; 8: 271-275
    CrossrefPubMedGoogle Scholar
  • 48 Peat MA, Sengupta A. Toxicological investigations of cases of death involving codeine and dihydrocodeine. Forensic Sci 1977; 9: 21-32
    CrossrefPubMedGoogle Scholar
  • 49 Pearson MA, Poklis A, Morrison RR. A fatality due to the ingestion of (methyl morphine) codeine. Clin Toxicol 1979; 15: 267-271
    CrossrefPubMedGoogle Scholar
  • 50 Cardan E. Fatal case of codeine poisoning. Lancet 1981; 8233: 1313
    PubMedGoogle Scholar
  • 51 Litman RE, Diller J, Nelson F. Deaths related to propoxyphene or codeine or both. J Forensic Sci 1983; 28: 128-138
    PubMedGoogle Scholar
  • 52 Havier RG, Lin R. Deaths as a result of a combination of codeine and glutethimide. Forensic Sci 1985; 30: 563-566
    PubMedGoogle Scholar
  • 53 Leslie PJ, Dyson EH, Proudfoot AT. Opiate toxicity after self poisoning with aspirin and codeine. Br Med J 1986; 6513: 96
    PubMedGoogle Scholar
  • 54 Kintz P, Tracqui A, Mangin P. Codeine concentrations in human samples in a case of fatal ingestion. Int J Legal Med 1991; 104: 177-178
    CrossrefPubMedGoogle Scholar
  • 55 Parke TJ, Nandi PR, Bird KJ et al. Profound hypotension following intravenous codeine phosphate. Three case reports and some recommendations. Anaesthesia 1992; 47: 852-854
    CrossrefPubMedGoogle Scholar
  • 56 Rademaker J, Severs M. Opiate related collapse in an octogenarian. BMJ 1993; 6898: 241
    PubMedGoogle Scholar
  • 57 Gerostamoulos J, Burke MP, Drummer OH. Involvement of codeine in drug-related deaths. Am J Forensic Med Pathol 1996; 17: 327-335
    CrossrefPubMedGoogle Scholar
  • 58 Kelly LE, Rieder M, van den Anker J et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics 2012; 129: e1343-e1347
    CrossrefPubMedGoogle Scholar