everybody. It's a pleasure to be here. I'm going to be talking about the epidemiology of opioid use disorder. I have no conflicts of interest or disclosures. First and foremost, we're going to talk about the epidemiology of opioid use disorder. To me, that means the incidents and try to characterize the patients that we see that have opioid use disorder or opioid-related disorders. We're going to use those terms somewhat interchangeably today. Specifically in the ICU setting, we're going to talk about the impact of COVID-19 on the epidemic, and finally, identify some opportunities to reduce harm in these patients. So first, let's make sure that we're talking about the same thing. DSM-5 criteria, opioid use disorder is defined as this by the American Psychiatry Association. You need two of the 11 criteria listed on the right-hand side, largely behavioral-related. Based on that scoring system, the patient will be characterized as mild, moderate, or severe. And it's important to note that this is not validated in the ICU. For coding purposes, we often use ICD-10 codes, specifically the F11 and T40 codes. F11 largely focuses on opioid-related disorders, whereas T40 is acute poisoning and ingestion. And for those of you that are caring for these patients in the ICU, you're also going to be dealing with these other terms, both physiologic and behaviorally related. So tolerance, which is certainly going to pose a challenge when you are trying to manage acute pain in the ICU setting, and also withdrawal can pose also complications related to acute care of these patients. So many of you have probably seen this CDC graph before, and it just illustrates the increasing incidence in fatality related to the opioid use disorder. Now interestingly, you see a plateau around 2017, 2018, 2019, and that was very encouraging for us to see. And then right around 2020 again, it started to pick up. The slope of the line increases substantially. You'll see mirroring the anti-opioid group is the synthetic opioids other than methadone. This is largely represented by fentanyl, specifically. So when you look at fatal overdoses related to medications, fentanyl accounts for nearly 70% of those cases. On the right-hand side, we have a heat map so you can get an idea of where you may lie geographically. West Virginia is at the top of that list. Now this is kind of an interesting slide to look at. So when you break down the fatality rate by specific drug, you see that again, fentanyl is leading the charge. But a couple years delayed behind fentanyl, and albeit a smaller magnitude, you see a similar slope associated with methamphetamine and cocaine as well. So let's take a closer look at those. When you look at the fatalities associated with methamphetamine, you can break it down by the presence or absence of fentanyl with that methamphetamine. And you can see that methamphetamine laced with fentanyl seems to be strongly associated with and driving the fatality of those overdoses. The same case can be made for cocaine. You see very similar slope when fentanyl is tied with the cocaine. Moving on to COVID-19, we saw kind of a plateau, like I said, 2017, 2018, and even into 2019. In 2020, we saw about a 30-plus percent increase in fatalities associated with opioids. There's several variables associated with this. These particular authors identified reduced access to interventions, increased stress and isolation, lack of resources, anxiety, and there's also concurrently a changing epidemiology of drug use landscape. So you can see on the left-hand side, 5,000 to 6,000 cases. The last several years have quite a bit of overlap. There's been a slight modest increase, but there hasn't been a substantial increase. And then you get to 2021, and this graph depicts the first six months of the opioid overdose in the red line. You see a substantial increase. When you break it down at the state level, you see that West Virginia, Kentucky, and Tennessee had the largest gains from 2019 to 2020, largely related to the COVID epidemic. So what does this mean for outcomes? When you look at patients who have opioid use disorder versus those that do not, you find that those with opioid use disorder have increased likelihood of hospitalization, ICU admission, and mortality. And we think this is related to the general immunosuppressive effects of opioids, but also they have less pulmonary and cardiac reserve as a result of their opioid use. So when they do get an infection superimposed with that, they're less likely to bounce back. This achieves statistical significance for all three of those variables. And finally, looking at ICU admissions for overdoses, this is from the Vizient Clinical Database. I'm a big fan of the Vizient Clinical Database. You can pull a lot of really interesting diagnosis codes and correlate it with medication. And over 160 hospitals contributed to this data set. Now, I should mention that the data may be a bit skewed in that the hospitals participating in this data set are largely urban and academic in nature, so it's underrepresentative of the overall population as a whole. But they identify a rate of 5.2 overdoses per 10,000 ICU admissions. That's a rate of 0.052%. So ballpark, that's probably about reasonable, about what we might expect. Now when we look at those patients more closely, most often they're female, they're white, variable age, we don't see a strong signal there. And most of them have some form of commercial insurance. When we look at the primary diagnosis that these patients present with aspiration pneumonia, they're unable to protect their airway related to respiratory depression, rhabdomyolysis, patients are found down in awkward positions, cut off circulation, anoxic brain injury, again, related to breathing, septic shock, related to IV drug use. And a high percentage, 10% of these patients actually require mechanical ventilation. So again, looking at incidence, what we've seen over the years, and I'll be at this date a bit dated, only running through about 2015, what you find is that the overall incidence of ICU admissions has gone up. Paralleling that, the frequency at which we see opioid-related ICU admissions has gone up. Now I would suggest to you that the scale on this graph is just a little bit misleading in that the rates or the slope of the line related to opioid use disorder incidence actually goes up steeper than the overall ICU admissions. As far as outcomes go, the graph on the right-hand side, what you're looking at is survival. And while the general ICU patient population has a relatively stable flat-line survival, the incidence of mortality has gone up substantially in the opioid-related group in the last several years. When you take a step back in your regression analysis and try to find signals in this big data set, again, I think you identify that there's some variables that might be related to the bias of the data set in general, large, urban, academic medical centers. It's hard to pull out a whole, whole lot from that group. So this kind of prompted us to do our own analysis. And I suspect many of you have access to the Trinetics database. And that's all we did was try to query that database and get a feel for what the incidence is. It includes over 80 health organizations, 100 million different unique patients. And we queried 10,000 random patients from each of those organizations. What we found when we compared the OUD to non-OUD group is that they're mostly the same with the exception of age. The OUD group, on average, is about a decade younger. And obviously, the incidence of diagnosis related to OUD. Otherwise, sex, race, ethnicity were very similar. So if you look at whether or not these patients have an ORD diagnosis and an acute poisoning diagnosis, so your F11 and T40 codes, we've increased over the last decade. And we're just about 1%. And that's probably a reasonable number. The Stevens paper that we showed earlier identified a rate of 0.052%. So we're at 1%. We're in the right ballpark. If you tease each of those variables out individually, you see a slightly higher incidence. Again, you see an increase over the last decade. But you're more in the neighbor of 2% to 4%. And if you use the LUCIS criteria, an either-or criteria, it's as high as 6%. Now there are some limitations to this data set. These diagnoses need to be made within one month of an ICU admission. So it wasn't necessarily tied to the admission. But there are challenges in using that diagnostic criteria because the diagnoses aren't really validated in the ICU. So sometimes it'll happen after the fact. I think this is an important ballpark number to keep in mind because what you're really interested in is understanding the frequency at which you have an opioid-tolerant patient or somebody with opioid use disorder because their physiology is going to be a little bit different. And that's going to change the course of the care in the ICU. That's really what we're concerned about. So the characteristics of these patients. Obviously, we have hypertension, diabetes, asthma, heart disease that are pretty common between the groups. But when you look at the most common comorbidities tied to these patients that have opioid use disorder, you identify things like depression and nicotine dependence and cannabis use and other behavioral issues like that. There's quite a big difference between the top diagnoses when you stratify by OUD compared to when you stratify by a non-OUD patient where you see a lot of the more chronic comorbidities. Right around 2017 is when you as the ICU caregiver started to see more patients coming to the hospital on buprenorphine and methadone. For years and years and years, methadone was the workhorse. Right around 2017, we saw more buprenorphine use. This predates changes to the X waiver. We had mounting data to demonstrate that the drug was relatively efficacious, relatively safe, and had less prescribing criteria compared to methadone. Some of the reasons driving that prescribing. I mention this because in the acute care of patients on chronic buprenorphine, especially when using for opioid use disorder where the average dose might be 16 to 24, even 32 milligrams, those occupy quite a few new opioid receptors. And it makes the acute management of pain a little bit more complicated. That's in contrast to patients that are using buprenorphine for chronic pain where they're half a milligram, one, maybe two milligrams. You don't see that same degree of occupancy. So looking at outcomes, readmission rates, about 470 patients looked at retrospectively to identify some of the outcomes. Their 30-day readmission rate was almost 20%. Their 90-day enrichment was over 30%. And those that came to the ED at 90 days but weren't actually admitted was 15%. I can tell you compared to the average patient, the non-OED patient, these numbers are a little bit higher. There is a little bit of a silver lining in that in regression, we identified that patients that were on or exposed to buprenorphine, that reduced their likelihood of being readmitted. So there's an opportunity there. Limitations to opioid-related disorder coding. There's a dyssynchrony between the DSM-4 and DSM-5 criteria and the ICD-9 and DSM-10 codes that are used. They don't map out well. Also when we do manual chart reviews and we try to look at that coding, there's also a dyssynchrony. So there's limitations to using the administrative and financial coding data and not using diagnosis data. There's also opportunities for harm reduction. Regardless of the environment that you're looking at, there are opportunities to reduce the impact of opioid use disorder and what you see in the ICU. If you can get naloxone in the hands of patients, regardless of the environment that they're in, it's going to reduce the likelihood of inadvertent overdose. Now reframing the question just a little bit, is ORD an iatrogenic condition following ICU? A little bit of a provocative question. And we've got five papers here that suggest that a pretty high proportion of non-surgical patients who come to the ICU who are opiate naive and require mechanical ventilation actually get discharged on opioids. And when you take it a step further and you look at using the 24-hour prior to discharge prognosis of opioid utilizations to predict how much post-discharge opioid they're going to need, we see a lot of overprescribing. Our organization is actually pretty similar to this. We're about 10% of these patients go home on opioids. I would say the answer to my question is that no, it's not an iatrogenic condition. Prescribed opioids certainly play a role in the opioid epidemic, but in this instance, I don't think it's driving it. What I would suggest to you is that this is an opportunity to make an impact on transitions of care. Really scrutinizing whether or not those opioids are necessary or not. Regardless of environment, prescribed opioids have a harm associated with them. This is a large national registry done in the Netherlands and identified that upon multivariate regression, opioid prescribing is associated with unplanned ICU admissions and death as well. So we know that opioids are not benign. There's a few other studies that have found similar signals. Again, limited in that it's retrospective, but it is something for us to consider. So in conclusion, the epidemic continues to worsen, in part fueled by COVID. Accurate opioid use disorder rates in the ICU are really, really, really difficult to elucidate. There's a host of limitations largely related to coding. And finally, there are opportunities. So really getting patients exposed to opioid use disorder and naloxone, optimizing those transitions of care and limiting unnecessary opioid exposure. I think some of our colleagues later in the talk are going to give you some of these details for us. With that, thank you. It's my pleasure to introduce Matt Dupree. He's an Assistant Professor of Pharmacy at the University of Kentucky. And today, he's going to be talking to us today about a balancing act managing opioid use disorder in the critically ill. Thanks, Joanna. Thank you all for being here and making it to warm Phoenix. I know where I'm from. It's a little bit cooler. So we're going to be talking about a balancing act managing in critically ill patients. My disclosure is I have some internal funding related to marijuana and invasive fungal infections, as well as a pilot on some deprescribing work. So my objectives for the next 15 or so minutes, we're going to compare and contrast opioid agonist therapy with respect to analgesic properties and utility for management of opioid use disorder, and then design a plan for an algo sedation in patients with OUD admitted to the ICU. We've all seen this before. We're pharmacists, physicians, nurse practitioners in the ICU. We know pain is common. So pain is common at rest. Pain is common with routine care in the ICU. And that incidence of significant pain or pain that patients say they want to go away is over half of our patients, if not more, in both medical and surgical ICU settings. We know that's also influenced by psychosocial factors. We don't have a really good understanding of all those, and there's some work that needs to be done there. So that's psychology of individual patients, as well as some of their demographic and cultural factors that we need to take into account. So the PADIS guidelines recommend that we use a protocol-based pain assessment and management program, which we know reduces mechanical ventilation length, ICU length of stay, pain intensity. And we should be using self-report as the gold standard. We know that in a lot of our patients, especially those that are mechanically ventilated or those that are nonverbal, we need to use our validated behavioral pain scales, not our vital signs. So we have our BPS, or behavioral pain scale, and then our CPAT, or the critical care pain observation tool. So what does PADIS say about analgesia? They recommend the analgesia first or analgesia-based sedation strategy. And opioids are our usual analgesic choice, despite mounting evidence showing that opioids increase delirium in a dose-dependent manner. But where do the guidelines fall on patients that come in with a pre-existing opioid use disorder? So their exact quote is, generalizability of study findings can be improved by including heterogeneous samples of ICU patients, specifically those with a known opioid use disorder. OK, we're off to a great start. We have no data in the latest set of guidelines. And they recognize that as an evidence gap. What are potential safety concerns associated with our protocol-based analgesia protocols, specifically post-hospital opioid use disorder? And Bill did a great job showing where some of this data is going. So as practitioners, one of our most important roles in patients that have opioid use disorder or potential opioid use disorder is a thorough patient assessment. Pain assessment, specifically patient-recognized pain, again, is our gold standard. But we need to make sure that we're also meeting the goals with patients. For individuals that are actively using opioids, individuals that are in recovery from opioid use disorder, we need to talk with them about what they should be expecting during their ICU stay and what their goals are during ICU recovery. So for some patients, that's, I want to remain abstinent of opioids during my ICU stay. For others, it's using opioids as a bridge to treat pain to get out of the ICU. For others, it's their first time being in a center like this and being given those choices. So we really need to be talking to our patients. And I know it's difficult. You have patients that are coming in intubated. They were intubated in an outside hospital. And we don't always have that opportunity. But we need to assess throughout the ICU stay. So one of the questions you can use, are you currently using opioids? Which ones are you using? How much are you using? How often? Patients should be able to ballpark what they're using. You may need to become familiar with street terms for what patients are using, how much is in a dime bag, et cetera. But this will help you figure out what your baseline is for what patients are using, what their expected tolerance levels are, and what you should be giving them in order to effectively manage their pain. And remember that patients don't always differentiate between prescribed opioids and opioids that they obtain from the black market or illicit means. Also keep in mind that some patients will have concomitant use of other substances that may complicate their management. So stimulant use disorder, cannabis use disorder may be problematic here as well. The next question, do you want to stop using in patients that are actively using? You need to reevaluate this throughout the ICU and hospital stay. This determines whether or not we should be furnishing things like methadone and buprenorphine during ICU stay, or if we should just be bridging with active full opioid agonist therapy. And then what are you using, or what have you used in the past for individuals that are trying to stay sober or trying to avoid opioid use disorder in order to figure out what medications they're on, how we can effectively manage them during their ICU stay, and what we need to do to bridge them back to outpatient therapy. A strong medication reconciliation, whether that's done by a pharmacist, a nurse, or the physician, is extremely important. And this is a case where you need to go into places you don't normally go for medication reconciliation. A lot of the data will be in your PDMP in your states that you can pull for controlled substances. But things like naltrexone use, methadone that comes from a clinic, are not going to be populated into PDMP. So just doing a PDMP search will often leave you lacking for the amount of data that these patients will have. It's important that you contact the pharmacy or for patients that are using methadone for therapy to contact their methadone clinic for multiple reasons. At the beginning, that is the most reliable source for patient dose, especially with methadone. These patients are titrated on a daily or weekly basis. And they are not the usual doses that you would see for individuals that are using methadone for pain. So contacting the clinic, letting them know that the patient has been admitted to the ICU, and that you need to reconcile their dose so that they can maintain opioid agonist therapy during their ICU stay is extremely important. They can also document that the patient has had an encounter with the ICU, that they may be receiving opioid agonist therapy. Because if they are required to have urine toxicology screens, they are now going to flag positive for using, which in individuals that are getting opioids for acute pain in the ICU, is a very different circumstance than individuals that are using in a recreational site. It's important to note that stigma from health care professionals can lead to barriers to patient access to care and to harm reduction strategies. So utilizing patient-centered language, talking to them about what is important to them, is important to making sure that they can access care. So why do we need this thorough assessment? We know that if we're not getting what patients are actually taking, we are putting them at risk for ineffective analgesia or under-treating their pain. We can also precipitate withdrawal in individuals that may or may not be using buprenorphine as an outpatient. This is also important for your staff safety. Individuals that are under-treated are more likely to become agitated, pull at lines, and become violent. That is a nursing and care practitioner safety standard. And then you can also put individuals at risk of relapse, but it's important to note that adequate analgesia in the setting of acute pain is less likely to induce relapse than individuals that have inadequate pain therapy, who would then be seeking for analgesia when they leave the hospital. So precipitation of withdrawal. Bill mentioned this briefly, but we have the Clinical Opioid Withdrawal Scale. Not those cows, but we abbreviate it as COWS. It's a 48.11 domain scale, which includes resting heart rate, sweating, GI upset, yawning, and irritability. Anybody that's had a patient that's intubated will know that most of these things you can't really tell. How do you tell what a resting pulse rate is in a patient that's on three pressers? I don't know. So this is not really useful in the ICU. It's a gap in our care. We have to utilize some of the domains in order to determine whether or not our patients are in withdrawal when they're coming into the ICU. So what are our medications? We have three mainstay medications for management of opioid use disorder that you need to be aware of in your patients. There's four lines. We'll talk about it. Methadone is a mu-receptor agonist, or a full agonist, and also has weak NMDA agonist activity. It's available orally and intravenously, and usually is dosed daily. It's important to note that for individuals that may be having issues with QTC prolongation, methadone is known to prolong the QTC interval, and it also blocks serotonin reuptake, so it is not a good choice in individuals that are at risk for serotonin syndrome. Buprenorphine is a partial mu-receptor agonist, and a weak kappa and delta agonist. It is available in sublingual, injectable, transdermal, and intradermal formulations. That can be given on a daily or monthly basis. Buprenorphine is the one drug that should be available in your PDMP, so you can get usually accurate doses on this just by doing your normal searches, but it's important to note that this can potentiate, or has the potential to precipitate withdrawal. Because you have partial agonism, but it is a very strong binder at the mu-opioid receptor, you are likely that if you treat patients that are on buprenorphine with a strong mu-agonist, you can knock buprenorphine off and get rid of a lot of that agonism and precipitate withdrawal despite giving opioid therapy. And when you initiate it in the hospital, there is an induction protocol that we will talk about. The second half is buprenorphine with naloxone. This is literally just a misuse suppressant so that individuals do not crush it up and inject it. And then naltrexone is our antagonist. This is not used as commonly as the other two, but this is for individuals that wanna remain opioid-free as an outpatient. This is available as a monthly intramuscular injection that is provided at a care center. So again, will not show up in the PDMP, and you need to go looking for this in order to figure out how to treat these patients. So what's our care plan? A recent survey of ICUs found that only 7% of ICUs have a protocolized plan for taking care of our patients with OUD. We need to make sure that we're titrating our opioid analgesia to effect, and then using our non-opioid adjuvants that are in the PADIS guidelines. So patients that are maintained on methadone before they come in, you can either administer the oral dose at the full dose that you would, you can give this down an NG tube or an OG tube, and then furnish additional opioid and non-opioid analgesics in order to titrate to pain relief. It is, again, important to notify the methadone maintenance program at admission and at discharge that the patient is in the hospital. And for individuals that do not have oral access, you can administer a total of 1 1⁄2 to 2⁄3 of the dose in divided daily doses, usually three times a day. For patients that are on naltrexone, nobody freak out that I put a chemical structure on the slide, please. This is, the important thing to do is determine when the last dose of naltrexone was and the route of administration. Some patients are using oral naltrexone, in about three days it'll be gone. The intramuscular injection lasts for about a month, and you're gonna be using high dose, extremely tight binding mu-opioid agonists in order to try to overcome that. It's very important in these patients to furnish non-opioid analgesics because of the blocking of the mu-opioid receptor. And then you wanna consider those strong mu-opioids. So, what are strong mu-opioids? The smaller the bar, the stronger the binding. So please avoid codeine in these patients, but things like fentanyl, morphine, hydromorphone, and intravenous buprenorphine or sublingual buprenorphine can be used in patients that are on naltrexone to potentially overcome that. But again, keep in mind that not all of these drugs have a ceiling effect on respiratory depression. And if you have patients that don't have a maintained airway, you're going to need to be monitoring for respiratory depression. So patients that are on buprenorphine as an outpatient, there are actually four different recommended ways of handling this. You can continue their buprenorphine at the outpatient dose and then titrate short-acting opioids. This does have a higher risk of respiratory depression because of how buprenorphine occupies those mu-opioid receptors. You can split the buprenorphine dose and give it every six to eight hours. You can stop buprenorphine and then titrate a full opioid agonist to effect. But keep in mind, buprenorphine has a long half-life, so this'll probably take you about a week for buprenorphine to wear off, and you're gonna be titrating doses daily as you go through. And then, when you start them back on buprenorphine, you have to go back through the induction protocol. Or you can convert to methadone at 30 to 40 milligrams per day and titrate opioid therapy. So the dosing for patients that are over 16 milligrams a day, it's recommended to drop to 16. For patients that are at 16 or under, you can keep them at their current dose. If pain control is inadequate, the recommendation is actually to decrease the buprenorphine because of the way it occupies that mu-opioid receptor, and then titrate up their other opioids. So does buprenorphine continuation work? A single-center retrospective study of 117 patients found that when they kept patients on buprenorphine, the amount of opioids they used both in the ICU and out of the ICU were significantly less than in patients that did not receive buprenorphine therapy. So we know that it decreases the use of full opioid, full mu-opioid agonist therapy, which may be important when we talk about delirium rates. We talked about buprenorphine induction, and there is a lot of literature out there, but in patients that you want to induce, this is a multi-day process. You have to monitor the patient for two hours after each dose, increasing the dose daily until you do not have withdrawal symptoms, and they're maintained throughout the day. And then Bill talked about this data, but in patients that are receiving opioid agonist therapy prior to hospitalization, we know that furnishing buprenorphine decreases the likelihood of patients coming back to the hospital. This is not something that we know about inpatient buprenorphine therapy, but if we start patients when they first come, the thought is that they will be on buprenorphine when they come back and hopefully will decrease readmissions on subsequent encounters with the ICU. So for all of you looking for the money slide, this is the one to look at. Patients actively using opioids should be monitored for withdrawal, and you should consider initiation of medications for opioid use disorder. For those that are already receiving therapy, for buprenorphine, 16 milligrams per day or less is the recommendation. For methadone, continue their dose, either give it as a full dose in the morning or divide it throughout the day for its analgesic properties. And the patients that are on naltrexone do not give more and anticipate that they will have higher needs for opioids than your other patients. So where do we go from here? Sorry, my personal plans got in here, but epi studies are needed for using MOUD in the ICU. What happens when we continue therapy from the community? What are our best practices for newly initiated therapy within the ICU? We need comparative effectiveness studies specifically between methadone and buprenorphine, but also looking at our other opioid agonists in the hospital. Is there a difference if we're giving patients hydromorphone versus fentanyl? And we really need to follow these patients for their post-ICU outcomes. We know about readmission, but the problem with a lot of our readmission studies is they're retrospective and patients are lost to follow-up. So we're not sure if they are living in the community or if they've gone and continued their opioid use and have died from other manners. With that, I will pass it along. All right. And our final speaker is Avery Tung, who's at the University of Chicago. He's a professor of anesthesia. He's gonna talk to us about the pros and cons of analogous sedation. One of the primary recommendations of the HAD-IS guidelines was to treat pain first. And so I'm curious to see. All right. Good morning. I'm Avery Tung. I'm a critical care and cardiac anesthesiologist at the University of Chicago, and I'm here to finish out this session by talking a little bit about walking the tightrope. And by tightrope, I think I mean, you know, how to get out of the hospital, you know, without a long-term opioid use disorder. Two disclosures before I start. I am the critical care section editor for ANA, the journal, and so if you will, I am paid to be skeptical about what I read, and you may see that skepticism come across. And two, I am a cardiothoracic and critical care anesthesiologist, so if I do have an experience base, it is primarily in acute post-operative pain. I've got to figure out a way to make this go forward. It's not. Okay. Maybe I should turn off the laser pointer. I can't forward a slide without it. All right. Three parts to this talk. I'm going to talk a little bit about, you know, I'm going to observe that we use opioids frequently in ICU and talk about why, you know, that we only recently have recognized the potential for post-discharge opioid use in patients who are opioid-naive, previously something thought to be very unlikely, and then finish with a look at things that we can do potentially to reduce post-discharge opioid use and how good are they. All right. The reason we use opioids in the ICU is because they work. And so I sat down, you know, sort of to create this show, and I made a list of all the reasons we use opioids, and that list started getting longer and longer and longer. And when you look at this list, you can see, you know, if you were talking to an alien from outer space, you'd tell them it's the perfect drug. Look, they suppress cough and gag reflexes, which is useful for intubated patients. They don't uptend consciousness. They have multiple routes of administration. So if you lose the anal route, you still have IV or even transdermal. They have synergistic sedative effects with everything else that you might use. They can ameliorate nearly all procedural pain. And if you do end up in a side effect, many of them can be reversed. In fact, you know, to drive that home, I'm just going to give you this clinical scenario. You have a 52-year-old man with COVID pneumonia. He gets intubated. You know, and despite Seroquel, Propofol, dexinfusions, he has persistent coughing spells, and every time he does that, his O2 saturations dive. I've given you a choice of drugs that you can add. You know, I'm going to guess that most of us would add fentanyl here. A small minority might add cis-atrocurium and just paralyze him so he doesn't cough. You know, but everybody agrees that you can add olanzapine until you hit the dose limit, and you're not going to stop him from coughing, you know, with this situation, which is why, you know, in 2013, it was one of the easiest recommendations to make. These are the 2013 guidelines. This is me here, you know, and I can tell you, we did argue about a number of things, but one thing we did not argue about was whether to recommend analgo sedation. So there's the question. There's the answer, you know. And the only reason it's a plus 2B and not a 1B is because there really wasn't a lot of data to see whether it worked, but it was definitely better than the Ativan drip that was currently in vogue at the time. Now when you're young, you say, ooh, that's cool. I get to be on a guideline. But when you get older, you realize that, you know, that guideline carries some responsibility and that people sometimes actually read what you write. And thus it was that by 2016, there were a number of papers observing that people actually did use analgo sedation. That is to say, opioid-first sedation strategies, this one here in the middle, this one from the Canadians, and the one on the right, a survey of 50 United Kingdom ICUs, both arguing that opioid-based sedation was a primary element, you know, of sedation strategies in these ICUs. And that was 2016, and then came something that I have to say we never thought would be true. And in fact, when I was a resident, they told me this could not happen. And this is the observation in the perioperative sphere, that if you are admitted for an acute indication and you have acute pain and that pain goes away, then your opioid use is going to go away also. You will not end up addicted. But when we studied it closely, adjusted for factors such as preoperative opioid use and other drug use issues, you can see that there is a non-zero incidence of patients six months after their knee and after their hip arthroplasty who actually have, you know, are still requiring opioids. In fact, if you look at the ones who are on opioids preoperatively, the rate is shockingly high. Now, it's not just prospective studies, you know, in 500 patients. It was also in large databases, retrospectively reviewed. These two published in high-impact journals, both of them observing that there is a non-zero incidence of people previously opioid-naive who are taking opioids six or 12 months after their surgery. And you can see, you know, depending on the surgery, between 1 and 1.4 percent over here on the right. The incidence at 6 percent at 90 days. And a series of patient factors that, you know, it's not quite clear whether those still shake out of the literature, you know, but they suggest that there are predictors that can tell us, perhaps, you know, what might work. Now, you know, when you look in the ICU, that has already been reviewed, but I just want to observe that, you know, we are culpable in the ICU. This is the Donahue paper published in 2019 in the Annals of Internal Medicine, one of the most cited papers in the whole post-opioid discharge space. You know, looking at 12 hospitals, 150,000 patients, five years, and finding, you know, that 48 percent of patients got an opioid when they were hospitalized, you know, and that if they were, had an ICU admission involved, and you can see those in the graphic here, that 60 percent of patients who had an ICU admission got their first opioid in the ICU. So, if you were admitted to an ICU in this hospital system between those two years, you're very, very likely to get an opioid, and if, as observed before, if you do get an opioid, your chances, you know, of being opioid dependent at six months was higher. Now, you think about the potential strategies for making that go away, you know, and so I've listed them, you know, just describing the space. Patient education is one. Tell the patient, you know, that it's not good to be on opioids. You know, in principle, it's a good idea, but what exactly do you tell them, and I'll get into that. Multimodal, and, you know, that involves, you know, non-opioid adjuncts like ketamine, lidocaine, gabapentin. Use less opioid, and that's the goal of multimodal strategies, because if you use less opioid in the hospital, maybe you'll use less opioid later. And then protocolized post-discharge opioid prescribing, so provider-focused interventions. And here, I'm going to put on my editor hat and say, be careful, you know, because if you have a plausible claim with retrospective evidence, and you really, really want it to be true, then the world gets sort of gray. You know, we editors say to ourselves, extraordinary claims require extraordinary evidence. If you want to say magnets cure cancer, you're welcome to, but your evidence better be very, very good, because the pretest probability is very low. But what about plausible claims that seem like they make sense, you know, and claims that we desperately want to be true? What about those? Should the standard of care be different for those? Here's an example. Here's a paper looking at opioid prescribing in hospital discharge and chronic opioid use one year later. You know, it's a descriptive study. They aim to characterize and describe. It was a retrospective cohort study, so, you know, a database that already existed. They found a very, very strong odds ratio four level association between opioid prescribing at discharge and opioid use one year later, you know, and the question is whether you're allowed to use the word contributes here, because contributes suggest a causal relationship, you know, and technically not true, but if it's something that, you know, is plausible, if it makes sense, if you really, really want it to be true, can you say that? Or, you know, as down here, they say opioid receipt increased for future chronic opioid use. That's also a causal word. It suggests a causal relationship, you know. Can you really say that here? That's a good question. Moreover, when you're working with pain, it's sort of squishy, you know, and here are two nuggets from the anesthesia literature. You know, if you wouldn't, not an anesthesiologist, you probably wouldn't know that both of them asking the question, what do you say when you're about to stick somebody with a needle? Do you say, this is going to hurt like heck, or do you say, don't worry about it, this is nothing? You know, and in both of these, the one on the left published in 2007 about IV insertion and the one on the right about putting in the epidural and, you know, giving the lidocaine real at the beginning. If you minimize it, they feel less pain, sort of an interesting observation. So if you're going to counsel patients to questions, what do you say? You say it's going to hurt, or do you say it's not going to hurt? Now, patient counseling has a sort of enthusiastic fan base. I've extracted text from two reviews of managing post-discharge opioid use, and you can argue whether these are causal language or not, but they both refer to a orthopedic trauma study where, you know, they looked at patients who got counseling and patients who didn't get counseling and found that the ones who got counseling used less opioids at six weeks, and that's the top one here. You know, we're more likely to stop opioid use in the bottom one, quicker time to opioid cessation, you know, in patients who had undergone orthopedic trauma. Pull that paper, though, and you find it's retrospective. You find that it's actually one surgeon who gave the counseling and a second surgeon who didn't give the counseling, so there's an automatic confounder that there are two surgeons and there's no crossover between them. Finally, when you look at actually what they found, what you see is that at six weeks, yes, there was less opioid use, slightly, in the patients who got counseling, but that difference disappeared at 12 weeks and then afterwards. So, you know, is it a thing or is it not a thing? I leave that for you to disguise. Here's another one. This one is famously sort of described in all sort of suggestions that patient counseling potentially helps reduce post-opioid discharge use. You know, this is one in orthopedic surgery award, actually the effect of preoperative education on opioid consumption, including telling them that opioids were bad for them. You know, they said randomized to the study group was significantly associated with decreased consumption, you know, which is good, but then when you say read it further, they say it has some limitations. You know, we looked at self-reports, so those who were incentivized to report less opioid use probably did, you know, so there's a confound there that the odds ratio was actually very small and that at the end of the day, you know, when they looked at how much there was, it was sort of very, very little. So now I can say, oh, come on, Avery, you're asking for too much, you know, this standard of truth is too high because when you think about it, it'd be very hard to do a prospective randomized trial of patient counseling because you've got to have one group that you don't tell them anything, and I don't even know if that's ethical in 2024. Add in crossover effects by, you know, caregivers, you know, who don't maybe know that, you know, the patient's in one side or the other, provider bias, dropout, loss of equipoise, and you find that you've got to study that even if you got it done, it wouldn't be convincing and if there was no effect, nobody would believe you because we all want it to be true. Patient counseling is plausible. Retrospective evidence does exist, you know, and little downsides apparent, so why don't we just do it anyway? Well, that's really where we were with inalgal sedation in 2013, which is why we're here in the first place, and let's say one day we find that, you know, withholding opioids leads to reluctance to take opioids leads to a limited functional recovery, then what are we going to say to those patients, you know, who now can't move their arm because their shoulder hurts, you say, is that just the cost of doing business? So left unanswered is the standard of evidence for saying this works or it doesn't work. Now multimodal strategies, I think, have already been gone over in this space before. I'm just going to direct your attention to these three papers, the one on the left, shoulder blocks don't reduce the long-term use of opioids after shoulder surgery, one of the most painful surgeries we do, over there on the right, ketamine for cytoreductive surgery doesn't help either, and the one in the middle you might say there's a word reduces here and that's something, but on the other hand, that's the only paper in the entire lidocaine space that says anything about it. Now what about provider-level education, and with this I'm going to finish. You really, really want it to be true, you know, just tell people to write for fewer doses. I'm a cardiac anesthesiologist, you know, this is a look at, you know, opioid use after cardiac surgery, and you can see there's a pretty much linear line between how many OMEs a patient gets prescribed, you know, on discharge and the likelihood six months later of being on opioids chronically. I actually took care of a patient for a stone or wound debris just last week and he said, I don't know, doc, you know, they gave me 100 oxys to take home with me. I'm like, really? He said, yeah, I took one, I felt dizzy, I got constipated, and I didn't take any other ones. I said, good, good for you. And this study looks like you can ratchet down the immediate prescribing of postoperative opioids. You know, this is new persistent opioid use after postoperative intensive care. You can see that over a time period there's a decrease in the incidence of it, you know, from 2000 to 2016, you know, and this is a look at the effect of the Opioid Safety Initiative, which is a veteran's hospital initiative on opioid prescribing, and, you know, these are for very, very high dose, 100 OMEs per day level, you know, prescriptions, and you can see that that level went down over time. So there is some suggestive evidence that it might work, but when you study it, and this is about as good a study as they come, 11,000 patients in each group, you know, this is at the Mass General Hospital, they went, you know, system-wide, so every section of the Department of Surgery there, they said, you guys are prescribing too much opioids, stop, you know, and so, you know, with signs like this, they start to describe and change the culture. What they ended up was reducing opioids prescribed at discharge in nearly every single opioid section, in every single surgical section except for vascular surgery, and you know those vascular surgeons, you know, and you can see the percentage of patients that received any opioid refill prescriptions, unfortunately, did not change pre versus post. I'm just going to leave you with one more thing before I finish, you know, and that is, you know, the idea of OxyContin, you know, which, as Purdue Pharma famously said in 1999, is the one to start with, the one to stay with, you know, and, you know, I actually, because there's construction on the Kennedy Highway, you know, I end up listening to podcasts, and so I ended up listening to Peter Berg, who is the creator and director of the Netflix series Painkiller, you know, on his Joe Rogan podcast, which I do listen to, and, you know, he said, you know, I was curious, I took an Oxy to see what it felt like, he said it was fantastic, he said, I can totally see how people get hooked, it's like being dropped into a vat of warm honey. Jim Zachney here, the lead author of this paper on the left, you know, he worked in the University of Chicago for many years and spent some time describing the likability space of different opioids, and what he found was that OxyContin was more likable than other opioids you might use. This one in the middle observed, you know, in patients who are pre-existing users of opioids that they liked Oxy better than hydrocodone, and the one on the right also, choice of significantly more users than hydrocodone because the quality of the high was viewed to be much better, you know, by 54% of the sample compared to just 20% of hydrocodone users. So maybe we could use a drug that's not Oxy. To summarize, because I think we're at the end of the time, opioids are a mainstay of mental status management in the ICU because of all the different reasons I've listed, flexible, titratable, no ceiling to the analgesic effect, well understood, commonly used, everybody knows how to use them. Unfortunately, a consequence which we did not realize until it popped up in the mid-2010s is a post-discharge opioid dependence instance, which depending, you know, on which paper you read, ranges from 1 to 10%, you know, six months later, and about 40% of patients discharged from the ICU at discharge from the hospital end up on an opioid prescription. That rate belies the actual harm of post-opioid use disorder because diversion can extend the number of patients who are potentially affected. Therapeutic options are limited, the effect of patient education is unclear, and multimodal strategies likewise, things that decrease immediate opioid use don't seem to decrease long-term opioid use, so maybe the game is best played after the patient's already left the hospital. And that provider-focused strategies can reduce opioid use on discharge, that's been proven. The question is whether they have any effect on opioid use six months later, because that's sort of an unexplored issue, as is whether likability ratings for OxyContin, which are off the charts compared to other opioids, may potentially play a role also. Thank you very much.

opioid use disorder

ICU settings

opioid dependency

COVID-19 impact

pain management

buprenorphine

methadone

critical care research