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Medical Student 8 Hour Buprenorphine Training
Session 2: Neurobiology
Session 2: Neurobiology
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Video Transcription
Welcome back to the training. I'm Dr. James Finch, an addiction medicine physician originally trained in family medicine, and I will be presenting Module 2, Neurobiology of Opioid Use Disorders. But before we move into Module 2, take a moment and reflect back on Module 1. In this module, along with the other didactics, we will introduce you to Bruce, one of the patients that we have created as part of our integrated case studies approach to this training. Bruce is a 40-year-old divorced criminal defense attorney in private practice and father of a 14-year-old son. He knows about buprenorphine because you're treating some of his clients, and he would like to get some help from you for himself. He's been using heroin regularly for the past five years. His goal in seeking treatment is to use buprenorphine during the week, and occasionally use heroin by snorting on weekends. As we go through this module, we will consider how Bruce's heroin use may have affected his neurobiology. We will spend time now looking more closely at the neurobiology of opioids. During this module, we will describe the effects of opioids, including the effect on positive and negative reinforcement pathways, discuss the difference between full agonist, partial agonist, and opioid agonist, and explore how these factors play out in terms of opioid intoxication, tolerance, overdose, and withdrawal. The term opioids refers to all compounds, either natural, semisynthetic, or synthetic, that react with our body's opioid receptors, including the endogenous opioids that naturally occur. Those derived from compounds occurring naturally in the opium poppy include morphine and codeine, and have traditionally been referred to as opiates. Since heroin is a derivative of morphine and is active as morphine, it is often lumped in with opiates, for example, on many urine drug screen panels. But it is officially a semisynthetic opioid, along with oxycodone and buprenorphine and others. Fully synthetic opioids include fentanyl and methadone. All opioids, whether natural or synthetic, react with the endogenous opioid receptors, varying in terms of agonist potency, receptor affinity, rapidity of onset, and duration of action. All of these characteristics are critical to a particular drug's abuse potential and or therapeutic potential. As you may recall, Bruce uses heroin, a semisynthetic opioid that may have shown up on a basic opioid drug screen when he came in for his visit. Bruce, like all human beings, has three types of opioid receptors, mu, kappa, and delta. They are located throughout the body in the central nervous system, peripheral nerves, gut, and cells of the immune system. Endogenous opioids are those naturally occurring in the body and activated following injury, pain, and stress. Most of the clinically significant effects that we will be discussing to both prescribed and illicit opioids are attributed to the activity at the mu receptor. Opioid receptors are located throughout the body. They're most densely concentrated in the brain associated with pain perception, the reward pathways, and respiratory function. But as previously stated, we can also see them in the spinal cord, GI system, and peripheral nerves, giving rise to the range of symptoms seen in opioid withdrawal. In this slide, you see opioids affect a variety of areas of the brain. Different areas will result in different responses. There are some areas where the opioid receptors are more densely distributed than others. When they bind to the thalamus region, they produce some of the analgesic effect that blocks or numbs pain. When they affect the ventral tegmental area, they result in a release of dopamine, which then has a significant effect on the nucleus accumbens. The nucleus accumbens is referred to as the pleasure or reward center of our brain. It is the profound release of dopamine within this area of the brain that can lead to addiction. We interpret or become conscious of the effects on this pleasure center within the prefrontal cortex. It is within the prefrontal cortex that we would identify a significant increase in Bruce's desire for and use of drugs. At the same time, downregulation leads to decreased concern over the risk and consequences of abuse associated with the effect on the medial orbital frontal cortex. We will return to this important dynamic of reward and risk in more detail in a moment. There are a variety of physiologic effects of opioids in the central nervous system. These include the relief of pain or analgesia, as we spoke of, as well as sedation, euphoria, pupillary constriction, and decreased heart rate. A critically important aspect of the central nervous system's effects is the slowing of respiration. It is this consequence that can lead to overdose death. However, partial agonist opioids, like buprenorphine, do not have the same effect as full agonists on the medullary respiratory center and its response to varying levels of CO2, resulting in an increased safety profile for these medications. Effects on the GI system include nausea and slowing of gut motility, resulting in greater reabsorption of water and subsequent constipation. It should also be noted that the effect of opioids on peripheral tissues can contribute to analgesia and modulation of inflammatory responses. It is important to understand that our motivation to do anything in life is neurobiologically driven. Dopamine is the primary neurotransmitter involved in motivation by mediating positive reinforcement within the nucleon's accumbens. There is genetic variation among individuals, resulting in variability in the degree of dopamine activation in response to a given stimulus. This elicits different degrees of liking, resulting in variable behavior in seeking that stimulus. This is associated with both healthy and unhealthy drives. This is the area of the brain involved in the enjoyment of food, sex, exercise, joyful social interaction, taking joy in our environment like a beautiful sunset. All of these are important to our individual and social well-being. But it is this same crucial reward system that can be hijacked by dopamine activation in the setting of drug use. The negative reinforcement associated with motivation is centered in the amygdala. This is the area of the brain that mediates the fight or flight response associated with anxiety, fear, and distress. This helps us avoid certain dangerous situations. These neurobiological functions of positive and negative reinforcement may occur at a largely unconscious level. But we interpret these motivations in the prefrontal cortex, the seat of the cognitive domains of contemplation and judgment that can serve to modulate our responses to these various stimuli. Bruce, like the rest of us, has done good things for himself and others through the course of his life and his experience to the associated positive rewards. But when he uses opioids, they stimulate an exaggerated release of dopamine in his system, many orders of magnitude above that released by his natural reward system. This becomes an increasingly difficult source of reward to deny. It increasingly overrides the healthy responses within the nucleus accumbens. As his neurology adapts more and more to the drug, Bruce may even begin to feel anxious when he does not have the drug, becoming more and more preoccupied with its use and less interested in other sources of reward. Frequent enough use leads to physical dependence and then withdrawal symptoms that increase the drive to persistent regular use. In parallel, the prefrontal cortex has become more preoccupied with need and desire for the drug and less able to deal rationally with the negative consequences and risks associated with ongoing use of the drug. Here we see a PET scan, neuroimage, of what Bruce's brain might look like, showing neurobiologic changes in the brain with chronic opioid use in the form of heroin. There is evidence of not only decreased dopamine release, but also a significant increase in amygdala reactivity following chronic use of heroin. On the left, you can see the decreased uptake in those areas showing decreased presynaptic release of dopamine, normal control versus heroin dependent. These changes have been shown to extend the period of acute withdrawal, and it has been suggested that the hypodopaminergic state contributes to the motivation to maintain drug use and relapse. On the right, you see the amygdala less prominent than the normal control compared to the subject exposed to chronic heroin use, like Bruce. This amygdala increased reactivity is a compensatory response secondary to the chronic exposure to heroin, a depressant, and is associated with withdrawal symptoms seen on discontinuation of an opioid following chronic exposure. Let's talk for a few minutes about how some individuals may have more vulnerability to these neurobiological effects, and therefore more vulnerability to addiction. Vulnerability to substance use disorders is mediated in a variety of ways, both genetic and environmental. This is often referred to as nature versus nurture, and is known to underlie many common medical conditions. What are some of the ways you think nature versus nurture plays out in relation to substance use disorders? Think about that for a moment. Genetic predisposition to addiction has strong research validation. How might this play out? Genetic factors may have to do with differences in opiate reactivity, degrees of dopamine release, or other neurotransmitters and intercellular signal variations between individuals. There also may be genetic variations in an individual's novelty seeking, avoidance of harm, levels of impulsivity, responses to stress, and concurrent psychiatric disorders, all of which may modulate an individual's response to an opioid or another drug. When we explore these issues with Bruce, we may find he is someone who is genetically predisposed to novelty seeking and risk taking. He may be more impulsive than others and make snap decisions without really thinking things through. Possibly this is further compounded by a genetic predisposition to mood disorders or other psychiatric problems. The environmental components associated with a vulnerability to a substance use disorder often overlap genetic predisposition. Patients with substance use problems will use more in the household and give messages related to that use that increase the child's susceptibility. This experience in the family is compounded by attitudes towards drug use among extended family, peers, and in the broader environment. Unfortunately, parental use of alcohol and other drugs also increases the child's potential exposure to adverse child experiences, frequently referred to by the acronym ACEs. With or without parental alcohol or drug use, adverse childhood experiences have been shown to significantly increase the potential of the child's having physical and mental health problems, including a substance use disorder. Another environmental factor associated with drug use disorders is the lack of healthy early childhood nurturing. This is often associated with the child's inability to develop healthy self-soothing skills. All of these environmental factors have a potential impact on age of drug use initiation, a factor strongly associated with the development of substance use disorders. These issues would need to be explored with Bruce in working toward reasonable therapeutic goals. What is his family history and genetic predisposition? His age of first use? What is his pattern of risk-taking and impulsivity? His psychiatric comorbidity? What does he think about the effect his drug use may be having on his 14-year-old son? Lastly, we know that the availability of alcohol and other drugs increases the likelihood of associated disorders. As was pointed out earlier, the increased availability of opioids over the last 20 years has had a major impact on the numbers of people in the United States with current opioid use problems. In this slide, we see a graph identifying the association between the dose of an opioid and the magnitude of its effect on the intrinsic activations of mu-opioid receptors. The upper graph depicts the activity of a full agonist, opioids such as methadone, morphine, or oxycodone. On the other hand, partial agonists, such as buprenorphine, represented by the circles of the middle graph, plateau, and there is a ceiling effect, well below the level associated with respiratory depression and arrest. Opioid antagonists, such as naltrexone or naloxone, represented by the lower graph, are shown to have no positive effect on the intrinsic activity of the mu receptor, and in fact, tend to block its activation by other opioids. Here we take a closer look at the opioid partial agonist buprenorphine, one of the frequently recommended drugs for medication-assisted treatment. As a treatment modality, it has a number of potential advantages. Like methadone, it is long-acting, so it maintains a steady level of agonist activity, preventing craving or withdrawal. With its high affinity for the receptor, it blocks the effects of other opioids, such as heroin, making it similar to an antagonist like naltrexone. Finally, as noted, the sealing effect gives it a good safety profile with minimal risk of overdose. Regulations regarding the use of opioid agonists for the treatment of opioid use disorders are quite convoluted. Methadone is allowed for that purpose, but only within the setting of a distinct, licensed opioid treatment program, often referred to as a methadone clinic. A legislative mandate, data 2000, allowed buprenorphine to be prescribed in an office-based setting for opioid use disorder. For a controlled substance to be used in an office-based setting, it must be a Schedule III, IV, or V medication and be approved for the treatment of an opioid use disorder by the FDA. Buprenorphine is classified as a Schedule III, and its various formulations have been approved by the FDA for this purpose. It is currently the only medication meeting both those criteria for general medical use. As noted, an important attribute of buprenorphine is its high affinity for the opioid receptor, an affinity much higher than most other opioids. The high affinity of the mu opioid receptor refers to the preference of the receptor for that compound and the strength of the bond of buprenorphine once it is in place. Because of this very high affinity, it will displace full opioid agonists from the receptor if they are on board when it is administered. As depicted in this graph, if another opioid is being actively used and is occupying the opioid receptors and buprenorphine is given to the individual, the full agonist will be displaced by the buprenorphine, and the drop in receptor activation will precipitate withdrawal, often rapidly and often to a severe degree. A more positive consequence of this high affinity is that once the patient is titrated onto buprenorphine, it is unlikely to be displaced by the use of other opioids. So, for example, a person with receptors occupied by buprenorphine will not respond to a slip using heroin or other opioids. Those drugs will not be able to displace the buprenorphine on the receptors. So, on the one hand, high receptor affinity can make initiating buprenorphine tricky in the setting of someone who is actively using another opioid. Timing of the first dose and titrating to effective maintenance dose require planning and patient education. But, on the other hand, the same high affinity is responsible for buprenorphine's effectiveness and preventing relapse in the face of craving and potential slips. Many of these patients, including Bruce, have been in withdrawal in the past, and it is a frightening and troubling experience. Naltrexone is an opioid antagonist and results in full blockade of the opioid receptor. It is available as a tablet, taken orally once a day, or as a long-acting IM injectable, administered monthly. If the patient takes the daily oral dose or is administered the monthly injection, they will have full blockade and no positive effect from other opioids. There is also a reduction in the craving for opioids, sometimes dramatically, thought to be secondary to a reduction in the effect of endorphins on the nucleus accumbens associated with the consideration of the use of an opioid. This effect is on the nucleus accumbens is also proposed for the reduction of craving for alcohol when the patient is administered Naltrexone. Naloxone is an immediate acting opioid antagonist that will be discussed in more detail in relation to reversing opioid overdose. Tolerance to opioids develops following the repeated exposure to these drugs. Tolerance is associated with changes in the number of receptors and how they function, affecting susceptibility to the opioid. There are differences in the level of tolerance for different opioid effects within the individual. Certain aspects of tolerance may develop rapidly, like increased tolerance to, and thus a decrease in sedation, euphoria, respiratory effects. But others, like constipation and pupillary constriction, develop little tolerance and will continue at the same levels as at the time of initial administration. It is also important to remember that individuals lose this tolerance if they abstain from opioids for an extended period, such as in treatment or incarceration. This puts them at serious risk of overdose if they return to their previous level of drug use. For the same reason, this is also a risk for those that have been on naltrexone and then start using again. They need to be informed that they are at increased risk of overdose if they relapse. Listed here are the signs and symptoms associated with opioid intoxication. It's important to take note of these, particularly the observable signs, such as pinpoint pupils. They will be useful in determining the level of use and tolerance. For example, how do Bruce's signs of intoxication fit with his description of his frequency of use and level of tolerance? The signs and symptoms will also be important in avoiding the initiation of buprenorphine administration when the person is actively using. Finally, signs of intoxication are important in terms of how they blend into signs of opioid overdose, a more serious, life-threatening condition. Here you see that some signs and symptoms of overdose are similar to those seen in intoxication, but some are significantly different and must be recognized and responded to. Overdose is not just calmness or mild somnolence, but decreased consciousness to the point of being difficult to arouse. Of primary importance is the state of respiratory drive, which is not just shallow, but is becoming slower or absent and associated with dusky or blue complexion. Treatment of an opioid overdose is the immediate administration of the rapid acting opioid antagonist, naloxone. It is administered either by nasal insufflation or injection. It's important, however, to understand that naloxone is a short-acting medication. It will typically be out of the system in approximately 40 minutes and will have a reduction in its efficacy earlier than that. Consequently, patients that have large amounts of longer or longer acting opioids, like methadone in their system, can go back into an overdose once the naloxone wears off. They therefore need continued monitoring and recurrent dosing, and that is why it is critical that 911 be called after administering naloxone. Most states in the country now have what are referred to as Good Samaritan laws associated with the administration of naloxone. This means that an individual in the company of someone who overdoses can hopefully administer naloxone, call 911, and remain with the patient until emergency services arrive. They will not be arrested for using or possessing opioids in that situation. Naloxone is lifesaving. Spontaneous opioid withdrawal occurs when an individual who is physically dependent abruptly discontinues or markedly decreases his or her use of all opioids. Also, if a person is opioid dependent and has opioids on board and is given a partial agonist, like buprenorphine, or an antagonist, like naloxone or naltrexone, they will go into precipitated withdrawal. Withdrawal has the features of a dramatic reflex sympathetic arousal. As stated, this is secondary to the physiologic changes that take place following chronic administration of an opioid and the body's attempt to adapt to the sedative and other effects of the opioid. Listed here are the signs and symptoms of opioid withdrawal. You'll notice many of these effects are opposite to those of opioid intoxication. This hyper arousal, secondary to no longer having the dampening effects associated with current opioid use. Take note particularly of the signs rather than the symptoms. Withdrawal is associated with a great deal of emotional distress and suffering, and it is useful to pay attention not just to how the patient says they feel, but how they look in order to gauge the level of withdrawal as objectively as possible. All drug withdrawals demonstrate general autonomic agitation, but a number of the listed symptoms listed here are fairly specific to opioids, including yawning, runny nose, goose flesh, body aches, and restless twitching legs, the source of the phrase kicking the habit. Recognition of these signs and symptoms will be important later when we talk about both the treatment of opioid withdrawal and the administration of buprenorphine. Opioid withdrawal symptoms will vary depending on the level of opioid dependence, how much and how often he or she has been using, the length of time since last use, and the type of opioid typically used, that is, long-acting or short-acting. Most of the short-acting opioids, like heroin or oxycodone, when discontinued will result in the onset of withdrawal symptoms within 6 to 12 hours. Typically, there will be a peak of these symptoms within 36 to 72 hours. The duration of short-acting opioid gross withdrawal is approximately 5 days. Longer-acting opioids, such as methadone or buprenorphine, will result in a more extended period of time prior to the onset of withdrawal symptoms, sometimes 24 to 48 hours, and can last up to 3 weeks or more. It's also worth noting that these are the times tables for gross withdrawal, that is, the person looking and feeling physically ill. Abstinence can result in a prolonged state of dysphoria, constituting a serious trigger of relapse. The treatment of opioid withdrawal is traditionally approached with a combination of medications other than opioids that are targeted at a reduction in symptoms. Clonidine is an alpha-2 agonist that will result in a decrease in presynaptic release of norepinephrine and, consequently, a reduction in anxiety and restlessness. Loperamide affects the gut mu receptor and results in a slowing of transit time in the intestine and a reduction in diarrhea. Ondansetron can help with nausea and vomiting often seen in withdrawal. A nonsteroidal anti-inflammatory medication can help with both muscle and bone aches. This is reviewed more thoroughly in a later module. However, another generally more effective way to manage opioid withdrawal is by starting either methadone or buprenorphine. Both of these are long-acting opioids and can be used to establish cross-tolerant homeostasis and then tapered, tapering the medication over a few days to a few weeks. This gradual tapering of these long-acting opioid medications reduces the severity of the withdrawal symptoms and other medications, including the ones above, can also be used here symptomatically, though often this is not necessary. It must be remembered, however, that unlike buprenorphine, the use of methadone for the treatment of opioid dependence must be through a federally and state-licensed treatment program. Understanding the neurobiology of the brain disease of addiction will help us understand and support our patient, Bruce, as he moves into treatment. Here are the main points for you to remember. Although humans have three types of opioid receptors, mu, kappa, and delta, the main target for opioids are mu receptors, which have multiple effects, including analgesia, euphoria, sedation, and decreased respiration and heart rate. Opioids take over the positive reinforcement, which causes individuals to seek out and use more opioids, and negative reinforcement, which impels individuals to avoid not having opioids, which can then result in fear, anxiety, and distress. Agonists, such as methadone, antagonists, such as naltrexone and naloxone, and partial agonists, such as buprenorphine, have distinct effects on the mu receptor. Because of its partial agonism, buprenorphine is unlikely to lead to fatal respiratory suppression, even at high doses. Opioid withdrawal has distinct symptoms and can be treated with supportive medications, buprenorphine or methadone. Overdose requires prompt treatment with naloxone. Now take a few minutes to check your understandings, and we'll see you again soon.
Video Summary
In this video, Dr. James Finch presents Module 2, Neurobiology of Opioid Use Disorders. He begins by referring back to Module 1 and introducing Bruce, a 40-year-old attorney and father who wants help for his heroin addiction. Dr. Finch explains that opioids, whether natural or synthetic, react with the body's opioid receptors, including the mu, kappa, and delta receptors. The mu receptor is most relevant to the effects of opioids. Opioids affect various areas of the brain, including the thalamus and ventral tegmental area, which release dopamine and contribute to pleasure and reward. Dr. Finch also discusses the physiological effects of opioids, such as relief of pain, sedation, and slowed respiration. He explains how Bruce's brain changes with chronic opioid use, including decreased dopamine release and increased amygdala reactivity. Dr. Finch also discusses genetic and environmental factors that contribute to vulnerability to addiction. He explains the difference between full agonist, partial agonist, and opioid antagonist medications, and the use of buprenorphine and naloxone in treatment. The video concludes with information on opioid withdrawal symptoms and treatment options.
Keywords
Neurobiology
Opioid Use Disorders
Opioid Receptors
Brain Effects
Chronic Opioid Use
Treatment Options
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Funding for this initiative was made possible by cooperative agreement no. 1H79TI086770 and grant no. 1H79TI085588 from SAMHSA. The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government.
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