Pain medicine specialist Chris R. Abrecht, MD, explains why the clinical focus on the physical pain of opioid withdrawal may be hampering effective treatment. Drawing on the latest literature and defining useful new terms, he illuminates the factors that keep patients dependent – i.e., why they often remain “so miserable” after the physical withdrawal period has passed – and offers a flowchart for managing hyperalgesia. Also: Learn which patients are candidates for buprenorphine therapy.
Division of pain medicine, and I'm the medical director of our pain management center. And I'm going to be talking about an entity that you won't, I think, find in an ICD 10 or whatever, you can call it future books, um, but which does exist, uh, complex persistent opioid dependence. Uh, this is for, I've struggled with this myself as a pain doctor, when I see patients and you aren't quite sure what's going on with them, many of them may have this particular diagnosis. So what I'm gonna talk about is briefly, addiction, the three stages of addiction, dependence with what I call a lowercase d. A brief review of what opioids actually do, not just pain relief, well, not just relief of pain, but global relief, uh, something called opponent process and allostasis, this cool word that you maybe haven't heard of, hydrocatiphia and dependence with an uppercase D, and then whether to taper or not. So starting off with this, addiction is Something that you can view in different ways. One, Is this process where there's a period of preoccupation about a substance, then a binge intoxication period followed by withdrawal and negative affect. And key concepts for this are you have a euphoria that's brought on by the use of a drug, and that's followed by overall lower levels of euphoria. Each time you take a drug, you have the same amount of euphoria from it, but your baseline for how you just feel all the time is lowered. So if you have a low baseline and you take a drug, that drug may just bring you back to what for other people is normal. And in an individual who struggles with addiction can be tempted to return to the drug to reduce the misery that is caused by the use of the drug itself. Uh, a lot of these, uh, references are excellent, and I think it can be good to take a peek at. Uh, this comes from, uh, George Koob, largely, who's an internationally recognized expert on alcohol and stress, neurobiology of alcohol and drug addiction. He's the director of the National Institute on Alcohol Abuse and Alcoholism. So going back to our picture here, yeah, binge intoxication, and then once you've passed that, you're in this withdrawal period. And usually, if we're gonna talk about opioids, cause I'm a pain doctor. Uh, the main thing that tends to drive a person to want to seek again the substance they were taking, it does apply to opioids and other things, usually more of this anxiety, dysphoria, irritability, sleep disturbances, malaise, people are just miserable, and that is what, more so than physical components like diarrhea, uh or myalgia. That drives someone to have a preoccupation with getting the next administration of the substance. So it's more this negative um affective state. In this addiction cycle that leads to continuation of the, the circle, and I'm not an addiction, uh specialist here, so you take what I say with some uh grain of salt, but, uh, I think this stands true. Now, dependence with a lowercase d, and this is what when we say dependence, usually I think comes to mind, Physical dependence. These are physiologic adaptations that occur if you use the drug repeatedly. If you have two cups of coffee a day and then you don't have coffee the next day, you may have a headache cause you're physiologically. Dependent on it. And most of these are short-lived. You can push through that uh caffeine headache, and then eventually it'll go away, um. And same thing applies to, to some degree. There's a lot of nuances here, but with the opioids as well. Most of the things we think about are physical. So if you go to cows, the clinical opiate withdrawal scale, uh, pulse rate, sweating, GI upset, yawning, pupil size, aches. Goosebumps, runny nose. Yes, there's others like restlessness and anxiety, but the bulk is really these physical symptoms. Uh, these changes are distinct though from what goes on in the brain's reward system, and that change in the reward system is what has a more prominent role in addiction. And another person I'm going to cite uh quite a bit in these articles is Jane Ballantine, who is a uh anesthesiologist and pain physician. She's really an internationally renowned expert in pain, in particular, the relationship between opioids and pain, and previously pain division chief at Mass General and then professor at University of Washington in Seattle. Um, And now kind of advocate advocates quite a bit on the evolving science of what opioids do. So, most of what I'm sharing is just kind of I found myself interested in these subjects and then found these other people who are really quite knowledgeable about these subjects, and that's what I've I'm sharing today. So opioids, uh, yes, they reduce pain intensity, but they also give this, what we can just call global relief, and this is based on some newer biological models suggesting that, uh, some of the relief we get is from a rewarding experience via mesolimbic reward pathways, which is separate from analgesic pathways. So if you take NSAIDDs, It reduces your pain intensity. And because you have less pain, you have less uh unpleasantness and negative affect. You have a, you know, a knee that's really bothering you, just keeps bothering you day in, day out, it affects you, you have a negative affect. If you take an analgesic like, uh, Toradol or whatever it might be, you have less pain, and you find yourself just less, uh, less irritable because of that. Opioids do the same thing to some extent. They reduce the pain, so therefore there is less of this negative affect, unpleasant, unhappy distress, but they also cause just global relief through mesolimbic reward pathways, and this pathway affects more relief from things like PTSD, depression, emotional dysregulation, stress, anxiety, just Kind of the feel better aspect of things. And these are all obviously very closely tied to each other, cause the more emotional dysregulation you have, the more unpleasantness and and prominent your pain experience is going to be. So opioids gonna do it all in some ways, but some of what they do, uh, in the short term is, is good, I suppose, but you can maybe see where I'm going with this. Uh, it can have longer term problems. So this is where we have this opponent process in theory, uh, opponent process theory and notion of allostasis, or essentially what goes up must come down and Make an impression on the ground. What that means is you initially use a drug for a, we call it positive hedonic processes and you take a drug and something good happens, the A process, and this is a pretty short time constant, and then afterward, there's the opposing the process, which is generally not as robust, we'll say, and you eventually enter a negative emotional state. And this is aversive. So you feel good, you feel not as good, and then eventually you get back to baseline. Is the thought that you can use this with, you know, just drinking alcohol, if someone has some amount of alcohol, they may feel good, and then afterward, um, feel bad, uh, the effects from that alcohol, not just hangover, but just more the emotional side and then getting back to normal eventually. Um, with repeated drug taking, the A process, the feel-good amount, stays about the same, and the B process or have the badness after the good is it sticks around a little bit longer. So if you repeatedly take a substance here, you can eventually have a B process predominant state. Which can result in hypercatiphia, which is where you have this negative emotional state overall. I saw this article in The New York Times. Uh, about, you know, what Ozempic reveals about desire and thought this picture was interesting cause they, they had this, uh, this cartoon initially thinking about not just food, but, you know, other things here as well, see alcohol and cigarettes, and then over time, and the patient is quite sad, uh, and over time less of that. And this New York Times article actually had some pretty good insights, uh, you have the link uh in there, talking about how, you know, how Ozempic works, uh, GLP-1 receptor agonists, reduces the way that hunger centers, um, tension, you know, for seeking food, and had this discussion of Uh, wanting and liking being two different things, or the pleasures of the hunt, like wanting something, and then the pleasures of the feast, or liking what you have wanted for a long time. And that these have distinct but connected circuitry, and this might sound familiar, I hope, but wanting kind of goes up as a drug increases, but liking plateaus or diminishes, leaving people frantically seeking something that no longer provides much, if any satisfaction. Uh, and made an interesting um. relevant point here that liking is more associated with the brain's natural opioids. Um, and then as an analogy, some just talking about methadone and buprenorphine, how you can satiate that craving by providing a consistent level, so you don't have ups and downs, um, but So the main point here is just the, the mention that the brain's natural opioid system really does affect a number of things and not just is there pain, is there not pain. But these natural opioids can do quite a bit. Um, yeah, so this is going back to saying here for the, you know, the pleasure of the feast versus liking something that's also uh in this similar pathway that opioids play into. So, uh, viewed yet another way, uh, talking about this opponent process theory and allostasis, uh, you feel good, something happens, you feel great, or you feel euthymic, normal, something good happens, you feel good, and then you get To baseline, you feel not good, and then eventually you get back to your normal state. So if someone has the emotional thermostat or set point, and Here you are, and something bad happens, good happens and bad, but then a number of just bad things keep happening to you, whether it's genetics, trauma, psychiatric comorbidities, substances, whether it's alcohol or drinking, and then eventually you get kind of pulled down to have a set point that is lower than it would be for for someone else. So we all just our body responds to to changes and Stability is maintained by, you know, above and below going back to the set point, but it can be altered, and you can have a new set point if you have multiple down events over time. So hyperktyphia and a lot of, uh, and this is from Kob, as I mentioned before, is the other half of hyperalgesia. So we talk a lot about someone has uh uses opioids quite a bit, they develop hyperalgesia, which is where you have this widespread sensitivity to pain. So like I'll say to my patients, uh, trying to explain this concept. OK, you're, you know, you're on the fentanyl patch for your back pain, but if someone cut your hand versus they cut my hand who doesn't take opioids, who do you think would feel the pain more? And Patients will often say, oh, I think I'll, I might, I'm really sensitive, I probably feel it more, and I say, yeah, you would, but you have all this fentanyl the systems you think you'd be feeling better, but it actually makes you globally more sensitive to pain, and then kind of, that's something that people can get, um, that their own biology is being changed by these substances. So, yeah, OAH is reset of the analgesic system, and where It's like this opponent process again. First something happens, then you go back down, and if you keep using that substance, uh, eventually you get to this lower set point, and the other side of hyper hyperalgesia is hyperktephia, derived from the Greek for dejection, sadness, or negative emotional states, and this again is from this presentation. Uh, by Doctor Kub, where a lot of these drawings apparently of, uh, absinthe drinkers, uh, they all look just depressed, and this goes back to the analogy of, uh, eventually having your emotional set point lowered, uh, due to this opponent process theory of I feel good staying the same, but then eventually you just get to a lower set point due to throwing off the normal reward systems. Uh, and a key point is that these, these key things of these key notions of hyperalgesia and hypercatephia are less likely to occur when you're restoring homeostasis. So if someone has acute pain, and they're given opioids, which is appropriate for some conditions. Um, you're less likely to be off kilter with where your set point should be, but if you're given an excessive amount, then you can have this process where it can override your reward pathways, and, or if someone has a genetic susceptibility or other reasons. Um, but if you're Not overshooting and you're appropriately treating uh the actively painful condition, then it's less likely to create this, some of these entities that I'm talking about. Uh, again, talking about this hyperktephia, uh, there's not a return to the pre-drug levels, but a shift of the balance points of your system if you repeatedly take these things. So you don't feel hedonically normal. You have malaise, irritability, anxiety, dysphoria, you're uneasy. I'm sure if you think of some patients who are chronic. on high-dose opioids, say for spine pain or something else. They are often having some of, you know, those descriptions there. They're kind of wondering what's going on. Is it this, the pain makes them irritable or the pain makes them depressed? it's, uh, that's what we're talking about. Um. And yes, so this can lead to the, the unhappy state of things is from Jane Ballantine, uh, where the drug is believed to be helpful only because continued use of the drug is needed to avoid the drug's own negative effects. So, you know, up, you take it, and then the, the A process and B process, A process, B process, eventually you're going to a new set point, and you can eventually get into a withdrawal period, and you have all of these hyperalgesia, it's just miserable, hyper, you know, hypercaphic, and then a life stressor, and, you know, relapse. This is, I think for, for heroin, what they're talking about here. Um, just another way of saying the same thing. Uh, this was in methadone patients, uh, patients with prior, uh, OUD. You have an A process and then a B process, you use something once. If you were to use heroin once, you go up, you go down, and then you get back to normal. Um, if you have someone, um, on methadone, they still have this, uh, this lower set point. Which we have to If you take the methadone, you make up for the difference that you have a lower set point, we'll say. And the key point of this is, this is dopamine they're looking at uh for these patients who's abstinent, uh, not on the methadone. The amount of time to, if you are not on the methadone, but you're off of it, to get back to a normal emotional set point, uh, emotional and just hyperalgesic or not a set point can take a long time, 20 months. I, I wonder how long it takes to actually get back to normal here, cause I have plenty of patients who We're on tremendous doses of opioids, and then a few years later, 3 to 5 years later, have a, a painful event for surgery, they need opioids, and then the tolerance is uh still there, I find. Yeah, and this negative response. The B process it seems to come back with a vengeance. So this is just a long change that can occur with these opioid use, so kind of rewinding, uh, some of this can take a very long time. So this is where we're getting to this dependence with an uppercase D or long term opioid therapy. We know poorly controlled pain, poor psychosocial status, unstable psychiatric, uh psychiatrically. Um And if you have someone like this, you know, the logical therapeutic intervention of opioid tapering and discontinuation can cause worsening of all these issues, cause they need those opioids to maintain that set point. Um, and this, uh, again, a process, if this is the first few dosing minus a B process, eventually you get back to a set point. And if you're someone who uses repeatedly, see here, a process brings you up, but then your, your set point ends up being, uh, lower, even though the blood levels are the same each time. So this is where we have this notion of opioid dependence with a capital D or complex persistent opioid dependence, or you have a patient who takes opioids chronically, there's no craving or compulsive use, uh, there's no harmful use that is not medically directed, and I take them exactly as prescribed. Uh, if you stop taking them though, or, you know, gradually or suddenly, there's, yes, physical withdrawal symptoms, but also more prominent, uh, hypertyia present and hyperalgesia actually. Uh, this can be a lifelong problem and a large part of it, again, is this reward deficiency. So what do we do, uh, to taper or not, uh, always assess a patient on opioids. Is it worth it? Risks, uh, benefits greater than risks? Yes. OK, continue. Risks are greater than the benefits, then you say, OK, maybe tapering makes sense. Um. If you get to the point where you cannot taper further, then this is where a lot of folks are stuck with, does this patient have opioid use disorder? I don't have a slide for the DSM criteria, but we, it's, you know, pretty well publicized, but do they have that? Uh, or Do they just feel miserable, irritable, they're saying like things are not going well, like it's just badness happening, and if that's the case, they're more in this opioid dependence category, but this term is really insufficient. I I would put someone here as complex persistent opioid dependence. And then options from here can be a lot of emotional support, someone's coming down to a lower dose, and you say, I hear you, explain this process of uh what you think is going on with opioid dependence, and complex persistent opioid dependence, slow things down, give tons of support. Patient education, and then see if you can go down further, or a conversion to buprenorphine. Um, There's another pathway here, but it's, there's a lot of stigma, of course, uh, in with these diagnoses and an overlap as well. Uh, so this is just a brief, uh, like five-minute video of actually Jane Valentine I've been talking about, uh, just Summarizing more eloquently and myself, uh, what I just talked about. Then I had more slides to follow this, but I'm just gonna let her talk a little bit. There are some words that are better understood in general parlance than they are in medicine. Dependence is one such word. Despite the fact that most people understand what it means to be dependent on a drug. When it comes to medical terminology, there is much confusion about how to define drug dependence and how it relates to drug addiction. There is no area in medicine where these distinctions and definitions are more important than in the treatment of pain with opioids. In this month's edition of Pain, we have written a topical review on the subject of refractory dependence on opioid analgesics. We argue that opioid dependence should be considered a distinct and separate phenomenon from opioid use disorder, stroke addiction. We make this argument not only on the basis of established and novel neurobiology, but also on the basis that the clinical presentation of dependence in patients who have been taking opioids continuously for months or years is not the same as addiction, even though there are some shared symptoms and some shared treatment needs. Confused terminology has been unhelpful in the debate over whether drug dependence is the same as addiction, a feature of addiction, or distinct from addiction. If we look at an older model of drug drug addiction, we can identify several areas of confusion. First, the word physical. Understanding of what physical means in this context can range from simply classical somatic symptoms of opioid withdrawal to the much broader brain adaptations to continuous opioid use seen in our next slide. Second, The use of the term substance dependence to denote substance addiction in earlier addiction criteria, which was based on physical dependence being seen as a common endpoint in the pathway to drug addiction. This was changed in the more recent DSM-5 criteria in no small part because it was recognized that patients taking opioids for pain could be physically dependent but not addicted. Third, whether the state of dependence itself is a risk factor for addiction independent of the genetic risk factors that initiate the spiral envisaged by the older model. Newer neurobiological studies have been able to expand our knowledge of each of the classic stages of drug addiction, but for patients with pain treated with opioids, we focus on the second withdrawal negative affect stage. This can be the main entry point into the cycle of addiction for someone taking opioids as prescribed and does not necessarily progress beyond this stage. We can now understand that the manifestations of this second stage, rather than being expressed simply as easily reversed physical symptoms, are complex, invasive, and elusive. When we actually face patients is when we run into difficulty with definitions. Take the case of Francy, who has been taking high doses of opioids for years and has been fully compliant. When her prescriber decides she should be tapered on the grounds of safety, she has tremendous difficulty tapering. Some would argue she meets the two highlighted criteria for opioid use disorder and therefore has mild opioid use disorder. Yet before attempting to taper, she would not have met criteria for opioid use disorder. She took opioids, understanding the treatment to be safe and effective. Nothing changed in her brain that reflects compulsive drug seeking. If she's given an opioid use disorder diagnosis, it's stigmatizing, may affect the treatment she receives, may affect her employment, but most importantly, is not neurobiologically correct, since she did not become dependent knowing her drug taking was harming her or having difficulty controlling her drug taking. Moreover, she has never manifest compulsive use or loss of control over use. We would argue, therefore, that she has opioid dependence and not opioid use disorder as currently defined. In conclusion, a refractory and complex form of dependence on opioids can develop, particularly when opioids are taken continuously for months or years. Despite many similarities to opioid addiction and overlapping symptoms, this complex dependence should be distinguished from addiction because it because it is not addiction either clinically or neurobiologically, and because it needs treatment that is similar yet different from addiction treatment. Yeah, OK. So just as another example, you had a 61 year old patient with PTSD, chronic pain from spine disease, who is on high-dose fentanyl patches. Over time, his pain function worsened. He has insomnia, anger, depression, worse PTSD. He has tried to wean multiple times and had in his mind that it was, it was caused by worsening spine disease, but imaging showed everything was stable, and his PCP told him about these new CDC guidelines, decided to wean his opioids, and then everything gets even worse. So, you know, these medications, which are already quite high, worsen things, and then going down worsens things. The thrust here was, well, maybe the best landing place here maybe for substance abuse treatment, but patient when sent to these places was told that actually didn't qualify as having that, and he didn't feel that way either. Another example, 43-year-old with foot pain from, you know, stress fractures on methadone, uh, for pain control. Uh, his, his methadone was lowered, uh, and then everything got worse, pain, mood, functionality. Uh, he has no psychiatric disease and was given this diagnosis of his PCP explained to him what he thought was going on, that he, um, he had complex persistent opioid dependence. And the patient was restarted on the prior dose Everything got better. And then after ongoing psychoeducation, the patient decided to pursue a very slow taper. Uh, this was tapered completely off over the course of a year. Pain persisted though, but not as distressful as before. And eventually, the patient was started on buprenorphine, and then that was slowly weaned over time. Um, patients are still weaning. This is, you know, years later, but it's committed to the opioid taper. So, this is where if you get to the point of can't taper, buprenorphine is a medication that is an option. And why is this? Yeah, buprenorphine, you know, partial mu opioid mu agonist, it also has kappa antagonism, so some anti-hyperalgesic effects, just a whole bunch of other things that we don't quite understand, opioid receptor like one. Um, important is that it has a high binding affinity and a very slow dissociation, so it doesn't have this fast on, fast off like other opioids, which is a large part of this opponent process that we've been talking about. Uh, has a long half-life, so you're unlikely to have, uh, withdrawal symptoms in between. So there are benefits as well. You can, however, still overdose with it. You can still get OIH hyperalgesia with it, and you can still get, um, typical side effects, we'll say, but better than full agonists. Uh, so when I'm seeing a patient, I think who's a candidate, uh, if someone has concurrent OUD, yes. Uh, anyone who is not tolerating weaning, and then any patient with a long-term opioid need, however, that may be defined. So key points here, uh, hyperalgesia and hypertephia, uh, is less likely to happen if you're treating an acute problem, restoring homeostasis, uh, treating pain. But over time, uh, You can develop this kind of new set point where opioids cause global relief of various conditions that 1 may have, and that then taking away that medication can put you at this lower set point where you have more of these symptoms present than otherwise. So I think then I will leave it at this. This is from a piece for another talk. I don't get too much into this from uh the pain center, but it's a beautiful building where we work, uh, and we try to do a whole assessment of the patients, um, but it can be a challenging thing to tease out here. But I think I'll just go and see what questions we, we might have.
