Hello, my name is Julie Kmyk, and today I'm going to be talking about methadone and opioid treatment programs as part of this review course. I'm currently an associate professor of psychiatry at the University of Pittsburgh School of Medicine, and I'm the medical director of an opioid treatment program called the Narcotic Addiction Treatment Program at UPMC. So this is a little bit of information about me. I completed a psychiatry residency at University of Pittsburgh School of Medicine, and then also did the Addiction Psychiatry Fellowship, and I've been the medical director at our ambulatory detoxification program in Bridge Clinic, as well as at our Narcotic Addiction Treatment Program, and I served as a president of AOAAM back from 2018 to 2020. I have no conflicts of interest to disclose, and here are the objectives for this lecture. At the conclusion of this activity, you should be able to cite legislation and regulations that have shaped the treatment of opioid use disorder over the past century, discuss the Dole and Eiswander study of methadone for treatment of heroin addiction, talk about some evidence for methadone, discuss current opioid treatment program regulations, and then describe the use of methadone in pregnant individuals with opioid use disorder. So I wanted to go back all the way to 1914, the Harrison Narcotic Act, you've probably heard of this. This was an attempt to carry out the International Opium Convention that occurred a few years prior to that, and this was the US's attempt to do that, and what they did is put a tax of a dollar on anybody dealing with derivatives of opium and cocaine, and they had to register annually with the tax department at that time, and what this did is it made it illegal to sell or give away derivatives of opium or cocaine without a written order form that was issued by the Commissioner of Revenue, and so people would get fined if they didn't do this, and sometimes they would get incarcerated. So people who weren't registered couldn't partake in interstate trafficking of drugs, and you couldn't possess narcotics if you hadn't registered or paid that tax. There was an exception that was made for those who were prescribed medication in good faith by a physician, and so that would be if you got prescribed an opium or some kind of other opioid derivative at that time, and if you were in violation of this act, you could spend up to five years in prison or up to $2,000 fine. So around this time, there were morphine and heroin clinics. They opened from 1912 to 1923, and by 1919, there were 44 clinics in the United States, and a lot of these opened in response to the Harrison Act and court decisions regarding the Harrison Act, because people weren't able to get over-the-counter drugs that they were able to get before that had cocaine or opium in them, and so they'd be in withdrawal, and so these heroin and morphine clinics provided maintenance or detoxification treatment for individuals with morphine. In the 1960s, there was a heroin epidemic in the United States, and then in 1961, there was a joint report that was issued by the American Medical Association and the American Bar Association that was questioning the drug policies of the United States and encouraged research on opioid maintenance. So in 1965, Vincent Dole and Maureen Eiswander published a research study in JAMA, and they both were working at the Rockefeller Institute in New York, and what they thought was that addiction was a disease, and it wasn't because somebody had weak character, and they thought that once somebody becomes addicted to heroin, there's going to be some changes in the brain that lead to craving and relapse, and they thought that methadone should be an effective medication to treat people who are addicted to heroin because it would block the euphoric effects by sitting on that opioid receptor and then prevent withdrawal and craving. Maureen Eiswander became familiar with methadone when she was working at the narcotic farm in Lexington, Kentucky. So in this study, they enrolled 22 patients. They were all men, and they were from 19 to 37 years old, and they all had addiction to heroin, and they had no other substantial addictions, and they didn't have any kind of psychosis, and they had already gone through other treatment with withdrawal and had relapsed and started using again, and so what they found is that once they started giving people methadone, they saw that there was a disappearance of what they called narcotic hunger, which is cravings or urges to use, and people could resist using drugs. They were able to better tolerate frustration. They stopped dreaming about drugs and largely stopped talking about drugs as well. There were four of those subjects that injected heroin while they were taking methadone, and they reported that they didn't feel the high that they normally would have, and they found that the subjects in the study were functioning at work and at school normally. The main adverse effects were sweating and constipation. The medication, though, was well-tolerated, and only two patients were discharged from this study. So after this study was published, a lot of clinics opened up in response. So what had to happen at that time is that the FDA had to issue these investigational new drug forms for methadone research, so clinics would open up and say that they're going to be conducting methadone research, and so they requested an IND, and so a lot of clinics opened up, and people started going and getting on methadone. So in 1968, there were fewer than 400 people that were enrolled in methadone maintenance programs. However, that was only a few years after that Dolan Isander study was published. And then in 1970, methadone became approved by the FDA for detoxification treatment, and then in 1973, it was approved for maintenance treatment of opioid use disorder. And then in 1973, there were 73,000 people who were enrolled in methadone maintenance treatment. So that was from 400 to at least 73,000 in five years. Now, there were several criticisms regarding methadone treatment, pretty much the same things that we hear today. There was the claim that people were just getting addicted to opioids by being prescribed methadone, methadone was being diverted, and children were getting poisoned from methadone that was being taken home. So a bunch of regulations and laws were passed over the subsequent years. So in 1971, some federal regulations became in effect, so the FDA issued these regulations for those INDs, and so they had strict requirements on the starting dosage of methadone, how often somebody would do urinalysis for urine drug testing, and recommendations for discharge. They also defined what efficacious treatment would look like. Then in 1972, some other regulations were put forward, and they said at that time, methadone for treatment of opioid addiction can only be dispensed by federally licensed programs. So that's where that all started. And you had to check for dual enrollment, so you can't be enrolled in a clinic on the north side of town and then on the east side of town, for example. So you had to be checking to make sure that people weren't enrolled in other programs. And then the eligibility for treatment was based on age and the length of addiction to opioids. They also set a maximum initial dose, and then also set up how much counseling somebody had to do at a minimum. And they had some very specific criteria for when people could take home doses of methadone to take unobserved. So they depended on the results of drug testing, the length of time in treatment, and they also had to have a dose that was less than 100 milligrams. So these regulations were really criticized as burdensome, and just an interference to the practice of medicine. There was no other drug, and there isn't really any other drug where the government tells you when you can prescribe it, to whom you can prescribe it, how much, what dose, and when people can take it, have medication to take home. And methadone can also be, besides the federal regulations, states can have regulations too that impact opioid treatment programs, as well as there could be some local regulations. At our program, we were accredited by the Joint Commission, so we have to do what they say to keep our accreditation. And we also get visited by our Department of Drug and Alcohol Programs from the state. We also have payers who are interested in what we're doing. So there's a lot of people that have their hands in, and this started probably back in the 1970s. And basically, you know, all these regulations end up being a departure from allowing physicians to use their professional judgment when making decisions about methadone. So the Narcotic Addict Treatment Act of 1974 was passed, and this was after some Senate and House hearings were held in 1972 and 1973 regarding diversion. And in this law, they amended the Controlled Substances Act of 1970. They also defined what maintenance and detoxification periods look like. They required a separate DEA registration annually for practitioners. And then they also stated that treatment privileges could be revoked if somebody wasn't complying with the standards of treatment. So there have been some changes since 1974. In 1980, one of the first changes was that they changed that period of dependence that somebody had to have from two years to one year. So you have to have like this opioid use disorder for at least one year to be able to get on methadone, whereas before it had been up to two years. And they also, in the 1980s, said that you can use procedures other than urine toxicology for toxicology testing, so oral swabs. They also expanded counseling for pregnant women. And then in 1993, the concept of interim maintenance treatment was allowed. So if a clinic has a waiting list, it can provide methadone to people who are on this waiting list, and those people don't have to partake in the counseling or meet the other requirements of the clinic. And that was in response to HIV. And then in 2001, there was a final rule that repealed existing narcotic treatment regulations that were enforced by the FDA. They created a new regulatory system based on an accreditation model, and that's why I was talking about how we're accredited by the Joint Commission. And then the oversight shifted to SAMHSA Center for Substance Abuse Treatment, so SAMHSA CSAT. So I mentioned a little bit about oversight of opioid treatment programs, so it's multilateral. And so we have SAMHSA, there's the states that oversee us too, so the State Opioid Treatment Authorities, or they'll call them the SOTAs, and then there's the Department of Health and Human Services, then there's the Department of Justice and the DEA. So there have been some changes that have occurred in this past year, actually just in early 2024, but I wanted to go over what treatment looked like in the past, because I'm not sure what you need to know for this exam. So I just want to go over some of the old criteria. So before COVID, people would automatically get one take-home dose for the day that the clinic is closed. So let's say the clinic is closed on Sundays, people would automatically get a dose of methadone on Saturday that they could take on Sunday. Or if they're closed on a state or federal holiday, they'd get a bottle of methadone to take on that holiday. To get further unsupervised doses or take-home doses, people had to be abstinent from drugs and alcohol, they had to be regularly attending the clinic, they couldn't have any kind of behavioral problems at the clinic, they weren't supposed to be engaging in any criminal activity, they had to have stable home environment and relationships, they had to have an acceptable time in maintenance treatment, so there was some standards for how long somebody was in treatment before they could get take-home bottles, they had to ensure that they were able to safely store the methadone, and they had to say that the rehabilitative benefit of the take-home doses outweighed the risk of diversion. So I mentioned about time and treatment. So the number of take-home doses was based on the time in continuous treatment, meaning when somebody started, they couldn't stop and drop out of treatment for a month and then come back and get the same take-home, it had to be continuous, so if you're out of treatment and you get discharged from the program, then your time in treatment starts all over again. So the first 90 days, you could get one earned dose per week, so that was in addition to that one day if the clinic was closed. And after three to six months, you could get, oh actually let me go back, for that zero to 90s, you could get that one dose automatically and then one earned dose per week. At three to six months, you could get two doses per week, six to nine months, three doses per week, and then nine to 12 months, six doses per week. After one year of treatment, you could get two, you have to come to the clinic twice, so you'd get 14 doses per month. And then after two years of treatment, you could get monthly take-home, so you'd come to clinic once per month. Now one of the things about that, the take-homes too, was that if you're in this, what they call short-term detoxification, you couldn't get take-homes for that. And usually that, those people, people would be in short-term detoxification coming off of methadone, or they'd enter the program and maybe they only get to 40 or 50 milligrams, and then they start tapering down over the course of like three months. So this COVID really changed things, and there were some changes that were issued basically on March 16th. And since then, things haven't been the same within methadone in terms of take-home doses, SAMHSA continued to have some suspension of regulations, and a lot of states also continued to suspend their regulations, and then SAMHSA rewrote the rules regarding methadone. So we'll go over that in a minute. But on March 16th, 2020, SAMHSA said states can request blanket exceptions for all stable patients at an opioid treatment program to receive 28 days of take-home doses of the medication for opioid use disorder, and a state can request up to 14 days of take-home medication for those who are less stable, but the OTP believes can handle it safely. Then in November of 2021, they extended those take-home flexibilities for a year, which would be effective upon the eventual expiration of the COVID-19 public health emergency. Then in April of 2023, they issued revised guidance on these take-homes. So before, you can see it was like stable and less stable, that's not very specific. They had a little bit more specific about what stable and less stable would look like or what you should be looking for, but what they said here too was that the suspension of those regulations or those take-home flexibilities, they're going to be effective until one year from the end of the public health emergency, and you probably remember that the public health emergency expired on May 11th of 2023. So SAMHSA had a year to get new regulations or new rules written to be effective before that deadline of May 11th, 2024, and they were able to do it. They published new rules on February 2nd, 2024, and they became effective on April 2nd, 2024. So this is that revised guidance regarding the take-home exemptions from April of 2023, and this basically has gone forward in these new rules that SAMHSA published back in February. So they said that you could offer an exemption from unsupervised take-home medication requirements of 42 CFR Part 8 if the state concurred with it. So this allowed an opioid treatment program to provide unsupervised take-home doses of methadone according to revised time and treatment standards. So what they said is in the first 14 days, you can get up to seven unsupervised take-home doses of methadone, and so just to illustrate that for you, let's say somebody started on August, now that would have been July 31st, and you see this calendar is August 2023, and so their first day in treatment is on the 31st. They could get seven take-home doses in the first two weeks, so I just highlighted them with yellow so you can see one, two, three, four, five, six, seven, that would be a way that somebody could do it to start on methadone in the first two weeks. And then treatment days 15 through 30, they could get up to 14 unsupervised take-home doses, and so I highlighted up to 14 days, actually, I think it's only like 13, and then after 31 days in treatment, they said that you could give up to 28 unsupervised take-home doses of methadone. Now in making these decisions, you have to use your clinical judgment and consider the following. The first thing is that the therapeutic benefit of unsupervised doses outweighs the risks. And then you have to also consider absence of active substance use disorders, as well as other physical or behavioral health conditions that can increase the risk of patient harm as it relates to the risk of overdose or the ability to function safely. So if somebody has an active substance use disorder and giving them unsupervised doses you deem unsafe, then you don't have to give people up to seven doses in that first two weeks or, you know, up to 28 doses after 31 days. They should be regularly attending for supervised medication administration, so they shouldn't just be coming here and there to get methadone doses. They're supposed to not have any kind of serious behavioral problems that are going to endanger themselves, the public, or others. There should be an absence of known recent diversion activity, and they have to be able to safely transport and store the medication. And any other criteria that the medical director or practitioner at the clinic considers relevant to the patient's safety and the public's health can be considered here. And when you are ordering these take-homes, you need to document this in the patient's medical record. So my thought is, you know, when somebody just starts at the clinic, it's hard to know a lot of these things. So on day one, it's hard to know, I mean, most people have an active substance use disorder when they're starting out on methadone. Some people do transfer into the clinic and they're stable on methadone, but a lot of times they're not. It's hard to know, you know, if there's any kind of behavioral health conditions that could increase the risk of patient harm. Of course, when somebody comes into the clinic, you're going to want to do a risk assessment. You're going to be doing a physical to make sure that their health is good to be started on methadone. But also at the beginning of treatment, you know, on day one, you don't have any kind of regularity of attendance basically that you're talking about. And then also it's hard to know about known recent diversion activity if they've never been given methadone. So these are all things that you can consider when ordering take-home doses. And those, I should mention that those things carry through in these new rules. So that it's all verbatim as what it said in April of 2023. Now, let's say that you do have somebody getting take-home doses of methadone and something happens. Let's say they come to the clinic and say, oh, my methadone was stolen or I drank too much of it and I ran out of it earlier. Then a lot of times we're going to have patients come back to the clinic for supervised dosing on a more frequent basis. So if there's any kind of concerns about safety to the patient or the public, you can have them come back in more regularly. And so the things that you can consider would be active substance use disorder that can increase the risk of overdose, presenting intoxicated to the clinic, concerns about their physical or mental health, if they lose their dose, if they lose their doses of methadone or they divert their doses of methadone, they're not taking it as prescribed. And then this reinstatement of take-home privileges that can differ based on your state regulations as well as your clinic policy. There's nothing written in the federal rules about reinstatement of these. It's going to be on clinical judgment. So when SAMHSA went through and they put out a notice for public comment about proposed new rules for methadone, they cited the following research that was done during the pandemic when they constructed those rules. First thing was that patients felt more respected as responsible individuals by being given these extra take-home doses. Providers also appreciated the ability to engage in the medical decision-making instead of just this formula that was laid out before by the federal and state government. They also found that diversion of methadone was low among patients who got take-home doses under the COVID flexibility. And data on fatal overdoses from January of 2019 to August 2021 showed no increases in deaths involving methadone during that flexibility. So there've been some other public health emergency changes that related to methadone regarding the initial history and physical. So when the public health emergency was announced and SAMHSA put out announcements about these take-home flexibilities, they also talked about the use of telemedicine. So use of phone or video for buprenorphine starts and for follow-ups for methadone patients at opioid treatment programs. So during the pandemic, people could get started on methadone. They still had to have that in-person visit. They had to have a history and physical that was done by a physician or advanced practice provider at the clinic. Buprenorphine, however, you could start that by telemedicine or telephone. And SAMHSA said that this flexibility will continue for one year after the end of the public health emergency. And the new rules that were published back on February 2nd, 2024, and became into effect on April 2nd, 2024, allow for telemedicine, a video visit for the methadone HMP. So if you think that you can safely determine a patient's safety for starting methadone by doing a telemedicine visit, you're allowed to do that now. It doesn't have to be in-person at the clinic. You can't use phone only though. And you probably remember that the DEA proposed some changes to begin at the end of the public health emergency that rolled back telehealth. And so then there was a public outcry about this. And so in May, 2023, the telehealth flexibilities for controlled substances, specifically with buprenorphine, those were extended to November 11th, 2023. And then in October, 2023, the DEA announced that the flexibilities are gonna remain in place until the end of 2024. And that gives the DEA time to rewrite regulations. So right now you can still prescribe buprenorphine by telephone or by video. And depending on your state regulations, you can start people on, you might be able to start people on methadone using video visits only. Right now, our state still has their old regulations in place. They're supposedly rewriting them. So right now we're still going by the more restrictive, which is our state regulations, which say that patients have to be seen in person. So I wanted to mention too, that opioid treatment programs, they do provide other medications for opioid use disorders, not all methadone. This was done as a survey of opioid treatment programs that was done back in September of 2023. And you can see overwhelmingly opioid treatment programs provide methadone, but they also do provide buprenorphine for opioid use disorder, as well as naltrexone. And so that's why those telehealth rules for opioid treatment programs are important to involving buprenorphine. As far as evidence for buprenorphine telehealth, there's no significant difference that has been found between telehealth and in-person buprenorphine induction in the following, rate of continued substance use, retention and treatment or engagement and services, ratings from clients and providers regarding the therapeutic alliance. And what they found too, is that telehealth has increased access to buprenorphine for opioid use disorder during the pandemic and wasn't associated with an increased proportion of overdose deaths involving buprenorphine. So just like they mentioned that there wasn't an increase in deaths involving methadone with these increased take-home flexibilities, with telehealth and buprenorphine, there weren't an increased number of deaths involving buprenorphine. So this is a map of the states and if they concurred with the SAMHSA flexibilities. And so if they were green, that meant that they concurred with both the flexibility of increased take-home doses, as well as using telehealth for starting people on buprenorphine and opioid treatment programs. If they're blue, they only concurred with the flexibility regarding take-home doses of methadone. And if they were red, they only concurred with the flexibility for opioid treatment programs starting buprenorphine through telehealth. And then the purple ones, they don't concur with either flexibility. So they don't have those extended take-home flexibilities and they're not allowing telehealth for buprenorphine starts with the purple. And then you can see the gray states, they didn't respond. And then not applicable is Wyoming because they don't have a methadone or an opioid treatment program. And back in 2023, there were 2,023 opioid treatment programs. So these are the revised 42 CFR Part 8 regulations. So the final rule, here are some highlights. They supported a more patient-centered approach. They have that updated criteria for the provision of methadone take-home doses. They promote shared decision-making. They added evidence-based delivery models of care like split dosing of methadone, telehealth, as well as providing harm reduction at the program. They reduced barriers to receiving care. So admission criteria, you just have to have a diagnosis of opioid use disorder. You don't have to have that time requirement. So you don't have to wait a whole year before you get on methadone. They also increased the time allowed for interim treatment. So that interim treatment was, let's say there's a waiting list. So it was from 120 days, now it's 180 days. So about six months. They also removed stigmatizing and outdated language throughout the rule. They're not using terms like detoxification. They're not using terms like MAT. Instead, they're using withdrawal management or medications for opioid use disorder. They also defined procedures for mobile units. So a methadone clinic could have a van that goes out into a remote part that administers methadone out in another community. So they defined procedures for that. And they also modified and updated certain provisions of accreditation and certification of OTPs. So I mentioned the federal criteria. Before April 2nd, 2024, you had to have that one year history of opioid use disorder. There were some exceptions for pregnant women, people who were released from correctional facilities within the last six months who had opioid use disorder and people who were previously treated at the clinic for up to two years after discharge, they could be readmitted. So this is no more, unless your state is restrictive like this. What the new federal rules say is that you just have to have a diagnosis of opioid use disorder. Now, also before they said that if somebody is under 18 years of age, they have to undergo detox or psychosocial treatment twice within the last 12 months and the parents must consent in writing. So that has changed as well. So if somebody is under 18, they don't have to attempt other treatment first. They don't have to go through withdrawal management or go to a rehab or anything like that, but they still do need a parent or guardian to consent. And then you can use telehealth if they have both audio and visual in real time for screening medical examination and consent can be provided verbally or electronically. The medical exam can be done at the OTP or by an outside practitioner with some limitations. So let's say somebody goes to see their primary care doctor and they do a physical exam and that can get forwarded over to the OTP, that might be okay. And then also there's always a recommendation of doing labs upon intake. So you can use labs that were done 30 days before or up to 14 days after somebody started treatment at the clinic. But also keep in mind that the patient does have autonomy and they can refuse labs and refusal of labs shouldn't preclude their treatment at the clinic unless there is some potential for this negatively impacting their treatment with medication. Now, OTPs are expected to either deliver additional services or have some kind of a partnership basically with offsite agencies where they can refer people to. So OTPs are expected to do a medical assessment and treatment, but you might have a clinic in town that you refer to people for if they have some kind of acute medical problem or acute psychiatric problem that you're not able to treat up the OTP. Counseling, a lot of times clinics are offering counseling in-house. It depends on state regulations as well. Vocational rehab might be offered in the clinic or you might refer out educational resources in the clinic or refer out as well as employment services. And one of the things too that was said by SAMHSA is that continuing on medication is not contingent on involvement in counseling. So let's say somebody is not doing the counseling, you can't say, okay, well, we're going to discharge you from treatment because you're not adhering to the counseling. That's not recommended anymore. Before I know patients would often, if they weren't participating in counseling, they could be discharged because they weren't adhering with their treatment plan. Now states could still be more restrictive than these federal regulations, or they could be changing their regulations to align with these new federal rules. We just have to wait and see. Now clinics have to engage in diversion control measures, and this often includes some kind of toxicology testing, so urine or oral fluids. And the federal government says that you have to do this with eight times a year, at least. Usually clinics are also doing what we call a 24-hour callback. So we'd call the patient up and say, hey, we want you to come in tomorrow, bring all your medication with you, and we're going to make sure to inspect it and make sure that you're taking it as prescribed. So the patient comes in, they bring their lockbox, which contains their bottles of methadone. Nurse will go and they'll look at the bottles, make sure that the color is consistent, the amount in the bottles is consistent, it hasn't been opened, and then the person would have, probably would have either urine or oral fluid toxicology done that day too. Another diversion control method is to check the PDMP. Also patients should be transporting and storing their medication in a lockbox, and supervised dosing is one of the last measures that we have. So clinics can remain open seven days a week or refer patients to another clinic for dosing when the clinic is closed, if they don't think that the patient can safely handle the methadone, or if they don't think that they can handle the methadone, or if they have a history of diverting it, or there's concerns about that. I've mentioned a little bit about toxicology testing already. It is part of that diversion control plan, and typically it's gonna be urine or oral fluid testing, and the federal regulations say that you have to do it at least eight times a year. States can be more frequent, so in Pennsylvania, they require monthly, and then you should be screening for the presence of methadone and metabolite. Now methadone is a synthetic opioid, so you have to test for it specifically. It's not gonna trigger a positive for opiates, and you should also test for other drugs that are prevalent in the area, so things like oxycodone, fentanyl, cocaine, benzodiazepines, methamphetamine, et cetera. Okay, I wanted to talk a little bit more about methadone and some of the pharmacology now that we went through a lot of these regs. So when methadone's been studied before, it's been repeatedly shown over the past 40-some years to decrease opioid and injection drug use, reduce transmission of hepatitis C and HIV, also reduces infections like cellulitis. There's often a decrease in criminal behavior when people engage in treatment. It's been shown to retain people in treatment, decrease overdose-related deaths, reduce sexual risk behaviors, and also improve people's physical and mental health as well as their social functioning when they're engaged in treatment. Methadone is listed as an essential medication by the World Health Organization. So methadone, when it's used for treatment of opioid use disorder, it's gonna be dispensed at a licensed opioid treatment program. It's typically liquid formulation. Less frequently, it might be a diskette or a tablet, and it may not show in the PDMP because it's administered, not prescribed, and also due to the confidentiality regulations of drug and alcohol treatment. Now, there were some changes a few years back to 42 CFR Part 2, and this may have changed, and some methadone might be in some PDMPs in some states. It's not listed in the PDMPs in Pennsylvania when somebody's getting it from an opioid treatment program. The aims of treatment are to alleviate withdrawal symptoms, block the euphoric effects of self-administered opioids, and eliminate cravings for opioids. Now, historically, an effective dose has been anywhere from 80 to 120 milligrams, but we're seeing higher doses with fentanyl. We have people at the clinic who are, you know, our curve, our normal curve has shifted over to the right, basically. You know, we have people in the high 100s, 200s, in terms of methadone. I know in some other states, people might have people on up to like 300 milligrams. But the effective dose, at an effective dose, people should still be able to function. They shouldn't have any kind of impairment of their physical or emotional responses. And as far as monitoring, we're not usually checking serum methadone levels to see if a dose is therapeutic. So it's not like a lithium level, for example. We might check the peak in the trough to see if somebody is a rapid metabolizer. So if the trough, or if the peak's two times greater than the trough level, we assume that they're a rapid metabolizer from that result. And we do monitor with ECGs for prolonged QTC. And I'll talk a little bit more about that later. So methadone is a fulminant opioid agonist, and it's also an agonist at the delta receptor. It's an antagonist at the NMDA receptor. And the NMDA system is involved in opioid tolerance and neuropathic pain. So that's why, with that opioid tolerance, why we don't necessarily have to go up and up on the dose over time. Methadone's about 85% bioavailable when somebody takes it orally. There is a range of anywhere from 67 to 95%. It reaches peak plasma levels after about two and a half to three hours. Now it's gonna be faster if it's solution versus tablets. And it's typically dosed once a day, except for when somebody is a rapid metabolizer or in pregnancy. And in pregnancy, metabolism speeds up, and we'll be talking about that later on. As far as pharmacokinetics, about 60 to 90% of methadone is plasma protein bound in the bloodstream. And it's predominantly with this alpha-1 acid glycoprotein or AGP. Now the thing about AGP is it's an acute phase reactive protein, and it can increase with stress, cancer, and opioid abstinence. So when somebody is going through opioid withdrawal, they can have higher levels of this AGP. And that can help decrease the toxic effect of methadone in people who have opioid use disorder. More methadone is gonna be protein bound than somebody who doesn't have an opioid use disorder. Methadone is pretty lipophilic as well. It has a really large volume of distribution and high tissue binding affinity. And so it's gonna accumulate in the fat tissue and be continuously released. And it can cause toxicity after repeated dosing. So that's why we have like careful protocols for getting people started on methadone. The half-life is typically 24 to 36 hours, but that range could be as wide as 8 to 120 hours, depending on the amount of adipose tissue that somebody has. Methadone is primarily metabolized by the CYP3A4 isoenzyme, but also 2D6, 1A2, 2C19, 2B6. Sometimes people have genetic polymorphisms of some of these isoenzymes, and that can account in variations in their metabolism. Methadone is going to undergo N-demethylation to its inactive metabolites, so it's going to go to EDDP, and that's what we often look for in the drug test, as well as EMDP. It also has two minor active metabolites, methadol and normethadol, and those are produced in small amounts. So, one thing about CYP3A4, it's auto-inducible, and so methadone can induce its own metabolism. We often hear about that with, like, carbamazepine, but methadone can be like that as well. And then tobacco use can increase metabolism as well by inducing 1A2, so that's something to keep in mind. Let's say somebody is a heavy smoker, and then they quit smoking, then they might have a little bit of sedation because they're no longer using tobacco. And there can be some drug-drug interactions that increase or decrease the methadone level, so there's some inducers that are going to induce the metabolism of methadone, so it's going to mean that they're going to have a decreased level. So, be careful when you're using things like phenobarbital, phenytoin, carbamazepine, rifampin, St. John's wort, dexamethasone, to name a few. As far as inhibitors, which might increase the level, we've got SSRIs, diazepam, macrolide antibiotics, grapefruit juice, cuticonazole, and verapamil. Now, in my clinical experience, I work on our inpatient withdrawal management unit, where we often use phenobarbital for withdrawal management for alcohol or benzodiazepines, and a lot of times we have people who come in who are on methadone maintenance, and they're coming off of alcohol or benzos, and we'll use that phenobarbital, and I haven't seen it induce withdrawal, opioid withdrawal, in those individuals, but it is something that, you know, has been written about in the literature, and a theoretical, at least. As far as elimination, it's biphasically eliminated, so there's alpha elimination, and that lasts 8 to 12 hours, and that can correspond with analgesia effect of methadone. Typically lasts for about 6 to 8 hours. Beta elimination is anywhere from 30 to 60 hours, and so that means that methadone is going to be long enough to prevent withdrawal, and that's why we do once-daily dosing of methadone typically. Methadone is largely excreted in the feces. It does get renally excreted to a much lesser extent, but we do measure, like, those inactive metabolites in the urine when we're checking urine drug testing. So, the renal excretion of unchanged methadone depends on the dose, the metabolism of an individual, as well as the pH. So, if somebody's got a pH that's higher than 6, the renal clearance is about 4% of drug elimination, and when the pH is less than 6, unchanged methadone is excreted, is about 30% of the dose. Now, renal excretion of the primary metabolite EDDP isn't pH dependent, so it's going to be coming out regardless of what the pH is, and so that's what I mentioned is tested in urine toxicology testing, and methadone doesn't accumulate in people with renal failure, and it's poorly removed by hemodialysis. So, people can be on methadone and have good maintenance with this medication, even if they have kidney failure or are on hemodialysis. As far as special populations, so let's say you have somebody with hepatic impairment. The half-life of methadone is likely increased, so use some caution. If somebody has renal impairment, you can dose them as you would with a patient who has normal kidney function, just using normal precautions. If somebody has respiratory disease, use some caution, especially if they have COPD or asthma due to the potential for respiratory depression. If somebody has increased intracranial pressure, use caution because methadone can increase that intracranial pressure. I wanted to talk a little bit about benzodiazepines and methadone. So, benzos can potentiate the rewarding and reinforcing effects of methadone or other opioids, as you know. There was a survey that was done of 191 people who were on methadone, and it found that 90 or 47 percent had a history of using benzos. And almost 46 percent responded that they used the benzos for their euphoric effects. And the six-month prevalence of benzo use among people taking methadone in different cities was a little bit different. So you can see Baltimore was about 66 percent, Philadelphia 53 percent, and New York City about 44 percent. And in people who regularly used benzodiazepines, what they found is that they received higher daily methadone doses, and they also used alcohol more frequently. Now, when somebody does use benzos plus methadone, it's associated with poorer general health, injury, accidental death, legal problems, as well as increased alcohol use. So just be cautious about this. Benzos have been identified in anywhere from 40 to 80 percent of methadone-related deaths. So let's say you want to start somebody on methadone. So we'll talk about the induction period. So induction is usually considered weeks one or two. And this is from these recommendations are from a panel on guidelines about starting methadone. And you can see some of this is from tip 63. But on another slide, I think I'm going to have some information about the clinical guidance, where this came from, the reference, and I'll point that out when I get to it. But anyway, when you start somebody on methadone, typically they're not going to be started on higher than 30 milligrams on day one. Now, that has changed with the new rules. Federally, you can start somebody on a higher dose. You just have to document. And then after two to four hours, you can reassess somebody. And if they're still withdrawing, you can give them an additional five to 10 milligrams and then document that. And so the old regulation said no higher than 40 milligrams on day one. Now, this new rule says that you can give up to 50 milligrams on day one or more if indicated and documented. Now, one thing to keep in mind is that it's going to take three to seven days to reach steady state. So dose changes typically should reflect this time period. And what has been recommended is increasing by five milligrams every five days. Now, there have been some commentary out there saying we need to be more aggressive in the age of fentanyl and increase doses by like 10 milligrams and maybe even more quickly than every five days, like maybe every other day or every three days. One thing to keep in mind, too, is not to use these equal analgesic dose tables to calculate the dose because they're not going to account for the effect of methadone that accumulates in the adipose tissue before the steady state is released. So you can't, you know, if somebody is on oxycodone, you shouldn't just go to a table and then transfer them to that equivalent dose of methadone. And it's hard to use this to have any kind of idea of how much fentanyl somebody is using when they're using fentanyl off the street because they could be adulterated with other substances. So it's hard to know how many milligrams of pure fentanyl somebody is getting or... So as far as induction risks, the greatest risk of overdose death is during induction. So some research studies before have found that 42% of clinic deaths occur during those first two weeks. And some research out of Australia done back in 1996 found that there were about 10,000 people who started on methadone and seven died in that first week. So that overall mortality rate was 7.1 per 10,000 inductions, basically. The risk of death increases with starting with an increased dose as well as with sedative use. And sedatives can be benzodiazepines, but it could also be things like alcohol. It could be also other opioids or it could be some other heavily sedating drugs like antipsychotics. Now, a meta-analysis found almost a twofold increase in mortality in the first four weeks of treatment compared to the remainder of time in treatment. So it is these first four weeks where it's more dangerous than later on in treatment. So this is an illustration about the plasma methadone concentration and how it builds over time. So what you can think of is somebody's starting out, they haven't had any methadone, so we're at time zero, they get their dose and it's going to rise and peak at about four hours and then it's going to start declining over the 24 hours and then they're going to get another dose and then it's going to start declining over the 24 hours and then they're going to get another dose the next day. Typically around this, you know, maybe they're going to dose at hour 25 or something, but this is just showing them coming at the same time the next day and then they're going to have another peak and it's accumulating because of this longer half-life. Then it's dropping down and then at 48 hours, so two days into treatment, they come back, they get another dose and then you get another peak and then it's slowly dropping down, but you can see that overall the slope of this line would be increasing. So during the first few days of treatment, the methadone is going to bind to plasma proteins as well as tissues and the blood levels are going to equilibrate with those tissue stores and then the half-life extends from anywhere from 13 to 47 hours. So we move on from induction to early stabilization and that's weeks three to four and patients are given the same dose for three to four consecutive days with no missed doses before the dose is increased. So patients, it's really important for them to come if they're only coming every other day and not dosing on, you know, every other day, that's hard to get stabilized on that, on that medication. So once tolerance is demonstrated and the patient's dosing regularly, you can increase the dose by five to 10 milligrams, assessing every three to five days if they need a dose increase. So maybe after two weeks, start going up by 10 milligrams, but again, people have been calling for more aggressive dose increases because of fentanyl. So maybe not doing five milligram increases, be more aggressive and get people onto a stable dose by doing 10 milligrams. As far as absences, if somebody misses dosing and they missed consecutively, that's going to prevent the tissue stores of methadone and then it's going to be difficult to evaluate the effect of the dose. So if somebody has only come in every once in a while, getting higher doses isn't necessarily going to help take care of the problem. They should, you know, start taking it every day and then protracted absences. So let's say somebody's missed three or four doses in a row, that's going to make that regular dose unsafe and you need to reevaluate that dose after somebody misses like three consecutive doses in a row. One thing too that the federal rules state is that you should avoid standing orders and automatic dose titrations. This should be individualized to the patient. They need to be assessed for sedation or intoxication with the medication before, you know, just not putting in their increased methadone by 10 milligrams every three days until they reach 120. That's something you shouldn't do. You should be seeing the patient or have somebody having eyes on the clinic like or eyes on the patient who works at the clinic like a nurse and assessing the patient for sedation. Now the late stabilization takes place from week five and beyond and patients can continue on the same dose for years, which I mentioned earlier about that and MDA function. As far as stable patients, they sometimes when somebody stabilizes, there are a lot of things in their life has changed. They find that they don't have to be on the same dose. They might want to come down on their dose a little bit and they want to see how they're doing. So usually if somebody wants to reduce their dose and they're stable on methadone, we'll do that cautiously. They can put in for like a one-time dose decrease, or maybe they'll put in that they want to decrease by a milligram every week. That's okay to do. You can't do those upward titrations, but the patient has control over their dose for the most part. If they want to come down, we don't make them stay on a high dose. In terms of changes in health, sometimes people might start new medications or they might have stress or maybe a new medical condition and that can trigger cravings and withdrawal. And so later on in treatment, sometimes people do need an increased dose to block the euphoric effects of other opioids or to decrease the cravings. So let's say somebody doesn't have really any change in their health or anything like that, but they just run into somebody and they start using with them again. And now all of a sudden, if they try to stop using fentanyl because they've been using for a few weeks, they feel sick. They might need an increase in their methadone dose to take care of the withdrawal from the absence of the fentanyl. Now, sometimes too, people are using alcohol or benzodiazepines and they come to the clinic intoxicated. That's going to cause some problems because it might not be safe to give them the regular methadone dose. So you might have to give them a lower dose or hold their dose. And then that can lead to opioid cravings and then cravings can lead to use. So it ends up being pretty tricky. You may have to consider the patient's safety in terms of what else they're using besides the methadone. Now, this is an illustration of what early and late stabilization looks like. So let's say somebody, it's day 30, so this would be later stabilization. And you're looking at the plasma methadone concentration and you can see that each day they're going, there's a peak and then there's a trough, peak and a trough, but it's pretty steady along, you know, from day 30 to 36. So once those tissue and blood levels have equilibrated and the person's getting their regular daily dose, the variations in the plasma concentrations are pretty small, which you can see in this illustration. There were three patterns of methadone overdoses that were discussed in this safe methadone induction and stabilization report, that expert panel that I mentioned that gave some guidelines for dosing the induction, the early stabilization and the late stabilization phase. So here's the reference if you wanted to look further into that, it's the Baxter article from 2013. So one of those patterns of overdose is single overdose. So somebody accidentally ingests methadone, they don't have tolerance to methadone, for example, if a child gets ahold of it, or if somebody purposely ingested it and they have low tolerance or they've lost their tolerance. So they could have an overdose from one dose. There can be accumulated toxicity. So toxicity develops gradually as the dose accumulates with repeated dosing. And usually this happens because of an overly aggressive induction. So you're going up by a high amount, but remember, let's say half-life is about 24 hours, 24 hours later, there's still about half of the methadone left. And that happens on a daily basis. So let's say you go up by 20 milligrams every day, you're going to still have quite a bit of methadone left that's accumulated, and that can lead to that toxicity. And then there's also combining methadone with another CNS depressant. So using opioids plus methadone, benzos, alcohol, antidepressants, antipsychotics. And so when they looked at deaths involving methadone and another drug, benzos were most frequently reported. So let's say somebody does miss dosing. What do you do? Well, if they miss one or two dose, days of dosing, continue with the same dose typically. So if somebody comes in, maybe they had to leave town unexpectedly for a funeral and they come back after two days and they were on 120 milligrams, you can restart them or they just get their 120 milligrams. Now, if they've missed three days in a row, typically we're going to reduce the dose by 25%. If they miss four consecutive days, reduce the dose by 50% and missing five or more, typically they get reduced to 30 milligrams. I'm sure you could reduce it to like 40 milligrams and be okay as well. And then you want to be titrate to the prior dose. So get them back to their dose, hopefully as quickly as you can. So increased by 10 milligrams every three days, assuming that they resume daily dosing. So hopefully, you know, let's say somebody was on the a hundred milligrams and their dose went down to 75 milligrams because they missed three days. Then after three days of dosing, you go up to 85 milligrams after another three days, go up to 95, and then you can get back to up to a hundred after another three. So that would take nine days total. This is an illustration of what happens when somebody misses a methadone dose. So this is the day down here. So day 30, somebody remember that other graph where it was pretty stable with the peaks and the trough, and it wasn't really changing much as far as the plasma methadone concentration. So let's say they were here on day 30, they had their dose, they were in steady state basically, and then they missed day 31. They didn't come in and dose. And then so you can see that the concentration falls over that 24 to 48 hours. And so it's like about to about 50 after 24 hours. And then it's about a quarter of the peak after 48 hours. And so then they start dosing regularly again, and then you're building up that dose day after day. So to get hopefully back up to where they were with their prior dose, and then they'll be at steady state again. As far as serum levels of methadone, I mentioned that we typically aren't checking these to see if they're in a therapeutic range. The therapeutic trough levels in the literature, they do range from 150 to 600 nanograms per ml. And measuring the trough levels to guide dosing isn't standard kind of clinical practice. Now, one thing that has been largely accepted is that a peak level that's above 1000 nanograms per ml is thought to be potentially toxic. So if you are measuring like peak and trough in somebody, and you see that their peak is greater than 1000, then you might want to decrease their dose or split their dosing. So the peak in the trough, so the peak is drawn three to four hours after dosing. And then the trough should be drawn in the morning prior to dosing. So if you are going to have somebody do this test at a lab, you have to give them two lab slips, one for the trough and one for the peak. Now somebody would qualify typically for split dosing if their peak and trough ratio is two or above. Now I just wanted to kind of show you this peak and trough and that idea of the toxicity. So let's say somebody's on a high single dose, that's the red line, and you can get into that toxic level, so that greater than a thousand, and then it's going to go down slowly over the course of the day. And let's say somebody's on a single dose but it's not a very high dose, you know, they stay in this therapeutic range. But if you had somebody who was getting split dosing, you're going to have, they're going to take the methadone in the morning and then it's going to peak probably around four hours and go down. And then usually they will take the dose anywhere from eight to twelve hours later, and then you're going to get another peak. I'm sorry, they might take the dose anywhere from four to eight hours later, and then you get another peak at twelve hours, and then it's going to go slowly down. But it's going to be more in the therapeutic range, so that might be the advantage. Instead of giving somebody a high single dose, like let's say 240 milligrams of methadone, they get 120 milligrams of methadone, and then they don't get into that toxicity. There is this concept of a methadone metabolite ratio, and what that is, is the serum methadone to the metabolite, the EDDP ratio, and that, what that does is it measures the rate of conversion from methadone to that inactive metabolite. And that can reflect the phenotypic expression of how the genes coded for that CYP450 isoenzymes. And so this difference in methadone metabolism explains why there's such variability between individuals in response to their methadone dose, those half-lives ranging from anywhere from, you know, 15 hours to 60 hours, or even, remember I'd mentioned 120 hours. So, getting this lab done can be useful to determine if somebody is an ultra-rapid metabolizer, if they're extensively metabolized, or if they have intermediate metabolism or ultra-slow metabolism. This hasn't been widely used at this time, but I just wanted you to be aware of it just in case. It's not something that I've been using much in clinical practice, but if you want to learn more about it, there's some articles that are cited below about it. As far as possible adverse effects of methadone, long list here. Typically the things that I notice that don't go away usually are going to be waking, constipation, and sweating. All these other things are possible. Dry mouth, that's possible with all opioids. QT prolongation definitely can be something with methadone that we're going to talk about in a little bit. Decreased libido, as well as sexual dysfunction, and hyperprolactinemia, that's all has to, is related to hormones, as well as the amenorrhea, that we'll talk about that in a little bit too. But so, usually I'll talk to patients about possible adverse effects of methadone when, before we start the medication, so they know. But usually people tolerate it pretty well. So the first thing that I wanted to mention was this opioid-induced hypogonadism, and so that's associated with erectile dysfunction, loss of muscle mass and strength, irregular menses or amenorrhea, flushing, sweating, loss of libido, depression and anxiety, as well as low energy, and osteoporosis and fractures. And so if you remember back on this slide, a lot of possible adverse effects that are related to this opioid-induced hypogonadism. And this can happen with long-term opioids of any sort too. So if somebody's been prescribed oxycodone for the long term, they could get this. QT prolongation is something else. And so methadone has been shown, especially at doses greater than 120, to prolong the QT. And over time, while somebody's on methadone, QT can prolong as well. And the QT interval is the time between the first deflection of the QRS complex and the end of the T wave. And what that does is it represents the time in which the myocardial membrane channels are activated during depolarization, followed by the repolarization of the ventricles. And the QT is corrected for the heart rate. And so that's why we say QTC. And normal ranges are anywhere from 300 to 440 milliseconds for men and 300 to 450 milliseconds in women. And prolonged QT is defined as greater than 450 in men and greater than 460 or 470 in women. So long QT syndrome and prolonged QT is something to talk about because sometimes people have congenital long QT syndrome. That's about an incidence of 1 in 2,500 in the general population. Now, people might not even know they have this until they're exposed to a drug that prolongs the QT interval. So maybe methadone is the first time that they take a QT prolonging drug, and then you find this out. And about 10 to 15% of people with medication-induced prolonged QT have comorbid congenital long QT syndrome. They could be asymptomatic, but they can also present with palpitations, seizures, syncope, cardiac arrest, and torsades. And it's estimated that about 4% of patients with methadone exposure develop torsades. And it's generally accepted that a QTc of greater than 500 is associated with that risk of torsades. And once somebody's in torsades, that can degenerate into ventricular fibrillation and sudden cardiac death. So here's some risk factors for prolonged QT to keep in mind. So if somebody has congenital long QT syndrome, but also looking at their potassium, if it's low or they have low mag, low calcium. So these are things that can be corrected. And also bradycardia is another risk factor, use of cocaine and amphetamines. So counsel your patients about abstaining from cocaine and amphetamines. Being female, having an age more than 65 years of age, underlying cardiac conditions, sleep apnea, and hypothyroidism. And then also being on certain medications. So things like macrolide antibiotics, fluoroquinolones, antihistamines, antidepressants, antipsychotics, methadone in high doses, or when given IV. And you can look up more QT prolonging meds on this website, Credible Meds. So you should have a cardiac risk management plan at your clinic. So do a clinical assessment at the beginning of treatment, which includes what medicines are they taking? A personal and family history of either structural heart disease. So if they have, you want to find out if they have long QT syndrome in themselves or their family, sudden cardiac death, MI, or heart failure. If they have a personal history of arrhythmia or syncope, if they're on any QT prolonging meds or substances, so it could be if they're using cocaine or amphetamines, methamphetamine. And also you want to make some changes to minimize the risk. So if somebody really wants to be on methadone and they're on, let's say they're on zeprazidone, which is an antipsychotic medication that can prolong the QT. Maybe they need to change off of that zeprazidone before they start on the methadone. But you have to have this risk benefit conversation with the patient. If they have schizophrenia and are on zeprazidone and stable, they might not want to be coming off of zeprazidone and would rather stay or stay on the zeprazidone and then start buprenorphine instead because buprenorphine hasn't been shown like methadone to prolong the QT. And oftentimes if somebody has prolonged QT, they're going to switch over to buprenorphine. So if there's concerns, then you can refer them for another medication for opioid use disorder, most commonly buprenorphine, but you could also consider naltrexone. So if you have somebody who has risk factors, you should do an ECG screening within 30 days of starting methadone. You can also consider doing it for everybody on admission, but sometimes that's preventative. You don't necessarily, if you have to go outside the clinic to get the ECG, patients may or may not do it. And if that's your policy that you have to have it done, that ends up creating some problems. So maybe doing that screening for any kind of personal or family history of heart problems or any kind of unexplained syncope, and then refer up for the ECG. And then it's also recommended that you do an ECG annually and when the dose exceeds 120 milligrams a day. And you should get one done on anybody with unexplained syncope or seizures. And if their QTC falls within the range of 450 to 500, you should have a risk benefit discussion regarding starting and continuing methadone. And when it's greater than 500, consider reducing the dose, assuming that they've already started on it. Address other contributing factors. So check and see if they're hypokalemic or hypomagnesemic, correct those things. And then there's also the option of changing to buprenorphine. I've had some patients that have been on methadone and they end up having arrhythmia or, you know, they have a syncopal episode, they get EMS comms, they do a rhythm strip on them, and they find out that they were in Torsades. And then they get admitted to the hospital and then the methadone dose is decreased. And then they get changed over to buprenorphine often. I mentioned weight gain being one of those adverse effects. So while somebody is using regularly, let's say they're using fentanyl, they might not be regularly eating. Typically we see a lot of weight loss when somebody is actively using. And they can also be using other substances that suppress appetite like cocaine or methamphetamine. And chronic opioid use has been shown to be associated with increased sugar intake. And so patients on methadone have been found to have increased consumption of sugary foods. And usually sugary foods in what we have are usually, you know, pretty highly processed, also include a lot of fat. So if it's a sugary food, you know, think about things like cakes, cookies, ice cream, all have a lot of fat as well as sugar and a lot of calories. And so people can end up gaining some weight if they have increased consumption of sugary foods. And so people with and without opioid use disorder, when they looked at this in research, who are on an antagonist like naltrexone, they have less preference for sugary foods. So that's interesting. And that might explain why some of your folks are gaining some weight. They're eating more than they did when they were using as well as eating more sugary foods. Now, here's one that I hear from patients sometimes, you know, when they're citing that reasons why they don't want to get on methadone. So they'll say methadone rocks your teeth and gets into your bones. So let's talk about dental issues first. Oftentimes people who are on methadone have poor oral care or neglect. They're not going to the dentist regularly or they're going infrequently because of anxiety about going or because they don't have access to services or maybe it's been so long and they're embarrassed to go. Also methadone as well as all other opioids can cause dry mouth. And when you have dry mouth, you're at increased risk of having dental caries. We talked about that high sugar intake that happens when people are on opioids or methadone have preference for that. And so high sugar intake has also been associated with dental caries as well. They might be using other substances that cause dry mouth, marijuana, smoking, alcohol, amphetamine, methamphetamine. There's also an altered, the altered microbiome from using can cause problems with, with dental, with dentition as well. And people who are using also can have reduced immune function. So those can explain, you know, some of these dental issues that people have. And why, why, and then, you know, they get on methadone and then they start going to the dentist and find out, you know, I got these cavities and things like that. It's not necessarily, you know, the methadone that's been running their teeth. It might have been neglect of care as well as, you know, eating more sugary foods and stuff like that. Also, as far as that getting into your bones, I think sometimes that just comes from people feeling like when they're going through withdrawal, their bones hurt. They'll often say to me, so they, you know, they're like, oh, the methadone is coming out of my bones. I've heard that quite a few times, but anyway, it's been shown to be associated with lower bone mineral density. And that could be part of that endocrinopathy from chronic opioid use. So remember that opioid induced hypogonadism, it can cause lower bone mineral density. And opioids themselves, not just methadone, can inhibit osteoblast functions, or remember the osteoblasts are what build up the bone. And other comorbidities can cause decreased bone mineral density, like smoking and using alcohol. Okay. So I've got some special circumstances for administering methadone. So there's this three-day rule for acute withdrawal, and that allows a practitioner who's not separately registered as a narcotic treatment program or a certified data waiver provider to administer narcotic drugs to a patient for the purpose of relieving acute withdrawal symptoms while arranging for the referral of treatment. So one thing I should mention is that the data waiver went away with that Consolidated Appropriations Act of 2023. Okay. But so what this old three-day rule said is that you could give not more than one day's medication to a person, you administer them at one time, you're not prescribing it. And then they can come back and you can give them a dose of medication two more times, like so three days in a row or 72 hours. And it says that you're not supposed to renew or extend that. Now the Easy MAT Act of 2020 allowed for three days of medication to be dispensed at one time. So that changed this old rule. And the attorney general was supposed to revise the rule within six months, but didn't. And saying that hospitals or physicians can apply for a waiver to be able to dispense either methadone or buprenorphine three days worth at one time, instead of that administer one day at a time and have the patient come back for three days in a row. So right now, it's still in the situation where you have to apply for this waiver. Now, let's say you have somebody who gets admitted to the hospital for some other kind of medical problem. You can maintain somebody on methadone or help them go through withdrawal management with either buprenorphine or methadone as an incidental adjunct to the medical or surgical condition. So this is from some of these rules about administering methadone and buprenorphine. So let's say somebody gets admitted for a primary medical or psychiatric problem. So endocarditis, or let's say depression with suicidal ideation, they can be administered opioid agonist medications, methadone and buprenorphine to prevent the opioid withdrawal that would complicate the problem. And somebody who's admitted to the hospital for one of those problems can be maintained on their usual dose of methadone or buprenorphine. Now, there was also a change regarding jails and prisons in the new rules that were published that were effective for April 2nd. So those new methadone rules basically, and that expand the waiver of OTP certification for jails and prisons to allow for them to be able to get equitable access to treatment. So let's say if the correctional facility is registered with the DEA as a hospital or clinic, then a physician or authorized staff can administer or dispense narcotic drugs to maintain or manage the withdrawal for somebody who's an inmate there as an incidental adjunct to medical or surgical treatments other than addiction. Now, if you do have somebody that gets admitted to the hospital, and they're a patient in OTP, it's important to get a release sign because there are higher levels of confidentiality beyond HIPAA for OTPs that OTPs have to follow. And sometimes the states can be even more restrictive. So I know our state is more restrictive as well. And so you want to verify the methadone dose when they last had their dose. And remember when somebody hasn't dosed typically for like three days in a row, their dose is typically decreased due to that presumed loss of tolerance. And then you also want to make sure that they're enrolled in treatment. So you're not just, you know, giving them 120 milligrams of methadone and then say bye, and then they can't go back. They're not in that clinic anymore. So then they're going to be in withdrawal once they get discharged from the hospital. And if they aren't enrolled in treatment, then you could start working with an OTP to get them enrolled upon discharge from the hospital. And when somebody does leave the hospital, they're typically not going to be discharged with a prescription for methadone, or they're not going to be with a prescription. They're going to return to the OTP for dosing. Now, if you went back to this three-day rule, perhaps you would be able to give them three days of medication if you have applied for this waiver to be able to do it. But that's a little bit more complex. Typically, when somebody's discharged from the hospital, they're going to return to the OTP for dosing. Okay, I think this is going to be pretty much one of the last sections here. I'm going to be talking about pregnancy and methadone in people who have opioid use disorder. So since the 1970s, maintenance treatment with methadone has been the standard treatment for heroin and then later pill addiction during pregnancy and now fentanyl. The rationale for opioid-assisted treatment during pregnancy is to prevent complications of opioid use, prevent the person from going into opioid withdrawal, also encourage prenatal care, encourage treatment for addiction, reduce criminal activity that could be associated with drug use, as well as high-risk situations, and also reduce the risk of infections that are associated with drug use because all these things can affect the developing fetus. So as far as when somebody is pregnant, when they're intoxicated, they can have periods of respiratory depression, aspiration, overdose, and then that can in turn result in hypoxemia, acidosis, intrauterine growth restriction, as well as fetal demise. So that's why we don't, it's better to have somebody on a regular dose if, you know, they're at risk if they're using fentanyl on a daily basis of having these intoxication and possible overdose events during pregnancy, which can harm the developing fetus. And then also we want to prevent withdrawal because when somebody's going through withdrawal, they can experience tachycardia, hypertension, nausea, and vomiting, and in turn that can result in miscarriage, preterm labor, premature rupture of membranes, as well as intrauterine growth restriction and fetal demise. And this can be related because of the repeated exposure to the fetus, to the opioid withdrawal, or it can affect the placental function. So there are some other complications that have been listed as far as complications of opioid use disorder during pregnancy. So placental abruption, chorioamnionitis, babies born with low APGAR scores, placental insufficiency, postpartum hemorrhage, intrauterine passage of meconium, septic thrombophlebitis as well. So remember that old pregnancy class system, well, methadone was a class C drug and there isn't any kind of updated pregnancy or lactation labeling for methadone. It's known to cross the placenta and it's also secreted in low concentration into breast milk and there's no known increased birth defects if somebody is taking methadone during pregnancy. Now there can be some barriers to somebody getting on methadone during pregnancy like lack of insurance or finances to pay the treatment, lack of transportation to get to the clinic to dose on methadone, lack of childcare. So if you already got a kid at home, a lot of times you can't take the kid to clinic or to your therapy sessions. It just depends. It's a little bit more flexible with telemedicine because some people do teletherapy. And so the childcare should be, hopefully can be less of an obstacle. Sometimes the person will have a concern about how methadone is gonna affect the fetus and then have concerns about the baby going through withdrawal. They also could have concerns that Child Protective Services can get involved because they're on methadone. They don't want anybody to know that they had an opioid use disorder. And so seeking treatment would be kind of admitting that they have an opioid use disorder and then they're worried that maybe their baby can get taken away once they deliver because of being on methadone. So as far as starting methadone in pregnancy, this can be done at a clinic in an outpatient basis or it can be done inpatient. So if somebody gets admitted to the hospital, the prenatal workup can be done at the same time. That's one advantage there. And they could get hooked up with their obstetrician. As far as timing, you can start it at any trimester, but it should be done hopefully as soon as possible. You don't have to be in any kind of withdrawal to start on methadone. And longer treatment has been correlated with longer gestation and increased birth weight. That's why we wanna start it sooner than later. As far as dosing, in the hospital, people typically start 10 to 30 milligrams and then adjust from there, going up five to 10 milligrams every four to six hours to suppress withdrawal. And in the hospital, they can get on a stable methadone dose in two to three days and then they would follow up at a local opioid treatment program where dose adjustments can be made every three to five days if needed. Maybe the person comes out of the hospital and is stable and they don't need further adjustments for a while. If you're doing it as an outpatient, probably be doing a more aggressive dose titration than you would normally, I would say, but still you wanna be safe about it. And so making sure that you're not gonna have that accumulated toxicity and overly aggressive induction. As far as changes affecting methadone levels in pregnancy, what happens when somebody is pregnant is that there's an increase in plasma volume by about a liter and the blood volume increases from four to five liters. And then so you're gonna have lower serum methadone concentrations because of its dilution. There's also gonna be an increase in metabolism and renal clearance. And then once somebody delivers and they're postpartum, the trough of the methadone level is gonna increase and renal clearance decreases because that metabolism is gonna go back to what it used to be. The plasma volume is gonna decrease and their renal clearance is gonna decrease. So you have to be careful once somebody delivers and probably reduce their methadone dose if they went up on it during pregnancy. So during that mother study, the study that was looking at having women be started on methadone or buprenorphine and comparing the maternal and fetal outcomes published in the New England Journal back in 2010. So what they found in there when they looked at the data closely and did some secondary analysis was that some individuals need dose increases during pregnancy and the average dose increases during pregnancy found the following. So a five to 10 milligram dose increase is what they looked at. And during the first trimester, 0.1 was the average number of dose increases. So not that many people or not that much of an increase during that first trimester. And then in the second trimester, it was 1.2 average number of those dose increases. So somebody might've gone up by five to 10 milligrams. And then during the third trimester, 1.5 was the average number of dose increases that somebody went up. So they might've gone up, let's say they were getting 10 milligram increments, they might've gone up by 15 milligrams during that third trimester. Another study called the PROMIS study looked at those average number of five to 10 milligram dose increases. And during pregnancy, they found it was a total of 3.7. So they didn't divide it out by trimester. And some people might need some split dosing of methadone typically twice a day because of rapid metabolism during pregnancy. And sometimes people need split dosing, but they also need a dose increase. So should you switch from methadone to buprenorphine during pregnancy? You know, sometimes people hear about, oh, okay, well, babies exposed to buprenorphine in utero had less neonatal opioid withdrawal syndrome than babies exposed to methadone, or they were in the hospital for a shorter period of time or had less treatment for NOWS. It's generally not recommended to go from methadone to buprenorphine during pregnancy because there's not really a good transition protocol that's been worked out yet. And when you transition somebody, it's gonna introduce the possibility for them to destabilize. And so you have to taper the methadone dose typically or go 48 hours or more without dosing prior to buprenorphine induction. Sometimes people might do a microinduction. So they might start on a small dose of buprenorphine. I did see a case series about this where they started people on microinduction of buprenorphine and then tapered them down off of the methadone. But in that study, there were a lot of, a good number of the people in that study were lost to follow-up. And so there's concerns about the maternal and fetal risks of going from stable on methadone to buprenorphine. And we just don't know, it hasn't really been evaluated closely. So I just wanted to look at some advantages and disadvantages of methadone. So with pregnancy. So some of the benefits or the advantages is that we've got years of outcome data for infant and child effects of methadone. Methadone has been shown to retain people in treatment. It's an easier induction, no risk of having precipitated withdrawal. There's lower risk of diversion when somebody starts on methadone until they get some time to recover. Methadone until they get some take-home doses. And it's relatively inexpensive. Now, some of the disadvantages or risks, higher risk of overdose because it is a full agonist compared to buprenorphine, which is a partial agonist and they have that plateau effect. QT prolongation is an effective methadone that can happen, especially at higher doses. It does take a longer time to get on a stable dose of methadone than buprenorphine. Studies have found more severe in neonatal opioid withdrawal syndrome than with buprenorphine. And then also daily dosing at the clinic might be a problem for some people. It's hard to get transportation or hard to spend time every day to get to a clinic to dose until you get granted some unsupervised doses. And then the other thing too is that there might not be a clinic nearby that somebody can choose to go to. As far as when somebody's in labor and delivery, methadone should be continued without interruption and it should be continued into that postpartum period too. And if somebody needs an epidural during childbirth, it's been shown to be effective. And also if somebody needs analgesia during a C-section, what they found too is that with C-section, women who are on methadone or buprenorphine sometimes require higher doses of oxycodone than women without an opioid use disorder. So this is that study actually looking at opioid utilization of women in methadone maintenance compared to postpartum women without opioid use disorder. So when they had a vaginal delivery, there was similar opioid utilization despite having higher pain scores for the women on methadone. And with cesarean delivery, the women on methadone had higher pain scores and required approximately 70% more opioid analgesic medication. So first line was recommendation is NSAIDs or acetaminophen for postpartum management for mild to moderate pain. And following C-section, individuals could need opioid medication for pain. Now, once somebody delivers, continue the methadone, but do you remember that those physiologic changes go back to the pre-pregnancy state regarding the metabolism, renal clearance, blood volume, and the effective dose during pregnancy might need to be adjusted down during that postpartum period. So you could maybe get down to that pre-pregnancy dose decreasing by five to 10% at a time. And now if somebody's sedated, they either report feeling sedated or you observe that they appear sedated, then make sure to decrease the dose. But this should typically be a shared decision-making process with the patient just to make sure, you know, that you wouldn't want to just be like, okay, well, you're here, you went up 20 milligrams during pregnancy, I'm just going to take you down. I would work with the patient more slowly to go down on that dose. Unless I've had some concern about sedation, I might be a little bit more aggressive than I would for somebody who's not appearing sedated. But I would make sure to talk to the person about that and get their buy-in on it. As far as neonatal opioid withdrawal syndrome, this was previously called NAS or neonatal abstinence syndrome. And what this is is a complex of symptoms and signs once the baby's born that is associated with the sudden withdrawal of whatever opioid that the person was using. And so some of the cardinal manifestations are increased muscle tone, autonomic instability, irritability, poor feeding, and impaired weight gain. And it's seen in about 30 to 80% of neonates who've been exposed prenatally to opioids. And it can begin within the first two weeks of life, but usually it starts within the first 72 hours of birth and can last for days and weeks. As far as the treatment, usually you're going to be using some kind of standardized scale like the Finnegan for four to seven days. And you begin treatment when there's three consecutive scores that are greater than or equal to eight, or when the sum of three scores is greater than or equal to 24. So there are different treatment methods. A lot of times what's used is oral morphine solution. Sometimes methadone can be used. One thing that you might've heard from in the past is Paragoric that's not recommended to be used by the American Academy of Pediatrics. Sometimes adjunctive meds are used like Clonidine or Phenobarbital. But largely what I've seen is the oral morphine. Lengths of treatment have ranged anywhere in one state from eight to 79 days. And the consensus duration is about 30 days. And long hospitalization is suboptimal because it's going to interfere with maternal bonding as well as breastfeeding. Also have the potential for nosocomial infections. And then also you're just high resource utilization having a baby there in the hospital. Now you might have somebody who wants to breastfeed and breastfeeding is recommended for most individuals. They've been finding too that the extended skin-to-skin contact, breastfeeding and rooming in can be helpful for NOWS. And some incompatible conditions with breastfeeding include HIV positive status with positive viral load and then continued use of drugs or alcohol. So it's important for the individual to talk to the baby's pediatrician to see if it's safe for them to breastfeed or to talk to their OB. Methadone is excreted in small amounts in the breast milk. And when they've done the study, they looked at doses that range from 25 to 180 milligrams. And those produce concentrations anywhere from 27 to 260 nanograms per ml, which is about 0.05 milligrams of methadone. So that little amount of methadone isn't going to be enough to treat the NOWS. And so the infant needs to still be observed and treated for NOWS, even if they're breastfed. Now you don't have to, once the baby, let's say the baby gets treated for NOWS, they come home from the hospital and you continue to breastfeed. And then once you stop breastfeeding, you don't have to worry that they're going to have the withdrawal because it is a very small amount. Okay, now I think this is the last section and it's about confidentiality and OTPs. So back a few years ago, 42 CFR part two got changed. And this is about patient confidentiality regarding disclosure and use of patient records pertaining to substance use treatment. So back in 1970s, this legislation was enacted to encourage people to get treatment. And there's a lot of stigma about getting drug and alcohol treatment. So people would be reluctant if their privacy wasn't protected. And you can see that people often experience discrimination and negative consequences from the stigma associated with drug and alcohol use. And this regulation prohibited unauthorized disclosure of records except in some limited circumstances. So these regulations have been criticized for a long time being antiquated. They're not in line with our current system where we have things in the electronic health records and exchange information. It kind of keeps everything siloed. And so just keep in mind though, that even though some things have changed with part two, states still could have more restrictive regulations. Now they put out a period for public comments and on these new proposed rules. And then revisions to part two were announced in July of 2020. And so what they've done is revised it so that you can have better coordination of care in response to the opioid epidemic while still protecting patient's confidentiality against undisclosed use and disclosure of the records. So part two, you still can't have law enforcement using substance use disorder patient records in criminal prosecutions against patients without a court order. And it's also gonna restrict the disclosure of SUD treatment records without consent except in some certain situations like a bona fide medical emergency, purpose of a scientific research audit or program evaluation or based on an appropriate court order. So as far as non part two providers, so let's say you are not working on an OTP and you have your medical records based on your own encounter, but you know they're on methadone. They're not explicitly covered by part two unless you've got some records from the part two program or an OTP and you incorporated them into your medical records. So you scanned them into your chart. The methadone program sent you over a bunch of records and then you put them in there. Those are still supposed to, you're supposed to keep those records that you got from the clinic segmented so that people can't see them. As far as non OTP or non central registry treating providers, they're eligible to query a central registry in order to determine whether somebody is on opioid treatment through a member program. I haven't really seen this in action in my state. We still, if we wanna find out at our clinic, if somebody is enrolled in another clinic, we have to send out this dual enrollment form. It gets faxed to a bunch of other programs within a certain mile radius. OTPs as part of this change are permitted to enroll in state prescription drug monitoring programs and able to report data into the PDMP when they're prescribing or dispensing medications from schedule two through five, as long as you're consistent with your state law. And as far as declared emergency from natural disasters like a hurricane that can disrupt treatment facilities and services, those are also considered that bona fide medical emergency. So you can disclose records without patient consent under part two. So for example, we have somebody, I don't remember when, a couple of years ago with one of the hurricanes, people came up from Florida and have family here in the Pittsburgh area. And we were able to contact their provider, their clinic provider to get their dosing information. Because that was considered a bona fide medical emergency. As far as fees and payments, Medicare does cover methadone now, and it also covers other MLUDs. And the Medicare benefit also will say that it's covering dispensing and administering MAT medications, if applicable, as well as the counseling, the group therapy, toxicology testing, intake activities, and periodic assessments. So these are things that methadone programs can bill for. Sometimes the billing is a bundle, meaning it's, you have to provide these services as part of your bundled rate. Some Medicaid state agencies also provide for treatment at OTPs or payment for OTP treatments. Some commercial insurances pay as well. And then individuals can self-pay at a clinic. Sometimes the rate might be $120 a week or something like that. Okay, so we finally reached the end. Here are some resources for you. So tip 63, this is available for free. It's a PDF document that you can access from SAMHSA. And it talks all about medications for opioid use disorder. So there's a big part about methadone. I'm guessing they're gonna update it now to reflect changes in the federal register. And then if you wanna see these new changes for methadone, you can look at the federal register. And here's the link for that. And you'll be able to read all about it. It's several, at least a hundred, maybe 200 some pages, I can't remember. And that's the end. So thank you so much for your attention and good luck on your exam.

Julie Kmyk

psychiatry

University of Pittsburgh

methadone

opioid use disorder

Narcotic Addiction Treatment Program

Dole and Eiswander study

federal regulations

COVID-19 pandemic

telehealth

pregnancy

QT prolongation

SAMHSA TIP 63

patient confidentiality