VOLUME 26, ISSUE 1

The FDA Kibosh on Codeine for Kids Update on Pediatric Pain Management – Oral Codeine

On February 20, 2013 the US Food and Drug Administration (FDA) released an update regarding the safety of codeine use in children after tonsillectomy and adenoidectomy A new black boxed warning (the FDA’s strongest warning) is being added to the drug label of codeine-containing products regarding the risk of death in children receiving codeine for post-operative pain management following tonsillectomy and/or adenoidectomy. A “Contraindication” is being added to restrict codeine from being used in this setting.

The FDA issued the initial safety alert in August 2012 in response to the Adverse Event Reporting System (AERS) database findings from 1969 to 2012 identifying 10 deaths and three overdoses associated with codeine. These children ranged in age from 21 months to 9 years old and many were recovering from tonsillectomy or adenoidectomy. All of the children received doses of codeine that were within the typical dose range. Consistent histories, genetic testing and serum blood levels of codeine and morphine pointed to the patients of being ultra-rapid metabolizers of codeine. Many deaths occurred in children who also had evidence of obstructive sleep apnea who may have been even more sensitive to respiratory depression from conversion of codeine to high levels of morphine.

Codeine has traditionally been used for management of mild-to-moderate pain. However, there is concern

regarding its unpredictable efficacy and safety profile. Codeine itself is a pro-drug of morphine and provides minimal to no analgesia without metabolism to active morphine. Codeine is metabolized by three different routes: glucuronidation to codeine-6-glucuronide (inactive), N-demethylation by CYP3A4 enzyme to norcodeine (inactive) and O-demethylation by CYP2D6 enzyme to morphine (active). It is the CYP2D6 conversion that is significantly affected by genetic polymorphism.

There are 4 basic groups of metabolizers:

  1. Poor metabolizers carry two inactive alleles and produce no morphine from codeine, and therefore, receive little-to-no analgesic effect.
  2. Extensive metabolizers represent the largest population and have typical enzymatic activity with predictable amounts of morphine metabolized from codeine.
  3. Intermediate metabolizers have some 2D6 activity. They have unpredictable analgesia with sometimes no morphine metabolized from codeine.
  4. Ultra-rapid metabolizers have a duplication of the CYP2D6 gene and have excessive metabolism.
    1. This group metabolizes a higher than predicted amount of codeine into morphine and are at increased risk for respiratory depression and death.
      1. This phenotype occurs in 1% of Caucasians, 10% of people from Mediterranean descent, and 30% of people from Asian or Middle Eastern origin.

In addition to genetic polymorphism, CYP2D6 and CYP3A4 are susceptible to many drug interactions. Many estimate that approximately 50% of medications are metabolized by the CYP3A4 enzyme and 25% are metabolized by the CYP2D6 enzyme and can potentially lead to higher morphine levels and increased side effects. In pediatrics physiologic differences compared to adults include: immature hepatic enzyme systems,

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