The risks of using codeine to treat pain or cough in children may often outweigh the benefits, sometimes even leading to death, and call into question whether its widespread use should continue in pediatric patients, according to an American Academy of Pediatrics technical report.
“It is clear that one of the keys to improving analgesia and reducing opioid-related adverse effects is both provider and parental education regarding the effective use of nonopioid analgesics,” wrote Joseph D. Tobias, MD, and his colleagues from the AAP Committee on Drugs’ Section on Anesthesiology and Pain Medicine (Pediatrics 2016 Sept 19. doi: 10.1542/peds.2016-2396). “The answer may not lie in using more medication or different medications but merely using more effectively other options that are currently available.”
Individual patients respond differently to codeine because the conversion rates of the liver enzyme that metabolizes codeine into morphine, CYP2D6, vary greatly according to genetic differences. Some children experience no therapeutic effect at all while others have stopped breathing or died, particularly those who metabolize the drug extremely rapidly. Those with at least two copies of the CYP2D6 gene have a particularly elevated level of enzyme activity. Also at high risk for respiratory depression or death are children with obstructive sleep apnea.
Poor metabolizers, who therefore experience less effect from codeine, include disproportionately more individuals of Northern European descent. Ultrarapid metabolizers, on the other hand, comprise approximately 29% of patients of African/Ethiopian heritage and 21% from Middle Eastern countries. An estimated 3.4%-6.5% of African Americans and whites are ultrafast metabolizers. Genetic tests can identify those at higher risk, but even children with normal metabolism can experience severe adverse effects.
The World Health Organization removed codeine from its list of essential medications, the U.S. Food and Drug Administration added a black box warning to labels of codeine formulations used for tonsillectomy and/or adenoidectomy in children, and the European Medicines Agency recommended against using codeine in children under age 12 years and in those between 12 and 18 years who have breathing difficulties.
Yet research has shown that the use of codeine for pain relief in children remains very common; codeine is prescribed more than any other opioid in some studies. Otolaryngologists, dentists, pediatricians, and family practice physicians, respectively, prescribe it most often, likely because few safe, effective therapeutics exist for treating pain or cough in children. Oxycodone has been used as an alternative, but this drug also lacks adequate data on its use, and hydrocodone has similar concerns with rapid metabolizers.
Although most of the serious adverse events resulting in codeine use in children have followed adenotonsillectomy in children with disordered breathing, the authors warned that “physicians cannot assume such problems will occur only” after such procedures.
“Given the increasing prevalence of obesity in the United States, it is likely that some patients presenting for nonotolaryngologic procedures may have undiagnosed sleep-disordered breathing and may also be at risk if they require extended postoperative analgesia,” they wrote. They called for better parental education regarding pain relief and more formal restrictions for its use in pediatrics.
The report did not use external funding, and the authors reported no relevant financial disclosures.