Excellent. Thank you so much. Thank you to everyone for being here this morning and talking with us about some of the dark side of the ICU and many of the challenges that we face on a daily basis. My task today is to talk about patients with chronic pain and considerations during the opioid epidemic. My practice is in the medical intensive care unit. I'm a professor of pharmacy at the University of Colorado. So that'll be the angle I'm coming at for this talk. I have no relevant disclosures to discuss. So my hope, when we get done with this, is to kind of talk about how the opioid epidemic is impacting our care of critically ill patients and how we prescribe pain medications. I'm going to talk a little bit about opioid tolerance and withdrawal in the ICU. And hopefully, using a patient case, talk a little bit about some of the tactics that we can use for managing pain with multimodal techniques and trying to look for non-opioid alternatives. And then talk a little bit about kind of chronic intensive care-related pain and discharge pain control. So nothing is more sobering than looking at opioid prescriptions in the United States. As we look back in time, 2012 was kind of the peak for this. But opioid prescriptions peaked at over 255 million, or about 81 prescriptions per every 100 persons. So this is significant. And if we think back, as pain being one of the vital signs that we had to deal with, we talked a lot about pain. And opioid prescriptions were pretty commonplace. The trend is downward now in that. But still in 2020, we had over 140 million prescriptions, or about 43 prescriptions per 100 persons in the US. And when it comes to opioid use deaths, of about 90,000 to 100,000 drug-related deaths in the US every year are attributable or associated with an opiate. So this is staggering numbers. If you think about just in 2019 to 2020, there was nearly a 30% increase in drug overdose deaths in the country. And the prevalence and the waves are somewhat changing. As you see, it's going up. But kind of the scary part is that these other synthetic opioids, the fentanyls, the illicitly manufactured drugs, are really what is spiking right now. And any opiates continue to go up. In our ICU, five, 10 years ago, we never locked up fentanyl infusions. And just in the last month, we've had to change our practice because we had fentanyl drips walking off of the unit, being unhooked from the patient's IV pole. That really shows you how big of a problem this is. And now we're having to contain everything at the bedside to make sure our patients are safe and well taken care of, even security measures. And it's important to note that opiates don't discriminate. So we have a really hard time of picking out the perfect phenotype of someone who's going to have an opiate use disorder and leave the hospital on an opiate. So these are things that we're still struggling with every day in the hospital setting. So talking about chronic opioid use and tolerance, the CDC defines chronic pain as lasting longer than three months. Chronic opioid use is defined as receiving an opiate on most days for a 90-day period, so thinking about 45 or more prescription days over that 90 days. Opioid tolerance occurs when a person using opioids begins to experience reduced response to the medication, requiring more opioids to experience the same effect. You'll see a variety of different definitions used in the literature, but this is somewhat kind of in the average. Opioid tolerance is something we'll see in the intensive care unit. This happens for any patient taking opioids or at these morphine equivalents for greater than one week. So just some examples here. Oral morphine at 60 milligrams a day, oxycodone at 30 milligrams a day for a week. These patients are at risk for opioid tolerance. Persistent pain in the ICU and in ICU survivors is a big issue for us. And if you look at the numbers, they're quite staggering. It varies depending on the study, but anywhere between one out of every three to three out of every four patients that leaves the ICU has some sort of persistent pain. And three to 8% of ICU patients have some new persistent opioid use post-discharge. So if you look at the graph on the right, looking at some of the VA data, you can see that although we're improving, there still is a significant number of patients that leave our ICU with a new prescription for an opiate. Predictors of this were severity of illness, organ failure, the amount of time they spent on the ventilator, and increased length of stay. On the left here is a trauma study. So looking at opioid prescriptions post-hospital discharge, and it shows that we have significant gaps that I'm gonna talk briefly about. So almost 3,000 patients, 74% were prescribed opioids at discharge. They looked at what explains the need for opioids. And if you look at the variability, and they included things like demographics, comorbidities, injury, hospitalization, et cetera, their models were only able to account for about 21% of the opioid prescribing use. So this makes it very difficult to attack this problem. And if you look at the six to 12 month outcomes following opioid prescriptions, if they had an opioid prescription at discharge, they were more likely to have chronic pain, and they were more likely to have significant more opioid use, et cetera. And this kind of, this bottom graph looks at factors that were contributing to the amount of oral morphine equivalents, or the number of pills that patients were taking. And again, these variables that we all would assume would have a big impact on whether a patient needs opiates and how much, really only accounted for a small percentage of the prescribing patterns. A different study, but looking at different types and distribution of opioids after seven, or within seven days after hospital discharge, you can see, as expected, the big drugs that are prescribed are things like oxycodone, hydromorphone, codeine. I think this is a very interesting study coming out of Critical Care Explorations just recently, this past summer. It looked at opioid prescribing patterns before, during, and after a critical illness. It's a single center, but over 3,000, or around 3,000 patients. The gray bars are the total patient cohort. Black is patients who were on an opiate prior to admission, and the light gray is people that were not on an opiate prior to admission. You can see that the people that are at higher risk for continuing on chronic opioids are those that, of course, came into the hospital on it, so that makes a lot of sense. But there is this cohort of new prescriptions that patients will start on after their ICU visit. The main finding or take-home from this study was that the more opiate-free days you had in the ICU, the less likely you were to leave or end up on chronic opioids. So the more things and interventions we can do to shorten the amount of time people spend on opiates, the bigger impact that we can have. And it was the things like the total amount of opiates they got during the ICU, or the severity of pain did not predict the need for chronic opioid use. It was more about the duration and the staying on the opioids longer in your ICU stay and later in the hospital. So hopefully I've convinced you that this is an issue. I think everybody agrees that opioids and the epidemic is a big issue. I think we have to start thinking about, as the previous commenter, the question in the previous, at the end of the previous talk said, you know, there's teams, there's things that we need to think about. We need to think about putting some of this on our checklist as patients start to improve and get out of the ICU, what can we do? We've got to think about opioid maintenance therapy. We've got to control our opioid over prescriptions. We've got to enhance our ERAS protocols and other things in anesthesia. We've got to really look to non-opioid analgesic effects and try to prevent or identify who's going to have these chronic ICU-related pains. So I always like to include a case. It's a case that I found difficult. We recently saw in the medical ICU. This is a 58-year-old female with epilepsy who was transferred to our ICU for status epilepticus that was refractory to multiple treatments. The hepatic and renal function was normal. The patient was intubated and placed on a propofol infusion at 50 mics per kilo per minute, midazolam infusion at six milligrams an hour, which stops the seizure. When they got to us, they had no further seizure activity on EEG. They have no allergies. They're on these anti-epileptic medications. And when I looked back at this patient's chronic opioid use and prescriptions of controlled substances, they were feeling oxycodone, 20-milligram tablets, 120 of them, five-milligram tablets, 120 of them every month for the last year. They were also on pregabalin at 200 milligrams three times a day, and occasionally they filled a benzodiazepine. So this patient is very high risk, but not an uncommon patient that we see in our ICU with chronic pain. So how would we approach this? So there's a few different options. I will tell you this is kind of the approach that we would take. So we first would assess their pain. We would treat their acute pain, but also think about their chronic pain. So we would estimate the opioid use before ICU admission and convert to morphine equivalents. We would consider cross-tolerance of their opioids and any physiologic derailments, such as organ dysfunction, drug interactions, et cetera, that would impact our use of the medications. We would have to worry about withdrawal in this patient. So we need some sort of assessment of opioid withdrawal. And then we would try to implement a multimodal opioid sparing strategy if we could, and supplement short-acting agents as needed for any acute pain the patient was having. So here's what we tried to do. We figured out that their oral morphine equivalents was about 100 milligrams. We did a 75-milligram conversion just from a cross-tolerance. Or if we looked at fentanyl, that's about 300 mics a day or 12 1⁄2 mics an hour. For this patient, since the EEG, they were no longer having seizures, we titrated off the midazolam drip, got the propofol down to 20 mics per kilo per minute. But their CPOT score was still five. We continued their home pregabalin. To account for their chronic needs, we did oxycodone 10 milligrams every six hours and a fentanyl infusion at 12.5. Now, sounds like a great plan. You put the plan in place, and you expect this to go really well. Well, as you come in Monday morning quarterback overnight, this is what happened. The pain score stayed four to five. They kept giving fentanyl boluses every hour, occasional hydromorphine boluses. And when I walked in the next morning, the fentanyl infusion was running at 250 mics an hour. So what do we do? We need to take a step back, and we need to think about this patient with chronic pain. So why are they having a diminished opioid analgesic effect? And how we anchored on this was opioid tolerance. This patient's on chronic opioids, so they're highly tolerant. That means they need more opiates. But is that really the case? Could this have been opioid-induced hyperalgesia? So if something that is affecting, we're giving them more and more doses of opiates, and that's actually hurting the patient, whereas we should have been tapering the opiates and looking for other therapeutic approaches. Or was this truly a worsening pain state, which it wasn't in this patient's case? So it was really kind of an anchoring problem that we ended up going up on the opioid tolerance and using more and more fentanyl to try to control this patient's, what we perceive to be, increased pain. So multimodal analgesia is tough, right? We read the guidelines, we read the PADIS guidelines. It tells us that we should do a lot of different multimodal approaches, but it's a very patient-specific approach, and there are a lot of different options. So NSAIDs, we know, work really well, but they're really hard to use in the ICU because of all the potential negative effects on platelets or bleeding, renal function, et cetera. Tylenol seems to be the easiest approach, but there are maximum dose considerations, hepatic considerations. Opioids seem to be something that we use quite frequently, and they are good at treating pain. The other agents that we've become a little more comfortable with, particularly during COVID, et cetera, like ketamine and others, are starting to become bigger players. The anticonvulsants, antidepressants, the neuropathic pain, we try to treat this as we can, but sometimes these are a little more slow to onset. We're not sure exactly how much it's helping. There's off-target effects and drug interactions. So what do we do? Well, I think the easiest approach for most of us in these patients is to start with acetaminophen. Schedule it, a gram every six hours, if they tolerate it. When we think about using opiates, it's really important, once you've established whatever their baseline needs are in chronic pain, that we're using more PRN or bolus-type approaches to treat acute pain. Pain-dose ketamine is a somewhat new strategy. I'll show you some of the data for that. Some of our alpha-2 agonist, dexmedetomidine, can be used. As we step on up, you may see other more low-level evidence options, lidocaine infusions, some of your, things like gabapentinoids. And then the last step is actually doing the opioid infusions, which we went to fairly quickly in this patient. So how do these adjuvants work? How much of an impact do they actually have? We've talked about the need to decrease the duration of opioid use in the ICU if we want to impact care. Well, this is looking at, this is a study by Wheeler and colleagues in critical care explorations in 2020. This column tells you the mean difference in oral morphine equivalents. So if you look at a drug like dexmedetomidine, about 10 milligrams a day. So not a huge analgesic effect, but it may help us with some of the withdrawal effects and other things with opiates. Depending on which study you read, you see varying effects of dexmedetomidine on pain control. Clonidine has a similar effect. Magnesium, small study, I won't really go into that, but it was part of the graph here. NSAIDs, similarly, will save you about 11 milligrams a day. Acetaminophen, highly effective over most broad studies, you know, somewhere between 30 and 40 milligrams of oral morphine equivalents. So again, that's why, and of the comparisons, it has a fairly strong effect. Gabapentin and some of the other, pregabalin, et cetera, can have some effects, particularly if the patient has neuropathic pain. So something you can keep in your armamentarium. Our patient was on this previously, so we continued the pregabalin. Ketamine. So ketamine has a lot of off-target effects, but when you look at a lot of the data, there is some improvement and reduction of opioid use here. You know, almost 40 milligrams a day of oral morphine equivalents in a couple of these studies that have been done. And again, similarly, with tramadol. I won't talk much about lidocaine. We've used it a few times. It is in the considerations. I find that we can test to see if it works, and if it does, then we can continue it, but we find a large number of patients that don't necessarily get any additional pain benefit from lidocaine and just would get the increased side effects. So our next speaker will talk a little bit about this. Chronic pain or chronic critical care-related pain is where I want to finish the talk, and that this is persistent pain for at least six months after ICU admission, which lasts at least three to six months and then was not present before ICU admission. And if you look at the black, this is extreme pain or discomfort. Gray is moderate pain or discomfort. And you can see that in all these studies that have been done, greater than 50% of our patients leaving the ICU have some moderate pain or discomfort. So this is why it's a huge issue with opioids and why it's a big deal in the current considerations of the opioid epidemic. So what are the strategies to mitigate this chronic intensive care-related pain? Well, the risk factors that we know are uncontrolled pain, pain of high intensity, and pain of extended duration. So if we can attack any of those things, we can help ourselves out. As far as strategies, I can't give you the magic bullet, unfortunately. There's definitely strong considerations for a multimodal approach to pain so that we can prevent opioid dependence. Non-pharmacologic approaches should be part of your armamentarium. I didn't really have a lot of time to go into that today, but there are a variety of different approaches we can take. I think there's careful consideration. I know as the intensivist, and we talk about things like fibromyalgia and chronic pain on rounds, the glassy eyes happen, and we were like, this is not an ICU problem when we want to punt to the floor team as we transfer patients out. There are a lot of things that we should do, and maybe include in your checklist as people are leaving the ICU. Can we get this patient off of opiates? What are our pain control options that we should transfer to the floor? Because we know that if patients are continually getting opioids, then it's easy for the discharge physician to check the medication and send it to the pharmacy when they leave. So can we use PICS clinics? Can we include addiction medicine to help us with these patients, to really target, in particular, those that have chronic pain and were opiates when they came in? So here's what we did for our patient after I walked in that morning, and the patient was a high-dose fentanyl. We started Tylenol at a gram Q6. We changed the propofol to dexmedetomidine and added ketamine at five milligrams an hour, continued the oxycodone and pregabalin at previous doses. So the result for this was we were able to decrease the fentanyl infusion down to 25 mics an hour, and we turned it off 24 hours later. You can see the ketamine and dexmedetomidine doses used here. We were successfully able to extubate the patient. Three days later, dex and the dexmedetomidine and ketamine were discontinued. We transferred the patient to the floor. Addiction medicine was consulted, and they started the patient on buprenorphine to help them at discharge. So that's just one case. The common case that we might see in the ICU, a very difficult case. Hopefully I've convinced you that the opioid epidemic contributes significantly to morbidity and mortality of our population. Chronic pain and opioid use is very common, but it's super complex and difficult to treat and manage. I think that if we can apply a systematic approach to multimodal therapies, that would be the preferred strategy with the goal to decrease the duration of opioid use in any of our ICU patients. And if we can get them off at least 24 hours before hospital discharge, it seems predictive of not ending up on chronic opioids. I think we can play a significant role, and there's gonna be a big consideration for our chronic intensive care-related pain that we're gonna need to be a part of in the downstream and post-discharge from the ICU. So with that, I thank you very much for your time and listening, and I'll be happy to take any questions. Do we have time? Thank you.

opioid epidemic

ICU

multidisciplinary approach

chronic pain

adjuvant medications

patient outcomes