Professor Kelly E. Dunn: Fighting Fentanyl with Naloxone: A lifeline Amid the Epidemic

Somebody would be suspective of overdosing and an individual would run to the room next door to get Narcan and they would run back and by the time they had gotten back the individual had already expired, had already passed, and the thought was, wow, is fentanyl so potent that it's producing these centrally mediated effects?

Good afternoon everyone. My name is Katherine Najafi Tagal. I'm an ophthalmologist by training and the Chief Medical Officer at Emory Pharma. Emory Pharma was founded in 2011. It is a full service contract research organization lab that is FDA registered, DEA licensed and CGMP and GLP compliant facility in Alameda, California. It is my great pleasure to introduce today's distinguished speaker, Professor Kelly E. Dunn. Professor Dunn is a Professor of Psychiatry and Behavioral Sciences at the Johns Hopkins School of Medicine and is the incoming Director at the Collard Institute for Addiction Medicine at University of Maryland. She's an expert in addiction science focusing specifically on opioids and opioids use disorder. Professor Dunn is also the Editor of Experimental and Clinical Psychopharmacology, an Oxford handbook on opioids and opioid use Disorders, a leading resource on opioid addiction treatment and research. Her pioneering work has significantly advanced our understanding of substance use disorders and she continues to be a key contributor to public health efforts aimed at addressing the opioid crisis. We are incredibly fortunate to have Professor Dunn with us today. Please join me in welcoming Professor Kelly Dunn.

Thank you, thank you for the opportunity to talk with you today. I'm excited to be able to review some of the data that we have in the field related to illicitly manufactured fentanyl and the challenges that that may be posing and maybe opportunities for advancement and inn to help address the current public health crisis related to opioids. So general outline, I'll just spend a moment or two talking about opioid trends, epidemiological trends, and then I want to cover some unique features of fentanyl and some of fentanyl's unique overdose risks and then talk about naloxone or opioid antagonist treatment for fentanyl related overdose. So the United States is experiencing an opioid crisis or public health emergency related to opioid related overdose. The figure on the right shows the contribution of all drugs, especially synthetic opioids, which is in the darker red, to opioid or drug related overdoses. We continue to see unprecedented rates of drug related overdoses in the United States exceeding 100,000 people per year. We did see a bit of a tick down in that rate in the past year for reasons that we're not entirely certain, which is promising. But it still equates to one overdose every five minutes. And in the past decade that equates to more than million people who have experienced a fatal drug related overdose. And that that's only one quarter estimated to be 25% of the actual overdoses that occur in the United States per year. The overdose crisis seems to be really concentrated in the United States relative to other countries throughout the world. The data on the left hand side show you there's 1,300 related deaths per 100,000 people that are attributed to substances that are driven by synthetic opioid exposure in the United States, which is double the rate that we have or that has been reported in Europe. Again, the overdoses are in part driven by the exposure, whether it's intentional or unintentional, to synthetically produced fentanyl. And this figure just shows you that this has. The replacement of fentanyl throughout the United States has been very ubiquitous. And so we'll talk in a few moments about why that may be the case. But essentially fentanyl products have been, or fentanyl has been synthesized and has been added or replaced the heroin product throughout the United States. And the data on the left hand side show you the number of fentanyl related overdose deaths in the United States in 2013, with the lighter colors being fewer and the darker colors being more. And then on the right hand side you could see that that has just spread throughout the United States. It actually started more on the, on the east coast and then worked its way over. And that for that reason, myself and my colleagues on the east coast have been really thinking deeply about this problem for a long time. So in addition to fentanyl as a, as a highly synthetic opioid being sold as heroin throughout the United States, we also now have pretty reliable adulteration of fentanyl with other products. And most specifically we're seeing xylazine. So xylazine is a veterinary sedative. It's used routinely in veterinary practice and preclinical research, has been for years. Was developed in the 1950s or 1960s. They initially started to develop it, to examine it for use in humans, but they discontinued that research because it was just viewed as not being safe. The threshold for adverse events was relatively high or, well, I guess the threshold was relatively low. So it's never been approved for use in humans. We are seeing, beginning in the early, maybe around 2010, 2012, we started to see reports of Xylazine being added to the heroin drug product in the United States. And that has increased in significance, in quantity. And the data on the left hand side show you that again, it's kind of moving from east coast to West Coast. And we'll see and we'll talk more about the overdose risks specific to fentanyl or I'm sorry, to xylazine at the end of this talk. But in general, what we've learned from talking with people that are selling at the, at the street level, Xylazine appears, we think that it was initially added to fentanyl in part to, as a brand differentiation. So fentanyl is very fast acting and when people are exposed to it, they need to use fentanyl multiple times a day. Xylazine is also a very significant sedative. And so by adding Xylazine to Fentanyl, it extends the level of sedation, the duration of sedation that somebody might experience and perhaps would necessitate fewer drug administrations per day. So we think that that might be why it was initially added. But now it just, its use seems to be more ubiquitous throughout the United States. And Xylazine has, it's a non opioid product, it's an alpha 2 agonist. And so we think that it has, it's having consequences related to things that would be specific to that type of medication, including hypertension. We're also seeing wounds that won't heal in our patient populations. So right now the majority of heroin that's being used in the United States has been replaced either in part or full by synthetically produced fentanyl. And a large amount of that also has xylazine that's been added to it. And many of them, our patients in various areas in the United States don't have much of a choice in what they can receive. They don't have the option to take conventional fentanyl or heroin anymore. They only have the opportunity to take fentanyl and they can't really choose whether it includes xylazine or not. So in addition to this, we're also seeing high rates of poly substance use. And so our patients, these data demonstrate high rates of co use specifically with stimulants. And in the west coast that's methamphetamine, and on the east coast that's heroin. The gray line shows you the total overdose mortality related to fentanyl exposure. And then the blue shows you fentanyl in combination with stimulants. And so you can see that that just continues to rise. We're calling this the fourth wave of our opioid crisis at the moment. There has historically, I guess, a deep connection with the use of stimulants, the co use of stimulants and opioids. And this is a trend that has come up really every decade since the 1950s, where we've seen this kind of period of intense co use that then remitted for a period of time. But this experience that we're seeing now is pretty unique compared to those prior experience because the co use that we're seeing is fentanyl, which is long acting. And in many places in the country it's methamphetamine, which also is long acting. And for the stimulants in particular, we have no pharmacotherapies that can help treat stimulant use disorder. And so this is a big concern. So our patients in Baltimore, for instance, are presenting to treatment with cohesive co exposure of fentanyl, xylazine and cocaine often, which just presents a very severe case. And this is just one more depiction of that. Where you can see again, on the left hand side you see the number of persons who are providing urine samples that are testing positive for fentanyl in conjunction with prescription opioids. The top right is in conjunction with heroin, and you can see that those are relatively low. In the bottom left and the bottom right you see the co use of fentanyl with methamphetamine and the co use with cocaine. And you can see that that's much more significant. And then finally, we've been thinking a lot about this in Baltimore for various reasons, but including, as was recently chronicled by the New York Times in a series of articles this summer, Baltimore has among the highest overdose rates in the country. And so our patients seem to be particularly hard hit with this kind of collateral use of xylazine, I should say exposure of xylazine, fentanyl and the stimulants cocaine, as well as we have other opioids in our, in our product as well, such as the nidazines, which are even more or even more potent than fentanyl. So this is kind of the backdrop of what we're working with here. And we started, so we saw in Baltimore the infiltration of synthetically produced fentanyl in our drug product in around 2019. That's when we started to see patients no longer testing positive on urine assays that had a morphine standard, which means that they were exposed to something like a conventional opioid, a commercially produced opioid or heroin or codeine or morphine oxycontin. Our patients only tested positive for fentanyl, which is its own urine test strip. And we haven't seen any sort of remission of that. In fact, we've not had maybe 1% of patients, five patients I can think of who presented to treatment since that time who actually tested positive on a morphine based assay. So it's a complete replacement of fentanyl. And we started to notice the experience of our patients was a bit different than what we had been used to. And I've worked in this field for almost 20 years now and I started to notice changes in their withdrawal expression and their just general experience that to me suggested maybe there was a fentanyl, something to do with the mechanisms of fentanyl underlying this. So let's talk a little bit. We started to dig into what fentanyl was because we had thought for a long time that fentanyl was a more potent. It is a more potent form of opioids. We often thought about it and talked about it in our field as really is that being kind of the defining feature of it, that it was pharmacodynamically more specific for the mu opioid receptor, which is the receptor that produces a lot of the opioid like effects. But in looking through the literature we came to realize that fentanyl is actually very different in very important ways that are probably in my mind contributing to the unique experience. So what is different about fentanyl? So it's an extremely strong opioid. It's estimated to be 50 times stronger than heroin in potency. And the level of euphoria or the subjective experience that it can produce. Fentanyl itself is believed by the DEA to be an ideal product for cartels and for drug distribution because it's relatively easy to manufacture relative to other forms of opioids and it's easy to hide in other products. And so fentanyl is a white substance which is very easy to hide in the heroin product on the east coast, which tends to be a white product, versus heroin on the west coast and the southern coast, which is usually more of a black tar heroin, which can't easily conceal a white powder like fentanyl. It behaves differently from other opioids in the body, as I'll show you in a moment. And then it causes rapid overdose. For reasons that we'll talk about in a moment, I do want to mention that when I say the word fentanyl I really, it is probably more accurate for me to say Fentanyls, because as you can see here, there are multiple different versions of fentanyl and they can be produced with very small changes during the chemical process. And in fact, we think probably as these clandestine laboratories are producing what they intend to be, illicitly manufactured fentanyl, small errors or changes in their design could lead to them producing a variety of these other forms like remifentanyl, carfentanil, l, fentanyl and so on. And so most likely our participants are being exposed to multiple different versions of these. But just for ease of use, I'll just, I'll refer to fentanyl. And then fentanyl yields a primary metabolite nor fentanyl, which is depicted here at the moment, we don't think that nor fentanyl has any psychoactive properties. Okay, so let's talk about fentanyl itself. So fentanyl is a medicinal product. It's, it was one of the first opioids that was synthesized. It was actually following meperidine, which is Demerol. It was, I think, the second opioid synthesized back in the 1950s. It was specifically engineered to be highly lipophilic. The goal was for it to cross the blood brain barrier very quickly. And in fact, for frame of reference, it's considered 1000 times more lipophilic than morphine, which is kind of our conventional prototypical opioid standard. As I mentioned, it's highly potent at mu opioid receptors. It's been FDA approved for decades for the use of analgesia and anesthesia and hospital settings and during post surgery, it's recognized as having relatively poor bioavailability when it's administered orally. And so it's often been prepared in other routes of administration. So transdermal patches, mucosal, parenteral roots, and here's a couple examples on the right hand side of ways that fentanyl has been produced. This is also in part designed because fentanyl can be effective at extremely low doses, micrograms, to be able to produce an effect which is very different from other forms of opioids and certainly can't be easily packaged in something like a capsule or a tablet that you might use to consume another type of opioid. So for years, for decades, fentanyl has been a mainstay for analgesia in the hospital system and it's still used for that purpose today. So when we talk about fentanyl, we are not talking about medicinal fentanyl, we're talking about illicitly manufactured fentanyl and the reason, there's lots of, I guess, discussion as to why heroin has been so rapidly replaced with illicitly manufactured fentanyl in the United States. Some of the, I guess the, the core reasons are listed here. So heroin production is rate limited by the life cycle of a poppy plant. So you have to actually grow a plant, let it reach maturity and then extract in a very time consuming, expensive process, relatively expensive process, the opium that can then be converted into heroin. In contrast, fentanyl can be synthesized with a three or four step process in a way that is easier than growing these poppy seeds. It had been that people that were producing heroin would need large swaths of land to be able to grow these poppy seeds in a clandestine way. And that has been alleviated by the shift over to illicitly manufactured fentanyl. So it's easily and quickly synthesized. It can be produced entirely from commercially available ingredients. And as I show you here, data have suggested that it's much cheaper to reduce a kilogram of fentanyl relative to a kilogram of heroin. And again, it's a white powdery substance so it can be concealed easily in other substances. And this book here on the right hand side, Dreamland, is a book that really did a nice job. It's an investigative narrative of how fentanyl has been distributed and infiltrated or actually heroin slash. Fentanyl in the book has made its way into rural America, which is an area that had never really had historically challenges with, with heroin products. They, they had more commercially produced opioid distribution, kind of extra medical distribution, but they hadn't really dealt with heroin. And so that's part of our ongoing crisis now is that these communities are really not equipped to scale up the level of care that they need to, to meet the needs of the patients that are in those communities. What do we know about illicitly manufactured fentanyl? And so I'll, I'll say this again during the talk, but it's important to keep in mind that most of the data that we have on how fentanyl behaves in the body and the, and the effects that it engenders are based on our understanding of medicinal fentanyl levels orders of magnitude smaller than what our patients are presenting to treatment with. And so a lot of the data, there's not a lot of empirical data that I can show you that really speaks to the clinical experience of patients and how it may be contributing at a person level to the challenges that we're facing in our opioid treatment infrastructure. But there's some data and so here's a good example. So this was a quasi experimental opportunity that we had in our research team. And my team members that led this evaluation are on the right hand side here. We have run in our research unit, it's a closed research unit. We've run randomized controlled trials where patients live with us, they're enrolled from the community, and then they live with us for up to 28 days on a controlled unit. So we know that they're not having any sort of extra use of opioids or other substances while they're in our study. And by routine, we had a standard procedure where we would have people enroll into our trial and they would stay with us for seven days where we would. And during which time we would stabilize them off of whatever opioid they had been using onto a standard opioid. And we did that so that we can kind of equate their level of physical dependence or acute physical dependence to be similar so that they could then be randomized into one of three different medication conditions for a randomized controlled trial. So I'm not talking about the outcomes of these trials here. I'm just showing you data from this initial opioid stabilization period, because that was identical across a study that ran from 2010 to 2016 and then a second study that started around 2019, which only enrolled people that had been fentanyl exposed by, by virtue of the changing drug product in our area. And so what we did is for days one through seven, all of these participants received morphine injections four times a day at 30 milligrams subcutaneously. And then we collected observer radiance of withdrawal, self reported radiance, and then also vital sign radiance of withdrawal four to seven times a day. So really granular assessment of what their withdrawal looked like throughout the day. And so again, we started to recognize that the patients that were admitting into our trials, and more recently we're having more severe and less managed withdrawal. And so we wanted to dig into that a little bit more. And so just to show you briefly, these are participant samples. You can see they're a bit misbalanced, in part because this was a convenience study. But in general, we saw no significant differences in the constitution of the groups. So we didn't see differences by race, by age, by ethnicity, by gender. The only big difference is, is that in order to gain entry to the first trial, participants had to test positive for opioids. And we were only testing for morphine based standards at that time. So 100% of these patients tested positive for heroin or for some kind of commercially produced opioid. In the second study, none of those patients tested positive for those substances and we had to shift entirely to a fentanyl assay. So we know that there was good differentiation in the opioid exposure between the two groups. So what did their withdrawal look like? So on the left hand side here I show you the self reported withdrawal. And on the right hand side it's the clinical, the observed radiance of withdrawal. And then across the X axis is the morphine dosing day. So day one is the day they presented to the treatment and then they were again, they continued to receive morphine 30mg sub Q 4 times daily for 7 days. And then the withdrawal rating is on the Y axis with a higher level representing more severe withdrawal. Then the light blue is our historical control group. So this is our group that was enrolled from 2010 to 2016. And then the darker group, the darker blue group are the individuals that were exposed to fentanyl. And if you look at our historical control group in the self reported withdrawal as an example, you could see that that morphine stabilization really worked pretty well for them. So they started off somewhat high on day one, which is to be expected, but then once they had a full day's worth of medication in them, their withdrawal really dropped significantly and it continued to decline to levels that were considered well managed throughout that seven day stabilization period. In contrast, the individuals who were fentanyl exposed, you can see that they started at about the same level on day one, but beginning on day two they had a significant increase in the severity of their withdrawal that really didn't, that started to remit but remains significantly different, significantly higher from that historical control. And if you're unfamiliar with the scale, the subjective opioid withdrawal scale, A rating of 20 signifies moderate and approaching severe your levels of withdrawal. So this is extremely high withdrawal for somebody who is receiving a pretty high dose of an opioid agonist during that period of time, as well as actually an array of other comfort medications because we needed. It was kind of an all hands on deck trying to help get these patients stabilized in part because we really didn't anticipate this difference and it was really surprising to us to see it again and again in patients that were presenting to treatment. And then on the right hand side you can see that the same pattern was to with observed ratings of withdrawal. So it wasn't just how patients told us if they felt, but it was the actual observance of physiological changes. So another way of looking at this is the percentage of participants whose withdrawal was rated in different categories. And so I'm showing you here just the self reported withdrawal data for people who are fentanyl exposed on the left hand side and people who were in our historical control on the right hand side. And this is again the morphine dosing day across the bottom, day one through seven. And this is the percentage of participants whose withdrawal met criteria for either no withdrawal, mild, moderate or severe on that self reported scale. And I think this really depicts this nicely. Clearly I should say that you can see in the fentanyl exposed group that there was significantly more people whose withdrawal met criteria for severe relative to the historical control. And it was persistent. And we saw this kind of inverted U shape where withdraw was worse on day two and then started to remit a little bit on day three and four. And again, keep in mind that all of these participants across both of these trials are receiving the same array of opioid medications and that the persons who are fentanyl exposed are receiving a variety of other medications as well. And then one of the questions is, is this withdrawal severity driven by one or two symptoms or is it just kind of across the board? And what these data show you is the mean increase in severity rating relative to the historical control for the self reported and the observed symptoms. And you could see it's across the board. So it wasn't just that our participants were craving more in a kind of artificially increased the scale across the board. Their experience was more severe then. Finally, I just want to point out the physiological nature of this. This is heart rate on the left hand side. And then on the right hand side, it's a percentage of participants whose heart rate exceeded 100 beats per minute, which makes them officially tachycardic. And you can see that again beginning day three, four and five, we saw significant increases in heart rate in our fentanyl exposed group relative to our historical control. And that we had significantly more participants who at some point on days, especially 3, 4 and 5 and 6 as well, their withdrawal or their heart rate crossed the threshold into clinically significant. And that's important for many reasons, including that this now warrants a higher level of care and intervention for these participants. This corroborates. These data show us that our intuition and talking with people in our anecdotal experience, once we were able to actually put it together and look at it quantitatively, it really showed us that this is different, the experience of our patients is different. Then we started to dig in to the literature to try to figure out why. We found some really interesting features of fentanyl that I hypothesize are contributing to the, to this kind of severe nature of the experience. Many of these things that I'm about to talk to you about, these different features or characteristics of fentanyl are summarized in this paper here. But again, the caveat to this is that the data that I'll show you and that are summarized in this paper are based on medicinal levels of fentanyl. They give us a good foundation to understand what's happening and what the experience of our participants and our patients. But there's probably a lot more that we have to learn and there could be very important variations in how these super therapeutic doses of illicitly manufactured fentanyl are behaving. So I want to talk through the adme, the absorption, distribution, elimination and metabolization of fentanyl to kind of demonstrate how it may be different from other opioids. So again, as I mentioned, the absorption of fentanyl, it's highly lipophilic and it's rated is considered to be a thousand times more lipophilic than morphine, which means it has very swift tissue penetration, particularly of highly profused areas like your brain and your lungs. This, the study on the right hand side is a human laboratory trial that compared the effects of various different opioids in individuals who were opioid, experienced, but not currently physically dependent. And they gave them in double blind ways, exposure to different doses of fentanyl, buprenorphine, heroin, morphine and oxycodone. And what you see here, the fentanyl is the diamonds, right here you can see that the ratings of high occurred at very small doses relative to these other substances. Right. So it takes just a very small amount of fentanyl to produce an effect that's equivalent to other feelings of buprenorphine or heroin or morphine. I should say there's been a number of studies that have looked at the subjective effect profile of medicinal fentanyl and have reported that the effects from participants, individuals who are exposed to fentanyl, can detect the effects within 30 seconds, 30 to 90 seconds. And the peak acute effects of fentanyl, the subjective effects occur within five minutes, but within 40 minutes, those euphoric subjective effects become undetectable. So it's an incredibly rapid experience for participants, which we know corresponds to a highly reinforcing substance. And so that makes it really potentially challenging. And also just, I guess concerning that, we know that this is just going to make it very difficult for people to abstain from. And you know, one thing that's important, I think about the data that are presented on the right hand side here, is that when when participants were asked about their experience of fentanyl relative to other substances in the late 2000s, the studies Reliab reported that the risk of fentanyl being used extra medically was very low because participants viewed it as dangerous. And relative to other forms of opioids that they could take, they would have preferred those. And so I think we didn't for a long time have fentanyl flagged as something of significant concern in our field because relative to other opioids, it didn't seem to be as it didn't seem to have the same risk profile. Okay, so absorption, right. So fentanyl crosses the blood brain barrier extremely quickly, produces effects of very fast, and within 40 minutes the effects are no longer subjectively detectable. Part of that is related to its distribution five minutes after fentanyl is injected. And these are laboratory trials that have been able to demonstrate this. The concentrations that are of fentanyl in the brain decrease by 90%. So it really is that rapid for participants. And it moves into the peripheral muscle, so it becomes sequestered in the peripheral muscle. And that's demonstrated for you or depicted for you on the right hand side in this figure. And 30 minutes after injection it has moved from the muscle. A Large percentage of it, 17% overall has moved from the muscle and it has become sequestered in fat and lipid stores. And the level in fat now is 35% higher than is what, than what's detectable in the blood plasma. Reliably. These various studies have found that the affinity for fentanyl to be sequestered in these lipid stores, that we see consistently higher levels in lipid stores than we do in the plasma. And again, the data on the right hand side kind of demonstrate that nicely that when the minutes after injection, if you look at fentanyl exposure in plasma, it was relatively high and then it decreased quickly, but then it was quickly redistributed into muscle, but in a more slow way distributed in sequester into fat source, but then it's remained there for an extended period of time and that even at 240 minutes post injection, they were still seeing significant stores in fat. And so this has some consequences. I think it probably has some consequences. I will say that for our patients we haven't been able to really adequately examine this because it's very difficult to collect venous samples from them and to do PK modeling from them, because the frequency of fentanyl injection often leads to poor venous access. If you look in the medicinal literature, again, fentanyl exposure in medical settings, particularly in anesthesia or surgical settings, they have reliably found this phenomenon that that is referred to as the wooden chest syndrome, which also is chest wall rigidity. And the likelihood, I guess, this is a consequence of exposure to fentanyl that may be related to this redistribution into the muscles or into the lipid stores. And so this is characterized by a sudden rigidity in chest wall, diaphragm, or upper airway muscles. And actually, maybe more, which I'll talk about in a moment. The likelihood of chest wall rigidity occurring is causally related to the dose if it's a higher versus lower dose of fentanyl, the speed of administration. So if it's pushed really fast in an intravenous line versus more slowly, and the route of administration if it's parentally administered. And so I point these out because this is the manner in which many of our patients are being exposed to fentanyl, right? These high doses went through intravenous lines very quickly. Chest wall rigidity does not only have to occur in close proximity to the administration of the drug. It can be detected as soon as one minute after administration, and it can remit quickly. But in the study that's cited down here, in 380 patients who are undergoing a bypass, about 8% of them developed rigidity hours after they were postoperatively exposed to fentanyl. That suggests to me that it is the sequestered levels of fentanyl that are coming out to the plasma in this delayed fashion that could be contributing to the muscle rigidity. And they know that the this was meaningfully related to fentanyl because they could reverse it with the antagonist administration. So naloxone is a potent mu opioid receptor antagonist that can push fentanyl off the receptors and reverse its effects. And then again, in a study of patients that were receiving fentanyl for anesthesia, 69% developed rigidity, 31% of which were severe. So in this case here, they show a number of patients in a surgical setting, again, medicinal levels of fentanyl, who are receiving various doses of fentanyl. And the squares represent the individuals who had some sort of measurable increase in muscle tone, some sort of rigidity relative to individuals who did not have this increase in muscle tone. And so in the field, this is commonly acknowledged. As a risk in surgical settings for individuals who are going to receive fentanyl exposure and they can kind of work against it. And if you were to have muscle rigidity in a surgical setting, they could intubate you to help with oxygenation. But in a field with our patients, those, you know, opportunities are not widely available. And there is some, some evidence of rigidity in overdose cases. It's very difficult to find these data and these data that are presented here. It's. It's actually two studies. One is it was a supervised consumption site in Vancouver where they. Patients could come in, or people could come in outside of treatment and just bring their drug product and administer it in the safety of a consumption site so that if they were to have an overdose, somebody would be available to help them. In that study, they found that 485 of around 1500 overdoses were rated by the staff as being atypical in nature. And then this shows you kind of the reason that they were rated as atypical. And by far the most common reason was muscle rigidity happening in about 15% of those individuals. And that occurred through jaw clenching, posturing, their arms being bent, their legs being held out straight, clenched fists, or overall stiffness. The challenges that have been reported in the field with our patients when this occurs is that if you have somebody who has experienced respiratory depression and their chest is rigid, you cannot administer CPR to that individual. If their hands are clenched, you cannot get a good oxygen saturation measure from their fingertips. Right? So they're. You can't open their jaw to administer rescue breathing if their jaw is clenched. And so it's structural changes that result from fentanyl exposure that are contributing or interfering with intervention for somebody who's experienced an overdose. And then a second study was performed on post. It was postmortem evaluation of persons who had experienced, whose overdose was attributed to fentanyl. And they found that in 50% of those individuals, they did not have detectable levels of norfentanol, which suggests that the fentanyl was, was never able to get to the liver to be metabolized. And so their, their interpretation of this is that overdose was actually secondary. It wasn't a centrally mediated effect. It was a structural effect from rigidity that prevented the lungs from being able to work metabolization. We do know that fentanyl is differentially converted. Well, it's converted to norfentanol, which again, is its primary metabolite. The conversion rate is dependent on the CYP3A enzymes. These are very highly heterogeneous throughout the population. And so, so it's unclear at the moment whether different alleles or different versions of the CYP3A enzymes will lead or are contributing to the differential effects. Right. So, you know, not everyone has muscle rigidity when they have fentanyl exposure, just some people do and we don't know how to predict it, but perhaps it could be related in part to the metabolization and then finally elimination. 85% of medicinally administered fentanyl is eliminated within three days. So it's really, in many ways, I think a fentanyl is not being. It's a short acting opioid with a long, I'm sorry, it's a long acting opioid with a short profile of effects. Right. So it's persisting in the system. It can be detected for up to 72 hours. 75% of it is eliminated in the urine. But we know that repeated exposure causes peripheral accumulation and that's what the data on the right hand side are showing you. So this is a study where they were administering consecutive doses of fentanyl at 20 micrograms on the top and 40 micrograms on the bottom. These were in animals and they were looking at their exposure, their analgesic response over days, and they found that with a lower dose of fentanyl, the 20 micrograms, you could see that their analgesic response, which is the solid line, was about the same on every day. But with the higher dose of fentanyl they started to see an enhanced analgesic response in subs in the later days, which they interpreted as evidence that the accumulation of fentanyl, likely in the peripheral lipid stores, was actually conferring a meaningful effect. Right. So the animals were having higher analgesia. And then we have some evidence of this in people where this was a study that was done in individuals who had been, who had admitted themselves to an inpatient treatment program and found that when they did serial urine testing on these individuals, they found that they tested positive for fentanyl for up to, I think it was seven days and then nor fentanyl for about two weeks. Right. And so they were in a controlled setting. So we knew they hadn't had extra medical use. Another phenomenon with fentanyl is this, this issue of secondary peaking. This is something that we see with medicinal doses again and it's evident in some people, but not all. And what it means that these are different plasma levels of fentanyl. And you can see that as time goes on, some individuals show this kind of increased plasma levels, this reintroduction of fentanyl likely from the muscle or lipid stores that goes into the bloodstream. And these secondary peaks are meaningful because, and here's another good example of how that, what that looks like. They're meaningful because there's been case, there's numerous case reports, particularly from the kind of the early days of fentanyl when it was used medicinally, where they found that people would be revived from surgery and they would be fine and coherent and then, you know, abruptly, two to four to eight hours later would go into respiratory depression and they would have to administer naloxone to reverse it. And so it suggests that the sequestered levels of fentanyl are clinically relevant and are being reintroduced to the plasma in a way that, that could be high enough to produce a respiratory event. So let's talk for a minute about fentanyl's unique overdose risks. We've touched on some of these already, but fentanyl directly reduces oxygenation. So the administration of fentanyl relative to other opioids, and this has been looked at in preclinical and human models, it reduces whole body oxygen within 10 minutes. It is mediated directly through Mu receptor activation. So fentanyl is more potent at the Mu receptor than other forms of opioids. And that seems to be be meaningfully associated with the oxygenation. Again, 70% more potent than morphine at suppressing minute volume. And there's less cross tolerance of fentanyl to morphine than other opioids. So for a long time, if an, if an animal or a person were exposed to an opioid like heroin and then they received morphine, their tolerance that they had developed to heroin was somewhat protective against the dose of morphine that they might receive. That, that relationship is not as true with fentanyl. So the relationship or the tolerance that an animal or person has to morphine does not protect them to fentanyl at the same degree, so they continue to be at greater risk. Fentanyl also directly produces apneas and hypo apneas and they are unique apnea events relative to, they're not just secondary to respiratory depression or low oxygenation. They're centrally mediated, they're dose dependent and they develop, they produce this kind of low level compensatory breathing in people. So it's somewhat, once people are familiar with it, it's somewhat recognizable. There's also structural changes. Again, fentanyl causes chest wall and muscle rigidity, which is that wooden chest syndrome that is independent of respiratory depression. So those two things happen at different timelines, they onset and offset at different times. And you can have one without the other. The chest wall rigidity can occur at doses that are lower than what is necessary to produce respiratory depression. And there's a hypothesis that it's noradrenerg, which suggests that it may not be reversible in naloxone, if that's, if in fact that's true. And then finally, fentanyl causes laryngospasms, which is a total occlusion of the vocal cords. And again, this is independent of muscle rigidity. It's not just that your vocal cords become rigid, they close. This is believed to be, or hypothesized to be cholinergically mediated. So again, not necessarily responsive to naloxone. This was is detectable and something that is routinely protected against in surgical settings by pre treating an individual with a blocker that can prevent the onset of this effect from happening. But once it occurs, it's extremely difficult, if not, you know, in some cases impossible to reverse it. You just have to wait for the fentanyl to be metabolized and it can occur extremely rapidly. And what this looks like functionally, these are data. This is just an example of a glottic closure. It's not taken from an example specific to fentanyl, but I've seen this presented in this context in the same manner. So this is on the left hand side, that is an open vocal cord and that on the right hand side is closed and that no air can get through this closure. Right, so this is significant. Well, not nicely. It aligns well with what we had been hearing from the field, which is that patients would, somebody would be suspective of overdosing and an individual would run to the room next door to get Narcan and they would run back and by the time they had had gotten back, the individual had already expired, had already passed. And the thought was, wow, is fentanyl so potent that it's producing these centrally mediated effects? But in fact, I don't think that as a field we really understood or recognized these structural changes that are occurring with high doses, high fast doses of fentanyl administration. In our last section here, we'll talk a little bit about naloxone or opioid antagonists for fentanyl related overdoses. So these again and fentanyl, I hope to have convinced you that fentanyl is not like other opioids and that it has risks, more risks in some way than other opioids for producing an Overdose largely because it has these structural consequences associated with its use. So naloxone is an opioid antagonist. It was originally developed back in the 1970s and approved for use in hospital settings to reverse opioid related overdoses or opioid consequences. It's very fast acting, usually will fully remit or be fully kind of eliminated within two hours. It was used routinely in that setting for a long time. And in the late 1990s they started to, it was actually a public health program, started to buy ampoules of naloxone, which is on the left hand side here as an example. And they created these aspirators that would screw onto the top. Well, actually the ampoules originally were injectable and they started giving them out and training bystanders on how to use them. And this developed into a whole distribution network that has been really robust and has really led a lot of the harm reduction in the United States for a long time. Eventually they developed these aspirators so you could administer naloxone internasally and which was a bit easier than the intravenous or intramuscular use. Finally, we had a company champion, an actual formal internasial version of naloxone which is depicted on the right hand side. And we've now seen a lot of growth in naloxone market for in the past few years. And I would be be really happy to talk in depth about the challenges and the experience of this field in moving from these ampules to this intranasal version because it's been quite a process. The goal modeling studies have suggested if we can get 80% of the population to cover to have naloxone available, then we will significantly improve overdose opportunities. Here's an example of the products that exist now. We have Narcan, which is the product that I just showed you. It's 4 milligrams meant to be administered in each nasal pass dosage. It's now available over the counter. Revive was just recently approved by the FDA and it's a 3 milligram dose. The dose was actually based on pharmacokinetic modeling. Narcan was actually based on the dose that was approved for use in hospital settings. So we don't really have a good understanding of the dose that's necessary for our current needs. Cloxado is an 8 milligram dose of naloxone also administered intranasally. And then we had an auto injector that was approved and has been discontinued by the company. And then another auto Injector, that's a 5 milligram dose that's been approved recently. And then in addition to naloxone, we have nalmiphene, two versions of nalmiphene. Nalmiphene is a long acting opioid antagonist. It's very similar in nature to naltrexone. It's different from naloxone in that it's again, it's a longer duration of effects. And you can see that we have both an intranasal version and an auto injector version. So the market for naloxone is pretty dense. There's a. Or for opioid antagonists, I should say it's pretty dense. There's quite a bit of competing products at the moment. The big question is, do we need different doses or what is the synthetic fentanyl exposure doing to our need for naloxone products? There's been a lot of evaluation of this, but these data here show you that this was a study that was done in Kentucky where they were able to track really closely over 33,000 overdose experiences whether the dose of naloxone that was given in the field changed over time as fentanyl became introduced to the local population. And you can see that what the data are showing you is that really there was no difference. So there was no real change in the route of administration that was being used, or the number, the percentage of individuals on the bottom here who needed doses that were less than 4 milligrams, between 4 and 8 milligrams or higher than 8 milligrams. So even though fentanyl made its way into Kentucky during this period, it didn't actually change the experience of the EMT professionals and the types of medications that they were giving people. So that's promising. But we also have some concerns about that. And so it's interesting because if you look in the field, that tends to be the report that we get back that naloxone is working. We don't need to make changes. The doses that we have, they work well. But then whenever we do these modeling studies, we see that they reliably suggest that we need higher doses or greater potencies. And that's what the data here on the right hand side show you, is that this is again a PK PD modeling study where they looked at fentanyl alone, which is in yellow, and then 2, 5 and 10 milligrams of intranasally administered fentanyl for both a 25 nanogram dose of fentanyl and a 50 nanogram dose. And you could see that as the dose of fentanyl got higher, they projected that you would need stronger doses of naloxone to be able to meaningfully reduce the fentanyl effects and reverse the respiratory depression. And then there's a lot of uncertainty about the need for these higher doses. Again, this is a big controversy in our field at the moment. And this was another. This is actually a human laboratory trial where they had people that were opioid experienced but not physically dependent and they administered different doses of fentanyl to them. And then they tested the ability of nalmiphene and two doses of naloxone to reverse the fentanyl effects. And what these data are showing you in the blue is that it was nalmoffine that had the most rapid reversal of depression, respiratory depression and sustained effects relative to the two versions of naloxone that were administered. So that suggests that in the face of these synthetic opioids, we really need to have these higher dose, stronger dose versions. However, that is not what people with lived experience or the harm reduction community want. There was a paper that was just recently published about a month ago that really spoke to this and they're saying that these higher doses, although they do reverse the respiratory depression effects, also significant, put the people into significant precipitated withdrawal. And so they come essentially out of an unconscious experience in extreme pain. And that can be problematic for lots of reasons. And so they are advocating that we don't create higher doses, we just provide opportunity for more frequent administration of smaller doses so that they can better titrate the experience for people. They also note that it won't reverse the set of effects of xylazine, which is really important. And these data here show you that the percentage of deaths associated with xylazine co exposure, which are the dotted line here, are continuing to go up. So we. Higher doses of an antagonist may not. It's not going to reverse xylazine. And there's been discussion in the field for a while that perhaps it wasn't really the antagonist. So when people received naloxone and then they weren't revived, maybe it wasn't the fentanyl, maybe it was the xylazine that was keeping them sedated, at least in some of these individuals, and that it was perceived as not working, but in fact it really was produced and effect. And these data here are from an animal study that shows that xylazine by itself on the top figure and then in combination with fentanyl, different Doses of fentanyl on the bottom produces its own respiratory depression or I guess, reduction in breathing. And that that is synergized when it's combined with fentanyl. So xylazine, this kind of rapid and ubiquitous addition of xylazine throughout the United States to our fentanyl products is likely going to have both synergistic effects on overdose risk as well as direct effects. And then we are also seeing again high rates of CO exposure. And these are data from Connecticut where they looked at the number of people who had an overdose that was attributed to both fentanyl and xylazine. And then what other drugs were they exposed to? And overwhelmingly in the green here you can see, oops, it was cocaine. An opioid antagonist is not necessarily going to reverse that, but we know that that can contribute to health consequences as well. So there's just incredibly high rates of polysubstance use in our patients. So let me conclude here with some take home message. So the take home is that drug exposure patterns have changed. Fentanyl has replaced heroin throughout the country and we have prominent co exposure of xylazine and stimulants. Whether that is intentional or not. Fentanyl, I hope I've convinced you fentanyl is different from other opioids. The overdose produced from fentanyl is both centrally mediated by its effects on the mu opioid receptor, but also through structural changes including muscle wall rigidity and closure of the vocal cords. Xylazine and stimulants increase the risk for this happening. And we have no antidote for xylazine overexposure. And then we have a growing array of antagonist treatments that are becoming available. The modeling study suggests that we need higher doses and longer acting antagonists. But the persons with lived experience pretty reliably ask that we not have those and that we instead have smaller doses in more frequent administration opportunities with protocols designed how to do that so that they could reverse the respiratory depression but not leave the person in a state of severe withdrawal. And so with that I'll conclude these are my collaborators at the Johns Hopkins University who have contributed to a lot of this work. And then, as was mentioned before, I'll be moving to the Choler Institute for Addiction Medicine in a couple weeks and hope that you'll follow us there. Thank you.

Thank you, Dr. Dunn, for this wonderful presentation.

Actually, I've been a cataract surgeon for so many years, so I've done so many surgeries and never had, thank God, any issues with use of fentanyl. Obviously we've had an anesthesiologist, you know, managing the drugs. Of course, the dosages that patients receive are so much lower than, you know, what I guess people use at the street level. And perhaps combined with Versed and propofol, maybe the, the side effects of the muscular rigidity is perhaps better managed. Has that been sort of the issue is that the Versed probably helps reduce that risk.

So I, I'm not entirely certain. I think you would probably have more expertise in that than I would.

Right. Well, I, again, thank you. I learned quite a bit and now I'm actually going to be paying more attention to see how much my patients are receiving. Fentanyl.

Fentanyl.

At each surgery.

I will open up the floor to.

Questions and I'll, I'll repeat the question so that it could be recorded as well.

Thank you so much, Professor Kelly, for your presentation. I have a quick question about the Ventolin is used IV that you said. But I heard that this state they use in the street by inhalation for the cigarette.

Right.

And do you know that. What about the distribution as this Better. It's worse than the iv. And can you compare, compare both of them?

Yeah. So that's a great, it's a great point. We are seeing generally, particularly in the west coast, but it's moving east that patients are shifting from intravenous exposures to inhalation. In part they're telling us it's because it's just, just their veins are so compromised that it's just easier to do that. I can, I don't know of data that have directly compared those inhalation of fentanyl to, in my, to my knowledge is not an FDA approved route. And so there haven't been studies that have really looked at that. I do think, I mean given we do know that, you know, the lungs are highly profused, there probably would be some sequestration there. So I imagine that it will have unique consequences. But I really can't speak to the differences between the intravenous and the inhaled. I think, I mean it just, it goes to show that, I mean we really. There's so much need to be able to study this stuff right now. And we're steps behind, I feel. Right. So we know that our patients need to know these things. We need to be able to be informed about the relationship between fentanyl and the various consequences, to be able to adequately treat them and identify new, new approaches. But we're just always catching up at this point just trying to figure out exactly what's Going on. Well, they are in dire need of some sort of support.

Thank you.

I have a question.

I mean this. Just looking at the map of us and the concentration of fentanyl use on the east coast and specifically I think I saw the. The black was in Virginia. Was that correct? Correct. Is that like a very concentrated area, West Virginia? Is. Is that because there's a factory there that's making fentanyl?

I mean, it's a good question. I mean, I think our understanding this area has always had a high trafficking route for opioid or for heroin products. But also this is the Appalachian area where there's just not. It's the. The penetration of heroin products into these rural areas has just been really high. And so when fentanyl replaces heroin, it just. That that's the consequences. So it could be. I mean there could be manufacturing places there. I have not heard that. I. My understanding is that most of it is manufactured out of the country and then trafficked in. But it's certainly possible. I think it really reflects more. So these are fentanyl related deaths, right? I think it reflects more a lack of treatment access, you know, lack of distribution of naloxone, kind of like systematic distribution of naloxone in the communities and so on. Okay.

I just thought if it's actually being trafficked, you know, through the borders, that you would have more concentration in the countries that are bordering, you know, where the drugs might be being trafficked from. But I guess your point is well taken that it's probably lack of, of access to health care also is playing a role in how many deaths are occurring, unfortunately.

Just one additional comment. So a lot of the trafficking doesn't come through the. For the east coast, doesn't come through the southern border. It actually flies in and then kind of goes down the 95 corridor. So it does. It starts off in that area, which is why we think things like Xylazine, you know, the kind of. The nexus of xylazine exposure started in. In Philadelphia, in the Pa. Philadelphia area and has kind of spread out that conforms nicely to the. Closely to the trafficking routes.

I see.

Thank you so much.

Question I have is top of the mind is is there a time where we would not be able to reverse these patients given that all these poly drugs situation that we're facing in terms of xylazine and other drugs, benzodiazepams and, and who knows what else might come next from abroad. What do you see what you hear on the street?

I don't want to diminish the value of naloxone or of the antagonist treatment, because that's really the best. I mean, when it works, it works well. But I think that there, I guess the reason I wanted to really emphasize the role of xylazine and these other substances is in part because there's opportunity for innovation there. Right. We don't have, we have an antagonist for opioids, but we don't have an antagonist for, for xylazine or for stimulants. And in my mind, we would really benefit from having multiple different medications that we can intervene with. I think the data suggests, I mentioned it's a bit controversial in the field as to whether we need higher doses of naloxone to reverse fentanyl. But the data do suggest that as long as, even in the case when that's necessary, as long as we have multiple doses available, we can eventually reverse it. I think we need more information about how to predict the chest wall rigidity and the vocal cord closures to understand who's at greatest risk for that and, you know, whether any of these other meds or the, you know, SIP enzymes might be contributing to it. As far as other drugs are concerned. The. One of the concerns that we have on the east coast are the nitazines, which are more potent. They're of kind considered, you know, a thousand times more potent than fentanyl. And they are synthetic forms of opioids. And we're seeing them pop up in our patients. And the challenge is that we don't. We can't really easily surveil these drugs because they don't show up. They don't cross react with any of our standard assays. So we have to specifically look for them in samples. And so our detection is always delayed. And we have to, you know, it's expensive. You can't do it on a wide scale. But we do know that they're showing up and that we're wondering if maybe it's contributing to some of the experiences that we're seeing in our patients. But we know so little about them that I think, again, it's us kind of responding to a public health crisis as it's happening to figure out the relationship between naloxone and nalmefine and those substances. I will say my understanding of the nitazines is that from an international level, there's less concern about them relative to things like xylazine because, because they're so potent, the belief is that they wouldn't have a lot of widespread use because it would just be. It wouldn't be as reinforcing and euphoric producing as some of the other products.

Thank you again, Kelly. It was a wonderful presentation, and let's give a round of applause.

It.