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Despite a warning by the FDA regarding the significant safety risks of opioids, a new study published in the journal Pediatrics finds that 1 in 20 children were still prescribed codeine after having a tonsillectomy and/or adenoidectomy, according to data through 2015.
The study analyzed the records of more than 362,000 children from a commercial claims database who underwent a tonsillectomy and/or adenoidectomy from 2010-2015.
After an investigation, the FDA—in February, 2013—issued a black box warning about safety and efficacy issues associated with prescribing codeine to children after the surgeries.
Researchers found that after the FDA warning, codeine prescribing after a tonsillectomy and/or adenoidectomy decreased by 13.3%.
However, 1 in 20 children, or 5.1%, were still prescribed codeine following a tonsillectomy and/or adenoidectomy in December 2015, almost three years after the black box warning.
Based on their results, the authors believe that more vigilance is necessary to reduce inappropriate codeine prescribing, while promoting the use of non-opioid medications such as ibuprofen to treat postoperative pain after tonsillectomy.
"Tonsillectomy and adenoidectomy is the second most commonly performed ENT surgery in children, following ear tube placement” according to Dr. Nina Shapiro, Professor of Head and Neck Surgery at UCLA, and author of the forthcoming book, HYPE: A Doctor's Guide to Medical Myths, Exaggerated Claims and Bad Advice: How to Tell What's Real and What's Not.
Shapiro explains that ENT surgeons who perform this procedure try to minimize the risk of bleeding during and after surgery, reduce postoperative pain, and finally, reduce the risk of postoperative dehydration that would require hospital readmission.
“ The issue of pain control has been a quandary in children , as increased pain has been associated with higher risk of dehydration, bleeding, and hospital admission,” she explained.
Before 2010, Tylenol with codeine elixir was the most commonly prescribed postoperative analgesic. But even before 2010, this drug had multiple reports of adverse effects, partly explained by the fact that it is a combination drug.
“The presence of Tylenol (acetaminophen) in the elixir precludes, or at best, alters the ability to use acetaminophen as an additional pain medication, as this would put the child at risk for acetaminophen overdose,” said Shapiro.
“Secondly, codeine itself is not an analgesic, but is a 'pro-drug'. It metabolizes to morphine for analgesic effect. However, variants in patients' P450-2D6 enzymatic activity can lead to either no therapeutic blood levels of morphine or levels multitudes higher than is safe, leading to respiratory depression and even death, especially in children with a history of obstructive sleep apnea, and more so in the hours following general anesthesia and airway surgery.”
And therein lies the danger: the variable metabolism of the drug itself, and its ability to induce variable levels of morphine in the bloodstream place all children at risk--but even more so in children with sleep apnea. Children with this condition develop more respiratory depression when they receive codeine, leading to a higher risk of death.
" Alternatives for pain control include 'round the clock' alternating ibuprofen and acetaminophen , each given every three hours for the first 24 to 48 hours after surgery," explained Shapiro. "However, there have been reports that ibuprofen may increase the risk of postoperative hemorrhage. A second option is acetaminophen alone for mild to moderate pain, followed by low-dose (half-therapeutic dose) oxycodone for breakthrough severe pain," she added.
“Many surgeons, myself included, have focused on methods of minimizing postoperative pain based on improved tonsillectomy techniques. I have been using coblation intracapsular tonsillectomy for several years, which has substantially reduced the need for any postoperative analgesia aside from acetaminophen."
Ultimately, stopping inappropriate codeine prescribing comes down to better communication with medical providers. Are text alerts, email messages, or even mandated educational modules part of the solution? And what about reaching out to pediatricians, who are on the front lines delivering care to millions of children?
"I don’t think much of the residual codeine prescribing after tonsillectomy and/or adenoidectomy is due to lack of awareness of the FDA black box warning," said Kao-Ping Chua, M.D., Ph.D., lead author of the study, and pediatrician at University of Michigan C.S. Mott Children’s Hospital. "I believe most of it has to do with clinical inertia – the idea that it is hard to change long-established clinical practices – and the lack of comfort with alternative pain management strategies."
To cite an example, Chua explains that "there are persistent concerns about whether ibuprofen increases the risk of bleeding after tonsillectomy, even though a recent Cochrane review of the literature did not find a statistically significant effect. Also, some providers may be uncomfortable with the side effects and abuse potential of alternative opioids like oxycodone and hydrocodone, even though codeine is the opioid that has been most strongly identified with respiratory depression and death among children after tonsillectomy and/or adenoidectomy."
As mentioned, much of the concern regarding alternatives to codeine have focused on the use of ibuprofen, and whether it can increase the risk of post tonsillectomy bleeding. The recent Cochrane Review clearly disputes any major concern for its contribution to producing any significant bleeding.
"The take-home is that ibuprofen was associated with a non-significant increase in the risk of bleeding requiring surgical intervention, meaning that there is insufficient evidence to conclude that there is not an increased risk, but also insufficient evidence to conclude that there is an increased risk," offered Chua. "The same review found that there was no significant increase in the risk of bleeding that did not require surgical intervention. Given both of these findings, I think it would be fair to say that ibuprofen has not been shown increase post-tonsillectomy bleeding."
Chua also explains that it is "also worth noting that Tylenol has also been found to be an effective pain medication after tonsillectomy and does not have any concerns about post-surgical bleeding, and many providers are now recommending either intermittment or around-the-clock Tylenol as first-line therapy."
While the goal of Chua's study was to evaluate the effect of the FDA black box warning in February 2013 that specifically prohibited the use of codeine among children undergoing tonsillectomy and/or adenoidectomy, the FDA went one step further in April 2017, when they expanded the black box warning for codeine, stating that codeine should not be used to treat pain or cough in children younger than 12 years of age. This followed the American Academy of Pediatrics’ September, 2016 statement that codeine essentially should never be prescribed for pediatric patients.
"The rationale for these newly added statements is largely the same as the original 2013 FDA black box warning," argued Chua. "In brief, there is genetic variability in the activity of the liver enzyme that converts codeine to morphine (the agent that actually confers the analgesic effect of codeine). About 1-2% of the population is an “ultra-metabolizer” with multiple copies of the gene for this enzyme. These individuals convert codeine to morphine extremely quickly, causing a rapid spike in blood morphine levels and the ensuing risk of overdose (suppression of breathing and possible death). What prompted the FDA to issue its initial 2013 black box warning was an increasing number of reports of death among children receiving codeine after tonsillectomy and/or adenoidectomy, most of whom were ultra-metabolizers."
"Of course, no one can tell who is and who is not an ultra-metabolizer without doing expensive lab work that may not come back fast enough to inform decisions about how to manage pain. Therefore, providers who prescribe codeine to children are rolling the dice that their particular patient is not an ultra-metabolizer with a high risk of overdose," offered Chua.
Shapiro points to a number of limitations of the study, specifically that it "does not account for age of the patients at the time of surgery, as younger children, especially those under age 3 years are at higher risk for postoperative respiratory compromise”. Secondly, “it does not distinguish inpatient versus outpatient surgeries, as many patients who stay overnight receive intravenous narcotic pain medication, and/or may have other co-morbidities,” added Shapiro.
Finally, she explained that “the study also did not differentiate whether or not the surgeries were performed by pediatric otolaryngologists [Ear Nose and Throat surgeons] versus general otolaryngologists. It would be interesting to see, in future studies the effect of delineating the data further.”
