Good afternoon. I'm Dr. Steve Wyatt, and I welcome you to today's webinar, in which we'll be discussing fentanyl and particularly pharmacologic properties of fentanyl and withdrawal mitigation. I'm delighted to introduce the speaker today, Dr. Kelly Dunn, Ph.D., and professor of behavioral pharmacology and research in the Department of Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine. Dr. Dunn has worked in the area of opioid use disorder treatment and withdrawal mitigation since 2005. Dr. Dunn has served in positions of leadership in the substance use disorder field, including incoming editor-in-chief of the Journal of Experimental and Clinical Psychopharmacology, president elected member of the board of directors for the College on the Problems of Drug Dependence, and the 2021 president of the American Psychiatric Association Division of Psychopharmacology and Substance Use. She's also the co-editor of the Journal of Addiction Medicine, and she serves as the editor for the Oxford Book of Opioids and Opioid Use Disorders. So it's with great pleasure I welcome Dr. Dunn. Thank you. Thank you so much, Dr. Wyatt, for that introduction, and thank you for the opportunity to come and speak about this topic today. So I was asked to talk about the opioid precipitated withdrawal syndrome and its relation to fentanyl, as well as the absorption, distribution, metabolism, and elimination of illicitly manufactured fentanyl. And this is a topic that we've, our lab has actually been delving into quite a bit, have been forced to delve into quite a bit in the past few years because of the adulteration of illicit fentanyl in the Baltimore heroin market. And so I'm excited to be able to put all of this together today, but as I hope you'll see from the end of the talk, I'm also hoping to inspire some people to do work in this area because there's quite a bit of unanswered questions that we have. And so quickly, I just want to note that I do have some disclosures. I have no direct conflicts of interest report, but I have done consulting with various companies in the opioid use disorder space in the past three years. And then the learning objectives for today are to learn about the peripheral distribution and excretion patterns of fentanyl, to understand how fentanyl might be interacting in unique ways with buprenorphine, and to learn the work that we've done to try to identify an operational definition for differentiating precipitated withdrawal from spontaneous opioid withdrawal. And so I'll start just by asking, what is fentanyl? And so fentanyl is an opioid that was synthesized in 1959. It was one of the few opioids available at the time that it was synthesized, and it was designed, it was iterated based on miparidine to be highly lipophilic. So it was engineered to be lipophilic, meaning fat soluble. And the goal was to have this cross the blood brain barrier very rapidly so that they could produce an opioid that had a very rapid onset of effects. It turns out that fentanyl is highly potent at the mu opioid receptors, and those are the receptors that are responsible for producing a lot of the opioid, the kind of prototypical opioid effects, including analgesia, but also euphoria or high associated with opioids. Fentanyl is used routinely in hospital settings quite successfully, and so it's used often for analgesia and anesthesia in both surgical and post-surgical settings. And it has relatively poor bioavailability for oral administration, and so for that reason, it's often administered in transdermal, mucosal, or parenteral routes. And you can see here on the right-hand side are a couple examples of some of the commonly used forms of fentanyl in surgical settings. And this would be a lollipop, and then this would be a transdermal patch along the bottom. And so why is fentanyl important now? So you're probably aware that we have an unprecedented rate of drug poisonings in the United States, and fentanyl is playing a very active role in this. And so this graph here kind of depicts the four waves of the opioid crisis beginning in around the late 1990s when we had this influx of a variety of commercially produced opioid products that were available for analgesia, and we saw a diversion of those medications and rates of use associated with them and corresponding rates of overdose and consequences associated with their use. And that lasted until about 2010 when we saw, for a variety of reasons, a shift from the use of those medications, the diverted use of those medications, to heroin, which was a potent and easily available, easily accessible form of opioids. And then in about 2015, 2016, we started to see a slow proliferation of illicitly manufactured fentanyl into the heroin product throughout the United States. That became much more prominent, again, kind of mid-2010s, and we see here this purple line that represents deaths related to synthetic opioids, and that's predominantly fentanyl, maybe exclusively fentanyl. And now we've entered into our fourth wave, our current wave, which is characterized by high rates of co-use of opioid products with stimulants. And this is a pattern that we've actually seen cycle in and out for the past several decades, kind of periods of time where we had a lot of co-use, and then it would shift to more exclusive use of one of those substances. However, now this is a unique experience for us because the co-use that we're seeing is this incredibly potent opioid, fentanyl, often combined with a very long-acting and highly potent stimulant, methamphetamine. And so it's a bit unprecedented for us as well in terms of determining best treatment outcomes or best treatment strategies. And so fentanyl becomes—illicitly manufactured fentanyl is driving a lot of the overdose deaths. And so what is illicitly manufactured fentanyl? And I think it's important to make this distinction between medicinal fentanyl and illicitly manufactured because there's a very clear need for medicinal fentanyl, but it's the illicitly manufactured fentanyl that's being added to the heroin drug supply that's really producing the consequences that we're seeing for our patients. And so there's a lot of reasons that we speculate that illicitly manufactured fentanyl has become— has kind of replaced the heroin product in the United States, but there's a few of the key reasons, one of them being that it's relatively easy to produce, relatively easy. So whereas heroin is a naturally-derived opioid that has to be extracted from a poppy plant, and a poppy plant has a life cycle that takes a while for it to grow, and it also has very specific conditions, environmental conditions in which it can thrive. So there's limited places geographically that it can grow. That's a rate-limiting step in being able to produce heroin. Fentanyl can be synthesized using chemicals that can be produced or procured commercially. And so when we saw this shift from the commercially-produced opioids to heroin, and we had this whole new market now for persons who were looking for heroin, the belief is that the cartels and the producers met this need by starting to develop fentanyl to replace it. And in addition to being relatively easy to produce, it's also believed to be cheaper to produce than heroin. So one kilogram of fentanyl is believed to cost around $3,500 to produce relative to $65,000 for a kilogram of heroin. And then finally, fentanyl is a white powder that can be very easily hidden in other substances. So it has a lot of these features that suggest that it might be – that we believe may have contributed to its kind of rapid proliferation of our heroin product. And I have this book here on the right-hand side by Sam Kionis, Dreamland, which I think is a really nice investigative summary of the manner through which heroin kind of penetrated the rural settings in the late 2010s, which is a trend that we hadn't seen prior to that and may have contributed to this onset of fentanyl-related overdose deaths. And so again, why is fentanyl important now? Well, we know in addition to having these unprecedented rates of use and overdose deaths related to drug poisonings, the deaths are predominantly driven by opioids. So about 65% of all drug-related overdose deaths in the United States annually are attributed to opioids, and that is almost exclusively – not exclusively, but highly driven by illicitly manufactured fentanyl. And then we're also seeing this continued proliferation of fentanyl. So in addition to it being added to the heroin product throughout the United States, we're also seeing that it's starting – excuse me, that producers are starting to purchase pill presses that resemble other drugs that would be otherwise commercially available, and they're pressing fentanyl into that. And so what that means is that we have an increased number of people who are purchasing drugs that they – medications that they think are diverted, things like – that are non-opioid medications, and in fact are actually pressed fentanyl, and we're having high rates of overdose deaths related to that because it's just completely unexpected exposure to fentanyl. So why is this so concerning? In addition – certainly we want to help abate the overdose crisis, but fentanyl, in addition to that, seems to not behave like other opioids. And so we, for the past several years, have been really delving into the medicinal fentanyl literature, which is really the only literature that exists on the fentanyl pharmacokinetics and pharmacodynamics, to try to understand more about the trends that we are seeing in our patients. Because the work that I do in Baltimore, we enroll individuals from the community who have opioid use disorder and are seeking treatment, and we evaluate various different forms of treatment. And we saw a shift in our patients in about 2019, where we started to see differences in the way that they were presenting. They were exclusively fentanyl-exposed, and we noticed trends that we thought were very unique relative to what we had seen in persons who had been heroin-exposed or had used other forms of opioids. And so what we've come to believe, and we believe that we have some data to support this, is that fentanyl produces a deeper physical dependence, or a different physical dependence, perhaps, and it seems to be more potent, or perhaps the physical dependence is related to its heightened potency. It seems to behave differently in the body, and we think that it may be interacting with buprenorphine, also known as suboxone treatment. And so I'll go into the details of this now. So what's the evidence that illicitly manufactured fentanyl may lead to deeper physical dependence? So we had an opportunity, kind of a quasi-experimental opportunity, with some of the work that we've been doing in Baltimore. We run, as I mentioned, randomized controlled clinical trials, and we have a very standardized protocol for how we do this. And so we recruit individuals from the community into a residential research unit, so they are in a controlled overnight environment, and we stabilize them from the opioids that they're using onto a short-acting opioid. And in this case, we've been using morphine, 30 milligrams, delivered subcutaneously four times daily. And that strategy had been very effective for us. And so we ran a study where we used that protocol from about 2010 to 2016, so kind of prior to the influx of fentanyl in our heroin product. And then that study concluded, and then we started a new study several years later after the influx of fentanyl into our product, and we noticed really profound differences in the experience that our patients had in response to the morphine. And quick, before I move on to this, I just want to attribute these data are a result of a study that was conducted by my colleague, Dr. Eric Strain, and then Dr. Cecilia Bregueria and Dr. Anjali Sharma will be presenting these data in manuscript form soon. And so I wanted to show you kind of these quasi-experimental data just to give you a sense of clinically what the differences that we're seeing in our patient population. And so before I show you the data, let me just show you the sample. So the sample one is our historical control. We had enrolled 102 people into that sample. In order to gain entry into the study, to be eligible for the study, they had to test positive on a urine drug screening assay for opioids. That's an assay that does not cross-react with fentanyl, so it means that they needed to have some non-fentanyl opioid exposure to be able to gain entry to the study. All of those participants met that criteria, so we know that they may have been fentanyl exposed, but they were not exclusively fentanyl exposed. The sample two, which is a more recent sample, is a smaller sample. It's about 30 people. We started enrolling them in about 2020, and for those individuals, we're finding that they test positive only on a fentanyl assay, so we have almost no exposure to non-fentanyl-related opioids. And so we have, again, this kind of quasi-experimental design, these two distinct populations. Aside from those differences, the populations look very similar. We're recruiting the same groups of people, so they're about the same age, they're in their early 40s, they have the same level of education, same relative racial background, slightly more individuals who have Hispanic ethnicity in the more recent sample, and then a similar distribution of men and women. And so what do we see? So I'll orient you to these graphs. On the left-hand side, this is our self-reported withdrawal severity scale. We use the subjective opioid withdrawal scale. It's a 16-item scale. On the right-hand side, we have an observed withdrawal severity scale, and that's the clinical opioid withdrawal scale, or the COWS. We collect these several times daily in both of these studies. Again, same identical design. And the data that you're seeing here for both of these represents the peak withdrawal severity for an individual averaged across the groups. And on the left-hand side, I'll just orient you again. On the x-axis, we have the morphine dosing day. So these are the days that they have been continuously enrolled in the trial and receiving morphine, and then the withdrawal severity on the y-axis with a higher level representing more severe withdrawal. And then we have the light blue representing the historical control, and then the darker blue representing the persons who were fentanyl exposed. And you can see that in both of these conditions, particularly in the self-reported withdrawal, when individuals enter the study, the level of morphine that we had historically given people actually managed their withdrawal really nicely. And so the historical control, you could see a steady kind of linear decline in their withdrawal severity during that period of time, which is exactly what the study and that stabilization period was meant to do. In the darker circles, you can see that we actually see much less managed withdrawal in response to the same identical dose of morphine, particularly in the few days after they are enrolled into the trial, and that their withdrawal remains much more elevated for several days. So this is up to day four that they're still not well managed with this relatively high dose of morphine. And we see a similar trend with the observed withdrawal. We always see slightly lower values on the observed withdrawal, in part because it takes a higher threshold of change before participants, before you can observe the withdrawal in an individual. And so this is one way of looking at this. And I think, to me, this was very impactful, just to see the difference in the withdrawal presentation. But another way of looking at this is to categorize it based on severity thresholds. And so in particular, with the self-reported scale, there's established severity thresholds that indicate no withdrawal, mild withdrawal, moderate withdrawal, and severe withdrawal. And so we also characterize participants based on that. And so on the left-hand side, you see our participants who were fentanyl exposed. On the right-hand side, you see the historical control. And then you see the clear would be no withdrawal, light blue would be mild withdrawal, yellow would be moderate, and then red would be severe. And these are the percent of individuals who had withdrawal that was within that categorical threshold at some point on that day. So their peak withdrawal was either mild, moderate, or severe. And as you see here, I think it's even more evident, the differences that we're seeing between individuals who are presenting with fentanyl exposure versus a historical control, with many more of those individuals having withdrawal that actually is considered severe withdrawal, despite the fact that they're receiving high doses of morphine subcutaneously every day, right? So all of these individuals across this entire, in both samples, are receiving the same maintenance medication. And yet, it's really having very little effect on the persons who were fentanyl exposed. And so we also look to see whether or not this was driven by any particular symptom. And having, you know, I've tapered patients off of opioids, illicit opioids, for many years now. And the experience has always been that individuals have a different expression of withdrawal, and typically have, I guess, variable symptoms that they present with as their leading symptom. And so we often talk to people about, what's the symptom that is the most severe for you? And how can we help you manage that? One thing that we've noticed more recently is that we're having a very high presentation where the primary leading symptom that patients are reporting is anxiety. And so we did also look at this just to see, are we seeing differences in the symptoms? Is it, are these differences in severity driven by one or two things? Or is it just across the board more severe? And you can see here, this is, these bars represent the mean increase in severity ratings across the right. If it goes to the left, then it actually means there was a decrease. And you can see that it really is kind of across the board where you're seeing increases in the symptoms. But anxiety is the prominent symptom that we're seeing an increase in. And anxiety, again, is a well-recognized symptom of opioid withdrawal. But it has not been the case prior to the past few years that it was the leading, one of the leading symptoms for most of the participants that came into our trials. And so that's a bit of a surprise for us. And then, again, we see the same kind of general increase in the majority of symptoms for individuals on the observed items as well. And so there's a lot to unpack here, and there's a lot more to look at. But one of the things that I think is another feature that we are seeing in this population that I think might be tied to anxiety is that we're actually seeing meaningful changes in hypertension and heart rate in this population. And so we collect these at the same time that we collect our withdrawal ratings. So we have really good sensitivity throughout the day of changes in hypertension. We have significant increases in hypertension in persons who are fentanyl exposed on days one through three of the trial. And then these data here present heart rate to you. And the data on the left show you the mean heart rate over time. And then on the right, it shows you the percentage of patients who are, who's at some point during the day, their mean heart rate crosses into a clinically meaningful, a clinically significant threshold. So at this point, once they're over 100, they're tachycardic. So this means that we need to manage them differently, right? So this now becomes a more, more of a medical situation than it had previously been when we enroll people into these trials, because we are having this kind of rebound, what looks like rebound hypertension or rebound tachycardia for mechanisms and reasons that I'm, we have not yet determined. But again, it makes it a different, it's a different experience for our patients now. And I think we feel pretty confident over time that one of the driving factors of this is the exposure to fentanyl. And so why might this be happening? So we've thought a lot about this because we really want to be able to help the patients that we're trying to treat. And we think that maybe something about the nature of fentanyl and the fact that it was so lipophilic might have something to do with the experience that these patients are having. And so we really, again, dove into this literature to learn more about the ADME, the absorption, distribution, metabolism, and elimination of fentanyl. And I'll note that, and so I'll show you some of the summarized data from that in a moment. I do want to present the caveat that all of what I'm about to show you is based on the medicinal literature, which is orders of magnitude lower than what our patients are being exposed to. And so I don't know how this will directly translate to our patients, but I think that it's an important foundation for us to be aware of, because I think that from once we recognize that fentanyl has this kind of unique pharmacokinetic profile, we can start to understand or to look at how we might be able to translate this into better clinical care for our patients. And so what I'm about to show you, I'll also note is something that we also just published, and that's currently in press in the Journal of Addiction Medicine. That outlines this in greater depth than what I'm able to go through here, given the time constraints. So again, just going through the absorption, distribution, metabolism, and elimination. When we look at the absorption, so we looked at a lot of the literature from the early days of fentanyl, where they compared it to various other medications. And what we learned is that they were very good at engineering fentanyl to be lipophilic. And in fact, they made it 1,000 times more lipophilic than morphine. What that means is that it has incredibly swift penetration into the tissues, meaning that it could cross a blood-brain barrier incredibly quickly. So in studies where they looked at the subjective effect profile in individuals, the point at which they can detect fentanyl for the first time, most individuals could detect it within 30 to 90 seconds. So within a minute of it being, roughly a minute of it being administered intravenously or intramuscularly, individuals could detect the effects of it. The peak effects generally lasted about five minutes, and then the effects were subjectively undetectable within 40 minutes. And so if you think about the experience of this for our patients, it somewhat reflects what our patients have told us, which is that they feel that they often need to use more frequently throughout the day because the profile of effects is so short. And I think that probably is supported by these pharmacokinetic or absorption data from the early days of medicinal fentanyl. And then the data on the right I'll show you, I show you because this is one of the few human studies that has been conducted to actually compare the relative effect profile of these, of various opioid agonists. And this was a study that was conducted in individuals who were all opioid exposed. So they had a history of opioid exposure and they were given, it was a within subject study, so they all had access. They were all exposed to all of these different formulations of opioid agonists, fentanyl, buprenorphine, heroin, morphine, and oxycodone. And what you can see fentanyl here in the diamonds, excuse me, required a much lower dose to produce ratings of high relative to other compounds like heroin, which is in the square or oxycodone, which is in the circle. However, you'll also, you may also note that the ratings of high, which is on the Y-axis here are lower than the ratings that were produced by these other opioid agonists. And that's a trend that we actually saw reported quite a bit in some of these early studies, which essentially was when they asked people, do you think, so persons who were using opioids, what their thoughts were on fentanyl, they often were not very interested in it as a primary opioid in part because they felt that it was too risky, it was too potent. And in part because the formulations that they had access to particularly in the mid 2000s were mostly transdermal patches or suckers, lollipops that were not really an ideal way to consume a substance. And so there were actually reports back during that period of time that said, we really don't need to worry about fentanyl. It doesn't really seem like an opioid of interest. And probably in those formulations, it certainly wasn't. But clearly we have evidence now that when you increase the dose to these super therapeutic levels that we are producing effects that are highly reinforcing for our patients. So fentanyl is absorbed incredibly quickly by the brain. Another component of fentanyl that I think is not well-recognized, but I think probably has some clinical significance is that it has essentially a three compartmental clearance meaning that once it goes into the brain and it's absorbed, it's rapidly redistributed. So five minutes after it's injected, the concentrations in the brain decreased by 90%. 56% of it is redistributed into muscle. Within 30 minutes of the injection, 17% of it has now moved into fat. That's the third compartment. So it goes from the brain, the central nervous system into muscle, into fat. And then the levels in fat are now 35% higher than what's evident in the blood plasma. And you can see that reflected over here in the figure on the right. This was a study that was done in animals and rodent models, but you can see that when they administered fentanyl in tissue, these were actually tissue samples that they took, but when they administered fentanyl intravenously, they had very high rates in the plasma, which is this small square here that kind of declined in a linear manner. And then you could see a slight redistribution into muscle that then slowly declined, and then a slower onset, but higher redistribution into fat that also had a slow decline over time. And this study actually took those data out to several days before they saw a full resolution of those. And what they found is it took about 72 hours for there to be a full resolution or a full elimination of those levels. And so, again, the early data from medicinal fentanyl suggests that the reason that this happens is because fentanyl is so lipophilic, it has such a high affinity for the tissues that in these early studies, there was consistently higher levels of fentanyl sequestered in the tissues than was available in the blood plasma. And so one of the, and I think in my, I don't know how this relates to the clinical experience of our patients, but I do know that often we have observed, one of the reasons that we started to delve into this literature is that our patients were having somewhat nonlinear withdrawal experiences where they would have this kind of increase in, it looked as though their withdrawal was well-managed and then they would have an increase in withdrawal that was somewhat unexpected and then it would come back down again. And so that's actually what made us, what prompted us to go into the literature and look at the pharmacokinetic profile. And so I do wonder if this is contributing to these kind of unique experiences of our patients. One of the other consequences of this distribution pattern is chest wall rigidity, which is also known as a wooden chest syndrome. There's some really great articles on this and a review article by Philip Teralva that he published a few years ago, just a couple of years ago, really goes into the mechanisms underlying wooden chest syndrome. And I would encourage you to look at that if you have interest in the topic. But wooden chest syndrome is fairly well-recognized in the field of anesthesia. It represents this rigidity in muscles that occurs in the chest wall and in the diaphragm and in the upper airway. There's also something called epiglottic closure where the vocal cords close, they seize shut. And this happens in response to fentanyl that is administered as a high dose and a high speed. So if you administer, intervene in a parenteral form of administration. So in a hospital setting, they learned very early in the medicinal literature that if they administered intravenous doses of high doses of fentanyl quickly, that it produces muscle rigidity in the individual. That rigidity is transient. So it can occur as soon as one minute and it lasts for about 15 minutes. But once it occurs, it's very difficult to reverse. And certainly the epiglottic closure, the vocal cord closures, you cannot reverse that. You can pre-treat to prevent it in a surgical setting, but you can't reverse it. You have to wait for the fentanyl to dissipate. In a hospital setting, you manage this by intubating the patient. But certainly in a non-hospital setting and with these super therapeutic doses of fentanyl, it seems likely that this is contributing to some of the overdose deaths that we are seeing related to illicitly manufactured fentanyl. This has not been well-studied at an epidemiological level, but there have been reports in safe consumption places that have reported unique characteristics of overdoses and have reported that there is an increased number of people that have had this kind of muscle rigidity or that required supplemental oxygen to help them until they were able to resume respiration. One of the consequences of this muscle rigidity is it can make it difficult to administer CPR to the individual in an overdose event. And the rigidity is not necessarily a rare event in these surgical settings. And so in these early studies, at least, they found that as many as 69% of patients developed some level of rigidity and 31% of those experienced severe rigidity. And so moving on to metabolization. So we know that fentanyl is metabolized into a primary metabolite, norefentanyl. Norefentanyl is believed to be relatively non-psychoactive. It is converted by the CYP3A enzymes in the liver. The CYP3A enzymes are part of the P50 family of enzymes. They're highly variable in the population, meaning that some individuals are classified as slow metabolizers. Others can be ultra-rapid metabolizers. Others can have a more normal metabolic profile. But the consequence of this is that individuals will likely have a different experience to illicitly manufactured fentanyl, or to fentanyl in general. And so it's difficult. At the moment, we don't have data, to my knowledge, that would predict how these enzymes might interact with fentanyl exposure to change the experience for the individual. But it will likely lead, it makes sense that it would lead to drug-drug interactions. And again, that's currently untested. And then finally, looking at the elimination profile of fentanyl. So in early studies, if you look at medicinal fentanyl, about 85% of that is eliminated within 72 hours. The majority of that is the metabolite. Only a small amount of that is the actual parent fentanyl product. It's predominantly eliminated through the urine, about 75%. However, there is evidence that repeated exposure to fentanyl results in more peripheral accumulation. So remember, when we talked about distribution, we said that fentanyl is distributed into the muscles and then back into the lipids, into fat, before it's slowly eliminated out. There's evidence from at least a few preclinical studies that show that that distribution, if you continue to administer fentanyl, the sequestration becomes, it increases, it accumulates, and it's meaningful. And it's more likely to occur with higher doses. And so this data on the right, just to give you an example of that, this is a study that was done with rodents. On the top, they administered 20 micrograms per kilogram of fentanyl. And on the bottom, they administered 40 micrograms per kilogram. And this was looking at analgesic response. So the response was tail withdrawal as a percent of the saline session. And the saline session is plotted for you here as a dotted line of both of these figures. And then on the X-axis, it's hours post administration. What you can see with the 20 microgram dose, when animals received that on a daily basis, they had a relatively similar response profile, an analgesic response profile relative to the saline. However, when they received the 40 microgram dose on consecutive days, beginning on day four, they actually had a heightened response, a heightened analgesic response to the same dose, which the authors attributed to this increased peripheral accumulation of fentanyl resultant from the higher dose. And so what's the evidence of this in people? Well, we don't really know the elimination profile in humans. However, we do have data from one study conducted by one of my colleagues who looked at the elimination of fentanyl and norefentanyl in urine samples. And so this study was actually prompted. This was collected, the data were collected in 2019 when we started to see this kind of full replacement of heroin with illicitly manufactured fentanyl in the Baltimore region. And what they found is that they had individuals who were presenting the treatment for primary fentanyl exposure who were in a residential treatment setting and had known abstinence or no exposure to any sort of additional fentanyl product. And these individuals were continuing to provide urine samples that tested positive for fentanyl and norefentanyl for several days. And so they actually tracked that out by taking serial urine samples and a sample of individuals here. And you can see the clear bars are the norefentanyl and the filled are the fentanyl. And these represent weeks, so week one, week two, and week three. On average, individuals tested positive, continued to test positive for fentanyl for about six days and started to finally remit about day seven, or decrease, I should say, by day seven. And then norefentanyl tested positive for around 14 days. In both of these cases, they had individuals who continued to test positive for up to three weeks. And so we are seeing perhaps a delayed elimination of illicitly manufactured fentanyl, although it's difficult to make these causative relationships because we don't know the level of exposure that people are having prior to entering these treatments. Another unique outcome related to illicitly manufactured fentanyl or fentanyl in general is this concept of secondary peaking. And so again, with medicinal doses, there's evidence in some people, but not all, that they have this kind of secondary peak of fentanyl that's re-released into the plasma. So this can occur 45 to 60 minutes post-dosing in most people, but it can occur several hours later for other people. And so these data here just show you an example of this. These are individuals who are undergoing surgery and they looked at the plasma levels over time. And what you can see is what you would expect with a single compartmental distribution or elimination would be that the fentanyl would have a linear decrease over time. However, in this case, because we have this kind of two or three compartmental distribution, which is believed to underlie the secondary peaking, there in some individuals, you see a linear decline and then an increased reintroduction of fentanyl into the plasma and then a decline from there. And so that's this kind of secondary peaking experience. These early studies reported this really in the context there were many case trials, case series that reported this. And they often reported it in individuals who had received fentanyl as part of a surgery. And the person they reported woke up, they were revived from the surgery, coherent, had no medication-related consequences. And then two hours later, they would abruptly go into respiratory depression that was responsive to Narcan or to Naloxone, which is the opioid antagonist, suggesting that it's an underlying opioid effect. And so they've actually built in procedures and safety mechanisms to monitor this when fentanyl is used in surgical and hospital-based settings. And another example of that here, these are two individuals who received either on the left-hand side, a 0.5 milligram intravenous dose and then on the right-hand side, 1.6 milligram intravenous dose. And what you can see in both of these cases is this person, if you look at their plasma levels, had a decrease and then a reintroduction of fentanyl to the plasma and then a decrease. And that reintroduction was somewhat delayed for the individuals that had the higher dose. And so I think that there's a lot of, we need to look at this more in our patient population and understand is this happening to our patients and what's the clinical consequences of this happening? And so this is really, we really researched this all in the context of, is this why we're seeing these interactions that we think we're seeing between buprenorphine and illicitly manufactured fentanyl? And so the basis of this is that in 2019, as I've mentioned, we started to see, we had individuals presenting to treatment that were primarily fentanyl, exclusively fentanyl exposed. And we had trials ongoing where we were trying to induct those individuals onto buprenorphine or suboxone. And if you're unfamiliar with that experience, historically, buprenorphine is a competitive agonist at the mute opioid receptor. And to induct somebody onto it from another opioid, we need to do so in kind of a standardized way. And so we would have people come into the clinic, they need to be in mild withdrawal following a period of acute absence from opioids. And then once they reached a threshold of about nine on a cow scale for us, on an observed withdrawal rating scale, we would administer four milligrams of buprenorphine, we would observe them for an hour under our observation, just to make sure that there was no precipitated withdrawal. And then we would give them a second four milligram dose, and that would be their maintenance dose for the day. And so we started to do this procedure with individuals who were fentanyl exposed. And that's what this case series represents to you here. So you can see on this individual, the black dots represent the withdrawal rating scale. And then the gray bars represent the cumulative dose of buprenorphine with the arrows representing the time points when those were administered. And then on the y-axis, we have the actual time. So we had this individual come in and we monitored their withdrawal for a period of time for several hours before they actually achieved a withdrawal of nine on our scale, which authorized them to be able to start this induction. We administered four milligrams of buprenorphine, waited an hour, and administered another four milligrams of buprenorphine, and what we saw was that their withdrawal was significantly precipitated. So that was a 19 on the scale, on a cow scale, which at the time was a pretty high value. And that seems more routine now. On the right-hand side, you see another example of this where again, we had an individual who came in, we monitored their withdrawal for several hours. We actually waited for this person's withdrawal to get a little bit deeper, to get to a 12, and then administered four milligrams of buprenorphine. You can see that that put that individual into extremely high levels of precipitated withdrawal. They actually, we actually admitted them to the hospital to receive care for that. They were fine, they were safe, but it was that level of severity that the person experienced in relation to a single four milligram dose of buprenorphine. And so we've now, we've done this many times now, and we've actually adopted the low-dose method of buprenorphine, which was the Bernese method that had been designed to help transition patients from the long-acting opioid agonist methadone onto buprenorphine. And we've worked with this quite a bit, but in the context of that, we've collected more data from other samples, just trying to learn, is this really what's happening? Are we really seeing this interaction between fentanyl exposure and buprenorphine? And one of the manners in which we investigated this was by adding a survey to this national dataset. So there's a group that has outcome assessments embedded in residential programs throughout the United States, and they let us submit, I guess, embedded questionnaires related to precipitated withdrawal in relation to buprenorphine and methadone in persons who were presenting for treatment for primary opioid use disorder. And so this is a survey of 49 treatment programs. The total sample was around 1,600 individuals who had presented for opioid use disorder treatment. And we asked them, the last time that you used buprenorphine or fentanyl, did you experience any sort of withdrawal? Or the last time that you used buprenorphine in close proximity to fentanyl, did you experience withdrawal? And how did that vary as a function of the time that you were exposed between that exposure? And so on the right-hand side, you can see across the bottom, the x-axis, we had individuals could say, I had that exposure within 24 hours of each other, 48 hours, 72 hours, a week and a month. And then this was the percentage of individuals who reported that they experienced withdrawal. You could see there was a significantly higher number of people saying that if I took buprenorphine within 24 hours of fentanyl exposure, then I experienced a withdrawal syndrome. And that significance also was true at 48 hours. In contrast, we didn't see any sort of significant relation between withdrawal and persons when they took methadone in close proximity to fentanyl. And then there was a subgroup of those individuals, 152 people who had done this and who had used or been exposed to fentanyl in close proximity to both buprenorphine and methadone in the recent past. And so we asked them to compare their experience when using fentanyl in relation to those two substances. And you can see the overwhelmingly, they reported higher withdrawal. More people reported having a withdrawal experience in relation to buprenorphine and not to methadone. So that to us suggests that there is this kind of phenomenon occurring. So the big clinical question for us has been, how do we know if we are doing this low dose induction and having people come in and we're giving two milligrams of buprenorphine to start, and they have an increase in withdrawal, is that withdrawal precipitated withdrawal, in which case we should stop dosing them? Or is it unmanaged spontaneous withdrawal? If it's unmanaged spontaneous withdrawal, we need to get ahead of that quickly because if we let it get too deep, it's very difficult to get it back under control, right? And so it really kind of dictates two different directions that we should go with our treatment. And if we make the wrong choice in either case, then the consequences for the person's experience could be relatively high, they could be very uncomfortable. But there's not been to our knowledge an operational definition of precipitated withdrawal. So we sought to develop one. And so we have, from our data sets, we have data from a naloxone challenge that we often do. And so the study that I showed you earlier where we administered, or we stabilized individuals onto morphine, part of that trial includes a naloxone challenge where once everyone is on morphine and they have the same kind of acute exposure, acute physical dependence, they undergo a session where they have a small dose of naloxone that's administered. We rate their withdrawal at 15 minute intervals using the self-report and the observed scale, as well as visual analog gradients, which are zero to 100 gradients, where we just say, are you having any bad effects right now? Do you feel sick right now? Right on a scale of zero to 100. And at the end of that period, we administer morphine again to alleviate any sort of residual experiences that they may have. It's a very discreet period of time, and it's usually very manageable for, it's uncomfortable, but manageable. But it provides us this unique window to be able to look at, can we identify an operational definition of withdrawal? And so we wanted to look at both the optimal time window, the thresholds of change that patients viewed as being clinically meaningful, and then what the syndrome actually looked like. And I'll just note that we have published this as well. And so I'll talk about it kind of at a high level, but the depth and the details of the analysis that we did are all presented for you here. And so looking at the optimal detection window. So we looked at, within this group of people, at 15-minute interval collection, what's the point that they achieved that they rated their withdrawal at the highest possible level? And on the right-hand side, you can see that we have both the self-reported withdrawal in the filled circles and the open circles or the observed withdrawal, and they tracked very closely next to each other. If you, so 51% of people, about 50% of people reported their peak withdrawal occurred within 15 minutes. That was our first time point. So it may actually have occurred sooner, but it was very quick, evident very quickly. That increased to about 80% by 30 minutes and to about 90% by 60 minutes. So we feel pretty comfortable saying that if you have an increase in withdrawal that is within a one-hour period, and certainly if it's within 15 to 30 minutes, that it's likely that it's precipitated and not spontaneous withdrawal. And then the second goal that we had is what's the actual threshold of change, right? So how many points do you need your withdrawal rating to increase before you can feel that it's precipitated withdrawal and not just unmanaged spontaneous withdrawal? And so the challenge here is that we didn't have a standard against which to compare this. And so we used our visual analog ratings and binned them into categories. So we have a zero category where they had no bad effects, no sick, and then what we consider mild, moderate, and severe. So one to 40 is mild, 41 to 80 is moderate, and then 81 to 100 is severe. Excuse me. And then what we've, we analyzed this and saw that if we consider these as different categorical ratings, and then we compare how the change in self-reported and observed withdrawal for both of these scales, what we found is that there was a significant difference between each of those categories. So every time the category shifted on the visual analog scale, it corresponded to a significantly higher rating on both the sows and the cows, and it did so uniformly for both of those scales. So we use these as our kind of standard. And then we said, okay, what's the threshold? How many points does somebody actually need to change their score before the patient shifts into one of the, into the higher category? So if they've rated their withdrawal as a bad effect in the mild category, what change is necessary before they say their withdrawal is now in the moderate category? And so what we found was that for the sows, for the self-reported withdrawal, that represented an increase from baseline of 10 points, which also is 15% of the scale. And then for the observed withdrawal, they had to have an increase from baseline of six points, which represents 12% of the scale. Excuse me, and the important thing to note here is that the, it didn't matter what our standard was. So if it was either a bad effect or sick, the scales performed the same. So it wasn't a function of our comparator. And then finally, we looked at the actual constitution of the syndromes and found that they did actually split into two meaningful factors. So the factor two, in particular, for the self-reported factor, if individuals reported or reported an increase in yawning, lacrimation, which is, so runny eye, runny nose, perspiring or sweating, and then hot flashes, that was particularly indicative of an increased severity of withdrawal. And then if you observed an increase in pupil dilation, or again, of runny eye or runny nose, then that was particularly indicative of withdrawal. And so to summarize this, what our take-home operational definition is, which I think is a starting place, is that if there was an increase of 10 points or 15% of the score for the self-report and an increase of six points or 12% of the score for the observed rating, within an hour of administration, it was likely to be precipitated withdrawal. And that independent of that, if we saw an increase in runny eyes, yawning, runny nose, sweating or hot flashes, or we observed changes in pupil dilation or changes in runny eyes and runny nose, that was also consistent with precipitated withdrawal. And so I'll conclude by just saying, I hope I've convinced you that illicitly manufactured fentanyl is not like other opioids. The data that we have regarding the ADME of medicinal fentanyl has implications, I think, for people who were exposed to illicitly manufactured fentanyl. But there are so many open questions in this area and we really need more data. Our experience has been that precipitated opioid withdrawal may be occurring when we transition individuals from fentanyl to buprenorphine, and that a good starting place in terms of an operational definition would be to look for a change in self-reported symptoms of 15% or 12% of the scale for observed withdrawal within 60 minutes. And so I'll end here just by saying, here's my contact information. And then a lot of the information that I just summarized for you is also in this upcoming handbook, which I've highlighted for you here. And then I'll thank the individuals who fund this work, which is Cure Addiction Now and the National Institute on Drug Abuse. And then I'll conclude. Very good. Thank you very much, Dr. Dunn. That was interesting. And we're all very troubled with what we're seeing in terms of the use of fentanyl and how to initiate buprenorphine and various changes in how we've dealt with people with opioid use disorders in the past. We had a couple of different questions. The first one was around xylithine. And I think this question came in around the time of hearing something more about the increased heart rate, I believe. And I have some questions around that. And that's in part because my understanding, I mean, we know xylithine is an alpha-2 agonist, a presynaptic agonist. And quite honestly, while I'm interested in your comments on this, I would think that it would actually slow the heart rate and have actually, we've had some discussions around, is it, granted, xylithine has increased the overdose and the death rate associated with fentanyl, but has it actually had an effect on the wooden chest syndrome because it reduces norepinephrine, the response of the body to norepinephrine by reducing the release of norepinephrine as an alpha-2 agonist? But do you have any thoughts on any of that? Yeah, it's a topic that we think about a lot. So we are now testing everyone when they present for xylithine exposure. There hadn't been an assay available for that, but there is one now. And so we'll go back and look at that. I do think, so looking back at the literature for xylithine, it does suggest that there might be some rebound hypertension if people were to become physically dependent on it. And so we actually think perhaps that's contributing to the experience of our patients. So I don't know that it's fentanyl only that's contributing to the hypertension, but it is certainly the drug product that they're exposed to in the Baltimore area. We also know, I know xylithine has been, we read about it a lot as being highly available in the Philadelphia area. And it turns out that it's been in the Baltimore area for quite a while. And we've had a recent study that looked at the collected syringes from safe consumption places tested. I think it was 60 to 80% of those syringes tested positive for xylithine. So it's likely that many of our patients are frequently exposed. We, for the same reason that you, so your comment regarding wooden chest, I think is a good one. I don't know how much xylithine would contribute to that, but it seems reasonable that maybe there would be some benefit there that some kind of interaction that might help reduce the incidence of wooden chest. We thought the same thing about lofexidine. And so we have studies that are actually ongoing, which is a similar mechanism of action to xylithine. And so we have studies ongoing looking at lofexidine in this population. And we're not, I'm not seeing, we don't measure wooden chest, we just measure the withdrawal syndrome, but it doesn't seem to be as profound an effect as I had hoped that it would. So I think, yeah, I think we have a lot to learn on that topic. The other thing that we're seeing is very high rates of stimulant co-use. And so that is likely contributing as well. And so part of it, it's difficult. We can't, those data can't really attribute specifically to fentanyl, but it is the clinical experience of the patients that we're seeing at the moment. I'm looking at some of the other questions. There is a question. One was around method on this flag nest. And that, you know, was that the primary reason this question came in primary reason that we were not seeing withdrawal problems compared to buprenorphine? And I think that's somewhat a given, isn't it? In terms of that part of the lecture. Yeah, so I think that probably may be referring to the figure that I showed where there was a little bit of, that there were some individuals that say that they had a withdrawal after they experienced, if they use fentanyl in close proximity to methadone, but it was higher when they experienced or we used fentanyl in close proximity to buprenorphine. Our interpretation of that, it doesn't, we wouldn't think that methadone would precipitate withdrawal. There's no mechanism that would suggest that it would. However, the way we worded the questions to patients, we didn't want to tip them off that we were looking at precipitated withdrawal. So we just asked, did you have any withdrawal in proximity to these medications? And our interpretation is just that it was probably not well-managed withdrawal. So the individuals, they answered, you know, that they had some withdrawal, but we don't think that it would suggest that methadone would precipitate it. We think, but we do think that the incidence of the fact that withdrawal was much higher, there was a higher incidence in individuals could buprenorphine exposure probably is indicative of precipitated withdrawal. Because of the higher affinity of buprenorphine than dropping it. Okay. Right, it's a higher affinity and then a lower ceiling out in the effects. So once it does, it pushes all the fentanyl off, but then doesn't fully replace it. Another question was methadone does not have any of the problems with precipitated withdrawal, which we just kind of talked about, maybe, and has good evidence for being superior medication for people with higher physical dependence and more severe obesity disorder. Earlier studies comparing methadone buprenorphine show better retention rates. Are you aware of any studies comparing methadone buprenorphine in patients in persons with obesity disorder using fentanyl? So I'm not aware of head-to-head studies, but this has been a topic of conversation and concern in the field, that if there is in fact a deeper withdrawal, buprenorphine is a scalable treatment model, but methadone really is not as scalable at the moment. The data in the case reports don't yet suggest that buprenorphine is not as effective. It does seem there, and frankly, the reports about transitioning patients from fentanyl to buprenorphine are themselves still a bit under discussion. So there are some areas of the country where they say they have no concerns, they have no trouble transitioning patients from fentanyl to buprenorphine, and then certainly there's areas like us that we have significant, we repeatedly see precipitated withdrawal. I don't know what the mechanism of that is, but it seems to be that if there's a difference between the medications, it's in the induction process. Once you can get patients on the medications, there's no reason to think that either of them would be better than the other. This does, though, I think speak to the need to be able to scale methadone in a different capacity because they're just, patients need, the withdrawal that they have is deeper, and we just need to have more access to medications for them. Yeah, absolutely. I'm sorry that we're gonna have to quit. I appreciate that you left your email for some to be able to reach you with other questions, and we thank you very much for this talk. It just, a whole bunch of questions come to my mind around things that you said, and so it's a very stimulating conversation. And again, from the American Osteopathic Academy of Addiction Medicine and myself, Dr. Stephen Wyatt here in Asheville, North Carolina, I thank you very much for presenting today. Thank you so much. Thank you for the invitation, and hopefully I've inspired some of you to please do work in this area and help us learn more about how we can help our patients. So thank you so much. Thank you. Bye-bye. Bye.

webinar

Dr. Kelly Dunn

fentanyl

pharmacologic properties

withdrawal mitigation

opioid crisis

illicitly manufactured fentanyl

pharmacokinetic profile

withdrawal severity