By Davidta Brown, Staff Editor

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For post-operative pain treatment, few drugs are as trustworthy, as tried-and-true, as codeine. Prescriptive confidence in the analgesic has promoted its use in children recovering from uncomplicated surgeries, but the spate of injuries and deaths of young children who had been given codeine after undergoing adenotonsillectomies has provoked a second, more calculating look at it. In light of new revelations in the relationship between genetic variation and pharmacology, specifically with regards to a gene known as CYP2D6, the FDA has instituted a boxed warning for all codeine-containing drugs, as well as a contraindication for all children who have had either an adenoidectomy or a tonsillectomy.¹

Codeine is an opioid analgesic used to treat mild to moderate pain. It’s also used for coughs and colds in conjunction with acetaminophen.¹ The biological activity of codeine depends on its conversion to morphine by an enzyme called Cytochrome P-450 isoenzyme 2D6 (CYP2D6) in the liver.² After this transformation, morphine is metabolized into its active form, morphine-6-glucuronide.^1,2 Only 15% of ingested codeine is actually demethylated into morphine, but the effects of the drug are still of clinical significance because of morphine’s 200-fold greater affinity for the μ opioid receptor over codeine.³

The gene that codes for CYP2D6 is highly polymorphic, with more than ninety known allelic variations.⁴ An individual’s phenotype for this gene is reported as a diplotype: 1 maternal and 1 paternal allele.⁵ The clinical significance of these allelic variations comes from their classifications as wild-type (also called normal function), reduced-function, or nonfunctional, and the biological effects of these allelic classifications are multiplied by the number of copies of each allele, which can be more than two in rare cases.⁵

Enzymatic activity directly affects drug efficacy and metabolism, and it is this metabolic activity that interests health care providers. About 75% – 92% of the population have allelic combinations that produce a normal range of CYP2D6 enzymatic activity, and these individuals are known as “extensive metabolizers”.²At the lower extreme are the “poor metabolizers”, the 5% – 10% of the population who have low enzymatic activity, and in whom codeine displays little to no analgesic efficacy.² Finally, there are the “ultra-rapid” metabolizers who, with two or more functional alleles, convert standard codeine doses into disproportionately large, potentially dangerous amounts of morphine, in a short period of time.²

Toxic effects due to such opioid excesses have been reported sporadically over the past decade, culminating in a report published in April 2012. This publication detailed one case of respiratory depression and two cases of death in children aged three to five; the two children who died were discovered to have been ultra-rapid metabolizers of codeine, while the one with respiratory depression was an extensive metabolizer.² The two fatal incidents occurred during the recovery period of a surgery to address obstructive sleep apnea, and in all cases; there were signs of morphine toxicity within two days of the start of codeine administration.^1,2

After analysis of these data, the FDA released a Safety Communication document in which it was conjectured that pre-existing breathing difficulties, for which these children received treatment, may have rendered them particularly sensitive to the type of respiratory distress that can result when codeine is suddenly converted to high levels of morphine.¹Ciszkowski et al. also suggest thatthe recurrent hypoxemia that can occur in children with chronic breathing difficulties may alter existing mu-opioid receptors, potentially leading to increased morphine sensitivity.⁶ In other words, genetic predisposition to ultra-rapid metabolism of codeine, pre-existing respiratory abnormalities, and the type of surgeries often prescribed to treat these abnormalities are potentially a perfect storm of respiratory failure and tragedy.

When the FDA first announced warnings about the risks of codeine in children who had been treated for obstructive sleep apnea with adenotonsillectomy, they urged health care providers to prescribe codeine at the lowest effective doses, for the shortest time possible, as needed.⁷ In late February 2013, these warnings were upgraded to a contraindication for codeine use in sensitive patients, and a requirement for a new warning on all products containing codeine, as previously mentioned.^1,2 Instead of codeine, it was suggested that analgesics like morphine, methadone, or a non-opioid treatment be prescribed to both poor and ultra-rapid metabolizers.⁵

Since genetics are the most significant determining factor in whether  codeine treatment will endanger a patient, and as these genetic traits can be analyzed in a laboratory, one might reasonably wonder why genetic testing is not performed prior to surgery as means of determining appropriate post-op treatment. Unfortunately, genetic disposition doesn’t guarantee an individual’s reaction to codeine. Recall that one of the three children who suffered serious complications from post-op codeine administration was at the normal, extensive metabolizing, enzyme activity level.¹ And perhaps the simpler truth is that genetic analysis is just not a part of the traditional health examination. However, as the intricate ties between genetics, protein functions, and pharmacology become less nebulous, health care could be on the verge of a brave new world of personalized medicine, of which codeine and CYP2D6 are just the beginning.

SOURCES:

1. U.S. Food and Drug Administration. FDA Drug Safety Communication: Safety review update of codeine use in children; new Boxed Warning and Contraindication on use after tonsillectomy and/or adenoidectomy. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm339112.htm
2. Racoosin J, Roberson D, Pocanowski M, Nielson D. New Evidence about an Old Drug – Risk with Codeine after Adenotonsillectomy. N Engl J Med 2013; 368:2155-2157
3. Thorn C, Klein T, Altman R. Codeine and morphine pathway. PubMed. 2011. [cited 2013 Aug 13]. Available at: http://www.pharmgkb.org/pathway/PA146123006
4. Owen R, Sangkuhl K, Klein T, Altman R. Cytochrome P450 2D6. PubMed. 2009. [cited 2013 Aug 13]. Available at: http://www.pharmkgb.org/gene/PA128?tabTypectapVip#tabview=tab3&subtab=
5. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Codeine Therapy in the Context of Cytochrome P4502D6(CYP2D6) Genotype. Clin Pharmacol Ther 2012; 91(2): 321-328
6. Ciszkowski C, Madadi P, Phillips M, Lauwers A, Karen G. Codeine, Ultrarapid-Metabolism Genotype, and Postoperative Death. N Engl J Med 2009; 361:827-828
7. Thompson C. Ultrarapid Metabolism of Codeine in Children Can Be Deadly. American Society of Health-System Pharmacists. 2012. [cited 2013 Aug 13]. Available at: http://www.ashp.org/menu/News/ PharmacyNews/NewsArticle.aspx?id=3768

Published by Rho Chi Post