The FDA recently released a Drug Safety Announcement about the use of codeine in young children after tonsillectomy/adenoidectomy surgery for obstructive sleep apnea.  I was somewhat surprised to see a safety announcement on a medication that has been in use for decades, but the release underscores our improved knowledge of drug metabolism and the broadening demographics of the United States.

My codeine isn’t working!

Codeine has little activity at opioid receptors.  The analgesic effects of codeine are actually caused by morphine, after the conversion of codeine to morphine at the liver.  The conversion is catalyzed by an enzyme called CYP2D6, part of the cytochrome system of enzymes that are involved in the metabolism of a number of compounds.

I have written about the addictiveness of narcotic pain medications.  People addicted to opioids often go to significant lengths to obtain prescriptions for narcotic pain relievers from healthcare practitioners. 

Emergency room physicians and nurses become aware of the efforts of ‘narcotic-seekers’, which range from faking pain symptoms or dental injuries to self-catheterization and instilling blood into the bladder to fake kidney stones.  Distinguishing those with real pain from those who are addicted and not experiencing pain is a serious situation, but doctors roll their eyes at some of the more-typical presentations.  One such situation is the patient who reports an ‘allergy’ to all of the weaker narcotics and claims that ‘the only drug that works is (insert Dilaudid, morphine, oxycodone, or another potent opioid here)

Codeine is one drug that is commonly rejected as ‘ineffective’ as part of a request for something stronger.  When I was a medical student, we assumed that requests for something other than codeine were disingenuous.  But at some point, maybe 15 years ago, I remember reading an article that described the conversion of codeine to morphine by the liver.  The article reported that the enzyme that performs the conversion exists in varying forms across the population, with some ethnic groups having more active forms of the enzyme than others.  Some people have very low levels of CYP2D6, and so get very little analgesia from codeine.  In other words, some of the people who claimed that ‘codeine never works for me’ were probably less disingenuous than doctors thought!

The latest FDA warning describes three deaths in children between the ages of 2 and 5.  The affected children were ‘ultra-rapid CYP2D6 metabolizers’ who were given typical doses of codeine for postoperative pain control, and converted the codeine to morphine more efficiently than expected.  The respiratory depressant effects of morphine, combined with some degree of post-operative respiratory obstruction, caused the death of those children and the near-death of a fourth.

About 6% of the people in the US are ultra-rapid metabolizers.  About the same number are poor metabolizers and have a reduced analgesic response to codeine.  In some ethnic groups, there are greater numbers of rapid metabolizers, particularly people of Greek or African/Ethiopian ancestry.  If you are someone who gets little pain relief from codeine or on the other hand if you get a very strong effect from codeine, you may want to look into G6PD testing, which can be ordered by physicians.  The enzyme activity is heritable to some extent, so your own enzyme activity may bear relevance to the activity of the enzyme in your children.

Expect similar issues to arise with other medications, as we learn more and more about how our bodies metabolize medications, and about the effects of those metabolites on enzyme systems.  The lesson also reminds doctors that there is wisdom to be gained by listening to our patients.


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