Hello and welcome to the PCSS MAT training on medication for opioid use disorder. I'm Melissa Weimer, I'm Assistant Professor of Medicine and the Medical Director of the Yale Addiction Medicine Consult Service at Yale University School of Medicine. My disclosure, I have received monetary honorarium on one occasion from Invidior related to speaking about opioid dependence and pain. The overarching goal of the PCSS-MAT trainings is to make available the most effective medication treatments to serve patients in a variety of settings, including primary care, psychiatric care and pain management settings. Our objectives today are to identify the rationale for using medications to treat opioid use disorder, describe effective medications for treating opioid use disorder, and explain the unique properties of methadone, buprenorphine and naltrexone. Let's start this module with a case. Jane is a 23 year old female with chronic low back pain from a motor vehicle accident that she sustained at age 16. She presents to your office asking for help to stop using IV heroin. She's been using opioids daily for about four years. She started using illicit prescription opioids then switched IV heroin daily about two years ago, when she could no longer afford illicit opioid pills. She has attempted non-medication-based addiction treatment in the past and unfortunately quickly relapsed. She also drinks approximately 14 alcoholic beverages per week, but has never had alcohol withdrawal symptoms when she stops drinking. She feels she can easily stop drinking alcohol. She denies other drug use. She denies other mental health or medical issues, but has had two opioid overdoses in the past year. She lives with her parents, who are very supportive of her. She is on probation for possession of opioids. She reports opioid withdrawal symptoms including anxiety, restlessness, nausea, stomach cramping and diarrhea. Her vital signs and physical exam are normal, except for gooseflesh, dilated pupils and bilateral upper extremity track marks. Questions that I would like us to think about are, is medication for opioid use disorder indicated for this patient? What additional work up or evaluation is needed to decide upon medication for her? Which medication to treat opioid use disorder is most appropriate for this patient and how will you address the concomitant alcohol use? So these are questions that throughout the training I hope that you will be able to understand and come to a greater ability to answer. So as you've probably learned if you've taken any of the other modules in this series, a substance use disorder is a chronic relapsing disorder, or brain disease. And similar to other types of chronic illnesses, such as Type II diabetes, hypertension and asthma, we see that unfortunately patients frequently relapse with drug use when they have this illness. And it's actually not very dissimilar from other illnesses that we know a lot about, like Type II diabetes, hypertension and asthma. So it's important for us to have this conceptualization when we're thinking about our patients who are struggling with substance use disorder, and help normalize the fact that unfortunately relapse is a part of the disease. Additionally, you've probably seen a slide like this before, which describes the stages of the addiction cycle. But this very important slide is from a review in New England Journal that Nora Volkow and George Qube and Thomas McClellan coauthored, describing the stages of the addiction cycle. And they helped put this into a format that helps us understand the neurobiology. And helps us understand that there are three distinct, all interrelated parts of the addiction cycle, including the binge and intoxication cycle, withdrawal and negative affect cycle or stage, and preoccupation and anticipation. These are all distinctly important as we think about and understand the illness, and then think about why it's important for us to have medication to help intervene within this stage. So as you can see on this slide, we list the DSM-5 criteria for substance use disorder. You've probably heard a lot about this in the different modules that you've been going through in this series. However, as you can see, and I'll go through here, in order to have a substance use disorder, you need to meet 2 or more of these criteria in a 12-month period in order to meet the diagnosis of a substance use disorder. As you can see on the left hand column, this is related to the DSM-4 criteria for abuse and dependence. However, we now have put those two together into this DSM 5 criteria. And in order to have a mild substance use disorder, you would meet 2 to 3 of the criteria listed here in a 12-month period. In order to have moderate substance use disorder, you would need to meet four to five of the criteria listed here. And in order to have severe substance use disorder, you would meet 6 or more in a 12-month period. What's very important to recognize is that in order to diagnose substance use disorder, you do need to go through this process. And it's important that you're documenting this process and thinking about this when you are seeing patients and evaluating them for the appropriateness of medication treatment. The last thing I'll say is that when we're thinking about the last two criteria, which are tolerance and withdrawal, it's important to recognize that we don't count these criteria if a patient is prescribed an opioid and taking that medication as prescribed. However, if the patient were prescribed an opioid and not taking that medication as prescribed, then you would be able to count those two criteria. So when we're thinking about why we are using medication for opioid use disorder, it's important that we think about what their inherent purposes are. And there are multiple different purposes that they serve. Number 1, they help allow a reestablishment of homeostasis of the reward pathways in the brain away from substances, so that patients are able to start using normal or normative reward rather than only reward that is associated with a substance. Next, we understand that opioid treatments allow for restoring emotional and decision-making capacities. They help control symptoms of opioid withdrawal. They suppress opioid craving, and they can actually block the reinforcing effects of ongoing opioid use, and we will talk about this more. Additionally, they promote and facilitate patient engagement in recovery-oriented activities. And coupled with behavioral interventions, we really have seen that medications help enhance the salience of natural healthy rewards, as we discussed before. They reduce stress reactivity and negative emotional states. They improve self-regulation, and they increase avoidance of relapse triggers. So all very important and, Help patients in their recovery path. The goals of medication are very important. And these are very important because we've understood, as we've used medications more, that the medications for opioid use disorder do reduce mortality, including all cause and drug-related mortality. They reduce the associated morbidity associated with drug use, whether that be the transmission of blood-borne viruses, such as hepatitis C and HIV. But the infectious complications of IV drug use as well, including endocarditis and osteomyelitis, which can be quite devastating for patients who use drugs. Additionally, we see that patients who are using medication are able to reduce and/or discontinue their opioid use. They're able to increase their retention in treatment. We see the improvements in general health and well-being. And additionally, we see a reduction in drug-related crime. So as you can see, these are all very important outcomes that we have come to understand, and have good evidence to suggest that these medications are effective for improving these outcomes in patients. So if we know that medications are so effective for all these important outcomes, why do we have such trouble getting these medications to patients? And unfortunately, access to the medication remains a key barrier in reducing mortality from opioid use. As you can see in this slide, on the left, shows a schematic of what occurred when we increased access to antiretrovirus therapy for HIV. As you can see, in the mid 90s, there was a increased access, and after that, you really saw a reduction in mortality from HIV and AIDS. When we look at that, compared to what has happened with the advent and the increased use of office-based buprenorphine therapy or naltrexone that's been released, naltrexone. Unfortunately, we have not seen the same reductions in mortality. In fact, we've seen increased mortality from opioids because this difficulty with access has continued. So what we hope is, with training such as this one, we will be able to train more people to understand the importance of medication. And start utilizing it more, potentially in primary care settings, or other settings where we know patients are accessing and looking for care. We also have, as I said, good data to suggest that using these medications is quite effective for reducing mortality. This was a study out of Baltimore in 2013, showing that when you adjusted for the heroin purity and the number of patients who were already being treated with methadone, which has been available since the 70s, there were statistically significant inverse relationship between the heroin overdose deaths and patients treated with buprenorphine. So with the increase in access to buprenorphine, we were able to see that patients were doing better and having less mortality. So again, very good data to suggest that increasing access to these medications is very important for these very important outcomes, and to reduce mortality. So we're talking about medication for opioid use disorder. I'm referring to three specific medications. Number one, methadone, which can be prescribed for the treatment of opioid use disorder only through an opioid treatment program or a methadone clinic, specifically. Then, second, we're speaking about buprenorphine, which can be treated and prescribed through an office. It can also be dispensed through an opioid treatment program. And then thirdly, naltrexone, which also can be used in an office or an opioid treatment program. We'll talk about this a little bit more. But I think it's important to recognize that there are some federal guidelines around what additional therapies are mandatory with these medications. And it's important to recognize that counseling is mandatory for any person who is treated in a methadone treatment program. For patients who are prescribed buprenorphine, providers do need to have the ability to refer for counseling, but it is not mandatory. And then counseling is optional with naltrexone treatment, but certainly encouraged. So all of these medication modalities, however, do require that a provider is providing medication management of some kind. And we will further define what that is throughout this lecture. This is an important slide to help understand how these different medications work. And when we start thinking about how they work, it's important that we understand their key differences. So when we're talking about methadone, for instance, we're talking about a full opioid agonist medication. So you see, on the the left axis, that is the percent of mu receptor activity. So as you can see, with methadone, a full opioid agonist, so fully exciting the opioid receptor. You see that as you give more methadone over time and the dose increases, you can actually have full saturation of the mu receptor, until there are no further mu receptors able to be saturated. Looking at buprenorphine, you see that because it is a partial opioid agonist, it actually never can occupy more than about 50% of mu receptor activity. So as you take more buprenorphine, you have slightly more effect. You'd have slightly more effect until you get to about 50% receptor activity, and it will never go above that mu activity. The reason is we call this the ceiling effect of buprenorphine. And this is one of the reasons that we think buprenorphine may be somewhat safer, when thinking about overdose risk with these medications, than methadone, which can have full opioid receptor activity. And conversely, you have naltrexone, which is a opioid antagonist, meaning that it completely blocks the mu receptor, and there's no actual receptor activity, other than a blocking effect. So the more naltrexone you take, you will never actually have excitation of the mu receptor. So a key, important difference when we think about these medications, how we conceptualize them, and then thinking about how they may be beneficial to different patients. In this slide, we have a table showing the different outcomes that are important for us to look at when we look at the medication efficacy for opioid use disorder. And then the studies showing what What the outcomes have been when we're utilizing this medication. So if we take the first row there and we look at methadone, we can see that all-cause mortality is reduced and based on four studies, treatment retention is increased based on six studies. Opioid use is reduced. That's any opioid use in six studies. And HIV and hepatitis C transmission has been reduced in multiple studies, as well as criminal activity was also reduced. So as you can see, and looking at all of the important outcomes, patient outcomes that we would like to see from a medication treatment for opioid use disorder, these are all positive outcomes. Similarly with buprenorphine, we see the same trend, that there's a reduction in all-cause mortality increase in treatment retention, reduction in opioid use, reduction in hepatitis C and HIV transmission and a reduction in criminal activity. I'm going to skip and come back to oral naltrexone for a moment and go to the extended release naltrexone. Similarly, we're seeing those important outcomes, a reduction in all-cause mortality, increase in treatment retention, decrease in opioid use, and a decrease in criminal activity. We unfortunately don't have any data about the hepatitis C or HIV transmission. So when we're looking at methadone, buprenorphine, and extended release naltrexone, we're clearly seeing that these outcomes that we find are important to patient outcomes are all showing that these medications are effective. Now, if we look at the oral naltrexone, you can see that there really aren't as many studies and the data is lacking for all-cause mortality, as well as a reduction of HIV and hepatitis C transmission. Although we do see that there was treatment retention, improved and reduction in opioid use, and a reduction in criminal activity, these studies it's important to note were all done in patients who had, were basically forced to have adherence either in a criminal justice setting or some other setting. So at this point in time, oral naltrexone is really not seen as one of the medications we utilize for patients with opioid use disorder. You can certainly utilize but our data is clearly not as robust as it is for the other three medications that are listed here. Okay, so let's focus on methadone specifically and then we'll go through and focus on the other medications. So methadone is a really old and interesting medication. It was developed in the 1930s during WWII as an alternative to morphine. It wasn't approved in the United States until 1947 when it was improved as an analgesic and an antitussive. In the 60s, it became, utilized for the first time as a medication to treat opioid use disorder. And that was through work that Dr. Vincent Dole did at Rockefeller University. It was not utilized in a federal program for methadone maintenance until 1971, which was really the first program of the typical methadone maintenance program that we think about. So as I discussed before, methadone is a full opioid agonist, so fully exciting the opioid receptor. It is indicated to treat opioid use disorder and opiate dependence. Some important things about methadone, it has a long and variable half-life. So the half-life of methadone can actually last anywhere from 15 to 150 hours. This makes it very unique and potentially very dangerous if the person who is prescribing it doesn't have a lot of understanding of how the pharmacokinetics work. It is approved to be utilized in an opioid treatment program with very strict federal regulation. So the federal government tells us that in order to use methadone for the treatment of opioid use disorder, we have to dispense it through an opioid treatment program. One exception being hospitals, hospitals are able to dispense methadone without being an opioid treatment program. Opioid treatment programs are mandated to integrate counseling into their treatment paradigm. And this is a federal requirement. There are additional specific eligibility criteria that determine whether a patient can be treated with methadone as well. The typical effective dose range for methadone is anywhere from 60 to 100 milligrams per day. However, some patients, and this is important too, may need higher dose and generally the idea of a capping a dose is not recommended by most people who prescribe methadone in maintenance programs. Methadone has greater than 40, sorry, 40 years of data supporting that it is safe, that it leads to sustained opiate abstinence that improves treatment retention in addiction treatment. That it reduces the IV drug use risk behaviors and reduces transmission of hepatitis C and HIV. However, as I discussed, it's important that we're carefully monitoring patients who are prescribed methadone. And we understand that the risk of mortality is the highest in the first two weeks of treatment because of the unique and complex pharmacokinetics of methadone. Additionally, we do know that methadone can prolong QTC. And this has been seen in about 23% of patients who have been treated with methadone. Finally, there are multiple drug-drug interactions that are important to be understood and recognized. And so there are certain medications that are contraindicated with methadone or that you need to be very careful about co-prescription with methadone. As I said, we have a lot of data to suggest that treatment with methadone improves mortality. And this was seen in a very nice systematic review that came out in 2017, showing that patients who are In treatment with methadone have a much greater reduce to all-cause mortality as opposed to those out of treatment. Similarly, if you look at overdose risk, overdose risk is greatly reduced in patients who are in treatment using methadone versus those out of treatment. If we were to recommend methadone for a patient, it's important that we understand the contraindications and precautions. And this information comes out of the ASAM National Practice Guideline from 2015 listing contraindications including hypersensitivity, respiratory depression. So there may be patients who have severe COPD or severe obstructive sleep apnea who may not be very good candidates for methadone because of its very long half-life and the ability to suppress the respiratory drive, particularly at high doses. Additionally, hypercapnia would be a relative contraindication as well as paralytic ileus and a QTC of greater than 500 Milliseconds, because of the ability of methadone to further prolonged QTc. And because we know that towards suds, which is a potentially fatal arrhythmia. The risk of it can increase precipitously, over a QTc greater than 500 milliseconds. We typically do recommend that patients who are prescribed methadone or have been who you're considering for methadone. Have a Qt, have an EKG prior to Prescription and that is monitored on a annual basis or more frequently if the patient is having certain symptoms like palpitations or history of sudden death in their family. Precautions that you want to know about and to speak more careful with would be concurrent use of other CNS depressant such as alcohol, other opioids and benzodiazepines because we know that they can interact and further suppressed respiratory drive. If they are being abused and taken with methadone. Liver disease is a relative precaution. Certainly, compensated liver disease likely will not increase risks. Though if a patient has cirrhosis or very severe liver disease, you would want to be careful and potentially. Limit the dose of methadone, drug interactions we discussed, very important that you understand what medications interact with methadone and that you are looking at that and potentially reducing doses or increasing doses, depending on the medication and how it interacts with methadone. And then finally, a relative contraindication would be or precaution that you should take as in patients with a QTc greater than 400 milliseconds. You would want to consider the potential for Methadone to further increase the QTc. So again it's not contraindication, but it's something where you might pose and think about ways to. Either reduce a risk of further prolongation of QTc. Or think about an alternative, such as buprenorphine or naltrexone, which we don't think really affects the QTc. Buprenorphine/Naloxone is the second medication we're going to talk about. This comes typically in a film or a tablet. The Buprenorphine component of the combination is an a 4:1 combination with the Naloxone. So, Buprenorphine/Naloxone was first FDA approved in 2002 for the treatment of opioids disorder and opio dependence. It is a partial opioid agonist which has a schedule three. As I said, it comes in this transmucosal film or tablet, it has to be taken sublingually. It can be dosed either once a day or alternative dosing would be every other day or even three times weekly if it's still remaining effective. It would be off label to use it twice a day or three times a day but there are people who do take it to more frequently than once a day. Typically 24 miligrams per day is usually the highest effective dose, as we showed you before there's a ceiling effect, where there is no more than 50% occupation of the mu receptor, and we do think that lowers overall opioid overdose risk, though. There, there still is some potential opioid overdose risk when taking buprenorphine. Buprenorphine can be prescribed in an office by MDs, DOs, PAs and NPs based on new federal legislation. However, anyone who's prescribing does have to have a DEA waiver, otherwise known as an X licence. The first year after receiving your X licence, you can treat up to 30 patients. Then after that, all providers can treat up to 100 patients. There were special legislation that was enacted. That does allow certain physician, MDs, and DOs, to prescribe up to 275 patients. Unfortunately, NPs and PAs can only increase up to a total of a 100 patients. The rationale for using the combination of Buprenorphine with Naloxone, was really in an attempt to decrease misuse or diversion. So Naloxone which is an opioid blocker is typically inactive in the combination unless the medication is injected. Naloxone has a very low bioavailability when the medication is used Sublingually. If a patient is opioid dependent and not an opioid withdrawal. typically, injection of the combination medication would precipitate withdrawal because the no lock zone component would become active if injected. However, if the patient is in opioid withdrawal, injection of the combination can potentially have some euphorogenic or opioid withdrawal relieving effects despite some information out there saying that typically patients would only have a negative effect. So we are learning more about this as we're treating more patients. But in general, the combination product is thought to have less diversion risk, and certainly to be safer if injected and does typically lead people not to misuse or inject the medication. There are several different commercially available transmucosal Buprenorphine formulations for the treatment of opioid use disorder. Those are listed here. It's important you recognize how they are different and that their doses can also differ. Generally the formulation you choose maybe more a byproduct of what the patient's insurance will cover, as opposed to inherent differences between the formulations listed here. However they are listed here. But again, it's a very very important that you understand how the formulations differ for instance, suboxone which is a the brand name of buprenorphine slash Naloxone, a dose of two slashes 0.5 milligrams is equivalent to a dose of suboxone off of 1.4 0.36 milligrams. Similarly, a dose of 8/2 milligrams of Suboxone is equivalent to a dose of 5.7/1.4 milligrams of subs off. So, it's important to recognize how the doses are different. I'll also just say here that there are other formulations of buprenorphine including Bell Buca. Blooper necks and BJU trans bees are actually not indicated for the treatment of opioid dependence or opioid use disorder. They are indicated for the treatment of pain. Which is outside of the the topic of this lecture. However, it's just important to recognize that that is buprenorphine. However, they are not FDA indicated for the treatment of opioid use disorder. Similar to methadone, there are some contraindications and precautions you need to think about. Certainly any hypersensitivity would be a direct contraindication to buprenorphine. We think of patients not already on buprenorphine undergoing a procedure where a full agonist treatment is needed. That would be a relative contraindication. So we're talking about patients who potentially are having a surgery or being treated with a full opioid agonist, where there's the potential to have precipitated withdrawal if you start buprenorphine in those patients, so that is a contraindication. Precautions would be concurrent use of CNS depressants like alcohol, other opioids, and benzodiazepines. Again, when used concomitantly with buprenorphine, they can potentially lead to an unintentional opioid overdose. If you were to give buprenorphine to a patient who was prescribed a full agonist, there is the potential for precipitated withdrawal. So that's something you have to be aware of and use buprenorphine cautiously with. And then severe liver impairment is a precaution that you would want to think about potentially lowering the dose, or being very careful about your monitoring of the dose. A newer formulation of buprenorphine is the buprenorphine implant known by the brand name of Probuphine. This was FDA approved in 2016 for the treatment of opioid use disorder in patients who have clinically stabilized on transmucosal buprenorphine of at least eight milligrams a day or less. So these are patients who are not using more than eight milligrams, but could be using less than eight milligrams. The medication consists of four implants that are 80 milligrams per implant, that need to be surgically inserted into the subdermal region of the upper arm, and they release buprenorphine over a series of six months. At the steady state, which is achieved after four weeks, they're comparable to trough buprenorphine plasma levels produced by daily sublingual buprenorphine dose of eight milligrams or less. There is a live training program that you must sit through if you were to insert or remove these medications, in order to have the special training to do so. Data showing that this medication was effective came out in JAMA in 2016, showing that there was a increase in the illicit opioid use compared to sublingual buprenorphine that was statistically significant. So compared to the sublingual buprenorphine, the implant appeared to have greater ability to achieve abstinence from opioids. There was a secondary analysis also showing the six months illicit opioid abstinence was not statistically significant, but a trend towards greater abstinence with the implant, and this was based on 177 patients. A very new medication that was just approved in 2017 is the buprenorphine depot injection, and it is indicated for the treatment of moderate to severe opioid use disorder. It is a monthly subcutaneous abdominal injection. In order to be stabilized to receive this injection, you do have to be stabilized on seven days of the transmucosal buprenorphine treatment first. The medication has two doses. The first is 300 milligrams and the second is 100 milligrams. There are two dosing options available based on our current evidence, and that's either 300 milligrams for six months or 300 milligrams for two months followed by 100 milligrams for four months. Peak buprenorphine concentrations do occur after 24 hours after the injection, and we see that the steady state is achieved in four to six months. After discontinuation, what's interesting about this injection is that patients can actually have detectable plasma levels for 12 months or longer after receiving the medication. And so in the trials that were done, we saw patients had fewer opioid withdrawal symptoms after discontinuation of the medication. The evidence for the injection is based on one Phase 3 trial. It was based on the evidence out of a CPDD meeting in 2017. People who received this injection had few significant adverse effects. The primary endpoint was the mean percent abstinence. And when they looked at the injection versus placebo, they saw that 41 to 43% of patients in the treatment arm had abstinence. The secondary endpoint was treatment success, and this was based on achieving 80% of the urine samples free of opioids. And this was statistically significant better in the treatment arm. So about 30% of patients having treatment success versus only 2% in the placebo arm, and which is what we would expect for patients not receiving any sort of medication treatment. So based on what we just talked about, all the different formulations of buprenorphine, what do we know about the effects of buprenorphine? And we have really clear evidence that started in the early 2000s showing us that buprenorphine is quite effective as a maintenance medication. So this was kind of a sentinel trial from 2003 from Sweden, showing us that buprenorphine maintenance was much superior to detoxification for treatment retention. So in this study, it was of approximately 20 patients, we saw that those who were maintained on buprenorphine maintenance were able to be, 75% of them, abstinent at one year of treatment. And none of the patients in this trial died secondary to any cause. However, compared to the detoxification protocol, 0% of the patients who were on the detoxification protocol were abstinent at one year. And, unfortunately, 20% of the patients in the detoxification protocol died. So you can see that at one year, the outcomes are very beneficial towards buprenorphine maintenance as opposed to detoxification. So the main point here is that similar to methadone, Being on this maintenance medication is highly effective for the outcomes that we know keep people safe and alive. That is reiterated here in the Sordo meta-analysis from 2017, showing that when patients are in treatment with buprenorphine, there is a greatly reduced all cause mortality. Similar greatly reduced overdose risk for patients who are on buprenorphine as opposed to those who are out of treatment. So let's think about how does buprenorphine compare to methadone? So we know methadone's been around for a very long time. Buprenorphine has been around for a while, but not as long. Are they actually equivalent in some of the outcomes that we're interested in looking at? So let's look at treatment retention, specifically. So compared to high doses of methadone, talking about doses of 60 to 100 milligrams, buprenorphine is actually quite comparatively good compared to methadone. So we're seeing similar outcomes in treatment retention with buprenorphine, similar to the high doses of methadone. However, if you use low doses of methadone, we're talking about 20 milligrams of methadone, we see but that is not as good at keeping people in treatment. So comparatively, buprenorphine compares very well to methadone. Similarly, if we look at the outcome of opioid abstinence, which is looked at through opioid urine results, we see that buprenorphine is similarly effective as the high doses of methadone. Again, faring better than the low doses of methadone, looking at opioid abstinence. All right, let's shift gears for a minute and talk about oral naltrexone. So we said that oral naltrexone really didn't fare as well as the other three modalities listed. But I think it's important for us to just talk about so you have some information about. So as know, naltrexone is an opioid antagonist, so it blocks all opioid receptors. It does come as a two formulations that we'll talk about, the oral naltrexone and the intramuscular naltrexone. It was FDA approved in 1984 for a blockade of the effects of administered opioids. The typical dose used is 50 milligrams per day. You can alternatively dose it three times a week by using 200 milligram doses followed by 150 milligram dose. It does have a half-life that allows it to be dosed as such. That being said, it's not widely used to treat opioid abuse disorder because, unfortunately, it has very low rates of patient acceptance. It has a lot of difficulty with the initiation. And it's quite hard to make sure the patients are adhering to taking the medication. So in a Cochrane Review, it was not shown that oral naltrexone was superior to placebo or no medication in treatment retention or illicit opioid use. So again, it's medication that you can use, but though certainly not one that we reach to as our first line treatment for the treatment of opioid use disorder. That being said, extended release naltrexone does fare a lot better, and we'll talk about why that is. But the main reason is because it's an intramuscular injection. So you've taken out the issue of adherence and you're able to get that full opioid blockade that you're going for. So it was approved in 2010 for the treatment of opioid use disorder, following medically supervised withdrawal. So you can't give this to patients who are dependent on opioids. The patient has to be off of opioids for a period of time that we'll discuss in a moment. So it's a 380 milligram injection that's administered intramuscularly once every four weeks or every 28 days. There are some people who may metabolize the medication quickly, and they may need the injection every 21 days. Our understanding of this medication is changing with some new important trials that came out in the last year. But really, when we're thinking about this medication, we're thinking about patients who may have failed agonist treatment, patients who may be confined to environments that don't allow them to have medication treatment, patients who don't have access to agonist treatment, patients with high risk of diversion, patients who are highly motivated or willing to taper off opioid agonists. Patients who don't want to be treated with an agonist, certainly. And then, you can also utilize it for patients who have concomitant opioid and alcohol use disorder because it is also FDA indicated for the treatment of opioid use disorder and alcohol use disorder. So extended release naltrexone, like I said, does require the patient to be abstinent from opioids. So if your patient's using short acting opioids such as heroin, you would want them to be abstinent for five to seven days prior to giving them this medication. If they were taking a long acting opioid such as methadone or buprenorphine, or extended release morphine or extended release oxycodone, you would want them to be abstinent for a minimum of seven to ten days. For something such as methadone, you might even want them to be abstinent for as long as 14 days. To confirm that your patient is opiate abstinent, you want to do a urine drug test and a naloxone challenge, which I'll describe in a minute. Naltrexone does have few drug-drug interactions, that makes it a favorable medication to use. However, it's important to recognize that you can have these induction delays. And if the patient doesn't get subsequent doses, then that really will reduce the overall effectiveness of the medication. So quickly, to describe the naloxone challenge, like I said, this is a giving a short acting opioid blocker to assess a lack of physical opioid dependence. Usually, you give it IV intramuscularly or subcutaneously. And you give typically 0.4 to 0.8 milligrams at a time. And if the patient does not have any withdrawal symptoms, then you would go to the extended release, giving the patient the extended release naltrexone. This is important to confirm because if you give a patient who is opioid dependent extended release naltrexone, that person could potentially go into very significant severe opioid withdrawal, and likely not do very well. Generally, naltrexone has been proven to be efficacious for opioid abstinence, compared to placebo. And there were two trials that were done showing this, one in the US looking at 60 people who were using heroin for 8 weeks. And then a Russian trial showing 250 people who were using heroin. And the Russian trial was able to show a significant reduction in opioid use, with a number needed to treat of 7.8. It was a fair quality study, but did have pretty high attrition, and it was only in young white males. So for a long time, we really didn't have a lot of great data about naltrexone. However, this has really changed in the last two years, when we've had a lot of important work done by people such as Josh Lee at NYU. And we're going to discuss those trials here. So Dr. Lee did his first study of naltrexone, extended-release naltrexone in 2016, was looking at its use to prevent opioid relapse in criminal justice offenders. This was an open-label, randomized, controlled effectiveness trial. And it compared six monthly injections of extended-release naltrexone with usual treatment, which was brief counseling and referral for community treatment programs. He was looking at adult ex-prisoners who had a history of opioid dependence, with the primary endpoint being opioid relapse. And he was able to show, with the Kaplan-Meier relapse-free survival, that extended-release naltrexone was better in time to relapse. So it was a longer period of time before a patient relapsed, so 10 and a half weeks, as opposed to 5 weeks in the usual treatment, Group. Same with opioid relapse event. We're seeing that there was less relapse in the naltrexone group, as opposed to the usual treatment. And then overdoses, there were 0 overdoses in the naltrexone group, compared to 7 in the usual treatment. The opioid use prevention effects, though, did wane after treatment discontinuation. So it's important that the patient's on the treatment in order for them to continue to have these benefits. So thinking about contraindications and precautions for extended-release naltrexone, again, hypersensitivity. Certainly, you wouldn't use the medication if your patient were physically dependent on opioids. Again, this would be a contraindication, because your patient would go into severe precipitated opioid withdrawal. If your patient was receiving opioid analgesics, this would be a contraindication. And then a patient in acute opioid withdrawal, because you would worsen that withdrawal. Precautions, there is some thought of a vulnerability to overdose. You can have some injection site reactions that are associated with injectable naltrexone that you want to monitor after injection. There's a risk of hepatotoxicity. So typically, we don't give this medication to patients who have liver function tests greater than five times the upper limit of normal. You would want to monitor for the development of depression and suicidality. And then finally, a precaution of thrombocytopenia or coagulation disorder, because there can be some injection bleeding risk. So as I discussed, some of the new trials out to show us the efficacy, effectiveness of naltrexone. So the first trial was from 2017, a Swedish trial, which compared naltrexone, extended-release naltrexone to buprenorphine. This was an open-label, randomized controlled trial. They randomized 159 patients, and 105 completed the study. This was a study that was done in an inpatient detox setting, had 12 weeks of followup. Their primary outcome was retention in treatment, and the proportion of opioid-negative urine drug tests, and the days of use of heroin or other opioids. They found that extended-release naltrexone was non-inferior to buprenorphine, though it's important to recognize that the buprenorphine they were using was a relatively low dose of buprenorphine. For treatment retention and decreasing opioid use at 12 weeks. They did see that there was lower use of heroin or other opioids in the extended-release naltrexone group. The secondary outcomes. The extended-release naltrexone was superior to buprenorphine in reduction of heroin craving, reduction in insomnia, satisfaction with treatment, life satisfaction, and reduction in pain. But there was no difference in anxiety or depression between the two groups. Then if we go to the Josh Lee X:BOT trial from 2018, this was a comparative effectiveness randomized controlled trial comparing extended-release naltrexone to buprenorphine. There were 570 patients who were randomized. 474 completed the trial. This was a trial that was done in 8 inpatient detoxification centers around the United States, or residential treatment programs around the United States. The sites utilized a non-opioid detox. I'm sorry, let me rephrase that. The sites that utilized a non-opioid detox had better success with the induction. I think that's a really important point when we talk about who did best, and who was able to get onto the medication. It was a 24-week followup, and the primary outcome was time to relapse, which was defined as 7 consecutive use days over 4 consecutive use weeks. And that was beginning no earlier than 21 days post-randomization. So if we look at the results of this trial, it's a little complicated, so I'm going to go through it here with you. So remember, they were comparing extended-release naltrexone to buprenorphine, and they did this looking at two different ways of looking at the data. So they did an intent-to-treat analysis, so that's the ITT, and they did a per-protocol analysis. The intent-to-treat analysis was done of all patients who were randomized, including those who did not actually receive the treatment. And then the per-protocol analysis include only patients who were treated with naltrexone. So looking at the top of the graph, you'll see the number of patients who were inducted to the study medication. Only 72% of the patients were able to be inducted onto extended-release naltrexone, as Compared to 94% of the buprenorphine patients, and that was clinically significant difference. When we looked at comparing patients who received extended-release naltrexone versus those who received buprenorphine, in the intent-to-treat analysis, we see that patients who were receiving buprenorphine clearly did better than those receiving extended-release naltrexone. Because it's important to recognize that most of the patients did not actually receive the extended-release naltrexone. And the relapse rates were lower in those patients who received buprenorphine. However, if we look at the per-protocol analysis, so that we're talking about 204 patients who received extended-release naltrexone, as opposed to 270 who received buprenorphine. You see that actually the differences that you were seeing in the intent-to-treat analysis are no longer there, statistically are no longer there. So patients actually did a little bit better on the extended-release naltrexone, as compared to the buprenorphine, and the relapse rates were very comparable. However, like I said before, patients were less likely to be inducted on extended-release naltrexone in this trial. And those people in the intent-to-treat were less likely to relapse if they received buprenorphine in the intent-to-treat, because more people were able to get onto buprenorphine. However, once the medications were started, Again, once people were inducted onto extended-release naltrexone, that statistically significant difference was not observed. So this is an important trial that showed that once you're able to get patients onto extended-release naltrexone, it appears to fare as well as buprenorphine. However, the real clear problem is, how do we help patients get onto extended-release naltrexone? And that's where I think the point I made about the programs that did the best, were able to be the most effective at getting people onto extended-release naltrexone were those that did not use opioids in their detox protocols. So I think there's an opportunity, when we're thinking about patients who may want to utilize extended-release naltrexone, to think about the protocol, the detox protocols we're using. And potentially, preferentially, use the non-opioid based protocols. All right, let's switch gears for a minute and talk about how do we deliver these medications, because there are many different models of care. And these models of care are important to think about, depending on the treatment setting that you're working inside. So there was a nice analysis that was done by Roger Chou and others, including Todd Korthuis and myself, actually. And we tried to look at all the different models of care that are around the country, and summarize them, and put them in one spot. So these are all listed here. I'm not going to go through them all individually, other than to say that if you're not sure of what model of care might work for you in your treatment setting, it would be important to look at this, the list of the different programs. And think about what's uniquely different about them, and what might be a good model for you to adopt in your treatment setting. There are many common components of the models that are listed there. Most of them are including some type of pharmacotherapy, typically buprenorphine or naltrexone. Typically, there's some sort of provider and community education that's listed there, in the different models. There's a lot of coordination and integration of opioid use disorder treatment with other medical and psychological needs, and psychological services. So again, look at these papers, look at the models that are listed there, and how you might integrate that into your practice. Important for us to also recognize, when you're thinking about medication management, what do we really mean? So if you plan to start utilizing these medications in your practice, what are your responsibilities as the medical provider? I would refer you to the medication management module that we have that describes this more in depth. But when we're thinking about medication management, what we're really thinking about is treatment of opioid withdrawal. Because that's really the beginning of getting somebody on one of these medications. We're talking about the initiation of the medication. We're talking about evaluation of the safety and effectiveness. We're talking about confirmation of adherence, so doing that through urine drug testing, pill counts, patient report. We're talking about evaluating the treatment plan based on the patient need and adherence, and then referral for or treatment of mental illness if needed. Typically, you may also want to think about doing some type of psychosocial needs assessment, supportive counseling. Integrating different case management options, linking to existing family supports, and then referral to community services. Let's talk a minute about the role of counseling. We've referred to that a few times in this lecture. So the purpose of counseling for patients who are receiving some type of medication is to modify behaviors that may be maintaining or reinforcing drug use. Help patients develop different coping strategies, encourage medication adherence, and treat or identify the concomitant mental illness that can complicate substance use disorder or trigger relapse. There's some evidence that show that psychosocial treatment improves adherence and retention in treatment, but these findings are actually mixed. So although we think there is definitely a role for counseling in patients who are receiving medication, the evidence behind its use is mixed at this time. The effective counseling modalities we know exist are certainly relationship building, which can be so important when you are treating a patient with opioid use disorder. And I can't discount that in any way. I think that's one of the fundamental, really foundational treatments that we are able to provide our patients who are struggling with opioid use disorder. And the ability for you to meet a patient where they're at, and to help them treat their withdrawal, and develop that relationship, it really goes a long way. In my experience, there are cognitive behavioral therapies that we know are quite effective. Contingency management is an important type of counseling modality that you can utilize. Relapse prevention certainly, and then motivational interviewing that we really find is sort of a fundamental and foundational part of treating patient with substance use disorder. So, We've gone through a lot of information here. Let's try to bring it back to the case that we initially discussed. And remember, this is a young female. She has some pain, chronic back pain, from a motor vehicle accident, though she is using IV heroin. She started out on prescription pills and now she's using IV heroin daily. She really has never tried a medication for the treatment of opioid use disorder. But importantly, she is drinking a fair amount of alcohol and that's something we need to think about and address and thankfully, she does have some really good support from her parents, but she's had some consequences of her use, because she's on probation and she's showing up in withdrawal. So how can we help this patient? So, in what medications should we use? So the first question we asked was, is medication indicated for this patient? Well, yes, this is definitely a medical. This is definitely a patient who could benefit from medication to treat her opioid use disorder. What additional workup or evaluation is needed? Well, this is a patient that I would want to do definitely, do a urine drug test. I'd want to do a pregnancy test. I would want to confirm her diagnosis with a DSM-5 evaluation. I would want to do a general medical evaluation, certainly look for other Potential illness, make sure that she is healthy and safe to be treated in your setting. How would you address the common alcohol use? Well, this is somebody who's drinking a fair amount of alcohol, so you may need to consider medically supervised withdrawal whether that be in an inpatient. Versus ambulatory setting that would be something you would need to consider. And then you would want to structure the care specifically to monitor this very closely. Because, the patient clearly is drinking enough that there would probably be some interaction with medication if you were to prescribe it. So thinking about the different medications we have, I think there's some pros and cons for which medication is really best for this patient. So, if you think about buprenorphine for this patient, a good thing would be that you can quickly stabilize her withdrawal you can treat that very effectively and efficiently. And you may get some beneficial treatment of her concomitant pain. So those would be some reasons why you might consider buprenorphine. One con would be there is that possible overdose risk, because if she were to continue using alcohol, that's certainly a risk. Methadone thinking about the pros and cons. Again, you can quickly stabilize someone's withdrawal when you're using this medication, and it may also be effective to treat pain. Similar to buprenorphine, there would be the risk potential risk for overdose with concomitant alcohol use. And then finally, if we were to consider XR-Naltrexone. One of the pros would be that, like I said, it is FDA approved to also treat alcohol use disorder. So that would be a pro.The other pro would be that there's no risk of withdrawal if she were to be incarcerated because it does not produce opioid dependence. The con would be there probably will be more severe withdrawal and there would probably be a delay and initiated treatment. Because she's coming to an opioid withdrawal. She's using a short acting opioids so you know that she's going to have to be off of this. Modality for at least three to five days before you go to initiate that therapy, ultimately the choice of which medication you're going to use really should be based on what the patients coming to you asking for, But we do know unfortunately that access to treatment, different treatment modalities, different insurance coverage and medication access will probably also guide your decision. So, you know if this were a patient that I retreating, I would probably most likely think about using agonist treatment with buprenorphine or methadone first. However, if the patient were very motivated to consider send a really soundtrack stone, I would certainly offer that to her as well. So all three could be utilized and like we've listed here there are different pros and cons of each medication. SAMHSA recently came out with this very important educational resource for us called the tip 63. I would encourage you to look at it and read it. It's excellent. Written by multiple experts in the field and I think you'll if you have questions about any of the slides or information that was listed here, you can find a lot more information that's written in tip 63. Freely available at the samsa store. The references for our slides are listed here. There were multiple references as you can see, feel free to go to the primary references. If you have any questions about the slides. Finally, I'll mention that the PCSS has a really excellent mentor program that I would encourage you to think about utilizing. This can be really important if you have specific patient questions or you're not sure about, How to get started treating patients with different medications or just different cases that you're struggling with. Please consider utilizing this really important resource. There's also a nice discussion forum if you have a clinical question that you can pose to the PCs discussion forum. And then finally, I think it's important to recognize our partners in the PCSS MAT training, who are listed here. Thank you so much for your attention and hopefully you've learned a lot more about medication treatment for opioid use disorder. Take care.
