Good afternoon, folks. I want to welcome you to our annual update on buprenorphine. I'm John Renner from Boston University. I've got Dr. Steve Wyatt and Dr. DC Park. Dr. Lavounas is not going to be able to join us. We were prepared for that happening, and apparently the demands of his job right now are keeping him occupied, but we will try to cover without him. This is a talk where we're going to give you some information on updates, but we're really looking forward to hearing from you. How many people in the audience are actually prescribing buprenorphine? OK. So I'm assuming that this is a pretty knowledgeable audience, and we're hoping that we're going to have opportunities to discuss and question each other and talk about things. And I think we're expecting to learn as much from you as you might learn from us. So I want to welcome you to this. And I'm going to begin by giving you a little bit of information on what's going on, particularly talk about things. You've seen this all before, but we're clearly in the midst of the fourth epidemic of overdose deaths. And right now, we're certainly on the East Coast. We're experiencing major problems with fentanyl and probably xylosine. And I expect that that's probably going to spread to the rest of the country if it hasn't yet. How many people right now have any xylosine in their part of the country? OK, so a majority of you. Well, I expect that the rest of you will probably be seeing it soon, because it's not going away anywhere quickly. And patients that get involved with it are very attracted to it. But I just want to, again, reiterate that we're struggling with the national overdose. And two or three years ago, I thought we felt like we were making real progress controlling the opioid problem. But the presence of both fentanyl and xylosine has sort of changed that. And I expect that over the next two or three years, there probably will be even more changes in our practice patterns as we try to adjust to both the imminent danger and the crises that have been presented, particularly by xylosine. I wanted to show you some recent data from the CDC. And a couple of things, one of the questions that people have asked is, well, what happened when the waiver went away? The government tried to loosen up things around prescribing buprenorphine. And I think their expectation was that there would be a large increase in the availability of buprenorphine. That hasn't happened. There has been a very minimal increase in the number of people who are prescribing. There's been a slight increase in the amount of medication being prescribed. But there's been no great increase. And there was also some concern that if there was more buprenorphine, there would be more overdose deaths or that that would have some problem. But diverted buprenorphine and problems related to that. And that also hasn't happened. Our sense that buprenorphine was a safe and effective drug has really been maintained by all the data that the CDC has accumulated. This slide, you've seen versions of this before. It just shows you areas that are hardest hit by the overdose deaths and 10-year changes. And this I found a little bit more interesting. Some of you may not have seen this before. This is the most recent data from the CDC looking at overdose deaths. And as I'm sure you're aware, that if we'd had this discussion three or four years ago, we would have thought of people overdosing on injectable heroin. That's what happened. And the most recent data, which was done for the last six months of 2022, in the deaths where they could actually identify the method of death, they discovered that only 23% occurred after smoking. 16% occurred after injection. So instead of the almost 100% we were seeing before, it drops to 16%. 16% occurred after snorting. And 14.5% occurred after swallowing. So to me, what this says is that this is related to xylosine and perhaps to fentanyl. But the things have changed. People are certainly dying. The overdose trends have continued. But it's not people injecting heroin that are dying. We're using a drug out there now that is really quite dangerous, even if you're only swallowing it. And we need to think about what it is we can do to try and moderate that danger. A few regulatory changes. The x-waiver has been eliminated. There's been an elimination of the caps on panel. So any prescriber can now treat as many patients as they like. However, eight hours of training was required once for all new DEA licenses or for renewed DEA registration after June of last year. Now it's been a little nebulous as to what that training has been. But anybody who had an eight hour waiver course qualifies. Anybody who recently graduated from medical school and has courses there where they dealt with opiates qualifies. And this eight hour requirement can be met by any kind of courses done by certified organizations. So what we're doing today, this course counts for an hour and a half if any of you need it to meet that requirement. I suspect it's probably not relevant for most of the people in the audience. But the activities here, there will be a number of things at the meeting today which someone could claim as part of that eight hour requirement. And I think the other thing that is of importance is that the government has really loosened up the requirements as far as telemedicine. And I think that's going to continue. I think they're permitting any federally qualified health care center. They can provide services, regional health centers, rural emergency rooms. Medicare patients are eligible. There's no geographic restriction on where the site is that is originating the telehealth. Some of these requirements may be ending at the end of the year. But I think most of them are probably going to continue. And I think in general, telehealth is with us. And it's going to be a major part of what we do to try and cope with the opioid addiction, particularly in rural areas and away from major centers. Now, new buprenorphine formulations, this again is not news to any of you. The sublingual formulation that we started with is obviously still available. We've got new depo formulations. Sublocade was approved in 2017. Bruxade was just approved last year. I think we're getting access to more flexible ways of trying to administer the medication. And we'll talk a little bit about how to use some of these things, though. We still would want to hear from you as to whether you're using them, whether you're having problems with them, whether you've discovered ways to use them more effectively. Anything that's worked for you would be interesting to discuss. And I'm going to turn this over to Dr. Park, unless you guys have any questions at this point, because we really want to have discussions. We don't want to spend a lot of time showing you slides. Any questions or anything so far? OK. Dr. Park? Thank you, Dr. Renner. DC Park, addiction psychiatrist from Boston University. Actually, that was a typo that I was worried about. There was a typo on the Bruxade dosing. For the monthly section of the Bruxade, it's a 64, 96, and 128 milligram dose. And we're going to talk about that. So since the ZupSolve, there has not been any newer formulary of buprenorphine. But as Dr. Renner mentioned, there has been Sublocade, and there has been Bruxade. So I'm going to talk about the rapid initiation of medications for opioid disorder first, and then I'm going to talk about the extended release. So the new center of care dictates that because the potenticity of the fentanyl these days and the high overdose rate, that the traditional, conventional way of starting someone on Suboxone as buprenorphine is not recommended any longer. The goal of the care is to get them on the therapeutic dose of buprenorphine as soon as possible, as safe as possible. And I think everyone has seen the what if you don't, the negative outcomes of if you don't do that, because patients are not going to come back to the treatment. And we are under the exemption of still not requiring a face-to-face visit to start buprenorphine. You still require initial screening, but this is the case where the good enough actually better than just pursuing the best. You do the phone screening. You do the initial screening for other social radiation, obviously other psychiatric emergencies, and need for any hospitalization needs. And of course, you're going to ask about the pregnancy questions, but you want to get them on buprenorphine as soon as possible. So this is just a brief review of the standard before the fentanyl era of how to start buprenorphine. You wait. I hear, actually, so my career has been that. It's been all fentanyl. Oh. Oh. So I'm told that when it was heroin, it was a lot simpler, it was a lot faster. You wait for 12 hours since the last use, their cow score will be predictably from 7, 8, up to 12, and you give them the first dose of buprenorphine, 2mg, 4mg, they feel better, they thank you, you feel better as a doctor. It was all simple back then. Not the case anymore. So we all know that the fentanyl, because it's more lipophilic, because it's more accumulated in the body, and because there's unpredictable half-life with the fentanyl analogs, the avoiding of the persistent withdrawal has been more difficult. I think people have been waiting for up to 48 to 72 hours before giving the first dose, and even then, people will still have persistent withdrawals. And that creates a major, major problem. Most patients before could tolerate 12 hours of mild to moderate withdrawal, but if you're asking them to wait, yeah, you're actually not waiting for buprenorphine, you gotta wait for 48 to 72 hours. My experience has been that over 90% of them will relapse, and they're not going to come back for treatment. So we're going to talk about different ways of people doing the induction of buprenorphine, but the goal is to, you wait for the cow's score to be a little bit higher, 10 to 12, or if they have a history of persistent withdrawal, you even wait for a higher cow's score. And it says before with the heroin, the first day, you kind of target 8 milligrams a day. We're going to say, you know, if they've been using fentanyl, aim for 12 milligrams on the first day. In my area of practice, in Boston area, I aim for 16 minimum on the first day. And if they're still showing signs of withdrawal and or cravings, I try to go up to 24 milligrams by the third day. I'm going to call them on the second day, I'm going to call them on the third day. And if they're still not stable, stable, if they're not sleeping well, I'm going to suggest going up to 24 milligrams. I cannot ask you to generalize that to your area of practice. It's going to depend on how lethal, how potent fentanyl is in your area. But you aim for the higher dose of buprenorphine to begin with. Symptom induction. If you think patients are at lower risk of relapse and they're more medically literate, you can ask them to actually do the, you can give them the prescription. Actually that's going to be the case for the health business, right? You do the screening over telephone and you're going to send the prescriptions to their pharmacy so they'll get it. And you kind of go over the detailed instructions of what signs and symptoms they should wait until they feel they're safe to start suboxone. That way you don't have to hold them hostage in your clinic if you're still doing in-office induction because right before with the heroin, you ask them, you get a call from them, you ask them to keep their last use the night before the clinic visit, they come back the following morning, and then they'll be ready for buprenorphine induction. That's not going to be the case with the fentanyl era. And you cannot just have them there for like eight hours just to see and wait if they're going to be in the sufficient withdrawal to avoid the precipitate withdrawal. So home induction can be considered for most patients. And again, but the same principle, rapid induction to therapeutic dose should be high priority. Continued weekly visits would be the recommendation. It doesn't have to be face-to-face. I mean, it'd be ideal if it's face-to-face. But if access is an issue, absolutely. Just call them on the phone whenever you can, whenever they can talk to you on stable treatment and monitor progresses. So before I start on the high-dose or micro-dosing induction or low-dose induction or high-dose or micro-dosing induction, how many of you have done the either inductions? Yeah? Micro-dosing? Micro-dosing. Okay, great. So this is not going to be a news to you, but if it is, I'm here to go over it. So micro-dosing or low-dose induction first developed in Bern, Switzerland. That's why sometimes it's referred as a Bernius method. At first I was like, you know, Dr. Bernius must be this guy. So I'm looking, I'm trying to look up literature by Dr. Bernius. That was not the case. It was just done in Bern, Switzerland. So if you think about the theory of the precipitate withdrawal, right, it's twofold, right? One is you're not occupying enough opioid receptors with the buprenorphine because you're giving them too low compared to high, high-dose of fentanyl that we're using. That's on one hand. The other hand, on the other hand, it could be also because of the rapid deactivation of mucoporeceptors. Well, it's not a complete deactivation when buprenorphine displaces the full agonist opioids from the opioid receptors. They'll go from 100% activation to about 40% activation, and the rate at which it is displacing the full agonist opioids can precipitate withdrawal. The idea of microdosing induction is that you minimize the effects of a sudden displacement of full agonist opioids with the buprenorphine. So while they're still taking full agonist opioids, as you will see, you know, you can do this with someone who's been on methadone maintenance or who's on someone who's still continuing to use fentanyl. I cannot tell them to continue using fentanyl while, you know, they're getting started on the microdosing induction, but the idea is that they're not going to go through a precipitate withdrawal by taking a very low dose of buprenorphine while they're not in opioid withdrawal. So back to the idea of gradually introducing the buprenorphine into the system, minimize the impact of the sudden displacement of full agonist opioids with the buprenorphine, and you can do this with cutting up the films, and, you know, it works the best with the films because tablets, most generic tablets of buprenorphine, they'll start crumble after a half tap. If you ask them to cut them up, if you ask the patients to cut them up into quarters, it's not going to be, you know, as consistent, it's not going to be as, you know, stable. Films a lot easier, and this is just a sample, you know, kind of protocol that, you know, people tried and started with the 0.5 milligrams. So that would be 0.5 milligrams of buprenorphine, that's a quarter films of 2 milligram, you know, that's available in the U.S. I actually wonder, so I know there's a 200 microgram formula available in Europe, and maybe if, you know, has anyone tried, is anyone from Europe, has anyone tried, like, 200 microgram? Yeah, and do you guys use that for microinduction? Great. And that's been going well. Okay. Great. Thank you. Do they have fentanyl? Is there fentanyl? But, so, Steve had a question, is there fentanyl in Australia, you know, or Austria? No. So it's been here. That was a comment. Belbuca is okay, too, if you can get paid for it. What? Belbuca. Yes, Belbuca, you know, Buccal. But it's not legal to use Belbuca. So only products that have been approved by the FDA for the treatment of opiate use disorders can be used in an outpatient basis for a person that has an opiate use disorder. In the hospital or someplace where you can, yeah. Or if you've got concurrent pain diagnosis, you could use it. So just to illustrate the, to capture the conversation, so Data Act back in 2000, and even with the elimination of X waiver, it still only covers the buprenorphine products that are approved for the treatment of opiate use disorder. So there are two buprenorphine products that I know, that we know of in the U.S. that are not approved for opiate use disorder treatment, which is Belbuca, the Buccal film, approved for chronic pain. Also Butrans, that's the transdermal buprenorphine patch. And we'll talk about how, so it is not legal to prescribe them to treat opiate use disorder. But if you're in an inpatient setting, you can dispense them, or if they have a concurrent diagnosis of pain, then you can prescribe it under that indication to facilitate the, getting them on buprenorphine or, you know, extended release of buprenorphine. So this is one example of a microdosing induction using the films. And then I think the protocol using the patch is covered in the methadone to buprenorphine transition. High-dose, microdosing induction is favored in emergency department or the inpatient setting. So the idea is that because, you know, one of the reasons for precipitate withdrawal in the starting of buprenorphine is because it's the lack of enough mucoporeceptor occupancy with the buprenorphine. We'll start with the high-dose. So there has been case series, case reports, and a lot of anecdotal stories, you know, starting with the 4-milligram, and then if they're stable after two hours, give them another 4 or 8 or 16. We've heard the, you know, starting with the 16 or even higher. We're going to stay with the 4 to 16-milligram as the first dose. Rapid titration is the key, often targeting up to a total of 32 milligrams in the first day. Now, this is usually because they got the support and the resource of the emergency department and the inpatient setting, they can also utilize some IV rescue opioids, you know, and they can also use some benzos as well. I think about, you know, my practice, which is an outpatient. I think about my colleagues, which is an outpatient, you know, that's because I don't have access to, like, telemetry. I don't have access to, you know, resuscitation, you know, team on the doorstep. I don't do the high-dosing or micro-dosing induction in my office. For those of you who are experienced in micro-dosing, do you guys do that? Are you guys in the ED or inpatient setting, or is it, do you guys do that in outpatient too? Outpatients. Outpatients. And how many, what's the dose that you start them with? So, two milligrams, and then every hour, if it's too sweet, you can go with two milligrams or whatever. Mm-hmm. But you start with a two milligram? Yes. Okay. Because, you know, the macro-dosing induction, and then you're often targeting the overall higher, you know, dosing in the first 24 hours. So in the ED settings, people have tried, you know, starting dose with the four milligram or even eight milligrams or 16 milligrams. I mean, with the two milligram, that makes sense to me. But yeah, anybody else who's doing macro-dosing as an outpatient, then we'll go here. Yeah. Great. Was everyone able to hear him? Should I repeat? OK, we're good. And there was another comment from here. I'm in 10th, and I was a hospital patient. OK. OK, great. I started with 8 milligrams. You started with 8 milligrams. OK, great. 2 milligram titration was a standard titration, right? So 2 milligram titration, so 2 to 4 milligram was the standard technique. But the difference is that he's doing it every hour, up until they get the 32 milligrams, or get the extended release of buprenorphine formula, because otherwise, patients have signed out. They're in the ED, and if you lose them on that day, you don't know if they're going to come back, or you don't know if they're going to be alive to come back. So that's the strategy. So macrodosing, rapid titration is key. Arrangement of follow-up is critical. So the need for the bridge clinic, or the lower threshold, kind of like a walk-in, referral centers to continue the medications is critical. Across various strategies, the perspective withdrawal risk remained low. The literature that we've reviewed, the perspective withdrawal risk remains less than 1%. Now, unless you have access to give the full agonist opioids concurrently with the macrodosing, avoid for patients with the recent consistent use of methadone. The keyword is consistent. So methadone, because of its very much slow onset, persistent, half-life nature, has more risk for a perspective withdrawal when patients on methadone maintenance have been introduced to the buprenorphine. I'm not talking about getting methadone for three days for a detox program like a week before. I'm talking about someone who's been on chronic maintenance therapy for a month or longer. So a couple of literatures from reviewing the macrodosing risk in the ED. I think that's the major concern when it comes to macrodosing. Again, it was very, very, very minimal. And it has been deemed very, very safe. 0.76% had perspective withdrawal. They're all positive for fentanyl. And the time to peak, time to have a peak, the CAS score ranged from 20 minutes to 220 minutes, depending on the dose. All those patients didn't sign out AMA. I don't know what they did to convince them to stay. But they eventually got started on the buprenorphine and discharged from the ED within the 24 hours. So just to review the different strategies with using the buprenorphine initiation, using the low dose. And this is more of the kind of like you start with the two. The first one is the standard protocol. You kind of wait for the washout. And you start with the 2 milligram. And give 2 milligrams in an hour. High dose, washout period, maybe shorter. But you load them with the high dose buprenorphine under close monitoring in the ED or inpatient setting, along with the utilization of the comfort medications. And then there's a crossover. So this is kind of like we're not condoning the continuous use of fentanyl. But we're telling them just if we do the low dosing, micro-dosing induction, if they have the chronic pain indication using the transom or patch, or the cutting of the buprenorphine film, it's not going to cause them to go into precipitate withdrawal even if they continue to use fentanyl. And the eventual goal is to get them on at least 8 milligrams of buprenorphine by the seventh day. And then, hopefully, you instruct them to quit the opioid use called turkey. And they don't go into withdrawal at all. So just to point out that that's, and many of you probably know this, that's commonly done in OTPs. So people can be maintained on their methadone. And then a low dose of buprenorphine is introduced over five to seven days. And then the methadone is just stopped because the affinity of buprenorphine is so much greater than the methadone. They're now on methadone, and they're not getting anything out of the, they're now on buprenorphine. They're not getting any of the effects of methadone any longer. And that's being done in OTPs in many parts of the country. Perfect segue into this slide. So we're going to cover the methadone to buprenorphine protocol utilizing the low dose induction. So the conventional way before was, actually, I did this for a patient in my clinic when I was a resident. So a patient on 110 milligrams of methadone was upset with the methadone clinic staff. He had brief laughs with the, I think, alcohol. And he felt like he was penalized. He was treated like a child. And he was determined, like, I want to get off of methadone. Change me to buprenorphine. And the conventional transition technique was that you go down on their methadone dosing 10 milligrams per week up until they get to 30 milligrams. Keep them on 30 milligrams for five days. Give them 15 milligrams on Saturday. And by Monday morning, they're ready for buprenorphine treatment. It was not a pleasant experience for the patient or for me. The entire, I think, eight weeks for him to go down from 120 milligrams to 30 milligrams, he was in mild opioid withdrawal. He was full of anger. He was still upset. But he was very, very determined. And he had cravings for opioids. But he made it through. And he got on buprenorphine. And actually, at least by the time I graduated from residency, he was doing well. So that was the conventional technique. So by taking the knowledge that we know for the microdosing induction, so the proposed, I think a lot of people actually are doing this already, is to use the microdosing induction. So they're continuing to get their methadone maintenance up until 120 milligrams. There have been case reports of patients who are able to get on buprenorphine while they were being maintained on higher dose of methadone. But when I talked to my colleagues about having a perspective withdrawal using microdosing induction, inevitably, patients were all on 150 milligrams, 160 milligrams, or 200 milligrams. I've never heard of a case where a perspective withdrawal happened despite using microdosing induction if their original methadone maintenance dosing was below 120 milligrams. So you used either the films, cutting up the films. If you can, I actually like the buprenorphine patch a lot. Because the onset of action for patch is peaks at about 24 hours after. If you use the 20 microgram per hour patch formula that's available in the US, their maximum peak level is about 0.5 milligrams over 24 hours. And it's a slight more bioavailability with the patch. So even if times two, it's 1 milligram buprenorphine within 24 hours. That's very, very small. And the introduction of buprenorphine is so much gentler and more insidious than the films. So they don't have to go through any tapering process of methadone. They're not in any withdrawal or mild. And therefore, they're at decreased risk for withdrawal. So again, disclaimer, transdermal buprenorphine patch is not FDA approved for opioid use disorder treatment in the US. But you can apply the transdermal patch on the first day. And second day, third day, you take it off. You give them half a tablet of buprenorphine. And then you gradually increase them. And then you get them on the eighth day. You stop the methadone. And you continue to titrate the buprenorphine. We've done this for several patients. Everyone actually feels wonderful. In fact, it works so well that one of the patients in the residential program, after he was able to get on buprenorphine, signed out AMA. He said, I don't need you guys anymore. So he left. To go over briefly the opioid antagonist therapy, extended release of Vivitrol, extended release of naltrexone, long-acting injection formulation. I will say that the extended release of naltrexone is a wonderful, wonderful medication. A lot of patients benefit from being on Vivitrol. Actually, so there's a lot of still stigma of buprenorphine treatment among patients. They come in, and they're in full-blown withdrawal. And they're absolutely declining any opioid antagonist treatments. And I try to facilitate them to get the extended release naltrexone. With a caveat, so once they're on the extended release naltrexone, they have a comparable efficacy to people on opioid antagonist treatment, either on methadone maintenance or buprenorphine treatment. The studies have shown that you lose about a third of patients while waiting for the fentanyl washout period. Because otherwise, you put them at the risk for a prospective withdrawal. The study says about a third of patients. In my anecdotal experience, I lose about 90% of patients before they come back. They stop, and I give them, maximize them on the comfort medications. But if they're an outpatient, 90% of people do not come back to get the extended release naltrexone. So different initiation techniques to get them on extended release naltrexone. You either maybe use the buprenorphine taper. And buprenorphine taper will reset the clock of the last opioid use. And you wait for 7 to 10 days, and you get them on the naltrexone. Or you don't offer buprenorphine taper. Since the last day of opioid use, you load them up on the clonidine and supplemental benzos. And you get them on the naltrexone extended release by 7th to 10th day. There has been studies looking at the micro-dosing with the naltrexone. So getting them on 1 milligram of naltrexone, 3 milligrams of naltrexone, 5 milligrams of naltrexone, and they get them faster on the extended release naltrexone. First of all, the micro-dosing of the naltrexone is not available in the US. So you've got to use the compound pharmacy. And that's been actually a major problem, a logistic problem for a lot of providers and patients who are interested in this. Just wanted to cover that there's a new opioid reverse medication on the market, nalmethane. This is alternative to naloxone approved by the FDA in 2022. It has longer duration of action than naloxone. So we all know that one of the risks of fentanyl because traditional naloxone has a half-life of about 10 to 25 minutes. And they can actually, if people make a mistake of just giving them narkin, they revive them, they're good, and they left, they actually are at risk for overdosing after narkin wears off. And nalmethane can actually offer advantage in addition to that. It is not available intranasally. So just keep that in mind. And as part of a counseling of my patients, I always tell them, look, if you narkin someone, that's not an excuse not to call 911. Because of naloxone, it wears off fast. And because fentanyl has been very, very strong, if you narkin someone, you always, always call 911. I'm going to have Steve up. Yes, sir. I actually do not. I actually do not. I actually don't have any experience with the nalmethane. One, because it's not available intranasally. And who wants to give it IV or IM or sub-Q when you can just carry a naloxone? That's one reason. And the second reason is that, well, because we mentioned the manufacturers, for other extent, released buprenorphine, nalmethane is for no profit by manufacturer Purdue Pharma. So just wanted to put that out there. Any other comments or questions? Not that I know of. It doesn't really, I mean if they're in like agitation, if they're still like high on cocaine, then I'll be a little bit more judicious with the benzos and kind of make them more comfortable. But, you know, any... So when I say buprenorphine, I'm assuming that everyone's using buprenorphine-naloxone combination. Everything that when I said buprenorphine, it was buprenorphine-naloxone combination. The only group of people who are recommended to get the buprenorphine-only monoproduct is pregnant patients. But that trend has been also changing as well. We have not seen any teratogenicity or any decreased negative outcomes in the mothers or fetus using combined products. But we've observed that when using monoproducts of buprenorphine, the clinical efficacy seems to be a little bit lower. So even for pregnant patients, buprenorphine-naloxone has been the standard treatment. Yes, sir? What do you say to patients who come in and say that they are allergic? To the naloxone, yes. Yes. Yes. What's the remedy for that? So there's no remedy. So there are a couple of patients who are coming in asking for buprenorphine-only product. I imagine for one, because they have a genuine allergy to naloxone. I've seen a patient showing me hives when they take buprenorphine products. And if it's a combined product, then I give them buprenorphine-only. But one thing to keep in mind is that the buprenorphine-only products, it is more abusable, as we know. And because it's more abusable, it's more divertible. It has higher values on the streets. So you want to find a balance between, I should have a really divergent control plan, not at the cost of harming the patients or not at the cost of being a barrier to their products. But eventually, at the end of the day, if I make sure that they're taking their medications, their level of buprenorphine has been sufficient, there has not been any red flags in their recovery or clinic. And if they're saying that the buprenorphine-only product is integral to their recovery, I'll usually allow that. With some vetting processes. Just a follow-up to that. In the last one, in the combined product, there's no order by availability. Is that true? It is. It gets observed somewhat, sublingually. So when it gets, people say it's minimal. But when I look at the UN level of buprenorphine, no buprenorphine, and naloxone, depending on people's habit of taking the medication, how long they keep it on the tongue, or how much of them they swallow the medication, some people can have naloxone, in a sufficient naloxone level in their system. I provide documentation biology, sorry. I haven't seen the patient comes in and... I see, I see. I haven't seen the eyes or anything, so... You know, so I think it's... Is this a comment related to his question? Yes. Okay. So, one of the things that when people say they are allergic to it, I will often ask is what symptoms do you experience? And often it's, I get nauseated, I get a headache, I feel terrible. You know, well that's, as we know, that's not an allergy. I will say that there is evidence that if people swallow the sputum after allowing the medication to properly be absorbed, they have a higher incidence of nausea and vomiting because there is more uptake of the naloxone and it passes the blood-brain barrier more rapidly than the buprenorphine. And so people get that response, like a little bit of withdrawal almost, and that can make them sick. So to advise people that to spit it out, they often will not have those symptoms. So instead of swallowing it after it's completely dissolved, they spit it out. We can sometimes get rid of that entirely. And in terms of anyone that has opioids on board and they were to inject, so if they've been using regularly and they inject buprenorphine, whether it's got naloxone or not, are going to have withdrawal symptoms. But if they're, one of the things that many years ago when we first started this and actually in the 90s when we had monoproduct, people would inject it and if you inject the monoproduct, you get the drug like right now. You get buprenorphine and people get high. I mean, it's an opioid. But if naloxone's mixed with it and they inject, then there's a slow onset of the initiation of that buprenorphine. And people don't inject drug to get high an hour later. So that's the real deterrent for it being injected. It's not that they can't get any buprenorphine if they inject the combination product. If I'm hearing you correctly, for the public health perspective, it is more if they want to divert buprenorphine, right? If they want buprenorphine to people who are choosing to take buprenorphine instead of fentanyl, then that should be all the better, right? So we should actually encourage it. So I think you can make a lot of arguments on the harm reduction spectrum. I mean, I'm not exactly on the buprenorphine in the tap water camp yet, but we should make the buprenorphine very much accessible as much as possible, right? And we should lower the treatment barrier, huge support of like a methadone van and mobile methadone treatment available. And how do we balance the safety of the prescription? How do we balance the safety of the medication itself? And that's something that we are monitoring, and I don't have the right answer or correct answer for that. So there are people who are abusing buprenorphine. When I think about how this particular opioid epidemic started was because reckless prescription of opioids accessible everywhere, right? Opium has been powerful. We knew that for the last 200, 300 years, but what oxycodone and all the other heroin has been available for decades. So why was this most problematic? Because of the availability of high potent oxycontin and others, and family members and their grandmothers had the access to the opioids. So this is to keep that perspective in mind. So I have some obligation to keep the medications as safe. You spoke of prison system. So I think about this patient often. There was one patient that I actually refused to get him on buprenorphine maintenance treatment in my career. That was a correctional officer who got charged and was going through the trial because he got caught with bringing 100 Suboxone tablets into his work. They only allowed to bring in one day's worth of Suboxone for themselves, but he got caught with 100 tablets of Suboxone at work. He had been free of opioids, and buprenorphine, he's obviously going through the trial, and he came to me asking if I could get him back on Suboxone, buprenorphine. And I told him, I could get you on Vivitrol. You don't have to go through the washout period of withdrawal. You need recovery from opioids. I can offer you extent of release naltrexone, but especially when your trial is still ongoing. And considering the risk for population in the prison, I just couldn't justify it. So that's one story. You had a comment. So you staggered the different formulas. So, yeah, as people know, FDA approved, you know, maximum dose of buprenorphine naloxone is 24 to 6 milligrams a day. Now, we often go over the FDA dose, you know, with a lot of different medications. So you follow, this is the classic case where you follow the patient, you don't follow the numbers. However, insurance companies will follow the numbers and they'll deny their coverage of medications based on, you know, how much dose, how much, you know, this and that. But we need to get through the rest of the slides. Thank you for your comments. And I'm going to hand it off to Steve. All right. So I'm going to talk about the management of both acute and chronic pain when someone is actually on buprenorphine. So for acute pain, as we know, buprenorphine would block most other full agonists. But it does depend on the dose and also the affinity of whatever opioid that you're using. So when there is, it can be challenging to find an adequate dose of whatever alternative opioid that you're using. But there are ways in which we can do this effectively. And we used to always take people off buprenorphine for a period of time. Some of us that have been prescribing for many years, you take them off for three or four days prior to starting, you know, before going into like surgery or something where they need to, it needs to be taken care of. And in this case, when people, we've begun to recognize that we can override it pretty easily. So if someone comes into the emergency department and they've had an acute accident and they need, they have need for acute management of pain, we can either use fentanyl products, which can challenge it depending on the dose of the fentanyl that you're delivering. And then, of course, we can use non-steroidals. We can use all the non-opioid type medications that can be very helpful along with regional anesthetics and various ways to control pain outside of the use of an opioid. So there are ways that it can be done very effectively and it's been figured out and they're managing pain quite effectively of people, for people on buprenorphine in the emergency department. So again, there's been, there was for a long period of time, some real controversy as to how you would prepare someone for operative procedure. And typically, we are now recognizing that people can, apart from tapering them, we can actually treat people for their pain while they're on buprenorphine. And one of the ways in which this is, or reasons that this can be so effective is that by treating them for their pain on top of their buprenorphine, so having them at 8, 16 milligrams, you can then, once the pain has resolved, once things have stabilized, you can taper them off the full agonist. They're still on their buprenorphine and they can, you know, still be covered for their opioid use disorder. So there's, this has been done extensively many, many times, been written up a number of times and has shown to be actually very effective. And so again, there's all sorts of ways in which buprenorphine can be continued while people are being managed for pain. Now once again, if it is minor pain, we would not turn to an opioid, but if it's more dramatic, a worsening pain problem, they need acute surgical procedure, we can override the buprenorphine with higher concentrations. So it's in part concentration of a medication like fentanyl. Hydromorphone is another one that's used frequently. So, and speaking of hydromorphone, what we've found is that for chronic pain, again, buprenorphine can be used nicely. It needs to be used in a split dose. So instead of giving, you know, having people wake up in the morning and take their buprenorphine and be covered for the day in terms of reducing their cravings and not having withdrawal symptoms, which they can do nicely in a 24-hour period, the buprenorphine needs to be taken in a split dose. The analgesic properties of buprenorphine are shorter than that which we use to cover cravings or withdrawal. So again, if people will take actually their standard dose and just split it, like if they're taking 16 milligrams a day, they take 4, 4, 4, you know, 4, 4 milligram doses. Or if they have worse pain at night, they may take 4, 4 and 8 at bedtime. So it really depends on how the patient experiences their pain in terms of a chronic pain problem. I had, I'm from North Carolina, and while working in Charlotte, I took care of and worked very closely with a hematologist there that had, was a specialist in sickle cell disease. And we initially, I was referred a number of her patients that had alcohol and cocaine problems that she was worried about how they were using their opioids along with these other drugs. And it was very successful in moving them off Percocets or whatever they might be taking for their chronic pain to putting them on buprenorphine and very successful in managing their sort of daily pain. When they would go into crisis, they would sometimes just split the dose to more effectively treat their pain. And if they continue to have problems, they would go into the emergency department, they would often be rehydrated or there would be workup in terms of whatever acute problem they may be experiencing in terms of an infection or problem that had started the sickle cell crisis. And then sometimes given a dose of hydromorphone and sent home. And we were actually extremely successful in reducing the number of patients that were coming into the emergency department and those that would subsequently be admitted to the hospital. So buprenorphine can be a really nice medication to work with patients that have chronic pain. And again, it's very successful in maintaining their chronic discomfort. And when they have an exacerbation, they just split the dose and often do much better. So I wonder if others have had much experience in working with patients with pain and have something different than what I've described. Yeah. Okay. Yes. So, are you describing sort of inducing them off their full agonist onto buprenorphine? Yeah, quite honestly, I have been interested and have worked with geriatrics, pain management people. It can be, buprenorphine is really an excellent analgesic and is safer for many populations like the geriatric population and either using butrans patches or, and they're often, some of the people that I've been working with, they'll be transitioned to buprenorphine in the hospital and then maintained with a butrans patch, but very successful. So I wouldn't shy away from necessarily using buprenorphine as for pain management and particularly in our population with those that have an opioid use disorder. So I actually have a question for you. I thought IV buprenorphine was not available in the U.S. No. No, yeah. I don't think I've heard of anyone using ibuprofen in America until you. Great, so you're a pioneer. Yeah. Has anyone else used ibuprofen? They have it in the hospital. There's Buprenax. Yeah, okay. Yeah. Okay. Yeah. It's available. Yeah, just going back to inductions, I will most frequently or more frequently, when I do an induction and people are going to go home, I'll give them clonidine to use for a couple, three days prior to initiating buprenorphine at home. And the transition can be very nice. And people do that often with the microinduction or just to reduce the symptoms that they're experiencing. One of the things about fentanyl is that people often are using it five, six times a day, if not more, because they lose the subjective feeling of being high. And when they lose that, they start to get this experience that they're going into withdrawal. And I know Andrew Herring at the University of California in San Francisco, who was one of the first people to start macro dosing, the idea that you want them into a significant withdrawal before you give them eight or 16 milligrams. And that's what they were seeing in the emergency department, but he stressed, you need to see some objective signs. So I also will send people home with the cows just to look in the mirror, see if their pupils are dilated, start to really feel some significant withdrawal experiences without getting real sick, but just that they are really in withdrawal before they start their buprenorphine. And they can manage that with a little clonidine for a day or two. Thanks, Steve. This next section is really included more for non-psychiatrists, because I think most of you understand the importance of psychotherapy and supportive services beyond the medication. But I have some concern that there are some individuals, prescribers who are starting people on buprenorphine, begin them almost with one month's supply and then see them very rarely. And the data that I've seen suggests these patients don't stick around in treatment. And I think it's important to at least look at the value of the therapy in terms of keeping people in treatment and the importance of building the relationship with the patient. Now, standard recommendations based on work with methadone clinics have for a long time sort of stressed how important counseling was. The benefits have been very well documented for many, many years. But recently there have been four different trials of buprenorphine that were all well done, and they showed that very brief physician monitoring medication visits was equal to, if not more effective than more intensive drug counseling. But it appears to be this is true in a selected group of patients. And part of what I'm talking about here is both you need to see patients develop a relationship, provide counseling, but there's no real evidence requiring drug groups or that certain kinds of drug therapies absolutely have to be part of your clinical program. It may be necessary for some patients, but I've certainly seen patients in clinics who have been forced to go to groups that they found very unhelpful to them. And I just wanted to sort of go over some of this information so that you have some general idea what the data shows and what the research has been from this. First of all, the VA has codified a certain kind of medical management. And this actually, I think, describes most of what I do, and I suspect it's probably common for many of you. And that is that you see your patients once a month, sometimes for 20 minutes, sometimes for 30 minutes. You check how they're doing. You may encourage them to keep doing well. You may see whether or not they're attending meetings, how well they're invested in changing their lifestyle, if you will, and try to just support their commitment to recovery. And the VA has sort of quantified this as a particularly legitimate type of treatment. Now, what these studies showed is that this treatment, which in most of these cases was administered during NIDA-sponsored research trials, can be very effective for a few people other than forced attendance at groups. And these are just a list so that you can see that Dr. Filene, Dr. Weiss, Dr. Ling, these are all people who are highly respected in our field and are very skilled researchers. So these are well-done clinical trials by skilled, experienced people. Now, if you look at these four trials and ask yourself what was going on, who were the patients that were involved in these trials, you see one trial was conducted in a primary care clinic and another was a psychiatry clinic. One was in a research clinic and there was a second one that was in a primary care clinic. In general, they tended to favor patients who were using prescription drugs in some cases, some cases IV drugs, but not a large number of IV drug users. So in some cases they were excluding people who were addicted to other drugs. So there was nobody in these trials who just happened to be addicted to alcohol as well as opiates or happened to be using a lot of cocaine as well as opioids. And they generally didn't have problems with menzos. So from my point of view, to some degree they were cherry-picking people who were very good candidates for responses to treatment. They weren't the basket cases that we sometimes deal with. They were the patients who you sort of knew that they were going to do well because you just looked at what their history was. And they all responded well to this. And they couldn't see in some cases that forcing, when they looked at the research data, they couldn't see that in some cases people were required to go to these intensive groups every week and didn't seem to make any difference. They did well if they just got individual counseling. And I think that what this does, at least in my mind, is reinforce the value of your relationship with your patients. I've got lots of patients now that I've been seeing 10 or 15 years. They check in with me on a regular basis. I'm not doing intensive psychotherapy because they're doing pretty well. But I maintain that relationship. And if they go on a vacation, I may not see them for two months. But if they're in town, they come in for monthly visits. And that's the standard way that I try to run my practice and I try to maintain those relationships. So I think you need to understand that I think simply providing medication by a skilled therapist who cares about the patient, who sees the patient, who has a good relationship with them, is a really powerful intervention. And it isn't, you know, a primary care doc who has, you know, 30 patients to see in a day, sees them each for about 10 minutes maybe, and sees them, you know, once every two or three months maybe. I think this is people that you really have gotten to know and are well invested in their treatment but are stable. And I think if there are many of you in this crowd that I know, we've been doing this for a number of years. I think we've all got some very long-term patients who at this point are doing quite well. And I think they need to stay in some connection with us, but I don't think that they need the intensive level of care that they required in the beginning. But that being said, most of these patients don't have severe concurrent medical problems. They don't have severe concurrent psychiatric problems. They don't have addictions to multiple substances. So if you ruled out those problems, then I think you have patients who can do very well with simply seeing you and getting their medication. But if your patients aren't at that point yet, they may need a lot more than that. And for those patients, I really encourage intensive investment in AA or NA. They really need to get involved in lifestyle changes, and that's going to be very important if they're going to recover and do well. And just to throw this in here in terms of the value of contingency management, but you guys all know what that is and know how effective it is. And I think we probably should use more of it than we do, but it is another way to help patients in this treatment thing. And now I'll turn this over to Dwight. I know that we're right at time, but just to say a few words about xylosine. Again, I know John asked how many people are seeing xylosine, but I wondered about whether that's regional. So people on the West Coast, are there West Coast people here, and are you seeing xylosine there? Yes? No? You're not? Yeah. That's what I've heard, that there's not as much on the West Coast. We're seeing it in North Carolina, but I know that some people – is there anyone from Alabama or from further south? And are you seeing xylosine? Yeah. Okay. And it's certainly here in the Northeast, and there's been some really dramatic evidence of that, like in the Philadelphia area. So xylosine is an alpha-2 agonist, similar to clonidine. One thing that I actually fairly recently learned, it does have mild kappa agonist effects on the opioid receptor, and that is part of the reason that there can be some mild response from naloxone, but to keep in mind that the kappa receptor is not involved in the medullary respiratory center, so it's not actually going to – it doesn't promote breathing the way naloxone promotes breathing with knocking out or blocking the mu receptors. So that's just one aside. The other is when it first came into being, when we started first seeing xylosine, people were giving six, eight doses of naloxone trying to wake people up, and they weren't waking them up because the naloxone is not working on that sedating aspect of xylosine as a tranquilizer. And so it's been important, and I know the paramedics that I work with in the Asheville area, the mountain area of North Carolina, they've become very attuned to that and the importance of just seeing that people are breathing and then observing them for their breathing, not expecting them to wake up the way we used to see people abruptly wake up when you've taken their high away and woken them up with naloxone. So again, it is a matter of watching them and not necessarily just keep loading up more and more naloxone thinking that you're going to wake them up. One of the terrible, many terrible aspects of the introduction of xylosine, and before I say that, one of the things to keep in mind, xylosine was added to a degree to make it more powerful, to make it a more sedating sort of enjoyable experience that people had using fentanyl, and that idea that they had to use so frequently, as I said before, that they needed to take fentanyl regularly throughout the day to kind of maintain their high or to just feel okay, xylosine actually started to extend that out some so people have more of a tranquilized experience for a longer period of time, so there was some reduction in the number of doses that people were taking fentanyl. But the problem, one of the big problems that we've seen with fentanyl is that the idea of these skin lesions and these ulcerations that take place, and that's been difficult to fully understand for pathologists, for people, because it is an alpha-2 agonist, which is a basal dilator. It's something that would actually dilate the blood vessels. We use catapress for hypertension, and that's how it works, but distally and sort of one of the things that we also know is when you use something like clonidine for a period of time, not very long, for just even a few days, people can have a rebound hypertensive episode, and that's what appears to be happening when people have been using xylosine for a number of days. They have an extended period or some period of time where they haven't had drug, and then they get this distal, very profound period of vasoconstriction that causes these ulcerations. And then the real problem is that so frequently people are on the street or they're just not in a position to really take care of themselves, and the ulceration starts to expand and potentially get infected. So how many people actually have wound care programs in your cities? We've started one in Nashville. They actually, if they do take care of them, if they could, before they get infected, keeping the wound moist and covered and clean, they can heal up pretty nicely. But unfortunately, so frequently these folks are even on the street, and the care of the wound is so poor that they've gotten terrible infections, and there are some reports of amputations secondary to these wounds. So that's what I have to say. There's one of the terrible wounds. So any comments about xylosine, things that you're seeing, or questions? Yes? How are you seeing it in your supply? Beg your pardon? In most users, we've been seeing it in methamphetamine. You've been seeing xylosine? Yeah. Oh, my goodness. Yeah. Now that seems really contrary because, you know, because it's going to counteract the methamphetamine. I will say it is interesting that we're seeing so much more methamphetamine. I work at a homeless drop-in center doing psychiatric and substance use treatment, and the number of people that are using methamphetamine with regularity is really outpacing now the number of people I'm seeing using opioids. And it's becoming more and more of a problem, which is very interesting because we've seen that over the last century, that as opioids rise, right behind it is stimulants, and then opioids go down, stimulants are a problem, and then people get buzzed out on their stimulants and they want something to control their anxiety or their sleeplessness, and they start using opioids, and it just goes in these sine waves for what has happened for 100 years now. I agree with you, and it's something as I've moved into, I was involved in some buprenorphine studies back in the 90s, and nearing the tail end of my career, I've become much more interested in prevention, and really we have a bunch of school-based therapists at the clinic where I work, and we've been looking at different things that we could do to better prevent what's going on, and I think there have been some good talks here. I think some of the genetic studies that are going on to really trying to identify kids at risk, so it's not just their genetics, it's obviously their environment also, but they're tied together, and what's happening at the home, what parents understand about watching their kids, and helping those kids that are at greatest risk, and those sorts of things. I think there's a lot of interesting things that are happening around prevention, and I actually think it's the only way out of this. I just want to add, yes, I agree with you that this primary intervention, prevention is very, very important, and part of the effort to cut down on the opiate prescriptions, making it mandatory to check the state PDMP, I think has overall, and it's constant, and Nosham talking about the opioid epidemic has, at least I think it comes, there's definitely a lot of effort. We've seen that in the Monitoring Future study, the perception of opioid risk has gone up among the teenagers, and even, so I just heard from my 17-year-old patient that it's not cool to bring pills to parties anymore. Obviously, you cannot generalize to the entire future generation. He's obviously in school, he's still in school, and he goes to a school party, but if someone brought pills to parties, they're like, oh, no, no, we don't do that, and I didn't hear that 10 years ago. We heard about the pill parties where teenagers brought whatever pills they could grab from home. Apparently, that's not cool, so, yeah, yeah. Something's working. We do have to go on. We're over our time right now. No, we actually go on to 5.15. Oh, okay, well, we do? Yeah. We start at 3.45. We have five more minutes. Five more minutes. Any more questions that anyone has? Yes, sir. I have not seen it, but that makes sense, because one of the things we go over clonidine's side effects is rebound hypertension. If you're using the clonidine as an antihypertensive medication, you know, three times a day, you don't want to, you know, just abruptly stop it. And I just imagine that the xylosine, you know, is times 100 for the rebound hypertension that's coming from clonidine. One of the other interesting things about xylosine is how many people have heard of wooden chest syndrome? Do you know that? Okay, so wooden chest syndrome is when people overdose and they have this acute response of a release of norepinephrine, and it results in just a tightening down of the chest so that you can't do CPR on them. They just stop breathing and their body is just tightened up entirely from the release of norepinephrine, this shock that the body is experiencing of an overdose. And xylosine is actually covering them to a degree because it reduces that norepinephrine response. So there's been, I had a discussion with a fellow from the CDC about, you know, this is something that they, we just don't know why xylosine was, you know, brought into the drug supply. But it does appear that, and paramedics that I talked to, they recognize it. They're not seeing that response as frequently as they once had. So it's not, I'm not saying that this is a pharmacologic choice and they're, you know, they had this all figured out, but it is one of the potential positives of having it be an alpha-2 agonist. So, interesting. Yes? So, like I said, I declined one patient who was going through a trial of, you know, being a correctional officer and got COVID, yeah. So, you know, it's the fentanyl and the COVID pandemic, I think, changed a lot, you know, right? I think I've, since that patient, I've not declined anyone on buprenorphine treatment. What I'll do is, if there was one patient who was a young female patient who only had a three-month history of opioid use disorder, and I recommended her to, you know, consider opioid antagonist treatment first. She tried that for two, three months, she relapsed, and I got her on Suboxone right then and there. The only thing, I would be concerned about concomitant prescription or concomitant addiction to benzos, alcohol, cocaine, you know, I mean, it's really complicated, they need to be in the hospital. And I think if someone's actively suicidal, they need to be in the hospital. But other than that, I think they need to be on buprenorphine as fast as possible, or on naltrexone. I don't think that we need to treat them. Do you mean in the hospital to initiate buprenorphine, or? Well, they need acute hospital care, and, you know, that's what I think. You know, I think that rather than you attempting to treat them outpatient, I think they need to be in a hospital. Right, when those disorders are active, and they come out of the hospital, would you consider buprenorphine? Oh, yeah, yeah. But I think if they're active, they certainly need the hospital care. We have time for one more comment. Last question. So I would say, actually, you probably need to wait longer if they've been on suboxone maintenance, buprenorphine maintenance, for longer, like more than six months. And so the current practice that I do is actually, I think a lot of you actually can share this. A lot of patients who've been on chronic buprenorphine maintenance, they have trouble tapering down the dose in a stabilized fashion, especially if they get down to four milligrams a day, two milligrams a day. What we've done is actually to give them, maybe one to three doses of buprenorphine extended release, subcutaneous. I don't have this experience with brixotic. I've had this experience with a sub-blockade. And patients have, especially if their goal is to be off of buprenorphine maintenance or to eventually transition to extended release naltrexone, by utilizing the extended release subcutaneous buprenorphine for one to three doses, they can just get off of them. Their urine still may be positive for buprenorphine for up to six months, seven months, or even up to 10 months, depending on how much buprenorphine maintenance has they been getting. But you can utilize that. But you definitely have to wait for longer than 10 days since their last injection of sub-blockade. I would think it's just very important also to keep in touch with the patient. If they're suddenly getting cravings back again or suddenly getting problems, then I think you need to act. But it certainly looks like there may be some people who can just gradually taper off and do fine. But there is very, very, very little research. Right. We're just telling you anecdotal stories at this point. And we don't have really solid research to back it up. Well, I think we will have to wrap things up. I want to thank you very much. You've been a terrific audience. We've learned a lot. It's been enjoyable having you here. And I hope you have a nice day. Thank you.

buprenorphine

opioid crisis

fentanyl

xylosine

overdose trends

induction methods

high-dose micro-dosing

precipitated withdrawal

opioid use disorder

medication adherence

naloxone inadequacy

psychotherapy

opioid addiction treatment