Welcome back to the PCSS online training. My name is Dr. William Wright, an addiction psychiatry working at the Atrium Health Addiction Services here in Charlotte, North Carolina. Welcome to Module 2, Neurobiology. So some of objectives we have for today on Module 2: I'll describe the physiological effects of opioids and the receptors, and describe the effects of opioids on the positive and negative reinforcement pathways of the brain. Describe the effects of agonists, antagonists, and partial agonist on the Mu receptor. Finally, describe and recognize manifestations of opioid tolerance, intoxication, overdose, and withdrawal. So as most things, let's start off with some definitions to make sure we're all using the same dictionary. So when we use the term opioid, what does that mean? In general, the term opioid it's like an umbrella term, like fruits. It's the overarching term that we use for anything that is an opiate, derived compounds from opiates, or naturally and synthetic analogs to opiates that we've discovered. So there is several different types. We have endogenous opioids like endorphins, dynorphins, enkephalins, they're naturally produced in the body, they're circulating throughout. We have opiates coming from nature such as morphine and codeine, and also natural stuff that we have tinkered with. Then you start getting into the thing that we really start making, and things like semisynthetic opioids like buprenorphine, heroin, oxycodone. Then fully synthetic opioids such as fentanyl and methadone, could of course have no analog in nature. While they're fully synthetic, we have to make them. So moving on to opioid receptors and physiology. Humans have at least three different types of opioid receptors located throughout the central nervous system, peripheral nerve, gut, and cells of the immune system. Obviously, we're still discovering and still learning. So right now we have three, though that may change in the future or subtypes may come out from them. When we talk about endogenous opioids, those opioids that are naturally made, naturally occurring in the body, it's part of the natural and normal physiological response that we humans have. That's why it is such an issue with exogenous substances and opioids, because we naturally have that, we naturally have receptors, we naturally have those things in our body already. So the system is already geared up for it. So there is three different types of opioid receptors, and they're Mu, Kappa, and Delta. The Mu being endorphins, the Kappa being the dynorphins, and then the Delta being the enkephalins. So most of the really clinically significant or things that we're worried about from day in and day out basis in the medical community are coming from those that are involved in the activity of the Mu receptor. This is where the effects of both prescribed and illicit opioids come into play. So that's also where the addictive effects of opioids occur, which is the activation of these Mu receptors. However, we're still trying to learn exactly what is happening with some of these other receptors under the opioid system. Whether they're involved in addictive process or not, maybe they can be helpful or not, we're still learning on that front. So as we mentioned, where are they located? As we also mentioned, the main targets of opioids are these Mu receptors. So where are these Mu receptors throughout our body? So there is a lot of concentration of these receptors in the brain. It's usually one of the biggest and most important organs when we're talking about addiction as well as pain. In talking about that, it has its effects on pain perception, the reward pathways are interfered and targeted by the opioids on the Mu receptors, as well as respiratory function, which will come in to play when we discuss both the effects of opioids on a system. But it's also found in the spinal cord, the GI system, and other peripheral region. Again, when you start thinking about symptoms of intoxication as well as withdrawal, you're seeing these systems in play and that's why it's so important to keep those places in mind when we're talking about opioids and their effects on the body. But as we mentioned, one of the biggest and the most important organs that it's affecting is the brain. The lovely little brain we have here showing a way version so that we can see deep into the brain and see the different regions that it is affecting. So the Mu opioid receptors are distributed pretty widely and ubiquitously within the brain. You can see here different structures that we've highlighted. This is the thalamus, the nucleus accumbens, ventral tegmental areas, as well as the prefrontal cortex. These little blue dots being the opioids that have gotten into the system and are targeting the Mu receptors and each of these individual areas. So what do they do? What happen when they target and they bind? So when they bind in the thalamus, the limbic regions, this is where it's producing some of the analgesia. The effects that initially we are using, especially exogenous opioids, for it to block pain, to numb the pain, to dull pain. So that's where the target of the analgesia is, the thalamus. Now when we start talking about when it's binding to the prefrontal cortex, this is the part of the brain that I had to think of called the adult brain, a part of the brain that is making decisions, the executive functioning, the rational part of the brain. It is here located in the prefrontal cortex. So when it's binding, it starts impairing that process, that adult thinking, that rational thing for the brain. As well as the importance of the use of the drug, it's all wrapped up and it's binding in the prefrontal cortex. Lastly, those deep structures, the NAc, or the nucleus accumbens, as well as the VTA, the ventral tegmental area, this is the part that is associated with the euphoria, the high, the positive effects of substance when we have issues with addiction. Not everybody has that triggering or at least not immediately. So this is the part of the brain that people are thinking about. While the other parts of the brain are just as important, so remember their actions and their effects as well. So their effects on the body. We talked about that big gray matter in the brain. Now the physiological effects of opioids on the rest of the body. So when we activate these Mu receptors in the central nervous system, it has a lot of things that it starts cascading down. As we mentioned, it has the analgesic effect, the sedating effects, the work affects within NAc and VTA, and a physiological response to the pupil constriction. The pupil getting really small, small, small, tight, tight, tight time till it's almost a pin point. Also, the respiratory drugs enters the brain, start being affected and become decreased and lowering their responses, as well as lowering responses on heart rate causing nausea. Again, going back to the previous slide where we said that it's got multiple different areas that the Mu receptors are in, the gut being one, the central nervous system being the other. So again, keeping in mind, this is why we say to keep that in mind. So if it's activated gut, that's where we get a decreased the motility, and you hear probably quite frequently that the folks that are using opioids for different issues, sometimes may have significant issues with constipation. It's because the opioid itself hitting those receptors in the gut is slowing that digestion down to the point where it's causing constipation. Also, when you're activating that receptor, other tissues like in the periphery, it's causing that analgesic effect as well, and modulating that inflammatory response. Again, the positive medical portions of what we're trying to opioids are seen in this area. Now, again, wanting to go back and discuss a little bit further this decreased respiration and why that's so important. Obviously, this is the main driver of why folks when they overdose, the potential for death resides here in the decreased respiration issue. So what happens? Why is that? It's with opioids also cause a decoupling, the decoupling response, so rising CO2 levels in our body. Normally, we have CO2 levels would rise and we would start reading different reading patterns to expel CO2. However, with the activation of the Mu receptors and the breathing centers of the brain, it detaches those two far from each other. So our breathing will start going down, but the condensation will lead to then start expelling more CO2. So we can actually have more and more and more and more and more and more CO2 level rising and our body won't do the natural responses to start bringing it out. So because of that, people will actually asphyxiate. That's how [inaudible] overdoses, they're blue and hypoxic from that decreased respiration and decoupling of the response drive. However, when we talk about other substances like the partial agonist from buprenorphine, those types of medications and substances don't affect the respiratory, which is such a crucial part of why buprenorphine products are so beneficial and this is use disorder. It's because it doesn't have that problem. So next objective, describing the effects of opioids on the positive and negative reinforcement pathways of the brain. So again, we have a nice view of the brain here. We have on the left side talking about positive reinforcement, and on the right side, negative reinforcement. So like most things in life, we think we have choices. A lot of times, our choices are actually directed by our biology. Motivation is also one of those. So we have parts of the brain, we work halfways, we also have stresses and pathways in the brain that act as balancing acts for each other. So in their work pathways, opioids stimulate the release of dopamine much, much, much more and even naturally occurring [inaudible] things. This is the part of the brain that keeps our survival intact and it's also what's important for the survival of the species. So this part of the brain is where we get that positive reinforcing for doing good things for both ourselves and our own survival, as well as the specie survival. So when we find a good source of food, a surge of dopamine saying, okay, this is good, this was non-toxic. I got some energy from it, positive. I found some good source of water, positive. I perpetuate the species, I found a sexual partner, we had children, we had offspring, good for the species, positive. The Middle Eastern sexual encounters. All those things naturally produce and release dopamine. However, opioids and other substances stimulate the release of dopamine to an exaggerated extent, much, much more. So our bodies have already have a system in place and so it really becomes hijacked when other substances make use of the same system. So it leads to when we use that substance an intense strong feeling of pleasure and gratification, learn from it. That substance made me feel really good, I want to get some more of that. It changes our motivation to the drive to continue to get that substance. On the flip side, the stress system, the emotional part of the brain, the amygdala, opioids actually decrease that activity. So it's involved in decrease in activity producing a relief from uncomfortable feelings like anxiety, fear which when you take away fear and anxiety of something you're much less to do it. If folks have a significant issue with public speaking or fear of anything, there are much likely to avoid that substance but they don't have any fear that substance or a less than degree of fear, they are more likely to do it. So when opioids decrease that activity, decrease that fear, decrease that discomfort of things, our bodies also remember that and want to make use of that more or at least not being afraid to do that. So all these things strengthen this motivation to continue to use, obtain and want the substance that has caused these reactions of motivation. This things then also go forward and have interactions with the prefrontal cortex that again, that adult decision-making part of the brain and putting it into memory and saying that well, I'm not really thinking about necessarily some of the bad consequences, just because my brain is telling me it's that's a good thing then I want more of it regardless of what happens, regardless of the consequences, regardless of me losing my job, my relationship is suffering, not paying bills, I'm now without a job I'm illustrating. It doesn't impact as much as you would think it was because it is interfering with that prefrontal cortex portion of the brain. So is this all just hypothesize, do we actually have some proof of this? We do. We have some neuroimaging that actually can bolster these thoughts on this concept of what we are talking about. In these slides you see here you can actually see some of these PET imaging, the positron emission tomography imaging that substances actually have activity in the brain. You can see in that top is normal activity in a normal brain, in the same area that we've been talking about the nucleus accumbens, the ventral tegmental area, the VTA, that there's changes in the actual physiology that we can see on imaging. You can see that lower part has a decreased uptake in those areas showing certainly binary decreased presynaptic dopamine release. All these things are being seen. So we know it's affecting the areas. The right side you can also see that the amygdala normal, not as prominent. But then that chronic care when you see at the bottom [inaudible] more. So we know these are the spots that are being infected, that are being targeted by these substances. Vulnerability to substance use disorders. What can we say? This is the ultimate nature versus nurture debate. Here we, as I pull up some of these components so that you can read it. It is actually 50/50. This is probably one of the best examples of having an equal partner, nature versus nurture. As we see here with genetics, we have things that our body has been programmed with because of how our genetics are made with the amount of OB receptors, the amount of dopamine response to it. Other transmitters, how our bodies respond to novelty and wanting new experiences and dangerous experiences. How our bodies respond to stress and do we seek it out or we want those folks that likes to have a little bit of edge? We folks that are more horrible with. Are we more impulsive, are we making this snap decisions without really thinking things through? Also the genetic portion of having psychiatric issues regardless of what happens. On the flip side of that coin, many are the things that obviously your body is not already having. It's the things that are happening to us from external, from the environment and how [inaudible] those things. So we can't control who our parents are or what happens when we're being [inaudible] , and the circumstances under that can't really change who our siblings are or their interactions with us, our friends sometimes or even the environment as well as those things go. A large issue being in adverse childhood experiences are also known as ACEs are a significant components to the environmental overlay for folks having substitutes disorders. The more adverse childhood experiences someone experiences in life, the higher the likelihood and more exponential the likelihood that somebody is going to have a potential issue with substances. Also not every psychiatric disorder. It's predetermined with genetics, sometimes we stretch it and how we deal with the world. Also come by psychiatric disorders, how we deal with stress. If we don't have any positive experiences of life, it's been a pretty, again, adverse [inaudible] , I think would be pretty detrimental to we don't know coping with things. Then also other things are drugs readily available in our environment? Are they not? That's a huge, if you've never exposed to it, you're obviously would never going to have an issue with it. But if it's readily available, like none of it happening [inaudible]. Have you ever prescribed a medication or were you not? Again, the access to it. Most prescription medications that find their way to others actually come from family and friends. So again, reiterating, the vulnerability and the likelihood of somebody having a substance use issue, it's a 50-50 split between how our bodies are made, the environment we live in, that nature versus nurture. For objectives, lets go on to describe the effects of agonists, antagonists, and partial agonists on the mu receptor. As you all can tell, I am a little bit Southern, so sometimes, even these words tongue-tie me as well. So as we see here, when we talk about some of the pharmacokinetics of opioid ligand pharmacology. Here at the top, you can see a full agonist like methadone, combining with 100 percent efficacy. Down there at the bottom, the antagonist such as Naloxone with no viability. It's actually blocking it. It's not actually binding to a receptor, and that's the whole point of it. Then right there in the middle, we have the partial agonist, the Buprenorphine, where we can see it's in between the full agonist and antagonist. So what are some of things being said when we talk about Opioid partial agonist therapy such as buprenorphine, you're utilizing that same kind of structure and the same responses to our benefit. To help us prevent withdrawal and also maintaining a steady level of opioid activity, much like methadone, but in the middle. So unlike Naltrexone that blocks these effects, we want some of those effects to mitigate withdrawals, to mitigate cravings, to give us some of the benefits without some of the negatives. Unlike full agonists, buprenorphine is a Schedule 3, and therefore, under the DATA 2000, on legislation, we can prescribe that kind of medication in a general office-based setting, as opposed to methadone that has much more restrictions, and oversight battle from The Federal Government. So also, because of its partial agonism, it is again, like we mentioned earlier, when we talked about the uncoupling of the CO2 and the respiratory depression and overdose deaths because of the respiration issues. This is also why, as you can see, that the respiratory issues with a partial agonist would not as high, not as likely as with a full agonist. Even at much higher doses, you don't have that respiratory depression, you have a ceiling effect as you can see, that caps off, it starts flattening out as opposed to full agonist. However, we also talked about binding affinities. So things that have high binding affinity for the opioid receptors like buprenorphine, will actually take the place of, kickoff, like a wrecking ball that Miley Cyrus referenced about. Coming in will actually displace agonists like heroin, like methadone or like oxycodone, there's full agonists that are already present on mu receptor, because buprenorphine substance actually likes to bind tighter to the mu receptor than even those full agonists. So as you can see from the full agonists at the top to partial agonist at the bottom, this is also why you have to have and discuss when the appropriate timing of initiating with partial agonist therapy is, because if you do it too soon and the person still has full agonist on those receptors, you will have a sudden precipitous drop in the amount of substance on those receptors, and that is what it's going to cause what we call precipitated withdrawal. You're going to go from zero to 100 on withdrawal symptoms, look at this split because of this drop and the receptor binding, and trust me, if patients come to you and they experienced this before, they know exactly what you're talking about when you're discussing with them. However, with folks that are naive with this, this is something you really need to discuss with them and making sure that, we'll talk about this later when we talk about induction and other assessment boards, that you really go over by the timeline issue, if you're doing both office inductions as well as its home-based inductions as well. So the antagonist therapy. So antagonists like Naltrexone. I'm a big sports fan and so when I'm talking to patients about the differences between full agonists, partial agonists, and antagonists, I start with a baseball analogy. If you think of mu receptor like a baseball mitt, and you think about the substance like oxycodone, methadone, whopping, whatever it is, like the baseball, full agonists, if you can hear me, like a baseball mitt. that baseball is full alone in that baseball mitt, and so it likes that receptor. The partial agonists don't really like sitting in that pocket of baseball mitt. It likes to go over on the side, maybe on the fall, that's about it. It's not full in the pocket, but it likes that pocket and it likes it a lot. It likes to stay there pretty tightly. With the same sports metaphors, then at this point, I'm going to switch it up a little bit. So antagonist on the other hand, are more like goalies in soccer and hockey. Instead of actually getting into the net, getting into that receptor, they're upfront, they are blocking that receptor, they're blocking any of the substance from actually getting into that receptor, and then from that binding of the receptor doing its effects. So it's blocking out like a good goalie in hockey or a good goalie in soccer. So lastly, describing and recognizing the manifestations of opioid tolerance and classification, overdose and withdrawal. So Tolerance, if we hear this term, what exactly does it mean? So there's two different versions of what tolerance means. So meaning that, with repeated exposure to opioids, you're needing more and more to give the same effects that you're going for, or that you're using the same amount and you're not getting the same benefits. Sounds the same, but it's a little bit different. But they're both meaning tolerance with these. So it also has physiological manifestations as well. It's a tolerance that develop at different rates, different extents, and with different effects. So keeping that in mind as well is very important as well. So some things will have a very quick onset tolerance to it, and some things will have little to no tolerance. So with things like sedation, euphoria, or the nausea, even to an extent that respiratory depression can have a fairly rapid tolerance built up for the person, some things sometimes have little to no tolerance with substances like constipation and pupil constriction. However, with tolerance, that also means that folks, when they find that they're not having the same effect. What is our natural human inclination to do? We're going to use more, but try to balance that tolerance, we are going to try to have more to get back to that effect, and we're going to keep needing more and more to attempt to get back to that effect. Sometimes, they never do, but they will continue to search and continue to try. Now, it's also important when you start thinking about recovery, and folks that are in treatment and recovery, is that when folks are without opioids for a given period of time, their tolerance will go down. So whether they're in a medically-assisted withdrawal program like detox center, whether they're in residential treatment, or sometimes whether they're on medications, all these things can sometimes decrease their tolerance, and it's important for patients to know and obviously not condoning and return to use, that whenever their tolerance goes down, if they were to use that substance again, that if they were to go back to using the same amount right before they stop. That is a very dangerous period of time. That is a very dangerous mindset to think, I can still use that same amount. Immensely, my mind says I can. Physically and physiologically, my body says I cannot. So their tolerance will have more likely greatly shifted to less tolerant and that they would have used that same amount, and they have significant issues even that if they were to go back. That includes being on medications like Naltrexone. So if we were to use the whole agent or inject able agents, and then would you stop that agent, the tolerance is going to go down. So if they were to resume their substance use, again, having to educate, saying, "Please, please [inaudible] your safety, " as we all do at the end of the day, making sure that you don't go back and use the same amount. So another phase, Opioid intoxication, all those physiological responses that we've been talking about, to the intoxicating effects of opioids. So what are they? When we think about opioids, if you want to think about it generically as a substance in the depressant family. So when you think about that, these signs and symptoms will sometimes probably make a little more sense and maybe make it a little bit easier to remember. So anytime you have a depressant, it's like the word says, I'm not necessarily doing sad fundamental hope sampling. They're very similar, is that it depresses, it lowers things. So in that regard, it's going to lower our heart rate. Bradycardia, it is going to lower our respiratory rate, Bradypnea, more shallow breathing, hypotension, it's going to lower our blood pressure, it's going to lower our body temperature, hypothermia, it's going to lower our alertness, sedation, it's going to lower our movement, it's going to lower our ability to think and speak, and all those things are lowered, so hopefully that makes sense. Also, we have the symptoms, so it's going to lower your pain, the Analgesia, it's going to lower that stress, like we talked about earlier when it's hitting the amygdala, causing some calmness and the somnolence as well. Euphoria, that's probably one of the outliers on that one, but if you want to connect it, it's lowering your stress responses, lowering your fears, your anxieties, and that, the amygdala can cause the Euphoria. So even lowering that stuff is causing the euphoria, so that's a good way that I generally try to remember some of intoxicating effects of opioids. When we start discussing and thinking about the unfortunate overdose. When we say overdose, that doesn't always necessarily relate and equate to death but there are symptoms of overdose that we need to be on the look out for as well. It's that slow down, that depressed effect to a significant degree. So again, decreasing and depressing the level of consciousness to a point of being unresponsive, to being unconscious, to being unaware. Again, very, very, very tight, very pinpoint pupils. You can't see any black in the pupil because it is so constricted. The breathing is so shallow, so slow, that it's even possibly stops and of course leading into potential cardiac arrest as well. Again, because of all these things, the blood slowing down, not being pumped as much, the oxygen not being pumped, both because of the decreased pulse as well as the decreased blood pressure. Also, as we keep talking about the uncoupling of the respiratory drive, CO2 and other things are building up, O2 is not circulating. So people who are still having an hypoxic look, there's the blue, purple lips, the cold extremities. So what do we do? This is obviously the big push for using reversal agents, which are in the antagonist family like Naloxone. A lot of folks have probably heard or called be a narc, or somebody being narc-ed. This is where it comes from. The trade name is NARCAN. NARCAN is a nasal spray. It's a pre-filled needle free device, doesn't have any assembly required. It is sprayed into one nostril while the patient or the individual is lying on their back. Again, this is a short acting medication. So even after somebody gets any of these agents, any of these simulations, it is vital that the individuals also know that the work is not done yet, that you still need to call 911. You still need to get them into emergency medical services pronto. Because it's the short acting nature of these Naloxone treatments. If there's still enough opioid in the system around those synapses, around those receptors, after the Naloxone is out of the system, those opioids can still come back and attach to the receptors and still cause overdose issues. That's why it has significant tons or abused a significant amount or abused synthetic agents. It's really important because they may need multiple rounds of the Naloxone agent to try to reverse some of the symptoms while they're getting and where they can then be monitored and have further assistance for their breathing, and their blood pressure, and their heart rate. Another trade name is EVZIO. This one is a pre-filled, auto-injecting device, making it fairly easy for families or other emergency personnel to inject Naloxone quickly into the agent. This is injected in the outer thigh. Once activated, it's kind of like those automatic defibrillator devices. It will actually walk you through and provide verbal instructions about how to deliver the medication, and what to do that [inaudible]. So withdrawal. This is the part of the phenomenon, part of the cycle that a lot of those suffering from opioid use problems are deathly afraid of. They will do anything and everything in their power to avoid withdrawal. I think this is the one thing that they can just get through withdrawal, they're fine. But as mentioned on other modules, this is only one small part of it, it is the part that you will be having folks come to seek treatment for. It's because they want to avoid withdrawal at all costs. So when we stop opioids abruptly or sometimes even gradually, you can sometimes start having withdrawal phenomenon. So what is that? That's when our bodies become physically dependent on the substance and because of the removal of that substance, our body is needing that substance to think that it's at a baseline. So when we administer things like an antagonist, naloxone, naltrexone, or even high affinity partial agonists like Buprenorphine. As we mentioned earlier, alluded to earlier, this also can stimulate and spur off a withdrawal scenario. So it's also very important again to understand what withdrawal looks like. What are the signs and symptoms to prevent these things from happening? Again, when we're trying to help individuals, if we unfortunately cause some of these, the therapeutic alliance, the trust our relationship that you're maybe trying to foster with this patient, they give them hell, [inaudible] maybe broken [inaudible] feel just so, so, so bad. But we're trying to help them. So opioid withdrawal in essence is a reflection of sympathetic arousal, physiological changes that oppose the acute affects of opiods. So again, as we've mentioned, think about the intoxication phase. Simple way of thinking about any kind of substance use, intoxication, and withdrawal is thinking about the exact opposite of what the intoxication phase looks like. So with that, here's some of the signs and symptoms of opioid withdrawal. So as we said earlier, when folks are intoxicated, they have that depressed outcome, so things are down. In the withdrawal phase, things are up. Things are going the exact opposite. They're starting to go a little bit hay wire in the other end of the spectrum. So having tachycardia, higher blood pressure, a little bit of a higher temperature, start having more of the yawns and problems with sleeping, staying up too much, and the inability to sleep is a big one that folks will talk about. "Doc, I can't seem to find any sleep. I just can't do it and this is driving me nuts. " As compared to the constricted pupils, very, very dilated pupil. You almost cannot be any coloration in their eyes whatsoever that their pupil is taking up the entire portion. Reflex is a little bit more exaggerated. Hyperreflexia, rhinorrhea, people doing the sniffs. That is the body's reaction to withdrawal, they're starting to have that rhinorrhea occurring. The sweating, the hot/cold flashes causing, again, gooseflesh, which again is just part of the erection of the skin and the arousal state. Again, with that up beat, you're going to start getting these muscles spasms in different areas. A lot of folks will complain about restless leg at night, which is also a contributor to the insomnia and being an issue. Where their muscles will spasm, their legs will jerk, their legs will kick. But they're also will start having muscle aches and spasms in their arms and their abdomen. So because of that, causing some nausea and vomiting. As we mentioned earlier, with the gut motility being decreased using these substances, imagine then the exact opposite. So you're going to possibly have some have loose bowels and some diarrhea. Folks will try to circumvent this themselves or this is also all these phenomenons; the worst flu, you'll hear that as well. I guess it's like the worst flu that I've ever had. Folks will sometimes chronically call up to work saying that they've got the flu and it's definitely not even flu season. Because of all the constellations of signs and symptoms that we're talking about look extremely similar to the severe flue. But it's like a feeling you're on steroids. So if you've ever experienced the flu yourself, imagine that times like a 100, if not more so. Of course, some of the kicker, as we mentioned, with the amygdala decreasing some of the fear and anxiety, they no longer have that in their system. So anxieties are going to start, almost popping out as a withdrawal phenomenon. So if you have that just in general then add it on top of this, somebody has issues with anxiety even before the substances were involved, it can be a double whammy and causing significant distress for somebody to go into withdrawals. To the point where they will again try to do everything in their power to avoid all these symptoms from happening. So some of the timing of these symptoms. So all opioids produce similar symptoms, and so it's important to get a chronology of each individual person's timeline of symptoms. Because everybody knows that some of things happen, and so getting a good time on helps you, will also helps the patient understanding of where they are in their withdrawal phase. So severity of the withdrawal can vary depending on how much you've been using, how long you've been using, but also the timeline depends also on the type of level field you've been using, allergy with a longer-acting opioids during your system, the longer the start of this, which are always going to be delayed. Of course, the more immediate release, the more shorter acting and it's going to be quicker onset. So as this table shows here, the shorter-acting opioids like heroin and oxycodone, you can get start having withdrawal symptoms as early as six hours with the peak roughly, they have three days into the process. That roller-coasters peeking then. Then about five to seven days and they'll start having some resolution. Now, if you start thinking about folks that have either been on methadone for opioids use disorders or had been finding methadone on the street to mitigate their withdrawal symptoms or even self-treating themselves that when they stop using, can't find, or otherwise, the longer-acting nature of this kicks that withdrawal or can down it as far as starts first coming out. So you may not start seeing some really withdrawing from methadone. So two days later, so keeping that in mind, especially for hospitals folks or somebody that had, some are going into hospital for surgery, or in an emergency setting and they're in ER for an extended period of time that these things may start coming out. So you when you start seeing again those signs and symptoms on the monitors or the anxieties coming out, that may be an indication that there may have been utilized longer-acting opioids. Again, the peak being in a three-day mark. Again, it could be a little bit longer, duration withdrawals can be up to three weeks. That's a long period of time and going through withdrawal, as we said, such an unpleasant experience. But to have somebody go through that potentially for three weeks is a pretty hard thing to tolerate and hard to swallow. So what do we do? How can we manage this? As we said, it's such an uncomfortable experience what as physicians can we do to help? So we can do some symptomatic treatment with medications like quantity and like loperamide, ondansetron, ibuprofen to target those symptoms as they arrive. I'd like to talk to my patients, among whom I remembers the game Whac-A-Mole from circus or the arcade games. You're sitting there, every time that mole's head pops up, you're whacking it down. That's what we're doing with these medications will appear. They're just trying to target that specific sentiment at that specific time without necessarily transfer for a longer term use. Because as we said, the general peak at about three days, shorter-acting opioids, usually it will be done withdrawal symptoms about anything in 5-7 days. So that's a window we'll be using these medications with. So when we also thinking about quantity and why is that, it is an Alpha-2 adrenergic receptor agonists and helps to define the symptoms of that hyper adrenergic surge, that's hypertension attack, the sweating comes into play, and so we can use that medication to lower those symptoms, and also can be helpful for the insomnias and anxieties, to ease that burden. Recently, just before even taping these modules, the FDA approved a more selective Alpha-2 adrenergic receptor called [inaudible]. So we'll see how that gets put into the scheme of things. The clonidine has been around, has been utilized for a long time in opioid withdrawal to help us out with these symptoms. But it is not as much of a select Alpha-2 as opposed to [inaudible]. It's one of essentially acting altitude. So also we can, as opposed to some of the [inaudible] that are scattershot hitting different symptoms. We can also use that same physiology to our benefit and make use of agents like methadone, buprenorphine to relieve some of these withdrawal symptoms, problems. Some folks with a plant that they gradually taper days to weeks to less than the intensity of those withdrawal symptoms, using again, that same binding, that same tickling of those Mu receptors to relieve those withdrawal symptoms. Now, that kind of approach is what we used to call a detox, but no longer in vogue. We are turning that medically-supervised withdrawal. If you hear that is all the intents of purposes that the same phenomenon as he talks were medically-supervised, or medically-managing, or medically-helping you through withdrawals. Detox can have a very stigmatizing perspective for folks and words matter and we'll talk about them [inaudible]. So the whole point is to make withdrawal as comfortable as we can. Now, let's not going to say that all discomfort is going to be taken away, but we can do our best, to try our best to get as much of it decreases as it can. Important point is there are numerous studies, repeated studies that just getting somebody through withdrawal without a plan afterwards has been shown to be ineffective at preventing folks from returning to opioid use. The highest peer to time for relapse is right after somebody comes from detox. If there's not a kind of place or if medications for maintenance are not realized. So layman and a lot of folks think that if somebody has gone through detox, they're, "cured, they're great, they're good, they no longer need help or assistance." However, we just know again, physiologically and psychologically that's not the case. So just keep that in mind when you're treating patients that just because you've gotten them to the withdrawal phase, the recovery process and the treatment process is not finished yet. So in summary, we've talked about a lot of things during this module. So humans, we have three different types of opioid receptors; the Mu, Kappa, and Delta. The one that you really need to keep in mind is that Mu receptor. That's the one that's really involved in addiction and use disorder phenomenon. But it's also the part that give us the analgesia. So again, yeah, there's good and bad after that receptor. Of course, we're still learning there may be some other receptors or other things that we're going to be learning in the future. So opioids also take over both the positive and the negative reinforcement systems in our body. So taking over the positive reinforcement causes individuals to want to seek out and use more and more opioids because we got a good feeling, we got that positive reinforcement that, "Hey, I like this, I want more of it." Also, interferes and hijacks the negative re-enforcement. It's least perceptually, it's taken away some of those negatives. It's taken away the fear, the discomfort. So I'm not as concerned about using that because it actually help take away the bad things that I didn't want. So this double-whammy of affecting both the positive and negative reinforcement systems further bolsters the addiction processes and the use of these substances folks are find themselves and now. Agonists, like methadone antagonist naltrexone, naloxone, and partial agonist; these medication categories have distinct effects on the Mu receptor. Because of the partial agonism we are working, as we continued to reiterate, it's unlikely to lead to as much the fatal respiratory depression even higher doses than those full agonists like methadone, which again is one of the boons for this medication and one of the positives with medication, and now actually opioid withdrawal overdose. Define symptoms intoxication are important to understand, importance to recognize when we're seeing patients that are coming to us specifically for issues. But even in the general population, if we see somebody with some of these things that potentially are the precursors to symptoms, it's well-worth knowing and their safety to be able to recognize these symptoms, but also knowing that there's different ways that we can treat withdrawal and overdose within a conservative manner. Other management support of medications like [inaudible] , loperamide, [inaudible] , as well as medication-assisted therapy such as buprenorphine. Then of course then an antagonist therapy as well to completely block that receptor. Different ways, different mechanisms in order to understand why these things work. So that way you can fully help your patient understand what's going to be the best treatment for them. So I thank you so much for listening to this module. Look forward to seeing you guys back in Module 3, and continue learning. Thank you so much.
