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Phenotypes and codeine toxicity: the hidden dangers
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Codeine has historically been among the most commonly used medications in the pediatric population for treatment of pain and cough. Its availability as a liquid preparation combined with acetaminophen has accentuated this use. In the past 5 years, however, potential dangers of codeine have been addressed in the literature, describing its propensity for significant metabolic polymorphism, resulting in increased production of active metabolic products.
In August, the FDA issued a drug safety communication about potential life-threatening adverse events, including death, from codeine use for post-tonsillectomy pain. The FDA had previously issued a public health advisory in 2007 on the potential dangers to infants from mothers nursing while using codeine. Hospital pharmacy and therapeutics committees throughout the United States are heeding these warnings and beginning to replace acetaminophen/codeine products with other analgesics.
Edward A. Bell
Codeine is a naturally occurring opiate from the opium poppy. Codeine displays relatively low affinity for endogenous opioid receptors, and its analgesic effects result primarily from hepatic conversion to morphine. Approximately 10% of a codeine dose is metabolized to morphine in much of the population. This can vary, however, within the population by genetically acquired drug metabolizing enzyme polymorphisms, which can lead to an increased (or decreased) production of morphine. During the past 5 years, case reports that describe children and adults who display these metabolic polymorphisms, and their clinical effects, have been published.
Codeine is hepatically metabolized via several pathways to inactive and active metabolites. Metabolism by the cytochrome P450 2D6 (CYP2D6) enzyme results in demethylation of codeine to morphine. Developmentally, CYP2D6 activity reaches adult values by approximately 2 weeks of age. It is thought that genetic variations in CYP2D6 activity play a greater role in codeine metabolism than normal pediatric development. CYP2D6, a major drug-metabolizing enzyme, is known to genetically occur as polymorphisms with varying activity.
Codeine and metabolizers
These polymorphisms are described as four phenotypes: poor metabolizers (PM); intermediate metabolizers (IM); extensive metabolizers (EM); and ultra-rapid metabolizers (UM). An individual with a PM phenotype does not metabolize codeine to morphine (no enzyme activity). An individual with a UM phenotype, a result of gene duplications, can produce up to 75% more morphine as compared with an EM (which represents most of the population). Clinically, codeine given to a PM likely will result in minimal or no analgesic effect, whereas codeine given to a UM may potentially result in significant toxicity or even death. It has been estimated that approximately 4% to 7% and 3% to 7% of the white and African-American populations, respectively, are codeine UM, and that up to 30% of individuals with North African and Saudi Arabian ancestry are UM.
Recently published case reports describing clinical dangers from codeine use in infants and children support these concerns. Koren published an interesting case report in 2006 that described the death of a 13-day-old term infant boy believed to be caused by codeine ultra-rapid metabolism by the mother, who was breast-feeding her infant son while taking normal doses of acetaminophen/codeine for episiotomy pain. A blood morphine concentration from the infant was found to be more than 30-fold higher than expected. The mother was determined to have CYP2D6 gene duplications and was classified as a codeine UM.
Voronov described a 29-month-old infant of North African descent who experienced apnea and subsequent brain injury after use of acetaminophen/codeine over 2 days for post-adenotonsillectomy pain. The infant was genotyped for codeine metabolism and was believed to be a UM. However, this case has been subsequently criticized by several additional authors for inaccurate genotyping and classification.
Additional case reports of children receiving codeine with likely ultra-rapid metabolism of codeine to morphine have also been published, including a report by Ciszkowski about a 2-year-old boy who received acetaminophen/codeine and died 2 days after adenotonsillectomy. He was found to have functional duplication of the CYP2D6 allele (UM phenotype). Most recently, a case series of three children who had tonsillectomies and exhibited adverse effects of codeine metabolic polymorphism has been published by Kelly. Two of these children, aged 4 and 5 years, died of what was likely codeine ultra-rapid metabolism and increased morphine production.
Given this information, it leaves many to wonder how pediatric clinicians should use codeine, if at all, when treating pain in infants and children. Many pediatric institutions are advocating reduced use of codeine and are removing codeine from formulary availability. Hydrocodone- or oxycodone-acetaminophen combinations have replaced codeine at some institutions. There are some limited data, however, that hydrocodone may also be subject to genetic metabolic polymorphism and subsequent increased risk of adverse effect.
AmpliChip CYP450 Test (Roche) is a microarray in vitro test that can identify an individual’s CYP2D6 and CYP2C19 genotype from whole blood. Although this test may be potentially useful in some circumstances, its clinical utility and ability to predict drug response and dose from codeine is not currently widely practiced or known.
Dangers of toxicity
During the holiday season, families gather to enjoy each other’s company. This can be an opportune time for young children to be exposed to potentially dangers substances and medicines. Medicines most frequently involved in young pediatric (aged 5 years and younger) poisoning deaths in 2010 were (in decreasing order): analgesics, antihistamines and sedatives/hypnotics/antipsychotics. In addition, cough/cold products and cardiovascular drugs rounded out the top 10.
Some medications can be potentially lethal to young children with just a small amount, such as one to two tablets/capsules swallowed. These include: cardiovascular products such as procainamide and flecainide (both are antiarrhythmic agents), clonidine, calcium channel blockers (eg, nifedipine, diltiazem or verapamil), or older antipsychotic agents (eg, amitriptyline, imipramine or thioridazine). Grandparents may be commonly using many of these agents. Medicines more likely to be found in homes with younger children can also be dangerous, such as iron tablets (as few as 10 tablets may be fatal to a 12-month-old) or camphor (commonly found in over-the-counter topical products).
The holiday season may, therefore, be an appropriate time to remind parents about the dangers of poisoning and to store medication products safely away when families gather.
References:
Bronstein AC. Clin Toxicol. 2011;49:910-941.
For more information:
Edward A. Bell, PharmD, BCPS, can be reached at: Drake University College of Pharmacy, 2507 University Ave, Des Moines, IA 50311; email: ed.bell@drake.edu.
Disclosure: Bell reports no relevant financial disclosures.