Hi, I'm Dr. Steve Wyatt, and I'm an addiction psychiatrist and a UNC adjunct faculty, University of North Carolina, and I'm located in Charlotte, North Carolina. And I'm here to talk to you today about opiate use problems and recommendations for medical management. This is part of the American Osteopathic Academy of Addiction Medicine Essentials in Addiction Medicine course. I have no disclosures. I don't speak for any pharmaceutical companies or have investments in them. I want to first go over indicators of patients that could have problems, have you understand and be thinking about as you see patients with opiate use disorders of the problems that they may have gone through or the predisposition they may have to the development of an opiate use disorder, and then we'll spend a fair amount of time talking about medications and psychotherapeutic interventions that could be helpful. So opiates have been a problem for centuries. It was not until the early 19th century, in the early 19th century, morphine was first formulated. It wasn't made available as a pharmaceutical until the 20s, and it was a boom because it made an opioid formulation that we could use much more effectively and understanding dosing and all that was really very helpful. Heroin then became available also as a pharmaceutical in the 1870s, and then in around the 1850s, the hypodermic needle and syringe were first invented, and both of these things, the better formulations of opioids and a better way to administer the medicine went a long way towards helping us use these medications effectively for patients in acute pain. During the Civil War, there was tremendous morbidity and mortality, and opioids became much more prevalent, all formulations of opioids, and it was apparent that it was becoming a significant problem in the population. If you read some of the newspaper reports from that time, it's really amazing how closely it matches kind of the turn of the 20th to the 21st century and the problems that we've been experiencing the last 20 years. As a result of those problems they were experiencing then, Congress enacted the Harrison Act in 1914 that limited the use of opioids by physicians then, only physicians, to problems that were identified as bona fide diseases, and we didn't see opioid use problems as a disease at the time, so consequently a whole lot of people got cut off from their opioids, and a number of physicians went to prison for disobeying that law. As a result of that, opioids went underground, and that's when a whole lot of different problems started and that's where you see this idea that it was really the start of the drug wars in this country. By not addressing opioid use disorders in the way that it could have been, and allowing physicians and the healthcare community to actually address it appropriately, we may not have ended up having nearly the problems that we had and continue to have in our country. So opioids work in a variety of ways, but the three receptors that we're most interested in, there are others, there's indication there's others, but the Mu receptor is the primary one we're interested in, it's most involved in analgesia and euphoria and the other problems that we see from opioids. The Kappa receptor is a very interesting receptor, and I'm going to speak about it a little more when we talk about buprenorphine, but its endogenous property is dynorphins, which are more of the sort of downer effect of opioids, the sort of blunting effect that opioids have, the potentially even mild depressive effect that opioids can have. And then there's the Delta receptor, and again it's the Mu receptor that is most clinically significant and is the receptor that is most involved in the illicit properties, the addictive properties of these drugs. The Mu receptor is very involved in the analgesic properties, the sedation that takes place with opioids, the euphoria that takes place, pupillary constriction, decreased respirations, decreased heart rate and nausea. I will say that there is genetic predisposition to some of this, however. Some people don't feel particularly euphoric on an opioid, they feel mildly sedated and nauseated and they want to get off them as quickly as possible. Doctors can build a tolerance to some of these properties after taking it for a while, and some people get mildly euphoric in a way that they get excited about it. They don't have nearly the sedation that some other individuals have, and these are the genetic predispositions to the disease of an opioid use disorder. They can certainly lead to it compared to those people that find it disorienting and dysphoric. And then some of these properties we have some tolerance to. People will have tolerance to the respiratory problems, so that's where we need to be careful if someone had been taking a particular dose of opioids, stops it for a while, thinks they can go back to that same dose and they overdose. So that's where we need to be talking to patients about it. But other things, there's not as much of a tolerance to pupillary constriction, there's not a lot of tolerance to that. People will still have pupillary constriction. Without mobility, there's not good tolerance to that. People will have chronic constipation that are taking better on long-term opioid treatments or opioid dependent. Activation of peripheral tissues also contributes to the analgesic properties of opioids and is modulated by and modulates inflammatory responses. And this, I will tell you, has to do in part with the hyperalgesia effect of opioids. That is, if they've taken them long enough, our systems through allosteric properties will try to counter the fact that you're not experiencing pain and we need to experience some element of pain to really exist in our environment or we get hurt badly, we don't get our hand off the hot plate soon enough, or we just are not as attentive to our environment. And so what happens is there are cytokine changes in the peripheral receptors of pain that allow us to be more sensitive to pain than less sensitive. So what has happened in the last 20 years, 25 years now, is that we saw this significant increase in the prescribing of opioids. And with that, more opioids available on the street. With that, more people trying, using, and getting caught up in using opioids and it became a problem. And what we recognized and what the federal government in many ways and the House of Medicine was the need to recognize that if we keep people on opioids, in this case, more than a week and certainly more than 30 days, which these are on the x-axis you see days, you're going to potentiate the problems and the possibility that the patient's going to be on opioids a year later. So that's where this idea that we're not going to, in the emergency department, prescribe a month of opioids. We're going to give enough until they can get to their primary care doctor or their orthopedist for follow-up. And so that then we have an opportunity to really address, does the patient need more opioid? Because again, it was this potential over-prescribing that took place that contributed significantly to the problems that we're experiencing today. And that you see in this graph, in 1999, we had been over-prescribing. We continued to do that through the early 2000s. We continue to see this rise in overdose deaths. And then in 2010, we've begun to really address this problem and people were recognizing it. And there were various state and national policies that were put in place to try to help physicians look more closely at how they were prescribing. There were restrictions on prescribing and people started really pulling back on how they were prescribing. And in some ways, that got people in trouble also. People that, again, like back in the turn of the 19th to the 20th century, all these people are on opioids and then all of a sudden they're not available anymore. They were turning to the street. And we started seeing this rise in heroin use and heroin overdoses. Since that time, we have had the introduction of the fentanyl products and heroin didn't go away, nor did pills entirely. So now it was the combination of the three with fentanyl really taking a lead place in this overdose problem. And it's continued to be a problem. As you see in these statistics, we saw another rise in opioid overdose deaths in the last year. And certainly COVID hasn't added to that because we know social isolation and other problems only worsen drug use disorders. Years ago we recognized that this was a problem worse than firearms or motor vehicle accidents. And so it was in 2010 approximately that the overdose deaths from opioids and overdose poisonings, because many times it's a combination, was overtaking firearms and motor vehicle accidents. And I think it's interesting that the automobile industry 60 years ago decided we need to do something about how this automobile that we're manufacturing is killing people. And so they put in mandatory seat belts and they put in airbags and engines that on a front end collision are going to fall to the ground instead of going into the driver's seat. And this reduced, had a tremendous ability to bring motor vehicle deaths down significantly. And I think it's a challenge to us as healthcare providers to think about how are we going to do this with opioids? How are we going to be able to use something that's so important to our practice of medicine, but at the same time make it more safe? Where can we use it and how can we use it more safely? Because we do need to use it and we need to recognize that we don't want this pendulum to swing too far, which it clearly did as we started to try to crack down on the use of opioids. I mean, we created this problem when we had widespread misuse and widespread prescribing. Then we created another little problem when we started cracking down on it so hard and that's still a problem. And we need to find this balance in between. We need to be treating pain effectively, but be screening for people that potentially are going to have or have problems to be able to prescribe more safely. Because we saw this significant problem and this problem continues to go on, this is 2019, we still have a significant problem amongst people that are misusing, that is taking opioids outside of how they were prescribed. And quite honestly, that includes you finished your prescription and you put it up in the medicine cabinet and then you have a headache two months later and you take an opioid for it. That's misuse of a medication. And certainly giving it to a friend or anyone else is actually illegal. And I think people need to understand this, that when they're done with these controlled substances, they need to dispose of them. At the same time, a number of those people are now dabbling in the use of heroin. So they're really using a combination of pharmaceuticals and heroin. And then of course, there's that population that are just using heroin or fentanyl, unfortunately. So I think it's really important to understand how these problems start. And I say that in teaching medical students and residents about this in particular, by doing that, by understanding these things, I think it can reduce some of the stigma around substance use problems in general, but certainly this population. To really recognize there's a whole host of things that result in why people have a propensity towards getting caught up in opioids. And the first one, they have no responsibility for at all. And that is genetics. And again, there are people that they take an opioid and I've heard these stories. For the first time as a child, they get robitussin with codeine and it lights up their world. They can't sleep, they're happy, they're talkative. And they also, the couple that I've heard about, went on to have significant problems starting as a teenager when they realized, oh, that's what that feeling was like. That's why I felt that way. And so again, it's not of any fault of the patient. Someone that gets sedated and nauseated when they first take an opioid, they're not going to take anymore. Then there's the vulnerabilities secondary to early childhood. And in particular, adverse childhood experiences. That's physical, emotional, sexual abuse, and neglect. Five to seven ACEs increases the chances of a substance use disorder in general, all substance use problems, by over 400%. That's amazing. And I think this is one area that we actually could do something about if we looked at the vulnerabilities of children and the difficulties that so many parents have in raising children. That group then goes on potentially to meet up with others that are struggling or have more dependent personalities or just tendencies and get exposed to drug. And if that happens early enough, their chances of developing a substance use problem increases dramatically. So a young person that first uses an illicit drug at 12, 13, 14 years old has a significantly greater chance of developing a real substance use disorder by 25 compared to the young person that might first try using a drug at 18 or 20. They're still at high risk, but not nearly the risk of those that had started at a younger age. Behavioral health disorders also are predispositions to these problems. That is depression, anxiety, PTSD, bipolar disorder, if it's not too severe. Those people with persistently and severe mental illness, profound schizophrenia, they're not high opioid use disorders. They're more inclined to get drugs that are easily available, like alcohol. They will not get caught up necessarily in opioids, which you got to be on top of it to keep your opioid habit going. You have to find money every day. You have to find potentially a new needle or needles in particular. So it's just, it takes a little bit of wherewithal to keep this going. And it's not typically a population that's cognitively impaired or with severely or persistently mental illness. Traumas are highly associated with this population. 85% of women that are injection drug users, 85% have some history of trauma and very often sexual trauma. It is also a population that's frequently disenfranchised. They have often, they're unemployed. Just a lower social economic group in terms of, or they get to that place because there's significant social drift that takes place with the onset of an opioid use disorder. And it often results in isolation. And these properties are highly associated with the continuation of long-term substance use problems. And it's what we have seen in some ways during COVID. Chronic pain has also been certainly a precursor to the development of an opioid use disorder that to recognize that chronic pain changes the brain. We develop new habits. We develop new ways to try to adjust to it. We add opioids to that. In some ways, it makes it more difficult to fully adjust to it, but it also develops a whole new profile of behaviors. And that's one of the problems with opioids in that the brain has a tremendous capacity to down-regulate pain over time in that we adjust to it. We adjust to how we're taking care of ourselves. And again, we have a tremendous potential for adjusting to the pain that is impaired with the use of an opioid. So when someone comes in following an acute episode. That is, they may have been in the emergency department with a, you know, broken ankle and they've been prescribed an opioid or they have a chronic disease that has been, they've gotten started on an opioid. If that's not taking place in the primary care setting or in a setting where the, where you're going to be at least taking care of them for a long period of time, then this needs to be done. We need to be getting a good medical history, doing a full physical exam. If they do have a drug use disorder, we should be looking for hepatitis, particularly if it's an injection drug use disorder, HIV, tuberculosis, checking for pregnancy, screening for other underlying psychiatric problems, looking at other substance use problems. People with alcohol use disorders have a greater propensity toward the development of an opioid use disorder, as do people with nicotine dependence. Not infrequently, these days, there is a correlation with the continued use of tobacco products and either an opioid, excuse me, a substance use disorder or a mental health problem. So we've done a great job of reducing in this country from nearly 50% of the population down to 15% of the population smoking cigarettes. But as we did that, we increased pretty dramatically the population within that 15% that has a substance use or a mental health problem. And so again, talking to students and residents, I'll often say, look, if this is an easy question to ask, and we ask it frequently, but if they answer positive, then have a higher index of suspicion that there is another or underlying drug use disorder. Laboratory testing, as I have also somewhat gone over, but we need to be testing for these things as people come in or we're considering keeping them on opioids or treating their opioid use disorder and then using urine drug screening and looking at those biopsychosocial problems that could interfere with them being successful in either managing their opiate problem or their chronic pain effectively. Once we've done that, then we can have a better idea, is this an opioid use disorder as defined by the Diagnostic Statistical Manual, the fifth edition? And there's 11 criteria and they're broken up into four areas. These are the same criteria for all substance use problems. There's impaired control, that is using longer periods of time than you want to, trying to cut back unsuccessfully, cravings, those sorts of things. You begin to see, I thought I was just going to have two drinks and I had this much. I thought I could stop these opiates, but boy, when I try, I have a real problem staying away from them. If we're doing that, if we're spending that much time and changing our life around the use of these drugs, then it's clearly going to impact our social set, our social lives. So there is social impairment. It can show up in work or family or find ourselves using in, you know, at times when we shouldn't be. And that then leads, some of those shouldn't be times are where it really results in consequences. And if it results in consequences and we continue to use, now you've got a significant problem, more severe, and people will have endocarditis and leave the hospital and a month later be shooting drug again. There's a fourth area that's pharmaceutical area and that's tolerance and withdrawal. For opioids, if they have tolerance and withdrawal but they're being prescribed a medication, that's not criteria for an opioid use disorder. It has to have some of these others for it to be an opioid use disorder. So it doesn't meet the criteria. Anyone that's taking opioids for longer than a couple of weeks is going to have some tolerance and potentially some withdrawal symptoms from stopping the medicine. So how do we determine with the patient what treatment might we consider? So what are the treatment options? And that the choice from among available treatment options for addiction involving opiates needs to be a shared decision between what the patient's preference is, what maybe they had tried in the past, and what treatment setting would be most appropriate for them. So there's a variety of ways in which we can do this, including what's not listed here but the ASAM patient placement criteria, which is multidimensional and looks at certain problems like toxic household, history of withdrawal problems, low motivation for treatment, comorbid medical or psychiatric problems. Those are the sort of things that we would take into consideration in deciding what treatment setting would be appropriate for the patient. One of those would be an opiate treatment program or an OTP. Some may refer to this as a methadone treatment program. And here we're really looking at what's the patient's psychosocial situation, comorbidity, risk of diversion that may be to be in a more of a control setting where they're being administered the medication on-site and there's an opportunity to be in touch on a daily basis, initially with nursing or or a counselor or peer support that could help the patient. Because at an OTP it does offer that daily supervision, they're typically then on agonist therapy, their methadone or buprenorphine, and either the patient will select for this or because you see this is a polysubstance, you know, use problem, I'm uncomfortable with taking care of it in my office, I think that in talking the patient you would be better served in a more controlled setting. Whether they failed office-based opiate treatment in the past could be an indication they need office-based treatment. And these days there are patients, and we're going to talk a little bit about fentanyl at the end of this presentation, but there are patients that just find that buprenorphine isn't holding them. Now I think sometimes that's really getting on successfully to buprenorphine as opposed to once they're on it that it's not holding them. But at any rate, there's been a little uptick in patients coming into treatment that are looking for methadone, that they really feel methadone would hold them better than buprenorphine. Office-based treatment would mean medications provided weekly or monthly, so they're given a prescription and they're not taking it and, you know, administered it on-site, and that would be for buprenorphine or naltrexone. Naltrexone as an oral therapy is used and recommended for patients able to comply with special techniques. I'm going to talk quite a bit more about naltrexone in a few minutes, but there's either the oral or the extended-release injectable. But those would be office treatments, along with buprenorphine would be an office treatment. Because it can be prescribed, it meets the criteria, and these are certain buprenorphine products. So it's a product, buprenorphine being a Schedule 3 medication, and certain buprenorphine products, not all products, certain buprenorphine products have been approved by the FDA to be used for an opiate use disorder. What are our goals when people come into treatment? This would include helping them with any withdrawal symptoms initially, but then they shouldn't have withdrawal symptoms, stabilizing their cravings, and reducing their opiate use. And we look at the goals of treatment being on somewhat of a continuum. Early on, it may be just minimizing harms from their use. So this could even be harm reduction, you know, successful needle exchange programs, and providing naloxone, and just keeping people alive long enough to be able to get into treatment. Then maybe early stabilization of their opiate use disorder, but then moving them over time, addressing psychosocial problems, other physical problems they may experience, and hopefully helping them develop social supports in their community, strengthening their family unit, and having long-term recovery. Medications that we use for this, again, buprenorphine, methanone, naltrexone, behavioral-oriented treatments can be very helpful. They're typically a part of all treatments, so even if it's medical management of treatment, we're talking to them about relapse prevention, what environments they're, you know, frequently frequenting, and those sorts of things. The ultimate goal really is long-term recovery with or without medication. That is, really moving on with their lives and no longer meeting those criteria of a drug use disorder. So people that say it's replacing a drug for a drug, no. Once they're on buprenorphine, naltrexone, methadone, they no longer meet that criteria. Their disease is controlled now, right? Okay. Treatment retention is one of the primary goals that we look at. We know the longer patients stay in treatment, the better they're going to do. Any studies that you look at examining whether a form of treatment works or not, typically is always going to have retention in treatment. If we can stay in front of patients, we can continue to work with them, they do better. And this has been shown over and over again. And in this case, the use of medications has been extremely helpful in doing that. The longer we can keep them in on medication, the better they do, and the longer they stay in treatment, the more we have contact with them, the more we can help them, again, with some of these other problems and their use of opioids goes down. It also improves mortality significantly. Those that are untreated, and that would include people that just go in for acute detox and think, that's all that's driving my disease. If I could just get rid of these withdrawal symptoms, I'd be all set. Well, that just doesn't work. They get out and they realize they get back in their community, they got cravings again, they have problems, and they're back at it. That population that continues to use has six times the mortality as the general population. Even people on medication have an increased mortality because it's such a dangerous disease, and it's a relapsing disease like every other chronic illness. So now let's talk about these three medications in particular. The one is methadone. Methadone is a full opiate agonist. The more that you give, the green line there, the greater the the potential of the drug to the point of overdose. So all the full opiate agonists have a place that they get to that results in significant respiratory depression and a change in the responsiveness of the medullary respiratory center to rising levels of CO2, and people just don't have a stimulant to take another breath. That's how people overdose on opioids. And methadone is long-acting, so it can be prescribed once a day, and that's one of the reasons that Niswinder and Doyle looked at this in the early 60s as a potential treatment of this population that continued to suffer from opioid use problems. It does have a weak affinity to the opiate receptor, so consequently when one starts, you know, if you were to switch from buprenorphine, excuse me, from methadone to buprenorphine, they have to be in mild withdrawal because otherwise buprenorphine is going to come in and drop them precipitously to that blue line that you see there, and people would go into the withdrawal. And when administered naltrexone or obviously naloxone, it would take them to zero and they would go into severe withdrawal. We do need to monitor them closely as we're titrating up on the drug because of the respiratory suppression. So we go very slowly, starting at 30 milligrams typically, go very slowly up to a therapeutic dose typically greater than 60 milligrams that I'm going to talk about in a moment. And we also need to be watching, particularly when they get to higher doses, that is above 100-120 milligrams, we see more QTC prolongation and it's important to start to monitor that. And many OTPs will actually be getting electrocardiograms even on admission, but certainly watching it closely in people with family histories or their own history of a cardiac disease and the potential for QTC prolongation. So methadone is recommended to be dosed between 60 and 120 milligrams, however some patients may respond to lower doses. Typically they need to be above 40 milligrams to keep out of withdrawal. Below 40 milligrams they're going to start to feel more withdrawal symptoms and typically above 60 milligrams, 60 or above, to really establish a reduction in craving and not allow for more euphoria from another opioid to take place. So we want to have them above 60 milligrams. Some people will find that even 120 milligrams are not holding them and will go to higher doses. So dose increases again should be in small increments, no more frequently than five to seven days to avoid over sedation, toxicity, and potential overdose. Psychosocial interventions are often included in methadone treatment programs or OTPs. It's actually mandated and to at least assess for them. Some patients aren't going to need much. Some patients are getting that, you know, they got a job, they got family, they're doing well, they stabilize, no question with the medication itself. But other patients have much more in the way of needs that should be addressed. Relapse prevention strategies are important and should be included in any plan of care of the patient receiving active outpatient treatment or ongoing monitoring of their status of their addictive diseases. You know, so we're doing things to stay in touch with them and continually checking in and trying to address are they having further problems. If the patient now has been on it for a while, wants to go to an outpatient setting, wants to transfer to either buprenorphine or potentially naltrexone, with buprenorphine we need to taper it down to 30 to 40 milligrams and then have them off it long enough for them to be in mild to moderate withdrawal before we would start the buprenorphine. With patients transferring to naltrexone, we need them have them off methadone for 7 to 10 days. Typically we're going to put them into a withdrawal program that I'll talk about a little later and then transition them on to naltrexone and potentially the injectable product. We need to warn patients if they're coming off methadone entirely that they would understand that they've lost their tolerance and if they start back on illicit opioids, if they particularly tried to go back on the dose that they had formerly been taking, they are at significant risk of overdose because they have no tolerance. And as I said before, we build tolerance to the respiratory suppression that takes place, but if you don't have that tolerance you're at high risk. So what about buprenorphine? Buprenorphine is a partial agonist. It has thus comparatively less respiratory suppression than full agonist and is unlikely by itself to lead to a fatal respiratory arrest even at high doses. So we actually don't know what the lethal dose of buprenorphine is. That's not saying that it's entirely safe, particularly if people have other physical problems that could impair their respirations, just other individual problems, but in general animal studies have shown that very high doses of buprenorphine does not result in that the same degree of respiratory effects as the full opiate agonist. It doesn't have the effect on that respiratory center, the medullary respiratory center, sensitivity to rising levels of CO2. So eventually people are stimulated to take a breath even with slowed respirations and I'm going to show you that by dose in a upcoming slide. But as a result of that safety profile, buprenorphine is a schedule 3 medication as I stated before. It has a long half-life which makes it a very usable medication because people can take it once a day. I was involved in studies of buprenorphine back in the late 90s before the release of suboxone and we had patients taking it on-site Monday, Wednesday, and Friday. So there can be dosing that we can use it that way. It also has a very high affinity to the receptor so it binds very tightly and consequently other medications can't get in at all or if they try it's just more difficult for so it blocks other opioids and potentially if they're in that area of the curve and I said this when I was talking about methadone if they're up here in the in the above the blue line which is the buprenorphine there and you give them buprenorphine they're going to drop precipitously to the buprenorphine level and potentially go into with a mild withdrawal and if they've been in withdrawal a number of times before and they feel it's coming on precipitously they feel like they're really going to get sick and sometimes it's expanded even more than it needed to be because of the psychological aspects of it. And it also has a slow dissociation, so it stays on the receptor for a long period of time. And that's one of the ways in which we see it being used for opioid withdrawal, that we can load a patient and then literally take them off it, but certainly we typically taper down on it, but they still are experiencing or have some effects of the buprenorphine a couple of days after having stopped the medicine. So when we look at the safety profile of buprenorphine, we recognize that nearly all fatal overdoses have been associated with polysubstance use. That is typically other sedatives like alcohol, benzodiazepines, barbiturates, because when it's used alone we have seen in a variety of studies that starting at a low dose and increasing the dose, we see respiratory suppression, but not a worsening. There's a ceiling to that up to 32 milligrams and beyond. That correlates well with the oxygen saturation, which also stabilizes. And so this is a very important aspect of buprenorphine and why we can use it effectively in the office, that it doesn't need to be only used in a controlled setting. There's also little in the way of cognitive or psychomotor effects, and that has to do with that kappa antagonist property of buprenorphine that is unlike full opiate agonists that are kappa agonists. And so there's not that mild dysphoric, mild blunting of cognition that can take place with chronic opioid use. So what's the rationale of putting buprenorphine and naloxone together? They are prescribed together to reduce the risk of the diversion to injection drug use. That's the primary purpose. And the reason that it works so well is that naloxone has minimal bioavailability when it's prescribed sublingually. So transmucosal formulations, if they're used appropriately, they have little in the way of naloxone absorption. So the patient's getting primarily the buprenorphine and they get the effect of the medication as we had hoped they would. Compared to buprenorphine alone, if it's injected, the combination product is often seen as a bad drug. People don't like it. Now, obviously, any buprenorphine that's injected while the patient still has opioid on board, they're gonna have withdrawal symptoms like what I showed you a moment ago. But if they don't have opioid on board, the naloxone will result in a slower onset of the buprenorphine. And I can tell you that one of the ways that we look at whether a medication has addictive potential or not is looking at the speed in which it reaches the brain. That is, I use the example of cocaine. Chewing coca leaves is far less addictive than snorting cocaine hydrochloride, which is less addictive than smoking cocaine bicarbonate or free-based cocaine or injecting cocaine. Both those are very rapid uptake into the brain. And we couple that using the drug and getting the effect immediately. And that increases the addictive potential of a drug. What buprenorphine naloxone does is the naloxone competes with the buprenorphine. It doesn't necessarily throw the person into withdrawal. They can have a mild feeling of withdrawal, but it's short-acting. Not much of an effect of the drug for 45 minutes or an hour. And I'll show you a graph of that on the next slide. As a result of this, there's far less diversion to injection use of the combination product compared to the monoproduct. So this is the graph that I just talked about. And what you see in the blue line is the monoproduct if injected. They get the buprenorphine effect right now and they find it intoxicating. If it's mixed with naloxone, there's a slow uptake of the medication. That is, it's competing for those new receptors. Naloxone, however, is a short-acting drug. So within 45 minutes or an hour, it's pretty well gone. And now buprenorphine really takes over. How long do we use these medicines or this medicine in particular? It's similar for methadone and naltrexone, but here we're looking at a study by David Tyleen at Yale. And you see the longer the patient is on the medicine, the better they do. And I talked about that in terms of retention and treatment. The potential for ED visits and overdose and other morbidity secondary to relapsing to opioid use problems increases significantly if people are taking off their medication too quickly. If we're tapering off the medicine, however, once patients have done well, and I will tell you, I will talk to patients periodically about coming down on the dose of their medicine, but I don't talk to them really about, unless they wanna talk about it, coming off entirely. But if they do, we start tapering very slowly, typically not more than four milligrams at a time, down to eight milligrams, four milligrams. Certainly then we're going down by two milligrams. And some people will just go down by two milligrams all the time, that's fine. Typically not going down more quickly than every two weeks. And then potentially getting them off. If they are going to taper off, sometimes we'll use clonidine or other medicines to help them with any further withdrawal symptoms that they're experiencing. And I'll talk about clonidine in a few minutes. But if they elect to come off and then kind of have a little safety net of being on naltrexone for a period of time after coming off buprenorphine entirely, well, typically you want them off buprenorphine, just like any other opioid, for seven to 10 days before starting the naltrexone. You can titrate up on with very small doses of an oral naltrexone, just to give them a little more safety if they're feeling at risk. But hopefully they've been on buprenorphine for a long period of time, they've stabilized, they've got some good stabilization behind them and they could do well. They do need to recognize again that they've lost, after a period of time, they will have lost tolerance to opioids. And if they were to relapse, that they need to be very careful about not going to the same dose of heroin or other drug that they were using in the past. What about naltrexone? So naltrexone is long acting. The oral medicine is four hours. It can be given on a 24, once a day dosing basis. The injectable product has a half-life of five to 10 days. It's typically injected at 380 milligrams once every 28 days, sometimes shorter, but usually 28 days. It is a full antagonist at the MU receptor. It consequently will competitively bind to that receptor. It has a very high affinity to the receptor, so it's gonna knock off other opioids that may be in this serum. And it will block other opioids. If someone's currently taking the medicine, they literally are not gonna get much effect at all from using another opioid. And again, if they have it on board, they would displace it and precipitate withdrawal. There are both the oral medication, been around for a long time, and it's 50 milligrams, and then in the injectable, which is 380 milligrams, and very effective in treating opioid use disorders. There's two different ways that we think it's most effective. And the first is a behavioral mechanism. That is, we can extinguish behaviors by completely eliminating it out of our lives, just getting it away from us long enough, and we can extinguish that behavior. And if we absolutely cannot have something, then we have a greater tendency to let it go. And it can be a real struggle for a short period of time, but we can get rid of it. Again, changing our environment a little bit and just not having that exposure to drug goes a long way in helping that. The other way in which this happens is pharmacologically, and that is, it is the endorphin release that has such a effect on cravings. Endorphins in stimulating the nucleus accumbens results in a dopamine release which stimulates our desire for things. It motivates us to wanting to do things. And normally, it wants us to have fun and laugh or watch our kids do well or eat a good meal or have a sexual experience. These are things that we can anticipate and we have motivation to experience them. Unfortunately, drugs of misuse can have a profound effect in that way. And what naltrexone does is it blunts that effect. And that's how it works with alcohol. Even drinking alcohol can have a blunted effect, but certainly thinking about alcohol or opioids, it can also blunt that effect. And we've seen some evidence that it can help with other drug use also. So it's something just to keep in mind. So naltrexone has a different mechanism of action from methadone or buprenorphine, and it may be acceptable to or effective for different subgroups of patients, patients that just don't wanna be on an opioid anymore. They're done with it. They don't want that to be available. And consequently, it's a more attractive and effective treatment for those patients. Oral naltrexone should be given daily, as I described, 50 milligram doses, can be given three times a week if it's being given in a supervised setting, which is when it's most effective. People just are not adherent to this. We may think, you got this really bad disease. All you have to do is take this pill every morning and it won't cause you a problem anymore. But there are many, many patients that just didn't work. And that's where the injection has been extremely helpful to a lot of people, because once you get the injection in, they don't have to worry or even consider using an opioid for at least another month. It is more expensive, but many insurances now, noting the efficacy, are paying for it. There's no recommended period of time that we would use these medicines, just like methadone or buprenorphine. Duration depends on clinical judgment. Because there's no physical dependence associated with it can be stopped abruptly without withdrawal symptoms. And patients who discontinue agonist therapy and resume opioids need very much to be warned of the risk of overdose. So once they stop this, at the point that you're saying, gee, you've done great, that's it. Or even while they're taking it, and because you know there's always a chance they're not gonna come back, they need to recognize, one, that they will have lost their tolerance, as I've talked about before. But the other is, opioid antagonists will increase the sensitivity to other opioids. So you take this long enough, you have an increased sensitivity to opioids. And so they're even at greater risk than if they were just not an opioid user at all. This is looking at the comparison of buprenorphine to naltrexone injectable. This was a study done by Josh Lee at Columbia. And there was a similar study done in Norway that was published in New England Journal around the same time. They came to very similar conclusions. And what you're seeing is, on the right, is all the patients that came into this study. And there was a significant drop-off in the naltrexone group that came into this study. The red line, because they didn't get started on medication. They dropped out. They couldn't get through that seven to 10-day period to actually get started on the medicine. When we take that away and compare the two groups, which is graph B, then they're very comparable. In fact, naltrexone did even a little bit better, although it wasn't significant. And that so much has to do with what kind of program were they in. These two programs, they were very comparable. But if we can support patients, look at other underlying problems they may be experiencing, help direct them to those problems. You may not do psychotherapy in your office, but you can recognize that they could be helped by someone that could do that, and to know those and look and be aware of those resources in your community can be very helpful to patients. So what are the medications that we use for opioid withdrawal? We use alpha agonists. And this can be clonidine, guathicin, which is really more stimulating, not used very frequently, but has some studies showing that it can be effective. And lefoxidine, which is newly available in the United States, more expensive, but has some properties that might make it helpful with some patients. And then we use the plus other meds and to alleviate symptoms, can be something to help them more with sleep or with achiness, those sorts of things. We might use trazodone to help them sleep or Motrin, a non-steroidal to help with some muscle discomfort, sometimes even a muscle relaxant some people will use. But those are the non-controlled substances that we can use to help people with withdrawal symptoms. We also can use buprenorphine, buprenorphine either with naloxone or without. And we can use that in the hospital, the emergency department, the office. So it can be used in an outpatient basis and opiate treatment program. We can use it all those places. There are outpatient, very effective outpatient treatments of opioids. It doesn't have the potential lethality of withdrawal from alcohol or benzodiazepines. People don't have seizure typically. So we can control it really quite nicely in outpatient settings if the patient's home environment is going to be supportive. And then there's methadone that can only be used in a controlled setting, hospital or emergency department or OTP because it's a controlled substance that can't be used for an opioid use disorder on an outpatient basis. But these are very effective ways to get people stabilized off whatever opioid they have been using. And then we taper down on these agonists short term to get them off. We use the clinical opiate withdrawal scale to monitor how they're doing. So some of this is objective and some is subjective. There is a subjective opiate withdrawal scale. Some of these start to be objective like muscle cramps and then lead to objective like diarrhea and vomiting. But again, these are very straightforward symptoms to be monitoring and it helps us understand what level of medication we want to prescribe. When we're performing opioid management, we need to recognize that at the completion of it, we need to be either getting people into a controlled setting or starting them on naltrexone. And if we're gonna start them on naltrexone from a full agonist or a partial agonist, we still need a period of time that they're off the medicine before we could start the naltrexone. And sometimes, and there's multiple studies looking at using small doses to transition them onto full naltrexone treatment. So you can use either partial pill, breaking it in half, breaking it in half again, getting 12.5 milligrams, or some people will use formulary pharmacies to create very small doses of naltrexone and then titrate them up to 50 milligrams and potentially the injection. Clonidine can certainly be used during that withdrawal period so that hopefully we can get them through that period of time they have to transition from any kind of opioid that is from the street or from buprenorphine or methadone onto naltrexone. The alpha-2 agonist will reduce the glutamate response, reduce the norepinephrine release because it's a presynaptic agonist. And typically, clonidine, we're using 0.1 to 0.2 milligrams every four hours. I typically am able to use it 0.1 milligrams for a week, but I'm not able to do that so I use it 0.1 milligrams three times a day and then 0.2 at bedtime. It is sedating, it can sometimes help people sleep a little bit better. And then we taper off that in a few days. It's very effective. There are studies looking at it compared to doing a full clonidine detox or medically controlled withdrawal compared to a methadone detox and it's very comparable. People feel quite comfortable if it's treated appropriately and typically this is done in an outpatient detox or medication withdrawal protocol setting. Psych-social treatments is limited in this talk, because there's another talk, I know, part of the Essentials Program around psychosocial treatments. But I'll just reiterate again, as I have before, that we really need to be assessing for their psychosocial needs. We need to be attending to those if possible. You don't have to do it yourself, but just know people in the community that can be called to help this patient or the person can be referred to. So supportive counseling can be very helpful. Getting family supports in, doing some family therapy, or at least engaging with family can be very helpful. And then trying to build a support system for the patient, which can happen with social support groups like NAAA, Smart Recovery, where they can begin to socialize more, have a social life outside of the drug use community. Peer supports can be extremely helpful. And so this is just a matter of understanding this, and as you start to do this work, just take a little time to talk with people in your community that might be available to help. Two populations that I want to address. One is adolescents. Too frequently we're not using medications in this population when we should be. And it's been a real tragedy in many settings. And to be using opiate antagonists can be very helpful. That is, particularly if young people have only been using opiates for six months or so, I would at least entertain the idea that maybe being on an antagonist could be helpful. I had a group of patients that I worked with in Connecticut that had, we used contingency management. That was parents paid for them, parents paid for them to get treatment, they got injections once a month, and they could stay in their home. And these were 16 to 22 year olds was that group. But I can tell you that it can be very effective in that population. At the same time, there are 16, 18 year olds that have been using opioids for three or four years. And they've been in and out of a couple of different programs and they continue to relapse. And they are definitely candidates for agonist therapies and using buprenorphine methadone can be very helpful. Now, buprenorphine is approved to 16 years old or above. Methadone is only approved and OTPs are only licensed for 18 and above. However, they can get a state waiver to treat under 18 if they meet certain criteria. So it's not like they can't bring in a patient that's younger than 18 years old. Again, to use psych social treatments in this population can be extremely helpful because if they started using that young, I would look very closely for other trauma history, behavioral health problems, environmental problems that they're having to deal with. So the other piece of this is to really be thinking about harm reduction in this population and talking to them about if they are gonna continue to use, what's safe practice? Is there a needle exchange in your community? We should be talking about this with all people that we come in contact with that are on the fence about getting into treatment. But in this population to really be recognizing that they're just high risk, they so frequently don't fully recognize the severity of the problem that they're dealing with and to be talking to them about sexually transmitted infections and blood borne viruses from injecting drug use is important. And they certainly can specialize frequently from being in a highly controlled setting or a specialty treatment setting where they're getting a combination of substance use treatment and behavioral health treatment. The second population that I wanted to bring up is the criminal justice system. Too frequently pharmacotherapy is not continued, particularly if they're in short term containment and then they're just released again, they're at huge risk of overdose. And so the American Society of Addiction Medicine has been very clear about recommending that these people should be maintained on their agonist or antagonist treatment. And if and when they are released in anticipation of that, they should have been started back on their medicine if it was taken off a good 30 days prior to discharge. They should be receiving some form of therapy while they're incarcerated, but we need to be addressing this prior to the termination of their incarceration. So let me say, we're going to finish here in a moment, but the last about opioids and respiration. So opioid peptides modulate respiration. They depress respirations through reduction in glutamate and how glutamate will induce excitation. So glutamate is an activating neurotransmitter in our brain and agonist activity at the medullary, mu and delta receptors causes this respiratory depression because it reduces that glutamate activation. And opioids then affect tidal volume and respiratory frequency. And buprenorphine does this to a degree also. But what also happens with full agonist is that there is a chemoreceptor inhibition that's mediated by the mu receptor that results in decreased sensitivity to changes in O2, but more prominently CO2. So we really, our reflex to breathe is dictated by rising levels of CO2 more so than falling levels of O2. And we lose that response and people simply just stop breathing. So they slow down, their CO2 level goes up and they stop breathing. So let me say a word about fentanyl because it's playing a role in this potential problems with using naloxone effectively. Fentanyl has a very strong affinity to the opioid receptor, very strong. And it consequently can challenge naloxone and has caused real problems in trying to move people from fentanyl onto buprenorphine effectively. And there's ways of doing that through microdosing and using large amounts, but we don't have any good definitive studies of how to do that effectively. And in fact, I'm a little skeptical about how that will be done because there's so many different formulations and toxicities of fentanyl out there. Fentanyl is highly lipophilic. So even though it's short acting, it stays in the system for a long period of time. It will rapidly equilibrate between the plasma and the central, the CSF and the central nervous system, resulting in fast onset of analgesia and potential respiratory depression, real potential. Fentanyl may be extensively redistributed to less highly profuse tissues and typically considered, again, very short acting when given by injection. So people will go out from this drug just rapidly after injection. Large doses of fentanyl can prolong the duration and action due to that saturation within the tissue. It stays in the system. It's not released rapidly. So do we need more naloxone with fentanyl? The easy answer is yes. And there's some good presentations. Again, there are not real good definitive studies, but there's good presentations identifying this. And there's now a move towards more rapid use more rapid infusions of naloxone because we have about six minutes between the time that a person actually stops breathing and significant brain death and potential irreversible overdose. And so in that this can take place so rapidly, we need to get naloxone on board rapidly and get it at sufficient dose. In 2015, almost one fifth of patients receiving naloxone from EMS required more than one dose. And this coincides with the increased fentanyl in the US heroin supply. It's just becoming ubiquitous. It's cheap, you can't smell it. It can be sent over the postal service. It's become a real problem and we don't have a good answer for it right now. Again, converting people from fentanyl to buprenorphine has become very difficult. We can use microdosing. We can, people are getting them into methadone, microdosing onto buprenorphine. There's a variety of ways that it can be done. Some people are recognizing that the need to have them at a higher CALS score that is the clinical withdrawal scale score, then putting them rapidly on a higher dose of buprenorphine. Some are going as high as 16 milligrams. So there's a variety of ways in which this can be done, but unfortunately it causes people that have been taking fentanyl to have withdrawal symptoms and then they don't think buprenorphine works for them at all. Whereas if we could get them onto it, they could be more comfortable. I've done a fair number of these conversions and used clonidine to help. So using clonidine along with buprenorphine and we can get them onto buprenorphine more successfully. But again, I'd like to give you a menu to do this, but it's not one size fits all. Naloxone prescriptions, there's then the injectable, which is very inexpensive and available. And it's 0.4 milligrams per milliliter and can be very effective. And these people often know how to use needles and it doesn't have to be given IV, it can be given IM. And then there's an auto-injector that kind of talks to you. It's quite expensive, but effective. And then there's the nasal spray, which is a more highly condensed formulation because we wanna add less fluid and spraying it into the nose so that it doesn't cause people to cough and cough out the naloxone. And very recently, there was approval for this eight milligram, which I believe is gonna be a 0.1 milliliter nasal spray that is called, and this is just a picture of what we think it's gonna look like. It's not actually on the market yet, but it was just recently approved by the FDA. But this can be used very effectively. I think the idea that people are recognizing that if someone goes out and their breathing gets low and they can't stimulate them, they need to go ahead and give a naloxone. And more and more, the using community is being schooled in this to actually start using naloxone more rapidly. Studies looking at naloxone and how it may be increased risk of continued use of substance use, which was a real concern by some, didn't just keep them alive. They were thinking that somehow they're gonna use in more high risk situations because now they think they can revive someone who has never been born out. And in this particular study, it looked at quantity of heroin use, frequency of polysubstance use, the addiction severity index, the drug composite score, looking at various impairment, life profile improvement, baseline one and three months providing overdose education in naloxone. And it saw no increase in the number of bags of heroin being used or higher risk behaviors. So clearly we need to be making this much more available to patients and really high risk patients that may be at home that are on high doses of opioids. So here you're seeing the patient selection for naloxone includes people with a history of overdose, emergency treatment for overdose or intoxication, suspected or known heroin or non-medical use of opioids, buprenorphine or methadone maintenance. They're still at high risk, receiving greater than 50 to 100 milligrams of morphine equivalents per day, changing from one opioid to another with increased cross tolerance, living in a remote location and difficulty with access to EMS. Not high risk, but if there's a problem, EMS can't get there quickly and or a request from a patient or concerned significant other. So why aren't more providers using these medications, talking about patients about these problems, addressing the problem more appropriately and either prescribing these medications in their office or at least knowing people in their community that do. We have under a half million people using are currently taking methadone, a little over 100,000 taking buprenorphine and a very limited number, 25,000 patients taking naltrexone. And these are recent numbers, approximately an equal number of patients receive treatment without medication. So as I've pointed out, this is not effective treatment if they're outside a controlled setting. So as they leave a controlled setting, they need to be having these medications available to them. It's not a philosophy. This is evidence-based practice of medicine. The barriers to people doing this work has been that they needed to take, that they may have actually taken the course, but they decided not to prescribe the medicine because they just took the course like you may be taking this course just to learn more about it, which is great. But if you're in this situation where you're seeing these patients to actually be prescribing the medicine would be even better. And they feel a need to have more training, certainly to then go through the full eight-hour training and, or look on the PCSS website where there's a whole host of videos and modules available to learn more, to get a mentor, to talk with others about what are the kind of ins and outs that you have concerns about. And then there's those that feel starting treatment with the, for opiate use disorders would be disruptive to their practice. And so they never wanted to start it. I can tell you some of that has to do with stigma. I hope that learning more about it, you begin to recognize that these are people just like everyone else. And I will also tell you that I haven't met someone that treats these patients that doesn't find it the most rewarding aspect of their medical career, that we really get the opportunity to see people change their lives dramatically. And so I will also say that those same people will say, these are some of the easiest patients I take care of after they get stabilized on their medication. And you do, if you're in a medical setting, then you're gonna also have the opportunity to help them with other physical problems that they're having, behavioral health problems potentially, or refer them for some of their social problems. Some would start it and then discontinue because of pre-authorization problems, reimbursement problems, fear of monitoring by the DEA, not having access to behavioral health providers, potentially time constraints and concerns about diversion. I will tell you that the first four of those pre-authorization is improved significantly. Reimbursement is somewhat improved. At least it's becoming more easy to bill for this treatment. DEA monitoring is almost gone. They're monitoring through the PDMP, the prescription monitoring programs. Not having access to behavioral health providers is not a restriction to the use of this work. To look for someone that's available in your community would be great, but it could be you connect with the local AANA group or peer support groups. Now, some of them still have a philosophy of no medication, but many of them are coming around to recognizing the value of medication for opioid use disorders. Time constraints, I can't control that. But again, so frequently, we don't see this as a big time burner. And concerns about diversion. If you monitor the patients well enough and talk to them and use the medications appropriately, you can always cut back on the supply that you're giving them if there's concern, maybe on the dose possibly, but this shouldn't be of great concern. So with that, I'll end. I would encourage you to take a look at the PCSS Now website, the AOAM website. We have, with the AOAM, a lot of resources and certainly mentoring that we could help you with. And ASAM, same, a lot of resources, a good organization. And then to look at the NIDA website or AAAP if the patient has a co-current alcohol use disorder. And Scope of Pain is also a good place to look if you're struggling with more patients that are co-current pain patients. And that's a project out of Boston University. And with that, I'll say thank you very much for listening for this period of time and goodbye. Thank you.

opioid use disorder

addiction psychiatrist

American Osteopathic Academy of Addiction Medicine

opioid prescribing

Mu receptor

genetic predispositions

chronic pain

methadone

buprenorphine

naltrexone

harm reduction strategies

naloxone

treatment retention