Get ready for more governmental regulation of opioids and maybe even some black box warnings added to the prescribing information for c0deine-containing drugs … just for everyone’s safety, of course.
According to this FDA Special Bulletin on Safety Information, three pediatric deaths and one case of respiratory depression were documented in the medical literature after children took codeine-containing compounds. The etiology for the deaths was allegedly because the children had a variation in their cytochrome P450 enzyme that caused the codeine to break down faster into morphine, high levels of which, according to the FDA, “may be fatal.” If your child or your patient is an “ultra-rapid metabolizer” of codeine, he or she could DIE.
The FDA also published a “Drug Safety Communication” that disclosed the studies on which its recommendations were based.
One case cited by the FDA as “proof” that codeine can kill you involved a 2 year old child with sleep apnea who underwent tonsillectomy and adenoidectomy and who died three days after surgery. At autopsy, the child had elevated levels of codeine and morphine in his system, had aspirated food particles, and also had bilateral pneumonia. No mention of how much codeine the patient’s parents gave the child, only of the dose that was prescribed. No mention of how bilateral pneumonia or aspiration in a young child can be deadly. The researchers concluded that the elevated morphine levels “may” have contributed to the child’s death. The FDA wants you to believe that there was a causal connection there.
Another article cited by the FDA was from the same authors who now found three additional cases of children who died after having tonsillectomy/adenoidectomy and were prescribed codeine. I didn’t purchase the article, but I also am assuming that there were no controls for dosing of the medication, only for prescription of the medication. In other words, I doubt that the researchers would be able to tell whether the parents accidentally just gave the child too much medication as opposed to whether some genetic variant caused higher than normal blood levels of the medication at normal doses.
I also did a PubMed search for “children codeine p450” and also “pediatric codeine p450“.
There was one Canadian case report of a mother who was an “ultra rapid metabolism phenotype” whose breastfed child had fatal opioid intoxication after the mother used codeine.
There was another case report from Canada of a 5 year old girl who died from hydrocodone overdose when she was taking both clarithromycin for an ear infection and valproic acid for seizures. The medications decreased metabolism of the drug and she also had a genetic defect that decreased the metabolism of the drug.
None of the other articles that I found mentioned pediatric death due to an interaction between opioids and cytochrome P450.
Now, based on 4 deaths out of likely hundreds of millions of codeine prescriptions, the FDA is “currently conducting a safety review of codeine” and is recommending that doctors use low doses of codeine for patients in pain or that doctors just use another medication completely for children in pain. The FDA also recommends that caregivers monitor patients for signs of opioid toxicity. These recommendations are already in the prescribing information for Tylenol with Codeine.
Oh, and the FDA also notes that doctors can always perform “FDA approved” genetic testing to see if children have the gene responsible for rapid metabolism of codeine.
I can’t help wonder what motivation the FDA has to issue this warning about 4 deaths in tens or even hundreds of millions of prescriptions that were hypothesized to have been caused by this mechanism. It’s not like codeine is a new drug or that the cytochrome P450 pathway is a new discovery. Why now?
Trying to justify the FDA’s existence/budget? Getting a cut of the fees for approving the genetic testing? Getting fees for some new pain medication so that it can be approved for use in pediatric patients? Something just doesn’t make sense.
Of course, now if sometime in the future a young patient dies from an alleged codeine overdose, there will be some newspaper article published and some lawsuit for millions of dollars in damages filed alleging that if only the negligent doctor had paid attention to the FDA warnings and performed CYP2D6 genotyping, the patient would probably still be alive today.
And people wonder why doctors practice defensive medicine.
Congratulations to the Wall Street Journal, NY Times, Washington Post, ABC News, Bloomberg News, NPR, and the Boston Globe for feeding into the hysteria. Hat tip to EM Today from ACEP for the links.