Dr. Kendall Williams (Host): Welcome everyone to the Penn Primary Care podcast. I'm your host, Dr. Kendall Williams. I'm honored today to have back on our podcast some of my colleagues from the Division of General Medicine here at Penn with a specialty in Addiction Medicine to talk about really the epidemic of our time. And that is the opiate epidemic, fentanyl in particular that started in 2013, crested to take the lives of over a hundred thousand people at one point. It is now, thankfully, seemingly reducing. In the last couple years, we've had somewhat of a reduction in the mortality numbers from the opiate use epidemic, but it's still a major problem. If you practice at Penn, our downtown hospitals through 2024 were getting more admissions for patients with opiate use disorder. And it's a major challenge on the inpatient services and a major challenge for us in the outpatient environment as well.

So, I'm really happy to have my colleagues back; Dr. Rachael Truchil is here again, she's in the Division of General Medicine; Dr. Maggie Lowenstein, who just had an RO-1 funded with addiction focus; and Dr. Ashish Thakrar is also here. Ashish, Rachael. Maggie, thanks again for being here.

Dr. Rachael Truchil: Excited to join. Thanks so much for having us.

Dr. Maggie Lowenstein: Thank you.

Host: So, I am still doing inpatient medicine. So, I do see most of patients that I see with opiate use disorder are in the inpatient environment. I do have a couple of patients in my outpatient practice. But for the most part, most of what I manage is inpatient. And so, we're going to actually have a little bit more of a focus in inpatient than our typical podcast, but we're also going to sort of jockey between, as we talk about the inpatient environment for management of opiate use disorder, also how that translates into the outpatient environment and how it mirrors.

So, I wanted to start with some very basic questions so that us, as providers, can understand what our patients are experiencing, what their lives are like, and ask intelligent questions about their opiate use disorder. So, mostly now in the modern day when we talk about opiate use disorder, we're talking about fentanyl.

And so, I'm going to throw out the question first. How does one get fentanyl? How does it come when you get it? How much does it cost? And then, I want to also help us gauge some numbers in terms of estimating the degree of use. So, let me just start with just those basic questions. How does one get fentanyl and how does it come? Maggie, let's start with you.

Dr. Maggie Lowenstein: Fentanyl is a street drug that is available just I think not-- obviously this is not pharmaceutical grade fentanyl or pharmaceutically manufactured fentanyl. This is typically illicitly manufactured fentanyl that is sold outside of the medical system. And so, I think this is typically. Coming through like street level drug dealers and I am not going to pretend to be an expert in sort of all the drug trade and how this all gets to where.

But essentially, people are usually purchasing this on the street. It typically comes in increments of bags, and then a bundle is sort of usually like 10 to 15 bags. And it typically comes as like a white powder, which becomes relevant because we're going to talk about some of the adulterants that are in there. And, you know, it's sort of hard to distinguish what. It all kind of looks physically the same. But there's also sort of other filling agents and things like that, but it comes as a white powder. People can mix it up with like a liquid and inject it. They can snort it. And increasingly, we're seeing people actually smoke fentanyl. And so, it can be sort of used through these various routes of administration. Yeah, I think that answers your question. Do other people have things to add?

Dr. Ashish Thakrar: Yeah, I guess I'll just add that fentanyl, it's commonly sold as a white powder. In Philadelphia, it's sold in bags. I actually have an empty one here. It's a small little glassy bag with a stamp on it. In Baltimore, where I did a lot of my training, it was sold in little like gel capsules that people would pack in there. It's a white powder. it can be sold in lots of different ways. But locally here in Philadelphia, bags and bundles is kind of the most common way.

And that's in distinction with other kind of geographic areas. In the West Coast, a lot of fentanyl is sold as pressed tablets. They're sometimes blue. It's also very regional there. So, you will also get white fentanyl powder there. But in some places, they'll buy what's commonly called fentanyl blues, which that powder can be colored and then pressed into a tablet. And then, occasionally, on the east coast as well, depending on where you are, sometimes it's common, sometimes it's rare, something that's sold called Percocet can be a pressed tablet of, again, what is fentanyl.

Dr. Rachael Truchil: Asking patients how much they're using can be helpful just to get an idea as to how frequently they're using and their overall level of dependence on the substance. So, somebody's risk of withdrawal and the severity of their addiction can be very different if they're using three bags a day versus two bundles a day. And so, asking patients specifically how much they're using is a relevant question.

Host: Yeah. Two bundles would be 20 or 25 of bags, right? As opposed to three or maybe even 30 bags, right, by the math that Maggie gave me. And so, I had a patient once who was very open about this. And I spent some time asking her about the dynamics of this. And she described that she would get a bag and she would put it in water, and then pull it up in a syringe and then inject it, right? So, she was using it as an injectable. I gather that's how most people are still using it. You mentioned that you can smoke it, you can take it by mouth, but I had the impression that most people are injecting it.

Dr. Rachael Truchil: I think there's a wide variety of ways that people use them. And I think oftentimes when patients are starting by initiating their substance use with maybe Percocet, they will then transition to sniffing fentanyl. And so, it becomes using powder and sniffing it similar to snorting cocaine. And then, sometimes that then transitions into injections. But we see a lot of patients that continue to use it intranasally and never transition to using intravenously. But there is definitely, as Maggie said, a trend towards increasing use of smoking and inhaling the fentanyl in Philadelphia.

Dr. Maggie Lowenstein: I will also say Ashish mentioned that just the way that drugs come is very regional and there's also a lot of kind of-- it's fairly dynamic in terms of trends of how people use it. And also even within the city, it's a little bit regional or there are many different kind of pockets of common ways that people use. And just like rachael's point about the amount that's used, the route of administration is very important to ask about both from kind of thinking about some of the infection risk or prevention strategies. And it also becomes relevant because a lot of harm reduction is really directed towards injection drug use.

And so, sometimes those interventions end up missing people who don't use by injection, which is large and in some places a growing group. The route of administration is relevant to ask too. I think sometimes in the hospital, especially when we're seeing infectious complications, we may see more people, higher proportion of people who inject just because, on a medical service, you're often admitting people with complications of injection drug use, although not exclusively.

Host: I want to ask about the cost, but I want to pause for a moment. Because at one point, when I was managing this, it came to me this idea that I think that this is the singularly most addictive substance that the human race has ever encountered. I mean, in terms of its overall effect, I've never seen addiction levels this high in folks. But I don't know, maybe that's a little out of bounds, but I've been very impressed by how addictive it is.

Dr. Ashish Thakrar: I mean, I guess when you're thinking about the severity of addiction, it sounds like maybe one of the things you're seeing, which is something we see every day, is the severe disruption to patients' lives that causes that continued use despite such profound consequences in people's lives. And it's so true and it's so visible, I think, with opioid use disorder, especially in Philadelphia when there was xylazine and a lot of people were injecting. I think it's very visible there. I think that severity of addiction is true for alcohol. And it's sometimes not as visible because we don't see people's livers externally, right? It's true for cocaine as well. It's true for I think a lot of substances, unfortunately. But yes, certainly with opioids, it's-- I think-- very visible, especially when you're working in the hospital.

Host: My measure of it is just the lengths to which people will go to continue using the drug. But that's besides the point. I want to talk about cost.

Dr. Ashish Thakrar: Actually, before we get to cost, can I just say just whenever folks mention that, I always just like to remind listeners so much of the joy of practicing addiction medicine is seeing the transformation from that to when people get better, because people do get better. And I think for audience members who maybe practice mostly exclusively in the hospital, you might not see that as much, but folks recover and people do get better and that bring so much joy to see that transformation. So, I just wanted to state that upfront to remind folks about that.

Host: Yeah. Ashish, that's a very good point. And I certainly see a skewed population in my circumstance. So, you know, when I was talking with this young lady about her opiate use disorder, I was somewhat impressed by the cost that she had to incur in order to maintain it. And I wanted to go over that with you, because I think it does affect other aspects of people's lifestyle, right? So, do we have any sense of what a bag of fentanyl costs on the street?

Dr. Rachael Truchil: My understanding is that a bag is anywhere between $5 to $10.

Host: Okay. So, somebody that is using, say, a bundle, which is 10 to 15, is looking at somewhere between $50 and $100 a day of cost, right? And so, it can be expensive, $1500 to $3000 a month, right?

Dr. Rachael Truchil: Yeah. So, a lot of people, you know, engage because there's many reasons to want to engage in recovery. And, obviously, there's a significant financial toll that this is inflicting on individuals as well.

Dr. Maggie Lowenstein: I mean, maybe just to say one piece, I do think that it's worth approaching patients who have a history of substance use with a particularly trauma-informed lens. Because either through addiction, through the lifestyle that is part of that, like people have experienced profound levels of trauma, including often at the hands of the healthcare system. So, I do think it's probably just relevant to point out to listeners that wherever people are presenting, whether it's like the hospital, the ED, or the clinic, that this is just good medicine in general, but I think being particularly sensitive to that with this patient population, because I think they've often received a lot of pretty subpar medical care and certainly sometimes outright discrimination. So, just coming in is very difficult sometimes. And so, I think just being sort of able to acknowledge that and to approach people with a particular care around potential trauma is like a really important piece of this, whether it's incarceration or sort of other traumatic experiences, sex work like you mentioned.

Host: So, let's talk about withdrawal, which we see in the inpatient as patients present to us oftentimes in withdrawal in the emergency department, but also I believe in the outpatient setting. I mean, I think the symptoms of fentanyl withdrawal are similar to the symptoms of opiate withdrawal, whether it's heroin or other forms of narcotics, often some GI symptomatology, nausea, vomiting, some piloerection, just an overall general feeling of unwellness, with maybe even feeling like you have the flu, chills and aches and so forth. Does that capture it or is there more to it when you're talking about fentanyl specifically?

Dr. Ashish Thakrar: No, I think you captured the key things. It's opioid. It's an opioid, and we're talking about opioid withdrawal syndrome, which is very well described. I think it's pretty useful to look at what is in some of the common assessments, COWS being the most common. So, I encourage folks to just look in MDCalc and just perform the assessment yourself.

You can generally know it when you see it, but there are also lots of mimics and some people are using multiple substances. And if they're hospitalized, they have many reasons to feel generally unwell. And so, it can take a little bit of clinical acumen to just try to assess does someone have objective signs of opioid withdrawal. The more specific symptoms there would be pupillary dilation, piloerection, like you mentioned, yawning, and then nausea, vomiting often typically accompanies that as well.

Host: Ashish, you mentioned COWS. And how obviously it's very helpful to quantify the degree of withdrawal and the degree of symptomatology, which is the reason for COWS. Are there any caveats about using COWS that we should be aware of?

Dr. Ashish Thakrar: Yes, absolutely. There are some caveats, I think. There is quite a bit of variability in the score that you'll get between different people who perform the assessment. The assessment includes questions like how dilated is the patient's pupils; and that can be dependent on your own physical exam experience, it can be dependent on the ambient light in the room. There are components of it that involve asking patients how they're feeling. And so, if they're feeling ill for other reasons, then that can confound that assessment as well.

Host: How about vital sign abnormalities just with fentanyl withdrawal? Patients can be uncomfortable, so I imagine they can be tachycardic, but they're not going to be hypotensive or necessarily hypertensive like we might see with benzo or alcohol withdrawal, right?

Dr. Ashish Thakrar: I think it's probably best just to talk about opioid withdrawal. So for opioid withdrawal in general, you can get tachycardia and hypertension. That's certainly part of it. It's typically not profound hypertension and tachycardia, and that's not normally the first symptom or the earliest sign, whereas for alcohol withdrawal, the adrenergic hyperactivity, hypertension and tachycardia are some of the earlier signs that you typically see. So if you're going to have hypertension and tachycardia from opioid withdrawal from any opioid, then you're going to also have other signs and symptoms along with it.

Host: And the reason I'm asking this question is because patients are often also using benzodiazepine, so they are drinking alcohol, or there's medetomidine, which we're going to talk about in a minute. And so, the vital sign abnormalities become, I think, a part of trying to figure out what it is you're actually treating.

Dr. Maggie Lowenstein: Oh, can I just add one thing about that too? I think you're right, there's a lot of confounding between potential overlapping withdrawal syndromes. The other thing that I think potentially confounds, as Ashish mentioned already, but just to reiterate kind of more explicitly is like the symptoms overlap with a lot of other clinical presentations.

And so, I've seen people who have sort of a history of substance use in their chart and come in tachycardic and hypertensive from appendicitis or something like that, which is completely physiologic, and then get labeled as opioid withdrawal and not get the full fresh assessment. So, I would just encourage people when they're seeing someone who, especially if they're ill enough to feel like they need to come to the hospital, to just not assume that some of the abnormalities that will elevate some of these withdrawal scales are attributable only to withdrawal and just kind of maintain a broader differential. I think that's something that trips people up a lot.

Host: So, that's fentanyl and I wanted to talk about that in its pure form, if you will. Fentanyl withdrawal or opiate withdrawal generally. But of course, the thing that's been omnipresent in the drug supply in Philadelphia for the last few years has been xylazine, and now that's transitioning to medetomidine.

But let's talk about xylazine first. It's an alpha-2 agonist. So, it's in the category in the family of clonidine, I think that's the drug we're probably most familiar with, which is also related to dexmedetomidine or Precedex, which we've used in the ICUs for sedation and other uses for a while. So, it's in that category, but it was a veterinary drug is my understanding, was not used by humans until it found its way into the drug supply. Does anybody know why it found its way into the drug supply? Is it just because it was cheaper and it could be added in?

Dr. Maggie Lowenstein: I think the theory or one of the theories that I've heard a lot is that it is a sedative. And so, one of the things about fentanyl is that it has a fairly rapid onset and then people go into withdrawal more quickly than something like heroin. And so, it perhaps prolongs the sedation. I don't think we totally know, but I think that's the theory. And that is what you see with some of these additional sedatives, whether it be xylazine or medetomidine. And like If someone is overdosing with adulterated fentanyl, and they're given naloxone to reverse their overdose, they will begin to breathe again, but they may remain sedated. And so, again, that's sort of part of this clinical picture, but I think that's the theory.

Host: So, the main effect we see of xylazine and that effect is these wounds that it causes on the extremities, in basically any part of the body. That can be quite dramatic and would lead to osteomyelitis that can be quite deep, and so forth, difficult to heal. It's always been confusing to me because my understanding is the wounds can occur remotely from your site of injection, and potentially through other forms of use other than injection. You can get xylazine wounds, but that's been contradicted by other things I've read. And I'm asking you guys for clarity on that. Can you get xylazine wounds without injecting it and without injecting it into the spot that you're getting the wounds?

Dr. Ashish Thakrar: I think there is a broad range of what wounds look like that have been attributed to xylazine. So, my simple answer to you is yes to all of that. There are some scattered ulcerations that patients will have in places like their knuckles, the back of their hands, places where even if they happen to inject drugs that are not places where they are injecting or some people who don't inject drugs seem to develop those ulcerations. Those seem similar to early stage xylazine wounds in other places like the dorsal part of the extremities that, if untreated and particular people inject into, can progress to become confluent areas of non-viable tissue, eschar being kind of the most common form of that. So, the kind of most severe wounds for patients that we're seeing, they often started as scatter ulcerations. They may have not been places where people started injecting. But in my experience, the largest wounds that we see tend to occur only among people who are injecting into those areas. And it sometimes is a complicated series of events where the wound was not at a place where someone was injecting. And then, it does become quite painful and maybe the area around it becomes a little more hypervascularized and it becomes a place where people do start injecting after the fact. And then, it can lead to a bit of a vicious cycle where the wound gets worse. And for people who do have those wounds who stop injecting into those areas, but who might continue to use, the wounds do seem to be able to heal.

Host: Yeah. Yeah.

Dr. Ashish Thakrar: So, it's kind of a complex interplay there.

Host: Yeah. I mean, I think the good news is for a lot of the patients we see, they still have good vascular supply. We worry about wounds in diabetics. Traditionally, those were the ones that we would see and be concerned about, which in that case you have microvascular destruction. But in this case, folks have good vascular supply and should be able to heal those over time.

Something I always tell patients to try and make them feel a little bit better about these wounds and the fact that they still can heal. So, that's, I think, our experience with xylazine. And then, you all have laid out in the lecture you gave for the division of general medicine, the fact that increasingly we're seeing more medetomidine as an additive in with fentanyl and less xylazine, which is good because we're seeing, I assume, less wounds as a result. But medetomidine is similar to xylazine in the sense that it's in that same family as an alpha-2 agonist. It's, as you noted in your slide, a hundred times more potent than xylazine. And you are seeing hemodynamic effects with it to the degree that I don't know that we're seeing with xylazine. So, as somebody who actively has medetomidine in the system, much like they would, if they had high levels of clonidine in their system, they'd be hypotensive, bradycardic, and so forth.

And then, similar to what you might see with clonidine withdrawal, you get a rebound effect. If somebody's withdrawing from medetomidine, they get hypertensive, tachycardic, they may have nausea, vomiting, and delirium. So, that can complicate our whole withdrawal management quite a bit.

Dr. Rachael Truchil: It creates a lot of problems, because you're dealing with withdrawal from multiple substances. And it turns out that medetomidine withdrawal for some patients presents with a very severe clinical syndrome that often requires hospitalization that is a challenging syndrome to get control of. And it's not something that we have a great understanding of which patients will have very severe medetomidine withdrawal and require that additional support, which patients won't. And so, there's a lot of uncertainty and no great guidelines to use to be able to help patients through that.

Dr. Maggie Lowenstein: Yes. So, I was going to say something similar to Rachael around some of the uncertainty. I think right now one important message is we're not seeing medetomidine in isolation. It's being seen in combination with opioids, again, typically fentanyl. And so, you know, I think one of the things that we're grappling with is sort of how to best manage the syndrome.

But I think one of the things that is clear is that we need to adequately manage opioid withdrawal. And so, you the backbone of it is really making sure that you have adequate opioid agonists on board. Typically, that's going to be a long-acting, ideally either methadone or buprenorphine as a kind of long-acting agent. And then, clonidine is really effective for opioid withdrawal or other kind of any clonidine or tine alpha-2 agonist, even prior to medetomidine presence. Those are really the two most evidence-based treatments for opioid withdrawal. We often add a number of different adjunctive medicines to treat sort of the withdrawal symptoms. And we also often, especially early on in the course, will add short-acting opioids, especially for patients on methadone where we can't titrate up quickly enough to perhaps meet their kind of the level of opioid dependence that they have, and that's commonly what we're seeing in the hospital. So, that is sort of the high-level backbone of how we're typically managing opioid withdrawal. And then, we sort of are more aggressive with some of the adjuncts for medetomidine withdrawal, and trying to target some of the specific physiology there. But as Rachael said, that we're not totally-- this is very much expert opinion and evolving rapidly. Happy to talk about that more or have somebody in the group talk about it. But I think really the main high level thing that hoping to get across, and this is that adequate management of opioid withdrawal will help the medetomidine and also help kind of disentangle-- there are a lot of overlapping symptoms between the two. And so if the opioid withdrawal's not adequately managed, some patients are thought to have really severe medetomidine withdrawal who maybe it's not as bad. And then, sometimes they really do have very severe alpha-2 withdrawal that's clear even with adequate opioid agonists. So, that's sort of the backbone of what we're trying to get across to people.

Dr. Ashish Thakrar: Yeah. Can I actually just emphasize that a little bit? We kind of jumped right to treatment or management of medetomidine withdrawal, skipping over what I hope is one of the biggest takeaways from this, which is evidence-based opioid withdrawal treatment. And practicing at Penn, and maybe it's Philadelphia in general, a bit of a peculiar approach that has developed here that I just want to highlight for folks is pretty atypical nationwide and doesn't really follow best evidence-based practice to be quite honest, that we're trying to like shift a little bit, really emphasizing that starting with buprenorphine or methadone as the backbone of opiate withdrawal treatment that has the best evidence. They're long-acting agents, they last long time, and they're also the cornerstone of long-term OUD treatment. People don't need to accept long-term treatment with them to get the best withdrawal management, which involves one of those two agents, and then using clonidine, or if you have access to lofexidine, which hospitals don't. So, clonidine for opioid withdrawal using the non-opioid adjuncts, scheduling them if you need to. And then, if you have any withdrawal left over after that, sure, using some short-acting opioids. And there's a reason why that's kind of the backbone of treatment because it has very strong evidence for it and seems to work very well. So, I think if we can start with that, then with the withdrawal that's left over, we can say, "Okay, is this medetomidine? Do we need to do something different? Do we need to address that differently?"

Host: And for providers practicing at Penn, you folks have really, I think, laid out a good initial management strategies, that can inform, you know, how to start. You start with methadone, you're adding oxycodone, you're adding Dilaudid IV. And I think, in many ways, what we're trying to do is really get people under control comfortable very quickly so that then we can start having the conversations about, "Well, where do you want to go from here? What potential pathway do you want to take into the future with methadone, with suboxone, and some of the other options available," right?

Dr. Maggie Lowenstein: Yeah, I think this is a common thing. It's very hard when you're sick. You're physically unwell, you're in the hospital, you're there again, probably for some other underlying problem, it's often hard to sort of make a decision in that very challenging moment. So, getting people's withdrawal stabilized has a lot of benefit. It helps them to feel better. It also, we think, helps them to be more likely to be able to stay in the hospital and complete the treatment that they need. And then, there's the advantage too that it helps to some degree to maintain some tolerance to opioids if they do go back out and use.

And then, I think Ashish's point I'll say one more time that is it's really important is, if we can initiate whether or not they're interested in it long-term, initiating medication for OUD like methadone or buprenorphine does give people just the chance to try it and, even if they don't end up leaving on it or planning to continue it, it gives them an option to try it and maybe feel better and get sort of a positive exposure to it. And then, many people are like, "Oh, I am interested in this." And so, there are a lot of benefits to really using those as your backbone, and to treating opioid withdrawal adequately just in general.

Host: Rachael, how does this differ? I see so many patients in the inpatient environment. And so if you are managing a patient who's, you know, actively using fentanyl, maybe has some medetomidine there too, I assume the same principles apply in the outpatient setting. You want to get control of their withdrawal symptoms as quickly as possible.

Dr. Rachael Truchil: Absolutely. I think having a conversation about what options make the most sense for patient. And the point that's worth making is that buprenorphine is something that can be prescribed by primary care doctors in an office-based setting. You could pick it up at a pharmacy, you can get a week's worth, you can get a month's worth at a time. And so, it's very accessible. Whereas methadone, when you're getting that outside of a hospital, you have to go to a methadone clinic in OTP, a treatment program that's licensed to be able to provide the methadone. And usually, that means going to a program every day to pick up that methadone for a period of time before maybe you're able to get some take homes.

And so, for a lot of patients, going every day to pick up their dose of medicine is very difficult. It's hard to be able to work and go pick up a dose of methadone every day. So for some patients, right away, they know that buprenorphine is going to be a better option for them. And so, trying to sort through what is the best option for some patients, methadone works better because at methadone clinics, it's a very structured environment. You have to go every day. You have some behavioral health interventions that you need to participate in. And that can be really helpful for patients to help structure their recovery. And so, really, talking with patients about what makes the most sense for their recovery. And just because a patient chooses one option doesn't mean that they're stuck with that. We can always help them to transition to another option later on, and we've done that successfully. So, starting with that type of conversation.

And then, if patients do decide to start buprenorphine, kind of having a conversation about what that's going to look like in the outpatient setting for them, and how are we going to do that comfortably. And for the vast majority of patients in the outpatient setting, it's going to be a normal standard induction, which usually looks like starting with a very low test dose of buprenorphine, usually 2 milligrams once patients get into moderate withdrawal. Usually, I tell patients four symptoms of opioid withdrawal that they can kind of objectively have counted. And then, they can do that 2 milligram test dose of buprenorphine, usually sublingual Suboxone, and then they take Ditestone. We go through test dose, we go through the administration instructions. And then, after an hour, as long as they're not feeling worse on that, then they take an additional 2 milligrams. And then, usually, we're doing well after that. they have 4 milligrams of sublingual buprenorphine in their body. And then, they can do an additional 4 milligram dose after that. And then, we're really rocking and rolling and getting them up to a good dose after that.

To get patients to be able to tolerate withdrawal in order to get them to the point where they can safely take sublingual buprenorphine, we treat them very aggressively with adjuvant medications to help them with the symptoms. And so, I usually will have a conversation with patients, you know, what are the symptoms that are most bothersome to you? And then, we decide what medications are going to be most helpful. Clonidine, as Maggie mentioned, is the cornerstone for treatment of opioid withdrawal. And so, usually, clonidine is most helpful. We often will treat with hydroxyzine, which helps with anxiety; ibuprofen for muscle aches, something for nausea, just basically whatever the patient's symptoms are that are most bothersome. And that is generally how we approach inductions.

And then, sometimes medetomidine gets in the way, and that is difficult. But usually we can get patients onto medication for opioid use disorder and maybe they're not able to stop using completely. But at least if we have them on buprenorphine, then we have them protected against accidental overdose from opioids. And that is a huge win and gives us some time to then think about how to work on reducing their use further.

Host: So, I want to drill down on a few of those elements. First of all, I just want to say upfront, because I think it came out when Maggie and another colleague of ours, Jeff Jaeger, had done a podcast on this, that both these drugs reduce mortality. My understanding is by 50%, which is remarkable, really. I mean, when you think about any drug that would reduce mortality by 50%, that's a very profound effect. So, it's really worth our time to get folks on these drugs.

Let's just talk about methadone. I want to drill down on that a little bit in some of the more real practical stuff. As you've noted, Rachael, you know, patients do need to get it from a methadone treatment facility. It has the advantage of providing other support to patients. But they do need to go there every day and that can be a challenge depending on availability of the facility and their location and so forth. But this is where kind of the bags and bundles discussion came in a little bit as I'm sort of guesstimating how much methadone do I need to give this person to make sure they're relatively comfortable in the first 24 hours, getting some sense of the quantity of their use. Do you guys dose the initial methadone dose based on what you perceive to be their degree of use, the volume, if you will? Ashish?

Dr. Ashish Thakrar: Not really. And I think it's very easy to get carried away with that, and try to say, "Okay, there's fentanyl, how much the fentanyl, and what could the MME be that you need? I would actually recommend people not really try to think about that in the same way we don't think about initial dose of diazepam for alcohol withdrawal based on if someone is using vodka versus beer versus a handle a day versus a six-pack, you know, a 12-pack a day, right?

The opioid withdrawal severity is dependent on like a wide range of features. One of them is the amount of exposure or time, but there are so many other factors specific to individuals. Sex plays a role, or sex at birth I should say, plays a role. So many other genetic factors play a role. About, I don't know, somewhere from 15 to 20% of people in other studies don't really have significant opioid withdrawal at all. So, it's despite heavy exposure, so it's quite variable. So, I would start if someone has fentanyl dependence and no other risk factors with 40 milligrams of methadone, and I think that's a good simple way to start if you're concerned for some other risk factors, hepatic impairment, they're on oxygen, to check the lower dose and we can always give more.

The key thing to remember about methadone is it takes three to four hours for peak effects after the oral dose. So, sometimes I'll see trainees say, "Oh, we gave methadone," and an hour or two later, they're judging the response before it had peaks effect. The other key thing to remember about methadone is it lasts a long time. The half-life is 24 hours. So, half of that dose you gave Monday morning is still there Tuesday morning when you're giving that same dose again. So, it dose stacks. And that's the reason we're cautious with going higher on the first days because we're nervous that if you keep giving that dose day two and day three, you're going to have dose stacking in day three possibly, right, when the patient's about to leave the hospital and leave a monitored environment.

So, I would just start with 40 milligrams of methadone for someone who has fentanyl dependence and no other risk factors. And you can give more. This is where addiction expertise I think can be helpful. We have a lot more experience with this medication and with dosing it. We have addiction consult services, we have expert pharmacists. We have other folks who can really weigh in to help guide things as well.

Dr. Maggie Lowenstein: And the dose that will help alleviate withdrawal. Like bad opioid withdrawal symptoms may not be the maintenance dose that eliminates craving. This is true for buprenorphine too there at much lower doses than typical maintenance doses. For many people, most of them with bad withdrawal symptoms should be managed. When we think about sort of getting someone a maintenance dose of a medication for OUD, we want to not only eliminate withdrawal, but we also want to try to minimize cravings and ideally additional use. It's sometimes not possible to get rid of all cravings, or all use, especially craving is triggered by many different like environment and other cues. But just to say that like all the safety precautions that Ashish mentioned are really important with methadone in particular because of its particular pharmacology. But the dose that will get people out of bad withdrawal is we typically used to think of as more like 40. I think now we think of as like 60, maybe 80. But really, these aren't insane high doses. And so, typically, you can get people there fairly quickly using these more cautious dosing approaches that are like in our health system guidance. Sometimes you'll see addiction medicine be more aggressive. This is a really evolving area in the literature, like, who and where are the places we can go faster and should. And in the hospital, we go much faster than many outpatient settings, which are more cautious typically. So, I think it's one of those things where the more you know about methadone, the more maybe you get a little bit nervous about it because you know some of the bad things that can happen if you're overzealous with it.

But also, kind of a moderate dose of methadone will really manage most severe withdrawal and help people feel much more comfortable quickly. And the long-acting nature of it is really helpful just in terms of leveling off people's symptoms and helping just to reduce the kind of ups and downs that we see with short-acting opioids. So, we often use that as a withdrawal minute. That's our sort of if we're not sure where we're going and the patient's kind of undifferentiated, that's often the medication we'll offer first for very severe withdrawal in the hospital. But buprenorphine is also an option.

Host: Maggie, you answered one of my questions about methadone because I know that, in the days before fentanyl, when we were treating opiate use disorder, that patients would end up in maybe 80 milligrams of methadone as a typical dose, somewhere in that range. But then since the fentanyl epidemic, we're seeing much higher doses, maybe 180 over 200, that if patients are ultimately leveling out at-- and I was nervous about this, "Oh my God, I got to get them up to that dose within three, four days, or they're not going to be comfortable. But you made the point that 40, 50, something like that, that patients can start feeling pretty comfortable and then that may not be their maintenance ultimate dose, but at least you could get them out of trouble with that dose.

Dr. Maggie Lowenstein: Yeah. And people do still end up on a pretty wide dose range. I don't know the data offhand, but I've seen outpatients who are on doses that are actually not that different than some of the doses that I remember from like my residency training. And then, we do have people on much higher doses. And I think there is just a lot of individual variability in all of this, that, you know, I think can sometimes make it challenging to, say, "Oh, this is where this person's going to land." But really, we titrate dosing typically to just the patient's sort of how they feel. And again, that kind of basic, like, we want to suppress withdrawal, we want to minimize craving, we want to minimize use or eliminate it depending on sort of where the patient is. And some people will be not at all oversedated on these very high doses. And some people may be completely fine and maybe even a little oversedated on doses of 100 or 120. So, it's really individualized. And I think a goal of getting someone to a dose that's going to help at least keep them comfortable before they leave is a really important goal. But yeah, I don't think you need to aim to get people to doses of 120 or 180 or 200 or whatever.

Dr. Ashish Thakrar: These medications, both buprenorphine and methadone, they kind of have three functions. One is they prevent and treat opioid withdrawal if it occurs. They, if they're working well, will prevent cravings and reduce cravings substantially, especially the cue-induced cravings. And people in the hospital aren't having the same cues that they have when they're in other environments. And then, the third thing that they do, if they're adequately dosed, is blockage effects. So buprenorphine, it binds to such tight affinity that when you use other opioids, the buprenorphine stays bound to those receptors. And so, patients don't get the reinforcing effects of using drugs when they're abusing other opioids when they're on buprenorphine.

And it seems to still be true for a lot of people with methadone, but part of what you're probably seeing is, because the potency of the other opioids being used is higher now than it used to be, I think a lot of methadone opioid treatment programs are trying to respond to that by saying, "Okay, if you're still feeling the effects of using the street opioids on 160 milligrams, well then maybe we need to go up. If you're still having cravings to use, maybe we need to go up to try to achieve the blockage effects." Each person is different though, and there are people who are using heroin who didn't get blockage effects from methadone. There are people using fentanyl who don't get that. There's a lot of variability here. We want these hard and fast rules, but we always just have to respond to the patients in front of us.

Host: I want to make sure that we spend a little bit drilling down on buprenorphine specifically, because it's my favorite drug for opiate use disorder. I just see so many different advantages in it. And just to be clear, when we talk about buprenorphine, it's usually complexed with naloxone and is known as Suboxone. So, it has the advantage over methadone that anybody with a DEA in the United States can prescribe it. I'm repeating some of the things Rachael said earlier, but just to set it up, my understanding is there are three forms of Suboxone. And I actually want to make a distinction with buprenorphine. Maybe you guys can clarify if you're using straight buprenorphine at times. But, Maggie, you educated me in our first podcast that you have a sort of a sublingual lifesaver-like form that was cheap. And I think Rachael had noted that earlier as sort of a 4 milligram suboral dose, versus a film, which is also put under the tongue or in the mouth and then dissolves.

And then, of course, we have Sublocade, which is a depo injectable form, I believe, given monthly of Suboxone, right? And so, we have a drug that has three different ways to be given. It can be given and prescribed by anybody with a DEA licensed in the United States. So, it gives flexibility to the patients. As you had mentioned, you know, it's a very strong agonist. So, it will displace all other opiates from the system, and it's just one of its disadvantages because with the naloxone effect, it can precipitate withdrawal is my understanding, if you have other substances on board. But because it is so potent, it can be a harm reduction strategy because patients who potentially overdose with other agents are protected to some degree, because the buprenorphine is so bound to the receptors.

Ashish, is there more that you want to add to that or correct on that?

Dr. Ashish Thakrar: Yeah. Maybe a little bit of both. I think that buprenorphine, it's available in lots of different formulations. That's the active ingredient. And I encourage all of us as physicians to talk about it as buprenorphine rather than using one particular brand name. Because there's so many different versions and they're all same molecule.

So as you mentioned, sublingual film, sublingual tablets, long-acting injectable, of which there are two. There's Sublocade or Brixadi. And then, there's also the IV formulation. There's also a patch formulation, although the patch is only FDA approved for pain, which are more relevant in the outpatient setting. I might even be forgetting some. So, lots of formulations. Suboxone is the brand name that's kind of most commonly known. I use the sublingual buprenorphine mono product fairly often as well. Some people like the taste more. It's really just patient preference.

And the key thing I just wanted to make sure I mentioned is it's buprenorphine itself that is responsible for displacing other opioids. It's actually not because it's more potent. It's only a partial agonist, but it binds with tight affinity. And those two things are what make-- it's the two sides of the same coin, right? On one hand, it can be disruptive to patients who have other opioids still present, and it can move them from full agonism to partial. That's precipitating withdrawal.

The other side of that though is if the buprenorphine is present. It binds with such affinity and it's only a partial agonist, so it protects against overdose if you have adequate plasma levels. So even if you use other opioids, the buprenorphines don't bound. The naloxone is there. It was added to prevent misuse of the product, because there was concern when buprenorphine first came about that it would be crushed, injected, snorted. And that naloxone is not actually bioavailable in the sublingual route, which is how it's mostly used.

Host: So, you're using straight buprenorphine without the naloxone component frequently, is that fair to say?

Dr. Ashish Thakrar: Not super frequently, but I would say occasionally. Sometimes patients just really don't like the taste of the film.

Host: Okay. And you're comfortable doing that?

Dr. Ashish Thakrar: Yeah.

Host: So, it gives you--

Dr. Ashish Thakrar: Absolutely. And I'd encourage everyone to be, yeah. Yeah.

Host: Good.

Dr. Maggie Lowenstein: There are some people we're not sure exactly if it's the formulation or the naloxone, but there are some people who do seem to be sensitive to the naloxone in the buprenorphine. And so, they may present with, like, some headaches or a little bit of increased GI distress and that's another reason, another sort of patient preference why you might select or elect to do the buprenorphine mono product.

The other time we see it historically is in pregnancy. That had been kind of recommended as the first line. The data that has come out in sort of the past recent years shows that it's probably safe to do both. And it's really not a big worry to have to switch people because the naloxone's not really bioavailable substantially that way. But just to say that that's the reason a lot of people sort of think of the mono product as being primarily for use in pregnancy. But I think I agree with Ashish. It's not the first line for me, but I do pivot to that in situations where there's patient preference or other reasons to do it.

Dr. Rachael Truchil: There's even different formulations of the buprenorphine and naloxone. And so, Suboxone itself has like an orangy type chemical taste to it that some patients are very averse to. There's also a product called Subsolv that has a minty flavor to it that some patients prefer. And so really, just working with the patients to figure out what is their preference and what feels like they'll be most likely to be able to adhere to, I think most of our practices.

Host: Rachael, when I was educated about this back-- it might've been, I don't know, years ago when I first did the training for Suboxone, you had to let people get into a withdrawal so that you could then give the agent and they wouldn't experience withdrawal. It would help them because the agonist effect would be more so than the antagonist of the naloxone. But if you are using pure buprenorphine, does that have to be an issue at all? Can you just sort of switch people over and just add it into the mix and then they can stop using fentanyl or whatever other opiate they're using?

Dr. Rachael Truchil: Yeah. Unfortunately, it's still an issue because if you have somebody who is using fentanyl and all of their mu receptors have a full agonist on it, and then you introduce buprenorphine, which is a partial agonist, but remember it has like a very high affinity for the receptor and you basically drop their mu receptors from the experience of having a full agonist to a partial agonist. That experience is precipitated withdrawal and they will feel very terrible with that.

And so, it's important that you wait a period of time that they start to experience usually we say mild to moderate withdrawal so that some of those me receptors open up, and that then the buprenorphine comes in and attaches to the receptors, provides the affinity, and then actually helps them to feel better in that moment. So, that really doesn't matter if it's a mono product or if it has naloxone in it.

Host: That's really helpful. I just watched a Star Trek movie where the enterprise got knocked out of warp speed. I don't if you've seen that movie. But as you were describing what happens when you drop down from fentanyl to buprenorphine, it's like being knocked out of warp speed, you know? I had to watch it on the plane back from scotland. Actually, it's quite good, by the way. Quite an entertaining film.

Dr. Rachael Truchil: One thing that is definitely also worth saying is there are now these great injectable options for buprenorphine that a lot of patients are actually coming and saying that they're interested in. And there's options now, which is great for patients to be able to choose what they want. There's Brixadi, which has a weekly and a monthly version; Sublocade, which is monthly. And it really is helpful for patients who don't like having to take a film every day for a variety of reasons. It's just nice to be able to give patients other options for other modes of administration.

It's also great for inpatients, when you've worked so hard to help patients get onto medication for opioid use disorder and to be able to give them an injection before they leave really helps when they're changing environments. And maybe they're going back to somewhere where they're going to maybe have more triggers for returning to use to have that medication onboard to help them with some stability in that early recovery phase can be really great.

Host: I'm glad you said that, Rachael. That was my last question. I wanted to ask about the injectables and how you're using them, both for maintenance of abstinence, but also as a harm reduction strategy and folks that do slip back into use.

Dr. Rachael Truchil: Yeah. So, we use them in both situations. I think they're wonderful for patients who want to just continue with buprenorphine are continuing with abstinence and doing great. It's a wonderful treatment and they're also great for patients who continue to use and are not ready to stop using, but really want that protection from accidental overdose, also maybe want to be cutting back on how much they're using, and are maybe still struggling with their use disorder, but are working on it. And this is a harm reduction standpoint where they are trying to work on their recovery but maybe just aren't there yet. And it's great because they don't have to remember to take that film every day to protect themselves. They have that injection in them and it's like this built-in safety feature.

Host: Well, before we leave this discussion, are there any last take home points you'd like to emphasize?

Dr. Maggie Lowenstein: Maybe I'll just summarize, I think we've emphasized this already, but I think just like really remembering the basics, like trying to get people on buprenorphine or methadone regardless of setting, both are highly effective, both reduced, all-cause and overdose mortality by 50% or more as you said. But it's worth noting these are some of the most powerful medications that we can offer and basically in terms of in any setting longitudinally.

So, using this opportunity, whether it's the hospital or outpatient, to really sort of plug patients in is important. And that those are really also the cornerstone of withdrawal management, regardless of what adulterants are complicating the picture. So, I'll start there. I bet others have things to add.

Dr. Rachael Truchil: Ashish, before you wrap up. I am going to. Also just say, thinking about some of the initial conversation that we had, I think it's really great when talking to patients to really be curious about their substance use. Ask them questions show an interest in their recovery because patients will answer your questions. And if you take an interest in helping them to be more healthy in a nonjudgmental fashion, where you're not telling them that they have to stop, that you really care about helping them to use more safely, and you think about what are the goals that are important for them, like what does health mean to them, they will really respond to that and you can really partner with them to help them achieve better health. And so, I think coming at it from like a curious standpoint, like what motivates them, what are their goals, can be a really powerful tool for the provider.

Host: Well said. I have had that experience when I take the time and people feel sort of the love, if you will, that they really do respond. Because we all want to be made to feel human in these interactions. And so, just being authentic and everything can make a big difference. Ashish, we're going to give you the last word.

Dr. Ashish Thakrar: I don't know if I could say anything to top that. I just want to echo everything that Maggie and Rachael just said. We have really good evidence basis for opioid use disorder and opioid withdrawal care. We might need to adapt it a little bit for Fentanyl and for adulterants. But starting with what we know works and treating patients compassionately in patient-centered ways, incorporating their goals and trying to match them and meet them where they're at.

Host: Well, the mortality numbers from opiate use disorder have probably halved in the last few years. I'm going to give all the credit to you guys and your colleagues nationwide. I don't know if, you know, that's actually the cause. But certainly, your efforts in educating us, as frontline providers, about the strategies that are most effective to keep people alive seem to be making a difference. And so, I really appreciate you coming on and continuing that process of education. I want to thank everyone else for joining the audience, for joining our discussion today. Please join us again next time.