For greater than 50 years codeine (3-methylmorphine) has been valued as a safe and effective form of pain relief in the pediatric population. Frequently being prescribed for post-operative analgesia and as an antitussive, codeine is now gaining traction as having a reputation for being a poor choice for both. About a decade ago the WHO even deemed it a step 2 medication in the pediatric pain ladder for moderate pain. This position has since been reversed in 2011 because of concerns that its “efficacy and safety were questionable in an unpredictable portion of the paediatric population.”5 However, its use is still widespread. During the years 2007–2011, otolaryngologists were the most frequent prescribers of codeine/acetaminophen liquid formulations (19.6%), followed by dentists (13.3%), pediatricians (12.7%), and general practice/family physicians (10.1%).4

Codeine in and of itself is not responsible for analgesia. Its analgesia is secondary to the conversion to morphine through the cytochrome p450 2D6 pathway. In the past there have been many articles regarding poor metabolizers and the ineffectiveness of codeine as it was not effectively metabolized into morphine and, therefore, its analgesic effect was poor.1,2,3

It is only in the recent past that the concern for codeine overdoses was brought to light. There are case reports regarding inadvertent pediatric codeine overdoses sparking ongoing pharmacogenetic research and changes to government and medical organizational policies.

There have been many advances in pharmacogenetics and how inter-individual genetic differences play a role in the metabolism of a drug. In particular, the CYP 2D6 pathway, by which codeine is metabolized into morphine, has > 70 different alleles with individuals inheriting one allele from each parent. Individuals are categorized as either extensive, intermediate, or poor metabolizers. Those individuals with duplicate alleles, ultrarapid metabolizers, that convert codeine into large amounts of morphine are at highest risk for respiratory depression, apnea and death, even at normal therapeutic doses of codeine. The frequency of the ultrarapid metabolizer genotype has been estimated at ~29% of patients of African/Ethiopian heritage, ~21% of those from Saudi Arabia and other Middle Eastern countries, and ~3.4% to 6.5% of African-American and white persons.6,7,8,9 Intermediate metabolism tends to be more common in Asians than in whites,10 but poor metabolism is less common.11 In February 2013 the FDA added a “black box warning” to the drug label of codeine and codeine-containing preparations. The warning advises healthcare professionals “to prescribe an alternative analgesic [to codeine] for postoperative pain control in children undergoing tonsillectomy and/or adenoidectomy.” A contraindication was added to restrict codeine use in such patients. The “Warnings/Precautions,” “Pediatric Use,” and “Patient Counseling Information” sections of the label were also updated.12 Recently, a review by the FDA of the Adverse Event Reporting System data from 1965 to 2015 in children who had used codeine or any codeine-containing products revealed a total of 64 cases of severe respiratory depression and 24 codeine-related deaths, 21 of which were in children younger than 12 years.13

Published reports and clinical evidence have shown the potential dangers of codeine as an analgesic and antitussive. Despite the FDA, the American Academy of Pediatrics, as well as the European Medicines Agency and Health Canada, all emphasizing these concerns, regular codeine administration continues. Until pharmacogenetic testing becomes commonplace and inexpensive allowing the tailoring of a specific drug to the individual, perhaps there is now enough evidence to limit the use of codeine.

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  1. May DG. Genetic differences in drug disposition. J Clin Pharmacol. 1994;34(9):881–897pmid:7983231
  2. Poulsen L, Riishede L, Brøsen K, Clemensen S, Sindrup SH. Codeine in post-operative pain: study of the influence of sparteine phenotype and serum concentrations of morphine and morphine-6-glucuronide. Eur J Clin Pharmacol. 1998;54(6):451–454pmid:9776433
  3. VanderVaart S, Berger H, Sistonen J, et al. CYP2D6 polymorphisms and codeine analgesia in postpartum pain management: a pilot study. Ther Drug Monit. 2011;33(4):425–432pmid:21743374
  4. Racoosin JA. Death and respiratory arrest related to ultra-rapid metabolism of codeine to morphine.
  5. World Health Organization. Unedited report of the 18th Expert Committee on the Selection and Use of Essential Medicines. Geneva, Switzerland: World Health Organization; 2011.
  6. Cascorbi I. Pharmacogenetics of cytochrome p4502D6: genetic background and clinical implication. Eur J Clin Invest. 2003;33(suppl 2):17–22pmid:14641552
  7. Tremlett MR. Wither codeine? Paediatr Anaesth. 2013;23(8):677–683pmid:23668390
  8. VanderVaart S, Berger H, Sistonen J, et al. CYP2D6 polymorphisms and codeine analgesia in postpartum pain management: a pilot study. Ther Drug Monit. 2011;33(4):425–432pmid:21743374
  9. de Leon J, Dinsmore L, Wedlund P. Adverse drug reactions to oxycodone and hydrocodone in CYP2D6 ultrarapid metabolizers. J Clin Psychopharmacol. 2003;23(4):420–421pmid:12920424
  10. Dean L. Codeine therapy and the CYP2D6 genotype. Med Genet Summ [online]. September 20, 2012.
  11. Sohn DR, Shin SG, Park CW, Kusaka M, Chiba K, Ishizaki T. Metoprolol oxidation polymorphism in a Korean population: comparison with native Japanese and Chinese populations. Br J Clin Pharmacol. 1991;32(4):504–507pmid:1958447
  12. US Food and Drug Administration. Drug safety communication. Safety review update of codeine use in children: a new boxed warning and contraindication on use after tonsillectomy and or adenoidectomy. Rockville, MD: US Food and Drug Administration;
  13. Seymour S. Briefing document, Joint Pulmonary-Allergy Drugs and Drug Safety and Risk Management Advisory Committee Meeting; December 10, 2015.

At North Shore Pain Management we provide advanced, evidence based, multidisciplinary and cost effective pain management. Our goal is to improve your ability to return to the activities you have been missing as well as provide a meaningful reduction in pain.