Reader response
Myron Yaster MD
From Jennifer A. Rabbitts and Tori N. Sutherland
We appreciate the PAAD members highlighting this important topic and their expertise and advocacy. In particular, Dr. Yaster should be recognized for his seminal research on pediatric pain management and advocacy for vulnerable groups.
We are fundamentally in agreement with the authors on many points:
· Appropriate management of acute and chronic pain is critical.
· Chronic postsurgical pain (CPSP) is both challenging to prevent and manage.
o Persistent pain could contribute to continued opioid use, as youth report pain as the primary reason for misusing opioids.1
o Undertreatment of acute postsurgical pain (and pre-existing pain) may be associated with chronic postsurgical pain.
· Opioids remain an important tool after surgery for acute, severe pain that is inadequately controlled by other medications, and in rare instances for chronic pain
Recognizing this is a complex issue, the points below should also be considered:
· Opioid stewardship efforts are clinically important.
o Approximately 67-92% of patients report unused opioids after surgery, increasing the risk of diversion/misuse.2
o In our study, high quantities of opioids were dispensed for minor procedures (e.g. ~26 5mg hydrocodone doses for endoscopy).3
· Multiple studies have concluded that patients use substantially less opioid with education on appropriate use, with no change in pain scores or satisfaction.4-6
o Safe opioid prescribing practices and observance of prescribing guidelines do not preclude providing adequate treatment.
· Prescription opioid use is independently associated with persistent opioid use and misuse, after controlling for high-risk patient characteristics (substance use disorder, chronic pain, mental health conditions).7, 8
· Although these findings are largely from the adult literature, persistent opioid use is associated with subsequent opioid use disorder (OUD) development, overdose, increased healthcare utilization and mortality.9, 10
o Among adults reporting illicit opioid use with the past 12 months, 39.2% reported their first opioid use involved opioids prescribed to them, while 36.1% reported their first opioid use was prescription opioids not prescribed to them.11
· If prescription opioids led to prevention of acute and chronic post-surgical pain, the incidence of the latter should have been low in the 1990s and 2000s due to high quantities of opioids prescribed after surgery. Instead, there was widespread recognition of CPSP during this period, and we saw an unprecedented increase in OUD cases, overdose events and death.
· Active trials (PCORI-funded) are studying use of opioids versus NSAIDs for pain management after minor procedures in children and adults. Results represent a critical next step to better understand optimal post-surgical pain management.
In addition, we would like to clarify the goal of our paper and correct (in italics) several mis-quotations (including the opening quote) in the PAAD commentary. Our primary aim was to describe current state of opioid prescribing practices in the U.S for adolescents undergoing surgery.
Regarding methodology, this manuscript underwent rigorous peer review with the JAMA network and utilized standard outcome definitions to facilitate comparison with prior studies. As stated in our paper, procedures were categorized into lower/medium/higher by the quantity of opioid in the first prescription using historical 2010 data from this dataset; the PAAD commentary incorrectly cites this grading (e.g., knee arthroscopy, high) as related to pain severity. However, we do note that we also considered procedures by anticipated pain as opioid dispensing often differed from typical needs. We agree that appropriate opioid prescribing has not been directly linked to the opioid epidemic, and we do not “attribute the opioid crisis to legitimate opioid prescribing by physicians” anywhere in this paper. The opening sentence of the PAAD “Persistent opioid use after surgery is a concern among adolescents and young adults…” does not appear in our paper.7 Our manuscript also does not state that “need for prolonged opioids following surgery is always problematic and unjustified”; rather we cautiously state that persistent opioid use “in rare cases may reflect development of an opioid use disorder.”
While we acknowledge our study is significantly limited by use of retrospective data, we hope that it generates thoughtful and collegial discussion around this important and complex issue. Many comments made by Dr. Yaster and colleagues highlight the critical need for research that can better guide our pain management practices, including the PCORI-funded study we described above.
References
1. Groenewald CB, Law EF, Fisher E, et al. Associations Between Adolescent Chronic Pain and Prescription Opioid Misuse in Adulthood. J Pain 2019; 20(1):28-37.
2. Bicket MC, Long JJ, Pronovost PJ, et al. Prescription Opioid Analgesics Commonly Unused After Surgery: A Systematic Review. JAMA Surg 2017; 152(11):1066-1071.
3. Sutherland TN, Rabbitts JA, Tasian GE, et al. Preoperative vs Postoperative Opioid Prescriptions and Prolonged Opioid Refills Among US Youths. JAMA Netw Open 2024; 7(7):e2420370.
4. Farley KX, Anastasio AT, Kumar A, et al. Association Between Quantity of Opioids Prescribed After Surgery or Preoperative Opioid Use Education With Opioid Consumption. JAMA 2019; 321(24):2465-2467.
5. Carender CN, Anthony CA, Rojas EO, et al. Perioperative Opioid Counseling Reduces Opioid Use Following Primary Total Joint Arthroplasty. Iowa Orthop J 2022; 42(1):169-177.
6. Alter TH, Ilyas AM. A Prospective Randomized Study Analyzing Preoperative Opioid Counseling in Pain Management After Carpal Tunnel Release Surgery. J Hand Surg Am 2017; 42(10):810-815.
7. Brummett CM, Waljee JF, Goesling J, et al. New Persistent Opioid Use After Minor and Major Surgical Procedures in US Adults. JAMA Surg 2017; 152(6):e170504.
8. McCabe SE, Schulenberg J, McCabe VV, et al. Medical Use and Misuse of Prescription Opioids in US 12th-Grade Youth: School-Level Correlates. Pediatrics 2020; 146(4).
9. Chua KP, Brummett CM, Conti RM, et al. Association of Opioid Prescribing Patterns With Prescription Opioid Overdose in Adolescents and Young Adults. JAMA Pediatr 2020; 174(2):141-148.
10. Brummett CM, Evans-Shields J, England C, et al. Increased health care costs associated with new persistent opioid use after major surgery in opioid-naive patients. J Manag Care Spec Pharm 2021; 27(6):760-771.
11. Powell D, Jacobson M. Estimates of Illicit Opioid Use in the US. JAMA Health Forum 2025; 6(5):e250809.
From Frank McGowan MD retired on Protein Kinase C Epsilon
Inflammatory (including hypoxic and ischemic) signal transduction in the heart was a major area of interest for our group and others for quite a while, and was initially stimulated by our attempts to understand and reduce ischemic-reperfusion injury in the developing heart. (A partial list of our PKC-related papers over the years is below). The role of activation of phospholipase C, D, and PKC isoforms was the basis for one of my first NIH grants. It proved to be a challenging area to study--at least for us--especially with regard to therapeutic manipulations--for many reasons. These included the pleiotropic activation and downstream mechanisms, subsequent crosstalk between the activated signaling pathways and their targets, significant time-,context-, species- and tissue-specific differences, etc. From experimental and therapeutic perspectives, the stuff we tried to do completely changed my (naive) view of how signal transduction was regulated and actually worked at the cellular and molecular level, and of the consequent difficulties of designing and implementing truly targeted and effective interventions.
McGowan FX, Cao-Danh H, Takeuchi K, Davis PJ, del Nido PJ: Enhanced neonatal myocardial preservation using a highly buffered, low calcium solution . J Thorac Cardiovasc Surg 108: 772-779, 1994.
(Results on PKC activation not included in this paper--which led to the “del Nido Solution in common use today—stimulated subsequent PKC work by our group over the next 10 years and was the basis for one of my first NIH grants looking at inflammatory signal transduction in the heart)
Buenaventura P, Takeuchi K, Glynn P, Cao-Danh H, McGowan F, del Nido P. : Inflammatory injury to the heart: The effect of protein kinase C activation. Surg Forum 45: 309-311, 1994.
MacGowan GA, McGowan FX, Du CW, Cowan DB, Solaro RJ, del Nido PJ, Koretsky AP : Ischemic dysfunction in transgenic mice expressing troponin I lacking protein kinase C phosphorylation sites. Am J Physiol 280: H835-H843, 2001.
Stamm C, Friehs I, Cowan DB, Cao-Danh H, Noria S, Munakata M, McGowan FX, del Nido PJ : Post-ischemic PKC inhibition impairs myocardial calcium handling and increases contractile protein calcium sensitivity. Cardiovasc Res 51: 108-121, 2001
PS from Myron
The role of Protein Kinase C is fundamental to almost all cellular functions. I suspect that a primer on this subject would be of great value for many of you. I will work with Frank on finding a review paper that we will feature in a future PAAD.
From Brad M. Taicher, DO, MBA, Chief of Anesthesiology, Pain and Perioperative Medicine, Children’s National Hospital Washington, DC
I completely agree with Dr. Murphy’s math (Reader Response, March 28th, 2025) that the opportunity cost of a pediatric anesthesiology fellowship over 25 years may well be $1.3M. However, (and maybe I am in the minority,) I do not personally see this as a cost, but rather as an investment - an investment in my happiness, satisfaction, quality of life, etc, and an investment that pays incredible dividends. I would challenge us to to ask colleagues at the 25th year of their career whether they would have chosen an additional $1.3M into their retirement fund if it meant they would not have had the privilege or the joy of caring for children every day of their career, and see where our organizational values currently exist.
I’m not arguing that we should not seek opportunities to make fellowship more financially viable, but rather that economics should not live in a vacuum. We are so fortunate to be able to do what we do every day, but a small part of that is because we are surrounded by individuals (anesthesiologists as well as surgeons) who, like ourselves, each gave up potential earnings in order to invest in a rewarding career rather than a 'job'.
From Norifumi Kuratani, MD.,PhD.,MPH, Anesthesiologist-in-Chief, Saitama Children's Medical Center, Visiting Research Associate, Teikyo University Graduate School of Public Health, 1-2 Shin-toshin, Chuo-ku, Saitama-City
Thank you for the excellent and comprehensive discussion on remimazolam in procedural sedation. As the authors of the referenced Japanese observational studies (#1 and #2), we would like to share some updates based on our more recent institutional experience.
While our initial data indicated that remimazolam could be safely used in ASA I–II pediatric patients, we no longer use it routinely for procedural sedation. In our current practice, propofol—though also off-label—remains our preferred agent due to its ease of titration, rapid onset, and broad familiarity among anesthesiologists. For most cases managed by anesthesiologists, we have found that remimazolam does not provide significant advantages over propofol, aside from its non-painful injection. That said, remimazolam may offer potential advantages when sedation is provided by non-anesthesia providers, given their greater familiarity with benzodiazepines and the availability of flumazenil for rapid reversal in case of adverse events.
In particular, we have found remimazolam to be highly useful in pediatric cardiac catheterization anesthesia and sedation. It enables deep sedation with minimal cardiovascular compromise and preserves spontaneous respiration, which may be beneficial for catheterization lab measurements. Remimazolam also provides a smooth post-procedural sedative state, which aids in maintaining hemostasis at the catheter insertion site. Our pediatric cardiologists have expressed strong support for its use in this setting.
We have also had favorable experiences using remimazolam as an adjunct to general anesthesia, particularly for achieving smooth and calm emergence (Anesthesiology. 2024 Sep 1;141(3):500–510).
Generally, we extrapolate adult dosing protocols, but we believe that further research is needed to establish appropriate pediatric dosing and to support the safe and rational integration of remimazolam into pediatric anesthetic practice. Thank you for continuing to highlight this important and evolving topic in pediatric sedation.