Thanks so much for joining us this afternoon as we talk about induction without withdrawal, low-dose buprenorphine inductions. We're going to introduce ourselves and then jump into the content. I'm Martha Ignashevsky. I'm an adult, child and adolescent and addiction psychiatrist working in Vancouver BC. I work in consult services at Vancouver General Hospital on the complex pain and addiction service and I'm the clinical lead of youth and women's substance use service at BC Women's and Children's Hospital. Hi guys I'm Nick. I'm a medical director at complex mental health substance use services. For this talk we're going to be speaking about some new techniques and some of them might not fall within the medical legal framework of what's available in the United States but we wanted to demonstrate what could be done pharmacologically and what we are currently practicing in in Vancouver and Canada. Go ahead Pouya. Thanks. My name is Pouya Azhar. I have a couple different hats so I'm an addiction psychiatrist and medical lead for our complex pain and addiction service. I'm a pain physician and I work at a transitional pain clinic which is a post-operative pain clinic and I also work outside of the hospital in the community with homeless youth with mental illness and addiction as well. Okay well I think there's still people coming in but we'll probably go ahead and get started and we're gonna start with the disclosures so we don't have any disclosures. Learning objectives. So we're going to describe buprenorphine low-dose inductions and how they can be used in an inpatient and outpatient setting and we'll talk a little bit about how this technique can be used in the chronic pain or prescription opioid use setting as well as well as complex populations such as geriatrics and adolescents and we'll talk about buprenorphine inductions and how we can use a rapid low-dose technique to get people on to the extended release deeper preparation buprenorphine and then we'll talk about a brand new technique that we recently published which is the transdermal buprenorphine low-dose induction. So I want to start with a video and then after the video I'll provide some more context around why I started with this video. I was pushed down a flight of 53 stairs from a security guard. I was using in a public washroom, ended up falling asleep in the stall where I was using in the washroom. The mall ended up closing. The security guard, there was two of them, the security guards were doing their rounds to clear the mall before they closed the doors and leave for the night and they found me in the washroom and told me I needed to get out of there and so I did. Reason why I was there in the first place was because it was pouring rain outside and I was just trying to get somewhere to get a little bit, get out of the rain, stay dry for a little bit and as they're escorting me out we're exchanging comments. They're belittling me, they're making fun of me. I was having none of it so I was returning the comments in return and I was three steps from the top of a series of three flights of stairs and I said something to him that pushed him over the edge and he shoved me from behind and I went flying down the remainder of the flight of stairs. Ended up landing on the floor, breaking my biggest bone in my body, in my left leg, my femur and screaming in agony. They ended up, one security guard picked me up from my right side, the other picked me up from my left side and they dragged me out the remainder of the mall. It's pouring rain outside remember and they threw me out onto the pavement in the pouring rain, threw my bag beside me and unlocked the door. And so, yeah, it's hard to talk about even still. You know, I like to start with patient stories. Justin is just an incredible young man, one of our patients. He's somebody I knew with my work through the, with the homeless youth population. So he was homeless on in Vancouver's downtown Eastside for four years, struggling with mental illness and addiction using methamphetamine and fentanyl. So when he was admitted to our hospital after that fall or the assault, you can imagine, here's somebody with exceedingly high opiate tolerance because he's using two, three grams of intravenous fentanyl per day. Tremendous amount of pain because he's broken his femur. So we have allergies to control in the setting of high opiate tolerance. Psychotic because he had most recently been using methamphetamine as well. And pre-op because he had to be rushed to the OR and have surgery for his fracture. So near the end, we'll circle back to Justin and talk about how we managed him in hospital and how he's doing now. In terms of the music we played, all of those artists either struggled with opiate use disorder or have died of fentanyl overdose. Juice WRLD Gerard, he died of oxycodone overdose a few years back, just a few days before his 21st birthday. And he's an absolute genius, genius of his time. And it was devastating for my for my children, particularly when he died. But what happened was his mom has created a foundation in his name to bring about awareness for mental illness and addiction. I'd encourage you guys to look it up. It's a great way to introduce the topic to young people. And Juice WRLD is interesting because he was a lyrical genius and much of his work was done through freestyle, actually all of his lyrics were done through freestyle rapping. So basically just off the top of his head. And it's interesting to think about how that relates to the creative process and how their creative process relates to research in general. So I'm not gonna sort of get too bogged down with this, but basically we know when it comes to creativity, there's three basic brain networks. So there's a default mode network and that's like the creativity network. It's a daydream network. It's the network where we free associate and come up with ideas with low inhibition. But then that's anti-correlated with the executive network. And this is the network where that sort of puts some checks and balances to the default mode network. So it just ensures that the free flow of ideas isn't gibberish, that there's some context to it. And so most importantly though, is a salience network. And this is a network that tags things as deeply interesting and meaningful before these these concepts are worked on through the default mode network. So for Juice, it was interesting because all of his lyrics were about his struggles with mental illness and using opioid intoxication as a means of coping, particularly with anxiety. So he chose something that was deeply salient to him and then he described how being he was in the free flow state. You know, athletes talk about it as being in the in the zone when he would come up with his lyrics. And I think that it's interesting that that's a similar process that some scientists talk about when they come up with novel ideas. Again, I'm not going to belabor this point too much, but just talking a little bit more about creativity and how that relates to research, we can use the analogy of skateboarding, which is something that's deeply meaningful to me. And so there's some characteristics that are necessary for interesting research that I think I developed through skateboarding. So one of those is being able to tolerate some amount of risk and uncertainty. And you know, we can't introduce anything new to the world, we can't venture into the unknown and be certain of the results. And there's risk associated with that, particularly when you're working with human subjects. And the other is that people sometimes talk about sort of the one great idea that changed everything. I think research shows that that's not usually the case. It's a culmination of small ideas that usually a team, but not one person, works together on to come up with these new concepts. And I think that's really how the research progressed with our team. We started with these small ideas, we encountered clinical problems, and we used creativity to solve them. So if you think of skateboarding being along the x, y, and z-axis, when you ollie, so that's jumping off the ground, you're going along the y-axis. So that's one move, it's a basic move, but it's very difficult. Now if you ollie and you kick your foot out, the board will spin along the x-axis, and that's a kickflip. So now you're combining two moves. But if you move your foot diagonally while you ollie, the board will spin along the z-axis, and that's a pop shove-it. So combine all of those three moves, and you have rapid microdosing, which is a 360 flip. All right. Okay, back to research. So I started my fellowship in 2014, and at that point, the fentanyl overdose crisis really was not much of a thing, and I wasn't really expecting to lose any patients. But then, as you can see, the overdose deaths escalated exponentially thereafter. And we're now, so I saw this transition where, at first, all of my patients were using heroin or prescription opioids. Then there was a transition where fentanyl was an adulterant to heroin and prescription opioids. And now we're in a place where many of my patients have never used heroin before. They started using fentanyl and all they can access is fentanyl. And that's changed the treatment landscape dramatically as well. So when you look at the percentage of fentanyl that's in overdose deaths back in 2012, it was 4%, and now it's well over 80%. I suspect it's actually higher than this. That's a problem, because we know that fentanyl is much more potent than heroin, and carfentanyl more potent than fentanyl. So you can imagine if there's one baggie with some powder in it, it's very easy to take one portion that has more fentanyl than another portion. And even though you're thinking that you're using the same amount, you could be using an order of magnitude more opioid, and that can result in overdose deaths. So treatments for opioid use disorder. Well, there are several where we work in British Columbia. Of course, buprenorphine, methadone. We use 24-hour extended release morphine. We have the IOD program, which is an injectable, primarily diacetylmorphine or hydromorphone, but there's a very limited injectable fentanyl program as well. And then extended release depopeprenorphine. Now, we're going to primarily focus on these two. So just a little bit of boring stuff in terms of the pharmacology of buprenorphine. I think this is important when we consider how these protocols came about. So, of course, buprenorphine is available as a trade name, Suboxone, which is a combination of buprenorphine and naloxone, a semi-synthetic opioid with very high affinity for the mu-opioid receptor, and a partial agonist for the mu-opioid receptor as well. It's also partial in many of the side effects. One of the ones we talk about primarily is respiratory depression and how there's a theoretical ceiling effect with regards to respiratory depression, meaning that it's difficult to overdose somebody with buprenorphine, which is true for our opioid-tolerant opioid use disorder patient. We've all gotten to trouble treating chronic pain patients with buprenorphine. I had a geriatric patient end up in ICU, unfortunately, with two milligrams of buprenorphine. So there is not a ceiling effect when it comes to treating patients who don't have a opioid use disorder, who may be relatively frail and opioid-naïve. Okay, so rapid onset and long duration of action. Really important characteristics of opioid agonist therapy. This is important. So the maximum plasma concentration is achieved between 40 and three and a half hours, 40 minutes and three and a half hours, and we'll circle back to why that's important. Elimination half-life around 24 hours. This is also important from pharmacological characteristics that the duration of action is actually dose-dependent, so you do need about 8 to 12 milligrams to have about 24 hours of action. Less important but interesting is that kappa antagonists, and that's responsible for some of the characteristics that make it a really good analgesic option or an anti-hyper algesic option as well. So we'll circle back to why these pharmacological pharmacokinetic parameters are important. So as Dr. Matthew already mentioned, you know, we're referring to microdosing as low-dose inductions now, and many of these protocols may not, you know, due to restrictions where others may work, may not be possible. So why does the buprenorphine induction challenge? I mean, I think I'm talking in front of a group of experts, so I wouldn't have to belabor this point, but basically we know that buprenorphine has high affinity for the mu receptors. It can essentially out-compete full agonists such as morphine or other opioids. When it binds to the mu receptor, it can block other opioids. So there was a time where we thought this was what caused precipitate opioid withdrawal, meaning that you're replacing full agonists with a partial agonist, you know, you're now not providing enough agonist activity, and therefore you're going to go into sudden severe opioid withdrawal. Is that how most people understand precipitate withdrawal? Yeah. I like to think of it a little bit differently, and so let's just, for example, I mean this is just all theoretical, but let's say we have a graph that's opioid agonist effect versus time, and let's just say somebody's using about 20,000 micrograms of IV fentanyl for 24 hours, which is like a moderate amount. You know, in hospital, when we use our fentanyl protocol, we have patients who use between 40,000 or more mics of IV fentanyl for 24 hours. Okay. And let's just say with that 20,000 mics, this person is receiving a 100% agonist effect. And let's just say we introduce 16 milligrams of buprenorphine immediately. What do you expect would happen? Precipitate withdrawal. Somebody's saying no. Okay. You're way ahead of, you're like, you're taking the wind out from under my wings. There's always a keter in the front row, right? Why am I not surprised you're in the back? Okay. Moving on. Do you want to come up here? You're okay there? I asked. I underestimated the audience. Okay. So, no, but essentially the thought is this person is going to be at an opiate deficit potentially if you introduce 16, I said milligrams, it should be micrograms of buprenorphine, right? But why is it that if you're rapid micro dosing them after 48 hours or seven days, depending on what protocol you use, 16 milligrams is going to be adequate agonist effect, right? Whereas here it wasn't. It caused precipitated withdrawal. 48 hours later, you're getting full adequate agonist effect with 16 milligrams, right? So it's the same amount of opioids. So something must have changed. Some people might describe, well, okay, time has gone by and opiate tolerance has changed, but you're also hitting them hard with the full agonists while they're being micro-dosed. So during this, these 48 hours, and while you're increasing the dose of buprenorphine, you're hitting them hard with hydromorphone, IV fentanyl, whatever full agonist you choose. And it's exactly what this, John, what was your name? Okay, yeah, it's exactly what Dr. Christensen described, how there's receptor level changes that occur when you introduce a molecule like buprenorphine. And that reverses many of the receptor level changes that happen when you're exposed to high potency, highly lipophilic opioids with high receptor affinity. And so some receptor level changes that have resulted in precipitate opioid withdrawal. This is a paper that we recently published a few months ago now that talks a little bit about the neuropharmacology of buprenorphine and the induction challenges. Okay, so this is our first clinical problem, and this is what we all encountered when we started practice, is that we have this amazing molecule. We talked about all the pharmacological parameters, why it's so good, but we have to now tell our patients, well, you have to go into full withdrawal to get this medication. And we know that many of our patients use, at a certain point, not to party and get high. They're using to avoid withdrawal, and they'll go to great lengths to avoid withdrawal before even attending to their most basic human needs, such as feeding themselves. And what does precipitate opioid withdrawal feel like? It's the worst feeling in the world. Oh my god, it's like, it's like somebody gave you 20 hits ass and kicked you in the nuts as hard as they could, and then told you to walk it off. You know, your body, everything aches. Every muscle, every hair, you feel pain in every muscle in your body. Every hair, every joint, every, your fingernails are even feeling pain, you know. And then you get the runs, the burning, burning runs like I got now, and they're horrible. It's just inflamed, and you keep thinking, okay, if I take a little of this, it'll make it better. Nothing can make it better, nothing. You just got to, you know, you've got to sweat it out for that 24 hours, 48 hours, however long it's going to be. And the thoughts I was having, like, you know, I was seeing aliens running around the room and stuff like that. You hallucinate, and it smells, you know, like I smell my dead wife's perfume. Like, she was right in the room with me, you know, and just, it was horrible. Precipitate withdrawal is horrible, and it's the most scariest thing on the planet to me. It's the worst. Okay, so the first solution we tried to come up with to counter precipitate withdrawal, to get around it, we looked at the pharmacology, and we realized that, okay, you know, then this is really before the fentanyl era was in full effect, but we realized that the binding affinity of buprenorphine and low-dose fentanyl was very similar, and that you can actually transition directly from low-dose fentanyl onto buprenorphine. So what we started doing is we created this protocol called the fentanyl bridge, where we would rotate people onto fentanyl patch, allow enough half-lives for their previous opioid to wash out, and then go directly from the fentanyl patch on to buprenorphine. It worked great for low-dose opioid use outside the context of unregulated fentanyl. Christian Schultz, he's one of my mentors, and I remember describing this protocol to him, this is like 2014, 2013, and he was like, well, you know, that's interesting, I haven't heard about it. He's a European researcher who now lives in Canada, but he's like, my colleagues in Switzerland, they've come up with this new protocol, they're calling it the Bernese method, and they're starting at low doses of buprenorphine and gradually titrating up the dose. And this was the brainchild of Robert Hamming, and I think I've shown both of these pictures in every presentation I've had, and I always wonder if they fully appreciate how much impact they've had on patients' lives with this protocol. So we adapted the Bernese method in our hospital, and this was our pre-printed order. And the Bernese method, essentially, you know, it's a micro-dosing or low-dose induction that occurs over several days, sometimes weeks even, and starting at very low doses and gradually building up the dose. We'll go into more detail around the pharmacology a little bit later, but this is the process that we first started being introduced to low-dose inductions, and just with the skateboard analogy, this was maybe our first, this was our Ollie. Maybe the Fenton Bridge was our Ollie, this is more like our kickflip. So what induction strategies exist at this point? You know, there's the traditional wait for the patient to go into withdrawal. Many of my patients end up leaving hospital or clinic before they get their adequate withdrawal. This is a protocol that was published, which I think it's more sort of research-based than anything. I can't see it as a clinical tool. The Bernese method, and then we adapted that, and we created a 48-hour low-dose induction. And then we created a low-dose induction as a means of getting people rapidly on to extended-release buprenorphine. And then we took that a little bit further, and we've created 24-hour and 6-hour ultra-rapid induction protocols. And now we have our transdermal buprenorphine induction protocol. Okay, so I'm going to hand it over to Dr. Matthew for the first case. Thanks. Thanks Priya. For the rest of the presentation, we're going to go through cases and then show how the different protocols were built over time. So the general format will be a case, a clinical problem, and then what the solution was that we came up with. So we're going to start with CM. She's a 16-year-old female. She was admitted to Vancouver Children's Hospital. She received CPR by her partner because she was suffering from overdose. Her Glasgow coma scale at the time was 3. She was resuscitated with naloxone. On admission, her urine drug stream was positive for opioids, amphetamines, and fentanyl. Her past medical history included untreated hepatitis C, and her psychiatric history included severe opioid use disorder, severe stimulant use disorder, ADHD, and a trauma history that included PTSD, intergenerational trauma, and her ACES score was above 8. So 10 is the highest we can get. This patient was under voluntary care. She was under protective services due to the parent-child relational problems. She was living in a group home for youth with high risk, and she spent much of her time with no fixed address. Her main attachments were her mother, her caseworker, and the staff of BC Children's Hospital. So at the time, she was using half to one gram of fentanyl intravenously every day. She's had five recent overdoses that required naloxone. She was also using stimulants in the terms of crystal meth, and she was using this intravenously daily. The reasons why she was using was that it took away the pain, and by pain, she meant the emotional pain from her PTSD. So her goal when she arrived at hospital was that she wanted to stop using fentanyl. So we looked at the treatment options available, and we thought this is someone that's young. We should try the first-line treatment, and that would be suboxone. So we started with the micro dosing. Well, we considered the micro dosing Bernese method, the one that occurred over seven days. However, we wondered if the patient would stay in hospital long enough to want to finish this protocol. So we thought, because of the risk of AMA, we would have to treat her in an outpatient protocol. We found that if you skipped the days where you gave 0.25 milligrams of suboxone and just started with the 0.5 milligrams, you wouldn't put the patient into precipitated withdrawal. So we made a modified protocol based on this, and instead of occurring over seven days, it took place over five days. So we shortened the time for induction without withdrawal by two days. Over time, and that wasn't with this case, but we've also developed strategies that people can adhere to this protocol. So this would be partnerships with the local pharmacies. So in Canada, things like suboxone, methadone, they aren't delivered by any sort of federal building. They're delivered in the regular pharmacy. So people go to pharmacies, the pharmacists give them their medication, and the pharmacists would witness their dose. We would also give early carries. So if people showed some sort of stability, we would move quicker towards carries. We'd have home deliveries, home starts, blister packs. We would build support staff outside that would communicate with the members of the OAT team. We'd provide incentives for picking up the medication. We'd have contingency management where we would give people gift cards if they were able to pick up their medications and take it on time. And also the use of outreach and telehealth. So this led to this case report where there was an accessible induction of buprenorphine using microdosing schedule and a sort of outreach. So this was that five-day protocol that we were showing and also the buildup of the outpatient treatments over time. So to make this a little bit more interactive, I'm going to start with a question. Which of the following statements is not involved in the theoretical basis of low-dose induction onto buprenorphine? A. Repetitive administration of very small buprenorphine doses should not precipitate opioid withdrawal. B. Because of the long receptor binding time, buprenorphine will accumulate at the receptor. C. Over time, an increasing amount of full mu opioid agonists will be replaced by buprenorphine at the opioid receptor while initiating receptor level changes related to opioid tolerance. Or D. Full mu agonists will replace buprenorphine at the opioid receptor. So what do you guys think the answer is? D? Yeah. This one was an easy one. Yeah, the answer is D. It was actually switched between the buprenorphine and the mu opioid agonist. Because we work in Canada, we don't work in the United States, we did want to ask the audience in the United States on an outpatient basis, what are the barriers to buprenorphine low-dose induction and what are the facilitators to buprenorphine low-dose induction? So I'd love to hear from you guys regarding this stuff. Has anyone actually done low-dose inductions here? Yeah. Okay. If someone wants to respond, if you can come up to the mic and then we can hear you. Right. So in Canada, as I mentioned, we give the medication from the pharmacy. So the pharmacist can cut up the buprenorphine. We also have pre-prepared blister packs for an outpatient basis. So the pharmacist at the hospital or the treatment center would pre-cut up the buprenorphine, put it in a blister pack, so it would be easy for the patient to be able to take what they needed to do at the time that they were supposed to take it. Anything else? Go ahead. Sure. Yeah, in the U.S. we also use, like, people can get buprenorphine anywhere in the pharmacies and in the past there were some, there was some pushback when you asked patients to cut the films from the pharmacist itself. Now that seems to kind of have resolved actually before we started doing low-dose buprenorphine inductions. But overall it's really kind of like, you know, you have to create a system where, like, you're giving the patient, like, very clear instructions, kind of like that table. That's the type of thing that we would give to patients to take home. And, you know, when you kind of take a bigger step back and you think of hospital level systems or clinics where you're actually saying to the patient, continue using, sometimes there's a little bit of pushback and, like, it's okay to continue using. Like, is that really, you know, kind of like the statement that we want to use with patients? But all in all, I mean, it works well and it's much better than having to wait for withdrawal or having the experience of having precipitated withdrawal. So facilitators are that we can use tables like that and barriers are we, we haven't yet created a system with blister packs and, like, you know, having the pharmacist cut it for the patients, but they can do it themselves. Sure. So we have developed some other protocols, which we'll talk about, which I think you guys, this was the very prototypical protocol that everything was sort of based off afterwards. Go ahead. We'll get to it. That's the rest of the presentation. Sure. Stick around. Go ahead. I just always wonder about this. Has anyone talked to the manufacturer of the strips and seen, is it actually perfectly distributed throughout the strips and how it's going to close it up? Yeah. Especially Pouya has been in a lot of contact with, in Devere. So hopefully there's some new products that they'll be coming out with. Go ahead. Hi, I have a question for Jake, but I have a question. Like I said, I wanted to have strips, but you have tablets. Do you have phones or do you have tablets? We tend to use tablets. I think if... Yeah. They had the smaller ones cut out there, but we tend to use the tablets and cut it. And it would be the pharmacist. It isn't perfect, but it seems to work well enough. After recently, I wrote a text message to a lot of people who have walked me through the program that I'm working with, and they said it's easier to cut a film than a tablet. So I don't know if that makes any... It didn't make sense to me. I felt like it's easier to probably cut a tablet, but they say it's... Film is easier, but the community place cannot do film. So for them to be able to induce patients at such a low dose, for us to be able to prescribe it is actually not possible. I don't have any thoughts on that, but... Oh, interesting. Yeah. The film is easier to cut. It's easier? For sure, 100%. But it's more expensive. And it's not covered for our patients. I've used the film for low dose inductions, but for our patient population, we just use the tablets and the pharmacy is comfortable cutting the tablets. At one point, we had them cutting the tablets into eighths. We just get a little crumble, but we've realized that you can get away with 0.5 milligrams. So quarter tablets, it's easy enough to do. Wonderful, thank you. Yeah. We'll take one more, and then I'll move on to Martha. Remind us more about the... Sure. Most substance users are basically pharmacologists, and they're gonna look back to the work that we do, and the fact that it's not the opposite of what we do. And so I think it's a system wide problem issue, getting access to the pharmacies, and who's paying for it, and having a provider. Many areas of the United States don't have access to pharmacies. I totally agree. I think it's more of an infrastructure problem than it is a pharmacological problem. Okay, so I'm gonna keep us going with the case, and then we'll jump into a little bit more discussion about the actual protocol. So thinking about CM, eight days later, she returns to the emergency room with another fentanyl overdose. At the time that you're seeing her, she's malodorous, she's disheveled. Her urine drug screen at this point continues to be positive for fentanyl and fentanyl and methamphetamines. And she unfortunately was unable to complete the low dose induction to buprenorphine as she lost the bubble pack and she relapsed, started using fentanyl at her previous patterns. In speaking with her, she indicated that her goal continued to be abstinence. She still wanted to initiate buprenorphine and really was motivated to do that, but needed some support to make that more successful this time. At the time of presentation to hospital, she was identified to have a cellulitis infection, and there was a clinical plan to admit her to a medical ward for a short admission for antibiotic treatment for up to one to three days, which leads to the problem that we run into in this situation is we now have a reduced protocol of up to five days, but we're not sure how long this patient's gonna remain in the hospital. She has a high risk of patient-initiated discharge. She may not need to be in the hospital for a five-day period of time for her medical issues, and her bed may need to be used by other patients. And so we run into the problem and the recognition of a need for an even more rapid buprenorphine induction strategy. And so that brings us into the next protocol that we pioneered in our hospital. So we went from the seven-day protocol. We're able to shorten that to a five-day protocol, and started thinking about what would be a possibility to make this happen in even a more rapid timeline. And so this took us back to a thought process around the pharmacology and pharmacokinetics of buprenorphine, which Pouya alluded to earlier, that the maximum plasma concentration occurs at a period of about 40 minutes to three and a half hours after administration of the medication. And depending on the dose that you're administering, you actually have a differential duration of action, so that seems to be dose-dependent. And at lower doses, you have a much shorter period of action in comparison to higher doses. And so these pharmacokinetic properties led to the development of a 48-hour low-dose buprenorphine induction strategy, which we see here on the bottom right corner of the screen. So the low-dose rapid induction strategy is the administration of half a milligram of suboxone every three hours on the first day. And then on the second day, we increase the dose to one milligram. So day one is a cumulative dose of four milligrams. Day two is a cumulative dose of eight milligrams. And then after that, you're able to initiate a patient on a therapeutic dose of suboxone, and we do that with doses of 12 milligrams, 16 milligrams, etc., and are able to successfully transition patients without initial opioid withdrawal or precipitating withdrawal. And so during this period of time, what we're seeing is a couple of different things. We talked about some of the receptor-level changes that happen during that period of time, that 48-hour period of time that we're administering suboxone, but we still have a relative opioid deficit, right? Patients in the hospital, they don't have their own supply, they are not using as we're starting the rapid microinduction. And so what we need to do actually is to treat the patient for their opioid withdrawal, and we do that with full opioid agonist. So this is the portion that may differ a little bit from clinical practice in the U.S. We don't have the same regulatory hate act that is in the U.S., and so we treat patients with full opioid agonist such as morphine or hydromorphone or oxycodone and increasingly fentanyl to meet patients' opioid deficits, keep them in hospital, keep them comfortable, keep them out of withdrawal, reduce the experience of significant cravings. And during this time, we're still able to initiate the suboxone successfully. We also use other adjuvants and adjunct medications for other types of withdrawal management that would be quite consistent with opioid withdrawal management. So we published this in a case series talking about the experience of the rapid low-dose induction of buprenorphine in inpatient settings. And you can take a look at that here. And so I'll open up some questions and some group discussion. So the question is, during low-dose induction onto buprenorphine, the concomitant administration of hydromorphone will, and the answers are A, cause precipitated withdrawal, B, improve cravings for opioids but not opioid withdrawal symptoms, C, improve opioid symptoms but not cravings for opioids, or D, improve both opioid withdrawal symptoms and cravings for opioids. You guys can feel free to scream out the answer if you know it. D, yeah, absolutely. So the answer is D. So in this situation, we're actually providing the opioid in order to support the patient through the transition process and the low-dose induction. It helps with the cravings. It helps with the withdrawal symptoms that patients may start to experience in hospital. And really allows for this to be a very successful and patient-centered treatment approach that tends to have really great success rates. I'd like to open up for a little bit of discussion to the group. And in recognition of the legal barriers that do exist in the United States around the provision of short-acting opioids, such as hydromorphone or others, for the treatment of withdrawal, if those were removed in the U.S., I'm wondering from the audience what people see as the pros and the cons of utilizing this method. I don't know about others, but at least at my institution, they usually will use methadone during that time period. They're not going to have headache or anything like that. Yeah. And so I think I've certainly heard that as a workaround, because we can provide methadone and suboxone for brief periods of time in hospital. So I've seen that happen. Yeah. This is a question. What kind of methadone dose are you talking about? And is this an offense on using population? And does that do anything for their opioid withdrawal? I'm not confused. Yeah. All right. I'm the medical director. Oh, you're in trouble. He's busted. You didn't know she was sitting back there. I think you need to really learn how to handle it where you can talk. Yeah. So we're avoiding this as an OECD, so we can actually do it. But with the 30 mg of methadone, we're able to keep them comfortable enough to do it on the tube, but if we can't, we send them to the OTC to get a higher dose of methadone in the background, and then just so we can get the buprenorphine from our site, and then they end up being on the tube for us. So we do need the higher dose, and we have to do it from the OTC. I think one of the trends has been that fentanyl really first showed up west coast of North America, and possibly in Vancouver, and has spread. So I think the amounts of fentanyl that our patients are using may be orders of magnitude higher than other parts of North America. So just for example, we also now have a fentanyl protocol, which we're not going to discuss, but for some of our patients, they require upwards of 2,000, 3,000, 4,000, 5,000 mics of IV push fentanyl per hour to keep them in hospital and out of withdrawal. So now we're dealing with doses of fentanyl that would ordinarily kill several people. So I think we're soon going to be in a situation where there's going to be a real need to have high dose parental full agonists to meet people's opiate requirements while they're being induced onto opioid agonist therapy. I will add that for many of my patients that I see when I am starting them on methadone as their opioid agonist treatment of choice, 30 or 40 milligrams of methadone really isn't sufficient to keep them out of withdrawal, and they're continuing to use their own supply on top of that. So while it is one creative strategy, given the limitations and the barriers that exist, it also isn't entirely successful for most of my patients. So that can be quite variable. So without getting into the weeds too much, in Canada we have started a safe supply hydromorphone program. It can be quite a controversial topic, but the doses are about eight milligram tablets, 14 a day, and so patients are dispensed that on a daily basis. In hospital, we'll use doses of eight to 16 milligrams, sometimes even up to 64 milligrams per hour. And that would be oral dosing. Sometimes we're using intravenous dosing of similar rates. So we really are using very high doses for our patients because they have such a high opioid dependence. Exactly. If I can interject, when you think of the intravenous or IOT program, so intravenous opioid against therapy program, and when you titrate people onto hydromorphone, they might be receiving 100 milligrams of IV hydromorphone three times a day as a maintenance. I mean, I appreciate that doesn't exist in the United States, but 100 milligrams intravenously three times a day. And that's the type of tolerance that we're seeing. And frequently there might be methadone use on top of that, plus ongoing fentanyl usage. So we're seeing really high levels of dependence. So I'd be jumping ahead. My question would be is when you're having this high of a use, I'm just thinking like 16 milligrams of buprenorphine. Am I hovering these people in the long-term setting? Because I know here, at least in the wonderful state of Florida, I get yelled at when I use 24 milligrams for a patient with pain and opioid use. And so I'm just wondering, like, how do you deal with that? Yeah, I think it's variable. There are some patients that will stabilize on 16 milligrams, and many patients that we're pushing to higher doses, 24 milligrams, sometimes 32 milligrams. What do you guys think? There are definitely patients that will stabilize on 24 milligrams of Suboxone. We'll show the case at the end. Yeah. I mean, I think from my experience, buprenorphine does have a sort of upper limit in terms. Once you exceed a certain dose, you may have to move to a full agonist like methadone at high doses. But yeah, sometimes we can't. 32 milligrams is our theoretical maximum, but you can go higher. This is a bunch of hands, so. This is anecdotal, but I was told that overdoses more frequently with buprenorphine provides about the maximum of analgesia you can get from it. Yeah, that's right. Like, once you get those higher doses, there's, I mean... Yeah. But you can think of it similar to the methadone for pain program. You know, you split it three times a day, you're dosing smaller doses, 100%, but I think we can distinguish the analgesic effect with its opiate agonist effect. And you do have to go much higher, yeah. And once a day, for many reasons, yeah. To go back to where that question came from, I would say, when you come in, what percentage of your patients are still viable if you end up being on a lot of therapy with buprenorphine? Whatever the dose. It doesn't really matter. What percentage of them have you found that actually sustain and will develop buprenorphine? Yeah. There's a couple of ways of answering that. So, sorry, Martha, but I found that it's much easier to stabilize people while they're in hospital, right? And you can meet the opiate requirements in hospital, and you can get them to a good dose of buprenorphine. I think there are so many factors that are driving their use in the community that oftentimes are not modifiable from our perspective. So the people with the highest opiate tolerance, the highest level of use, they usually have the most chaotic circumstance in the community. And it's rare, but not impossible to achieve long-term abstinence on buprenorphine alone in this population. And we'll talk about a case at the end of the presentation, but I think those high tolerances also speak to the level of chaos that is in their community circumstance. Okay. We'll take maybe one more question or comment. Go ahead. What about having patients keep themselves comfortable as an outpatient with therapy when they're using opiates? So this protocol that we're talking about right now is a hospital-based protocol. I think the experience is the majority of our patients have a lot of social disorganization, a lot of chaos in their lives, that it's quite difficult to actually adhere to the every three-hour dosing regimen, and that can be a bit of a barrier in the community. Even in the hospital, it can be a little bit of a resource-intensive protocol, right? Requires nursing staff to be checking cows very frequently, to be providing the dosage of medication, to be giving the as-needed doses of medication, which is really driven by a patient request as opposed to scheduled dosing of medication. So we will talk a little bit about some strategies that we've come up with to actually overcome some of those challenges. So why don't I pass it on to the next steps of the case? We're rapidly running out of time, so I'm just going to try to blast through this, and then... Okay. So the patient was admitted three days later with another fentanyl overdose. So what happened was she had stopped buprenorphine the second day after she was discharged. So induction in hospital, like we're describing, was successful. We were able to get her on to a good dose of buprenorphine. She went back to the same chaotic lifestyle as a young person who was homeless, and she stopped taking her medication she was using with her boyfriend, and she's back on to intravenous illicit fentanyl. Her goal was still abstinence. So at this point, the thought was, well, you know, this is still her goal, so perhaps extended release depot preparation of buprenorphine may be the treatment of choice for her, given her inability to take medications every day. So next problem was that, I'm not sure, I suspect it's the same here, but for us, due to the product monograph and health Canada regulations, basically extended release buprenorphine can only be started after a patient has been stabilized on H24 milligrams of sublingual buprenorphine for seven days. And that's a major barrier, particularly you can imagine in this type of circumstance. We only have a couple days with this patient in hospital before she leaves again. But this was actually the very first patient that ever received extended release buprenorphine in Canada. So we have this 16-year-old girl who needs extended release buprenorphine, and we only have a couple days. So we looked at the pharmacology, and we realized, well, you know, it's a little bit nonsensical to think that we have to wait seven days. She's already demonstrated that she can tolerate buprenorphine, and this is a life-saving measure. And from a pharmacological perspective, there's nothing saying that we have to wait seven days. So what we did was we just rapidly marked her doser back on to buprenorphine, and then gave her the injection right away. And this is now really our standard of care, in that we're not waiting seven days. It's not reasonable. You know, Endeavour submitted this to the FDA and Health Canada, and it still hasn't been approved, so the product monograph hasn't been changed. But this is really our standard of care. So induction course, her cows remained maximum of six throughout the induction. It was unchanged after she received the extended release buprenorphine. No precipitate withdrawal at any time. So she was discharged home a few hours after she received the extended release buprenorphine. So we can go through some questions. And just so everyone knows, when we're saying extended release buprenorphine depot, that's referring to supplicate. Yeah, I'm trying not to use a trade name, but yeah. Because they'll be redundant. Okay. We're amongst friends, so it's okay. Supplicate. Yeah, so basic question, which of the following side effects are associated with supplicate, but not sublingual buprenorphine? Respiratory depression, precipitated withdrawal of a starved-in patient that has used opioids but not yet in opioid withdrawal. Cardiac QTC prolongation. Decreased GI motility. Anybody in the back want to take a stab at this? All right, yeah, so QTC. Okay. It's not a contraindication, as far as I'm concerned. There are no contraindications to buprenorphine. Sometimes I get calls from docs who are like, I have a patient who's on benzos, should I put them on buprenorphine? Or I have a patient who has a QTC of 500, should I put them on buprenorphine? As far as I'm concerned, if the patient's on benzos and using fentanyl, that's a much more dangerous circumstance than a person who's on benzos and we have them on buprenorphine. Really, no absolute contraindications to any formulation of buprenorphine. We talked about how it's difficult to translate this protocol to an outpatient setting because there is a requirement of dosing every three hours. This is a rapid micro or low-dose induction protocol that we described, where we're dosing it based on time to max serum level, which is three hours. This was a problem. To solve this problem, this is really cool because it's a real nice example of using creativity and applied pharmacology to solve a real clinical problem that will impact patient care. We thought about, okay, well, we maybe have maxed sublingual delivery of buprenorphine for low-dose inductions. Is there another way of administering buprenorphine that will mimic the pharmacokinetics of low-dose inductions but will not require Q3H dosing? We had one of our colleagues in the Department of Pharmaceutical Sciences model what it would look like if we use transdermal buprenorphine patches for buprenorphine inductions. Here, as you can see, each peak is a three-hour sublingual administration of buprenorphine, starting at 0.5 milligrams. This here is the serum concentration that you would achieve. You're building up the serum concentrations. You go to one milligram, you're building up serum concentrations. Here we're at a point where you can introduce a full dose of buprenorphine without precipitator withdrawal. This line, this is the transdermal administration of buprenorphine. You put on patches on day zero, just once, and then you put on more patches in 24 hours, beginning of day two, and the serum levels build up. Then you can just simply go from that on to a full dose of buprenorphine without precipitator withdrawal. You can imagine in an outpatient setting, the patient puts on patches, next day they put on more patches, and then they're on a full dose of buprenorphine. It's really cool. This is what the protocol looks like. Day one, we apply six 20-microgram patches, which equals a total of 120 micrograms per hour of transdermal buprenorphine. On day two, we'll add an additional six patches for a total of 12 patches, and we'll leave that on for another 24 hours. At 48 hours, we take off the patches and we give the full dose. But like we've said a few times now, you still have to hit them hard with a full agonist during these 48 hours. If it's in an outpatient setting, like in Canada, we do have the capacity to prescribe full agonists in an outpatient setting, but usually it's not successful because it's hard to prescribe enough. As somebody mentioned from over here, it's hard to say this, but I tell my patients, for the first 48 hours, you are going to continue to experience cravings and withdrawal. Most of my patients will continue to use fentanyl for the first 48 hours until they're comfortable. Yeah. And this is what it looks like. So first 24 hours, second 24 hours, and then they're good to go. In my mind, this is a game changer just because it's so convenient for patients and for nurses. This was the paper that we published on the protocol, so you guys can look it up. And interestingly, and this isn't yet published, but we've also been able to directly from transdermal to sublocate. So that cuts out another step and makes it even more convenient. So just to kind of take it home, we do have a few other protocols that we publish and are kind of proofs of concept that we're working on to see really how far can we push that threshold in terms of titrating up buprenorphine without causing preceptor withdrawal. What we've found is if you start to go below 48 hours, it becomes less and less reliable and your chance of preceptor withdrawal is higher and higher. And you sort of have to pick patients carefully. Okay, back to skateboarding. So as you can see, we started with some basic concepts. We started with a clinical problem. How do you get people on to buprenorphine without preceptor withdrawal? We started with a fentanyl bridge, which was a basic technique, it was like the Ollie. And then we sort of, as a team, we put our heads together, we were creative, and we were able to sort of build on different protocols. And I feel like the transdermal rapid low dose induction is probably our 360 flip at this point. And so we're going to talk a little bit about chronic pain, but low dose inductions are really a fantastic way of getting people who do not have an opioid use disorder, but may have been on 160 milligrams of oxycodone for the past 25 years off of oxycodone and on to a low dose of buprenorphine and then taper off. And I find that it works beautifully for opioid induced hyperalgesia as well. And particularly in the geriatric patients, when we do this, all three of us have done it, and sometimes they just come alive, and they feel so great, and they're so grateful that they're off of their full agonizing. So this was the outpatient protocol. It's chronic pain setting. This was interesting, and I'll just spend 30 seconds on this, but we encountered a clinical problem in our critically ill patients, where you may have a patient who's mechanically ventilated, who's critically ill, who may have high opioid tolerance, and they may be on a high opioid infusion. And when it comes time to wean the infusions and extubate them, once you start to wean the opioid infusion, they will go into opioid withdrawal because their tolerance is so high, and they can become agitated. And then you put the infusions back on, and you're churning up the propofol and Presidex, et cetera. So what we thought about, why not use an opioid that's long-acting, that does not decrease respiratory drive in this population, and that we can introduce in the background? So we did this case where we low-dose-induced a patient who was mechanically ventilated. Once we got them on a good dose of buprenorphine, the propofol and Presidex remained on. We weaned the hydromelphone infusion. Their opioid requirements were being met with buprenorphine alone, and then they were able to then extubate them, and it worked beautifully. So it's just an interesting, again, application of a technique that we already know to solve another clinical problem. Was that an opioid user before? This was an opioid user before. Yeah. That's where the high opioid tolerance came. But potentially, you might have patients in the ICU sometimes who've been there for a long time, and their opioid infusions have sort of gradually gone up, and now they're on really high doses. And they've developed that tolerance, and now you're trying to wean the infusions, and they're going into withdrawal and becoming agitated. So we just have some other studies ongoing as well. Running out of time. I think that we may want to leave some time for ... How much? 25 minutes. Oh. We're not running out of time. Okay. It's okay. It's okay. Conclusion? Yeah. Rapid low-dose induction techniques. I think they're great. 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And then we've demonstrated that you can use low-dose induction successfully to get people on their medication. And then we've demonstrated that you can use low-dose induction successfully to get people on their medication. And then we've demonstrated that you can use low-dose induction successfully to get people on their medication. And then we've demonstrated that you can use low-dose induction successfully to get people on their medication. And then we've demonstrated that you can use low-dose induction successfully to get people on their medication. And then we've demonstrated that you can use low-dose induction successfully to get people on their medication. And then we've demonstrated that you can use low-dose induction successfully to get people on their medication. So I ended up discharging him on both buprenorphine and hydromorphone, followed him on an outpatient setting and tapered off with the hydromorphone. And he's remained on buprenorphine ever since. He's doing beautifully. He went back to his mom for some time. Now he's living alone. He's working full-time. He's kind of a patient advocate now. He's done a few talks with me. He's gone to conferences, et cetera. So here's somebody who came into hospital after being homeless and using IV fentanyl methamphetamine and was psychotic to being treated in the hospital, being placed on buprenorphine and doing beautifully now. So to your point, it does happen. And we do get patients comfortable, stable. But oftentimes, there are other factors at play as well. That's our presentation. We do have time. So we can open it up to discussion. OK. That was the first hand way back there that went up. So the first question, is that a question about buprenorphine versus methadone? Or is it just low-dose inductions? I would say almost 100% of my patients, I do the rapid low-dose induction on. And most recently, the transdermal induction. It's just quick. If things happen and they want to leave hospital before the four or five days, they're already on a good dose of buprenorphine. It's pretty seamless, particularly with the transdermal protocol. I don't see a good reason. I certainly don't ever see a reason to put somebody into withdrawals. I haven't done a cow scale outside of the research setting in a very long time. And then the second question, many of these protocols came about urgent clinical need. And that's how the case reports came about. And now we do have ethics, and we do have RCTs going in our hospital. But it was really out of an urgent clinical need. Even that low-dose induction onto sublucate, the first sublucate dose in Canada, the thought was she's already had multiple overdoses. She's going to die if we don't do something right now. So it was kind of out of a sense of urgency. I think there was a kind of losing track. So go ahead. Go ahead. That's right. That's right. Yeah. Or psychiatric conditions. Yeah. There's a hand over there. Yeah. Rarely in post-op settings we do, but our PCA pumps have a maximum limit that's programmed in. And that became kind of a barrier. And I just figured it's sometimes easier just to write the orders separately. What we do sometimes do is instead of writing them PRN, I'll write them as scheduled and withholding parameters. Because sometimes patients will be embarrassed to ask, or will forget to ask, and then some time will go by. They'll go into withdrawal. So I sometimes find that scheduled dosing works better, withholding parameters.

low-dose buprenorphine induction

protocols

challenges

pharmacology

Bernese method

rapid low-dose induction

full opioid agonists

withdrawal symptoms

sustaining buprenorphine therapy

extended-release depot buprenorphine

transdermal buprenorphine patches