Response to the American Academy of Pediatrics statement on codeine: let's consider CYP2D6

The American Academy of Pediatrics (AAP) issued a statement last Tuesday that codeine should not be used in children. As discussed in the article, pharmacogenetic variation can affect response to codeine, which is metabolized into its active form by the hepatic enzyme CYP2D6. Thus poor metabolizers are unlikely to benefit from codeine, and ultrarapid metabolizers can experience high concentrations of morphine that may result in respiratory depression or sleep apnea even at normal codeine doses.

While we agree that the variability in patient response to codeine is important to consider, we feel that the AAP did not give enough credit to the power of CYP2D6 genotyping prior to treatment. The article devotes only two sentences to the possibility of pre-emptive genotyping, saying “although CYP2D6 genotyping that could identify patients at higher risk is available (although currently expensive), patients with normal metabolism are also at theoretical risk of high morphine levels. Therefore, further investigation is required to determine the value of such testing, which will depend on the population in whom it is applied.”

It is unclear what is intended by the claim that “patients with normal metabolism are also at theoretical risk of high morphine levels”, as no citation is provided. Patients who are CYP2D6 normal metabolizers are expected to have normal morphine formation. Furthermore, codeine is still an appropriate and effective drug choice in the majority of cases, regardless of the population. As the AAP statement points out, ~29% of African/Ethiopian, ~21% of Saudi Arabian and other Middle Eastern, and ~3.4 - 6.5% of African-American and Caucasian patients are expected to be ultrarapid metabolizers, with even lower frequencies of poor metabolizers, meaning that the majority of patients will receive the intended benefit from codeine treatment, contrary to what one doctor was quoted as saying in at least two media outlets (another article here).

While pharmacogenetics is still in the early stages of clinical adoption, it can be an effective tool for improving patient therapy, particularly when drug alternatives are not simple. In the case of codeine, the official AAP statement urges caution in using alternative analgesics, including oxycodone, hydrocodone, and tramadol, because they also are metabolized to some degree by CYP2D6 (though more than one public media article presented comments by one of the statement authorssuggesting that hydrocodone or tramadol be used instead of codeine, without any caveats). Instead, AAP suggests NSAIDs for mild to moderate pain, and an IV drip for greater pain, though these therapies also require clinician education to avoid postoperative bleeding. If further education is required to deliver care, why does this curriculum not consider CYP2D6 pharmacogenetic information, which could make the effects of codeine more predictable and restore its value as an analgesic? As for an alternative to the antitussive properties of codeine, CBS and CBS local New York suggested that popsicles or honey be used.

We are concerned about the misinformation and creative interpretations related to the AAP statement that have been communicated in public media. Chicago Tonight reported that “children are among those considered to be ‘ultra-rapid metabolizers’ of codeine”, which implies to readers that all children are CYP2D6 ultra-rapid metabolizers; they are not. Similarly, a Huffington Post article stated that “children are specifically less capable of metabolizing codeine than adults because the enzyme changes as the body matures into adulthood.” While functional CYP2D6 activity is not appreciably expressed in fetal liver, it increases rapidly after birth, and CYP2D6 genotype is expected to be equally reliable for inferring phenotype in children as it is in adults.

CPIC has published a freely downloadable guideline for adjusting codeine therapy based on CYP2D6 genotype.  The guideline recommends using alternative therapies -- specifically not hydrocodone or tramadol, which are also metabolized by CYP2D6 to some degree -- in patients with genotypes predicting poor and ultra-rapid metabolizer status. The “black box” warning on the FDA label for codeine can also be viewed at PharmGKB.

In the meantime, please pass the medical-grade popsicles.