Good afternoon, everybody. Welcome to today's webinar on extended-release buprenorphine case reports. Today, we have three presenters who will be presenting case studies that involved their use of extended-release buprenorphine and some complications so we can learn from their experience. My name is Julie Kamik, and I'm going to be your moderator for this session. Today, each presenter will have 20 minutes. They will present for 15 minutes and then have a five-minute Q&A session following their presentation. So please enter your questions in the Q&A during the relevant presentation. Our first presentation is Pain Management in Patients with OUD on Extended-Release Buprenorphine by Dr. Anna Marie South. Dr. South graduated medical school from Wright State Boonshoft School of Medicine in 2016 and completed her internal medicine residency at the University of Kentucky in 2019. For the last five years, she's worked as an academic hospitalist for the Division of Hospital Medicine and as a consultant on the Addiction Consultant and Education Service at the University of Kentucky. She's board-certified in internal medicine and addiction medicine. So I'm going to turn it over to Dr. South. Thank you so much for the introduction. It's my pleasure today to talk to you about Pain Management in Patients with OUD on Extended-Release Buprenorphine. And this presentation is based on this publication that I published with some of my colleagues in the Journal of Addiction Medicine. If you want to reference it, it's available here. Our learning objectives today, we're going to talk about first, why is there a need for pain management in patients with OUD on Extended-Release Buprenorphine? And then we're going to talk about the patient-centered approaches that we used in the patients that we saw, and also talk about the different pain management strategies that we applied for the different types of pain our patients were experiencing. So first, I want to acknowledge there's a knowledge gap here, which is why we wrote the case report. There's a lot of clinicians that in general feel uncomfortable with pain management in patients with opioid use disorder who are on buprenorphine, and a lot of clinicians that don't specialize in addiction medicine are not familiar with the extended-release buprenorphine formulation. So they sometimes don't know what to do when they see these patients come in to the hospital with pain. There's no guidelines in the literature. There's limited case reports, which is why we wrote the case reports to add to the literature. Just to get us all on the same base about buprenorphine, it's obviously a life-saving treatment for opioid use disorder. It's a partial opioid agonist with a long half-life that has a high affinity to the mu receptor and a slow dissociation from the mu receptor. So this is all true for sublingual buprenorphine, the same as extended-release buprenorphine. There's a ceiling effect on respiratory suppression, which is why buprenorphine is so effective in preventing overdoses, but that ceiling effect is not present when it comes to its analgesic effects. So it's a very effective analgesic medication. And for the patients that are on extended-release buprenorphine, the serum concentrations are more consistent than the sublingual product can provide. So there's no daily peaks and troughs. So it's just more of a smooth concentration that our patients can experience. This is a slide from a different ORN presentation by Dr. Loffall about the different extended-release buprenorphine formulations that you can reference online. I just wanted to include it here so that you guys know which buprenorphine extended-release formulations I'm referencing. At the time that we saw these patients, our institution only had the column on the left side available, so I'll be referencing the 100 and 300 milligram injections. So now let's start with our cases. Our first case, patient A, is a patient that's experiencing acute pain after a knee replacement. So this is a planned surgical intervention. We have a 52-year-old man who has severe opioid use disorder and sustained remission. He's on extended-release buprenorphine and has been for the last two years. He's undergoing a knee replacement due to severe osteoarthritis, and he received extended-release buprenorphine 100 milligram 27 days before the surgery. His main goal during the surgery was he did not want to be discharged with any full agonists. Initially inpatient, after the knee replacement, he received a peripheral nerve block. He got some NSAIDs and acetaminophen, and then he was given as-needed oxycodone 5 to 10 milligram by mouth Q4 hours. The patient did not feel that that triggered his cravings. At the time of discharge, he once again did not want to be discharged with any opiates. He was discharged with scheduled NSAIDs and Tylenol, and he received a script for sublingual buprenorphine for the 8 milligram film and was instructed to take a half a film, so 4 milligram, every 4 to 6 hours as-needed for pain for the first 4 days after release from the hospital, then every 8 hours for 3 days, and then every 12 hours for 7 days. He followed up with his addiction medicine physician and reported that his pain was controlled excellent on the NSAIDs and acetaminophen with the as-needed sublingual buprenorphine. He did not have any cravings for illicit opiates. He did not have a return to use, and he wanted to continue to receive the extended release buprenorphine, so he got another 100 milligram injection, and he still remains in remission from his opioid use disorder. So, his pain was managed very well for a planned surgical intervention. Our next case describes a case of an acute surgical intervention in an emergency setting, so unplanned. Patient B is a 24-year-old female who has severe opioid use disorder, and she's in remission on extended release buprenorphine for the last 10 months. She presents with acute lower limb ischemia from an embolic event due to chronic fungal endocarditis. Prior to this, she had received extended release buprenorphine 100 milligram 12 days before the event, so this is an unplanned surgical event with a complicated hospitalization. She initially underwent an emergent thrombectomy and fasciotomies, and the surgical team gave her oxycodone 5 milligram every four hours by mouth as needed, but that did not result in adequate pain control, and the patient actually at that time wanted to leave the hospital patient-directed, so that prompted a consult to the addiction medicine consult service. When we saw the patient, we recommended anesthesia to be consulted for a patient-controlled anesthesia, PCA, so that's where patients can push a button to administer medication, and she was started on a PCA with IV hydromorphone, and she was receiving 0.2 milligram every six minutes is when she could push her button, and she received a total of 18.5 milligram of hydromorphone in the first 24 hours, and reported adequate pain control with that. She also received adjuvant medication with acetaminophen and NSAIDs at that time. On post-op day four, she felt she was ready to be transitioned off the PCA, and we calculated her morphine equivalence, and with that, transitioned her to oxycodone 15 milligram by mouth every four hours as needed, as well as two milligram IV morphine every four hours as needed, so this could be interspaced, so she had something available every two hours as needed. Her pain was adequately controlled with that. She then underwent a heart valve surgery for the fungal endocarditis, so for the second procedure, once again, anesthesia managed a PCA that had hydromorphone and ketamine in it. She was able to get 0.25 milligram every six minutes again, and she self-administered between 24 to 10.4 milligram of hydromorphone per day for the next seven days, with the 24 being immediately post-op, and then gradually decreasing over the next seven days. We once again calculated her morphine equivalent, and we were able to transition her request on post-op day eight to five milligram every four hours as needed. She did not want to be discharged with full agonists and received methocarbamol and duloxetine at the time of discharge. She followed up with her addiction medicine provider and received another dose of extended release buprenorphine, 100 milligram, 43 days after receiving her initial dose. Due to the continued concentration of the buprenorphine being present, we call it the tail, she did not have any withdrawal symptoms or cravings, and she at this time still remains in remission from her opioid use disorder. So this was a case of acute pain management in the setting of a surgical emergency. Our last case is a case of chronic pain in the setting of malignancy. Patient C is a 74-year-old female with severe opioid use disorder. She's in early remission on extended release buprenorphine, 300 milligram, that was administered 14 days prior to hospitalization. During this hospitalization, she was diagnosed with stage two uterine serous carcinoma, and she initially was really adamant that she did not want to be on full agonists for pain management. Initially, we gave her sublingual buprenorphine, eight milligrams, three times a day on top of the extended release buprenorphine that she had received 14 days prior to admission. Her pain was not controlled, so we increased it to 16 milligram twice a day and still did not achieve adequate pain control. So then she was agreeable to trying some full agonists. She was given oxycodone, 10 milligram by mouth every six hours, and when her pain was controlled after two days, she requested for it to be decreased to BID, and she had good pain control on the low-dose oxycodone with the high-dose sublingual buprenorphine. She later passed away in hospice. So this was a case of chronic pain in the setting of malignancy. So we demonstrated there's three different types of patients for us. We had two types of acute pain, ones with planned surgical intervention where we were able to proactively make a plan for our patients, and one with a surgical emergency where we actually in the beginning were being more reactive when it came to pain control, as well as our third patient who had chronic pain from malignancy. For all of these patients, it was crucial to ask our patients what their goals were. So all patients at some point expressed the desire that they wanted to avoid full agonists. Patient A and B did not want to be discharged with full agonists, and patient C initially didn't want any full agonists at all. When these patients followed up outpatient, our patient A, after his knee replacement, was very proud of himself that he was able to be discharged from the hospital without full agonists, and that he did not have any increased cravings and did not have a return to use. Patient B, like I said initially, had such severe uncontrolled pain that she almost left the hospital before she was medically ready, which would have put her at a significant risk to her limb and her life. So it was crucial for us to switch from a reactive point of her pain control to a proactive pain control management and talk to her about what procedures to expect and how we were going to manage her pain. Patient C, unfortunately, was not able to get another dose of extended-release buprenorphine outpatient because we were not able to find a palliative care provider that was able to provide both extended-release buprenorphine and full agonists. She met her goal, though, which was pain control, and she was actually able to return to a residential treatment and to complete that treatment despite having to interrupt it for treatments for her malignancy, and it was her goal to complete a residential treatment program before she passed away. So this just highlights that it's really important to have an individualized patient-involved approach when it comes to pain management. We know that buprenorphine has a wide variability in pharmacokinetics, which is why we do individualized dosing when it comes to treatment of opioid use disorder, and the same can be true for the treatment of pain for our patients with opioid use disorder on extended-release buprenorphine. There is not a defined therapeutic window that we're trying to hit for urine drug screens or serum drug screens, but instead it's talking to the patients, seeing how they feel their pain is controlled and what we can do to improve it. We know the half-life of extended-release buprenorphine is significantly longer than the transmucosal formulation, which is why our patients were not experiencing withdrawal even with a break in the administration of the extended-release buprenorphine as it happened with the second patient I presented. There's a lot of case reports that show that urine drug screens can still be positive in pregnant patients six months after they have last received the extended-release buprenorphine without any sublingual buprenorphine being present. Human laboratory studies are unfortunately limited. However, there's one study that shows that there's a continued opiate blockage four weeks after extended-release buprenorphine 300 milligrams was administered when these patients were challenged with six milligrams of hydromorphone. They did not experience a euphoric effect. However, this study did not look at the analgesic effect, which is where we try to fill in with our case report. We do need to remember that buprenorphine was initially FDA-approved as an analgesic, and we do know that it is possible to have targeted pain management in our patients with extended-release buprenorphine. So in our cases, we exploit supplementation with sublingual buprenorphine, including at higher doses, as was done in the third patient. We used full agonists, both PO and IV, including a PCA, and then a lot of non-opioid adjuncts, such as acetaminophen, NSAIDs, gabapentin, muscle relaxers, ketamine, and duloxetine. So in conclusion, it is possible to provide effective analgesia for our patients on extended-release buprenorphine. However, the approach needs to be individualized, and it needs to be very patient-involved, and needs to be adjusted based on the patient's evolving needs. The doses that we use of all medications need to be titrated to effect, and that might require higher potency and higher doses of full agonists than we might use in patients that are opioid-naive. It is always beneficial to have a multidisciplinary team approach. So we used our pharmacy colleagues, our colleagues in palliative care, and in anesthesia. Unfortunately, there are several key barriers, including the fact that a lot of clinicians are still unfamiliar with the extended-release buprenorphine formulation, which is why events like this are so important to educate people. And there's also limited access to palliative care, especially in the rural setting where I practice. And these are the references, and with that, I will open it up to questions. Okay, we had a couple of questions come in, and they're actually the same. It's about, did you consider giving patient A or patient B a 300 milligram injection at the time of surgery for patient A? Yes, so it was discussed with patient A to give the higher dose prior to surgery. However, the patient declined to do that and wanted to wait until after surgery. For patient B, this was an unplanned surgical event, so she had gotten her regular dose two weeks prior. We did not discuss giving her the 300 milligram dose, and that was for logistical reasons because she was already inpatient, and we can give extended-release buprenorphine inpatient, but we bill it to an outpatient insurance, so we can only give it on the day of discharge. So logistically, it was not possible for us for patient B. Okay, thanks. We have another question. What happens when the patient on extended-release buprenorphine is using daily fentanyl? What are the long-term effects of extended-release buprenorphine with fentanyl use? So, I think this is a little bit different than the cases that I presented. All of our patients were in remission, and I'm assuming this question is asking about illicit fentanyl. From my understanding, people continue to use sometimes on top of having extended-release buprenorphine. Substance use is an expression of the disease. If somebody is using fentanyl on top of the extended-release buprenorphine, they might not feel the effects based on the study that I mentioned where they looked at the hydromorphone, challenging people with hydromorphone, and the hope would be then to explore with a patient why are they continuing to use fentanyl on top of the extended-release buprenorphine? Are their cravings not controlled? Is there something else going on in their life that's triggering substance use that we can discuss with them and address with them? And then, is long-acting buprenorphine covered by most insurances as far as you know? I'm not an insurance expert. So, for us in Kentucky, it is covered by Medicaid, and I think that depends state-dependent. Sometimes, we run into issues with private insurances. Yeah, and that's been my experience as well, and I'm in Pennsylvania. Okay. Well, I think there's just one last one that came in. They understand why dilaudid or morphine might be able to override buprenorphine, but since buprenorphine binds so tightly to the opiate receptor, why would oxycodone be considered as a potential effective pain medicine? Can it really displace the buprenorphine off the receptor at those doses? I'm not sure if I quite understand the question. I think they're talking about the binding affinity that the buprenorphine wouldn't be able to get replaced, especially the buprenorphine from the extended-release. Yeah, I don't think the goal is to displace the buprenorphine. The goal is to add on top of the buprenorphine. That's how I think about it. So, we tried the oxycodone, and it worked in our patient. She reported that both the oxycodone and the morphine was effective for her. A lot of times, we use the morphine for times like dressing changes or things when we need a little bit more quick onset, but the oxycodone was also effective. Okay, very good. Thank you so much for your presentation. We're going to switch over to our next presenter. If we do have time, if everybody finishes earlier, then we'll be able to have more questions too. So our second presentation is Extended Release, Buprenorphine in Pregnancy by Dr. Alexander Hubbell. Dr. Hubbell is certified by ABPM in addiction medicine. He completed his fellowship at the University of Minnesota following a brief time in full spectrum outpatient family medicine practice. He moved to Minnesota in 2013 for family medicine residency. And after he completed medical school at the University of Iowa. He currently practices at M Health Fairview in Minneapolis where he sees the full spectrum of outpatient addiction medicine, teaches medical students and residents and help support addiction management and primary care at the systems level. So I'm gonna turn it over to Dr. Hubbell. Thank you. All right. So I wanna talk about a couple of cases of using Extended Release, Buprenorphine in Pregnancy. So funding disclosure for ORN. So just a disclosure, I will be discussing off-label use. This is an FDA approved medication, sublocated but is not approved for use in pregnancy. So talk a little bit about evidence of efficacy because this is gonna be a bit of a risk benefit discussion, you know, going beyond the FDA approved usage. And we're gonna talk about what literature is out there. And again, risk benefit discussion and trying to see if we can think about this in terms of the new products that are gonna be more widely available. So in general, when you're thinking about how do we treat opioid use disorder in pregnancy, it is really important to understand the context of how much incidence of opioid use disorder has risen over the course of the last 20 years, 25 years. And especially for patients with lower socioeconomic status, 14.6 per 1,000 deliveries for Medicaid recipients versus 6.5 for the general population. And then of course, looking at the morbidity mortality, the pregnancy associated overdose deaths that have risen just in that short three year period between 2017 to 2020. And we know that overdose rates have risen since then. And when we're looking at evidence-based recommendations, both ACOG and SAMHSA, CDC is borrowing their recommendations to use gold standard treatment methadone or buprenorphine for pregnant people with opioid use disorder, of course, in conjunction with behavioral therapy and medical services. So when we're thinking about this and thinking about possible use of extended release buprenorphine, I wanna do my best to treat my pregnant patients as much with the current base of evidence of people who are not pregnant and applying that same idea of what's top base of evidence, knowing that we are using a similar approach for pregnant patients versus not for gold standard. So if we look at, is this actually extended release? Is there a benefit beyond our gold standard of buprenorphine sublingual? It was approved in 2017 and we've shown higher abstinence rates and the largest trials, several hundred participants with really great abstinence rates for people who are continuing to be followed. And then if we look beyond that and we look at safety in the non-pregnant population, over a thousand people showing a safety profile was very consistent with other buprenorphine products. There are certainly reports of intradermal injection that cause more problems, but in general, mostly mild and non-treatment limiting. And then a secondary analysis of this same study that was done, the recover study, trying to piece apart different routes of administration and different severity of substance use disorder. People who are using IV drugs, IV opioids consistently, if they are maintained on high dose, 300 milligram doses, which is different than the normal hundred milligram maintenance dosing. If they're kept on the high dose, they had higher abstinence and retention rates in treatment. So efficacy for different reasons, for different populations that are showing benefits. And as a quick review to showing kind of serum levels and why this is, when we're using maintenance dosing, we're keeping a consistent level, but if we have more severe disease, consistent with ASAM recommendations, using higher doses of sublocate being effective, I don't want to belabor this point too long, but we're using this to block fentanyl and to block respiratory depression from overdose, for fentanyl that would cause overdose. So, yeah, I guess I want to get into more specifics about the sublocate and why that's relevant to pregnancy, but I think good to review some of these things and just to put this in there to note how serum levels are comparable to different sublingual doses and encourage you to follow this link to Sarah Spencer's PDF on this, her presentation on this. It's really informative and helpful and some challenging populations up in Alaska. So the reason why there is hesitancy around using sublocate specifically in pregnancy is the excipient that's involved. It's N-methyltupirolidine, NMP. It's used in pharmaceuticals. It's used in basically trying to keep things shelf stable, stabilizing compounds. I think it's used in food. It's got all sorts of different, if you look it up on the internet, it's got all sorts of different safety profiles for different reasons. There were studies in female rats with sublocate with containing this excipient. And they did, one of the main concerns that people bring up with using sublocate in pregnancy, and I'm talking specifically about sublocate now, not extended release buprenorphine, because of this excipient. And I'll come back to that point. But when they found a reduced number of viable fetuses in their investigation, they were using 38 times the maximum recommended human dose, 900 milligrams per kilogram. There was no change in fertility. And the, what is the NOAA? Something about adverse effects limit. It was, I looked it up yesterday and I forgot it already. Anyway, if we look at a lower dose, 150 milligram per kilogram oral dose, that was investigated in a separate study. There are no discernible differences in field development. It did show reduced survival. But again, this is still many, many times the maximum recommended human dose. And this was an oral dose. So not even given the same, in the same way. The abbreviation is NOAA observed adverse effects level. Thank you. So it's 600 milligrams per kilogram, NOAA observed adverse effects for female mediated developmental parameters. So even some reassurance that slightly lower than massive doses are showing relatively improved safety. And certainly when you're talking with women and protecting unborn fetuses, you wanna be very careful about these adverse effects. So I'm not trying to discount them, but trying to just give as much evidence as I can find about what's out there in terms of the risks. So I'm sharing these stats and these ideas with my patients when I'm talking about the risk benefit discussion. The current case reports that are out there, if you try to search for this, we published one this year, but before that it was five patients total. The first report was two pregnant people. They were receiving monthly injections when the pregnancy was identified. They stopped re-pregnant from treatments. They had zero problems going through the process of delivery, no birth abnormalities. Everything was great, but they didn't have any injections throughout. The other paper with the three patients with a previously stable on sublingual buprenorphine switched to extended release while pregnant. I don't believe they described exactly why, or if they did, then I missed that part when I was reviewing this again. They had undesirable side effects. Euphoria, which is gonna be talked about in our next presentation. Some withdrawal and cravings, which incidentally are reported as sort of, withdrawal and cravings are improved experience for most people in other studies. They use sublingual buprenorphine to overcome those withdrawals and cravings. It was effective, but all these patients said, I don't wanna do this anymore. I'm done with this. And they just took ongoing sublingual dosing and did fine throughout the pregnancy. Interestingly enough, they all had positive buprenorphine. Well, actually one of them stopped it altogether and didn't have any, no, I'm sorry. That was the first study. Excuse me, I'm talking over myself. So they did not continue. They did great with their pregnancy with the sublingual dosing. So the one injection did not affect their pregnancy in any meaningful way from what I could tell from the reports. So my case reports, we had two people that came in for treatment. The first one is a 27-year-old G2P0020, past medical history, opioid use disorder, ADHD, tobacco use disorder, came into the ER, IV heroin and fentanyl use for two years, was not pregnant at that time. They induced her on buprenorphine in the ED, but she did have nausea and vomiting with a sublingual formulation. We did continue to follow her in clinic, continued to have the same reaction to the sublingual film. So we put her on the extended release and that was within one month of showing up. Nausea and vomiting resolved completely when she wasn't using the sublingual films, but then the day she got her second injection, she found out she was pregnant. So we did our discussion of risks and benefits. We talked about how for her, sublingual buprenorphine was a tough sell. She's worried about getting more nauseous with pregnancy. The sublingual was already causing that. And she was finding the extended release very helpful, keeping things very even for her. We talked about the risk that we found in those studies and how there's no human studies that are showing fetal demise, adverse fetal outcomes. It's just these sort of massive doses in rats. And she said, this is helping me enough. I don't want to go back to using. I'd rather take on that risk based on how helpful this is. So had two more a hundred milligram injections on schedule. So 300 twice, a hundred twice, all within a month of each other. Great prenatal visit reports, no concerns. We actually slowed down her injection schedule every six weeks with some patient centered discussions to reduce exposure to the excipients as her abdomen was growing, maybe limit potential discomfort. And then she had sublingual buprenorphine available if withdrawals developed. None of that happens, no opioid use, no cravings. Her newborn spent five days in the NICU essentially for monitoring. I think it was standard at that hospital. It was not at our hospital. So I wasn't able to really be involved. No medications for withdrawals, had no abnormalities, no issues. And I've continued to see her and she's actually transitioned off extended release buprenorphine at this point. No withdrawals, no concerns, doing fantastic. The only thing that's come back is nightmares, unfortunately. But baby's doing great and has been a stabilizing factor for her in life. Case report number two, 35 year old G2P1011. She had a more complicated history with multiple substance use disorders, some chronic back pain. When I saw her, she was already on XR-Bute for four years. She lives up in Northern Minnesota. So it was hard to get her into the clinic. She had this lower extremity edema. That was the main concern she had with any buprenorphine management. And did a lot of this monitoring via video. She had an unexpected pregnancy. And she came to me and she said, I'm pregnant, what do I do? So we talked through the risks. We talked through the benefits. She is saying how crucial this has been for her to maintain abstinence. She said, I guess I can go back to the sublingual, but I don't know what that's like anymore. It's been four years. So just with her concern about possible return to use being the main risk of changing, she wanted to just stick with it. And we discussed how can we, like with the other patient, talk about can we decrease the exposure? So we did decrease her dose to 50 milligrams instead of spreading it out like we did with the other patients. So that's just the nurse taking the vial and dumping half of it. And so that started in the first trimester. There were times where she couldn't make it in for appointments. She couldn't reach out when she was having trouble with refills. She had a really demanding job that, she sometimes just wasn't able, I think with her ADHD, wasn't able to kind of remember to ask for refills off hours and she couldn't call during hours, couldn't come for a monthly injection on time because it was three hours away. So there were times where she had buprenorphine tablets to supplement to get through some withdrawals. Had an uncomplicated full-term delivery. No problem with the hospital course on either side for mom or baby. Baby's doing well. Unfortunately, mom did return to methamphetamine use, but she is doing much better with a long-term residential. So I think the only discussion that goes beyond this is just the idea that this new Brixati formulation does not have NMP in weekly formulations. So it would be a very viable tool to use to avoid that risk that is associated with the excipient if they come back for weekly formulations. Of course, getting patients to show up weekly for injections might be difficult, but the risk benefit always needs to be discussed. And this is another way to help provide tools for patients to work with that balance. And there is a huge multicenter trial underway with this Brixati formulation weekly that's hopefully going to be having results released in the next year. And I just wanted to mention too, beyond just abstinence and retention, patients see significant benefits in improved quality of life, increased employment. And so, you know, thinking about our patients, we got to go beyond just the sort of the numbers that we like to look at for abstinence and retention. So that is my references and glad to take some questions. Okay, great. Thank you so much. We have a question about basically if somebody is maintained on extended release buprenorphine throughout the pregnancy, does the neonate have to be treated for opioid withdrawal after delivery? And I think you somewhat covered that during your talk here. In the case reports that we've had, in the cases that we've seen, we have not had anything that was abnormal outside of what we normally expect from buprenorphine. In the two cases that I've presented and I've followed personally, there was no withdrawal treatment that was needed for the neonates. Another question, how does the stigma of OUD and IV drug use deter, or does the stigma deter people from seeking and staying in treatment from your experience? It really, it's a huge factor. And I think especially in pregnant persons, the way that legal complications or legal consequences can be a factor in whether or not they access care. In Minnesota, a couple of years ago, we finally passed a law that allowed for the clinician to decide whether to report to our protective services, state DHS protective services. If they are having ongoing care, we can prescribe buprenorphine and don't have to report people. And I think there's many states out there that still, if a patient is prescribed buprenorphine, they have to be reported to the state. So I can imagine being somebody who's pregnant, wanting help, but if I get help, then I'm at risk for getting my baby taken away. It's an awful calculation to have to make. And so I think more than anything, just the stigma that pregnant persons face in terms of seeking care and getting help that's nonjudgmental and supportive is pretty difficult. There's great articles of the exceptions out there, but I think a lot more difficulty than help, unfortunately. In your presentation, you had the abbreviation NMP. Somebody's just asking you to repeat what that stands for. Yeah, so that is N-methyl-2-pyrrolidine. You can find it in the package inserts, the FDA package inserts for sublocate and brixotic, if you just do a Control-F search for NMP in those documents. Let's see, do you know of any data regarding evidence of problems among pregnant patients who've received extended-release buprenorphine during the first trimester before pregnancy was known? I have not seen any. The one case report that talked about the first one, two pregnant people receiving monthly injections when their pregnancy was identified, they did not have any abnormalities that were noted. Neither of my patients had any abnormalities that were discovered, and I have not seen any other case reports or other discussions about that when I've tried to reach out to colleagues in different areas. And then we have a question here. As far as your procedure, did you have your patients who chose to continue on the extended-release buprenorphine sign something, saying that they agree? Is there some kind of signed consent? I did not have them sign. I very thoroughly documented our discussion in my chart. So that was where I didn't feel the need to sign because I had a decent therapeutic relationship with them. And I don't know how much that is protected legally, as long as the documentation is there that the discussion was had. And then you did mention about abdominal, like the sub-Q administration in the abdomen and maybe being uncomfortable. Had you thought about alternate sites or is there anything, any literature about alternate sites? They, so I've talked to Indivior, who's a company that makes sublocade many times. I believe it's Indivior. And they do not have any recommendations for alternate sites. I think they're doing research on that. What we did do is try to go as far lateral as possible to have as much subcutaneous space as we could for the injection on the abdomen. Okay, well, thank you. We're gonna move on to our next presentation. Okay. And so our third presentation is Extended Release Buprenorphine Causing Iatrogenic Opioid Intoxication and the need for surgical excision by Dr. Simone Base. Dr. Base is a family medicine physician and recent graduate of UCSF Primary Care Addiction Medicine Fellowship. Her clinical focus is in perinatal substance use with a particular interest in the postpartum period and the gaps in care between pregnancy and primary care-based services. She works as a PCP at Family Health Center, provides hospital-based medical and addiction care at San Francisco General Hospital, and provides dyad-based primary and substance use care, and in the Team Lilly Postpartum Clinic, a family-based clinic for postpartum people and their infants impacted by substance use disorders. So I'd like to turn it over to Dr. Base. Thanks so much. Can you see my slides? Yes. Wonderful. I think my video, for some reason, it's not giving me permission to share, but that's okay. I'm gonna talk about a case of a long-acting injectable buprenorphine that actually needed to be removed from somebody, to be explanted. And so my learning objectives are to, you know, in this era of long-acting injectable buprenorphine being such an exciting tool that we have to really explore the potential harm that can come with giving it to somebody who doesn't have adequate opioid tolerance. And then if you're confronted with that situation, to think about the pros and cons of removing a long-acting injectable buprenorphine depo, and then how to do it. So our case is a 38-year-old male with a history of HIV and methamphetamine use disorder, who had had several admissions for unintentional opioid overdose. And he presented to our emergency department for sedation and respiratory depression. Four days prior to presenting to our ED, he had received an injection of long-acting injectable buprenorphine 300 in his primary care clinic for quote-unquote opioid, for overdose prevention. And 20 minutes after the injection, he began to experience fatigue and profound difficulty staying awake for more than 30 minutes at a time. And then shortly after that, EMS was called, and he was brought to a nearby ED. In that ambulance, he received naloxone. And then in the first ED, he received naloxone again. But the providers in the emergency department had assumed that he had intentionally used opioids, and so was discharged from the emergency department with injections to seek substance use care. The next day, he presented to another emergency department for sedation, nausea, and vomiting, and abdominal pain. Again, he was presumed to have intentionally used substances and was discharged without any treatment, without treatment, but with some SUD recovery resources. He continued to have trouble staying awake for the next few days. And finally, four days after the initial injection, his case manager helped him come to our emergency department, where I met him for the first time. On my evaluation, he confirmed that basically, in 20 minutes after he got his injection of LAI, I believe, flupe, he started feeling incredibly fatigued, and that he had not used any other opioids. He, on exam, had a respiratory rate of about 10. His other vital signs were normal. He seemed sedated. He repeatedly faltered during our interview. His speech was somewhat slurred, and he had pinpoint pupils. So, I did some chart digging at that point, and these are some just screen shots from his EMR. So, if you go here to the hashtag sublocade, what you see is it says, patient reports last dose was administered to the gluteal area. At this time, in our medical system, we didn't have CAM2038 or Bruxadi. So, there was no long-acting injectable version of buprenorphine that was appropriate to administer in the gluteal area. So, when I first saw this, I was concerned that maybe, actually, what he had received was naltrexone and not buprenorphine. And then, kind of continuing to dig through his chart, what I saw was given naltrexone, 380 milligrams, and then, in one note, and in the subsequent note, plans to give sublocade. So, it seemed to me like there was some sort of confusion here about what medication the patient was intended to be receiving, but that certainly, he, at some point, received naltrexone, and then, somehow, that got confused and switched to a long-acting injectable buprenorphine. So, when I saw him in the emergency department, my differential for his sedation was, basically, he has ongoing substance use, he has some sort of medical illness just causing encephalopathy, or this is from the buprenorphine itself. So, we got some additional labs. You know, his labs were pretty unremarkable, unfortunately, and though urine toxicology was ordered, it was never collected. So, at this point, I pretty much was convinced that it was, in fact, the buprenorphine because of, A, his very clear timeline of his sedation starting pretty much immediately after receiving the injection, and B, him having, really, a syndrome of opioid intoxication, and C, which I didn't include in the slide, his primary care street medicine doctor actually called me and was like, Simone, I've known this guy for 10 years, he uses meth, he does not use opioids, he did not intentionally use opioids. So, knowing that we were convinced that this was the long-acting indexable buprenorphine depo that was causing his sedation and respiratory depression, things we were thinking about was, one, how do we get this thing out of his body? If we excise it, is that an option? If so, how? Two, okay, what if we don't take it out of his body, but we just antagonize the impact of the buprenorphine? Would we put him on a naloxone drip? Would we give him PONL check zone? The second option was really not an option because the patient was, by the time I met him, received naloxone eight times and was just absolutely uninterested in any further naloxone. And then, if we took it out, how long would he have symptoms for? So, after a discussion with the patient, he agreed to have the LAI bup surgically excised, and we actually ultimately admitted him to the hospital, and general surgery was consulted for the excision, primarily because, it's pretty shallow, it's not that hard to excise, but his respiratory rate was sort of tearing naloxone the whole time that he was in the emergency department, and because he so adamantly did not want naloxone, we felt like it would be the safest option to have sort of more control of his airway and do this in a more controlled setting. So, some of the concerns that we had, one, do we try to remove this as quickly as possible in the emergency department, or do we send him to the OR for more monitoring of the sedation? Do we give him naloxone preemptively, or do we just have it around in case his respiratory rate drops during the excision? There are some theoretical concerns. Typically, when we inject them, LAI bup, we tell patients, like, don't press on it, try not to manipulate it, because, theoretically, that will cause the buprenorphine to seep into the serum more and maybe increase levels, and so would us ultrasounding the depot cause that as well, since he was already so sedated? Could we cause iatrogenic harm by kind of ultrasounding it and manipulating it? And, like, most of all, will it work? Will removing this depot actually resolve his sedation and respiratory depression? In terms of guidance that existed, there really were no case reports of this out there, but what did exist was in the manufacturer's instructions that the depot can be surgically excised under local anesthesia within 14 days of injection. We were just four days after injection, so it was an option. However, there was not really any guidance beyond the fact that it was possible. This is the op report, but I think more helpful are the photos, actually. So some notes from the surgeon. Ultrasound was not very helpful for them in visualizing the depot. As you can see in the bottom left corner, it is a hypolipoic on ultrasound, and so it was not particularly helpful. And the second thing that they noted was that the buprenorphine depot really adhered to the subcutaneous fat around it, and so having cautery equipment was really helpful for them in removing it. And so whereas we may have considered doing this in the emergency department, not having seen this happen in retrospect, it was much better to have done it sort of with surgical expertise, because it wasn't as if the depot just popped out. It actually came out attached to quite a bit of subcutaneous fat. And then in this next section, I'm just gonna talk about sort of what happened after we removed the depot. And as a reminder, before we get there, we think about two nanograms per milliliter as sort of the dose of buprenorphine that blocked the rewarding effects of opioids and what we sort of shoot for when we're trying to treat opioid use disorder with buprenorphine. So the day after the depot was removed, 24 hours later, he certainly seemed better, but he was still somewhat sedated. His speech was still somewhat slurred. And we were able to collect serum buprenorphine levels 12.4 and 48 hours after excision. And what we saw was both 12 and 24 hours after the depot was excised, his serum levels remained above two, which makes sense. We know that buprenorphine has a long half-life. And it wasn't until 40 hours later that we had sort of dropped below the threshold of two nanograms per milliliter. So as I mentioned, when I saw him 24 hours later, still very sedated. 36 hours later, he was notably better. And that somewhat correlates to when his serum buprenorphine had dropped below two. And he said, though he was speaking more clearly and was more awake, he didn't feel totally back to baseline yet, but he was feeling well enough to leave the hospital. So the lessons that we learned from this case, one is, you know, nobody had ever given this patient long-acting adipose buprenorphine with the intention of preventing overdose on purpose. This was a case of like a swish cheese where somebody who was intended to get naltrexone accidentally got buprenorphine. But there is certainly a lot of talk about using long-acting adipose buprenorphine for overdose prevention. And I think this case really highlights the harms of doing that in somebody who doesn't have adequate opioid tolerance, because as we saw in this patient, it effectively caused pretty close to an opioid overdose. On that note, I also, it highlighted for me the importance of being specific with diagnoses. In many, many places in this man's chart, he carried the diagnosis of opioid use disorder, which he does not have. He somehow, at some point got labeled with that disorder after unintentional opioid overdoses due to contamination of his drug supply or his equipment. So because he had overdosed unintentionally, somebody labeled him with opioid use disorder. And because somebody labeled him with opioid use disorder, nobody thought so hard about the fact that he was getting long-acting injectable buprenorphine, when in fact, he just didn't have the tolerance for it. In this case, I certainly saw the benefit of sort of an operative controlled setting for the removal of the Sublake depot. I think what's not clear, I was at a conference about a year ago where there was a poster with another case of where a depot was removed, this time within one day of the injection. And in those photographs, it looked like there was less adherence to the subcutaneous fat. So what I don't know is, depending on how long the depot has been in the body, does that impact how much it adheres to the subcutaneous fat and how important it is to have sort of cautery equipment in an operative setting. And then the final learning point for me was sort of the expectation of timeline for symptom resolution. Certainly, it took at least 24 hours. So for the first 24 hours, there was no chance he could have gone back to the community but sort of in the 24 to 48 hour windows when the symptoms started resolving and he sort of was safe to return home. I can take questions at this point. Okay, awesome. That was a really interesting case as well. I wanted to ask, because you have those notes that the patient was receiving extended release naltrexone before and then it just was, but he was saying that his last injection was in his gluteal muscle, but it obviously looks like he took, or the sublocate was taken out of his abdomen. So were you able to clear all this up with him? Yeah, yeah. So basically, none of those injections happened in our hospital, but what it looks like happened was in the clinic where he was getting his injections, the injections were nurse administered but provider ordered and those things didn't necessarily happen on the same day. And the naltrexone injection had been at a different clinic than the sublocate injection happened. So basically at one clinic, they were like, you keep overdosing because there's fentanyl in your meth or fentanyl on your pipes when you're smoking meth. And so we're gonna give you naltrexone so you don't keep overdosing unintentionally. He goes to a different clinic and somebody misreads the chart and says, this guy got an injection for opioid use disorder, let's give him another injection for opioid use disorder. A doctor ordered it one day, it arrived the next day, the nurse administered it and kind of nobody caught that it was the wrong medication. And was there actually 28 days in between the naltrexone injection and the- Yeah, it was a full month. That's a great question, yeah. Yeah. That's really important about the communication too about that. And I was a little bit puzzled too. I thought, well, maybe they were trying to give the naltrexone because of the methamphetamine, maybe they were trying to help with that with using bupropion or something in addition, but it was because of the overdoses they did that. We have a few more minutes if anybody has any questions for Dr. Vase. We did have a comment that that was such an interesting case. And since we do have five minutes left too, if you have questions on the other cases, we can also entertain those now too. Somebody had asked, what was the patient, for Dr. Vase, was the patient upset about getting that wrong injection? Or how would- Yeah, it's a really good question. We are very lucky he's very close to his primary care doctor and she was able to sort of communicate with him throughout the entire process, what was going on and apologize profusely. And so he was very understanding of what happened. Anybody else have questions for either Dr. Vase, Dr. Hubbell or Dr. Sealth? I know that there were some unanswered questions before, but I think some of them got answered, some typed answers too. I typed a couple answers to people individually to not distract from Dr. Vase's presentation. So I wouldn't get in the main chat. Yeah. Well, we do have four minutes. Dr. Sealth, there was a question on here for the pain control. So what would your approach be to advocate for patient's dignity to be managed for their pain when a surgeon or provider is resistant to prescribing higher doses of short-acting agonists or prescribing sublingual buprenorphine in addition to their injection? Yeah. And commented that they work in an outpatient-based setting. Yeah, so unfortunately we do encounter that quite a lot. And my first question is always asking the other clinician what their hesitation is to then try to discuss this further. And a lot of times the reason is stigma. A lot of times people worry about worsening someone's opioid addiction by giving full agonists. So then I discuss with them about how uncontrolled pain can be a trigger to return to use and can be a trigger to like leave the hospital before their patients are medically ready. Like it almost happened in our second patient. And then I just try to basically address each issue and explain that opioid use disorder is a medical disease like any other medical disease. And that in times of exacerbation it needs to be managed more intensely, just like with diabetes. If people have an exacerbation after surgery, we prescribe more insulin. And our surgeons really understand that. A surgery is a stressful event for the body that requires maybe different insulin management than for somebody that has diabetes that is well-controlled otherwise. And then kind of applying that to opioid use disorder is really helpful. But I think always seeking the conversation between clinicians is really helpful. So that's what we did with our first patient. We actually talked to the orthopedic surgeon and asked them if they would usually prescribe full agonists for pain management and then explain that this patient didn't want that. And we wanted to prescribe sublingual buprenorphine instead. And that was also another reason why we did not give the long acting injection sooner in the patient because insurance then would not have paid for the sublingual here in Kentucky. So there's logistical, they don't pay for the sublingual if someone has gotten an extended release in Kentucky. I know in other States it's different, but I hope that answered the question. Yes. Okay. Okay. In the outpatient setting, would you consider a full agonist rather than just additional sublingual buprenorphine for pain control? I think it depends on the patient and the scenario, what type of pain is going on, what is expected. And like I said, it's a patient-centered approach. So I would seek the conversation with the patient and then with the other clinicians that are involved to see what is more appropriate. And then as I've mentioned in Kentucky, sometimes we have issues getting the sublingual buprenorphine covered if extended release has been administered. Somebody did also ask a follow-up there. Would you increase buprenorphine sublingual or use possibly a patch after they're off with the full agonist? So I think we are once again limited by what our insurance pays for. And we also do not have the patch on formulary here in the hospital. So I think in an ideal world, that patch would be a great idea too. But I think yes, increasing the sublingual would be a great idea too. Not that I need my voice heard, but we take the exact same approach, Dr. South, as far as patient-centered full agonist versus post-operatively. I just really want to echo exactly what you said. We have very similar approaches with our team over here. I appreciate that. Thank you. Just for the audience to hear also, that's not abnormal at all. Okay. I think, yeah, it's six o'clock now. So I think we'll wrap up for today. I'd like to thank Dr. South, Dr. Hubbell, and Dr. Vase for their excellent presentations. They were very interesting and enlightening. And I'm glad that we were able to do this today. We do have another webinar next week, and we're going to have Dr. Kirsten Smith, who's going to be presenting on creatine consumers in the United States, what clinicians need to know. And this will conclude today's webinar. Please complete the survey on the AOAAM education page, where you registered for this webinar to claim your CME credits. And thank you so much again to everyone for attending, and we'll see you all next week. Thank you so much.

extended-release buprenorphine

opioid use disorder

pain management

pregnancy

sublocade

N-methyl-2-pyrrolidone

Brixati

surgical intervention

multidisciplinary collaboration

clinical documentation