Hello, my name is Julie Kmyk, and today I'm going to be talking about a comprehensive review of opioid use disorder. This is a little bit of information about me. I am an addiction psychiatrist at the University of Pittsburgh School of Medicine, and I'm the medical director of our Narcotic Addiction Treatment Program, which is a licensed opioid treatment program, as well as the medical director of our Ambulatory Detoxification Program and Bridge Clinic, so I work with people, predominantly I work with people who have opioid use disorder, and this is a special interest of mine. I have no financial conflicts of interest to report, and I'm going to be talking off-label about some medications, Clonidine for opioid withdrawal, as well as Trazodone and Mirtazapine for sleep. So here are the objectives for this lecture. At the end of this, hopefully you're going to be able to talk about opioids and their pharmacology, as well as the epidemiology of opioid use disorder and some medical complications of opioid use disorder, be able to talk about the diagnosis of opioid intoxication, withdrawal, and opioid use disorder as defined by DSM-5, also talk about treatments for opioid withdrawal, and then talk about the pharmacology of buprenorphine, as well as naltrexone for treating opioid use disorder, and then explain the role of opioid antagonists in the treatment of opioid overdose or toxicity. So first I'm going to be talking about opioids. Here are some commonly used opioids, these can be misused by people, commonly prescribed as well, so tramadol, buprenorphine, codeine, morphine, hydrocodone and oxycodone, as well as oxymorphone, and then methadone, we commonly see that for treatment of opioid use disorder, but sometimes it's used for pain, and then fentanyl, either illicitly manufactured or pharmaceutical fentanyl, and then heroin. As far as the bioavailability of opioids, it's going to depend on the route of administration. So with some opioids that are misused, they're used intravenously, but also in medicine we're using opioids intravenously too, but you're going to have 100% bioavailability when it's done that way, and then we could also use opioids IM or sub-Q, sometimes people will smoke them and that has about a 50% bioavailability, and then less than that would be intranasal use or snorting the drug. It's going to be more than, a little bit less than smoked is what I want to say. So opioids are lipid soluble and they cross the blood-brain barrier as well as the placenta, so crossing the blood-brain barrier is how we get the effects from the opioids, and crossing the placenta, we have to be aware of that because if somebody's pregnant, then the fetus is exposed to those opioids too. The mechanism of action of opioids in general is that they're going to bind to the mu-opioid receptor in the nucleus accumbens as well as the ventral tegmental area of the brain, and they will release GABA, and that in turn leads to dopamine release, and that is how the rewarding sensation comes from using opioids. Opioids are eliminated by metabolism from the liver, they're broken down into their metabolites and then they get excreted by the urine and feces. We have four opioid receptors that I'm going to talk about here in this presentation today. So the mu-opioid receptor is what we are targeting when we're treating opioid use disorder, but it's also what's stimulated where the rewarding sensation comes from, so you get analgesia from the mu-opioid effects, people become physically dependent because of its opioids effects on the mu-receptor, it also can lead to respiratory depression, pupils being smaller, euphoric feelings from using, and then also decreased GI motility. And then Kappa receptors are sometimes talked about too, especially in terms of buprenorphine, but they can, when Kappa receptors are stimulated, it can lead to some analgesia, but also dysphoria, and they can also have anticonvulsant effects, dissociative effects, and then you can get smaller pupils as well as a diuretic effect and sedation. We also have the Delta receptor too, and that has analgesic effects when stimulated, and can also reduce anxiety and depressive states. And the Delta receptor also can regulate learning and memory. There are convulsant effects too at this receptor, and some of the physical dependence can be because of stimulating this receptor as well. And then there's no susception, and that's when you have agonism of these receptors, you have anxiety and depression, appetite can be stimulated or suppressed, and then you can also develop tolerance to the mu-opioid agonist because of this. Here are some endogenous opioids and their receptors, so endorphins, they're going to be selective for that mu-opioid receptor, and calphalins for that Delta receptor, and then dynorphins at the Kappa receptor. And then you have nociceptin and orfanin FQ, and they're selective for the NLP or opioid receptor-like peptides, and then endomorphins and morphiceptin are selective for the mu-opioid receptor. I wanted to talk a little bit about the concept of cross-tolerance. So you can have long-term exposure to an opioid, and then you're going to develop tolerance to that opioid. And the term cross-tolerance means that when you have tolerance to one opioid, you also have tolerance to something that's structurally similar, an opioid that's structurally similar. And it might not be complete, and that's why sometimes when people are on chronic opioids for pain, their physician will rotate opioids, and then the person has more analgesic effect from the new opioid. And cross-tolerance is why we can use like methadone or buprenorphine to treat opioid use disorder, because it's going to stimulate those receptors and take care of the withdrawal that somebody's experiencing. So I'm going to switch gears a little bit and talk about emerging opioids. So one that you've probably heard of is kratom. Kratom, or the name for this plant is mitragyna speciosa, and it's a psychoactive tropical plant, and it's native to Southeast Asia, and it's part of the coffee plant family. And there's some common names there. Bang, Tom, Ketum, Biak, and it's been used since the 1800s in Southeast Asia for its stimulant and opioid-like effects. And when it's been used in this way, it's been used typically to boost energy, reduce depression, reduce coughs, alleviate pain, and it can be a substitute for opium. And kratom in the United States is an unregulated herbal remedy, and the DEA did put it on the drugs and chemicals of concern list. It's often sold as a dietary supplement, and you probably see these around town. You might see a sign where they're selling CBD, kratom, maybe delta-8-THC. So in the smoke shops a lot of times, you're going to see it there, and also online you can buy it. It's available in capsules, whole leaves, liquids, and powders. People sometimes consume it as a tea. You can chew on the leaves. And this, you can't really detect by standard drug testing. You'd have to order a special test for it because it is not going to trigger a positive on opiate or opioid drug testing. So kratom has two alkaloid components, and they're both mu-opioid agonists. So there's mitragynine as well as 7-hydroxymitragynine, or 7-HMG. And the raw plant contains higher concentrations of mitragynine than 7-HMG. And as far as the potency, mitragynine is 13 times more potent than morphine, whereas the 7-hydroxymitragynine is 46 times more potent than mitragynine, so it's going to be even more potent than morphine. And this is a partial agonist at the mu-opioid receptor and possibly at kappa receptors. And it binds as a partial agonist and antagonist at the delta opioid receptors. And we're not sure, but it can also affect other neurotransmitters in the adrenergic system as well. And just a note that the 7-hydroxymitragynine has higher affinity for the opioid receptors and possibly more better bioavailability and CNS penetration than mitragynine. As far as dosing, 1-5 grams can lead to stimulating and energizing effects, whereas a higher dose like 5-15 grams has more of a mu-opioid effect. So people get euphoria, sedation, analgesia, relaxation at those higher doses. And the effects can begin as soon as 5 minutes of using it. And the half-life for somebody who's been using it regularly can be 23 hours. And some of the effects can be reversed with naloxone. So here are some adverse effects that people might experience while they're taking kratom. Tachycardia, agitation, drowsiness, nausea, dizziness. It can have either affect the blood pressure by lowering it or increasing it. People can complain of constipation as well as tremor. Appetite might be decreased. They could also have seizures and psychosis. And once people are using kratom for a long period of time, they can develop physical dependence. And it might develop a little bit more slowly than other opioids, for example, compared to using oxycodone. So some animal studies found that there is physiologic dependence and they looked at these studies looking at conditioned place preference. So where the rat typically prefers to be. Also how tolerant it is to antinosusceptive effects. And also cross tolerance with morphine. And what they found in humans is that humans who chew leaves typically like they might start off with one to three leaves and then they can increase up to 10 to 30 leaves per day using three to 10 times per day. So that's demonstrating some tolerance to the effects. The withdrawal syndrome is similar to opioid withdrawal, which we're going to talk about later on in this webinar. And there have been some case studies reported of babies who were born to women who are using kratom that needed treatment for neonatal abstinence syndrome or neonatal opioid withdrawal. There's also some case reports of seizures, drug-induced liver injury from kratom, as well as psychosis, QT prolongation, and arrhythmias. Regarding toxicity for kratom, looking at a study that was looking at poison control centers, there was a 10 times increase in calls to poison control from 2010 to 2015. So you can see it went from 26 calls in 2010 to more than 260 in 2015. And 65% were isolated exposures to kratom, so no other substances. But when it was used with other substances, typically they were alcohol, opioids, benzos, acetaminophen, and other herbal products. These are some data from the analysis of state unintentional drug overdose reporting system, or the SUTRS system. And they found that there were 152 deaths involving kratom from July of 2016 to December of 2017. And kratom was determined to be the cause of death in 91 of those 152 people, so that was almost 60%. And kratom was the only substance that was involved in seven decedents. As far as kratom positive or kratom involved deaths, about 80% of the decedents had a history of using substances, and about 90% of the decedents had no evidence of current pain management, meaning they weren't getting prescribed opioids for pain. And when they looked at other substances, they found that multiple substances were detected in almost all of the people who died. Fentanyl and fentanyl analogs were 65% of kratom positive decedents and 56% of kratom involved decedents. As far as other drugs, heroin was detected in about 33%, benzos in about 22%, and prescription opioids in 20%, and cocaine in about 18%. So next drug is called tianeptine. This is an atypical tricyclic antidepressant, and it's been approved for use in Europe, Asia, and Central America. And what I've seen mostly is, as far as marketing, it gets marketed under Coaxil or Stablon. It's not approved in the United States, so it's not approved by the FDA. It's unscheduled here as well. And the street dose can be anywhere from 500 milligrams a day to more than 4,000 milligrams per day. And when people use this, they often also use opioids, Fenibut, alcohol, benzodiazepines. And when it's sold on the internet, it's sold as a research chemical. So I mentioned before that it's an atypical tricyclic antidepressant, and its mechanism is it's thought to enhance serotonin uptake, but now there's newer evidence that contradicts this and shows that it has a low affinity for serotonin transporters. It's also thought to increase dopamine signaling, modulate glutamate signaling, and that modulation of the glutamate signaling is thought to be responsible for that antidepressant mechanism of action. And it also stimulates the mu and delta opioid receptors. And when people take this, they take it for its anxiolytic effects, mood enhancement, as well as euphoric effects. Here are some adverse effects of this drug. You could have withdrawal syndrome, which would include nausea, vomiting, diarrhea, tachycardia, hypertension, tremor, agitation, anxiety, sweats, muscle aches, chills, and depression. There are case reports of withdrawal dependence and treating people who are dependent on this drug with buprenorphine, naloxone combination product. There's also been a case report of toxic leukoencephalopathy, as well as case reports of deaths from this drug. And then there've been some studies that showed that calls to poison control centers have increased from 2000 to 2017. So regarding those calls to poison control, most commonly what people are reporting are neurologic effects in almost 50%, cardiovascular effects in about 33%, and GI effects in about 10%. And when people do come to the emergency department with complaints about this, most commonly what's administered are fluids, benzodiazepines, and oxygen. And when in this report, when they knew what the level of care was, about 44% were treated, evaluated, and released from the emergency department, whereas 24% were admitted to critical care. So next I want to talk about loperamide, our common antidiarrheal medication. This is peripherally acting, it's a new opioid agonist, and typically the max daily dose for this is about 16 milligrams a day. At therapeutic doses, its actions are contained in the GI tissue because it's poorly absorbed, and it comes out of the CNS by a P-glycoprotein membrane transporter. But when it's in super therapeutic doses, meaning doses more than 70 milligrams, it can cross through that blood brain barrier and cause opioid-like effects. And sometimes people use these super therapeutic doses to self-treat opioid withdrawal, or they might use it for the euphoria. And most people that are misusing this have a history of opioid use disorder, and reports started to show that misuse of this drug started to surge after 2010. So that's right when we were kind of in the midst of the opioid epidemic. And it doesn't trigger a positive urine drug test, you're going to need a blood test for this. So doses greater than 100 milligrams can result in life-threatening cardiac effects. So it can widen the QRS, it can prolong the QT interval, people can have syncope, sudden death, and ventricular dysrhythmias. In June of 2016, the FDA issued a warning about serious cardiac problems associated with high doses of loperamide. And so the FDA encourages clinicians to consider loperamide misuse as a possible cause of unexplained cardiac events. So if somebody's in cardiac arrest, QT interval, prolongation, syncope, or if they have torsades or other ventricular arrhythmias, keep this in your differential. Next, I want to talk about xylosine. So xylosine, you've probably all heard of it. It is a centrally acting alpha-2 agonist, and it can result in sedation, analgesia, and euphoria. And it does reduce sympathetic outflow, and that's going to cause decreased peripheral vascular resistance, as well as heart rate and blood pressure. This is originally a veterinary medicine sedative, and its use was first reported in Puerto Rico around 2001. And in Puerto Rico, it was called anesthesia de caballo, which is horse tranquilizer. And it's not an opioid, but it's often mixed with non-pharmaceutical fentanyl, possibly to extend fentanyl's effects. It's not a federally controlled substance, but some states have made it a controlled substance. And now, at first, people are like, oh, this is getting stolen from veterinary practices. But now, it's more likely to be imported from overseas. You might hear of patients calling this tranq, or if it's mixed with fentanyl, calling it tranq dope. As far as epidemiology, it's been identified in the continental US in some drug samples as early as 2006. Its prominence first began in Philadelphia, and it's been found in more than 90% of drug samples tested in Philadelphia in 2021. And it's been becoming more common across the country since then. It's most prominent in the Northeast, and then next in the South, and then westward. And it's been identified in toxicology samples tested from June 2021 in 36 of 49 states. As of March of last year, or of 2023, fentanyl and xylosine were found in drug seizures in 48 states. So it's widespread. And estimated drug poisoning deaths involving xylosine increased by more than 1,200% from 2018 to 2021. Now, intoxication from xylosine looks like CNS depression, hypotension, bradycardia. And then people might also have depressed respirations because of its use with fentanyl. And you can use naloxone to reverse fentanyl, but there isn't a reversal agent for xylosine. And typically, you're not going to see this on urine toxicology unless you're testing for it specifically. Now, people do experience withdrawal syndrome if they stop using xylosine because you can develop this physical dependence on it. And withdrawal symptoms might start 6 to 12 hours after the last use. And typically, what people complain about are irritability, anxiety, depressed mood, as well as restlessness. So there's limited data on how to treat withdrawal. There's a lot of case reports. And some suggestions of what to do are using alpha-2 agonists because this is an alpha-2 agonist. Soclonidine is commonly used. So you can use 0.1 milligrams every eight hours as needed. Just remember to hold for hypotension. Lofaxidine, also another alpha-2 agonist. This has an approval for opioid withdrawal. And you would follow dosing instructions for that. Tizanidine has been used as well to help, 4 milligrams three times a day. And then dexmedetomidine can be used sometimes in inpatient settings. One of the things we see with xylosine are skin ulcers. So these were noted way back in Puerto Rico in the 2000s. And people are more likely to have skin ulcers if they're using xylosine plus heroin at that point versus heroin alone. So you could see when they looked at this back in Puerto Rico, it was about 38% when they used xylosine and heroin. And with heroin alone, 7%. So the skin ulcers start as small, round lesions. And they develop into ulcers over time. And they can progress to become necrotic. And people can develop secondary infections as well. And the tissue damage can occur at injection sites, also sites distant to where the patient's injecting. So it doesn't have to be right where they're injecting drugs. And even if the person's not injecting, they could get tissue damage distal to how they were using it. So let's say they were using intranasally. They could still get some ulcers. And the treatment includes typically hydrogel, debridement, topical antibiotics, sometimes non-adhesive dressings. Also using metahoney to help with it. OK. So next I want to talk about epidemiology of opioid use disorder. Let's first talk about this opioid epidemic and how it started. So from 1999 to 2008, the number of opioids that were prescribed in the US quadrupled. And so this is thought to be basically how this opioid epidemic, the beginnings of it. The reason why prescribing really got kicked up during those years is multifold. First, there was a consensus statement from two pain organizations, the American Pain Society and the American Academy of Pain Medicine in 1997. And they said that there was little risk of addiction and overdose in pain patients if you prescribed them opioids. And they quoted this statement from a letter to the editor in the New England Journal that was published back in 1980. And in that, it said fewer than 1% of patients become addicted to opioids. And that was looking at patients that were admitted to the hospital and given opioids over a short time while they were in the hospital. But this statement was repeated over and over in a lot of different literature. Also at that time, there was a greater emphasis in assessing and treating pain. You might have heard pain is the fifth vital sign. And then Purdue Pharma produced OxyContin. And then they had several different educational meetings where they were promoting OxyContin as safe and effective. And you can see they funded more than 20,000 educational programs on pain. And they were encouraging long-term opioid use for pain. They were supporting professional societies. They had some influence on the Federation of State Medical Boards, as well as the Joint Commission. And as far as opioid misuse, these are some older figures because we're not looking as much at prescribed opioids in terms of research because it seems like now people, since there have been some changes in opioid prescribing, a lot of people can be starting out with using fentanyl or heroin. But anyway, looking back, roughly 21% to 29% of patients who are prescribed opioids for chronic pain misuse them. So that's almost like 1 in 5 or even a little bit higher. And between 8% to 12% develop an opioid use disorder. So that's pretty high. That's pretty remarkable. It's much, much higher than that less than 1% that Porter and Jick had written about. And an estimated 4% to 6% who misuse prescription opioids end up transitioning to heroin. Nowadays, I don't see too many people who started off with prescription opioids recently that transition to heroin or fentanyl. A lot of times when I have people come in, they're coming in and started off by using fentanyl or bags or pressed pills of fentanyl. And about 80% of people who use heroin first used prescription opioids. And in 2005, only about 9% of people using opioids started with heroin versus in 2015, 33% of people who used opioids started with heroin. So you can see the change there. So here's some data about opioid use disorder over the years. There's a NSARC study, so National Epidemiological Study of Alcohol and Related Conditions. And there were different waves of this. And so they compared two waves, the wave from 2001 to 2002, and then the third wave from 2012 to 2013. And what they found there was that non-medical prescription opioid use increased by 161% between 2001 and 2012. And non-medical prescription opioid use disorder increased by 125%. When they looked at heroin, they found that lifetime heroin use increased almost five times and the lifetime prevalence of heroin use disorder increased approximately three times. Next, I'm going to have some figures from the National Survey on Drug Use and Health. And this is done annually. And these are the most recent data that I have. These are going to be from 2022, published in 2023. So everything's always like a year behind. But this is a figure looking at the type of opioids that people were misusing in the last year, people 12 and older. So you can see that the greatest number are people using prescription opioids. So 88% of opioid misusers have been using some kind of pain pills. And then 5% or 461,000 people are using heroin alone. And then you have that overlap of people who are using both prescription pain relievers and heroin use. So that's about 587,000 people. And that's 6.6%. Now, the misuse doesn't mean that they actually have opioid use disorder. Just means that they could be taking it in ways other than prescribed or using more than prescribed. Now, this figure is actually looking at opioid use disorder in the past year by age group. And there's three different years here. So there's 2015, which is the blue, 2018, which is the brick red. And then the olive green is 2022. And these are, again, from the National Survey. And you can see, as far as everybody in the study, 12 and older, in 2022, you can see that more than 2% had opioid use disorder compared to back in 2015 and 2018. It was down less than 1%. And then looking at specific age groups, you can see that as far as opioid use disorder, it's highest in 26 and older in the most recent year in 2022. But look how much that increased. Like it went from less than 1% to about 2.5%. Oh, sorry. It went from a little bit greater than 1% to about 2.5% from these age groups here. Oh, one thing I should mention, too, is that in that latest survey and in prior studies, they weren't looking at illicitly manufactured fentanyl. So in these numbers here for opioid use disorder in 2022, they're not counting illicitly manufactured fentanyl. So they'd asked about heroin. They asked about pill opioids. So I mentioned about prescription opioids and people misusing those. And this is a figure looking at where did people obtain... So a lot of times when I see people, they'll say they got them off the street. But you can see in this chart here that about 41% got through a prescription or stole from a healthcare provider. The stealing from the healthcare provider is less than 1%. It's 0.4%. It's that real small piece of the pie there. But most of the time, it's a prescription from one doctor. So almost 40%. And then about 2% said that they got prescriptions from more than one doctor. And then look at the other side, the orange, about 44.6%. So this is the greatest piece of the pie. They were given or they bought it from somebody or they took it from a friend or a relative. So somebody that's probably pretty close to them, not just some drug dealer off the street. But then you have the green section here, buying it from a drug dealer or a stranger. That was almost 9% of people. And then the other almost 6% said some other way. So these are all of the opioid measures that they have in that national survey. And this is from 2022. So they have different categories. So the first one is prescription opioid misuse. Doesn't mean they have a use disorder, but you can see that's like 8.4 million people. Prescription opioid use disorder is 5.6 million people. So a good percentage of those people who are misusing. And how many people started using within this last year? Well, that's what this is, Rx Opioid Misuse Initiates. So 1.3 million. As far as how many people are using heroin, about 1 million. And then people who have heroin use disorder, a little bit less than 1 million at 900,000. How many people started using heroin in this last year? 73,000. And then looking at opioid use disorder. So looking at prescription opioids and heroin only, that's about 6.1 million. And then they added this new measure of looking at prescription or illicitly manufactured fentanyl use. So 991,000 or almost a million here. And then the other thing that they added too was looking at kratom use. So 1.9 million people were using kratom. I wanted to look a little bit more at some specific demographic characteristics. So this is looking at pain reliever misuse in the past year by race. So you can see that in terms of percentages, about 2.8% of white individuals versus 3.8% or African-American or black individuals. And then 5.1% of Native Americans or Alaskan Natives. And then at the lower end, we have Asian Americans at 1.4%. If people identified as multiracial, that was up to 4.4%. If they were identifying as Hispanic or Latino, 3.3%. And then as far as non-Native Hawaiians or other Pacific Islanders, that was at 1.8%. And you can see heroin use in the past year. And I put some different figures from different national surveys here. And so way back in 2002, about 404,000 people were using heroin in the past year. And then you see how that really started rising. A good 13 years later, it more than doubled at 828,000. And now in 2022, people are saying, more than a million people are saying that they used heroin in this past year. One of the things that's often looked at too is what's the perception in terms of people who are using and their need for substance use treatment? So now in the national survey, instead of just having people 12 and older for this measure, they divided it up so they have people, adolescents 12 to 17 years of age in this one on the left, and then adults 18 and older. And these are their perceptions of the need for substance use treatment. And so you can see in both, a majority don't think that they need treatment, either adolescents or adults. And then in terms of who actually seeks treatment, 0.5% of adolescents sought treatment, and 2% didn't seek treatment but thought they should get treatment. Whereas in the adults, 0.8% sought treatment, and then about 4.5% didn't seek treatment but thought they should get treatment. So they're somewhat similar, but there's a little bit more insight in terms of possibly needing to get treatment in the adults versus the adolescents. And when they ask people, why didn't you seek treatment in the last year? And this is for the adults, not the adolescents. So 61% said they're not ready to start treatment, 53% said that they weren't ready to stop or cut back on using, good 42% said that they didn't have insurance coverage for substance use disorders, and almost 50% were worried that it would cost too much. 52% said they didn't know where to go. There's still worries about what other people are going to think, so about 46% endorsed that. And then 42% said they just didn't have enough time to get treatment. And then almost 80% said that they thought they should handle this on their own. They also asked in the survey about receipt of medications for opioid use disorder in the past year for people 12 and up, and 0.8% or about 2.4 million people have received medications for opioid use disorder in the last year. And of the 6.1 million people with opioid use disorder in the past year, about 18% received medications for opioid use disorder in the last year. These are a little bit older data, but they're the best that I could find looking at individuals receiving medications for opioid use disorder by year. And so blue is 2016, brick red is 2017, and the olive green is 2018. And then on the bottom I have the different meds for opioid use disorder. So we've got methadone, buprenorphine, naltrexone, and then all of the medicines combined. So you can see over time the medications have grown. Say from 2016, you had about 345,000 people who were on methadone versus 2018, 450,000. And then looking at buprenorphine, that went from 520,000 up to 648,000. Naltrexone, you know, there's not as much uptake of naltrexone, but it did also increase with time from about 46,000 to 73 some thousand. And that all together, you can see that people back in 2016, any MOUD was about 900 some thousand versus now, or versus 2018 is about 1.1 million people. Okay, I want to shift gears a little bit and talk about morbidity and mortality from opioid use disorder. So here are some complications of opioid use disorder. Obviously, we all know about overdose. And then in terms of people with OUD, they have increased mortality that's six to 20 times higher than the general population. Often too, they're more prone to getting infections like cellulitis and abscess from injection drug use typically. And then we've talked about with xylosine, people getting wounds because of using fentanyl laced with xylosine. People also can present with osteomyelitis, septic emboli, endophthalmitis, endocarditis, HIV, and hep C. As far as hepatitis C, there's some data that suggests that 20 to 30% of people become positive for hepatitis C within two years of starting injection drug use, and about 53% are positive within five years. As far as overdose deaths from 2000 to 2014, there was a 200% increase in deaths involving opioids, and opioid overdoses increased 30% from just July 2016 to September 2017 in 45 states. Now in 2021, we had a big rise of drug overdose death in the United States. It got more than it got over 100,000, so 106,699. And that was after the pandemic. And the age adjusted rate was 32.4 per 100,000. And opioids were involved in more than 80,000 overdose deaths. So that was about 75% of those deaths in 2021. And 88% of opioid deaths involve synthetic opioids other than methadone, so that means fentanyl. Typically, it's going to be illicitly manufactured fentanyl. And drug overdose death rates involving synthetic opioids other than methadone increased 22% between 2020 and 2021. And the rates of death involving heroin declined 32% between 2020 and 2021, and that's largely because fentanyl has replaced heroin. So you can see this figure looking at the drug-involved overdose deaths ranging back to 1999 to 2021. So there's a couple of things I wanted to point out. There's four different waves that people often talk about. First is going to be with prescription opioids. So you can see the deaths from prescription opioids are this lighter blue line, and you can see how it rises up over the years, and then kind of plateaus in the 2010s, and it's gone down a little bit, but it's kind of stayed about the same. And then the second rise was involving heroin, so that's going to be that darker blue line. So we look along the bottom, and then around 2011 or 12, those deaths started to increase, and the slope of that line goes up appreciably. And then you can see that it kind of is starting to go down, and it went down a lot between 2020 and 2021. And then the third wave is going to be from fentanyl. So that's the synthetic opioids, that light gray line, and so it's along the bottom. It's all mixed in under here, all these other colors. But you see the rise happening in 2018, and it's a pretty steep slope from 2014 to 2017, and then not as steep between 17 and 19, but then gets really steep again in 2019. And so 70,000 people, more than 70,000 people died from synthetic opioids or from fentanyl in 2021. And now the fourth wave is psychostimulants with abuse potential. So what they're talking about here is methamphetamine, and that's that yellow line. So you can see that along the bottom of the graph here, and then it starts rising in like 2013, 14, but its slope isn't as dramatic as the fentanyl one until we're getting to like 2017. It's getting steeper and steeper, but then in 2019 to 2021, you can see it's at probably its steepest point here. And psychostimulants were involved in 32,537 deaths in 2021. So this is looking at opioids or overdose deaths involving any opioids. So that could be natural or semi-synthetic opioids, methadone, other synthetic opioids like fentanyl, and then heroin. And then there's two lines on here. Orange is for females and yellow is for males. And you can see that more males are dying than females, but the number of females dying has also gone upwards. You can see the slope of the line increasing over time and a little bit more dramatic from 2019 to 2021. And this is looking at overdose deaths by type of opioid, and this is ranging all the way back to 1999 again. And the figure five or the panel on the left is looking at national overdose deaths involving heroin. And so you can see heroin in combination with synthetic opioids other than methadone is the yellow line. And the grayish line, or maybe it's a little bit greenish looking, is heroin without any other opioid. So you can see heroin without any other opioid, that was the highest originally. And then it really slopes up from 2010 and peaks around 2015 and then starts declining in 2016. And then you can see the heroin in combination with other synthetic opioids or with fentanyl basically, it really starts rising in 2014 and it goes higher than just heroin alone. And it kind of levels off in 2018, 17, 18, and then it goes down a little bit in 2021 in this graph here. Now, figure four on the right is looking at national overdose deaths involving prescription opioids. And so it still is a problem. And you can see back in 1999, there were less than 5,000. But looking at 2021, more than 16,000 people died from prescription opioids or deaths involving prescription opioids. And so the yellow line on this one is prescription opioids in combination with synthetic opioids. So people are using fentanyl with the prescription opioids. And you can see how that starts taking off again in 2014, 15, and goes up and is rising over the years. And then prescription opioids without any other opioid, well, that was typically what was happening anywhere from 1999. And then it started to decrease, peaks up in 2011, and then starts decreasing down and down. And more and more we're getting co-ingestant of synthetic opioids. And this is just looking at the overdose deaths with any type of opioid from 2001 to 2021. And again, this illustrates those different waves. So you have any opioid, that's the black line. So that's everything that we're including here in this graph. And then at the beginning, natural and semi-synthetic opioids. So those would be things like oxycodone, hydrocodone. The green line is methadone. There was that peak in 2005, 2006, and that's when there was some increased prescribing of methadone for pain, not from methadone clinics. But you can see that's kind of stayed a little bit on the lower side. And then you see heroin, how that picked up. So you can see it a little bit easier in this graph than the one before. And then you can see synthetic opioids other than methadone, this dark blue line and how that spikes up. So looking at some demographic figures here, so age and gender. And these are looking at front at 2017 and 2018. And blue is 2017 and red is 2018. And then we've got different age groups. So males 15 to 24 years of age, and then females 15 to 24, and then males 25 to 44, and females 25 to 44. And then we've got males and females, the last two that are 45 to 64 years old. So the annual number of opioid overdose deaths, greatest you can see in the male group from age 25 to 44. And then next it's going to be in that male group from 45 to 64, followed by females 25 to 44, and then the older female group. And the adolescents are in emerging adults. It's not a trivial number. You can see in males that it was, you know, almost 3000 people were dying in 2017 and 2500 in 2018. And then for females, more than 1000 each year. So looking at race, as far as overdose deaths involving opioids, they've almost doubled in black Americans since 2000. So this was often thought to be a problem with white or Caucasian individuals with overdose deaths in the early 2000s. But overdose deaths involving black Americans has doubled over the years. And drug overdose deaths in black individuals between 2015 and 16 increased by a high amount, by 40%, compared to the overall population increase of 21%. So affecting black individuals more. And this graph is showing the annual number of opioid overdose deaths by race and year in 25 states and Washington, DC. So one thing I want to point out is that there are relative increases in looking at these different demographic groups. So for black individuals, the increase was 44%. Then looking at Native Americans and Alaska Natives, that went up by 39%. And looking at white individuals, it went up by 22%. So black individuals aged 15 to 24 years old experienced the largest relative rate of an increase from 2019 to 2020, and that was by 86%. And this is looking at the annual number of opioid overdose deaths by race and year. And so looking at 2017, the blue and 2018, the red. So Caucasian individuals were at greater than 37,000 in 2017, and then 35,000 in 2018. But looking at African Americans, 5,500 in 2017, and it rose to more than 6,000 in 2018. With Latinos or people who are Hispanic, it went from almost 4,000 in 2017 to 4,300 plus in 2018. And then the number of Alaska Natives and Native Americans, that was around 400 each year. And then as far as Asian Americans or Pacific Islanders, that stayed around 350 each year. Okay, so done looking at a lot of those graphs there. Now we're going to talk about opioid use disorder and the DSM-5 text revision criteria. So to be diagnosed with an opioid use disorder, you have to have a pattern of use that causes impairment or distress, and you have to meet at least two of the 11 criteria within a 12-month period. So I'm going to go over these different criteria here. So the first six are on this page. You're taking or using opioids in larger amounts or for a longer time than originally intended. You've tried to stop or cut back, or you want to stop or cut back on your use. People spend a large amount of time either getting, using, or recovering from their opioid use. They have cravings or strong desire or urges to use opioids. They're not fulfilling role obligations like going to work or school or fulfilling things at home because of their use. They continue to use opioids despite negative social or interpersonal problems that are caused or exacerbated by their opioid use. They give up or cut back on activities that are important to them because of their use. They use opioids recurrently in physically hazardous situations, so things like driving a car while they're under the influence. They continue to use opioids despite having a physical or psychological problem that can be exacerbated by their opioid use. And then they can exhibit tolerance or withdrawal. So to have a mild opioid use disorder, you only have to meet by having two or three symptoms. Moderate is four to five, and severe is six or more. And there are some specifiers you can say on maintenance treatments. So if somebody is on buprenorphine or methadone or naltrexone, if they're in a controlled environment, you can note that as well. So that might be in a rehab situation or incarceration, hospital, something like that. People can be in early remission. So that means that they haven't met criteria for opioid use disorder for three months or longer and less than 12 months. You can still have cravings, but you haven't met the criteria for the full-blown opioid use disorder. Sustained remission, people haven't met criteria for opioid use disorder in greater than 12 months, but they could still have cravings. But cravings is only one of those 11 criteria. Now, one thing you should note that you can't make a diagnosis of opioid use disorder by if they only have tolerance and withdrawal, and they're taking a prescription opioid as prescribed. So if somebody gets prescribed oxycodone for a few months, it's expected that they're going to become tolerant to its effects and have withdrawal when they stop using. But if they've been taking it as prescribed, they don't have any of these other criteria. They're not giving up activities. They're not using in physically hazardous situations or not fulfilling role functions. Then they're not going to be diagnosed with an opioid use disorder. It's just an expected consequence of being prescribed an opioid for a long period of time. Next, I want to talk about opioid intoxication. So to have this diagnosis, you have to have recently used an opioid. And there has to be some kind of clinically significant change, either behaviorally or psychologically, that developed during or shortly after the opioid use. So somebody became euphoric or they became dysphoric. They had either psychomotor agitation or retardation. They showed impaired judgment. And so in these individuals, you might see a pupillary constriction, or let's say somebody does have an overdose, they could have dilation from the anoxia. Or besides having constricted pupils, they're going to have one of these other that developed shortly after using the opioids or during the opioid use, drowsiness, slurred speech, impaired attention and memory. And for this DSM diagnosis, you can't attribute any of these symptoms to another medical condition. And they're not better explained by another medical condition or intoxication with another substance. Opioid withdrawal. So to go into opioid withdrawal, you have to either stop or reduce opioid use that has been heavy and prolonged. So typically several weeks or longer. Or you could have opioid withdrawal if somebody was administered an opioid antagonist after a period of opioid use. So let's say somebody gets naloxone after they'd been using fentanyl, or somebody takes naltrexone after fentanyl, they could have opioid withdrawal. And they would have three of the following criteria within minutes to several days after they stop, cut back opioid use, or they get an antagonist. Dysphoric mood, nausea or vomiting, muscle aches, a runny nose, watery eyes, dilated pupils, pyeloerection, sweating, diarrhea, yawning, fever, insomnia. And so you have to be able to say that the signs and symptoms in criteria B cause clinically significant distress or impairment. And they're not attributable to another medical condition or another withdrawal syndrome or intoxication. So I wanted to go over a few treatments that are available for opioid withdrawal. You've got alpha-2 agonists, you've got clonidine, guanfazine, or lofaxidine, and you can use this in addition to some other medications to alleviate symptoms. So the other way that you could do this is by using buprenorphine naloxone combination product or buprenorphine monoproduct. Typically, you're going to use the transmucosal formulations, and these can be used in hospital, in emergency department setting, office, or in an opioid treatment program. Obviously, with the alpha-2 agonists, you could use them anywhere. And then methadone, it's going to be administered typically and not prescribed in a hospital or an ED setting or in a licensed opioid treatment program. So it's not something that you're going to write out a prescription for. Here's a timeline of opioid withdrawal and looking at these different grades. So in early withdrawal, they have grades one and two. In full withdrawal, grade three and four, typically. So some signs and symptoms that you might see early on are going to be lacrimation, rhinorrhea, some diachoresis, people might be yawning, restless, and have trouble sleeping. And this can start anywhere from eight to 24 hours after they use a short-acting opioid or up to 36 hours after using a long-acting opioid. And then grade two in that early withdrawal, they'll have dilated pupils. You can see some goosebumps, muscle twitches, muscle aches, joint aches, abdominal pain. And then in full withdrawal or grade three, they can exhibit tachycardia, hypertension, tachypnea, might have a fever, anorexia, just people typically have no appetite. Also nausea and extreme restlessness. And this can start one to three days after a short-acting opioid and anywhere from three to four days after a long-acting opioid. And then grade four withdrawal, they'll have the diarrhea, vomiting, could be dehydrated. Also you might see hypotension, hyperglycemia, and they could be curled up basically in a fetal position. And duration of withdrawal with short-acting opioids is typically seven to 10 days. With long-acting, it's going to be a little bit longer, be 14 plus days. Typically people will measure withdrawal, if you want an objective measure of withdrawal, using the COWS, that's the clinical opioid withdrawal scale. And you can see it measures several different things. You can get the resting pulse rate, sweat, sweating, restlessness, pupils, and then just looking at these other things, GI upset, anxiety, irritability. Now, one of the things that you have to look at too, is it does have some things in italics here. So resting pulse rate measured after a patient is sitting or lying for one minute. So they shouldn't just walk into your office and then get their pulse rate. Another thing would be like GI upset over the last half hour. So to score somebody, you're not going to score them based on if they said, oh yeah, I had some nausea last night, or I had loose stool last night, and you're seeing them the next day. So there are other opioid withdrawal rating scales, and they include the CINA, that's the Clinical Instrument Narcotic Assessment, and then the SOWS, Subjective Opioid Withdrawal Scale. And in there, you're not going to have some of these objective measures like the resting pulse rate or observation like you're wanting. It's going to be all self-report. So why do we use alpha-2 agonists for opioid withdrawal? Well, opioids, they do inhibit cyclic AMP in addition to being an immune opioid agonist. And when somebody stops using opioids chronically, the cyclic AMP levels in the locus coeruleus rise, and that results in norepinephrine release. And the alpha-2 agonists can suppress that noradrenergic hyperactivity in the locus coeruleus. And so it's going to help with things like aches, runny nose, watery eyes, that hot and cold temperature dysregulation, diaphoresis. So it's going to suppress some of those withdrawal symptoms. As far as dosing, clonidine's been used off-label since the 1970s for opioid withdrawal, and you could use anywhere from 0.1 to 0.2 milligrams every four hours up to 1.2 milligrams a day. In my experience, I'm not using that high of a dose. People's blood pressure usually doesn't tolerate that high of a dose. I often use the 0.1s and maybe up to 0.6 milligrams in a day. I haven't really seen too many people get 0.2 milligrams at one time. But again, that's because if I'm using that, it's in the hospital. And a lot of times we just get people on buprenorphine to help them. But if you are using this, that would be like the dosing, but just do be careful about looking at their blood pressure as well as their heart rate with these higher doses of clonidine. And then you start tapering the dose after three days, especially if they're using shorter acting opioids. Usually the withdrawal is going to peak at about day three or four. And typically you can use this for up to 10 days. Sometimes people keep taking this and they still feel kind of sick. But what I've noticed is a lot of times it's just because the clonidine really just suppresses their energy levels and makes them feel just kind of down, especially if they're taking it every four hours. So talking to people about tapering down off of it can be helpful. And the dosing can be limited by hypertension and bradycardia, like I mentioned. And then the adverse effects that people typically complain about are going to be dry mouth, feeling sleepy and low energy or fatigued. Lofexidine, this was approved back in 2018 for treatment of opioid withdrawal. And it's been used in Europe for years. And what you do with this one is take three 0.1 milligram tablets four times a day and the dosing is supposed to be guided by symptoms. And so your total daily dose shouldn't exceed more than 2.88 milligrams or 16 tablets. And no single dose should be more than And no single dose should be more than four tablets or 0.72 milligrams. And then gradually reduce the dose one tablet per dose after over two to four days. And then this is indicated to be used for up to 14 days. And the advantage of this is that it was shown to produce more rapid resolution and symptoms, less hypotension. So that's important. And also retained people longer in treatment than clonidine. As far as some adverse effects of lofexidine, again, we're going to worry about hypotension, bradycardia and syncope, the somnolence, the dry mouth, also QT prolongation, CNS depression when you're using with other CNS depressants, and then also increased risk of an overdose if they resume using after withdrawal. Some of these things also, I should mention, apply to clonidine too, because you could have some CNS depression when they're using the clonidine with that, or if they stop, or if they resume using after they go through withdrawal with clonidine, they have that increased risk of an overdose. Now the CYP2D6 inhibitors can increase plasma levels. So for example, peroxetine can increase the plasma level. And then poor CYP2D6 metabolizers can have more adverse effects because that's what this drug goes through in terms of metabolism. So they might have more of these side effects. Now I mentioned that you can use the alpha-2 agonists along with some other adjunctive medicines to help with associated symptoms. So oftentimes for anxiety, I'm using hydroxyzine panoate. Uh, I tend not to use benzodiazepines, uh, just because of overdose risk as well as, um, sometimes when you start a benzo, it's difficult to get people to stop taking them. Um, and we can treat some of these symptoms, you know, the anxiolytic effect of clonidine, but also hydroxyzine has, can, can be helpful there too. As far as diarrhea, usually I'm using loperamide, but sometimes I might use divinoxalate atropine if the withdrawal or the diarrhea is severe, it doesn't respond to the loperamide, but don't forget about, uh, people might try to self-treat their diarrhea with loperamide and that can lead to QT prolongation and torsades like I talked about, um, in the beginning of this presentation. Nausea can treat with undancetron or other antiemetics if, if they're not responsive to the undancetron, but I usually try that one first and then insomnia, uh, using trazodone, melatonin, mirtazapine, uh, for, for sleep. So buprenorphine can also be used for treatment of withdrawal. It's a mu partial agonist and it has a really high affinity for the mu receptor and a slow dissociation. And it's usually combined with naloxone to prevent people from misusing the medication. Um, usually, uh, it hasn't been recommended in the past to use the monoproduct, uh, except in certain situations. Now you only need to have a DEA license to prescribe buprenorphine before you have to have this waiver and everything, but that all went away. I'm going to talk about that in a little, a little bit later on in this presentation. You need to have, the patient typically needs to be in withdrawal to start the medicine. So a cow is an eight or greater, uh, to prevent precipitated withdrawal. And we'll talk about that on slides 89 and 90. You can also use microinduction or macroinduction. And we'll talk about that a little bit later on. And it's well tolerated. Usually the most common adverse effect is going to be sweating, constipation, headache, nausea, and you can individualize a taper. So if somebody doesn't want to be on buprenorphine long-term, you can make the taper as short or as long as you want. Um, as far as buprenorphine versus clonidine, there have been prospective randomized and open label study of buprenorphine versus clonidine. So they enrolled 344 men and women who had opioid use disorder, and they had a 13 day medically supervised withdrawal study. And they were either in an inpatient setting or an outpatient setting. And so when they did the analysis that they adjusted for level of care, so inpatient versus outpatient. And what they found is that those who received buprenorphine were nine times more likely to have achieved, achieved treatment success. So they went to an appointment and had a negative urine toxicology compared to those who received clonidine. And they were also 22 times more likely to complete treatment. And about 70% we see who received clonidine dropped out by day four versus 12% who received buprenorphine. So the buprenorphine versus clonidine, if you want to retain people in the withdrawal management treatment, it's been shown to be more effective for that. Then you could also use methadone for treatment of opioid withdrawal. It is a full new opioid agonist. You don't have to have any specific level of withdrawal to start. However, it wouldn't be wise to start it when somebody's intoxicated. And typically people would be starting with a withdrawal protocol at 20 to 30 milligrams a day. You might have to increase slightly to alleviate the withdrawal symptoms and then decrease the dose. So if the withdrawal is not alleviated with 30 milligrams and you observe them and they still have signs of withdrawal, give them another 10 milligrams. And maybe depending on your setting, maybe more up to 50 milligrams to start and then start decreasing the dose over time. So there was a study that looked at reducing the dose by 3% versus 10% per week. And they found that there was higher retention if you did these lower reductions, less withdrawal and less illicit opioid use. However, only 40% achieved abstinence in either group. And when there was another study that looked at starting at methadone 35 milligrams a day and then reducing over 21 days, that didn't really offer any advantage in alleviating withdrawal or achieving abstinence compared to just stopping and using clonidine. I think the most important thing to kind of remember here is that withdrawal management isn't really the recommended standard of care. It's maintenance treatment because of the high risk of return to use when people are withdrawn from opioids, as well as the high risk of having an opioid overdose and death. You might have also heard about naltrexone-assisted withdrawal. So there was a study, this was a randomized open-label study. They had 150 people and they compared naltrexone-assisted withdrawal versus buprenorphine withdrawal management. So you can see the protocol here. So on day one, they got ancillary medicines to support abstinence. That'd be like things like clonidine and those other symptom treatment meds that I talked about. And then on day two, they got buprenorphine, two milligrams, every one to two hours, up to eight milligrams. And then in that naloxone-assisted group on day three, it was a washout period. They didn't get any more buprenorphine or, but on day four, they started on low dose naltrexone. So they gave them a one milligram and you can see how they increased the naltrexone over time here, getting up to day seven, they were at 25 milligrams. And then day eight, they gave them the shot of 380 milligrams intramuscularly. And then in the buprenorphine group. So remember that first day they got two milligrams. Well, actually it was on protocol day two. They got two milligrams every one to two hours, up to eight milligrams, and then they tapered down. So they got six milligrams, four, four, two, and one. And then they had to wait another seven days to get the naltrexone shot. So that was the end point of this too, is to be able to get this injection. And then they were able to get that on day 15. So the participants in the study that used that naltrexone assisted withdrawal were significantly more likely to be successfully started on naltrexone. Cause you were able to start it on like day eight versus day 15 for people who were on that buprenorphine assisted withdrawal. And so you can see it was 56% of the people who were in the naltrexone group versus 32.7% in the buprenorphine. So that's a pretty good number. Withdrawal group. And as far as receiving a second naltrexone injection at five weeks, the people in that naltrexone assisted group, it was 50% versus about 27% who underwent the buprenorphine assisted withdrawal. You might've also heard about anesthesia assisted rapid opioid withdrawal. So this isn't recommended, but I just wanted to let you know about it just in case it ends up on the test. The patient undergoes intubation and general anesthesia, and then they precipitate opioid withdrawal by infusing high dose naloxone or giving an IM injection of naltrexone. And they maintain anesthesia until the withdrawal symptoms subside. And then the patient is extubated and then monitored. This isn't recommended. Published data showed that there's no improvement in 12 month abstinence rates compared with standard withdrawal management. And it's associated with a substantial rate of serious adverse events in the research study, almost 9% in one study. So I'd already mentioned that withdrawal versus maintenance. Withdrawal management alone results in high rates of relapse or return to use, about 10 to 20% only remain abstinent. And then you have that added risk of accidental overdose and death once you go through withdrawal. Maintenance medicines for opioid use disorder are recommended as the standard of care. So you've got buprenorphine and buprenorphine extended release. And when I say buprenorphine going forward, I'm most likely, you know, I'm talking about buprenorphine and buprenorphine naloxone combination product. Methadone and then their naltrexone extended release. So let's talk a little bit about these medications for opioid use disorder. So these medicines have been studied for years and they're an evidence-based treatment basically to decrease opioid and injection drug use, reduce transmission of hep C and HIV, also decrease criminal behavior, retaining people in treatment has been shown to be effective with these meds, decreasing overdose and death, reducing sexual risk behaviors, such as trading sex for money or drugs, and also improving people's physical and mental health, as well as their social functioning. Like they can get a job and work a steady employment. These are the FDA approved medications for opioid use disorder. So we have full agonist methadone. There's also leva alpha acetamethadone that was approved. It's still approved by the FDA, but it's not marketed. And I'm not going to talk about it any further. It was taken off of the market or because of once it got a warning about QT prolongation and partial agonist. So we've got buprenorphine, buprenorphine naloxone combination product, and then buprenorphine extended release products. And then the antagonist naltrexone and naltrexone extended release. And I'll talk a little bit more about why I wouldn't recommend naltrexone, just the tablet formulation in coming slides. As far as substance use treatment and race, some studies have been done and they found that black individuals with opioid use disorder are more likely than white individuals with opioid use disorder to be recommended to receive methadone treatment than buprenorphine. A study in New York City found that residential areas with the highest proportion of black and Latino, uh, low-income individuals have the highest methadone treatment rate. And buprenorphine was more accessible in areas with the greatest proportion of white, high-income patients. And Black and Latino individuals are anywhere from 3.5% to 8% less likely than white individuals to complete treatment for substance use disorder. So the first drug I want to talk about is methadone, and I'm only going to talk about that a little because there's a whole other presentation on methadone. So methadone clinics started after Dylan Eiswander published a study in 1965, and it's a full mule good agonist. It has a half-life of anywhere from 24 to 36 hours on average. And the average therapeutic dose is 80 to 120 milligrams a day, however, we're seeing higher doses with fentanyl. And it usually can take weeks to get to a stable dose because of the pharmacokinetic sub-methadone, and that's discussed in these other slides. But it is dosed once daily for opioid use disorder, except for people who are rapid metabolizers, and pregnant individuals are rapid metabolizers too, so including pregnancy. It's dosed at licensed treatment, opioid treatment programs under federal and state regulations, and patients typically receive take-home doses of methadone or unobserved dosing of methadone when they're stable. So for more information on methadone, see the presentation entitled Methadone and Opioid Treatment Programs. So buprenorphine. So you can see there have been some changes. The Drug Addiction Treatment Act of 2000 was passed, and that amended part of the Controlled Substance Act, and it allowed for physicians to prescribe and dispense certain medications for opioid use disorder. And then in 2023, the Consolidated Appropriations Act of 2023 ended the data waiver. And what that ended was that you had to complete appropriate training, certify that you're qualified, and file a notification of intent with the Secretary of Health and Human Services. So you no longer have to do that. The physician was also assigned an ex-DEA number. Well, that's no longer relevant either. You just need a DEA license. And then the other part of the data waiver said you can only prescribe or dispense Schedule 3, 4, or 5 controlled substances that have been approved by the FDA for use in detoxification or maintenance treatment of opioid use disorder without registering as an opioid treatment program. So that still stands. You still can only use Schedule 3, 4, or 5, but really the only medicine we have is buprenorphine and it's Schedule 3. And then the other thing was that originally it said you could only treat up to 30 patients at one time. And then they made those changes, allowing 100 and 275. Also they had the changes over time allowing nurse practitioners and so on to be able to prescribe. But now you don't have to keep any log or there's no patient limit in terms of prescribing buprenorphine. So here's an abbreviated history. So buprenorphine started getting researched in the 1980s and 90s. And then that 2000 is when the Data Drug Addiction Treatment Act was passed. And then in 2002, Suboxone and Subutex, those brand name products of buprenorphine, naloxone and buprenorphine were approved by the FDA. And then in 2006, they changed it to allow physicians to treat up to 100 people at any one time after one year and filing one year after filing their notification of intent with the DEA. And then in 2016, there were two big changes. So CARA, that Comprehensive Addiction Recovery Act, I think it was, allowed additional prescribers. So advanced practice nurses and physician assistants. And at that time, they had to complete 24 hours of training and be supervised by a physician if it was required by state law. And in 2016, they also expanded to allow people to treat up to 275 people at any one time if they had added qualifications in addiction or worked in a qualified practice setting. And then in 2018, the SUPPORT Act was passed and that allowed additional prescribers. So nurse anesthetists, clinical nurse specialists and nurse midwives. And allowed qualified physicians to start treating 100 people after filing this notification. So it changed from originally you could only treat 30 people at any one time. But if you met this qualified physician, you could treat up to 100. And then in 2020, the EASY MAT Act was passed. And I think I'm going to talk about that in a few slides. And then in 2021, physicians and advanced practice providers could file a notification of intent and receive an X waiver to treat up to 30 people at any one time without completing that data waiver training, that eight hours. Or in the case of advanced practice providers, 24 hours. So they were trying to expand things then. And then in 2022, the DEA said that practitioners can apply to dispense three days of narcotic meds to treat withdrawal. And that was basically them trying to enact this EASY MAT Act. So in this case, it would be you could apply for this waiver to dispense three days of buprenorphine or methadone as long as you meet certain criteria and get this waiver from the DEA. And then in 2023, that data waiver is eliminated. You only need to have your DEA to prescribe buprenorphine. And you have to take an eight-hour substance use disorder training. Doesn't necessarily have to be in buprenorphine. And attest to completing this eight-hour training with the DEA renewal. Now if you already had a data waiver, you could use that as, say, that you got your eight hours of substance use disorder training. Or if you didn't have the data waiver, you could still do that eight-hour buprenorphine course and use that to check that attestation when you renew your DEA and say that you have completed eight hours of training. I talked about buprenorphine a little bit earlier on. And it's pharmacology with being a partial agonist and having that high affinity for the receptor and slow dissociation. And it's usually combined with naloxone to prevent people from misusing the medication. And so, you know, if somebody were to crush up the tablets of buprenorphine monoproduct and inject them, they would maybe develop some euphoria from it faster than they would if they were to dissolve buprenorphine naloxone combination product. And then you just need your DEA to prescribe it. There's different induction methods of kind of that traditional induction where you need to be in mild withdrawal to start. And then you get a cows of eight or more, and then you start two to four milligrams of buprenorphine and getting up to 16 milligrams within a matter of one or two days. There's other induction methods, the micro dosing and macro dosing, especially if somebody's been using non-pharmaceutical fentanyl, or if somebody's transitioning from methadone, or if they have a pain medicine and they don't tolerate withdrawal amount well. And buprenorphine is pretty well tolerated. Its most common adverse effects are sweating, constipation, headache, and nausea. So in 2002, it was approved by the FDA for treatment of opioid use disorder. And I already talked about its pharmacology here, but as far as that partial mu opioid agonism, that means it has a ceiling effect. So it's safer if somebody were to take more than prescribed or an overdose. And that's around 32 milligrams where that ceiling effect happens. And so it also has decreased respiratory depression compared to full agonists. Now because it is a partial agonist, it can precipitate withdrawal if you give it before somebody's in mild to moderate withdrawal. As far as naloxone, it's used as combination. It's an opioid antagonist. It's not going to be absorbed significantly if the medicine is taken as directed. So taken under the tongue, it's only about two to 10% bioavailable. And the recommended formulation for most patients is going to be that combination product of buprenorphine naloxone. That's because that buprenorphine monoproduct has been associated with higher abuse liability as well as a street value. And it's metabolized through the CYP3A4 isoenzymes. There's different buprenorphine products for opioid use disorder. Now remember from data 2000, it has to be labeled for opioid use disorder. So it could be withdrawal or dependence, you know, because some of these things are older. These products are older and got approved when we had different nomenclature. Buprenorphine or Subutex is the monoproduct. There was a product called Probufine, which are some rods that you could get put in somebody's arm if they were stable with their opioid use disorder on eight milligrams or less of buprenorphine. But those are no longer marketed. There's buprenorphine extended release that's under the brand names Sublocade and Bruxade. And then there's buprenorphine combination products. So there's the brand name Suboxone film. There's generic buprenorphine naloxone film, generic buprenorphine naloxone tablets. And then there's the brand names Zubsolve tablets. And you're not supposed to be using the following for opioid use disorder because they're indicated for pain. So Buprenux, that's IV or IM. And Butrans, the transdermal buprenorphine patch, it's very small doses in micrograms. And then there's Valbuca, which is a buccal strip. So the other reason why you wouldn't want to use these is, well, you're not going to be using an IV or IM medicine for opioid use disorder maintenance treatments. But as far as that transdermal or the buccal strips, they're very low. They're not going to be high enough to suppress withdrawal. And they're not going to be high enough doses to suppress cravings. So that's why we wouldn't use them anyway. Since they are used in these microinduction protocols, I think I will be talking about that. And typically that's going to be on an inpatient setting. It's hard to maybe prescribe these in an outpatient setting unless somebody does have a pain disorder. And oftentimes they require a prior authorization. So here's a table of the formulations. And so you can see we've got this tablets. We've also got some sublingual films, that buccal film. Suboxone, the brand name says that you can put it on the inside of your cheek and let it dissolve. Or you can put it under your tongue. And then we have the long-acting subcutaneous injectables, Supplicade and Bruxadi. Bruxadi just came out in fall of 2023. So I wanted to show you this dose equivalence table of the transmucosal formulation. So you could use it on your tongue or on your cheek. So buprenorphine tabs, the generic tabs of the monoproduct only come in two and eight milligrams. And we often think about buprenorphine in eight milligram equivalents because that was, you know, how Suboxone came out or the Subutex came out in eight milligrams. So buprenorphine naloxone tablets and films come in eight slash two milligrams. So a four to one ratio of buprenorphine to naloxone. And Suboxone brand comes in eight slash two. Zubsolve, the equivalent dose to an eight milligram buprenorphine is 5.7 milligrams of buprenorphine. And the reason this is, is because it's supposed to have higher bioavailability, dissolves more quickly under the tongue and so you get more medication. So you don't need to have as much of a dose. And then that's about a four to one ratio to the 5.7 to the 1.4. And you can see like there's other doses as well. In the tablets, you can get, the tablets are only in eights and twos, but the films come in all, the generic films come in fours, twelves, as well as the eights and the twos. And then Zubsolve, the equivalent of one milligram, that would be if you cut like a buprenorphine film, like a two slash 0.5 into half. So one milligram film is equal to 0.7 milligrams of the Zubsolve. And they even have a Zubsolve where if the person wants to just take one tablet a day, they can do 16 milligrams, but you can see there's some different doses here that you can select. I guess the reason people like Zubsolve, it does have a different taste. They say Suboxone tastes pretty like orange. And so they don't necessarily like, some people might not like the taste compared to that menthol flavor. And it does dissolve a little bit more quickly than the tablets, the generic tablets and the films. Okay. To start on buprenorphine using this traditional induction, patients need to be in opioid withdrawal. I've already mentioned cows greater than eight or equal to eight. And if somebody is converting from methadone to buprenorphine, they should be at 40 or lower and not dose for at least 36 hours prior to starting buprenorphine. And the first dose is typically two to four milligrams of bup up to eight to 12 milligrams on day one. And then day two and beyond the dose can be increased to suppress withdrawal cravings and opioid use. So usually, you know, like 16 milligrams on day two, if needed later on, you can go up to 24 milligrams. Usually, you know, it does take about five days to get into steady state. So depending on how symptomatic the patient is, is how you're going to increase that dose. And induction can be accomplished in a few days. And if the person is using non-pharmaceutical fentanyl, they should have a cows of greater than or equal to 13 to 15 to start to avoid precipitated withdrawal if you're using this traditional induction. I mentioned about precipitated withdrawal before, and this has become more common due to non-pharmaceutical fentanyl. I didn't have people complaining about this before when it was just heroin. Fentanyl's really lipophilic. It accumulates in the fat tissue and it gets slowly released. And so these microinduction and macroinduction protocols reduce the risk of precipitated withdrawal. And what precipitated withdrawal is, it's rapid development of withdrawal symptoms within hours of taking the partial agonist or an antagonist. So usually within one hour, people are experiencing symptoms. That's when the serum level of buprenorphine can peak. And treatment for withdrawal, the precipitated withdrawal, you would increase the buprenorphine dose. It depends on what you want to do here. I would be a little bit more aggressive, but you can do two milligrams every two hours up to 24 milligrams, or you can increase it by eight milligrams every two hours up to 24 milligrams. Sometimes people might not want to take any more buprenorphine. And then if you are a, let's say you're doing this at a methadone program, you can give a methadone instead, or you could do symptom treatment, giving them antiemetic, IV fluids, benzos often because of the psychomotor agitation that develops. So and using clonidine as well. As far as that microinduction, to start a buprenorphine, you don't have to be in any opioid withdrawal, or you can be a mild withdrawal. And people can continue using an opioid agonist for the beginning of treatment. And typically on day one, they're going to get anywhere from 0.5 to one milligram of buprenorphine. And this is accomplished by cutting like a two milligram film into quarters or into half. And you can take up to one to two milligrams in that first day. Sometimes people are a little bit more cautious with this as well, maybe only getting a half of a milligram in that first day, and then increase the dose daily. And patients should stop using the opioid agonist when they get to about 12 milligrams of buprenorphine, if they haven't already stopped. And then they can get on that maintenance dose of 16 milligrams or maybe even a little higher depending on what's needed within a week by using this procedure. And here's just a microinduction protocol here where we have them. These are two milligram films. You can see the first three boxes and they cut the two milligram film into four pieces and they get one milligram in that first day by taking a dose in the morning and afternoon. And then on day two, they're taking a half and a half or a total of two and so on. And then you can see on day four, it's just eight milligram films. Usually what I'll tell my people is that if they're tolerating pretty well and I see them or talk to them or have a nurse talk to them quite frequently when they're doing this, we can speed this up to get them onto a therapeutic dose. Sometimes this just prolongs things and people are pretty miserable, but they're tolerating it well. And we don't have to go this slowly. If they tolerated the four milligrams, they could probably go up to eight the next day and then 16 the following day if they tolerate all of that. But sometimes people are very, they've had an experience of precipitated withdrawal or they know somebody who did, and they're very cautious and don't want to take these doses and they just take little pieces and they never actually get up to a high enough dose. And then so they're dealing with undertreated withdrawal and saying, oh, this Suboxone or this buprenorphine is making me sick. But really what it is, is they're just having spontaneous withdrawal or undertreated withdrawal. The macroinduction, you don't need to be in opioid withdrawal, but you can be in mild withdrawal and you give higher doses to start. Some more mule opioid receptors are occupied and you're less likely to feel withdrawal. And the induction dose is typically anywhere from 12 to 32 milligrams of buprenorphine. And it's recommended you might start with smaller doses, but you give them regularly over the course of a day to get to 12 milligrams or higher. As far as maintenance, the doses range from 12 to 24. Sometimes now we're seeing more, some people get up to 32. There's right now, there's a NIDA clinical trial study looking at higher dosing at 32 milligrams. Stable patients usually, the stable patients I have can get maintained on lower doses. Sometimes they request to cut down on their dose, don't feel that they need it. And sometimes you might need to get a prior authorization depending on the insurance company or Medicaid in your state for doses above 16 milligrams. It just depends on how things are in your area. And sometimes if you're trying to use that buprenorphine monoproduct, they're not going to, insurance might not pay for it without a prior authorization. Half-life of buprenorphine is 24 to 36 hours, so you can, patients can take it once a day. I know a lot of times though, patients if they're on two films a day, they take it twice a day. They don't want to take both films at once. Or let's say they're on three films, they might split up to TID. But they could take all of it in the morning. There's a greater concern for diversion at higher doses. Maybe they don't need that high of a dose, but they know somebody else who's sick or something and might give it away. But in terms of when they've done a study, and this is a very small study, pet studies don't typically include a lot of people. But this pet study that was published in 2003 looked at opioid receptor occupancy at different doses. And I only put the two conditions here, 16 and 32, but they had a couple other conditions as well. But you can see anywhere from 79 to 92% of the receptors were occupied at 16 milligrams and 84 to about 98 were occupied at 32 milligrams. So they didn't have a 24 milligram condition, unfortunately. But somebody might be sitting at that 78.9% of their mu occupancy and still having cravings, or they might still have some withdrawal or something like that. Or they could be at that 90%, but it's not 100% of the receptors are occupied, so they might need higher doses. So I would listen to the patient and engage in shared decision-making in terms of the dosing. And if you're examining them and they're still having withdrawal, it's not just 16 milligrams or nothing, you can go up on the dose. Buprenorphine treatment, as far as doing other treatments or therapy and stuff, there's nothing federally that says that you have to, that people have to engage in therapy or any more. You don't have to certify that you'll refer people to counseling or that you can refer people to counseling with that data waiver. But typically how it works is that people are coming to the office or doing telemedicine visits on a weekly basis to start and get a week's supply of the medicine. And once the prescriber feels comfortable increasing the length of the prescription, so go up to two weeks and eventually get up to once a month. Usually people are coming in and doing toxicology testing, like giving a urine specimen, or if they're doing telemedicine, they might go to a lab out in the community and do the urine toxicology. And some people might be required to do some form of psychosocial treatment. It might be a state requirement, or it might be a third-party payer, but it's not federal government telling us this. And when a patient's stable, then you want to advance their treatment, so decrease their visits and increase their supply of medicine. And if there's instability, return to more frequent visits as indicated. So if somebody starts using it again, have them come in and see you a little bit more often or do more telemedicine visits, or refer them to therapy, or maybe they need an intensive outpatient program, trying to address whatever is going on. As far as toxicology testing, there's no federal regulations about how often you have to do toxicology testing, and states can have regulations about this. Third-party payers might tell you what you have to do to pay for them to pay for the buprenorphine too. And usually the testing's done at office visits, or it can be done randomly. As far as you're in toxicology tests, you want to test that's reliable, convenient, you get the results in a timely manner, and possibly might want to observe it. So usually we're using urine drug testing or oral fluid testing. Oral fluid's nice because you can observe it without being invasive, but it is a little bit more expensive of a test depending on what you're using. Regardless of the testing matrix, it's ideal to test for both the presence of buprenorphine and the metabolite Norbu, test for other synthetic opioids, so oxy, fentanyl, methadone. And then just remember that opiate tests for morphine, codeine, heroin, and sometimes hydrocodone. And then you want to test for other drugs that are prevalent in the area, like benzos, cocaine, amphetamine, methamphetamine. And there's a module that you can see regarding urine drug testing or toxicology testing for more information. As far as counseling, there's no federal regulation that you have to get, that somebody has to go to counseling or you have to refer anybody. States might have some regulations regarding this, so just be aware of what's in your state. And 30-party pairs might have some kind of requirement too. As far as adverse effects, I kind of touched on these earlier, so sweating, constipation, headache, insomnia, sometimes some nausea from the medication, hypotension, sexual dysfunction, seizures, and then also hepatitis or hepatotoxicity. That's very rare, and this has been shown to be a safe medication to use in people who have hepatitis. To actually dovetail on that here, buprenorphine and liver health, there was a multi-center prospective study to examine the safety of buprenorphine. So they enrolled 740 people who had opioid use disorder. The median dose was 24 milligrams and the mean dose was 22. And the participants were monitored for 24 weeks, and 2% had extreme elevation of transaminase levels that warranted medical attention. And those extreme elevations were more likely due to somebody having hepatitis C or B seroconversion during the study, or they were using illicit drugs during the first eight weeks of the study. And this suggested that factors other than the exposure to buprenorphine was responsible for that hepatotoxicity. And buprenorphine's been studied in adolescents, pregnant women, people with HIV, and significant liver injury was rare in those populations. Just a few words on long-acting injectable buprenorphine. So there's the brand name Sublocade. To start this, the prescribing information says that you need to be on seven days of transmucosal buprenorphine, 8 to 24 milligrams. And then the first two doses of the injection are 300 milligrams sub-Q for two months. And then on the third month, you move down to 100 milligram for maintenance. However, if somebody doesn't tolerate that, they can go back up to 300 milligrams. And the minimum time between doses is 26 days. It takes four to six months to get into steady state. If somebody were to miss a dose, give it as soon as possible. So some delay in treatment up to two weeks, they probably aren't going to have any kind of clinically significant impact. After somebody reaches steady state, patients who stop injections might have buprenorphine detectable in their plasma for up to 12 months. And there hasn't been any kind of correlation between plasma and urine concentrations that have been studied. The other long-acting injectable buprenorphine product is called Brixoti. And this was approved in 2023 and marketed in 2023. And it's weekly and monthly injections. And it's indicated for people with moderate to severe opioid use disorder who've started with at least one dose of transmucosal buprenorphine. So that's the difference between that sublocate, which says that you have to be on a week's worth of doses. And there's a REMS program that you have to complete. There's one else for sublocate too, a REMS program. And the medicine isn't to be given to the patient, neither the Brixoti nor the sublocate. It gets delivered to the healthcare provider to inject. And there is a risk of harm and death if the patient were to inject either sublocate or Brixoti IV. The nice thing about this one, it doesn't need to be refrigerated, but you need to follow the DEA and state regulations about storing your controlled substance. Same thing with sublocate too. So as far as who's appropriate for Brixoti, so the weekly version is somebody who's tolerated at least a single dose of four milligrams of a transmucosal buprenorphine product or somebody who is already on a transmucosal buprenorphine product. It doesn't have to be, you know, just one day or a single dose. Brixoti, the monthly version isn't intended for people who aren't on buprenorphine. So let's say you have somebody who's not on buprenorphine. You give them a test dose of four milligrams of transmucosal buprenorphine. They tolerate that. You give them the 16 milligram Brixoti injection, the weekly one. And then if they're having some symptoms of withdrawal three days later, you can give them an additional eight milligram of the weekly injection to get them to that weekly dose of 24. And let's say they're still struggling. You could give them an additional eight milligrams for a total of 32 in that first seven days, but make sure that it's at least 24 hours after that last injection. So here's a chart about converting people from sublingual or transmucosal buprenorphine products. So if they were on less than six milligrams, six milligrams or less, they'd get the Brixoti eight milligram weekly injection. And then you can see if they're on these other doses of buprenorphine, you could give them weekly or monthly. If somebody's on, you know, regular doses of buprenorphine sublingually, I don't know that I would necessarily start them on the weekly. I would just convert them over to the monthly because who wants to come back in a week and get another shot? So as far as transitioning from weekly to monthly, let's say somebody did, they weren't on any kind of buprenorphine product. They just got that four milligram sublingual dose times one, and they got a weekly shot, and then they want to get, you want to give them the monthly of the next week. So you can see the conversion here. As far as injection sites, with the sublocade, you're injecting it in the abdomen sub-cube, and this is similar. You're going to do it sub-cube, but you can give it in the abdomen, the thigh or the buttock, and it's going to be sub-cube. You can also do it in the arm, but if they are not on buprenorphine and they're starting Brixadi weekly, don't use the upper arm site until they're in steady state. Just to keep it simple, I just don't use the arm. As far as sedatives in buprenorphine, there was a study in Finland that looked at opioid-associated overdoses, and they found that 29% of over 1300 found buprenorphine in 29% of 1300 opioid-positive cases of overdose. And buprenorphine poisoning was the cause of death in 182 out of almost 400 positive cases, so 47%. And in most buprenorphine poisonings, 92% of those, no other opioids were involved, but benzos were found in about 82% and alcohol in 58%. And there was only one fatal poisoning that was from buprenorphine alone. As far as using benzodiazepines in buprenorphine, a retrospective study was done looking at people that were prescribed buprenorphine, and they found that there were more emergency department visits in people who had a benzo prescription versus those without. And they also found that there was an increased odds of accidental injury related to the ED visit during treatment if you had benzodiazepines plus the buprenorphine, so that odds ratio was greater than, or was 3.7. And there was an enhanced effect among females, so you can see the odds ratio there was 4.7. Overdose wasn't associated with benzodiazepine misuse history or the prescription though. Moving on, I want to talk about naltrexone for treatment of opioid use disorder. So naltrexone, tablets were approved back in 1984 for opioid use disorder, and they've sent a release injection was approved in 2010. It's an opioid antagonist, and it has a really high affinity for the mu-opioid receptor, and it's going to displace bound mu-opioid agonists, so it can cause precipitated withdrawal. And the way that this works is it blocks opioids from binding to the receptor, and so people don't have the euphoria that they would get from illicit use. It's also going to prevent analgesia from opioids too. So naltrexone tablets are usually prescribed 50 to 100 milligrams per day, and the extended release is 380 milligrams once monthly intramuscularly. And it does have a more difficult induction because you need to be abstinent from opioids for seven to ten days. Naltrexone is metabolized by the liver, so you should check the liver functions prior to starting and periodically during treatment. And then we have a list of adverse effects. The most common is going to be nausea with the oral formulation. You can see the other effects here. Precipitated withdrawal is a big one to look out for, so you've got to make sure that they're not using opioids within seven to ten days. And then there's a lot of other side effects within seven to ten days. And then there's the warning about hepatotoxicity. That's why we want to check the liver function too. And this could be a good choice for patients that have both opioid use disorder and benzodiazepine use because they're not getting an opioid plus benzo, or somebody who has both opioid and alcohol use disorder because this medication has been approved for treatment of alcohol use disorder. As far as evidence for oral naltrexone, there was a Cochrane review that looked at 13 studies that had over 1,100 patients, and it concluded that there hasn't been an adequate evaluation of oral naltrexone for opioid use disorder to say whether it's effective or not. But we know clinically that it's typically associated with poor adherence, and then we're concerned about overdose risk because of people losing tolerance and then resuming their use of opioids. As far as evidence for the extender release naltrexone, there was a double-blind placebo-controlled randomized study that people were randomized to a placebo or to 380 milligrams of naltrexone extender release. And those that were randomized to naltrexone had a median of 99.2% opioid-free days compared to 60.4%. And they had a greater change in their cravings. They were retained in treatment longer. And the naloxone challenge that they did during the study confirmed that 17 people in the placebo group had relapsed and became physically dependent on opioids again versus one in the naltrexone group. So what's the difference between buprenorphine and naltrexone, or what's the evidence? Well, there was a study that was done looking at buprenorphine naloxone versus extender release naltrexone. It was a Norwegian study, a randomized clinical trial, and it lasted 12 weeks. And they had almost 160 people that they randomized to getting either naltrexone injection every four weeks or buprenorphine naloxone sublingually administered daily, anywhere from 4 to 24 milligrams. And they all had to go to counseling. And they found in the study that naltrexone XR was non-inferior to buprenorphine in terms of retention, proportion of negative urine drug tests, and illicit opioid use. There was another study that was done here in the United States, and it was a 24-week study, multi-site, and it was open label, and it was randomized controlled, and a comparative effectiveness trial. And they enrolled 570 people. What they found in this study was that fewer participants were able to start the extender release naltrexone than the buprenorphine. So only 72% started naltrexone versus the 94% in the buprenorphine group. And that accounted for a greater number of relapse events by 24 weeks, fewer opioid negative urines, and fewer opioid abstinent days. As far as patients, when they said, okay, let's just look at the two groups or the people who started on either naltrexone or buprenorphine. So they successfully started their medicine. The 24-week relapse events were similar across study groups, and they also had a similar rate of opioid negative urines between the groups, and there was a similar number of opioid abstinent days. So basically, if you can get on the naltrexone, then it was shown to have similar outcome measures, but it's a hard thing to get on because you have to be abstinent for seven to 10 days from opioids. And so a lot of times people fall out of treatment during that period. So you want to match treatment to the patient needs. So I have some differences here between methadone, buprenorphine, and naltrexone. So methadone's only had an opioid treatment program at this time. And sometimes, you know, you're not going to have an OTP in your area. It's relatively inexpensive. Patients might prefer to be on this medication, but it does require quite a few trips to the OTP for observed dosing, especially at the beginning of treatment. There's no need to go through opioid withdrawal to start it. You can take it during pregnancy, and it can help with chronic pain, but it's typically just once a day. And we know that methadone is more helpful for chronic pain when it's dosed more frequently during the day. Buprenorphine can be available at an OTP or a doctor's office, and it can be costly depending on the provider, but the medication is generic, so you could get that. And insurance will pay for these visits, you know, to go and see the doctor if somebody has insurance. And it could require weekly visits to start off, you know, to go to the office, and also go to the pharmacy to pick up the medicine. You can start it with or without withdrawal, depending on the micro induction, traditional induction, or macro induction. It can be recommended to be used during pregnancy, and it can help with chronic pain too. Naltrexone, you can get this at a doctor's office or a licensed OTP as well. Medication can be quite expensive, $1,200 to $1,400, maybe even more. And it's gonna require monthly visits to the office to get the injection. And you have to go through withdrawal and abstain from opioids for seven to 10 days to start, and it's not recommended during pregnancy. Okay, so I'm gonna talk about some special circumstances for administering methadone and buprenorphine. So there's this three-day rule for acute withdrawal. And so that allows a practitioner who's not separately registered as a narcotic treatment program or a certified data waiver provider. So that all kind of went away. To administer narcotic drugs to a person for the purpose of relieving acute opioid withdrawal symptoms while arranging for the referral of treatment. So, you know, back, this was very helpful when you had to have a data waiver to prescribe buprenorphine you could administer the medicine. You could also administer methadone at a time or at once, and then they come back the next day and get another dose, or they can come back the next day and get another dose. You're not supposed to carry out this treatment for more than three days or 72 hours, and you're not supposed to renew this or extend this period. The EASY-MAT Act I'd mentioned earlier allowed for three days of medicine to be dispensed at one time though. So I could give somebody three days of buprenorphine naloxone to take home and take on their own while they're trying to get into treatment elsewhere. Now, one thing about that is that the attorney general was to revise the rule within six months, but they didn't. So in 2022, that's when the DEA said that you can apply for that waiver to be able to dispense three days of medication. As far as treatment of hospitalized patients, if you admit somebody to the hospital for another condition, like let's say they go to the psych hospital for depression or they're admitted to the medical hospital for cellulitis, you can treat their opioid use disorder or opioid withdrawal as an incidental adjunct to that medical or surgical condition other than the opioid use disorder. So you can continue them on, let's say they're on buprenorphine, you can continue them on that or on methadone, or you could start buprenorphine or you could start methadone to treat the withdrawal. And you don't have to have that data waiver anymore in general, but if you were following this rule, it said that you didn't need the data waiver anyway. And if you're gonna use methadone, you don't have to be registered as a narcotic treatment program. Now I wanna shift over to overdose and naloxone. So as far as respiration, it's principally controlled by the medulla, the respiratory center there with some peripheral input from chemoreceptors. And the control of respiration is from the dorsal respiratory group, likely produces our breathing rhythm and influences the ventral respiratory group. And that has efferent fibers that innervate muscles of respiration. So respiration can involve activation and inhibition. So the excitatory amino acids like glutamate, but also the GABA mediated inhibition. So GABA A and B receptors have a high density in both the DRG and the VRG. And the chemoreceptors are located in the carotid and aortic bodies, and they are gonna respond to changes in blood gases and be stimulated by decreases in oxygen. And they're also stimulated, but to a lesser extent to increases in CO2 and decreases in pH. So opioids can modulate respiration, deep depressed respiration by reducing glutamate induced excitation. And there can be agonist activity at the medullary or mu or delta receptors. And that's gonna decrease respiratory rate as well. So opioids can affect the tidal volume as well as the respiratory frequency. And agonism at the Kappa receptor either has no effect on respiration or can stimulate respiration slightly. And at the chemoreceptors, inhibition can be mediated by mu opioid receptor binding. And that can result in decreased sensitivity to changes in oxygen and CO2. And particularly that response to increase CO2 if somebody is not breathing. So we have these other factors that can influence overdose risk. So I already mentioned glutamate and GABA, how they mediate control of respiration. And that's explains how benzos and alcohol can contribute to overdose. So benzos and alcohol can facilitate the effect of GABA at the GABA A receptors and alcohol also decreases the excitatory effect of glutamate at the NMDA receptors. And there are individual differences in susceptibility to overdose and they can be mediated by somebody's metabolism like their glucuronidation or like the CYP3A4 and 2D6 isoenzymes. And overdose can occur when there's a loss of tolerance at both a cellular level or a pharmacokinetic level. And somebody who has a high tolerance that can also increase risk because they're gonna need to have higher and higher doses of opioids to get an effect. So they're gonna be exposing themselves to greater doses. Pulmonary edema can be a consequence of overdose and that can contribute to death as well. So we know that with overdose, there's gonna be decreased oxygenation of the brain and the heart. And so somebody becomes unresponsive, they are anoxic and they can turn blue or ashy. And then they can ultimately die. The respiratory depression itself can last like one to three hours and can be reversible with naloxone. And so naloxone I had mentioned is made in combination with buprenorphine for buprenorphine naloxone but on its own, it's used to reverse overdoses. So it's an antagonist, it has a high affinity for the mu receptor. It's gonna displace bound agonist and also prevent other agonist from binding. And it can work within minutes and it's effect lasts anywhere from 20 to 90 minutes. And it's been approved for intravenous use, sub-Q, IM or intranasal use. Typically in the community, it's gonna be used intranasally. Naloxone has been used for over 40 years in hospitals and then even since the 1990s in community settings. And it's been used in emergency departments and by paramedics also responding to overdoses for years. So here's some possible adverse effects of naloxone. So let's say somebody, you give this to somebody who's not breathing because you think maybe they overdose but they're not using any opioids, it's not an overdose. There's not gonna be adverse effects. Somebody given naloxone can have tachycardia, hypertension, hypotension. They could have a seizure but in an overdose event that could also be due to anoxia. Nausea or vomiting, diaphoresis and then other opioid withdrawal symptoms. And when they've talked about some severe symptoms in the prescribing information, those have been seen with post-op reversals of anesthesia. As far as naloxone access laws, a lot of states have enacted those since the mid-2010s and they can cover the following but it's gonna depend on the state. Civil liability for the prescriber, criminal liability. If the lay person has civil liability or criminal liability and then also pharmacists can dispense it without a patient-specific prescription from another professional. So like having a standing order and also are they authorized to give it to third parties? So can I write out a naloxone script for a mom or a dad who's using opioids? So those are the different naloxone access laws. So third-party prescribing is that last one. There are also naloxone prescription laws. So 16 states have enacted these since 2016 and that mandates or they mandate or recommend that you prescribe naloxone if you meet certain criteria. And so these are some of those criteria and you're gonna have to look at your state to see if you have a naloxone prescribing law. Prescribing opioids at or above a certain threshold. So it could be anywhere from 50 to 120 morphine milligram equivalents a day. If you're co-prescribing benzos and opioids, if they have a history of substance use disorder or opioid use disorder, history of overdose, history of mental illness, respiratory disease. The last three, the respiratory disease, chronic pain and risk of returning high opioid dose when somebody is no longer tolerant, those are less common in the laws than the other ones that I mentioned. Five states require that you educate somebody about naloxone but don't require that you prescribe it. So here's a graph of or a chart with some states that have naloxone prescription laws. So you can look for your state here but you can see that there's some that say must, they're the blue ones, must co-prescribe naloxone. And red is may co-prescribe naloxone. The green is must notify the patient about naloxone but not required to co-prescribe. And then the gray is not addressed. Now, as far as fentanyl and naloxone, it's been thought, well, do you need to have more naloxone or a higher dose to reverse fentanyl? Well, fentanyl does have a stronger affinity to the mu opioid receptor than other opioids and naloxone. And it's highly lipophilic and it rapidly equilibrates between plasma and the CSF. And so you can get a fast onset of action of the analgesia and respiratory depression. And it ends up getting essentially redistributed to less highly perfused areas. And it's typically thought to be short acting when it's given IV. However, large doses of fentanyl can prolong the duration of action because of saturation of the tissues. So do you need more naloxone with fentanyl? Well, there've been some studies looking at some data. So like in 2015, almost 25% of patients who got naloxone from EMS required more than one dose versus one in six in 2012. And that coincided with increased fentanyl in the US heroin supply. So it was a correlation there. And then another study that was conducted from 2022 to 2023 of pre-hospital administration of naloxone, four milligrams versus eight milligrams. I don't know why that changed, I'm sorry. When they're looking at four milligrams versus eight milligrams, they found no differences in survival, the number of doses received, prevalence of most post naloxone signs and symptoms, combativeness and hospital transport refusal. So somebody refusing to go. However, what they did find is that those people that received eight milligrams had a higher prevalence of signs and symptoms of opioid withdrawal than those getting four. So sometimes people are critical of naloxone thinking that people are gonna use more because they have the safety net. Well, there was a study that compared the quantity of heroin use, so the bags per day, the frequency of polysubstance use, meaning the mean number of days in the past 30 that they used several different substances, the addiction severity index, drug composite score. So that's an indicator of impairment from drug use. And so they looked at this at baseline one and three months later after they provided overdose education and naloxone. And they didn't see any increase in the number of bags per day that somebody was using or higher risk behaviors over the course of the study. So how do you select somebody for naloxone? Well, if they have a history of overdose, that's a good reason to give somebody naloxone emergency treatment for overdose or intoxication. If you suspect or know that they're using heroin or other non-medical opioids or fentanyl, they have opioid use disorder and they were recently released from a controlled environment like incarceration or a hospital or a rehab. Buprenorphine or methadone maintenance, just because they're on treatment doesn't mean that they're not at risk for using. If somebody is receiving greater than 100 milligrams of morphine equivalents in a day, changing from one opioid to another because of that incomplete cross-tolerance, if they live in a remote area or have difficulty accessing emergency services, or if somebody requests it. You also would consider somebody who's getting a prescription for opioids and they have these medical conditions like smoking, COPD, asthma, so any kind of respiratory problems. If they have renal disease, liver disease, cardiac disease, HIV, or AIDS, if they are known to be drinking heavily or you suspect that they're drinking alcohol heavily, if they're using benzos or other sedatives, if they're on an antidepressant or have a psychiatric diagnosis, or if they've recently been released from incarceration, detox, mandatory abstinence program. There is now over-the-counter naloxone available. So back in November of 2022, the FDA announced that certain naloxone products have the potential to be safe and effective for over-the-treatment counter use. And in March of 2029, the FDA approved Narcan 4 milligrams nasal spray for OTC use and it is available in stores and online. And then in July of 2023, the FDA approved a second naloxone nasal spray called Reviv, I think, or Revive for OTC use. And that's supposed to be available by 2024, early 2024. And other formulations are still available by prescription. So if you're going to prescribe naloxone and you want to prescribe the intramuscular formulation, you have to prescribe vials and syringes. And the dose is 0.4 milligrams per ml. So you would inject one milliliter and then you'd need to, it depends on the size of the vial. Sometimes it's a one milliliter vial. Sometimes it's 10 milliliters. There's also a brand name called Simhi and it's already, like it's already, all you got to do is like take off a guard and then you inject it into the person's muscle. And it's five milligrams per 0.5 milliliters. That's the concentration of the naloxone there. Intranasal is much commonly used more in the outpatient setting or community setting. So there's the brand Narcan nasal spray. It's four milligrams per 0.1 milliliter. There's the generic naloxone nasal spray. And then there's this new one that I mentioned called Revive that's supposed to be available. And then there's another one, a nasal spray called Cluxado and that's eight milligrams, 0.1. So it's a higher dose. And so if you are prescribing this to patients, it's okay to put several refills on their prescription. Last one I think that I'm going to be talking about here is Nalmethine. This was approved by the FDA in May of 2023. And this has a high binding affinity to opioid receptors and it is an antagonist. And the big difference between this and naloxone is its half-life. So 10.8 hours versus up to two hours for naloxone. And so as far as the dosing, if somebody, you come upon somebody who you don't know if they're dependent on opioids, the first dose is supposed to be 0.5 milligrams per 70 kilograms and then the second dose can be given. And then if somebody has opioid dependency, you want to give them a smaller dose because you don't want to, you want to get them breathing again if they're overdosed. You don't necessarily want them up and uncomfortable in the withdrawal. So you give them that smaller dose of 0.1 milligram per 70 kilograms. And if there's no withdrawal in two minutes, you give 0.5 and then one and so on. Now, if that dose of 1.5 milligrams total per 70 milligrams or 70 kilograms doesn't have an effect, a higher dose isn't likely to produce an effect. Now it's given IV, but it can be given sub-Q or IM if you can't get venous access. It's not for intranasal use. And it's available by prescription and it says that it's intended for use in the hospital and community settings. However, I don't know that this is that easy to use in a community setting because of all these different dosing parameters around it. So it seems easier to give a naloxone nasal spray. So here are some resources for further study, finding out more about medications for opioid use disorder in the SAMHSA tip 63. It's free, it's available online as a PDF copy. There's the clinical guidance for treating pregnant and parenting women with opioid use disorder and their infants. And this is also published by SAMHSA and available online. Then there's the SAMHSA advisory, evidence-based whole person care for pregnant people who have opioid use disorder. So it's a little bit updated. So you can see it was published in March, 2024 compared to that other guideline that I showed you. And then there's this TAP 32, clinical drug testing in primary care, another SAMHSA publication that's available free online in a PDF. Here are some additional resources. There's archived webinars on our AOAM website. So you just got to go to that education page. There's free content on PCSS Now. There's webinars that are either upcoming that you can watch or some archived ones. There's the buprenorphine waiver training that you can register for there online or live if you want to review it. And then there's also the Opioid Response Network. There's lots of educational programs there and resources as well. So that's going to be the end of the slides today. Thank you so much for your attention and good luck on your exam.

opioid use disorder

pharmacology

diagnosis

epidemiology

treatment options

commonly misused opioids

tramadol

buprenorphine

codeine

morphine

methadone

fentanyl

heroin

opioid receptors

opioid crisis