So why are Methadone or Buprenorphine different, and what is this thing about Naltrexone? So to answer these questions, we need to understand a little bit more about how Heroin works. So Heroin binds to those same opioid receptors as endorphin in the reward center of the brain and produce an unbelievably intense euphoria. Heroin also is snorted and injected. So it gets into the brain really quickly, and it's very short-acting, last sub most about 40 to 45 to 60 minute, and it does cause physical dependence. So this graph shows you a little bit about them what happens over time, which is that the first time somebody uses they feel really high. Then fairly quickly, they'll go through this normal range or that comfort zone, and then into withdrawal or being sick. As you can see that feeling of being high doesn't last very long. If you then look over time, not to 24 hours, but now over days or weeks or months, what you'll see is that the first time that somebody uses heroin, that is the most dopamine surge that they will ever have, and they'll feel the highest with the most intoxicated that they ever will, and then they go back to normal, and then they'll use again and they get high, but now they don't get quite as high but they go back to normal. But then over time, now what you're getting is actually that most people when they're not using heroin spend most of their life in withdrawal, and now they're not using to get high, they're using to just feel normal. So if you ask people who use heroin when was the most high that you ever felt, it will always be the first time I got high and that drive, and that craving to get back there, is what a lot of people are looking for. Well, Methadone and Buprenorphine, the way they work is that they also bind to those opioid receptors, where endorphin sits in the reward center of the brain. But methadone is taken orally and buprenorphine is put under the tongue or sublingually. They are very long-acting, you take them once a day. They do cause physical dependence, because they are opioid agonist or have similar structures as to an opioid. But in people with an opioid addiction at the correct dose, neither methadone nor buprenorphine overstimulated that reward center. Now, naltrexone is slightly different. So Naltrexone binds to the opioid receptors, but it's taken orally or injected such as Vivitrol. It's also very long-acting. So orally it's once a day, injectable it's once a month, but it does not cause physical dependence because naltrexone is not an agonist as you'll see it's something called an antagonist. So therefore it causes withdrawal and people who actually have opioids already in their system. Something called precipitated withdrawal in opioid-tolerant individuals. So if you think back to the graph of heroin and it's dose-response compare that to this with methadone or people morphine. Here, when people take their daily dose of methadone buprenorphine they don't get high, they just stay in that normal called a "Comfort Zone range." Their dopamine might go up a little bit and then it slowly tapers off. But as long as you take the dose every 24 hours in ever go into that sick or withdrawal phase. So looking at a little more closely at how these three different medications work, methadone as I mentioned is an agonist and it is also what's called a Full agonist. That means that methadone when people take it, it sits really squarely in that something called the Mu opioid receptor, and it activates that receptor when it sits in there, because it sits in there really like a tight key in a lock. Buprenorphine which is also an agonist but it's really something called a partial agonist, and that is because it sits in the receptor but not quite as snugly as methadone does. So it's a key that fits in the lock, but you got to jiggle the key a little bit to get the door to open. Naltrexone is what's called that opioid antagonist. So it actually doesn't really sit in the receptor. It sits on top and it just blocks that receptor completely. Now, all three of these methadone, buprenorphine, and naltrexone also block anything else from getting into that receptor, but Naltrexone does not activate the receptor or that cell the way that methadone and buprenorphine do. So if we then look at that activation activity, so how much those cells respond to the binding of these different chemicals that a Full agonist like methadone activates those receptors 100 percent. But buprenorphine, because it's a partial agonist, doesn't activate those cells 100 percent, they activates that at low doses and then it stops, it reaches a ceiling, and you can keep pushing the dose, and pushing the dose, and pushing the dose, but you're never going get to 100 percent. Naltrexone because it is a complete antagonist doesn't activate the opioid receptor, the Mu opioid receptor at all. So in fact it's not even on this graph because it would just be at zero. So now I've told you about how the medications work, these three medications. Well, how effective are they for the treatment of opioid disorder? Well remember, the goal of treatment is to return to productive functioning because there is no cure. Studies have found that these medications reduce drug use by about 40 to 60 percent. Now, you might say well that's not very good. But when you look at actually treatment of opioid addiction compared to treatment of diabetes, asthma, hypertension, there really the success rates, really are very comparable. The one thing we know, is that the strongest predictor of recovery from an addiction is retention and treatment. So we really need to help keep people in care. But this is data from a study that shows you some of these relapse rates for addiction and other chronic illnesses. So as I mentioned that 40 to 60 percent of the people who have an addiction will be able to manage that addiction over their lifetime compared to 50 to 70 percent of people with hypertension, 50 to 70 percent of asthma, and maybe even a little bit lower for people with type one diabetes. So it's not really that different from other chronic illnesses. The other thing we know from large bodies of evidence over decades is that the benefits of treatment for opioid agonists includes reductions in risk of HIV infection, reductions in the risk of infection with hepatitis C and B, increasing rates of employment, decreasing crime, and increasing length of life, really important. That happens both with buprenorphine and with methadone. For example, buprenorphine, there have been number of outpatient clinical trials to compare the efficacy of daily buprenorphine to placebo and to methadone, and they find that buprenorphine is more effective than placebo, and about equally as effective as moderate doses of methadone. Here's a couple of examples where researchers really were able to demonstrate improved adherence to HIV medications for example, among IV heroin users in an outpatient medical clinic who were treated with buprenorphine, and the same thing that Sullivan found in this HIV clinic in New Haven. This is data from one of the first studies that looked at buprenorphine compared to methadone, and the important take home message from this is that the doses have to be adequate. So if you look at the top line of the yellow triangles, that represents low dose methadone. That was, in this study, 40 to 60 milligrams of methadone a day. Compare that to the orange line of the orange and of diamonds, where that is high-dose methadone in this study was 80 to a 100 milligrams a day. The effect of high dose methadone and a dose of buprenorphine is pretty average, is about the same. But both of those are much better than the low dose methadone. LAAM, just as an aside, is no longer on the market. So we're not even going to talk about that. The other important message on this slide besides having an adequate dose, is also to realize that none of the medications really get people to completely stop all opioid use. So much like people with diabetes who sometimes will eat a piece of cake or sometimes will eat that candy bar, that people with an opioid addiction sometimes may still use opioida once in a while. So the other outcomes that had been looked at with respect to medications in the treatment of opioid addiction, have been what happens if the patient tapers off the medication? This is really where we see its positive impact because many of the methadone studies, 50 to 80 percent of people who taper off their methadone relapse within a year. Even when you look at just people who have an addiction to prescription opioids and are taking buprenorphine, over 90 percent of people in this one study relapsed after tapering off within two to four months, and very sadly, opioid overdose fatality rates go up tremendously, particularly in the month after tapering off compared to when people are in treatment. This is data from a study from Norway that looked at what happens to individuals in terms of their mortality before, during, and after treatment with methadone. As you can see for both men and women, that when people are in treatment, their mortality drops significantly compared to either before or after. So people then say, "Well, okay, fine, maybe medication has to be part of treatment in order to help reduce mortality and improve quality of life. But how long do people really need to be on it?" Well, this slide shows some data from a study in Chicago, where they followed individuals in different forms of treatment for substance use disorders, and they tried to figure out, over what period of time do you need to be abstinent or in recovery before your relapse risk really drops pretty significantly? It looks like that people who have continuous recovery or continuous abstinence for three to five years, or sometimes for five years or even longer, that's when their risk of relapse drops below 15 percent for the next 12 months. So we now think about this as long-term treatment, and treatment that includes a medication has the best potential for the best outcomes. But, methadone and buprenorphine or suboxozone can be misused. People can overdose on methadone. It's not quite as easy on buprenorphine, suboxozone is the sublingual film of buprenorphine. For naltrexone, people need to be opioid free for 7-10 days before you start it because as an opioid antagonist, if someone has other opioids like either full agonists or partial agonists like methadone or buprenorphine respectively, and they've taken that or they've used heroin, and now you give them naltrexone, and you give them a shot of naltrexone, that naltrexone is going to kick out those other opioids and now put the person into withdrawal, that precipitated withdrawal. They will not come back and will not be happy with you. The other important thing to note is that these are not treatments for other substance use disorders, with the exception of naltrexone that also is FDA approved for the use in treating alcohol use disorder. But benzodiazepines, alcohol, cocaine, other pills, people can have multiple substance use disorders. These days, that really is more the rule rather than the exception. But with all this data, one of the things that we now really recommend is that all patients with opioid use disorder should be offered medication as a component of treatment, that really is becoming the standard of care. The choice of that medication though, is a medical decision that is best left between a physician and a patient because it depends on someone's history, their physical examination, other laboratory testing, and the patient's choice. There are some factors to consider. Methadone is heavily structured and regulated. You can only receive it for opioid use disorder in a specialized opioid treatment program. Buprenorphine can be expensive, but it's less structured. It can be prescribed by a trained physician or now nurse practitioners, physicians assistants, in an office. Naltrexone is contra-indicated if people have chronic pain, and need prescription opioids as part of that chronic pain treatment or acute pain. As I mentioned, behavior change is the name of the game. So medications can be very helpful, and there's good evidence for them. But there are other components of comprehensive drug addiction treatment that we need to think about, including treatment for other mental health conditions, treatment for other medical conditions, vocational services, family services, legal services. It really spans the gamut.
