CLINICAL PRACTICE GUIDELINE: CYP2D6 GENOTYPING FOR SAFE AND EFFICACIOUS CODEINE THERAPY
Main Article Content
Keywords
Codeine, morphine, pharmacogenetics, CYP2D6, guidelines
Abstract
This guideline is intended to provide a basis for informed decision-making regarding genetic testing to identify those individuals who will not benefit from codeine therapy, as well as those who are at an increased risk for codeine-induced toxicity. This guideline addresses the following key questions: 1) Should genetic testing for CYP2D6 be performed in patients prior to the initiation of codeine therapy? 2) How should patients with an indication for codeine therapy be managed based on their genotyping results for CYP2D6?
References
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2. Volpe DA, et al. Uniform assessment and ranking of opioid mu receptor binding constants for selected opioid drugs. Regulatory Toxicology and Pharmacology 2011;59:385-90.
3. Gasche Y, et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. The New England Journal of Medicine 2004;351:2827-31.
4. Sistonen J, et al. CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenetics and Genomics 2007;17:93-101.
5. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clinical Pharmacokinetics 2009;48:689-723.
6. Brousseau DC, McCarver DG, Drendel AL, Divakaran K, Panepinto JA. The effect of CYP2D6 polymorphisms on the response to pain treatment for pediatric sickle cell pain crisis. Journal of Pediatrics 2007;150:623-6.
7. Foster A, Mobley E, Wang Z. Complicated pain management in a CYP450 2D6 poor metabolizer. Pain practice: The Official Journal of World Institute of Pain 2007;7:352-6.
8. Susce MT, Murray-Carmichael E, de Leon J. Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2006;30:1356-8.
9. vanderVaart S, et al. CYP2D6 Polymorphisms and Codeine Analgesia in Postpartum Pain Management: A Pilot Study. Therapeutic Drug Monitoring 2001;33:425-32.
10. Willmann S, Edginton AN, Coboeken K, Ahr, G, Lippert J. Risk to the breast-fed neonate from codeine treatment to the mother: a quantitative mechanistic modeling study. Clinical Pharmacology and Therapeutics 2009;86:634-43.
11. Dalen P, Frengell C, Dahl ML, Sjoqvist F. Quick onset of severe abdominal pain after codeine in an ultrarapid metabolizer of debrisoquine. Therapeutic Drug Monitoring 1997;19:543-4.
12. Kirchheiner J, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. The Pharmacogenomics Journal 2007;7:257-65.
13. Moore RA, Derry S, McQuay HJ, Wiffen PJ. Single dose oral analgesics for acute postoperative pain in adults. Cochrane Database of Systematic Reviews, CD008659 (2011).
14. Madadi P, Avard D, Koren G. Pharmacogenetics of opioids for the treatment of acute maternal pain during pregnancy and lactation. Current Drug Metabolism 2012;13:721-7.
15. League Table of Analgesics. http://www.medicine.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/Leagtab.html [Accessed April 5, 2012].
16. Samer CF, et al. Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety. British Journal of Pharmacology 2010;160:919-30.
17. Stamer UM, Stuber F, Muders T, Musshoff F. Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesthesia and Analgesia 2008;107:926-9.
18. Kelly LE, et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics 2012;129:e1343-7.
19. Hutchinson MR, Menelaou A, Foster DJ, Coller JK, Somogyi AA. CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. British Journal of Clinical Pharmacology 2004;57:287-97.
20. Ferreiros N, et al. Fatal and severe codeine intoxication in 3-year-old twins--interpretation of drug and metabolite concentrations. International Journal of Legal Medicine 2009;123:387-94.
21. Madadi P, et al. Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control study. Clinical Pharmacology and Therapeutics 2009;85:31-5.
22. Sistonen J, et al. Prediction of codeine toxicity in infants and their mothers using a novel combination of maternal genetic markers. Clinical Pharmacology and Therapeutics 2012;91:692-9.
23. Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant - an ultra-rapid metabolizer. Paediatric Anaesthesia 2007;17:684-7.
24. Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. The Journal of Pharmacology and Experimental Therapeutics 1996; 278:1165-74.
25. Wadelius M, Darj E, Frenne G, Rane A. Induction of CYP2D6 in pregnancy. Clinical Pharmacology and Therapeutics 1997;62:400-7.
26. Gaedigk A, et al. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clinical Pharmacology and Therapeutics 2008;83:234-42.
27. Madadi P, Koren G. Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use. Pharmacogenomics 2008;9:1267-84.
28. Blake MJ, et al. Ontogeny of dextromethorphan O- and N-demethylation in the first year of life. Clinical Pharmacology and Therapeutics 2007;81:510-6.
29. de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Glucuronidation in humans - Pharmacogenetic and developmental aspects. Clinical Pharmacokinetics 1999;36:439-52.
30. Eckhardt K, et al. Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain 1998;76:27-33.
31. Poulsen L, et al. Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. European Journal of Clinical Pharmacology 1996; 51:289-95.
32. Williams DG, Patel A, Howard RF. Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability. British Journal of Anaesthesia 2002; 89:839-45.
33. Chen ZR, Somogyi AA, Reynolds G, Bochner F. Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. British Journal of Clinical Pharmacology 1991;31:381-90.
34. Desmeules J, Gascon MP, Dayer P, Magistris M. Impact of environmental and genetic factors on codeine analgesia. European Journal of Clinical Pharmacology 1991;41:23-6.
35. Lotsch J, et al. Can extremely low or high morphine formation from codeine be predicted prior to therapy initiation? Pain 2009;144:119-124.
36. Molanaei H, et al. Influence of the CYP2D6 polymorphism and hemodialysis on codeine disposition in patients with end-stage renal disease. European Journal of Clinical Pharmacology 2010; 66:269-73.
37. Shord SS, et al. The pharmacokinetics of codeine and its metabolites in Blacks with sickle cell disease. European Journal of Clinical Pharmacology 2009;65:651-8.
38. Yue QY, Alm C, Svensson JO, Sawe J. Quantification of the O- and N-demethylated and the glucuronidated metabolites of codeine relative to the debrisoquine metabolic ratio in urine in ultrarapid, rapid, and poor debrisoquine hydroxylators. Therapeutic Drug Monitoring 1997;19:539-42.
39. Yue QY, Hasselstrom J, Svensson JO, Sawe J. Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine. British Journal of Clinical Pharmacology 1991;31:635-42.
40. Yue QY, Svensson JO, Alm C, Sjoqvist F, Sawe J. Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation. British Journal of Clinical Pharmacology 1989;28:639-45.
41. Derry S, Moore RA, McQuay HJ. Single dose oral codeine, as a single agent, for acute postoperative pain in adults. Cochrane Database of Systematic Reviews (2010).
42. Ciszkowski C, Madadi P, Phillips MS, Lauwers AE, Koren G. Codeine, ultrarapid-metabolism genotype, and postoperative death. The New England Journal of Medicine 2009;361:827-8.
43. 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;368:704.
44. Madadi P, et al. Safety of codeine during breastfeeding: fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine. Canadian Family Physician 2007;53:33-5.
45. Yue QY, Svensson JO, Sjoqvist F, Sawe J. A comparison of the pharmacokinetics of codeine and its metabolites in healthy Chinese and Caucasian extensive hydroxylators of debrisoquine. British Journal of Clinical Pharmacology 1991;31:643-7.
46. Madadi P, et al. Genetic transmission of cytochrome P450 2D6 (CYP2D6) ultrarapid metabolism: implications for breastfeeding women taking codeine. Current Drug Safety 2011;6:36-9.
47. Eissing T, Lippert J, Willmann S. Pharmacogenomics of Codeine, Morphine, and Morphine-6-Glucuronide Model-Based Analysis of the Influence of CYP2D6 Activity, UGT2B7 Activity, Renal Impairment, and CYP3A4 Inhibition. Molecular Diagnosis & Therapy 2012;16:43-53.
48. Innocenti F, et al. Single nucleotide polymorphism discovery and functional assessment of variation in the UDP-glucuronosyltransferase 2B7 gene. Pharmacogenetics and Genomics 2008; 18:683-97.
49. Caraco Y, Tateishi T, Guengerich FP, Wood, AJ. Microsomal codeine N-demethylation: cosegregation with cytochrome P4503A4 activity. Drug Metabolism and Disposition: The Biological Fate of Chemicals 1996;24:761-4.
50. Vree TB, Van Dongen RTM, Koopman-Kimenai PM. Codeine analgesia is due to codeine-6-glucuronide, not morphine. International Journal of Clinical Practice 2000;54:395-8.
51. Lotsch J, et al. Evidence for morphine-independent central nervous opioid effects after administration of codeine: Contribution of other codeine metabolites. Clinical Pharmacology & Therapeutics 2006;79:35-48.
52. Brouwers MC, et al. AGREE II: advancing guideline development, reporting and evaluation in health care. Canadian Medical Association Journal 2010;182:e839-42.
53. Guyatt GH, et al. Going from evidence to recommendations. British Medical Journal 2008;336:1049-51.
54. CYP2D6 Allele Nomenclature. http://www.cypalleles.ki.se/cyp2d6.htm. (Accessed Dec 3, 2012).
55. U.S. Food and Drug Administration. Classification of In Vivo Inhibitors of CYP Enzymes. http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm - classInhibit (Accessed April 5, 2012).
2. Volpe DA, et al. Uniform assessment and ranking of opioid mu receptor binding constants for selected opioid drugs. Regulatory Toxicology and Pharmacology 2011;59:385-90.
3. Gasche Y, et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. The New England Journal of Medicine 2004;351:2827-31.
4. Sistonen J, et al. CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenetics and Genomics 2007;17:93-101.
5. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clinical Pharmacokinetics 2009;48:689-723.
6. Brousseau DC, McCarver DG, Drendel AL, Divakaran K, Panepinto JA. The effect of CYP2D6 polymorphisms on the response to pain treatment for pediatric sickle cell pain crisis. Journal of Pediatrics 2007;150:623-6.
7. Foster A, Mobley E, Wang Z. Complicated pain management in a CYP450 2D6 poor metabolizer. Pain practice: The Official Journal of World Institute of Pain 2007;7:352-6.
8. Susce MT, Murray-Carmichael E, de Leon J. Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2006;30:1356-8.
9. vanderVaart S, et al. CYP2D6 Polymorphisms and Codeine Analgesia in Postpartum Pain Management: A Pilot Study. Therapeutic Drug Monitoring 2001;33:425-32.
10. Willmann S, Edginton AN, Coboeken K, Ahr, G, Lippert J. Risk to the breast-fed neonate from codeine treatment to the mother: a quantitative mechanistic modeling study. Clinical Pharmacology and Therapeutics 2009;86:634-43.
11. Dalen P, Frengell C, Dahl ML, Sjoqvist F. Quick onset of severe abdominal pain after codeine in an ultrarapid metabolizer of debrisoquine. Therapeutic Drug Monitoring 1997;19:543-4.
12. Kirchheiner J, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. The Pharmacogenomics Journal 2007;7:257-65.
13. Moore RA, Derry S, McQuay HJ, Wiffen PJ. Single dose oral analgesics for acute postoperative pain in adults. Cochrane Database of Systematic Reviews, CD008659 (2011).
14. Madadi P, Avard D, Koren G. Pharmacogenetics of opioids for the treatment of acute maternal pain during pregnancy and lactation. Current Drug Metabolism 2012;13:721-7.
15. League Table of Analgesics. http://www.medicine.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/Leagtab.html [Accessed April 5, 2012].
16. Samer CF, et al. Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety. British Journal of Pharmacology 2010;160:919-30.
17. Stamer UM, Stuber F, Muders T, Musshoff F. Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesthesia and Analgesia 2008;107:926-9.
18. Kelly LE, et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics 2012;129:e1343-7.
19. Hutchinson MR, Menelaou A, Foster DJ, Coller JK, Somogyi AA. CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. British Journal of Clinical Pharmacology 2004;57:287-97.
20. Ferreiros N, et al. Fatal and severe codeine intoxication in 3-year-old twins--interpretation of drug and metabolite concentrations. International Journal of Legal Medicine 2009;123:387-94.
21. Madadi P, et al. Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control study. Clinical Pharmacology and Therapeutics 2009;85:31-5.
22. Sistonen J, et al. Prediction of codeine toxicity in infants and their mothers using a novel combination of maternal genetic markers. Clinical Pharmacology and Therapeutics 2012;91:692-9.
23. Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant - an ultra-rapid metabolizer. Paediatric Anaesthesia 2007;17:684-7.
24. Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. The Journal of Pharmacology and Experimental Therapeutics 1996; 278:1165-74.
25. Wadelius M, Darj E, Frenne G, Rane A. Induction of CYP2D6 in pregnancy. Clinical Pharmacology and Therapeutics 1997;62:400-7.
26. Gaedigk A, et al. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clinical Pharmacology and Therapeutics 2008;83:234-42.
27. Madadi P, Koren G. Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use. Pharmacogenomics 2008;9:1267-84.
28. Blake MJ, et al. Ontogeny of dextromethorphan O- and N-demethylation in the first year of life. Clinical Pharmacology and Therapeutics 2007;81:510-6.
29. de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Glucuronidation in humans - Pharmacogenetic and developmental aspects. Clinical Pharmacokinetics 1999;36:439-52.
30. Eckhardt K, et al. Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain 1998;76:27-33.
31. Poulsen L, et al. Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. European Journal of Clinical Pharmacology 1996; 51:289-95.
32. Williams DG, Patel A, Howard RF. Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability. British Journal of Anaesthesia 2002; 89:839-45.
33. Chen ZR, Somogyi AA, Reynolds G, Bochner F. Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. British Journal of Clinical Pharmacology 1991;31:381-90.
34. Desmeules J, Gascon MP, Dayer P, Magistris M. Impact of environmental and genetic factors on codeine analgesia. European Journal of Clinical Pharmacology 1991;41:23-6.
35. Lotsch J, et al. Can extremely low or high morphine formation from codeine be predicted prior to therapy initiation? Pain 2009;144:119-124.
36. Molanaei H, et al. Influence of the CYP2D6 polymorphism and hemodialysis on codeine disposition in patients with end-stage renal disease. European Journal of Clinical Pharmacology 2010; 66:269-73.
37. Shord SS, et al. The pharmacokinetics of codeine and its metabolites in Blacks with sickle cell disease. European Journal of Clinical Pharmacology 2009;65:651-8.
38. Yue QY, Alm C, Svensson JO, Sawe J. Quantification of the O- and N-demethylated and the glucuronidated metabolites of codeine relative to the debrisoquine metabolic ratio in urine in ultrarapid, rapid, and poor debrisoquine hydroxylators. Therapeutic Drug Monitoring 1997;19:539-42.
39. Yue QY, Hasselstrom J, Svensson JO, Sawe J. Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine. British Journal of Clinical Pharmacology 1991;31:635-42.
40. Yue QY, Svensson JO, Alm C, Sjoqvist F, Sawe J. Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation. British Journal of Clinical Pharmacology 1989;28:639-45.
41. Derry S, Moore RA, McQuay HJ. Single dose oral codeine, as a single agent, for acute postoperative pain in adults. Cochrane Database of Systematic Reviews (2010).
42. Ciszkowski C, Madadi P, Phillips MS, Lauwers AE, Koren G. Codeine, ultrarapid-metabolism genotype, and postoperative death. The New England Journal of Medicine 2009;361:827-8.
43. 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;368:704.
44. Madadi P, et al. Safety of codeine during breastfeeding: fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine. Canadian Family Physician 2007;53:33-5.
45. Yue QY, Svensson JO, Sjoqvist F, Sawe J. A comparison of the pharmacokinetics of codeine and its metabolites in healthy Chinese and Caucasian extensive hydroxylators of debrisoquine. British Journal of Clinical Pharmacology 1991;31:643-7.
46. Madadi P, et al. Genetic transmission of cytochrome P450 2D6 (CYP2D6) ultrarapid metabolism: implications for breastfeeding women taking codeine. Current Drug Safety 2011;6:36-9.
47. Eissing T, Lippert J, Willmann S. Pharmacogenomics of Codeine, Morphine, and Morphine-6-Glucuronide Model-Based Analysis of the Influence of CYP2D6 Activity, UGT2B7 Activity, Renal Impairment, and CYP3A4 Inhibition. Molecular Diagnosis & Therapy 2012;16:43-53.
48. Innocenti F, et al. Single nucleotide polymorphism discovery and functional assessment of variation in the UDP-glucuronosyltransferase 2B7 gene. Pharmacogenetics and Genomics 2008; 18:683-97.
49. Caraco Y, Tateishi T, Guengerich FP, Wood, AJ. Microsomal codeine N-demethylation: cosegregation with cytochrome P4503A4 activity. Drug Metabolism and Disposition: The Biological Fate of Chemicals 1996;24:761-4.
50. Vree TB, Van Dongen RTM, Koopman-Kimenai PM. Codeine analgesia is due to codeine-6-glucuronide, not morphine. International Journal of Clinical Practice 2000;54:395-8.
51. Lotsch J, et al. Evidence for morphine-independent central nervous opioid effects after administration of codeine: Contribution of other codeine metabolites. Clinical Pharmacology & Therapeutics 2006;79:35-48.
52. Brouwers MC, et al. AGREE II: advancing guideline development, reporting and evaluation in health care. Canadian Medical Association Journal 2010;182:e839-42.
53. Guyatt GH, et al. Going from evidence to recommendations. British Medical Journal 2008;336:1049-51.
54. CYP2D6 Allele Nomenclature. http://www.cypalleles.ki.se/cyp2d6.htm. (Accessed Dec 3, 2012).
55. U.S. Food and Drug Administration. Classification of In Vivo Inhibitors of CYP Enzymes. http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm - classInhibit (Accessed April 5, 2012).