Dr. Lorraine I. Kelley-Quon - Treating Pain in Kids: How Opioids Influence Health and Addiction at Every Age

All right. Well, good morning, everyone. Um, why don't we go ahead and get started and welcome to our combined, uh, general surgery and anesthesia grand rounds. I know there are a lot of folks who are zooming in. I think we have a lot of folks from the MGH who are joining us as well. And so, it is, uh, my pleasure, uh, to introduce this year's Weitzman, visiting professor in Health Services Research, and that's It's Doctor Lorraine Kelly Kwan from Children's LA. And, uh, as many of you know, we established this lectureship about 5 years ago, and it was really, uh, to kind of honor and celebrate uh those in our field who have made a huge impact in either the understanding or management. Of, uh, conditions in our field that have really kind of broad public health relevance. And so today's lecture is definitely no exception to that. And, uh, so as far as a little background, so Doctor Kelly Kwan is an attending pediatric surgeon at, uh, Children's LA. Uh, she is an assistant professor with the dual appointment both in, uh, surgery as well as population in public health, uh, at the Keck School of Medicine and, uh, is actually been a, a superstar in the space of health services research. But what we're gonna hear about today, uh, really is her work, uh, in the space of, uh, opioid prescriptions and the public health implications as they pertain, uh, to children's surgery and really kind of the scope and, and a deep understanding of this. And so she is extraordinarily well published in this space, uh, a number of, uh, publications and high impact journals. She's been featured in Time. Magazine for her, uh, incredible work and, uh, also very well funded through the NIH and also, uh, a recent recipient of a $7 million Priori Award, uh, for the comparative effectiveness of, uh, exploring, um, opioid sparing, uh, pain management in the postoperative care of kids. So, so, really, uh, extraordinary work and, uh, and she's the real deal. So we're really excited to hear, uh, what she has to say today. Um, I do want to, before we start, uh, acknowledge Stuart and Jane Weitzman. Uh, as you know, the Weitzmans have been huge benefactors, uh, to the organization as well as our department. And of course, they've funded my chair, which I'm extraordinarily grateful for, and they've made this lectureship possible over the past 5 years. And so I do want to acknowledge their generosity and support. Uh, so with that, without further ado, uh, Doctor Kelly Kwan. All right. So good morning everybody. I'm, I'm very impressed with everyone waking up so early. Um, I'm operating on 4:00 a.m. time zone in the Pacific Coast. Um, so I appreciate everyone coming in today. Um, I also appreciate everyone who's logging in, um, remotely. Um, I wanted to also take this time to just start, uh, with a story from when I was a pediatric surgery fellow. Um, I know there are a lot of trainees, um, in the audience today, and I'm sharing this story really cause I want to highlight that we really, when you are In the midst of your training, there's a lot of busyness and noise, and taking a moment to listen to the stories of the patients that you are caring for and thinking about how their stories reflect larger challenges in the healthcare system and our society in general, really can impact and inspire you to really dig, dig in and do very meaningful research. So when I was a pediatric surgery fellow, I did my fellowship, uh, at the Ohio State. I was in Columbus, Ohio. Um, and if anyone has been following the opioid epidemic, the Midwest was particularly hit hard by the opioid epidemic. Ohio specifically. And I vividly remember, um, we had one teenage patient come into um the pediatric surgery service and he had been in a car accident and he had multiple rib fractures and he had several very severe contusions, and he was admitted for pain management. And as he was getting ready to go home, I ran the list with the intern in the morning, and I said, oh, make sure that you send this kid home, um, with some opioid medication because of his rib fractures. Um, and my intern said, OK. And then I followed up with him at the end of the day and I said, oh, did that, did that young man, did he actually, did he go home OK, get discharged home OK? And my intern didn't really answer. It's straightforward. And he said, yeah, well, eventually. And I said, well, what do you mean eventually? He said, well, I wrote him a prescription for opioids just like you had instructed me to, um, and I gave it to him, but then this teenage patient, who was about 1516, actually saw the script and gave it back to the intern and said, I'm sorry, both of my parents have, um, substance use issues, and I just don't feel safe having this amount of narcotic medication in our house. And I thought, oh wow, OK. And I asked my intern, I said, well, how many tabs of um oxycodone did you write for? And he said, I wrote for 90 tabs of oxycodone, and I thought, 00 my goodness. I said, well, why did you write for so much? And he said, well, and this is his 2nd rotation as a brand new surgery intern, he said, well, I just came off of the surgical oncology service. And on that service, I sent everybody home with 150 tabs of oxycodone. And so I thought, 0, 90 tabs would potentially be, be appropriate. And I was so, I was so taken aback by this interaction for so many reasons. The first was that we, I, I I thought, wow, we cannot let children be the gatekeepers of opioids within the community and within the home, especially if parents have substance use, um, problems. And I thought, wow, we hadn't done as a medical community, a great job at educating this intern and setting them up for success. And I thought this is something that I really want to dig into and think about in my career. So I'm gonna be talking about several projects today, um, that I've done along the way inspired by a lot of the things that I saw when I was a pediatric surgery fellow. Um, so these projects are supported by uh CTSI team science grants and also, um, I'll be talking a little bit about, um, my RO1 looking at, um, infant opioid exposures. All right, so let's dig in. Um, this slide, you've, a lot of you have probably seen this data. This was published in the New England Journal at the end of 2022. These are the leading causes of death among children and adolescents in the United States from 1999 to 2020. And if you look at these, um, the top three causes of death for US children are firearm injury, motor vehicle collisions, and drug overdose. Um, and you can see the purple line for drug overdose recently exponentially started increasing. So drug overdose very recently overtook childhood cancer as the third leading cause of death in children in the US. This is a very important statistic. I'm increasingly um involved in more advocacy, um, in this space, and this is the statistic. that makes legislators pick up their ears. This is a problem that is impacting children and as a pediatric surgeon, these four things are the 4 things that come through my clinic doors. So I need to be involved in generating research, um, and thinking about how I can change these curves. So why is drug overdose such a leading cause of death in children in the US suddenly now? Well, it's because of this. Um, this is data out of the CDC. This is the National Vital Statistics System. Um, there are basically three different waves of the opioid epidemic. So the first wave began in 1990s, early 2000s when there was a rise in In prescription opioid overdose deaths. Now, a lot of you probably are aware that this coincided with the pain as the 5th vital sign movement, the overprescribing of prescription opioids, and also the mass marketing of OxyContin. Subsequent to this, there was a rise in heroin overdose deaths, and now we're in the 3rd wave of opioid overdose deaths where there has been a very exponential rise in synthetic opioid overdose deaths largely attributable to um the presence of fentanyl in the general drug supply. So what I want you to focus on is that there is a purple line and that is representing the fentanyl-related overdose deaths. But you can also Look at the teal line that represents the commonly prescribed opioids. Uh, that line has not gone down. It is really stabilized. So there's now two different problems when we're thinking about opioid-related overdose deaths. There is overdose is secondary to commonly prescribed opioids and then overdose is secondary to fentanyl and the drug supply, and there are really two different ways that these need to be addressed when we're thinking about um child health and how and how it impacts the patients we care for. So an important concept, um, a lot of people are very surprised, especially people who are outside of medicine, when I tell them what my research is on and that I research opioid use in pediatric populations. A lot of people don't think about children when they think about the opioid epidemic, but pediatric opioid prescribing mirrors adults. All of these waves and overprescribing of prescription opioids. It was happening in the adult population. It was also happening in the pediatric population. Greater than 1 in 10 high school seniors report non-medical prescription opioid use within the last year, and if you ask graduating seniors if they have ever misused prescription opioids, about 20% of them will say yes. Most adolescents who misuse prescription opioids are given them for free. Opioids are in our communities. They are in our medicine cabinets, they are frequently on the kitchen counter. They are very easily accessible, and surgery is the most common reason that a child will have a prescription in their home, surgery and dentistry, and this is why this is something that pediatric surgeons need to care about. Um, so with this in mind, um, the American Pediatric Surgical Association back in, uh, 2018, um, myself and several other pediatric surgeons, um, decided that what we needed to do was review all of the literature that had been published looking at opioid prescribing and generate guidelines for opioid prescribing. Um, and when we, when I led this project, we knew it couldn't just be pediatric surgeons coming around the table and creating a guideline. It, we had to engage all stakeholders. So our team included representatives from pediatric anesthesiology. We had a PACU nurse on our team. We had a general surgery resident. Um, we also partnered with, um, one of my colleagues, Doctor Matthew Kirkpatrick. He is an addiction scientist. Um, and also we had representatives from the American College of Surgeons and also, um, Um, from the American Academy of Pediatrics. And basically what we did was we spent a year, year and a half years reviewing over 14,000 manuscripts and then in the two days leading up to the ABSA meeting, um, in 2019, we sat in a room and we reviewed all the literature and we decided what What literature could inform guidelines for how to prescribe opioids safely? And ultimately what we did is we generated this document. This was um published in November of 2020, um, and this was the 1st, 1st, publication outlining guidelines for opioid prescribing for children and and adolescents over, uh, after surgery. Um, this particular publication, um, got a significant amount of, um, press and coverage because really nobody had dug into this literature, specifically looking at how it impacts on children before. Um, so we generated 20 different guideline statements. We're able to grade them on our strength of recommendations, level of evidence, grade of recommendations, and the quality of evidence, um, that was available. And there's really 3 things that we, uh, 3 basic pillars of opioid stewardship, um, that we identified with these 20 different guidelines statements. The first pillar is that Anyone who is prescribing opioids to a child or an adolescent needs to recognize the risks of prescription opioid use. So I can tell you that this particular pillar was informed in large part by an entire decade's worth of evidence within the addiction science space that I, as a practicing surgeon, had never read before. So I'm gonna talk about some of the literature that um we included in this particular review. Um, but I really wanna highlight that so much of this particular document was informed by science that had been going on for decades, but science outside of medicine, science that was happening in the clinical, um, psychology realm and behavioral sciences. And I really wanna emphasize that thinking broadly about children's health means also thinking broadly outside of medicine in general, and thinking about other fields that are interested in Uh, uh, high risk behavior and how it impacts children and families. Um, so this is data from, uh, the household survey. So the household survey is a survey that is run by the Department of Health and Human Services. It's a survey that has a random sample of US citizens, and they, um, one of the things that they Measure is substance use. So this survey asked questions about cannabis, about tobacco use, and this survey has been going on since the 60s and been surveying adolescents, young adults, and um older adults about prescription opioid misuse. And so what this paper did. Which I really liked is they took several, several, several cohorts of that survey, and they overlaid them together, um, based on age, which you can see on the, um, on the X axis at the bottom. And what I want to highlight is they were measuring the overall percent of the emergence of non-medical prescription opioid use, uh, within the last year. Uh, on the Y axis. And you can see that the emergence of prescription opioid misuse, this is happening in the 12 to 17 and the 18 to 25 year old age bracket. So if an individual in their lifetime is gonna struggle with um substance use specific to prescription opioids, it is going to start when we are seeing them in early adolescence. And this is why this is a space where we really need, um, we really need good evidence. And the thing that I've learned in partnering um with a lot of my addiction science colleagues is that teen substance use is really shaped by the world around them. And I think sometimes this is really hard to remember as a clinician. Um, an adolescent sometimes can be twice as tall as you and be talking, um, to you in a very mature way, but you have to remind yourself that the adolescent brain is still developing, and they have unique responses to socio-emotional influences and peer pressure that someone who is an adult is not going to respond to. So they are uniquely at risk, um, of struggling um with substance use because of this. Um, one thing, um, that I, uh, often hear, um, from clinicians is like, well, we know that adolescents can be at risk for substance use problems, but if an adolescent uses a prescription as prescribed, isn't their risk of future misuse, um, pretty minimal? Um, and that's actually not true. So use of prescribed opioids before 12th grade is independently associated with future opioid misuse. Um, so this data is informed by something called the Monitoring the Future study. This is a study that's run out of the University of Michigan, um, and this is also a study in which they randomly sample, um, adolescents throughout the United States, and every year, um, they ask about substance use, um, and each year, uh, the questions change reflective of whatever is going on. Um, In the population. So right now, there's lots of questions dedicated to vaping, etc. cannabis use, um, and it changes as time goes on. So in this particular, um, study of that survey, um, they surveyed over 6000, uh, 12th graders, um, uh, when they were graduating, and then they surveyed them again when they were 23 years old. And this study found that legitimate opioid use before high school graduation was actually independently associated with a 33% increase in the risk of future opioid misuse after high school. And this is in teenagers who had little to no history of drug use throughout high school and who When they were graduating, said they strongly disapproved of illegal drug use, um, when they were a senior. So even using prescription opioids as prescribed does increase the risk of that individual when they're aging out of our care, um, potentially, um, having a substance use, uh, challenges. Um, so this is one of my primary, um, mentors when I, um, first joined, um, CHLA and USC, Doctor Adam Leventhal. So Doctor Doctor Leventhal is a clinical psychologist, um, and, uh, he has spent a lot of his time looking at adolescent and young adult cannabis use and, um, Um, uh, tobacco use. And when I joined, I joined, uh, CHLA back in 2017, and at that time, he had just finished recruiting a cohort of students from the LAUSD and he had initially recruited them in 2013. This is called the uh Happiness and Health Study. Um, and he then every 6 months for their entire high school experience, um, uh, he conducted surveys in their classroom. An entire classroom time was dedicated to conducting the survey, and he was able to follow over 90% of that cohort up through graduation. And the thing that's really unique about this particular, um, This particular group of uh students is that in the first survey, this survey asked about problematic substance use, so if when they had first started high school, if they were using cannabis, alcohol, nicotine, other drugs, um, it also Had several validated metrics of depression, delinquency, peer opioid misuse, and also captured family and personal socio-demographics. So this is a baseline survey that happened right when these teenagers started high school. And then every 6 months afterwards, Um, his research team asked about all of these different substances that they were interested in tobacco, cannabis, and they also asked about, um, non-medical prescription opioid use. And when I started in 2017 at CHLA and he agreed to be my mentor for my K Award, he said, you know, I've, I've been, I have this data set, and we've looked at a lot of different substances. And I think I asked about opioids for all of these kids, but I've never actually looked at the data. And so this was this really incredible opportunity for me as a pediatric surgeon to partner with someone in clinical psychology who didn't go to medical school but has this huge wealth of data, knowledge and experience to do some very, to generate some very impactful studies. So I highlight um our relationship. Because there, um, especially at any university, there are many people outside the walls of a hospital who can really augment your understanding of the science that informs our practice and what our patients are experiencing. So the first thing we wanted to do was identify factors that are present in early adolescence that there are then associated with later non-medical prescription opioid use. So this is what's going on when um teenagers first come into high school that influences their likelihood to later misuse prescription opioids. And we found that in their freshman year, if they are using cannabis, if they have um alcohol problems or in general um screen positive for uh drug abuse, that increases their likelihood of later um prescription opioid misuse. But then we also found that depression also increases the likelihood of this, as does mania and hypomania. So in thinking about how can we identify adolescents who are most at risk of struggling with prescription opioids, thinking about it when they're first starting high school, and now we're talking about, well, maybe we should even be earlier, we should be thinking about middle school. This is what we need to think about. The next question we asked was, well, not everybody misuses prescription opioids in the same way. And what we, what we found is we asked, well, in the last, we looked at the question asking, in the last 30 days, how often have you misused prescription opioids? And if you look, there's about 4 different populations that are identified. When you Ask teenagers this question. So the first population, uh, is, uh, the, the bulk of, of, uh, adolescents reporting misuse is minimal or experimenters. So these are people who misuse prescription opioids once and then they're pretty much done. Um, the second population we call the low de-escalating. So they start high school and they maybe experiment a little with prescription opioids and then it tapers off. But then there are two populations that are really concerning. So this is the escalating moderate, so they start off experimenting with prescription opioids and it escalates throughout the course of their high school years. And the frequent persistent. So I want you to specifically look at that frequent persistent curve and the apex of that curve. That apex happens around 10. So that means 10 out of the 30 days in the last 30 days they were misusing prescription opioids, that's 1 every 3 days. That's very frequent. So now what we wanna do is looking at this, we've actually followed this cohort into young adulthood. What's happening with these kids after, after they leave high school who were members of the, these high-risk trajectories and did that increase and continue and lead to further problems of substance abuse in early adulthood. And the factors that were most predictive of which sort of trajectory an adolescent would fall into, um, was their gender, whether their friends were misusing prescription opioids, if they had other substance abuse, um, challenges, and also impulsivity and delinquent behavior. And then finally, um, this paper, um, we wanted to ask the question, well, does any prior opioid use predict later heroin abuse? So heroin abuse in adolescents during high school is very rare, but because this cohort was very large and because they were surveyed every 6 months. And because we were able to follow them for so long, we were actually able to pick this up. So this is the first prospective study that identified a prospective association with new onset of prescription opioid misuse and heroin abuse even within the uh the confines of the high school years. So, all of that data really informs the first pillar of the opioid prescribe opioid prescribing guidelines that we really need to as clinicians recognize the risks of prescription opioid use. The second thing that we wanted to highlight in our guidelines was that clinicians really need to maximize non-opioid analgesics. So one of the non-opioid analgesics that is, you know, very useful, especially for pediatric surgeons is uh IV acetaminophen. So IV acetaminophen was approved by the FDA for pediatric use in 2011, um, and we wanted to do a study looking at doing an interrupted time series analysis because what happened in 2014 was the company that made IV acetaminophen changed and then the cost of IV acetaminophen went from $14 to $35 per 1 g vial. And when that happened, hospitals actually began limiting use of IV acetaminophen and availability in an effort to reduce costs. Um, so on this interrupted time series analysis, you can see that the slope of the curve of uptake of IV acetaminophen, this is for, um, children undergoing, uh, appendectomy, um, it actually changed over time. Um, so this data was generated from the Pediatric Health Information System database. A lot of you have probably used this data set. Um, this data set rep, um, this data set gathers data from the all hospitals within the Children's Hospital Association. It represents 20% of, uh, children cared for in hospitals in the US and 50% of critically ill children. Um, so this is a snapshot of what's happening in children's hospitals. I would argue this is potentially some This is potentially something that is even more problematic outside of children's hospitals. Um, so, uh, it's very important, um, as a clinician to advocate for IV acetaminophen use. Um, we wanted to know in the study, well, you know, the hospitals are eliminating cost, does it actually cost more overall looking at all costs. So we actually found because this fortunately has a standardized unit costs in their reporting. That while the individual pharmacy cost did increase for any child receiving IV acetaminophen, when you actually factor everything in and factor in Um, inflation over time. Median pharmacy charges actually decrease when a child receives this because they get less opioids over time. So looking just at the price tag of an individual, um, medication doesn't tell the whole story. So if you are at a, a facility where you do not have this available, encourage, uh, encourage the leadership within that facility to look broadly at the overall pharmacy charges and how they actually may be improved by expanding, uh, utilization of IV acetaminophen. Uh, another thing we did in the guidelines project was we identified, um, data that highlighted procedures that children could undergo that potentially could have an opioid-free recovery. Not that they wouldn't receive opioids in the operating room, but after these surgeries, when a child is ready to go home, a lot of these surgeries are outpatient procedures. They could potentially go home, um, just with ibuprofen and Tylenol and don't necessarily need a prescription opioid. And one of the surgeries, um, that we highlighted, uh, in the guidelines, uh, was appendectomy. This is potentially a surgery that can be done and children can be sent home, uh, without an opioid prescription. Um, so shortly after we published, um, our guidelines, um, we conducted this project. Um, uh, CHLA is a member of the Western Pediatric Surgery Research Consortium. So this is a consortium of 10 children's hospitals in the western US. I, you guys have a very similar consortium here on the East Coast. And we perform quality improvement projects together. We perform, uh, randomized controlled trials together, prospective studies, etc. For pediatric surgeons, these types of consortiums are very important because so much of what we treat is very rare. So any one hospital, it's very challenging to get enough numbers and enough power, um, to show a Difference, um, in certain outcomes. So these consortiums provide, uh, a wonderful opportunity, um, for collaboration, um, and improvement of care for, um, pediatric surgery. So for this particular project, it was soon after the guidelines, um, came out, we all sat around the table and said, oh well, we should do a project looking at minimizing opioids after appendectomy. And I vividly remember all of the surgeons around the table saying, well, you know, I don't think we really need to do this project because none of us prescribe opioids after appendectomy. And it was so funny because in real time, people started texting their residents and nurse practitioners and their partners, and we found out just sitting at the table, oh. Actually, a lot of us are still giving opioids after appendectomy, and I was really struck by that moment because even as the surgeon who is the leader of a surgical team, we may not understand the nuances of what's happening when our when our children we care for are being discharged home. So we, we, we all agreed that we should do a quality improvement project, um, to minimize opioid prescribing after appendectomy. Uh, and so what we did is all of us were members of and still are members of NSQUIP. So NISQWIP is the National Surgical Quality Improvement Program. Um, this is an interface that hospitals, um, have in which they can track clinical outcomes data like surgical site infections, hospital readmissions, ER visits, um, for multiple. Different conditions that we treat as um, as surgeons. There's an adult version, there's also a pediatric version. Um, so we all had Nisquip, um, but something that Nisquip didn't track at that time was prescription opioids. Um, but one of the nice things about Nisquip is you can actually create variables in Nisquip that are important to you in your own hospital and track them. So we all created the same variables in our Nisquip. And started tracking opioid prescribing. And so this study ran over the course, I think it was um 2020. So you can see January to March, you can see the overall percent of opioids prescribed at discharge between our different hospitals. Each line is a different hospital. So you can see that some hospitals didn't prescribe opioids after appendectomy, but some hospitals, almost 70% of the children undergoing appendectomy at their hospital, uh, were receiving opioids. So we did, um, so we in the middle of, uh, 2020, uh, introduced this intervention and did two PDSA cycles and we were able to get the mean, um, percentage of opioid prescribing to go from 17% down to 4%. Uh, and we also tracked, uh, patient satisfaction with pain control and also 30, 30-day ER visits which again are already tracked in this book. Um, and we were able to show that we could minimize opioid prescribing, but we really didn't have any significant change in patient satisfaction with pain control or 30-day ER visits. Um, so this was, this was really This is really meaningful for several reasons. Number one, there's about 900 families that otherwise would have been given opioids that weren't given opioids. So those are families that now don't have opioids sitting in the kitchen cabinet and the kitchen counter, um, available to the community potentially for diversion. Um, and the other thing that made this, um, very meaningful is this is sort of the first time that multiple hospitals came together and used leveraged Nisquip to do quality improvement across multiple different hospitals at one time. So, uh, I am, uh, the, uh, surgeon champion for Nisquip at CHLA, and one of the fun things I get to do is make real-time tables for myself, which I get a lot of satisfaction off of looking at our own Nisquip data. Um, so Nisquip actually started tracking opioid prescribing for 2023. So I went last week while I was putting this talk together into Nisquip, and I was, and I wanted to know, well, how many patients Patients at my hospital, CHLA are receiving opioid prescriptions. So I can now tell you that about 22% of patients are receiving opioid prescriptions and I'm working with my SCR to find out which patients um are receiving it and how that's being prescribed. Um, and so this is like a new tool that is now everyone who has Nisquip can follow. Um, and I was also very happy to see that none of the kids that were, uh, from CHLA were receiving codeine. But the other thing that I was really excited to see is now we have an entire year's worth of data looking at all Nisput pediatric hospitals and seeing how often opioids are prescribed. So for all of the surgeries that NIP tracks, about 29% of children in Nisput are actually receiving an opioid prescription. So is that, is that appropriate? Is it inappropriate? We don't know, but we can at least have data now and track this. And this, this room brought me a lot of joy last week when I looked at this. Um, so I looked at specifically at appendectomies, and I wanted to know at CHLA I wanted to make sure no one was getting opioids at CHLA and that looks like it's still the case for 2023. And then I wanted to look at nationally, um, children captured in NSB undergoing appendectomy, are they receiving opioids or not? And I was so happy to see that only about 5% of children are receiving an opioid after appendectomy. Now, there's lots of reasons that an opioid could be appropriate for a child after appendectomy, but I was just really proud of that particular number because of the data I just showed you. A few years ago, there were hospitals in which 70% of patients at those hospitals were receiving opioid prescriptions. And in 2020, there was a survey of abscess surgeons, and it asked them how often do you send a child home with an opioid prescription. And at that time, 40% of abscess surgeons said that they prescribed opioids after appendectomy routinely. And now in 2023, we already got that number down to 5%. And I just think this is a huge win. So much of research is a long haul, but I, I've been so encouraged with how rapidly um my partners in the pediatric surgical community has embraced concepts of opioid stewardship and actually been able to move these percentages in a very real way. You know, as I alluded to earlier, there are populations who potentially benefit from opioids, and one thing that is lacking from all of the data that we reviewed and, um, and that informs the guidelines project is really there's not RCT level evidence behind this. So as um Doctor Rangel highlighted, so, uh, I partnered with the University of Michigan and I am co-PI on the comparing. Analgesic, uh, regimen effectiveness and safety for kids. So this study has actually been run in adults by University of Michigan right now, and we just got funding $7 million from Pkori to start running this in children. And so what we're going to be doing is we are going to randomize adolescents undergoing 3 different common outpatient elective surgeries associated with an opioid prescription. So knee arthroscopy, cholecystectomy, and tonsillectomy. And adolescents are gonna be randomized to either receive uh acetaminophen and NSAIDs or acetaminophen, NSAIDs, and low-dose opioids, and we're gonna measure their pain control after surgery. We're gonna measure side effects uh in the weeks following. Following surgery and we're also gonna measure long-term outcomes such as the emergence of um persistent opioid use, um, and opioid use disorder. So this is, I can tell you 5 years from now, we're gonna have great RCT level evidence to answer this question. Um, and it's going to be a very heavy lift, but it's very important for our patients because there is likely some benefit to opioids and we don't want to go on the other side of the spectrum. And not be sufficiently treating our patients' pain when we should be. Um, the other thing I want to highlight, so her guidelines project was published in 2020 and our, uh, literature review spanned all the way up to early 2019. Um, so at this point, uh, those guidelines are about 5 years old. Um, and as I've highlighted, there has been a lot of new literature and data in this space. So I was very fortunate to also partner with the American Academy of Pediatrics to create, um, their first clinical practice guidelines for opioid prescribing. Um, so we did a very similar process, um, with this group as I did, um, previously with APSA. Um, this is a multidisciplinary group, uh, Of pediatric anesthesiologists, pediatric surgeons, um, ER physicians, etc. and we reviewed the literature and, uh, generated, um, several key action statements or guidelines. Um, this is coming soon, this October, so if you come to the National Conference and Exhibition in October for AAP, this is something that we will be presenting. Um, so I'm also really proud of being a part of this project because as I highlighted, there's been so much movement and literature, um, built in this space that really, um, updating these guidelines, this is the perfect time to do it. The final thing that we highlighted um in our guidelines project was that families need to be educated on safe usage, storage, and disposal of prescription opioids. Um, so this is a project that was led by, uh, Doctor Marjorie Odegaard. She was a previous fellow in my research lab. And what we did was we ran several focus groups at CHLA and we recruited families, both English and Spanish-speaking, and we asked them, What their experience had been receiving prescription opioids, and what type of education do they want from their healthcare providers uh about prescription opioids. And the thing that I was sort of most overcome by was the first of these five themes. Um, the first thing that they, the families told us was they are already Coming to the hospital with a fear of overdose and opioid addiction on their mind. They are aware of the opioid crisis, and a lot of information that they were being given when their child received an opioid prescription is they would receive a prescription and then be told about all of the terrible things that can be associated with that prescription. And there was a huge cognitive disconnect with families and why are you giving me this prescription if there are so many things wrong with it. So it really um struck our research group that there really needs to be, yes, an acknowledgement of risk, but also acknowledgement if a child is gonna receive opioids, the family needs to know why it's appropriate to receive opioids. Um, also, uh, families are really empowered to control their opioid use. I was very impressed by, uh, some of the texts from the adolescents we recruited for these focus groups and how they wanted, they themselves wanted to make sure that opioids were stored correctly. They talked about their neighbors and their neighbors' children coming to the house and they wanted to make sure that the house was safe when the neighbor kids come over. Um, this whole project really reminded me of how much I just really love taking care of adolescents because they've really just step up to the plate and they wanna do the right thing. So when you have a teenager who wants to do the right thing, you have a family that wants to do the right thing, and you educate them, um, taking into account the different themes that they, that they're looking for, I think that that'll result in, in patients and families really being empowered in this space. A lot of families also desire alternative pain management, be that non-opioids or even non-pharmacologic interventions. Um, and they also come to physicians with a lot of previous knowledge, um, on opioids and beliefs and preconceptions on how to manage pain. Um, something I wanna highlight that children's hospitals specifically can do is introduce infrastructure to encourage safe opioid disposal. Uh, this green bin is an opioid disposal bin we have at CHLA. It was installed in July of 2019. When this was installed, ours was the first children's hospital in the Western United States to have an opioid disposal bin on campus in the pharmacy where people are receiving their opioid prescriptions. Um, I recently looked at this data a few weeks ago, and less than 50% of US children's hospitals provide an opioid disposal bin on campus currently. So this is something specifically that children's hospitals can expand, uh, capacity in. Um, for families that perhaps live far, um, from your hospital, um, the DEA has an online search tool, um, for a local opioid disposal bin. This is the URL here, um, and I put in the zip code, um, for this hospital, and you guys have a disposal bin, great job, great job, guys. Um, and so if you have a family who lives far away, they can put in, um, their zip code and find a disposal area that's very close to them. There's a lot of CVS and Walgreens, um, that have bins on campus. Something important for healthcare providers and hospitals in general to be aware of is that as of April 2023, the FDA is now mandating drug companies to make prescription opioids dispensed in outpatient settings coupled with prepaid mail-back envelopes uh available. Um, so this is a planned implementation for 2024, but I don't think a lot of hospitals in general are aware of this, um, that they can receive these envelopes from the companies that make opioid prescriptions. So this is live in 2024, um, and it's something that needs to be taken up and it's really primed for implementation science evaluation. I also wanna highlight the importance of Narcan or naloxone co-prescribing. Um, so Narcan is a nasal spray that reverses opioid overdoses. We've talked a lot about opioid stewardship and opioid prescribing, and that's really addressing that teal line that I showed, um, uh, in the opioid, uh, the opioid overdose epidemic, uh, slide. But really none of that is Gonna address the overdoses secondary to, to fentanyl, um, but having more Narcan in the community in general potentially can move that needle. So it's available for purchase, um, over the counter at drugstores, um, and I very highly encourage, um, anyone who's prescribing an opioid to consider co-prescribing it. There are some, um, uh, insurance companies that will cover, um. Prescribing of Narcan. So I have a 12 year old, he is going into middle school next year. I have Narcan actually in my purse right now. We have Narcan in our first aid at home and uh Doctor Ruby Barks, she's the junior fellow in my lab. She gets a special shout out, um, right now, um, because I told her this statistic right now. I told her that 67% of adolescent overdose deaths. Uh, when those occur, 67% of them have a bystander nearby who could have intervened, and naloxone is only administered in less than 50% of cases. And that's because Narcan is just not widely available in the community, and it is not widely something that people are comfortable administering. But Ruby gets a special shout out because she heard this lecture, she Carries Narcan on her person and a few weeks ago saw someone unconscious outside of Starbucks and administered it and resuscitated them and then called an ambulance. So this is something that if you are someone who knows CPR this is something that you should be, um, uh, you should be educated on how to use, um, and something you should have at your home, um, first aid kit. Um, this is particularly important, um, locally for me in Los Angeles. So we have had a significant number of fentanyl overdose deaths, even deaths that occurred on school campuses in Los Angeles, and LA County is actually a hotspot for teen opioid overdose-related deaths. We had 111 deaths from 2020 to 2022. And the other two counties who are, um, have a high adolescent overdose rates are Orange County and Maricopa County, so also in California and then in Arizona. So I really want to highlight this because this is very different than what was happening with the opioid epidemic previously within even the last decade. It was very much isolated. Isolated to uh the Midwest, but I am in Los Angeles and this is impacting, uh, my local community right now, so there needs to be different factors to move this needle. Um, Narcan is now carried in all LAUSD schools, and in 2023, it was used 31 different times, uh, for students. I also want to highlight the importance of community engagement. I live in a, uh, a small city called La Nenata in Los Angeles. We have had several adolescents who overdosed on opioids in our community. My lab is hosting a uh opioid. Take Back event in April and we're also gonna be distributing Narcan. And we were very much set up to succeed in this endeavor by our partners at University of Michigan who're running the RCT with. They have a toolkit if you want to run this, uh, locally at your own institution. Um, they have A lot of resources um to inform you how to get materials together, how to partner with law enforcement, and you can, if you wanna move the needle locally, you can even start doing it, um, right now. This, uh, effort is being led by one of my very resourceful medical students, Odessa Bello right now. All right, and the last part of my talk, uh, I'm gonna, I'm gonna talk about, um, a lot of the work I've been doing that's been funded, um, by my RO1 right now. So, most people are surprised that I study opioids in children. They are even more surprised when they learn that babies receive opioids and also it impacts their health outcomes. So as many of you know, infants frequently receive opioids for procedural sedation and analgesia. Um, they receive opioids for intubation and post-operative recovery. Some of them require methadone, and if they receive excess exposures to opioids, it can impact their overall brain development. Um, this is a study we did looking at fizz, just generally looking at all hospitalized infants over a 10-year period in fizz and looking at whether or not they received opioids during hospitalization. So in general, in the United States, 20% of hospitalized infants receive opioids during hospitalization and about 0.8% of them receive methadone. Uh, we then wanted to look at, uh, opioid and methadone prescribing for infants with surgical necrotizing entercolitis. Now this is a population that potentially receives multiple procedures, multiple operations, has multiple prolonged exposures to opioids. Um, this is a project led by one of the senior fellows in my lab right now, Doctor Olivia Keen. Uh, and we found that overall prescribing in the mean days of postoperative opioids, uh, it's actually increasing a little over time, looking at 2013 to 2022, and the curve for mean days of opioid, uh, postoperative opioid use for children with necrotizing enterocolitis, it is closely mirrored by the same curve looking at overall likelihood of methadone. And why does that matter? Well, We found that the longer that these babies receive opioids after their surgery for necrotizing enterocolitis, the more likely they are to require methadone. We also found that once they receive methadone, those infants stay 21 days longer in the hospital, they have 10 more ventilator days, and they have 16 more TPN days. So these are very expensive hospitalizations for very high-risk infant populations. Um, so a lot of this, uh, work informed, um, my RO1 looking at the impact of opioids on health outcomes for hospitalized infants, and really the central hypothesis of this project is that opioids opioid use varies widely for high-risk infants with higher use leading to substantial increases in neurocognitive disability and overall healthcare utilization. And so what we're doing with this project, we're gonna use data from PIS. So PIS is a very rich data source for multiple reasons. Number 1, it enriches for those critically ill patients who are most likely to receive opioids. Number 2, it also tracks um medication exposures as I've highlighted here. It's one of the few administrative data sets where I can see whether or not a child received opioids during their hospitalization and for how many days they received opioids. So we're merging PIS data from All of the 9 hospitals that submit data to PIS in California with data from the CPQCC. So the CPQCC is the California Perinatal Quality Care Collaborative. Uh, this is a collaborative in California that tracks high-risk infants after they're discharged from the hospital and tracks their neurodevelopmental outcomes and also, um, their interaction with, um, Uh, occupational therapy, physical therapy, etc. So I'm basically gonna, we will be creating a unique clinical and neurodevelopmental data set where I will be able, where I will be able to assess inpatient opioid exposures and how that pairs with long-term neurodevelopment. Uh, this is, uh, hot off the press paper that just came out, um, last week and, uh, JAMA Network Open. Um, we looked at these high-risk populations, so these are infants undergoing, uh, emergent abdominal surgery. These are infants undergoing echocanulation. These are infants undergoing a cardiac surgery, and we wanted to know how much of the variation in the amount of opioids they receive is influenced by the hospital and the region that these infants are cared for in. And you can, I really thought that when we did this study, I would see one region performing better or worse than another region, but what you can see, looking at the Midwest, Northeast, South, and West, there's a huge spread in the cumulative and the likelihood of receiving opioids for these high-risk populations and the likelihood of receiving methadone. And there is a huge Spread for the number of days of opioids received and whether or not they received methadone. So when we're talking about quality improvement in the next generation of opioid stewardship, we really need to look at the neonatal populations because there's a huge amount of variation at the hospital level uh that can be addressed and there's no one part of the country that's doing, um, doing differently than another region. Finally, I wanna highlight that in addition to variations in care, um, secondary to opioids that can impact long-term clinical outcomes, these infants are very expensive. Neonatal, um, NICU stays are some of the most expensive hospitalizations, uh, and many premature infants require months of care with costs exceeding over 300,000. Um, we recently did a cost analysis for high-risk hospitalized infants, and we found that each day of opioid use was associated with an average marginal effect of over 4000 in standardized unit costs, and when you control for comorbidities, it's still significant at about 2000 additional. Dollars per day. So really, we need to track opioid cumulative opioid uh days um for NICU babies in addition to improving their clinical outcomes because it's also gonna potentially um control their healthcare costs which are already very high. And really I want this work to inform quality improvement efforts to minimize variation in pain management strategies and also we're really hoping that this data is gonna support payment policies that facilitate long-term follow-up for these hospitalized infants. Uh, finally, I wanna, uh, finish off today highlighting the importance of having your work, um, dovetailed with, uh, health policy. So I'm a member of the Southern California American College of Surgeons Advocacy Committee. Um, the guidelines project that I mentioned today has been highlighted in the 2023 Congressional Budget. And every time I'm in DC, which for many of you, a lot of our meetings in DC are in DC, I make time to meet with legislators to talk about opioid policy and how it impacts. children. So I've advocated for safe prescription opioid disposal, disposal infrastructure and I've also advocated for expanded access uh to Narcan both in schools and in communities in general. So when you are thinking about, um, problems that impact your patients, Make sure that you also leverage your connections as a voter and an active citizen, um, because so much of what we see as, um, people who care for critically ill children impacts the health policy as well. Um, so, in, uh, thinking about how to incorporate opioid stewardship in your own practice, consider the implication of prescription opioids for all populations. Um, when you're thinking about how to incorporate it every day into your practice, leverage QI infrastructure such as Nisquip, um, to track opioid prescribing, consider co-prescribing Narcan. Um, advocate for installation of an opioid disposal bin in your hospital if you don't already have one, and utilization of mail-back envelopes, sponsor a local takeback event, um, and also meet with your legislators and vote. And I also wanna highlight that a lot of the ways that I have thought about this particular problem are really scalable to so many of the other things that we see as um people that care for critically ill children, and think broadly about your patients and the problems that they are encountering and how you can incorporate research quality improvement and community engagement. And advocate for your, uh, your patient's health ultimately to improve the health not only of your patients but their communities and families. All right, thank you so much and I look forward to your questions. Yeah, and is this on? Yeah, so incredible work, incredible talk, and I'm sure there will be a number of questions, uh, from the audience. You know something about opioids. I, I do, yeah. Uh, I, I wanna thank you, that was a wonderful talk. I, I, this is near and dear to my heart. I'm an advocate. I'm on your team, um. Two things I just want to point, not questions. I just want to point out that anybody, I, I'm an anesthesiologist, anybody who's attending the ASA meeting this year, or national meeting in Philadelphia, the, um, fellow who's running the meeting has made arrangements to distribute Narcan to everybody who wants and as many as they want to take. I, I have it in my handbag right now, um, so. The ASA, if you want to put your order and send your favorite anesthesiologist um, bring you back one. It's free, it's not even $48. Uh, and the second thing I wanted to point out was, I, I mean, you have so much data. One of the things that, that a point that I like to point out is the actual number, like you say, oh well, 7%, dah blah blah. The The University of Michigan, I'm sure you're familiar with the Harbaugh paper, where she showed that 4.9% of kids who go home with an opiate prescription are still refilling opiates at 6 to 12 months later. 4.9%. That makes it the most common uh risk of any. Surgery that we do, and it was absolutely independent. You would say, oh well, you know, it's probably just the scoliosis or the pectus or the kids with the, the big surgeries. It was totally independent of the type of surgery they were having. Uh, Michigan's made a concerted effort to work on this, and they've gotten it down to about 3.5%, uh, but still 3.5% of the kids going home on opiate prescriptions. Becoming addicts is still too many kids. Yeah, so I think what you're highlighting is, is very important. And, uh, so when we think about quality improvement, a lot of us talk about surgical site infections, which are very important. Antibiotic stewardship is, you know, a lot of opioid stewardship has been based off of the movement made. In the antibiotic stewardship space. But overall surgical site infections, around 3%. If overall, like children continuing to use opioids is around 5%, I think we need to move that more. Um, and it's something we should be tracking. Yeah, you're correct. Uh, now for something completely different. Um, going to neonates. Um, I, I really appreciated your data on, on neonates and the variation of practice and how that's managed. In my early career, I covered a level 2 NICU for many years, uh, particularly one that managed, um, severe NAS. Um, and I think the Venn diagram of neonates exposed to opiates needs to include that group of, of infants born. Um, addicted to opiates, um, What I noted there was there was tremendous variation in how they were weaned off. In the centers where they were born on extremely high doses, they would be weaned off on a combination of morphine and phenobarbital. In the centers where they were born with some exposure but not extreme doses depending on whatever local methadone clinic was there, um, they were weaned off on just morphine. When you're looking at the data on these surgical patients who are on high dose opiates, that sort of thing. Is there anyone working on using adjuncts like phenobarbital or other meds to wean them off faster? Yeah, that's a great question. So Presodex is something that is increasingly used and has some neuroprotective effects. I've been thinking a lot about how I can look at this because just as you highlighted, there are multiple different ways that you can, if a child becomes physiologically dependent on opioids, there are multiple different methods in addition to prescribing methadone that people may use. They may use clonidine, they may use. and there's huge variation in that. And no one has also looked at really what are the long-term neurologic outcomes of that. Because if you transition to methadone, methadone is an opioid, so that is continuing their opioid exposure, and Presodex does have some opportunity to have some neuroprotective effects, but we haven't, not a lot of people have looked at it in that particular space. It's something that I'm increasingly looking at. And also, I think, I didn't mention it in this talk because I think it's a whole another aspect of this, but there is a pharma. genomic component to this. We as individuals come in with genetic, unique genetic profiles that may predispose us to metabolize opioids in one way or another or predispose us to have an increased risk for later substance use problems, and that may translate even to a neonate and make them maybe more likely to require opioids for a longer time. And we really don't think about that, so it may not even be that everyone needs to just have a standard number of days of opioids, and maybe we should customize it. Based on an individual genetic profile. I mean that's something that I'm just starting to think about and generate data for, um, but it speaks to your, your question and that different babies are different and they react differently and how can we give them the right medication that minimizes the risk of acute withdrawal sy uh symptoms and a seizure in the NICU, um, but also not have them physiologically dependent and have a prolonged hospital stay. Great. Well, well, thank you, and we're at the top of the hour, so I, I would invite other folks who have questions to come up, uh, and speak with uh Doctor Kelly Kwan, but, uh, again, we wanna, uh, thank you for taking the time to spend a few days with us, and for this spectacular talk and for the spectacular work. Thank you. Yeah I'd like just to add a remark to, to, on behalf of the department to, to thank you for joining us as our Weitzman, uh, visiting a lecturer this year. Uh, the impact that you've made is incredible. Some of us have to spend our entire career trying to make a difference. And you've demonstrated you made a difference very early in your career and congrats for that. There's obviously more work to be done. I also want to comment on the impact of this, uh, lecture series that Doctor Engel has put together, um, You and your predecessors have contributed along with the work that he has done to the outcome of children worldwide. Um, we had the opportunity, uh, well, maybe a few months ago, where, where Mr. Weitzman, uh, came to town to visit, and we had him spend a few hours meeting, we actually have 3 Weitzman chairs in the department and he's endowed a lot of things. Uh, and he made a presentation. At the end of the day, he said to me, This is the best investment I've ever made. Uh, so we'll, um, I took a picture of you I sent to him. Uh, he, he'll appreciate it. I don't know what shoes you're wearing, but I won't, I won't send that to him. Uh, and, and, uh, and so, uh, I, I wanna also uh, express, uh, thanks to, to Doctor Engel for conceiving this, this, uh, visiting lecture series, uh, and to Doctor Shamburger for, um. Uh, for making it happen, uh, with, with the, uh, the resources that the department was lucky enough to have. So, thank you, Doctor Rangel, and thank you so much for joining us. We're looking forward to the rest of the day, uh, where, where we're gonna have interaction at a more informal level. Thank you all. There's a huge audience on Zoom. So thank you to those members that are of, uh, anesthesia care, uh, Payne who joined us, as well as some colleagues from around the city who were invited. Thank you very much.