Lewis Nelson: The Art and Science of Buprenorphine MAT Induction

Dr. Mark Leeds [00:03] Dr. Lewis Nelson, welcome back to the podcast. How are you today?

Lewis Nelson, MD [00:07] I’m good, thanks, and thanks for having me back.

Dr. Mark Leeds [00:09] Thank you. And I just want to introduce you. You are the chair of emergency medicine at Rutgers New Jersey Medical School and board certified in emergency medicine, toxicology, and addiction medicine. Is that correct?

Lewis Nelson, MD [00:30] That’s right that is right yeah

Dr. Mark Leeds [00:31] And I just wanted to say that I previously had oh what’s Dr. Lloyd Sederer Dr. Lloyd Sederer had been on the podcast a while back and I told him that we had done an interview and that we’re going to talk again and he was really impressed he’s like how do you even get dr nelson on the podcast wow you have to ask yeah yeah so And yeah, so you are clearly a recognized expert in the field of emergency medicine and addiction medicine. And it’s really a pleasure to be able to speak to you and share this with people.

Lewis Nelson, MD [01:07] Well, thanks for that. And it’s my pleasure. I really do enjoy talking with you about this stuff.

Dr. Mark Leeds [01:12] Thank you. Thank you. So, yeah, we were just before turning on the recording, we were talking and I wanted to discuss today the induction with buprenorphine. Induction meaning like when you start taking buprenorphine, like a person who’s been taking opioids like fentanyl, heroin, oxycodone, or one of many different opioids that can be misused, or even if they’re not being misused, for whatever reason, a person wants to or needs to get off of an opioid. And a good solution is buprenorphine, which a lot of people know as suboxone. That’s kind of like the Kleenex a genericized word for buprenorphine. But yeah, there’s a difficult transition for some people going from the opioid to the buprenorphine, and they call that induction. And to me, I have kind of a model in my head of how that works. But when I start explaining it to people, it always comes out sounding more complicated than it should. How would you describe the induction process?

Lewis Nelson, MD [02:11] Well, I think what we’re really doing is we’re transitioning somebody, whether it’s methadone or buprenorphine for that matter, from a low quality street bought opioid to something that’s pharmaceutical in nature and very predictable in quality. What we’re we are in a way replacing one opioid one dependence for another we know that I mean I think people sometimes frame this as one addiction for another which is a mischaracterization but we are really replacing an opioid that you buy on the street or you know from some place that’s not a pharmacy with something of high quality and very predictable content The advantage of these two medications in particular is that they’re able to do what opioids do to you to prevent you from withdrawing. And they’re not particularly psychoactive. So you don’t, at least with buprenorphine for sure, you don’t really get high. So the push to continue to use it, chasing the elusive high, goes away. Now, methadone is a little bit more psychoactive than buprenorphine, but not necessarily in the same way that heroin or fentanyl are. And that has to do with the pharmacology of the drug. But I think really that’s what we’re doing is we’re giving people an alternative to continuing to use street bought drugs in order to prevent themselves from withdrawing. Remember, as you know, many of these people stop getting high the same way they used to when they first started using heroin or fentanyl. And now their entire reason to continue to use opioids is to prevent themselves from withdrawing.

Dr. Mark Leeds [03:57] Yeah, that’s a big part of it, that terror of fear of withdrawal. And I’ve personally never been through it. And from hearing it described by people, I think it’s something that we have to take seriously. That, you know, I don’t think, you know, you know, someone said, you know, if someone says to a person who’s addicted, you know, you deserve this, you just have to go through it, suffer through it, or rehab programs that make them go through a really uncomfortable withdrawal period. I don’t think we can really imagine like how bad that is without having gone through it. And it sounds really terrible. I mean, and there’s a lot of different symptoms, you know, there’s chills, there’s depression anxiety and muscle aches and you know I’ve heard it described in fact rush limbaugh had described it on a talk show he said it’s like the flu times a thousand or something like that and it’s but I think it’s probably even worse than that I mean the way you know the one that the one symptom that really scared me thinking about it was muscle cramps like leg cramps you know because I hate those and just the idea of like having like severe, you know, and then a lot of people don’t like the restless leg, their legs kicking around uncontrollably. So yeah, it’s a really uncomfortable, horrible thing for a person to go through. And people, that’s a big part of it. So people just don’t want to suffer and feel that.

Lewis Nelson, MD [05:18] I would agree totally. And I think that what you’ve just described nicely is physiological dependence, which are the physical manifestation withdrawal. There is that whole component of psychological dependence and withdrawal, which is also quite terrifying of the craving and anxiety and compulsive need to go and procure more drug in order to prevent the withdrawal. So those two combined are quite daunting. And when you speak to people, this whole idea of avoiding being quote unquote dope sick is what drives them to continue use drugs in many cases.

Dr. Mark Leeds [05:54] Yeah. Yeah. And that’s one of the difficult things. We have the three drugs that we can use for treating opioid dependence, the naltrexone, buprenorphine, and methadone. And the way it seems to work, you have the methadone is the easy one. And let me know if you have to take a break for a second. So yeah, methadone is the one relatively easy to start that a person can start that the same day. You can take fentanyl on a morning, then go into the methadone clinic and take methadone that same day. And the transition is fairly quick, but then the downside is now you’re stuck going to a methadone clinic every morning indefinitely. And then you have the next one, buprenorphine, where you have a relatively short transition, but not dangerous, but uncomfortable. The person has to go and withdraw for usually 18 to 24 hours. With fentanyl, it can be longer. So there’s a more difficult transition than methadone, but the benefit is now you can long-term see a doctor monthly and much easier. You can go on vacations and have a lot more freedom. And I think it’s a better experience. Like you were saying, that methadone is more psychoactive. And most of my patients describe buprenorphine as they feel as if they were never addicted. They don’t feel sedated. They don’t feel like it affects them mentally. They are able to function and do their jobs and take care of their families. And it’s as if they were never even on a drug to begin with when they’re taking it. And then you have naltrexone, which I haven’t had a lot of success with that with opioid addiction. The transition is more difficult. They have to be like a week or two or something like that free from opioids to be able to start naltrexone. And I know Vivitrol was promoted a lot, and maybe it still is being promoted as being a great treatment, but I haven’t personally seen a lot of success with that. Although I think there’s some new implants that might work really well. I’m not sure about that.

Lewis Nelson, MD [07:57] Well, I would agree. I think that naltrexone has a bit of a niche following. You need to really want to not be using opioids at all. I mean, there’s the transition period, as you’ve said, is quite difficult. You have to truly be off opioids, both sort of, so to speak, detoxified from them, and then maintain a period of that 10 days or so where you can’t use, despite all the cravings, any opioid. What then, of course, occurs is you get the naltrexone injection, infection which will prevent any of the opioids you use from causing any psychological effect. The craving may still be present and you have to be really willing to not use any opioids ever, at least in the 30 days of that drug that you’ve just got injected into you as psychoactive. I mean, the daily use of oral naltrexone is probably not going to be very effective for that reason. Most people are not going to be able to not use opioids and follow their cravings. It’s just that they’re that intense. So people who have a good, for example, if you’re threatened to lose your job, if you use opioids, you might be willing to take naltrexone or get divorced or have some other major life impact if you continue to use opioids. Many people might agree to do that the problem too with naltrexone is it’s said to take away some of the other pleasurable aspects of life because some of the things we normally gain pleasure from are some of those effects are mediated through endogenous opioid release as well as dopamine and other things so there does tend to be a little bit of a blunting of some of the pleasurable parts of life now again many people are willing to do that and it’s a very effective drug if you’re able to take it But you’re right. The other two are much more user friendly. They do tend to have different patient populations in whom they’re successful. The commitment to go to an outpatient treatment program for methadone is real. But many people like that medication because it is the easiest to transition to because you can start it exactly as you said, the day you decide you want to stop using street bought drugs, whether it’s heroin or fentanyl or oxy or anything else. Now, to talk about buprenorphine, because I think it’s probably, it’s my go-to opioid treatment drug, or my go-to MOUD, right, medication for opioid use disorder, because it really is the easiest from a user-friendliness perspective, because you can get it by prescription anywhere, I mean, from any physician or prescriber, and you can get it filled at a pharmacy. And while not all pharmacies carry it for political and other reasons, it’s generally pretty acceptable. Methadone, of course, requires you to go to an OTP, which are limited in number and not always available depending on where you live. Some people have to drive many, many miles to get to one and have to go on long waiting lists in order to get into one of those clinics. We spend a lot of time, and as you know, I work in an emergency department, but I also work in an outpatient setting. In an inpatient setting, we spend a lot of time trying to get people induced or initiated on buprenorphine without having to go through that initial withdrawal process that you talked about. There are multiple different ways that we approach that. I mean, the classic way is you wait till your withdrawal score on the COWS scale is 8 or 13 or something elevated. And then you give them buprenorphine and it blunts the withdrawal. And in a model, that works very well. In practice, for the reasons you’ve already made so clear, nobody really wants to withdraw. They want to transition like you do on methadone from one substance right on to methadone. Now, with buprenorphine, it’s harder to do that. But there are two models that we use to get that done, right? We call them, I like to call them microdosing and macrodosing. The one thing I would say, and we could talk about that if you’d like, but the one thing I would say is that the conventional model of using a two milligram or four milligram dose off the bat is probably the worst model to use during the current climate of fentanyl use. When they were studied back around 2000, 2002, when buprenorphine was first approved in the United States, there was essentially no such thing as fentanyl. We didn’t really start seeing that in earnest until around 2013. So back then, everybody was using opioids, using oxy or hydrocodone, oxycodone, hydrocodone or heroin. And pharmacologically, those drugs are very different, even though they’re opioids, than fentanyl. And the transition from those opioids, heroin, oxy, hydro, and drugs like that to fentanyl has really required us to change the way we use buprenorphine and maybe even the way we use methadone to some extent. It might also have changed the way we use naltrexone, although we use it so infrequently. But the washout period, so to speak, for fentanyl is longer than it is for oxy and heroin. So it does change it. But for the other two in particular, I’m sorry, for buprenorphine in particular, the mechanism by which we start so many buprenorphine had to change. The old model, the classical model that was FDA approved does not work.

Dr. Mark Leeds [13:39] Yeah, and that’s a really important point to make. And you had explained to me before, I had thought that this issue with fentanyl was something unique to fentanyl analogs that were not regular fentanyl. You know, fentanyl from China is, I think, a little bit different molecularly, or it may be. But you had explained to me that this is actually a property of fentanyl in general. Like if I went and took a vial of fentanyl from the operating room and used it every single day, I’d have the same problem. It gets sequestered in fat cells. It gets stored in the body where other opioids don’t get stored in the body. And then when you try to quit and you’re waiting for that ideal time of like 18 to 24 hours or whatever it is to start your buprenorphine, that time really drags out to like maybe 48 hours, 72, maybe even longer with fentanyl.

Lewis Nelson, MD [14:31] That is definitely part of the issue. And all of the fentanyls, whether it’s fentanyl or any of the analogs, carfentanil or phenylfentanil or fluorofentanil, all of them are lipophilic, which means they like the fat and they sit in your fat, even if you’re thin, you still have fat, and they leach out over time, causing your blood levels of fentanyl to be maintained even when you’re not using. With heroin, it doesn’t do that, right? The heroin is metabolized to morphine. Morphine doesn’t store in your fat. If you continue to use it, you go up and down your blood level, up and down with each use. But when you’re not using, your blood level is pretty low. It can approach zero. Whereas with fentanyl, even when you’re not using, assuming it’s not a single dose that you’ve used, but you’ve used it over a period of time, so you’ve built up fat stores. When you’re not using, you’re still maintaining an elevated blood level of fentanyl. And what that means to your brain is that it’s continually, the receptors, the opioid receptors are continually bathed in opioid. So they develop deep, deep dependence. They change, they adapt to the continued presence of the opioid so that when you take more drug, you’re more resistant to it, more tolerant to it. And when you stop taking drug, you have a lot more withdrawal associated with that discontinuation. So it simply stated the withdrawal syndrome and the difficulty in starting on buprenorphine in particular, or analogously, the withdrawal that’s initiated by naloxone when people get it is worse with fentanyl and the fentanyl analogs than it was and still is with heroin or the prescription opioids like oxycodone. So really, fentanyl and its analogs have been a game changer. And there’s a new class of drugs out there, the nitazenes, which are fentanyl-like and increasing in prevalence. You know, if you look, each state does their own analysis. And within states, there’s different regions, of course. But I can tell you in my state in New Jersey, the latest data I saw was that of the fentanyls that we see, 75% of them are plain old fentanyl. And the analogs are only 25%. They are changing all the time, right? And you never know what you’re going to get and you never know the concentration of any of them in the product you’re going to get. But the amount of drugs that we see that contain only heroin and no fentanyl or analogs is below 3%. So everything has fentanyl in it and some have only fentanyl in them.

Dr. Mark Leeds [17:20] Yeah. Yeah. And it makes sense that they’re doing that. I mean, it’s I’m sure that fentanyl is cheaper and easier to get than than heroin.

Lewis Nelson, MD [17:31] Exactly it’s from a marketing perspective it’s a windfall profit right it’s much less to manufacture and purchase import and things like that and then there’s a markup on the street because it’s so potent you need such tiny little amounts in the sample that you’re selling somebody that there’s a big there’s a big profit margin there

Dr. Mark Leeds [17:51] Yeah so yeah I wanted I wanted to talk about the microdose and macrodose induction. I thought the idea of the macrodose induction, like where a person, you know, they, and it sounds like it’s great for the emergency department, especially if someone comes to the hospital and they’re, they were taking fentanyl and maybe they’re withdrawing a little bit and you want to start them and you can’t keep them there for one, two, three, four, five days. You know, you need to do something with them probably in the next 24 hours or so or less. And so instead of saying, we’re going to start you with 0.5 milligrams or two milligrams or whatever, you say like, well, let’s start you with 24 milligrams or 16, 24, maybe even 32 and completely block all of your opioid receptors. And I actually have a friend who has been doing really well on buprenorphine for years. And we talked about this and I told him that we were going to be having this conversation. And he said, oh, I can tell what happens I’ve tried that he said I took 24 milligrams once in the early days when he’s trying to get clean or get opioid free and he took I think he said it was 24 milligrams and he said it was torture for 12 hours he said it was the worst withdrawal for 12 hours he wished he hadn’t done it but then there’s nothing he could do because his receptors were all blocked and he said about 12 hours later he felt fine the buprenorphine took over and everything was fine after that. I don’t know if that’s a typical experience.

Lewis Nelson, MD [19:20] Yeah, you know, I do see that. I think there’s a little, when you speak to people that do this a lot, there’s some variable experience, which may be regional. And whether it’s regional because of the drug supply or because of the expectations of the patients, you know, in some places, buprenorphine, you know, buprenorphine precipitate withdrawal is a known entity, and people are very fearful of it. And I do think there’s a big psychological component to how that happens. And in some areas, people don’t really know much about it. It’s not something they think about. So where I am, I don’t really see a lot of precipitated withdrawal, even though we have a high fentanyl burden here in my region. But yeah, 80 miles down the road in Philadelphia, it’s a completely different world. And there just seems to be either two populations of drugs that people are using or two different mindsets of the population. So I would say that about 80% of the people who I use macrodosing for do not develop any signs of precipitated withdrawal. And these are people, and I usually start with 16, but I quickly give either eight or 16 more and I get up to 32 pretty quickly. I would say that most of them transition pretty easily. I either do it before they withdraw, particularly if it’s heroin or methadone that they’re trying to transition off of. Those transition off fairly well, or oxycodone, some of the non-fentanyls. Now, again, we don’t see a lot of those people anymore because the street drug supply is almost completely containing fentanyl. But when we did see those drugs much more prevalently, the macrodosing model works really well. And we would have almost no precipitate withdrawal. Now, I’d say I see probably about 20% of my patients who we use macrodosing, on developer precipitate withdrawal syndrome. And you’re right, those that do develop it 12 hours later are chilled and they feel fine. But it is a daunting period of time to go through. The ability to predict who’s going to develop precipitate withdrawal is essentially non-existent. It is, I can’t tell you based on your age or your race or even the amount of drug you tell me you use or the type of drug, short of if you really didn’t use any fentanyl, we really can’t tell who’s going to develop it. And we can’t develop how severe it’s going to be. But the paradoxical treatment for precipitate withdrawal from buprenorphine is more buprenorphine. And we’ve gone up to 64 milligrams. And even then, sometimes we have people that don’t get better. But as you’ve already said so nicely, they do go through a pretty terrible 12 hours, but then they calm down and everything becomes peaceful again. But I would agree that if I knew who those 20% of people were, I’d be able to avoid them. In the emergency department, it’s probably the most practical way to do things on the inpatient side or in a population in the ED who has a support system, who are able to be compliant with a little bit more of a complicated regimen that here’s a big dose of buprenorphine taken now. I do like, I think I prefer the macrodosing model because it’s almost assured not to cause precipitated withdrawal. And in that model, we start with very small doses, depending on what exactly we’re using to begin. We start with somewhere in the range of a half a milligram. If you have the strips, the films, it’s easy to cut them. If you don’t, some people take a two milligram buprenorphine tablet and just swallow it, right? Because we know the bioavailability of buprenorphine, the amount that actually gets into your body after swallowing it is pretty limited, about 10 or 15 or 20%. So we know that two milligram dose is going to only provide you with less than half a milligram systemically. Some people like to use transdermal or transmucosal patches to do this, right? I don’t usually do that in my practice, but some do. But the small dose, and then you repeat that in a few hours and a few hours more, so at the end of the day, you’ve given them about two milligrams. And then the next day you start at one or two milligrams and you build up a little bit more that day. So you maybe get to either two or four milligrams at the end of that day, or you can even give two milligrams that whole day. And then the next day, depending on how rapidly you want to do this, you increase it a little more. Or what we’ll usually do now is a three-day titration upwards. So it’ll be half a milligram approximately the first day, two the second, and eight or 16 the third. And we’ve had pretty good results. There are other models which are five or seven-day papers. They’re really escalations or titrations. And they all have, I think, pretty good results. As an emergency physician in the population I deal with where two impatient do a seven-day taper. I think writing it out on a piece of paper and trying to explain it to most people is difficult. Whereas the three-day, I say taper, I should keep saying titration or escalation. The three-day works pretty well. And the risk of precipitation is exceedingly lower than it is with macrodosing. But I like macrodosing because it’s so quick. And if you’re willing to take the risk, and I tell people that there’s a risk, But it’s very different than it being unculturated in the group psychology of buprenorphine. Me just telling somebody this is a risk. It doesn’t usually happen. 80% chance it’s not going to happen. It’s very different than, oh, my God, everybody gets it. So it works where I am, and I have pretty good results. And the data out there, depending on what you read, supports exactly what I’m saying. Either nobody gets it or everybody gets it, and it’s everything in between.

Dr. Mark Leeds [25:22] Well, you know, what you said about swallowing the two milligram tablet, that’s really intriguing. I had never even thought about that. You know, we always tell people, well, don’t swallow it won’t work at all. But the idea that you could take a two milligram and just swallow it like a regular pill and you might get half a milligram out of that. And maybe you could do a very gradual titration or we could even call it a reverse taper or something like that. That might even make it really easy. Tell someone, swallow on the first day, swallow two the next day, spread out, or maybe three the next day or something. And then at some point you say, now you’re going to take that same tablet and keep it under your tongue and do it differently. But yeah, that’s really intriguing. And then I think that I’ve read, there’s a name for that, the microdosing. But in some places, I guess they do it as a, I don’t know if you’d call it harm reduction, but like while the person is still using their drug, that you kind of use it to kind of sneak up on the receptors, you know, that you gradually increase the buprenorphine while the person might still be using fentanyl on the streets. And at some point when they get up to like a, you know, 12 to 16 milligrams or something like that, then they can just stop their fentanyl because the receptors are blocked enough.

Lewis Nelson, MD [26:38] That is the way it’s usually done, certainly with the compliant patient population or as an inpatient. And it’s usually called a cross taper, although it’s not technically a cross taper because you’re not tapering both drugs. You’re increasing the buprenorphine dose while maintaining the full agonist opioid dose. And if it’s street use, you can tell the person to keep using. And when you get up to eight milligrams of buprenorphine, just stop using the street drug. When it’s done as an inpatient, it’s a little bit more controlled because doctors and nurses managed to do the titration schedule. But that is certainly a model that people use. Either of those, whether it’s the true cross taper, whether one’s going up and one’s coming down. So you’re lowering the dose of the full agonist opioid while you’re raising the dose of buprenorphine. Or the other kind of cross taper, which isn’t really a dual taper, where you’re increasing the buprenorphine dose, maintaining the full agonist opioid. And then on day three, five, seven, depending on the method of titration you’re using, you just stop the full agonist. And I think more people do the latter, where you maintain the full agonist opioid while you’re up tapering, up titrating the buprenorphine. I think it’s a little bit simpler, particularly if not in a hospital setting.

Dr. Mark Leeds [28:00] Okay. Yeah, that makes sense. I mean, and yeah, and for those patients that are, they just can’t, can’t stop, or they’re afraid to stop, or they can’t, you know, it makes sense, you know, here’s something you can do and to get started, you know, even if you can’t stop having the fentanyl dealer show up your door every day, at least you can take, you know, and that just, again, it sounds like such a great idea. Just swallow this two milligram tablet. It’s not barely going to do anything. It’s not going to hurt you and do whatever you’re still doing, or hopefully you’re not taking any more fentanyl either way. And we just go from there. It does sound like a great idea.

Lewis Nelson, MD [28:37] That’s right. I mean, remember, a lot of these are not strictly evidence-based. There’s not randomized controlled trials, looking at these, comparing them. Many of these just personal practices that people have developed and we’ve all shared and tried. There’s probably as many different mechanisms of doing this as there are people that do it. Honestly, one day we need a trial of 25 different models that we’ve all implemented and seeing which one does best. But these are really hard to do. I mean, part of the problem is you don’t know what people are using. We’re comparing to some extent apples and oranges, perhaps. In areas of the country that don’t have a lot of fentanyl, they’re not seeing it. In some areas, it’s all fentanyl. Some people are using milligram doses of fentanyl daily, many milligram doses. And some people are using smaller, much smaller doses. They haven’t gotten quite up to the levels of tolerance that you need to have to use milligram dose of fentanyl. So we are going to have a hard time really getting to the root and really understanding what the best practice is. But I think the best practice is the one that you’re comfortable with, seems to work for your patients, understanding that if it’s not working, you have to have an escape route. If you cause precipitated withdrawal, what do you do? And even that, I’ll tell you, even that there’s a lot of practices on how to manage it. I told you, my practice for managing precipitated withdrawal is to get more buprenorphine. There are places where when you have precipitated withdrawal, they just give you a lot of comfort meds, right? They’ll give you ondansetron, they’ll give you a clonidine, they’ll give you some diazepam, and other places will give you fairly large doses of full agonist opioids. There are people I’ve spoken to, they’ll give people two or three milligrams, two or 3,000 micrograms of IV fentanyl to try to overcome some of the precipitate withdrawal induced by buprenorphine. So there are a lot of models, even for managing that. That latter one scares me. It makes some conceptual sense. But even as somebody who practices in acute care setting, I don’t love the idea of giving people 10 or 20 times a therapeutic dose of fentanyl, even on a monitor. I just can only see bad things happening, but they do it. And they seem to have what they claim. And we all claim. I mean, I don’t mean to say that in a negative way, but they claim that they have very good results with it.

Dr. Mark Leeds [30:49] Yeah. Yeah, that is scary. I didn’t think that. I thought there was like that the law was strict about that we can only use naltrexone, buprenorphine, methadone. And once you know a person’s addicted, you know, if there’s a psychological dependence or addiction or opioid use disorder issue that we’re not supposed to use any other opioid other than buprenorphine or methadone for treatment.

Lewis Nelson, MD [31:12] Well, it depends what you’re treating. And you’re right. I mean, I think there are laws specifically about and that, you know, these were the methadone maintenance treatment laws in the 70s. And you know you know goes all the way back to the harrison narcotic act in the 1914 or 17 whenever whenever that was but certainly you’re not supposed to do that being said there’s a difference between treat you know maintaining somebody on long-term opioid use medications moud and treating withdrawal and there’s also a difference between doing something in a hospital and doing something as an outpatient and there’s also this whole relief valve of doing something to keep somebody in the hospital for other reasons right so you for a lot there’s a lot of wiggle room around that those those those laws and I think in the current climate where we’re addressing as a nation, a discourage of the opioid crisis. I don’t see people coming after anybody very readily for doing something that makes medical sense. I mean, I’m much more concerned about the people that are prescribing 2000 oxycodone tablets for somebody who has knee pain or something. That’s the problem. The problem is not a bunch of earnest doctors in emergency departments and hospitals who are trying to overcome withdrawal. I just don’t see those as equivalent.

Dr. Mark Leeds [32:43] Yeah, that makes a lot of sense. I think I had sent you a thing. There was a forum that I was involved in that was another interesting way of approaching it, that this one doctor said she had found the Goldilocks range of treatment where she would give, I think, 0.5 milligrams of buprenorphine and then do the macrodose the second day. So I guess that’s like another one of many variations of doing it. And when you said macrodose, I think you had said that if you do macrodosing, you don’t at one time give the big dose all at once, like 24, 32 milligrams. You start with eight and see how they react and then give another dose after that.

Lewis Nelson, MD [33:26] I personally start with 16. Yeah. Based on. That’s what I do. Yeah. You know, I think eight’s a little low. So if you think about it from a pharmacological perspective, right, what we’re doing is we’re replacing on the opioid receptor, a full agonist opioid that’s either still present and the person’s not in withdrawal or slowly moving off and opening up additional opioid receptors. As the drug is metabolized. So now they have low or moderate cow scores. So we’re trying to put back on in a fairly large quantity, a partial agonist opioid. We know it’s going to have less agonist effect on the receptor than the full agonist does. But we also know that if you give more partial agonists, you can gain a small amount of additional agonism. In no way will a partial agonist ever become a full agonist. But you can maximize partial agonist effects. Because remember, what any drug does when it’s on a receptor is it’s on and off and on and off quickly. And when we talk about receptor affinity, what we’re talking about is how much of a given time frame, say a second, is the drug attached to the receptor versus off the receptor. So we know that drugs that have high affinity, like buprenorphine, are on the receptor more in a given time period than a drug with low affinity, say heroin or fentanyl. Heroin is not a good example. Morphine or oxycodone. And so what we’re doing is we’re knocking off a low affinity opioid with a high affinity opioid, but then we’re going to give more of that high affinity opioid to maximize the time that it’s sitting on the receptor. Thereby giving us relatively more agonist effect so it’s not just I’ve given 16 or I’ve given eight and I filled up all the opioid receptors I’m now overdosing the opioid receptors with buprenorphine so they maximizing that partial agonist effect that’s why I think you have to probably start at 16 as a minimum yeah

Lewis Nelson, MD [35:54] 24 is fine and I’m not sure there’s anything wrong with that some people might even start at 32. I don’t think there’s a problem with that. I just have done 16. I’ve had pretty good results with it. As we see people coming in with higher dependence and higher tolerance to fentanyl, we might need to raise that dose. I know that there is a big discussion that’s ongoing. And I don’t use a lot of methadone in my population. But the standard dose of methadone historically to stave off withdrawal in the ED was 10 milligrams or 20 milligrams maybe. And now people are raising that to 30 or 40 milligrams just to kind of control the craving and the physiological withdrawal that people are experiencing. So that may be due to the increased tolerance and dependence associated with fentanyl. And that might be a real deal. There was even discussion about looking beyond the standard up titration of methadone. You know, you start with your 30 or 40, and then you go up every three or four days by 10. People are now going up every day or going up by larger doses every day because the dependence that people have due to these multi milligram doses of fentanyl is so deep that standard amounts of methadone just don’t cut it anymore. And they’re trying to do the same thing that I’m discussing or I’m describing. We’re trying to maximize the agonist effect on the opioid receptor by by bathing them. So as soon as one molecule leaves, instead of waiting for that molecule to reattach to the receptor, another molecule is there to take over. And that’s a nice pharmacological construct to think through how these drugs work. And it is governed by affinity. This is not potency. This is all and it’s not about about activity at the receptor it’s about affinity how quote unquote tightly does that opioid bind remember tight doesn’t mean it’s stuck on there right all of these drugs are on and off all the time

Dr. Mark Leeds [37:49] Yeah oh okay yeah because I and I think I mentioned that to you before I was under the impression at one point based on a lecture I went to that buprenorphine latches on the receptor never lets go and it you know the receptors have like I guess a three-day turnover and I so my the way I had imagined it was that one molecule is sitting on the same receptor until the receptor goes away but that’s not exactly how it works

Lewis Nelson, MD [38:12] That is definitely not how it works and that would be an irreversible binding agent and there we don’t use those almost anywhere in healthcare

Dr. Mark Leeds [38:20] Okay yeah that makes sense so well yeah so it’s like it’s I actually read the way you’re describing it kind of reminds me of a passage in Arnold Schwarzenegger’s Encyclopedia of Bodybuilding in reference to protein. He said, you know, he recommends more protein than what a nutritionist would recommend. And he said he called it the police theory or something. There’s never there’s never a police officer when you need one on the streets. So if you just flood the streets with police officers, you always have one. And that’s kind of the idea is like put more than you need in there. So you never have to worry. There’s always a molecule there when you need it.

Lewis Nelson, MD [38:56] Yeah, I like that analogy. It sort of, it makes sense. It resonates.

Dr. Mark Leeds [39:00] Yeah. Yeah. So that’s, now suppose doctors out there, they love this idea of macrodosing, you know, like now that makes sense. It’s relatively easy. And, you know, we start someone at 16 and now they call and they’re like, well, I’m having withdrawal. You just cause precipitated withdrawal. They’re one of those 20% that are not ideal for that method. And you’re like, okay, take another eight, take another eight, you know, and you get them up to 32 milligrams within a short time. And they’re still having the precipitate withdrawal. They’re like, okay, doctor, I hate you now. You really ruined my life. I’m now stuck with this for at least 12 hours, like you say. Then would it would probably be a good idea to give like some of those comfort medications, like maybe clonidine. I use gabapentin. Is that a bad idea? Because it seems to help people.

Lewis Nelson, MD [39:47] We’re back to the same discussion we had before that there’s as many different ways There are practitioners who do it. I think that any of those works, I tend to use some anti-nausea agents like ondansetron. I like Clonidine occasionally. Some people like Benzodiazepines, which would be the equivalent in a way of gabapentin as sort of a sedative calming agent. I think those are all fine. You don’t want to snow the person, right, because they may vomit and then aspirate. So it’s not necessarily something that you want to do. But there really is no best practice to this. It’s a little bit of personal preference. You might ask people to share decision making. Do they just want to run through it or do they want to have something to take the edge off? We have seen people, and I will be perfectly honest, who have gotten so sick from precipitated withdrawal, at least ostensibly. That’s what it’s from, that they’ve needed to go to the ICU. I mean, they’ve gotten that hard to imagine. They’ve literally required intubation and either super high dose opioids, or sometimes we use dexmedetomidine, which is kind of clonidine-like in many of its aspects, to reduce, mitigate the severe withdrawal. It’s uncommon. It’s case report sort of data, but we’ve seen it. I think we’ve probably all seen some of these cases and it does haunt me a little bit, but it’s uncommon enough that I think it’s a risk that’s worth taking. And I don’t know if there’s something unique about those people, honestly, that we could even possibly identify going forward, but right now we just don’t know who they are.

Dr. Mark Leeds [41:32] Yeah. I just remembered probably one of my very first cases of starting someone on buprenorphine and he took it in the office. I was really strict back then. Nowadays, people are more experienced and you can send a patient home and tell them I’m there if you need me, you can call me, text me anytime or whatever. But yeah, back in the beginning, you had to have the patient right in front of you taking it. And so this guy took his first dose and he started getting sick. I’m like, well, you told me you hadn’t used heroin for 24 hours. He’s like, okay, fine. I lied. I used it this morning. And he started getting really sick. And like, we just weren’t familiar with it. It looked really bad. He’s shaking and sweating and he looked really sick. So we called 911 and the paramedics came in and they’re wheeling him out on the gurney out to the ambulance. And as he’s going out, he’s like, he looked really terrible. He’s like, please just give me another one. It’s getting this stuff out of my system give me he’s like I got one in my pocket just let me take it and he probably was right we just didn’t know any better back then

Lewis Nelson, MD [42:32] I tell you there’s a lot of great information in the street about pharmacology and to really help us understand and it’s why I say you got to talk to people and see what their experiences are sometimes they give us a lot of really good insight into what we need to be doing

Dr. Mark Leeds [42:46] Yeah so one one final thing so now that we’ve gotten the patient onto buprenorphine, now they’re stable. And I personally, I prefer like at least in the first few months to like more rather than less, like 16 milligrams seems to be like what most people in my practice would be on. You know, some people are strictly like, I don’t want any more than eight because that’s what I’ve heard is the right amount. And I don’t want you overdoing it with me, but 16 seems to be good. And it seems to be relatively easy to taper from 16 to eight, you know, when a person’s ready for that. Excuse me. But the, I’d say the next scary thing after induction, getting a person on buprenorphine is when everybody around them starts saying, how soon are you going to get off of this? And some people think, you know, a two week taper is a good idea for a week taper, get off of it fast. Other people might stay with it for a month, two months or three months. And anyone from their family members to friends, to coworkers, to the guy at the convenience store down the street, You know, like anybody they talk to will say, you know, get off that stuff. You just traded one addiction for another, which we know is not true. And, you know, people quit the medicine too early or they feel like they’re cured. They’re like, I feel great. It’s like I was never even addicted. I’m perfect. And I even skipped a day and I still felt good. And, you know, and so then that’s the biggest danger. Like, would you agree that like at least a year or so, like some people might say six months, I’d say minimum a year for most people of staying on buprenorphine is ideal.

Lewis Nelson, MD [44:15] Yeah, I’m in the same camp as you. I don’t think this is the kind of drug that you go on and off of on a regular basis. I think one of the nice parts about some of the depot medications is that you don’t have to do this on a daily basis and it maintains a much more consistent blood level. So there are, you know, and there’s a new one that was just approved, a new depot formulation of buprenorphine. But even if you take it every day, I still think that there’s got to be a reasonable period of time that you’re on. And I would say a year is certainly on the short end of what that is. And if you look at the methadone model of maintenance, and I personally like buprenorphine more than I like methadone, but that model is years of treatment. Now, there are many places, and I’ll tell you, when we studied this a couple of years ago in my state of New Jersey, 70% of the opioid treatment programs, not the methadone OTPs, but the treatment programs that manage people with opioid use disorder, 70% of them were abstinence only. So you might get a couple of days of bupe to be tapered or methadone to be tapered off of it. And then you’re going through counseling and therapy and this and that in order to maintain your sobriety, your recovery. I think that’s a problem. I mean, I think the evidence basis for medications is extremely strong. And the idea of being on a, and I know people don’t like the word opioid substitution because it harkens back to the substituting one addiction for another. But you, as I said at the beginning, you’re substituting one dependence for another, but you’re giving somebody a pharmaceutical, not a street preparation. And you’re giving something that’s legal and not illegal. So it really is a complete transition in concept. Even though it’s still an opioid. And I think that the abstinence-based programs are probably destined to fail most people. Not that there’s not a high failure rate with medications, but it’s well lower a failure rate than it is for the other treatments that don’t involve medications.

Dr. Mark Leeds [46:22] Yeah. The people in the world of the Sinclair method for alcoholic, like where they go on naltrexone and they keep drinking and they gradually taper off of the alcohol. They talk about something called the alcohol deprivation syndrome, that if you go cold turkey off of alcohol, like you would do so in most rehabs, that you can get off of alcohol and feel fine. And somewhere down the road, maybe two or three months out, that you’re going to suddenly out of the blue get intense cravings for alcohol. And that’s where most people fail, that the rehabs graduate you as a success. They’re like, look, you’re alcohol free, go home, you’re fine, go to meetings every day. But at some point, physiologically, for whatever reason, they have intense cravings. And that probably, I would assume, happens with opioids also. When a person goes to rehab, cold turkey, they detox, and now they come out opioid-free. Even if they’re going to meetings every day and in a recovery program and going to therapy, at some point down the road, they’re going to deal with intense cravings. It could be a physiological opioid deprivation syndrome.

Lewis Nelson, MD [47:20] I think that’s very reasonable. You know, undoubtedly, some people do find this way, just like people could stop drinking and not withdrawing. Some people could stop smoking and not crave. But in general, without either good genes, good luck, really strong support, I think that it’s destined to have a suboptimal outcome. And I would agree with what you just said.

Dr. Mark Leeds [47:43] Yeah, that makes sense. So Dr. Lewis Nelson, thank you so much for joining me. And I really enjoyed this conversation. It was great. Thank you.

Lewis Nelson, MD [47:52] It’s my pleasure. And thank you so much for having me. It’s been fun. Thank you.