Welcome to the Providers Clinical Support System for medication statistics treatment. This is a waiver training, this is module 4. My name is Dr. Steven I'm an addiction psychiatrist and the Medical Director for Addiction Medicine at Atrium Health in Charlotte, North Carolina, and I welcome you to this module. So this particular module, we're going to go through a few things around the pharmacology of these medications that are typically used, and the only ones approved for medication assisted treatment of opioid use problems. And we're going to look at them contrasting the pharmacologic features of methadone, buprenorphine a lot. So we'll describe the efficacy of these various products and identify substances that potentially could have dangerous interactions. So methadone spin available the longest and this is a synthetic opioid that occurs in both the R- and S-enantiomeric form with all its activities due to the R-methadone. It was first discovered in 1937 and received FDA approval in 1947 for the treatment of pain and coughing. It's a very effective pain medication. And then in 1970, as was reviewed in Module 1, it was approved for supervised withdrawal, so as in medications that help ease the withdrawal from other opioids or even methadone. And then in 1973, we had the introduction of methadone as a opiate maintenance therapy for people with opiate use disorder. It's metabolized in them in the liver and it's an by intestinal cytochrome c. Cytochrome 3A4, and most. [COUGH] Methadone is ultimately excluded in the biliary tract. But small fractions enter the urine and are detectable in urine drug testings. Again it is a synthetic. So you're not going to pick it up in urine drug testing for opioids, for a standard opiate screen. You have to ask for methadone specifically. The oral viability when swallowed is quite variable, between 36 and 100%. So major features of buprenorphine is one, we're going to refer to full agonist, partial agonist and antagonist. Methadone is a full agonist and I'll explain what that means in a moment. It's very long acting half-life is between 15 and 60 hours. This is in part because of the active metabolites. It has a weak affinity. However, it's the mu receptor. So the potential that it displaces other, other opioids and in particular in comparison to methadone excuse me, compared to buprenorphine or natrexone, it's much weaker. But it can be displaced by those partial agonists or antagonists, and therefore it would precipitate withdrawal. And again I'm going to explain this in a moment. It does take constant monitoring secondary to the effect that it has on the on respiratory depression. And also, QT interval prolongation. So it's something that we want to be careful about in prescribing to someone that has a history of either QT prolongation or heart disease arrhythmia in some way you would want to check that out even family history. So here you have the full opiate agonist that is the more that you give, the more the effect that it has up to the place where it essentially causes respiratory suppression. And actually changes the effect of rising CO2 levels on the modularity respiratory center, resulting in essentially a fixation. So it no longer is responding the way that it normally would and a person just stops breathing compared to an antagonist that really has no particular no intrinsic activity on the opioid receptor, it attaches and blocks it and I'll go over that in a moment. And buprenorphine which has intrinsic activity up to around 40% and then tapers off and so it has this ceiling effect that we talked about. So in that buprenorphine has a higher affinity to the full mu receptor. There's no higher affinity compared to the full mu receptor. If buprenorphine is given at a place where it's up in this range above buprenorphine, then it would precipitously take a patient down to that level of activation that is buprenorphine and they would feel as if they're going into withdrawal. Now they don't go into full withdraw. But they start to have those symptoms and it reminds them of times potentially when they did go into full withdrawal and they feel sick they don't like the experience. So buprenorphine is a semi synthetic analogue of thebaine, which is a precursor to morphine, and it was approved by the FDA in 2002 as a schedule three medication for the treatment of opiate use disorders. It metabolized in the liver mainly by cytochrome P450 3A4 and has less active metabolites nor buprenorphine. Which is important to remember because we can sometimes have a better sense of how a patient's taking their medication by getting both buprenorphine and norbuprenorphine levels. So if a patient just put a little buprenorphine in there talk screen to two attempt to show that they're taking their medication when they're not, they obviously would not have the metabolites. So it is something that we do use sometimes clinically, but in terms of it being an active metabolite, it's significantly less active than buprenorphine. Most buprenorphine is ultimately excluded in the biliary tract, but small amounts again and or the urine so it is detectable on urine drug screening. That again would need to be asked for, now there are radio mean assay tests that you can use so point of care testing and detect buprenorphine. But otherwise you would need to get a confirmatory or you're not going to see it show up as an opiate. Because of the extensive first-pass metabolism, buprenorphine has low oral bioavailability when swallowed, so significantly less, and so, therapeutic formulations use other routes. The most common route that we know about or that is used and the first one made available to us was the sublingual administration and the bioavailability there is about 30% of the medication that the patient actually takes. So here, you see, again, it's a partial agonist. It comparatively has less respiratory suppression. And there's no evidence in an adult that it results in respiratory arrest when used as prescribed. So I'll show you that in a CRAFFT in just a moment. It is very long acting, 24 to 36 hours. So there are ways and there's been research. I was involved in some research trials at Yale in the 90s, where we actually administer the medications three times a week. So we did it on site, and it was doses large enough to hold patients for 48 to 72 hours. [COUGH] The affinity is also very high with this medication. And so it blocks other opioids. So once this is on board and there's a full therapeutic dose, patients can't take other medications and get much of an effect out of them. Now there's some caveats to that, particularly as we talk about pain later. But in terms of euphoric effects, if they were to use heroin on top of buprenorphine while buprenorphine is at a therapeutic dose, they're not going to get any significant euphoric effect from the drug, from the heroin. And because it displaces them, as I said before. So here, if you have a full opioid agonist on board and you give buprenorphine, it bumps the buprenorphine because of this higher affinity. And it drops them down to this level. And they were to feel as if they're going into mild to moderate withdrawal. So it precipitates that withdrawal. It also has a slow dissociation. So there's some evidence that it even is retained for the life of the receptor, around 72 hours, but again, that's quite variable. But it has this slow dissociation, which makes it a very good medication for what we're trying to do, and that is take the medicine typically once a day. It can be prescribed twice a day. But typically, patients will find they can take it once a day. It holds them very nicely for that 24 hours. And they don't feel much in the way of fluctuation at all once they've reached a therapeutic blood level. So, again, it works because of this high affinity and slow dissociation in preventing withdrawal symptoms. It reduces cravings. I would have you think back on my description of a drink of water. When we get more and more thirsty, we think about getting water more frequently. When a person has created an environment in their brain that's now needing opioid, the longer they go without it and even after withdrawal, the more they can have a stimulant, various stimulants in the environment results in them wanting it more. Buprenorphine cuts that off. It results in them feeling as if they had that drink of water. And that is just no thought of it. It's not a physical experience, it's just the thought is reduced significantly. They can have a memory of having used, but that's very different than a craving. And so it, on top of all this, decreases the effect of other opioids. Again, that high affinity, if they use a full opioid on top of it, they're not going to get that euphoric effect that they had had. But it is unlikely to block all the effects from an opioid taken after the initiation of buprenorphine. Because the binding to the mu receptor is that dynamic process and, And so there's variations within that mu receptor activation. And the important piece there is as we talk about pain later, how can we work? How can we deal with pain problems that a patient might be experiencing while they're on buprenorphine? So there are various formulations now of buprenorphine. We make the choice of formulation. Primarily, I will say what's as a patient's insurance paperwork, because there's a few brands of buprenorphine naloxone, which is a combination product compared to the mono product. So there are a few brands out there. The mono product is now only available for the treatment of opioid dependence as a generic. It may be patient preference that they've used one product or the other. Or they had difficulty with one product, so they've changed to another product. There's taste differences. There's ways in which, the speed in which it's dissolved, it's different. You should keep in mind safety profile. So there are products that are individually wrapped like Suboxone film is in a foil wrapper. Zubsolv and Bunavail also come individually dosed. And this can reduce and it has shown actually to reduce the potential that children would get into the medicine compared to the tablets that would come in a pill bottle. And if the child got the pill bottle opened, can take a large amount. And, in fact, this is the one population that's most severely affected with toxicity to buprenorphine, and that is infants. That's the only reported deaths very clearly associated with just buprenorphine. Again, there have been deaths from buprenorphine, but there's not been a clear report of an adult dying from buprenorphine alone. It's typically when mixed with other medicines. Though there are formulations, the buccal film and sublingual films, tablets, as I said. The difference there is the tablet take a considerable amount of time to dissolve compared to the films. That is, the generic tablets actually, the product Zubsolv dissolves quite rapidly. And then there's subdermal implants. And more recently, the availability of a depot formulation, that is, a subcutaneous injection, and then slowly dissipates. Actually, the formulation is similar to the formulation of long acting injectable naltrexone. So it's a polymer that dissolves over a period of time. And so there's this slower dissociation absorption into the system. All of these have been approved and shows similar efficacy in the treatment of opioid use disorders. Buprenorphine for transdermal or path or intravenous are only available as analgesic medications. Now there is one formulation, sublingual formulation that was approved for pain alone. It is a mono product, so it's buprenorphine alone, not buprenorphine attached to or being combined with naloxone. And this is a product called belbuca and it is not approved for opiate use disorder only for pain, but it is a sublingual formulation of available for pain. So the reason that we prescribe buprenorphine with naloxone, the only reason for this is to reduce injection drug use. That's the only reason it's there and I hear various things people talk about. I won't go into those other ideas to confuse you, but it is there to reduce the injection drug use of this product. And it has shown in large naturalistic studies to reduce injection drug use of this product of this medication. It results as a result of the difference in metabolism in precipitated withdrawal injected. And so the idea is that naloxone is not well absorbed compared to buprenorphine alone, buprenorphine, and buprenorphine in combination with naloxone. There's been clear evidence that there's a reduction in injection drug use. And so the idea that adding naloxone to this product results in a difference when it's injected, but not when it's taken orally or sublingually. That is very little is absorbed sublink of the naloxone is absorbed sublingually compared to buprenorphine. And so it really doesn't have much effect, I only say in looking at pregnancy where we will have then switching women over to the mono product. We do it on a one to one basis and I've done it many times and there's little to no change, all right? It's more around taste or other side effects. But when you add, and then when you go back to the combination product buying the pregnancy, again, little to no change in terms of the efficacy or they're feeling withdrawal, or cravings, or anything. So very little of the naloxone is absorbed sublingually, but when it's injected, there is a difference. And now, I'm going to go through that in a subsequent slide, but it's important for you to understand that is the reason why naloxone is added. And it's a very important reason one of the reasons that we stress that the combination product should be used really exclusively. I know there's reasons why we might use the mono product, but if it all possible, I would encourage you to use the combination product. It is less likely to be diverted, we know the mono product has a higher street value, there's just a variety of reasons why it really is important that people try to always use the combination product. So there are, again, these various formulations, there's suboxone, which is the combination product. They're pretty much all four to one combinations that is, let's say four milligrams of buprenorphine to one milligram of naloxone. Similar with Zubsolv, Benomyl different bioavailability. So there's different dosing, but it's still an important one combination. Then there's the mono product that's only available at sublingually generically, but then mono product, the implant and the injections. So these are now available have been approved by the FDA for long term maintenance of patients on buprenorphine. Naltrexone treatment uses naltrexone as long acting medication that has a very high affinity to the opiate receptor. But it competes with a receptor in that it blocks the receptor from activation from any other opioid. It does have an active metabolite and that also works as an antagonist. It is very effective at very low doses. So down to 2 nanograms per milliliter. And even at that low level continues to block all the effects of opioids. Naltrexone tablet was approved for blockade and yet the problem with an oral product has been poor compliance. So it really didn't work very effectively as a treatment for opiate dependence. Because of the poor compliance, people would stop taking it. And typically within 24 to 36 hours, they could get an effect of a full opiate agonist. The introduction of naltrexone injectable for the treatment of opiate use disorder had a better efficacy, secondary to the fact that we can give the monthly injection. And then during that period of time, they would remain blocked from using any other full opioid antagonist. And this can be, An appealing choice to patients, because they don't want to be on any form of an opioid any longer even though the stimulation of the dealing of opioids is dramatically different with methadone and particularly buprenorphine. But at the same time, it often can be the choice and they just know that they're completely blocked from the use of any other opioid. So here's our graph again, this is full antagonist. So it blocks the the opiate receptor completely. It has this then competitive binding to the receptor. It's very long acting, the half life orally is around four hours, but again, at the doses that we give, they have protection for a good 24 hours. The IM injection can be five to 10 days, but again, those thing levels can bought to very low doses, again, two nanograms per milliliter and they still have protection. It has a very high affinity to the opiate receptor and therefore, blocking all other opioids and displacing those that might are up on board. It would precipitate withdrawal, however, and that's the importance of having people off any opioids for seven to ten days prior to the injection. We can start with low doses sooner than that orally and and titrate people up to a form 50 milligram dose which is how the oral is Formulated, and those tablets have been available since 1984. And the injection for opiate dependence was made available in 2010. It, again, was available for alcohol dependence earlier than that. So the mechanism is therapeutic in two ways. There's a behavioral mechanism that is blockading the reinforcing effects of heroin that leads to this gradual extinction of drug seeking and craving. So they just can't use. And so we know that when something's not available, we have less desire for it if it's completely, completely unavailable. I sometimes describe it as liking mint chip ice cream. And if I'm sitting watching a movie and I know it's in the freezer, I might periodically think when would be a good time to pause this movie and get ice cream? Whereas if it's just not there, I stop thinking about it. And you think for a moment if this is something that you want available. If it's not available at all, you stop thinking about it. We know that, in part, this is true with people that are in prison for a long period of time. They may crave it for a short period of time getting into prison. But when they're there and if there's no drug available, they stop craving it. They may have thoughts about using again, but they don't have the constant thought that is associated with craving. The pharmacologic mechanism is that it decreases reactivity to drug conditioning cues, decreases craving, thereby, minimizing the pathologic response contributed to relapse. That is, it blocks some of the endorphin release that's often associated with cravings. So as we start thinking about something that we really like, we actually have endorphin release. And that can be rather profound in cravings resulting in significant increase, frequency, and intensity of the craving, and therefore, results in people relapsing. Whereas naltrexone will block some of that endorphin release. It doesn't block it entirely. People still can enjoy things and get back to a regular life, but that profound release that's associated with craving is reduced. And this is the way in which it's used and is effective in the treatment of alcohol use problems, but it has the similar effect with opioids. So naltrexone has a different mechanism of action than methadone or buprenorphine. And it may be acceptable or effective for different subgroups of patients, thus helping to attract more patients into effective treatment overall. So again, some people just don't want to be on an opioid or they have a certain occupation that they can't be on buprenorphine or methadone. And consequently, naltrexone is a good alternative. In terms of efficacy of these different products, activation is full. The full of your agonist activates 100%, methadone and buprenorphine and, But with antagonists, it blocks it. So, again, the reinforcing aspects of methadone is higher than buprenorphine. But buprenorphine is reinforcing still. And people need to be aware of that. There will be some withdrawal symptoms from coming off buprenorphine, but none with naltrexone. Naltrexone and naloxone are very short acting opioid antagonists. These do not have reinforcing properties and that people are not physically dependent on them. Comparing the mechanism of action, methadone, again, is a full agonist, buprenorphine a partial agonist, naltrexone antagonist. Dosing, typically, people will stay out of withdrawal at 30 to 40 milligrams of methadone. But not until you're above 60 milligrams does it have this blocking effect, that is, reduction in the effect that a person would get using any other opioid on top of 60 milligrams of methadone. But we typically look at the therapeutic effect of methadone in the 80 to 100. And you'll often see doses at 120 or even 140. Buprenorphine is most effective between 4 and 32 milligrams. However, at 16 milligrams, we see on a couple of different studies almost 95% no activation. And so, consequently, rarely would you need to go above 16 milligrams. And I do think that's important. That's important because of some of the clinical use of buprenorphine that we'll go over later. But the more you give, the greater the potential that the patient will recognize they don't need to take this much, and then it starts getting diverted to the street. And that's one of the things that we certainly will try to prevent. So typically, somewhere between 4 and 16 milligrams is the therapeutic dose. And across the country, the average dose is 12 milligrams. Naltrexone comes as a 380-milligram depot injection. And just to reiterate, the oral medication, which we sometimes will use as a bridge before starting the injection, and some individuals will actually take the oral, choose the oral over the injection. Again, doesn't have as good effect. But if a patient's highly motivated, it can work effectively, and it's a 50-milligram pill. The advantages to methadone is that it is only prescribed in highly structured and supervised settings. Those are opioid treatment programs or methadone centers. And sometimes can, because in part of this availability or the idea that it's only prescribed in controlled settings, and some of the medication aspects itself can be more helpful to some individuals than either buprenorphine or naltrexone. Buprenorphine, on the other hand, can be prescribed in the office because it has a higher safety profile. And so, consequently, there's less risk in terms of it being a risk to the individual or a risk to society being available. Naltrexone, no potential addictive properties and/or diversion risk. It is also available as an office-based treatment. And it's an option for individuals seeking to avoid any use of an opioid. Methadone needs careful monitoring, because there's a fair number of drug-drug interactions I'll go over in a moment. And also because it does result in some QT interval prolongations. So if a patient has a history of an arrhythmia or family history of arrhythmia there may be a reason to go ahead and get an EKG. It's not an absolute requirement. Some methadone treatment programs do go ahead and get EKGs before initiating buprenorphine but again, it's not an absolute requirement. If you do get into higher doses it may be prudent to actually go ahead and get an EKG but typically we're looking at doses above 120 milligrams. Buprenorphine there is the concern for diversion. I will say that most of the diversion that takes place of buprenorphine and that's typically the combination product. If you're using the combination product most of the diversion is sold on the street so that people can kind of refrain from using opiates for two, three days and then start using heroin or other opiate, full agonist opiates. So we know that it does that's typically how it's used. And there are reports of dissolving and injecting the combination product but I'll go through why that's not prevalent in an upcoming slide. Naltrexone patient does need to be off full opiate agonist for a period of time and so it does put them at risk during that time that you're kind of waiting to get the all the opiates out of the system before initiating it. And that can often be one of the reasons that it doesn't work well because people don't show up to get the shot because they've relapsed. And there are also concerns around pain management in that it blocks all other opioids and so typically we would either use a non-opioid pharmacologic treatment of pain. Or in a surgical setting it can be overrun or overridden by the use of potent dental analogues typically. So, if we look at the efficacy and adverse side effects of these different products we see a variety of things. So the benefits of methadone have been retention in treatment. And I've said this in a earlier module it is really how long people stay in treatment. How often they're coming back into the healthcare setting. They have an opportunity to speak with a counselor or physician, nurse where there's continued reinforcement of their remaining abstinence and moving forward with their lives. And looking at other problems that may arise or had occurred while they were using opioids or dependent on opioids. So, methadone compared to buprenorphine has been shown to be more effective although it is somewhat dose-related. And this study actually used a smaller dose of buprenorphine but they both have been very effective in increasing retention to treatment over time. And again, the longer people stay in treatment the greater the chance that there's less other opioid use and actually less other drug use if that's continually reinforced. So looking at a large Cochrane Review of 31 trials over 5,400 patients comparing buprenorphine, placebo, and methadone. Buprenorphine was an effective medication in retaining people to treatment when doses were greater than 2 milligrams. And there was suppression of illicit drug use at doses 16 mg or greater and this was based [INAUDIBLE] trials. Buprenorphine also appeared to be less effective in methadone when used at these lower doses 2 to 6 milligrams. But when used at fixed doses 7 milligrams or greater there was not a difference between methadone at doses greater than 40 milligrams and that is both suppression of opioids and retention to treatment. So again, they can both be various effective but throughout this training you're going to hear bits and pieces and that is, who would I want? Who would I suggest be on methadone or buprenorphine or naltrexone? So there's some variability that we'll be going through but it's all these ideas as to how I might suggest a patient be treated. Who's appropriate for my treatment and what I do in my office? And that can be variable between physicians, obviously, and advanced nurses. So when we look at dosing compared to efficacies, so this was a 6 week trial fixed dose. These were patients that were given 1 milligram which you see is not highly effective. But when we get into 4 milligrams there's more and greater efficacy, and 8 milligrams increases that again, and 16 milligrams above that. So, I just would encourage you to recognize that first of all 8 milligrams can be very effective for many patients. We don't need to jump to higher doses right away. Typically we'll stabilize people on 8 to 12 milligrams and then if there's continued cravings then we go up on the dose. Patients can all stabilize their withdrawal symptoms once they reach a steady stage. So typically I'll talk to patients about if I started them at 8 milligrams a day, they come in 3 to 5 days later and I talk to them about their experience. They'll say well, later in the day I start to feel some withdrawal. I'll ask them, how was it last night compared to the first night that you took it? The first night it was more difficult. And I'll tell them then as you reach a steady-state you'll become comfortable, it's a very strong high-affinity medication they're going to become comfortable on any dose between 4 and 8 milligrams, really even less than that. Obviously people will eventually be out of withdrawal entirely if they stop opioids. But it's the craving. It's the craving. It's the reason that we go up on the dosing. We want to decrease that wanting. That constant reminder that like I can't do anything until I get this opiate problem under better control. That's when we go up in the dose. And I think this is sort of reiterates what I just said. And here we're looking at 1 milligram, not highly effective, whereas the turquoise line squares is 4 milligrams. Not as suppressive immediately as compared to the aid to the black triangles or the 16 the purple diamonds but over time they have very similar efficacy. And so just to work with patients very closely initially try to talk to them about how they're changing their lifestyle. What they're doing differently to get to suppress these symptoms. But over time lower doses can be really quite effective if the patients continually coming to treatment, taking the medication as prescribed, and doing some of the work. Well if they take 16 milligrams a day they will not be using other opioids. It's just they don't get anything out of it. But if they are compliant with treatment they can be at lower doses and still do really quite well. When we look, however, at how long a patient should be on the tapering, this was a study by David Pavlina at Yale, They were on 12 weeks, Excuse me, at 4 weeks there was the beginning of the taper. And then as patience with tapered off, those that were tapered off had less retention in treatment. And this was I described this in the module one that Keiko study was very similar to this. And that taking people off the medication does not keep them in treatment frequently. There's outliers but there's about a 10% retention in treatment over a one-year period with discontinuation of medication versus just treatment and it's just so important to keep that in mind. Compared to in this study showing greater than a 60% retention in treatment at 14 weeks with maintenance treatment with buprenorphine. So again, I think to not think of it as like an antibiotic that you're going to eradicate the problem with 10 days of medication, it doesn't work that way. And, so there's no specific time in which we maintain people on medication. There are some people that do well coming off a shorter period of time than others and it is patient-specific. And I really think in working closely with patients that's how you make this decision. Now, you may taper down on the dose which then can reduce potential diversion and impact on the individual. But if they're doing well. They're continuing treatment. They're continuing to move their lives forward. Who's to say that they should come off this medicine? There's certainly no evidence of that in the literature. So buprenorphine for the treatment of prescription drug dependence this is a large multicenter study showed that there was minimal or no, Use of opioids. This was what we were looking for and it was a successful outcome. There was four prescription opioid dependent patients. A reduction in opioid use during buprenorphine treatment compared to standard medical management. And if tapered off buprenorphine, even after 12 weeks of treatment, the likelihood of unsuccessful outcome was high. And that's patients receiving counseling in addition to standard medical management. So I've shown you the Keiko trial, David Eileen's trial, and now Roger Weiss is trial all indicating that 12 to 14 weeks is not adequate. So certainly, acute withdrawal like the Keiko study using buprenorphine over a 5 day period to withdrawal people it just doesn't work well and that's with good psychotherapeutic interventions. The most common adverse effects with buprenorphine is headache. It can be managed with aspirin, or ibuprofen, acetaminophen. There's no contraindications to using these medications for headache. I will say that to a degree there can be some reduction in headache when people are using the combination product. If they allow the medication to dissolve adequately and make sure that there's adequate time for buckle absorption and so that they get less of any kind of, they override by naloxone and swallowing it. The other could be and this can happen with nausea that can be seen and that is to have patients actually spit out the sputum instead of swallowing it. Then there's certainly not going to get much on any naloxone and sometimes the stomach irritation can be resolved. Constipation can happen. You encourage patients to stay well hydrated. They have a less constipation than while they're on a full opiate agonist. Encourage patients to eat a high fiber diet and patients can take stool softeners or laxatives to also helps this. Dry mouth can happen with any opioids, so there's a histamine effect and this can be managed again with good hydration and maintaining good oral hygiene. One of the things that patients often come in with is significant problems, dental problems those that have been abusing opiates for long periods of time. They sometimes think it has to do with methadone but it really has to do with long-term problems with gingivitis and just poor oral hygiene over a long period of time and so it can be a real problem. In terms of safety, there's really negligible cognitive changes and there have minimal psychomotor changes. The cognitive changes in part has to do with something that's not reviewed in this training entirely but that is to point out that buprenorphine is a kappa antagonist. So opioid kappa receptor antagonist compared to full opioid agonist that are kappa agonist. And it can result in some The antagonism of this kappa receptor is different than the agonist, in that agonist will cause some reduction in motivation, some just sort of depressive symptoms. And so when people get on buprenorphine, they often feel sort of just a clearing of that experience, they have sort of a brightening of their affect. It can be even mildly stimulating for some patients, not a euphoric stimulation, but just feel like a weight has been lifted off of them. Particularly some patients that I've had where they've been on high doses of pharmaceutical opioids, and you convert them to buprenorphine, and they just feel better, they feel brighter. They have more motivation to get on with various things in their lives. But the psychomotor aspects in part has to do with the changes in respiration. And with buprenorphine, we actually see a reduction in the rate, down to 10 or 12 breaths per minute, and consequently some reduction in oxygen saturation. But we do not see that same uncoupling of the respiratory center responsiveness to rising levels of CO2. So we do not know of an adult individual that has died from buprenorphine alone, I said that earlier. There's no clear evidence that fatal poisonings have taken place without patients complicating their treatment of buprenorphine with other sedatives. Naltrexone has also a dose response curve. This is just really how the study establishing the efficacy of 380 milligrams of the depot product. Here you're really looking at the retention in treatment associated with naltrexone. So there was a higher proportion of opioid patients over at this 24-week period, decreased craving scores, and improvement and retention in treatment. So again, opiate-free urines, decreased cravings, and retention in treatment, so clearly has has shown efficacy over placebo. Two significant randomized trials were released in the last year. One was in Norway, the other in the United States. And overall findings show that once the medication was initiated, and that's one of the caveats is to get people through that abstinent period. But once they get through that and they actually get the first injection, that there was comparative efficacy between buprenorphine and naltrexone. Although you need to have those therapeutic levels of buprenorphine to show the similar efficacy. Naltrexone was more difficult to initiate due to that need to have people medically supervised for a period of time, getting them through that period in which they need to be abstinent. So I'm going to review now some of the potential drug-drug interactions that you should be aware of. There are more difficulties with methadone than with either buprenorphine or naltrexone. Methadone can inhibit, excuse me, the SSRIs can inhibit the metabolism of methadone and increase blood levels, and you should be aware of that. Fluvoxamine is a significant inhibitor and can literally make changes that can be mildly dangerous. And so consequently, we avoid fluvoxamine in the treatment of depression and/or anxiety in these patients. Carbamazepine increases metabolism, so people could have some feelings of mild withdrawal on starting carbamazepine. And methadone will impair the metabolism of tricyclics, so you can have some increase in those anticholinergic effects that one sees often with the treatment of depression or anxiety with a tricyclic. You want to avoid, actually it's contraindicated that one would use a monoamine oxidase medication for the treatment of depression while a person's on methadone. There is no drug-drug interaction of concern in using lithium. With buprenorphine, buprenorphine is metabolized again by the cytochrome P450 3A4, and drugs that increase or decrease this enzyme can result in serum level changes. And so those that inhibit, that are inhibitors of this system would increase buprenorphine. And those that are inducers, that is, increased activation of this enzymatic system, will decrease buprenorphine levels. But few of these interactions have been shown to be clinically indicated. Now, again, fluvoxamine, I have seen it with that, where there'd be some changes in buprenorphine levels that would be clinically indicated. But for the most part, buprenorphine has much less of drug-drug interaction problems that are really, we understand it pharmacologically. But we don't necessarily see much in the way of clinical changes. On the other hand, we do want to be very careful in combining any sedative-like medications with buprenorphine. So there is an additive and/or synergistic effect on the central nervous system using benzodiazepines or alcohol. And it also is more complicated interactions with opioids, and that is the degree of physiologic dependence on the user. And this has to do with how you're starting buprenorphine and also what dose you would go to to suppress opioid desire. And so again, if patients take it on a very regular basis, they will have a reduction in their cravings and they have less, we see far less abuse of other opioids with buprenorphine. Because buprenorphine has that high affinity, it's really going to block, for the most part, other opioid use while they're taking it on a regular basis. There is some QT interval prolongation with buprenorphine, but it's clinically You know, there's no clinical significance to that association. So we don't typically see a clinical problem with QT intervals in the use of buprenorphine. So let me go through clearly the abuse potential, let's say. So when we talk about the version of buprenorphine or buprenorphine naloxone, we're talking about it in two ways. One is diversion to the street, and that is sale of buprenorphine. And the majority of that is sale to defer people from having to use an opiate for a day or two or three or five. And you will see many patients come into treatment that have used it on the street and they used it to be able to get to work and not worry about drug for 24 hours. And so, this is sometimes referred to as a therapeutic diversion, if there is a certain amount of harm reduction that takes place. But that's not, obviously, our goal. Our goal is to get people taking it on a regular basis, because if they're taking it for three or four days and then shooting drug for the other three or four days, they're still at significant risk of overdose and other physical problems associated with injection drug use and or just using an opioid and then all the psych-social problems associated. So that's diversion. The product still being used sublingually. What we're talking about here is when using it by injection. And so, if you use buprenorphine by injection the mono-product, it's going to affect the opiate receptors and people are going to get a mild to moderate, moderate actually, opioid effect, if they inject it. Agonist, added to if you're on buprenorphine and you and you take an opioid, heroin, let's say on top of it, the buprenorphine would, would displace those full agonist effects. Or if they're on an agonist, buprenorphine as I showed you before, would drop them down to that buprenorphine level and precipitate somewhat strong. So it's either protective, if they're on buprenorphine and they and they take an agonist, or it precipitates withdrawal, if they got agonist on board. Buprenorphine followed by an antagonist, buprenorphine remains on the receptor but the effects of the antagonist has a slower onset and will eventually precipitate some withdrawal. So, What I would say, you are going to hear about people injecting the combination product. The difference, and the reason why it's not typically the drug of choice is that when you inject the combination product, let's say you have no other opioid on board and you inject this, you're going to have competition between buprenorphine and naloxone. Bupernorphine actually has a higher K value than naloxone. So it's going to compete, no question. At the same time, naloxone, this combination of buprenorphine and naloxone, naloxone passes the blood brain barrier more rapidly. And it slows the onset of buprenorphine. And as I said in an earlier module, it's the speed in which the drug gets to the brain that that really encourages that the addictive qualities of a particular drug. So for these reasons, the combination product has been shown in large naturalistic studies to reduce injection drug use. It's just not a highly sought after product. It's not saying you don't get some effect. I want to be clear about that. But at the same time, it has a lower street value than the mono-product and it has these qualities. The mono-product has these qualities of rapid onset that make it more easily diverted and there's more liking of drug than the combination product. And these are the reasons why we just so encourage that people use the combination product. All right, so benzodiazepines, benzodiazepines with buprenorphine has been shown to be fatal and these were first identified or reported in the literature from France in the 1990s. These were quite high doses of both buprenorphine and and benzodiazepines and most of the reports the benzodiazepine was used by injection. But when they're used therapeutically, there's minimal to no respiratory effects. So part of the reason that benzodiazepines became so available and more of great value to our therapeutic armamentarium for the treatment of anxiety was because it's much more safe than barbituates. So when they became available in the 50s, they quickly took over because they are typically quite safe. And the same is true with buprenorphine. As I've shown you, it has a ceiling effect to the respiratory problems that can result from its use. But the combination in high doses can result in people having problems. We also know that just therapeutically, people that are using benzodiazepines with buprenorphine, often, its associated with disinhibition and just other poly substance use. And it's just not an indicator of a person being in strong recovery. So used as prescribed however, benzodiazepines in combination with the buprenorphine has been associated with more accidental injuries, because of the sedation, but not other safety or treatment outcomes, okay, if it's used as prescribed. Again, this is controversial, because we really try in every way possible to get people off benzodiazepines when they're trying to be in recovery. The American Psychiatric Association has no treatment, that is, no treatment for anxiety that indicates long term use of a benzodiazepine. This is a whole other area of interest in lectures, but I really encourage people to look at other modalities for the treatment of anxiety and then having a person on Xanax or Klonopin every day for years and years and years. So the FDA in 2016 had a black box warning stating that this combination could result in increased sedation and potential death. Which is true. It's there used outside of the way that they were prescribed. However, they put out another to come in 2017 stating that medication assisted treatment however should not be withheld if a person's on a burprenorphine. So my practice and I think it's important for you to be comfortable with how you would be doing this. So if you have patients that that are on benzodiazepines that you know are caught out on their opioid pain medication or using opiates by injection and you feel their candidate for this treatment, and you are comfortable. Starting the treatment and then working with them as I do to try to reduce their benzodiazepine, and potentially start treating their anxiety in a different way. That's fine. On the other hand, if you are clearly uncomfortable starting someone on buprenorphine rather than on benzodiazepine, then don't do it. Send them to someone that could do that, would be willing to work with them and taper them down. And many times people get comfortable with using buprenorphine and they become more, and more comfortable with taking on more complicated patients which some of these patients can be. The combination use of these drugs increases the risk of serious side effects, but the harm caused by untreated opioid addiction can suddenly outweigh those risks. Okay, so that more people are going to have either increased morbidity or mortality from continued opioid use than treating people with this combination. So careful medication management by a healthcare professional can certainly reduce these risks, because you're in touch with them regularly. You're hopefully tapering down the dose, maybe adding an SSRI or some other treatment for their anxiety. If in fact, on stabilization of their opiate use disorder, they don't have a significant reduction in their anxiety which is very commonly seen. So the FDA guidance for health professionals was to take several actions precautions to develop a treatment plan with buprenorphine or methadone in combination with benzodiazepines. So educate patients about these risks. Potentially taper the benzodiazepine and any other CNS depressant. Verify the diagnosis of patients receiving prescribed benzodiazepine or other CNS depressant for anxiety, or insomnia and consider other treatments. I can't tell you how many people I've been able to stabilize their opiate use, then start talking. I've got good sleep hygiene and their sleep problem resolves significantly. But certainly using something other than benzodiazepine which are only, even the Z drugs are only really supposed to be used for a couple of weeks if that to just sort of jumpstart their sleep initiation along with good sleep hygiene techniques and people do very well. Recognize that patients may require medication assisted treatment medications and definitely, and their use should continue for as long as patients are benefiting from use, and you're continually seeing those intended goals movement, and those intended calls. Coordinate care to ensure that prescribers are aware of the patients buprenorphine and methadone so being in collaboration with their other treatment providers. Checking the prescription monitoring program to see that they're not getting other control controlled substances and then use drug screening and we will be talking about the sun in later modules, but the idea that you would understand how to monitor patients for both their use of the medications that you're prescribing and other drugs that they would be getting on the street. Buprenorphine and alcohol, it's also something to be avoided. It is clearly a CNS depressant and there's some evidence that treatment with buprenorphine can help reduce cravings for alcohol, and certainly there's this potential thing you are seeing them regularly you're asking them about their lives. You can start to interact around their alcohol use. Certainly there have been patients that get their opiate problem under control and fall into drinking regularly and this is something that you want to help them avoid, obviously. So alcohol use disorder is associated with higher rates of relapse to opioids. I say this part also around cannabinoids. Any intoxicant, if they are taking it will result in the resolve being reduced to being then stimulated by their drug of choice which is often opioids. So you really want to be very careful about using or any intoxicant they may be using and this is getting into really full recovery. So again, buprenorphine does has its potential for intravenous use. It's estimated that per dose tablets are more likely to be diverted than films and the mono product is more likely than the combination product. So yes, I am reiterating this over and over again. There's very clear evidence that the mono product has greater abuse potential. So in a survey of these 4,000 patients and treatment programs in the United States relative rates of diversion, there was twice as many people were diverted the tablet compared to the film. And six times, over six times as many people were diverted the buprenorphine mono product over the combination film. So the combination product is the standard care in general use and that's a very important part of what we're describing. Again, there are things that one would put into consideration in prescribing the mono product, but certainly not in a initiation of the treatment. Over a long period of time, there may be reasons that you would go to the mono product. But for the most part, you really want to stabilize patients significantly before you consider that and I'm talking like a year into treatment, significant period of time before you would consider the mono product. There is a price difference and that's probably one of the biggest reasons why I hear physicians will take some of their stable patients that are paying cash for the product and move them to the mono product. But the cost of the medication, insurances will often not cover the mono product and the cost differential has reduced in recent years. Naltrexone initiation. Again, official prescribing information recommends that patients would be free of any opioid for seven to ten days before initiation of drug or it will or could precipitate withdrawal. This can be very challenging. Non-opioid medications for withdrawal can be used like clonidine, alpha two agonist. And this can be helpful in reducing any further symptoms the patient might have. We try to do non-methadone or buprenorphine withdrawals so that right from the last time they take their either prescribed opioid or a listed opioid right from that day they started their 7 to 10-day period. If you use methadone or buprenorphine for withdrawal, then you're going to wait 7 to 10 days after you've started the withdrawal. Inpatient and residential treatment programs, where this medication-assisted withdrawal can be accomplished is really an ideal setting because they're in a controlled setting. They get both medication and psychotherapeutic interventions that allow them to be more comfortable during this 7 to 10 days. And more rapid methods of naltrexone initiation are under development. That is, using low dose naltrexone in two, three, four days following their last use of any kind of opioid, hopefully tapered down, but you can use these low doses to protect them to a degree. And then taper up to 50 milligrams and start the medication. So treatment adherence can consequently be quite challenging, but it's certainly better with long-acting injectable. They do not have an opioid on board any longer when they take naltrexone. So sometimes to describe that to patients can be a little upsetting. And they think that they'd be more comfortable on buprenorphine. But for the most part, it's been very successful. The oral has not been so successful and it's not recommended, and so the preferred formulation is a long-acting. And a treatment plan should include counseling, this anticipatory guidance, that is, how they're considering people, places and things, how they're changing their life in some ways. And we try to reinforce those things or get people more engaged through motivational techniques and emphasis on adherence with ongoing counseling. It is more difficult because they're not physically dependent on this as they would be on methadone or buprenorphine. So they have less tendency to keep coming back into treatment. And that is psychotherapeutic treatment or even relapse prevention treatment. But they're also now using opioids. So it's a challenge and this is a challenge. Involvement with a significant other may be helpful in supporting adherence to that monthly injection. I did this with families of adolescents. They were 18 to 24 years old, not necessarily adolescents, but they were living at home. And in order to continue to live at home, they had the contingency of getting their injection on a monthly basis for a period of time. So some patients will experience subacute withdrawal symptoms after the first injection, but that typically resolves. And soreness at the injection site is most frequent side effect that people will report. If it's given appropriately, that is, deep IM, we don't typically see that, but it is very important that it be not just given into the fat of the buttock. And so the main safety concern is really risk of relapse when the injection is discontinued. However, I will say people come off buprenorphine for two weeks, and then they relapse. If they go back to the same dose with their loss of tolerance, the same dose of heroin that they might have been using before starting, they're at significant risk of having a problem also. So people do need to be informed when they stop using that they stop taking their medication, that they understand that they've lost tolerance. And, once again, it's important for people to understand these things. So in summary, medications as a treatment is compromised, Excuse me, comprised of methadone, a full opioid agonist, buprenorphine, a partial agonist, naltrexone, an antagonist. It occupies the receptor without activating. Ongoing treatment with medication-assisted treatment is effective at improving retention in treatment and decreasing use of illicit opioids. And in contrast, short-term treatment with medication-assisted treatment is tapered off after a brief period of stabilization is not very effective. So 90% of people will relapse in the first year if they're just acutely withdrawn using medication-assisted treatment in a short period of time, and that can be up to 12 weeks of treatment. Sustained recovery is what we're looking for. Pharmacodynamically, combination of methadone or buprenorphine with other central nervous system depressants may increase the risk of sedation or respiratory depression and overdose. This risk is most clearly shown with benzodiazepines, particularly if used by injection. These are the references which we'll look at and follow. Again, this is very strongly evidence-based treatment and very effective over time. So thank you very much.
