Tonsillectomy is among the most common of pediatric operations. In this issue of Anesthesiology, Einhorn et al. report on a prospective controlled trial of single-dose intravenous methadone administered intraoperatively to children and adolescents ages 3 to 17 yr undergoing elective tonsillectomy with or without adenoidectomy. They evaluate the impact of the intraoperative methadone on postoperative rescue opioid administration (primary outcome), as well as several secondary outcomes (some preplanned and some in response to reviewers’ requests) including side effects, recovery parameters, and pain scores.

Given the current trend toward reduced perioperative opioid prescribing a reader might ask whether adding a long-acting opioid represents “a step backward.” Consensus guidelines, clinical trials, and scoping reviews support managing pain after tonsillectomy by scheduled administration of a combination of acetaminophen and nonsteroidal anti-inflammatory drugs, commonly ibuprofen. This approach can generate mild to moderate postoperative pain scores for the majority of pediatric-age patients. Nevertheless, even with combined use of acetaminophen and ibuprofen, a substantial percentage of patients, particular older children and adolescents, experience episodes of moderate to severe pain both in the early postoperative period and for up to 2 weeks postoperatively.  A subset of patients experience inadequate pain relief even with combination regimens that include codeine, tramadol, or tramadol plus gabapentin or oral morphine.  There clearly remains an unmet need for more effective postoperative analgesic regimens after this common operation.

We commend the authors for conducting their study with a thoughtful and pragmatic design. Unlike many published adult and pediatric analgesic clinical trials in the United States, the patients were ethnically/racially diverse. The study’s findings are notable. Compared to standard care (fentanyl), patients receiving methadone, especially at the higher dose of 0.15 mg/kg, had a reduced requirement for rescue analgesia, and reduced treatment for emergence agitation in the postanesthesia care unit (PACU), with no serious adverse events, no adverse impact on the time course of emergence or extubation, and a shorter duration of PACU stay. Rescue opioid sparing is an established pragmatic primary outcome measure for pediatric analgesic trials.  A significant limitation of this study is that postoperative analgesia was not standardized, but varied according to the practice pattern of each individual otolaryngologist. It is plausible that an alternative design with strong interdisciplinary collaboration and a highly structured education program for parents to encourage adherence to a standardized round-the-clock acetaminophen–ibuprofen regimen might have reduced the need for rescue oxycodone dosing in some percentage of cases. 

Despite some promising findings, there are multiple reasons for practicing anesthesiologists and otolaryngologists to be cautious and to await larger studies before the introduction of intravenous methadone into routine clinical pathways for children undergoing tonsillectomy outside of carefully designed clinical trials:

  1. This study was more than a pilot but not a large, definitive clinical trial. The study sample was not large enough to detect infrequent severe adverse events. A very large number of children (i.e., millions) received codeine after tonsillectomy over many decades before case series of fatalities emerged, and laboratory/forensic investigation identified a pattern and provided an explanation based on genetic variation in drug metabolism.
  2. The study appropriately excluded patient groups expected to have increased risk of airway obstruction, impaired ventilatory drive, and/or unusual opioid sensitivity. Unless supported by future large clinical trials in higher-risk patient groups, we recommend even greater caution with methadone administration for children with additional risk factors, including age less than 3 yr; airway, respiratory, cardiac, or neurologic anomalies; sleep study–confirmed or clinically suspected obstructive sleep apnea; and morbid obesity.
  3. Based on current practice and consensus guidelines in the United States, postoperative outpatient opioid prescriptions after tonsillectomy are infrequently utilized in younger children but still commonly written for adolescents. Providing good analgesia while obviating the need for an outpatient opioid prescription would be especially important for the adolescent subpopulation. Einhorn et al. attempted to stratify enrollment from wide age groups but ended up with very few adolescents in their study. Future clinical trials are needed to clarify whether intraoperative methadone will give a meaningful impact on pain and rescue analgesic requirements in the adolescent age group.
  4. The study is not powered sufficiently to detect modest differences in pain scores over the 7-day postoperative period. Nevertheless, it is notable that median pain scores post-PACU did not differ between groups. Methadone’s analgesic duration is extremely variable, but most patients are unlikely to receive substantial analgesic effect beyond 24 to 36 h after single intraoperative 0.15-mg/kg doses. A larger dose, e.g., 0.2 mg/kg, might provide more prolonged analgesia, but might also delay recovery or increase the risk for postoperative hypoventilation.
  5. The children and adolescents in this study all underwent traditional extracapsular tonsillectomy. Future studies should evaluate efficacy and side effects with newer operative approaches that may produce milder postoperative pain, including intracapsular tonsillectomy. 

Health services research currently reflects a tension between two prominent trends. Reducing variation in care by the use of standardized protocols is widely regarded as a desirable goal of perioperative quality improvement. A quality improvement initiative reduced practice variation and reduced overall outpatient opioid prescribing after tonsillectomy without adversely impacting balancing measures. 

Against this motif is the movement toward personalized medicine that emphasizes individual differences that can influence outcomes and responses to treatments. There is a growing literature on factors associated with individual differences in pain trajectories, analgesic requirements, and side effects after pediatric tonsillectomy. Personality trait clusters, child and parental behavioral traits and genetic variants  have been associated with greater or lesser postoperative pain severity. Bioinformatics approaches and clinical–demographic variables were used to identify gene variants associated with increased risk for opioid-induced respiratory depression.  A notable finding in the current study was that high pain scores in the PACU were associated with higher pain scores through the 7-day postoperative study course. 

Suppose that future large studies support the general safety and efficacy of single-dose intraoperative methadone for analgesia after tonsillectomy. What might be the implications of the study by Einhorn et al. and the studies cited in the previous paragraph for practicing anesthesiologists and otolaryngologists? Fast-forward to the future. Imagine it is 7:15 am and you are an anesthesiologist and an otolaryngologist embarking on a busy operating room day with 12 unique and very diverse patients undergoing tonsillectomy. How might you apply clinical trial results, demographic characteristics, psychologic profiles, and genetic information to individualize safe and effective postoperative analgesic prescribing? Certainly not by hand-calculating odds ratios in the preoperative area! However, given the pace of advances in data science, digital health, bioinformatics, learning health systems, and artificial intelligence, we can envision that in the not-too-distant future, there will be “an app for that,” incorporating all the types of information cited in the preceding paragraph into a platform for evidence-based individualized perioperative analgesic prescribing. In a learning health systems framework, such an application would continuously refine its prescribing recommendations based on ongoing collection and processing of safety and effectiveness data collected prospectively using digital health and mobile health tools.

In the meantime, the optimal management of pain after tonsillectomy remains a challenge and merits further study, including additional clinical trials of existing analgesics, initial studies of new analgesics with novel mechanisms of action and studies of individual patient differences that influence pain trajectories and postoperative risks.