The American Academy of Pediatrics (AAP) is no longer recommending codeine use in children because it can be either ineffective or too effective—leading to respiratory depression and even death.
Many hospitals have already removed codeine from their formularies for children, and the US Food and Drug Administration (FDA) is slowly moving toward a full ban, proposing a strong recommendation against pediatric use of the medication in late 2015.
Joseph D Tobias, MD, chief of Anesthesiology and Pain Medicine at Nationwide Children’s Hospital, professor of Anesthesiology and Pediatrics at The Ohio State University in Columbus, and lead author of the AAP’s recommendation, says he hopes to alert physicians to the potential dangers—including mortality—related to the genomic variation in codeine metabolism.
“Given the dangers and its lack of advantage over other oral opioids, we need to stop using codeine in any clinical situation,” Tobias says.
Codeine has been prescribed as both an analgesic and an antitussive agent in pediatric patients for decades. Its analgesic effects are produced when the codeine is metabolized by the liver into morphine, but Tobias says there is substantial genetic variability in the hepatic enzyme that guides this process, causing a wide variation in patient response ranging from no effect to high sensitivity.
Unanticipated respiratory depression and death have occurred in some children who received codeine, attributed to their rapid metabolization of the medication. Tobias says patients with obstructive sleep apnea also are particularly at risk.
Variation in codeine metabolism was first recognized as a result of poor efficacy, mainly in individuals of northern European Caucasian descent. On the other end of the spectrum, observations of ultrarapid metabolism were later found in patients of African/Ethiopian, Middle Eastern, and African American heritages.
Tobias says a recent review by the FDA of the Adverse Event Reporting System from 1965 to 2015 revealed a total of 64 cases of respiratory depression and 24 codeine-related deaths—21 of them in children aged younger than 12 years—related to the use of codeine or codeine-containing formulations.
Several US and global health organizations including the World Health Organization (WHO) and the FDA have recently issued “stern warnings” about adverse effects stemming from codeine use in children, Tobias says.
In March 2011, the WHO removed codeine from its list of essential medications for children out of efficacy and safety concerns, and in August 2012 the FDA issued a safety alert regarding the use of codeine in children following tonsillectomy, adenoidectomy, or adenotonsillectomy. By 2013, the FDA added a black box warning to codeine and codeine-containing preparations for pediatric patients, urging alternatives for controlling pain in children undergoing tonsillectomy and/or adenoidectomy. In 2013 and 2015, Health Canada and the European Medicines Agency followed suit, recommending against the use of codeine for pain relief in children aged younger than 12 years and in older children with breathing problems. Multiple agencies across the globe have also recommended against or banned the use of codeine as an antitussive in children.
The problem is that there are few child-appropriate pain medications, as well as evidence-based therapies for children with cough. As a result, codeine has been widely used for more than 50 years, and in 2011, it was prescribed to more than 800,000 patients aged younger than 11 years—more than any other opioid studied, according to the clinical report. The most common uses of codeine/acetaminophen formulations were by otolaryngologists (19.6%); followed by dentists (13.3%); pediatricians (12.7%); and family physicians (10.1%).
Many physicians in the United States have already switched to prescribing oxycodone for pain relief because it’s an active analgesic, not a prodrug like codeine. However, data on the use of oxycodone is currently insufficient to endorse widespread use of oxycodone in infants and children, Tobias says. The FDA approved the use of OxyContin—an extended-release formulation of oxycodone—for children in 2015, increasing the extent of research that could be conducted in order to facilitate an increase in the evidence-based data available to physicians prescribing the medication.
Hydrocodone is another alternative for analgesia in children, says the report, but it is also affected by metabolism, with ultrarapid metabolizers having up to eightfold greater plasma concentrations of hydromorphone, and poor metabolizers experiencing minimal analgesic effects.
Although intravenous morphine has been used extensively in children, there has been little clinical data on the oral elixir, the clinical report notes. Other lesser-used alternatives include tramadol and tapentadol, but little research on pediatric use has been performed for either of these alternatives.
Non-opioid alternatives, including nonsteroidal anti-inflammatory drugs, acetaminophen, dextromethorphan, and dexmedetomidine, may provide some relief, but also require additional research into their safety and/or efficacy, according to the report.
As an antitussive agent, codeine is available as an over-the-counter formulation at pharmacies in 28 states and the District of Columbia, despite the fact that its value in suppressing cough is unproven, says Tobias. The FDA recommended in December 2015 that the use of codeine to treat cough in children aged up to 18 years should be contraindicated, but the agency has yet to take final action on the recommendation.
Tobias says pediatricians need to improve their education of parents on the use of codeine as an analgesic and antitussive in children, and more formal restrictions should be placed on the medication. He also recommends that research into both opioid and non-opioid medications be performed to better understand the risks and benefits of these medications as alternative options for treating acute pain.