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 am going to be talking about a entity that you won't. I think find uh in an I CD 10 or whatever you call 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 a 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 allo stasis. This cool word that you maybe haven't heard of Hydro Phia and dependence with an uppercase D and then whether to taper or not. So it's 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, and 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. And a lot of these uh references are excellent and I think it could be good to take a peek at. Uh This comes from uh George Coo, largely who's an internationally recognized expert on alcohol and stress neurobiology of alcohol and drug addiction is 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 go to talk about opioids cause I'm a the pain doctor. And the main thing that tends to drive a person to want to seek again the substance they were taking this, it does apply to opioids and other things. Usually more 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 the preoccupation with getting the next uh administration of the substance. So it's more this negative um effective state in this addiction cycle that leads to continuation of the, the circle. And I'm not an addiction uh specialist here. So you have to take what I say with some uh grain of salt. But uh 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 physiologically dependent on it. And most of these are short-lived, you can push through that uh caffeine headache and 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. G I 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 uh has a more prominent role in addiction. And another person I'm going to cite uh quite a bit in these articles is Jane Valentine who is a uh anesthesiologist and pain physician, is really an internationally renowned expert in pain, in particular, the relationship between opioids and pain. Uh previously Pain Division Chief at Mass General and then professor at University of Washington 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 uh knowledgeable about these subjects. And that's what I've been 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 nsaids, 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 a knee that's really bothering, you just keeps bothering you day in day out, it affects you, you have a negative effect. If you take an analgesic like uh Toradol or whatever it might be, you have less pain, then 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 uh 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 um emotional dysregulation, you have the more unpleasantness and, and prominent your pain and 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 and theory. Uh opponent process theory and notion of all of stasis or uh essentially what goes up must come down and make an impression in the ground. What that means is you initially use a drug for a, it calls it positive heic process. As then you take a drug and something good happens the A process and this is a pretty short time constant and then afterward, there's a opposing B 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 and not just hangover, but just more of 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 having 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 bro predominant state which can result in hyper Katia, which is where you have this negative emotional state. Overall, I saw this article in the New York Times. Yeah, about, you know what Ozempic reveals about desire and thought this picture was interesting because 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 uh this New York Times article actually has some pretty good insights. Uh You have the link uh in there talking about how you know how Ozempic works. Uh G LP one receptor agonist, it 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 just but connected circuitry. And this might sound familiar, I hope but wanting kind of uh 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 a interesting um relevant point here that liking is more associated with the brain's natural opioids. Um And then as an analogy, I'm just talking about methadone or buprenorphine, how you can see that craving by providing a consistent level. So you don't have ups and downs. Um But so the main point here is that 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 what I was saying here for the, you know, the pleasure of the feast, for instance, 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 allo stasis, 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 and you feel not good and then eventually you get back to your normal state. So if someone has the emotional thermostat or set point, uh here you are and something bad happened, 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 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 uh uh down events over time. So hyper Kia and a lot of uh and this is from Cobe, as I mentioned before is the other half of hy 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, you have all this fentaNYL in 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 uh substances. So, yeah, oah, is reset of the analgesic system um 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 Kate uh hyperalgesia is hyper gate derived from the Greek verp injection, sadness or negative emotional state. And this again is from this presentation um by Doctor Coop where a lot of these drawings apparently of uh absent drinkers and 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 that, 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 hyper Kia 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 overshoot 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 hyper gates. Uh There's not a return to the predrug levels, but a shift of the balance points of your system if you repeatedly take these things, so you don't feel he toly normal. You have malaise your ability, anxiety dysphoria, you're uneasy. I'm sure if you think of some patients or chronically 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 Valentine. 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 to a withdrawal period and you have all of these hyperalgesia, it's just miserable, hyper, you know, hyper and then a life stressor, uh you know, relapse. This is, I think for, for, um just another way of saying the same thing. Uh this was in uh methadone patients, uh patients with prior uh oud, you have an, a process and then ad 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 they 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 I 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 hyperalgesia or not a set point can take a long time. 20 months. Uh 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 uh 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 re 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, psychiatrically, 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 because 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, 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 for 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 take them exactly as prescribed. Uh If you stop taking them though, for you know, gradually or suddenly there's yes, physical withdrawal symptoms, but also more prominent uh hyperopia present and hyperalgesia actually, uh this can be a lifelong problem. And large part of it again, is this reward deficiency? So what do we do uh to taper or not? Uh always as assess the 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 GSM 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 is 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 in myself, uh what I just talked about that I had more slides to all this, but I'm just gonna let her talk a little bit. There are some words that are better understood in general poll 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've 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 end point in the pathway to drug addiction. This was changed in a more recent DS M five 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, neuro 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 effect 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 Franky 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 take her, 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 neuro biologically correct since she did 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 neuro biologically. And because it needs treatment that is similar yet different from addiction treatment. Ok. So just as another example, you had a 61 year old patient with PTSD with chronic pain from spine disease who is on high dose fentaNYL patches over time, his pain function worsen. He has insomnia, anger depression, worse PTSD. He has tried to wean multiple times and had in his mind that it was worse, it was caused by worsening spine disease. But imaging showed his everything was stable and his PC P 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 or 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 and 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 PC P explained to him what he thought was going on that he, you know, he had complex persistent opioid dependence and the patient was restarted on the prior dose and everything got better. And then after ongoing psychoeducation, the patient decided to pursue a very slow taper. The this was tapered completely off over the course of a year. Pain persisted though but not as distressful as before. And eventually the patient 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 uh this is where if you get to the point of you can't taper. Buprenorphine is a medication that is an option. And why is this, you know, buprenorphine, you know, partial mu opioid mu agonist, it also has Kappa antagonism. So some anti hyperalgesia effects does a whole bunch of other things that we don't quite understand opioid receptor like one. Um I 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 as a long half life. So you're unlikely to have uh withdrawal symptoms in between. So 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 hyper Kia 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 this is a beautiful building where we work at 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.
