<v ->Hello everyone.</v> I'm Dr. Melissa Weimer, Associate Professor of Medicine and Public Health, the Medical Director of the Yale Addiction Medicine Consult Service at Yale University School of Medicine and School of Public Health, and today I'll be talking to you about medications for opioid use disorder. My disclosures are listed here. All of these financial relationships have been mitigated. Our target audience today is you, and I hope that you will get some good information out of this talk. 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 including extended release buprenorphine, and extended release naltrexone. We're going to start with a case, and we will end with this case at the end of the presentation. So Jane is a 23-year-old female. She has chronic low back pain from a motor vehicle accident she sustained at age 16. She presents to your office asking for help to stop using injection opioids. She's been using opioids daily for about four years. She started using non-prescribed opioids, then switched to injection opioids daily about two years ago when she could no longer afford non-prescribed opioids. She's attempted non-medication based addiction treatment in the past, and has had return to opioid use. She also drinks approximately 14 alcoholic drinks per week, but has never had alcohol withdrawal symptoms when she stops drinking. She feels she could easily stop drinking alcohol, and she denies other drug or tobacco use. She denies other mental health or medical issues, but has had two unintentional 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 goose flesh, dilated pupils, and bilateral upper extremity track marks. So some of the questions I would like you to think about as we discuss her case, and as you hear more through this presentation are, for this particular patient, Are medications for opioid use disorder indicated? What additional workup or evaluation is needed to decide upon medication for this patient? Which medications for opioid use disorder is most appropriate for her given all the things we discussed? How will you address the concomitant alcohol use that she describes? And what options are available to reduce harms from ongoing opioid use? So I'd like to take a step back before we get too much farther into the discussion to talk about the spectrum of opioid use. This is an iconic figure that you will see throughout substance use literature, and this was designed by the late Dr. Richard Saitz. What this figure clearly illustrates is that there is a spectrum of opioid use starting at individuals who do not use opioids at all, or abstinence, and that you can have what we may not describe as healthy, but you can have low risk use of opioids; however, as your consumption of opioids increases, and you start to have consequences which could include health consequences of opioid use, you start to get into unhealthy opioid use, and this starts at risky use, progresses to problem use, and then as you start to have even more consequences of your substance use, or your opioid use, your consumption gets higher, becomes daily, or near daily, that is when you develop into the moderate and severe substance use categories. So I think this figure is helpful to conceptualize how you can see opioid use going from low level use, and then extending up into substance use disorders. So here's another way of looking at the natural history of opioid use disorder. When individuals use opioids for the first time, or the first few times, that we would call acute use of an opioid. In that acute use period you can have analgesia, euphoria, and stress relief. As opioid use becomes more chronic or long standing, individuals will describe that they start to develop tolerance to the effects of opioids and then physical dependence, and this means that, particularly for tolerance, that you're having to either increase the dose of the opioid that's used to achieve the desired effect. You're also, with physical dependence, needing to continue the use in order to feel normal or avoid withdrawal, and you can see that here in the figure, as individuals again in acute use feeling the beneficial effects of opioid use, and then as time goes on, starting to have some of the non-beneficial effects of opioid use, which folks like George Koob have described as the dark side of addiction. We also know that substance use disorder, particularly opioid use disorder, is a chronic relapsing biopsychosocial medical disorder, and similar to other chronic medical illnesses such as type two diabetes, hypertension, and asthma, we can see that individuals who have substance use disorder can have periods of recurrence of use on the same par with other chronic illness, so in this figure showing that 40 to 60% of individuals can have recurrence of use, which for substance use disorder is typically recurrence of substance use. So you can see that behavior repeated over time in an individual who has a substance use disorder, or an opioid use disorder. The gold standard for diagnosing a substance use disorder, here we're describing opioid use disorder is the DSM-5, and when you're asking these questions, these 11 criteria, it's important that you're thinking about the last 12 month period of time. I'm not going to go through all of these, but just to describe that these are the 11 criteria that you would want to explicitly talk to your patient about to see if they have an opioid use disorder, and if they meet two to three of these criteria, that would be a mild opioid use disorder, four to five of these criteria in a 12 month period would be a moderate opioid use disorder, and six plus would be a severe opioid use disorder. Important to recognize that in opioids that are prescribed for use of analgesia, we do not count tolerance and withdrawal or physical dependence as criteria for an opioid use disorder, because these are expected side effects of prescribed opioids over time. So when I'm talking about opioid withdrawal, what are some of the symptoms that I'm talking about? So in acute opioid withdrawal what you will see are typically the symptoms that are listed here, mydriasis, yawning, piloerection or goose flesh, myalgia, diarrhea, nausea, vomiting, insomnia, and autonomic hyperactivity such as tachycardia, diaphoresis, lacrimation, or rhinorrhea. These symptoms typically, for short acting opioids, will start at about six to 12 hours after the use of the short acting opioid. For longer acting opioids, such as extended release opioids, non-prescribed fentanyl, methadone, we typically see these symptoms occur after 24 to 48 hours. For non-prescribed fentanyl, or other high potency synthetic opioids, we can actually see some of these symptoms not start actually until 72 hours after use. It's important to note that these symptoms can continue for one to seven plus days. Typically they do, they are worse in the beginning, and then they start to taper off, and you can see that here. Something that people don't always recognize is that you can have protracted opioid withdrawal, and this can be a key factor in individuals having recurrence of opioid use, so this protracted withdrawal can actually occur over weeks or months, and this can be characterized by insomnia, mood disturbance, and then importantly craving for opioids. So when we're talking about medications for the treatment of opioid use disorder, what is the purpose of these specific medications? There is ample evidence to show us that these medications are really essential to allow reestablishment of balance in the reward pathways that can become disordered in the brain, and move people away from substance use or opioid use. They can control and treat the symptoms of opioid withdrawal, particularly buprenorphine and methadone. They importantly reduce opioid cravings, which we just said can be an important reason why people go on to have recurrence of substance use. They block the reinforcing effects of ongoing opioid use. They promote and facilitate patient engagement and recovery oriented activities and, coupled with behavioral interventions, you can see that individuals will move to have enhanced salience of natural and healthy rewards away from substances. They reduce stress reactivity and negative emotional states, improve self-regulation, and increase avoidance of triggers that may promote ongoing substance use. The goals of medication for opioid use disorder are to importantly reduce mortality, and this is both all cause mortality and opioid related mortality, and we see that they're very effective at doing that. Also reducing associated morbidity to bloodborne viruses such as HIV and Hepatitis C, infectious complications from injection drug use such as infected endocarditis, abscesses, or other injection related infections, reduce or discontinue opioid use, increase retention in addiction treatment, and improve general health, wellbeing, and quality of life. Despite having great evidence that these medications work and are quite effective, there are importantly many misconceptions about particularly opioid agonist medication treatment for opioid use disorder. Some of the barriers that you may hear individuals talk about, or families talk about. Number one, probably the most common barrier or misconception that I hear about is that opioid agonist medications such as buprenorphine and methadone are substituting one drug addiction for another. I think it's really important when we're talking to patients and families about medications for opioid use disorder, particularly opioid agonist medications that we're helping educate them on the actual use of these medications, provide information about the effectiveness of these medications in treating the disease of addiction and reducing mortality, and importantly helping to show that individuals who are on these medications do not have any of the symptoms or behaviors that individuals who are not on these medications have. So these are some ways that you can help educate patients and families, and importantly get patients on these life saving medications. Some folks will say that medications for opioid use disorder require addiction medicine or psychiatry evaluation, and in fact that's not true. These medications can be started in the emergency department, in the hospital setting. You don't have to have a specialty evaluation, and importantly, particularly if someone is hospitalized or sent to the emergency department for say an opioid overdose or opioid withdrawal, this can improve their ability to stay in the hospital to receive medication that they may need for another medical condition, and we know that it reduces premature discharge for patients seeking medical or surgical care. The third misconception I'll talk about is that special training is required to prescribe buprenorphine and thankfully in April of 2021 this was reduced, so now individuals, prescribers, physicians, and advanced practice providers can obtain a DEA X number to prescribe buprenorphine for up to 20 patients without special training, and I'm going to talk about how to do that. Medications for opioid use disorder are indicated for individuals who have opioid use disorder, individuals who have opioid use disorder and chronic pain, individuals with chronic pain and opioid misuse, adolescents greater than 16 years of age, pregnant persons, and individuals involved with the criminal legal system, and this is a really important group of people who are particularly underrepresented in receiving medication treatment. Despite knowing these medications are effective, knowing that they reduce mortality, knowing that they're highly effective, we see that access to them remains a key barrier in reduction of mortality benefit that we know occurs. So you can see here that it's showing the benefit, comparing the benefit of antiretroviral therapy that was started in the early 1990s and how that had a significant reduction in mortality for individuals. Similarly, when buprenorphine was approved in the year 2000 to be utilized in the outpatient setting, we see that there was a potential benefit of mortality, but because access was so difficult to obtain, mortality continued to go up, and the same for extended release naltrexone. Despite it becoming available in the early 2000s, we did not see the mortality benefits that we know they could have caused. So here you can see that when we adjust for heroin potency, and the number of individuals receiving methadone, there was a statistically significant inverse relationship between opioid overdose deaths and individuals treated with buprenorphine, so we see as buprenorphine became more available, we can see that mortality risk is reducing for individuals. So this shows us that when we have accessible treatments within buprenorphine and methadone, that mortality reduces. Again, despite knowing that these medications are highly effective, most Americans with opioid use disorder do not receive these essential medication treatments. So our best estimates are that about two and a half million people aged 12 plus have an opioid use disorder in 2020. Despite knowing that there are many individuals with this disorder, only approximately 11% of them received medication treatment in the past year, so that means that nearly 90% of individuals who have an opioid use disorder did not receive these essential life saving medications. So when we're talking about medications for the treatment of opioid use disorder, the options that we're discussing are methadone, which can be provided in an opioid treatment program, also can be provided and started in hospital settings, buprenorphine, which can be provided in office based settings, and opioid treatment program and hospitals, and extended release naltrexone, which can be provided in the office space setting, opioid treatment programs, and hospitals. When we're starting and thinking about these medications, certainly referral for evidence-based treatment, counseling, recovery supports, and harm reduction is also recommended; however, importantly, counseling is not mandatory for medications when we are starting these medication treatments, and all medical modalities can benefit from clinicians who are engaged in medication management. We discuss that opioid use disorder is a chronic illness, and like other chronic illnesses, it can benefit from the chronic disease management approach to opioid use disorder, meaning that we can employ medications, recovery supports, and psychosocial counseling all together to benefit patients, but even though we know that we can combine all of those things, it's important to recognize that you don't have to, and some individuals may not want to engage in these types of treatments. We should still offer these patients, these individuals, medication treatments. The way these medications work, they all are effective and work on the opioid receptor. You can see here a graphic showing that methadone is a full opioid agonist. That means it fully activates the receptor, the opioid receptor, and has complex pharmacokinetics. This also means that because it is a full opioid agonist that you can have risk of overdose during initiation, particularly the first two weeks of treatment. After those two weeks you see that patients have great benefit for reduction of mortality. Different from methadone is buprenorphine, which is a partial opioid agonist. It has high receptor affinity and its ceiling effect, so it never occupies more than 50% of the opioid receptor. This does mean that you can have the risk of precipitated withdrawal, particularly when individuals are using high potency synthetic opioids, which unfortunately most individuals are inadvertently being exposed to this given the contamination of the opioid supply in our country. This also means that individuals must be in opioid withdrawal before initiation. There are some newer approaches that can reduce the need for individuals to be an opioid withdrawal. We'll talk a little bit about that. Then finally, naltrexone is an opioid antagonist. That means that it competitively binds the receptor, and has no opioid activity. Individuals who start this medication need to be fully abstinent from opioids prior to initiation and this could take up to 10 to 14 days before individuals can safely start this medication. That time period can be quite risky for individuals. In this table, we've tried to quickly summarize some of the landmark trials, meta-analyses, and systematic reviews that have been done to show us the efficacy of medications for the treatment of opioid use disorder. You can see here that methadone, which has the longest evidence for its use reduces all cause mortality, increases treatment retention, decreases opioid use, decreases HIV or Hepatitis C transmission, and decreases criminal activity. Similarly, we see those effects for sublingual buprenorphine. Newer to the market is extended release buprenorphine. We don't have as much data to show outcomes; however, we do show that it also increases treatment retention and decreases opioid use. Oral naltrexone is not an FDA approved medication for the treatment of opioid use disorder. We do have some data to show that it can increase treatment retention and decrease opioid use and criminal activity; however, importantly, it did not, and has not shown all cause mortality benefit, and also importantly, many of the studies that were done to assess its efficacy were done in controlled settings such as the criminal legal system. Extended release naltrexone has also shown a reduction of all cause mortality, treatment retention, and any use of opioids in criminal activity. There have been some really pivotal trials that have shown us, again, reiterating repeatedly the reduction of mortality associated with the use of opioid agonist medications, specifically methadone and buprenorphine. So this study, done by Dr. LaRochelle and others, showed that opioid agonist medications for the treatment of opioid use disorder were associated with a 40 to 60% reduction in risk of all cause mortality. This was done in a large cohort of patients, greater than 17,000 in Massachusetts, who had had a nonfatal opioid overdose between the years of 2012 and 2014. They were able to show this reduction of mortality, but importantly, again speaking to access issues, fewer than a third of the participants received these medications in the 12 months after their overdose. When they did have these medications, it was associated with reduction in all cause mortality. They did not see the same reduction in all cause mortality with naltrexone. We also have studies showing that there is a high risk of mortality for individuals who are hospitalized with some either complication of an opioid use disorder or an opioid related concern, so here we see in this study that was done in 2021 that in the first days after hospitalization, days one to two, there is a four and a half times higher risk of opioid related death, particularly in those individuals who are not offered medication treatment for opioid use disorder, and then as you progress, days three to 14, there's a two times higher risk of opioid related death. This is highest for individuals who are admitted for a psychiatric reason, have premature discharge, and then, importantly, in those individuals who have greater length of stay, greater than seven days in the hospital, and this is likely related to a reduction of tolerance that individuals are having during hospitalization, particularly if they are not receiving opioid agonist medications. I do a lot of work in the hospital and see the benefits of the use of medications for opioid use disorder in the hospital on a daily basis. So we know that hospitalization for individuals who have an opioid use disorder is a reachable moment and an opportunity to save lives, and in fact, medications for opioid use disorder are the gold standard of treatment, and it's the gold standard of treatment for individuals who are admitted to the hospital for an opioid related condition. When we offer these medications to individuals in the hospital, we see that there's an increase entry into addiction treatment, increased retention in addiction treatment, and increased completion of medication, medical, or surgical treatments. This is vitally important that individuals are getting this type of care. Then when we look out, we see that there's a reduction of opioid use, there's a reduction of 30 day and 90 day readmission, costs are lower for these individuals, and then importantly, all cause mortality are lower for these individuals. So let's talk about these medications individually. We're going to start by talking about methadone. Methadone was developed in the 1930s, actually during World War II as an alternative to morphine. In 1947, it was approved in the United States as an analgesic and antitussive agent. In the 1960s, the first utilization of it as a medication to treat opioid use disorder was done by Dr. Vincent Dole and Dr. Marie Nyswander by Rockefeller University. In 1971, the first federal program for methadone treatment was started. We talked about that methadone is a full opioid agonist indicated for the treatment of opioid use disorder. It is also indicated for the treatment of chronic pain; however, for the purposes of this talk, we're only going to be talking about it as a treatment for opioid use disorder. It has a long and variable half-life, can be 15 to 150 hours. This is really important when we're thinking about initiation and ongoing treatment, particularly in that first two weeks of treatment. Federal regulation requires that it is dispensed outside of the hospital emergency setting in a licensed opioid treatment program. Again, this is different if you are dispensing it or administering it in a hospital setting or emergency department setting. Opioid treatment programs integrate counseling into their treatment paradigm. There are specific eligibility criteria that individuals need to meet in order to be eligible for a methadone treatment, and the typical effective dose range is 60 to 100 milligrams per day. Some individuals may need a higher dose, some individuals may need a lower dose. We have greater than 50 years of data showing that methadone is very safe, reduces overdose risk and mortality risk, increases treatment retention, reduces injection drug use related behaviors, and it reduces transmission of HIV and Hepatitis C. But we talked about the fact that it can have complex pharmacokinetics, so it needs careful monitoring, particularly during initiation, and it can have effects on the cardiac system of the heart, particularly prolongation of the QTc, so we do recommend, and there are clinical guidelines that recommend screening, EKGs for some individuals who may be high risk to have prolongation of QTc. It's also important that you're recognizing the drug-drug interactions that can occur between methadone and other medications your patients may be prescribed. Another graphic here showing that when individuals are treated with methadone, their all cause mortality during treatment is much lower than those individuals who are out of treatment. Similarly, overdose risk is reduced when individuals are in methadone treatment, and then increases when they are out of methadone treatment. There are some different contraindications and precautions you should think about when you're prescribing, or thinking about prescribing methadone to a patient. Certainly it's contraindicated in individuals who have an allergy or hypersensitivity to it. You might think about it not necessarily being the safest opioid agonist treatment for an individual who has respiratory depression such as severe COPD, if they're oxygen dependent, or they have severe obstructive sleep apnea, individuals who are hypercapnic, individuals who have paralytic ileus, and then we really want to think about, again that cardiac risk, so if an individual has a QTc greater than 500 milliseconds, you may need to consider a different opioid agonist treatment for them. Precautions, we want to think about if an individual is using other central nervous system depressants such as alcohol and benzodiazepines, you may consider a partial opiate agonist to be a safer treatment. That does not mean that you cannot use methadone in these individuals. It's just something that you want to think about and counsel the patient about. Decompensated liver disease can also be a reason where you may consider a partial agonist over a full agonist. Certainly drug interactions are important to think about and recognize, so if your patient is prescribed some of the medications that are metabolized by the cytochrome p450 types that are listed here, you may reconsider use of methadone for those individuals. And then if, again, there is risk of QTc prolongation, or history of arrhythmia, particularly any sort of history of torsades, you may really want to think about partial opiate agonists such as buprenorphine over methadone. Going on to buprenorphine, which we'll talk about in its combination form. Buprenorphine combined with naloxone, film or tablet, comes in a four to one combination. This was first FDA approved in 2002 for the treatment of opioid use disorder. We discuss it is a partial opioid agonist Schedule 3 typically comes as a transmucosal film or tablet. It does come in other formulations, but those are not FDA approved for the treatment of opioid use disorder. We will talk about the subcutaneous formulation in a moment. Dosing of buprenorphine is typically once daily or two to three times daily. Usually we use 24 milligrams as the highest effective dose. There may be some individuals who benefit from a higher dose than 24 milligrams. Typically individuals who are stabilized, however generally benefit from the 24 milligram dose. There is a ceiling effect where again you only have 50% occupancy of the opioid receptor; however, this does reduce opioid overdose risk. You can absolutely initiate buprenorphine for individuals in their homes in this unobserved home induction process, and we're not going to go into the specifics of the different induction strategies; however, I will mention that there are effective low dose initiation strategies, less than two milligrams of buprenorphine that can be effective for individuals with high exposure to fentanyl or other high potency synthetic opioids, and contrastingly high dose initiation, doses of 16 to 24 milligrams may be needed in some situations where maybe the emergency department or other situations where you're quickly trying to stabilize a patient, and this can also be effective. The X-waiver is still needed in order to prescribe buprenorphine to patients; however, you do not need to do the eight hour training or the 24 hour training that was previously required, so now it takes less than eight minutes actually to go online, apply for the waiver, and then prescribe this lifesaving medication for your patients. So you can see here the QR code. I'll also list the various free training that we have to get more information about how to prescribe this medication, and this will allow you if you go through and do this application to treat up to 30 patients in the first year of receiving the waiver. If you do want to treat more than 30 patients, you would need to go on and do the required training. The reason that buprenorphine and naloxone is combined was initially thought that the naloxone being present in the combination product would reduce misuse or diversion. The naloxone; however, because it's in a very low dose, and because it's given sublingually or transmucosally is mostly inactive, and really it doesn't affect patients unless, in some patients, it's injected, so it has a very low bioavailability when it's used sublingually or transmucosally. If your patient were opioid dependent, and not in opioid withdrawal, it is possible that injection could precipitate withdrawal. If your patient was in withdrawal, injection of the combination product can have some opioid withdrawal relieving effects. There really is some debate on the effect of the combination product used in injection. Typically we do recommend the use of the combination product; however, I wouldn't withhold the medication if a patient refuses to use the combination product. There are some different commercially available transmucosal formulations listed here. You can see that they are all sublingual. They're either a tablet or a film. Their dose ranges are listed here. It's important to know what you're prescribing to your patient, and then know how the doses correlate to each other. Buprenorphine does have contraindications and precautions to know about. Certainly there can be hypersensitivity, that would be a contraindication. I do see that extremely rarely. If your patient is not already on buprenorphine, and is undergoing a procedure where they'll be receiving full agonist opioid treatment, you may not want to initiate buprenorphine directly before that procedure. Precautions, think about the concomitant use. If a patient is using alcohol, other opioids or benzodiazepines, though I, in practice, see the patients are able to safely receive buprenorphine with benzodiazepines, particularly if a patient does have an alcohol use disorder that is not treated, buprenorphine could be medication treatment that you reconsider. If you are prescribing buprenorphine to a patient who's on a full opioid agonist that's not using the low dose approach, they can have precipitated withdrawal, and then we generally do not use this medication if a patient has fulminant hepatic failure. Buprenorphine does come in a Depo injection formulation. This was approved in November of 2017. The Sublocade version is a monthly subcutaneous, abdominal injection. Generally patients are receiving seven days of the transmucosal product before switching to the buprenorphine based on the package insert; however, many patients can actually receive lower fewer days prior to receiving the injection. It comes in two dosage options, 300 milligrams and 100 milligrams. Generally the two dosing options that we have, based on the current trials are 300 milligrams for six months or 300 milligrams for two months, followed by 100 milligrams for four months. That does not mean that patients cannot continue on this for longer, and we do have trials now showing that the longer individuals are on this medication, the better benefit that they have from the medication. Generally peak buprenorphine concentration occurs at about 24 milligrams after the injection. Steady state is achieved four to six months after getting this medication consistently, and then after discontinuation, patients can have detectable plasma levels for 12 months or longer, so sometimes we can actually use this as a way, if a patient's having difficulty tapering to, as an off ramp to buprenorphine, though again being on on buprenorphine is superior to being off of buprenorphine in terms of mortality benefit. The trials looking at these medications, so there's Sublocade, and now there's a new pending product called CAM 2038. When they were looked at in clinical trials, very few people had significant adverse effects. Looking at the primary endpoint of abstinence and treatment success, they were able to see that individuals had good abstinence, so reduction of opioid use and treatment success, good treatment retention as well. We know that ongoing maintenance of buprenorphine is far superior to detoxification, and this is born out for any type of detoxification from opioids, so when this was a trial from 2003 showing that individuals who were "detoxified from opioids were not abstinent at one year," and there was actually 20% of these individuals had mortality. For those individuals who were maintained, or continued on buprenorphine treatment, there was 75% abstinence at one year and 0% mortality. Showing the same slide for buprenorphine, we see the same outcomes that we saw for methadone showing that being in treatment with buprenorphine reduces all cause mortality, being in treatment for buprenorphine reduces opioid overdose risk as well. Treatment retention, comparing buprenorphine to methadone, we see that their effects are quite similar. So when a patient is receiving a therapeutic dose of methadone and a therapeutic dose of buprenorphine, we see similar treatment retention benefits. When individuals are seeing the lower doses of methadone, we see that they are dropping out of treatment, so again, speaking to the need for patients to be on therapeutic doses of these medications, similar effects for comparing buprenorphine to methadone for opioid urine effects, so again, buprenorphine showing similar results to the higher doses of methadone. Again, this is the 60 to 100 milligram doses. Oral naltrexone, we talked about, is not an FDA approved medication for the treatment of opioid use disorder. It's rarely used. We'll talk about it briefly. It is a an opioid blocker. It has the two formulations, oral and intermuscular. The intermuscular formulation is approved for the treatment of opioid use disorder. Oral naltrexone was approved in 1984 as a blockade against opioid agonist treatment. The dose, if you were to use it, is the same for alcohol use disorder, which is 50 milligrams per day. We don't use it for individuals with opioid use disorder because of low rates of patient acceptance, difficulty with initiation, and really high rates of individuals not using it for this purpose. A Cochrane Review did not find oral naltrexone superior to placebo or no medication in treatment retention or illicit opioid use, so again, I would not reach for this medication for an individual who has an opioid use disorder. You will see people who may ask about it. You can share these outcomes, and if they're interested in naltrexone, offer them the intramuscular version. So the intramuscular extended release naltrexone was FDA approved in 2010 for the treatment of opioid use disorder following a medically supervised withdrawal. The dose is 380 milligrams administered intramuscularly once every four weeks. Some patients may metabolize this medication more quickly and may need the injection every 21 days. We do see that some of the opioid overdose benefit does reduce after 21 days, particularly in those individuals who may be using high potency synthetic opioids, so keep that in mind for individuals who are treated with this medication. You may consider it in individuals who are confined to environments that do not allow opioid treatment. Hopefully these environments are reducing as we understand the benefit of full agonist opioid therapy; however, there still are many environments where individuals may not access these opioid agonist treatments. The individual does not have access to agonist treatment, if they do not want to be treated with opioid agonist treatment, individuals who have concomitant opioid and alcohol use disorder, this could be a medication treatment that is effective for them, and if they have not benefited from agonist treatment or higher level of care, it could be something that you consider, but again, it's important to recognize that the mortality benefits we're seeing really are greater for the opioid agonist treatments. Individuals do need to be fully abstinent from opioids prior to receiving this medication and it is vitally important that you're confirming they're abstinent from opioids. So for short acting opioids, this is typically five to seven days abstinent from opioids. Long acting opioids, typically seven to 10 days. If this was methadone, you may need to wait as long as 14 days. If someone has had exposure to an opioid prior to receiving this medication, and when I say exposure to opioids, I mean consistent exposure such that they have physical dependence on that opioid, you may want to do a naloxone challenge. The process of a naloxone challenge is essentially giving short-acting naloxone to confirm that the individual does not have ongoing dependence that's going to cause them to have withdrawal when you give the extended release naltrexone. Extended release naltrexone has few drug-drug interactions, but the delay that that is needed prior to giving it can reduce its overall effectiveness, so this is really an important thing to think about when you have someone that you're treating for opioid use disorder, if they're going to be able to be safe during that period of time, safe meaning not having overdose risk during that period of time that they need to be abstinent from opioids. There are trials showing that it is efficacious for opioid cessation compared to placebo, so some of the trials are listed here. Probably one of the best trials we have is from Josh Lee and others from 2016 showing that in 308 individuals with criminal legal involvement there was a reduction in their time to next opioid use. Some of the precautions and contraindications are listed here. Again, certainly if they have an allergy, you wouldn't want to use this medication. If a person you're treating is currently physically dependent on opioids, you really want to avoid this medication until you can confirm abstinence, and that they're not going to have withdrawal from giving the medication. If someone does have withdrawal from giving extended release naltrexone, it can be quite challenging to treat. If they're currently receiving opioid analgesics, that would be a contraindication, and if they're currently an opioid withdrawal, that's also a contraindication. Precautions, you want to think about the potential overdose risk during that period of time that individuals need to be abstinent from opioids. That is really, really important, and if they're not in a controlled setting where they may be at risk for opioid overdose, I would not use this medication. You can have injection site reactions from giving the injection, decompensated Child-Pugh C liver disease. You want to think about the risk versus benefit of giving this medication. There may be times when the benefit outweighs the risk, but you want to think about that carefully, and if a patient has really severe thrombocytopenia, or a coagulation disorder, you want to think about the potential bleeding risk of giving an intramuscular injection. There have been some trials that have been done looking at extended release naltrexone compared to buprenorphine. In these trials, the one from 2017 extended release naltrexone was non-inferior to buprenorphine, though the buprenorphine used in this trial was relatively low dose, and it was non-inferior for treatment retention and decreasing opioid use at 12 weeks. In the Lee et al trial from 2018, it's important to note that, in this trial patients were less likely to be inducted onto extended release naltrexone because of the period of time that they needed to be abstinent, so this was one of the ways that it was not more effective, so patients were less likely to receive it; however, in those individuals who did receive extended release naltrexone compared to buprenorphine, there was not a statistically significant difference between the two medications once they were started on the medication. So thinking about these medications comparatively, some of the pros versus cons, some of the pros of buprenorphine, you can quickly stabilize a patient who's in opioid withdrawal. It can also concomitantly treat pain. Some of the cons could be the possible overdose risk if a person is using concomitant alcohol, but we know that providing this medication has great benefit, and we shouldn't be withholding it even in individuals who we consider high risk, such as those using benzodiazepines or alcohol. Methadone can also quickly stabilize patients, may be more effective to treat pain, though honestly in my experience, I think that buprenorphine treated for these patients can be better, because you can dose it more frequently during the day. There is that possible overdose risk for individuals who are using concomitant central nervous system depressants such as alcohol, but again, we don't want to withhold this medication, lifesaving medication from those individuals, and we want to work with them to try to stabilize them from both substance use disorders. Extended release naltrexone does concomitantly treat alcohol use disorder, and that could be a reason why you might reach for this medication in someone who has both use disorders. There will be no risk of withdrawal if your patient is incarcerated. That could be one reason to use it, though again some of the difficulties of getting patients onto this medication are something that you really want to think about. Certainly you cannot use it, extended release naltrexone, if a patient is in severe withdrawal, and this delay in treatment could be quite challenging for individuals who are really having severe withdrawal. Ultimately the choice of the medication should be a patient-centered conversation that you're having with the patient, and hopefully that they're able to access these treatments in any of the programs that they're going to, and hopefully they are not having insurance coverage issues. We really want to be able to provide these medications so that they can have access to their life saving benefits. There are various models of care for treating individuals with opioid use disorder. They are listed here. I think it's becoming vitally important that whatever model we are using is the lowest barrier, most open access treatment model we can think of, because we know that getting patients, individuals on these medications is so vitally important, and the quicker we can do that, they can be the most safe and most effective. So here are some of them listed here, but really again, thinking about how can you design a model of care that patients can access same day, and without going through laborious processes of initiation. When you're thinking about delivering these medications, thinking about delivering it with this chronic disease management approach is helpful, so can you build in recovery supports, mutual support groups, peer recovery supports, coaches, other wraparound services. If individuals are homeless or have unstable housing, can you wrap that into the care that you're providing to them? If individuals are interested, providing psychosocial counseling, evidence-based treatment, such as cognitive behavioral therapy, contingency management can also be quite helpful, but your relationship with the patient, as a clinician, is also really, really effective, and this medication management that you're providing to the patient shouldn't be discounted. When we're talking about medication management, what we mean is that you're treating their withdrawal, you're initiating the medication, you're evaluating its safety and effectiveness, you're confirming that they're doing well on the medication. You're doing periodic urine drug testing, but you're also talking to the patient. You're evaluating how they're doing in treatment, determining the level of care that they need, and if they're not doing well, making sure that you're providing additional resources that they could benefit from. If they're having trouble with mental illness, or other issues such as homelessness, or unstable housing, or food insecurity, providing those supports to the patient, recognizing it, talking with them, building the relationship to support them. It also means that we're looking at all their psychosocial needs. We're providing supportive counseling within a non-judgmental relationship. We're providing case management, linking to existing supports either within the community or their family system, and really wrapping as many services as we can around them, including harm reduction and education to keep them safe, and to keep them on the medication and engaged in treatment. Counseling certainly has a role, though some individuals may not initially want to access counseling and that is okay. When they are interested, the purpose is to help them learn how to modify behaviors that can maintain or reinforce drug use, develop coping strategies that can help them avoid drug recurrence, encourage staying on the medication, taking it as prescribed, to have the most beneficial effect of it, treating and identifying concomitant mental illness that can either complicate their substance use, or be a powerful trigger for drug recurrence. And there is some evidence showing that providing these treatments can improve adherence in treatment retention, but the findings are mixed and some individuals, like I said, may not want to access these treatments. That is okay. Don't discount the medication management that you're able to provide, the counseling that you can do in your office through brief treatment, relapse prevention planning, talking to your patients, providing education, and non-judgmental care. Some of the effective treatment modalities that are provided via counseling are this relationship building, cognitive behavioral therapies, contingency management, relapse prevention, motivational interviewing, peer, or other recovery supports. So let's go back to that case that we started at the beginning. So remember, Jane is currently 23. She identifies as female. She's been using opioids for a while, including injection use. She does have some concomitant alcohol use, but does not describe having alcohol withdrawal. She denies having mental illness or other medical issues. She's living in a supportive environment with her parents. She does have some criminal legal involvement, and she's currently coming to you describing opioid withdrawal. So is medication treatment for opioid use disorder indicated for this patient? Absolutely, yes. What additional workup or evaluation is needed to decide which medication is best for this patient? We want to do an initial urine drug screen to determine are there other substances that you might want to think about and provide some education to her about. We want to ensure that she's not pregnant, and we also want to talk to her if she plans to get pregnant, about reproductive health. We want to do our DSM-5 evaluation. We want to do a general medical evaluation, ensure that she doesn't have any unstable medical issues that could complicate her care. We want to offer her HIV screening, Hepatitis C screening, other types of sexually transmitted infection screening. She does describe using alcohol, so we want to talk to her about the alcohol use. We want to determine if we think that she's at risk for alcohol withdrawal, provide that care to her if she is, and then we want to structure the care so that we're monitoring this, and providing support around the alcohol withdrawal or alcohol use disorder if there is one. What if we talk with Jane and she says, "Thank you for the information, but I'm not ready to stop using opioids." Well, I think it's important that we accept that some patients may have that goal, and if that is their goal, there is still a lot that we can do. Again, the relationship, the open door, the nonjudgmental approach that you have with the patient can really be life saving. That education that we're providing with other evidence informed approaches such as she's using injection drugs, can we prescribe her syringes so that she can more safely inject? Does she have intranasal naloxone at home? Does she have someone that she lives with, namely her parents, who know how to use it? It's one thing to provide it to a patient, but if they don't have someone in their home who knows how to use it, it doesn't work. So you need to make sure she knows how to use it. Her parents know how to use naloxone, and then namely that she has it at home. Provide her the information around syringe services. a number to call where she can access these services. These can sometimes be delivered in the mail, or brought to her if she's someplace where she doesn't feel safe to access it. Provide her really detailed education around safer injection practice. In my practice, unfortunately, I see so many complications of unsafe injection drug use. Our patients need to be armed with information of how to do this safely. Know how to use alcohol swabs, make sure they know that they're washing their hands before their use, using a clean needle. All these things are important that we're providing patients this education. Consider PrEP as a treatment for her pre-exposure prophylaxis. Many others, again, that open, non-judgmental approach can go a really far away. A lot of the things I just described encompass harm reduction, so how can we reduce her harm, even if she's not ready to accept methadone, buprenorphine, or other modalities of treatment? So like people living with other chronic illnesses, people with opioid use disorder can have various goals and readiness to change. So we want to acknowledge that, recognize that, and be with her along that full continuum. These harm reduction strategies are practical and essential, and they also reduce morbidity and mortality, particularly for individuals who inject drugs. Here's a nice figure showing some of the different harm reduction equipment that you can talk to your patient about. Some key factors to think about, ensuring patients know that using alone can be really, really dangerous. Not having naloxone can be really, really dangerous. Again, make sure someone has it who's with them. Using alcohol swabs to clean their skin. Avoiding oral contamination, not licking the needle or the injection site after use. Using a clean water source, using your needle once, and then discarding it. Avoiding injection in high risk areas such as the neck or the groin, covering your injection site after use, and then if they're using stimulants, or opioids and stimulants together, make sure they're using something safe to mix with, such as vitamin C that you can usually obtain from many of the syringe service programs. When all else fails, always remain non-judgmental and supportive. That goes such a long way. Leaving the door open, provide the naloxone, provide that future support. Connect them with peer support if you have it readily available. Make sure they have numbers to access those in the future when they may need it. Provide information to the syringe service programs and these other support programs so that when they are ready to access treatment, or to reduce their use, or they want to be safer with their use, that they know how to do that. So thank you for your attention. I hope that you've learned a lot through this presentation. You can find a lot more information about many of the things I discussed in TIP 63. Please access that. It's readily and freely available, and here are some of the many references that we discussed throughout the talk. Thank you again. Take care.

opioid use disorder

medications

methadone

buprenorphine

extended-release naltrexone

case study

DSM-5

mortality

harm reduction strategies