Hello, my name is Sam Galvano and I'm here today to talk to you about multimodal analgesia. We're going to focus on ketamine and intravenous lidocaine. We'll talk about a couple of other non-opioid related aspects of pain management as well. Our objectives for this lecture will be to define analgosedation or to redefine it and review it. We'll talk about myths and misconceptions regarding the use of analgesic adjuncts with a particular emphasis on ketamine and lidocaine. We'll also review the scientific literature and pharmacotherapeutic properties for commonly used analgesic adjuncts in the ICU. And then finally list some components of a multimodal pain approach that can be used for critically ill adults. I don't have any disclosures that are related to this talk. I do receive funding from the United States Department of Air Force and the United States Department of Defense, but nothing related to this work. We'll try to make this a problem-based approach. We'll talk about assessment tools and definitions which are necessary to begin this discussion. We'll also talk about a couple of clinical scenarios that you might encounter and then hopefully dispel or confirm some myths about analgesics and then obviously reviewing the pharmacology. Any discussion regarding analgesia really has to start with a quick review of assessment tools. In 2013, the Society of Critical Care Medicine created the ICU Liberation Campaign which was based on the publication of the Clinical Practice Guideline for Pain, Agitation, and Delirium. This was updated in 2018. And this recommends a stepwise approach to pain assessment with a regular assessment for delirium using a validated tool. We all know delirium is a major problem in our intensive care units. Up to 50 to 80% of our patients who are mechanically ventilated will have delirium. But it's not just delirium. There's also downstream effects from delirium such as long-term cognitive impairment and post-intensive care syndrome. The PADIS guidelines foster the delivery of excellent care in these areas and stimulate the completion of pragmatic patient-centered research across each of the important critical care domains. It's really important to understand these guidelines because that serves as the fundamental basis for how we approach analgesia in the ICU. We can't talk about sedation without talking about pain. This is the ICU Liberation Bundle which we're all familiar with. It's a good review and you can see here that one of the prominent aspects of this is the choice of analgesia and sedation and understanding the importance between the depth of sedation and choosing the right medication. Analgesia has a big part of that and can hopefully avert delirium. Assessing and preventing and managing pain is also a major goal for every patient in the intensive care unit. The numerical rating scale is really the one that most of us are familiar with. It's a 0 to 10 scale. And this is a very useful starting point for assessing the need for analgesia in critically ill patients. There's also the behavioral pain scale which is used in some units. This has been validated in particular in cardiac surgery patients. You can see the score ranges depending on facial expression, upper limb movements, and compliance with ventilation. In a small study at UCSF, both the behavioral pain scale and NRS were used and delirium was also assessed with the CAM ICU. You can see that self-reported NRS and behavioral pain scores unfortunately are not very well correlated. The NRS score was 0.3. So they can't be used interchangeably. But they are tools at our disposal. The NRS is always one that we can fall back on and use. Then there's the clinical pain observation tool which is also scored higher the score the worse. Unfortunately this score did not include heart transplants, chronic pain, psychiatric illness, and the N was only 105 in this study that looked at this. But it did have high interrelated reliability and multiple other studies have since validated this as another tool that we can use. The important point is an emphasis on pain relief and discomfort prior to instituting sedative hypnotic agencies of paramount importance. Using opioids alone or in combination with traditional sedatives is a major foundational aspect of our care in any critically ill patient. But managing the pain and discomfort first before providing sedatives which have no analgesic properties is also a primary concern for all of these patients. And that's what the emphasis will be on this particular talk. Opioids we know opioids are bad in terms of the side effects. Nausea, vomiting, constipation is a big problem. Respiratory depression, prolonged hospitalization, higher readmission rates, higher mortality, and there are several references here. This is a big problem. And in fact patients have even had higher mortality rates or associations with higher mortalities with higher analgesic needs. Respiratory depression is a major problem. We want to keep our patients spontaneously breathing, attempt to liberate them from the ventilator whenever possible and as soon as possible. And so anything we can do to prevent opioid related adverse events is certainly of interest to the modern practicing intensivist. Let's talk about some clinical applications. So I'm going to give a couple scenarios here and some of these are rather extreme but these are scenarios that I've experienced in my own practice as an anesthesiologist intensivist and neurointensivist. We'll start with this patient who's a 42 year old patient, intravenous drug abuse and polytrauma. Patient had a femur fracture, rib fractures, had an exploratory laparotomy, winds up in the unit on ketamine at 2.0 mg per kilogram per hour and dexmedetomidine at 1.7 micrograms per kilogram per hour. These are hefty doses. And so this is a patient who was turned over to me by another colleague and the overall paradigm here was we want to reset him. We want to see if we can reset the receptors and not have to use any opioids. So that's why we're on these high doses of ketamine and dex. So the question is, is this a really good approach? Does this work? What's the role of ketamine in this approach? And that's what we'll talk about next. We'll focus on ketamine. So ketamine has certainly seen a resurgence during our last COVID pandemic but it's been used by many of us for many years. And in fact, this was initially synthesized in 1962, tested in 1964 by Kelvin Stevens out of Wayne State University. It was originally synthesized as an alternative to PCP. Onset of action is very quick, less than one minute, because it's very lipophilic. It crosses the blood brain barrier rapidly with a near immediate onset of action. It may accumulate in obesity. That's something that we're still concerned about because of this lipophilicity, but usually you'll wind up with an onset of action within 30 to 60 seconds after Ebola, sometimes even faster than a minute. So it's a very rapid acting agent and potentially very useful. As linear pharmacokinetics, half-life is about five to 12 minutes. It can be longer in critically ill patients. It's metabolized by the liver, primarily the P450, and it does have an active compound, but only one third the activity of the parent compound. And it's 47% protein bound. Now the S-antanomer is more potent as an analgesic, but not available in the United States. But some of our colleagues here at the conference and the Congress may know about this in their practice. We don't have this in the United States, but that is worth, especially in this discussion about analgesia. Now ketamine does have degree of opioid receptor blockade. Multiple receptors are blocked by ketamine, at least experimentally, but this drug is not reversed by naloxone, which is interesting. So it's not a pure mu blockade as we would see with a pure opioid. Probably has more to do with the NMDA blockade. There's some GABA inhibition as well. Most of us know about the NMDA blockade, but there's also the GABA inhibition and it also has some anticholinergic effects at the CNS level. It also results in increased release and decreased reuptake of norepinephrine, dopamine and serotonin. That's an important point that we'll emphasize here in a few moments regarding the hemodynamics that you sometimes see with ketamine. But this is the effect you get with ketamine, dissociative effect. Dissociates the thalamus from the limbic cortex. Patients wind up in a cataleptic state. They seem awake, but they can't process or respond to sensory input. Their eyes are open. They'll have nystagmus. They will actually have conservation of laryngeal and corneal refluxes, both advantageous, especially the laryngeal refluxes if we're using this for sedation in a non-intubated patient. But the patient reports being completely spaced out or dreaming, disconnected from their environment, detached from their surroundings, a concept known as derealization. Or detached from their self, which is a concept known as depersonalization. This is all due to the decreased interneuronal activity at the NMDA receptors and the GABA receptors. There's also a disinhibition of parietal neurons that enhance glutaminergic firing, such as a, quote unquote, glutamate burst that can occur. The point to understand these effects, some patients this works really well. Others, when they wake up, will ask you never to give them this drug again. How do we dose it? This is the big question that comes up in critical care. We want to avoid those dissociative effects whenever we can. You saw the patient that we presented here was on a very high dose. The anesthetic and dissociative dosing has been recommended to be right around the 0.5 mg per kg range. That's over a 40 minute period of time after the drug is given at that dosage. Now where do we know this from? We know this from a classic study that was in healthy volunteers, where they dosed the patients from a range of 0.1 to 0.5, and they seemed to observe those effects that we just mentioned, the dissociative effects, more prominent when the dose was greater than 0.5 mg per kg. That's where we get this threshold effect, but it's different for every patient. When you have a patient on an infusion, that can also be much different. There's a whole bunch of both pathophysiologic and physiologic effects that ketamine can impart upon the nervous system. This is just a general overview of what we can see with this, but we see everything from hypnosis to degrees of analgesia. There can be actually antidepressive effects. You can see that that occurs everywhere from the channels, NMDA in particular, but also some calcium channels, as well as other neuromodulatory effects. Even gene expression has been shown in vitro, and of course, some cellular effects, which we see with just about all anesthetics as well. What are some other effects that ketamine can have? Does it have a positive or negative effect on the myocytes? This is a commonly discussed aspect in, again, pharmacology of ketamine. We see this in textbooks, and there are papers that support direct myocardial depression in some studies. However, it's that ability to affect the reuptake of neurotransmitters that actually causes an indirect sympathomimetic effect that counterbalances that direct myocardial depressant effect that's been studied and reported. If you want a really good review on this, Mike Mazzefi's paper from 2015 is outstanding. He talks about the use of this drug in cardiac patients. There's also a whole bunch of other effects that this drug can have that may be beneficial. Could be neuroprotective. Actually, it is neuroprotective in many studies. It can lower IL-6 and IL-10 levels. It can attenuate drug injury, lung injury rather, and sometimes has been also shown in some of the literature to decrease troponin release. All good things, potentially, but the dosing range when you look at the literature is highly variable. In fact, in this review, most of the studies were from small case series, and most of these series were from patients that had status asthmaticus. It did show that morphine consumption was decreased. They didn't show a change in ICP or cerebral perfusion pressure, which is important to remember because most textbooks in the past have really taught not to use ketamine in patients that might have intracranial pressure. We'll talk about that in a minute. Tube feeding tolerance increase. This is a really big benefit for patients that may have had surgery recently or may have GI issues where that's not something we want to deal with. Always want to try to feed our patients in accordance with our SCCM and Aspen guidelines. This is a drug that may help a little bit with that. Certainly high-dose opioids will not help with tube feeding because they can cause constipation and GI dysmotility. You may see less norepinephrine use as well, again, because of that indirect sympathomimetic effect from the decreased reuptake of neurotransmitters. We've seen that in studies where increased mean arterial pressure has been reported. There's a lot of good effects. This is a good review of the use of ketamine in the intensive care unit published in 2017. So how do we dose this? Well, again, we know about that dissociative threshold in healthy volunteers, but it's less clear what the dose may be in critically ill patients. Highly variable. It's really going to depend on your own clinical judgment. I know that always sounds like a cop-out, but it's really true. Maintenance sedation, we look at anywhere from a 1 to 3 milligram per kilogram bolus, which is basically an induction dose that we would give in anesthesia to secure an airway. And then we look at a range of anywhere between 0.1 to 2.5 milligrams per kilogram per hour. It's highly variable. There are some patients, like the patients we just presented, that may have a really high dose, and that can be highly variable. I think the point with all drugs is to choose the lowest effective dose that you can, keeping in mind that those dissociative effects are not always well tolerated by patients. So lowest dose possible. I usually start at 0.1, 0.2, try to keep it between 0.5 and under 1, but some patients may need a little bit more in terms of that milligrams per kilogram per hour. You have to make a call. I think with this talk, the goal should be looking for other adjuncts we can add in to address the pain component so that you don't have to wind up with a very large dose. Keep in mind, a dose of 2, 2.5 milligrams per kilogram per hour is really equivalent to the dose we would use for a total intravenous anesthetic in the operating room for surgery. So that's a very high dose. Here's another take on some dosing regimens that was published in 2016. You can see that they go with a lower bolus in this case, 0.2 to 0.5, and then a much lower hourly dose, working up as needed, but really trying to keep this down to the lowest possible dose that you can get away with. So unfortunately, I wish that we could give you some really high level evidence on the dosing, but this is what we're left with in the literature. And again, trying to pick a lower dose to start is probably a reasonable option. Even at that dose, you will see a lot of the benefits of opioid sparing. You may see some improvements with the GI motility. Opioid sparing is a really big one because if we can get away with less opioids, that's usually always a good thing. And again, this is just another good review for your own records. If you want this paper, please let me know. I'll happily email it to you. What about the analgesic properties? That's the whole point of this talk. So there is an analgesic effect at the muscarinic receptors. It's not all about the mu receptors as stated because we can't block this with naloxone like an opioid. But in most of the papers, just about all of them, it is pretty clear that this drug, ketamine, does reduce opioid consumption. The equi-analgesic dosing is unknown. I can give you one study that was done by Josh Miller and Vic Barbata back in 2015. So in the ED, they looked at some patients that had abdominal, flank, or low back pain or extremity pain, and they tested ketamine compared to intravenous morphine. They used a dose of 0.3 mg per kilogram compared to morphine at a standard dose of 0.1 mg per kilogram morphine. And so what they found with that was no real change in the numeric rating scale for pain, but they did see that there was a faster onset of analgesia with ketamine. And so that was interesting. So just about equivalent at a dose of 0.3 mg per kg to a pretty good dose of morphine at a rate of 0.1 mg per kg of morphine. So that's really, in my opinion, one of the best papers, again, that Miller reference from 2015, that really got at this concept of equally analgesic dosing. But if you were to ask me exactly how much ketamine is required per milligram unit of morphine, outside of that paper, I think it's a very difficult question to answer. Again, every patient's different. Ketamine does have analgesic properties, but they're not always as powerful as the opioids. So I think that really gets at a multimodal approach is something that we should really be looking at. We should be looking out for some of the adverse effects, tachycardia. It can increase myocardial oxygen consumption. The psychotropic effects, going back to that slide and the dissociative effects, one in three patients, and it's not reliably protected by benzodiazepines. There is some protection by benzodiazepines, but as we know in critical care, we try to avoid those drugs whenever possible, most of the time. And there is up to a 7% hallucination rate. Have to watch out for some patients that wind up with hypercelebation. I've seen this several times in my career, something just to watch out for. It's not terribly common. I had a hard time finding what the exact incidence is in the literature, but it is something that you will see in some patients. And then emergent reactions. So we'll talk about how we can maybe manage that with some other agents, but certainly emergence reactions can occur in about 30%. And it is a metagenic, potentially. I know we talk about opioids and nausea and vomiting with opioids all the time, but ketamine itself can be a bit metagenic in some patients, just something to think about. And the hypotension is really in patients who have catecholamine depletion. That's where we'll see this side effect the most. So for instance, a patient in hemorrhagic shock may not respond well to ketamine. They may actually become hypotensive if they get a large dose. So we usually watch our dosing in patients who are hemodynamically unstable, especially in any patient who's been unstable for a little bit of time because they may be catecholamine depleted. One thing you can do as they emerge is give some benzodiazepine, and again, it doesn't reliably in every case prevent the psychotropic effects, but it can help prevent some of the emergence reactions, which is a little bit of a different reaction than just the pure dissociative effect. There's at least one study cited here where they gave two milligrams of lorazepam or Ativan after the ketamine was stopped. That was for procedural sedation. And they found that emergence delirium was decreased with that dosing regimen. Some patients have pleasant dreams. Not everybody who's dissociated is really upset with that. Some patients actually don't mind that. So dissociative effects are not always bad, but it's probably the one thing with ketamine that we have to worry about the most. Now, can you give this to patients who have potential increased intracranial pressure or head injury? And the answer is you can. You can give this. It's safe. This is an excellent article in 2010, now 12 years old, very good review of kind of some of the medical mythology. So don't hesitate to give this with a patient who's got a TBI. We do not restrict this in our patients at Shock Trauma Center if we need it. And then recent indications, which many of you are probably familiar with, it's been described for use with COVID-19 ARDS, loading dose of 0.5 milligrams per kilogram and dosing ranges around the 0.5 to 1 milligrams per kilogram per hour. They did have used this in ECMO. We have used it in ECMO and some of our ECMO patients where I work as well. And it can decrease your vasopressor requirement in these patients. What about that ultra-rapid detox? So going back to that patient who was on these really high doses of dexmedetomidine and ketamine, no opioids, so there was a concept that has been published in a couple of papers here you can see that we've cited. Really ultra-rapid detox, if you want to detoxify somebody, the answer is not going to be ketamine by itself, at least not described in the literature. So the idea that with this patient who had IV drug abuse that we could get away with no opioids, probably not the wisest decision because if you're going to do ultra-rapid detox, that's really described as a volatile anesthetic with an infusion of naltrexone or naloxone. You could combine it with dexmedetomidine, which we'll talk about in a minute. Ketamine's really not a described part of the ultra-rapid detox regimen. So just going back to that initial patient that I remember receiving on sign out, it's a good adjunct. Ketamine can definitely reduce your opioid requirements and it does have analgesic properties. Usually use it as a low dose. It's not good as a sole agent necessarily. There are side effects, which we've discussed, and it's not really indicated for ultra-rapid detox. I do have to mention the Ketased study group that looked at this for rapid sequence intubation in acutely ill patients. I know we're talking about non-opioid options in this talk, but it's worth mentioning that in this study, this was 234 patients who got etomidate, 235 got ketamine, and the intubation conditions were the same and there was no blood pressure change between the two groups. More adrenal insufficiency in the etomidate group. Interestingly, there was up to, and that was 86%, but interestingly, the ketamine group also had some adrenal insufficiency. They found up to 48%. So this idea that etomidate is always the bad guy, yes, it does have a higher, there's a higher proportion of patients who will have adrenal insufficiency, but ketamine can also cause that in some patients as well. At least in this, that's one of the findings from this study. But the point being, it's a really good drug for induction. It's one of my drugs of choice for induction because of the hemodynamic effects, which are very favorable, as well as some of the analgesic effects that we can get early on, and opioid sparing. Lidocaine. I will admit that lidocaine is one of the drugs that I've really questioned the use in critically ill patients, and I'm glad that I was able to review the literature for this, because there's a lot of purported benefits, but some of us in our practice are not always sure. I haven't really used a lot of it historically, although more recently. Lidocaine is a sodium channel blocking agent. It's 60 to 80% plasma protein bound. The half-life is prolonged in the heart, liver, renal failure, so that's something we have to be aware of. And is there an anti-inflammatory effect? There's a lot of in vitro data that may suggest that. Once again, with critically ill patients, we're always trying to get their nutrition status bolstered as quickly as we can, and there are some data that suggests an early return to a bowel function with the use of lidocaine. And it also may work as an anti-hyperalgesic, which is good. But what does the literature really tell us about lidocaine? So all of these purported benefits. It's a pretty safe drug overall, because many of us have used this for other indications over the years. But what does the literature really tell us about lidocaine? Well, here's what we really have. Probably, I think, the best review out of Cochrane 2018. 68 trials, over 4,000 patients. Now, it's important to remember that this was really looked at in surgical patients, but that's a population where we'd be very interested in this drug. Open or laparoscopic abdominal surgery or other surgical procedures were part of the inclusion criteria, and the doses that were studied were ranging anywhere from 1 to 5 milligrams per kilogram per hour. And the conclusion they had was, we are uncertain whether IV lidocaine improves post-operative pain compared to placebo. They did note, in most of the studies, there was a decrease in the numeric rating scale for pain. There was an uncertain risk for ileus reduction. Some signal there, but not enough from the Cochrane methodology to really say that that was a definite benefit. There weren't any data on adverse effects with this study, which is one limitation from this pretty thorough meta-analysis. But they did show a decrease in pain, so that is something that was teased out. And see here, the forest plots here. Definitely, one of the things that they found with this that I think has really stood out to me was, on this forest plot, you can see the post-operative morphine administration on the very bottom was significantly reduced, favoring lidocaine. So once again, anything we can do to reduce opioids is a good thing. You can see the pain reduction is variable, and a lot of good pain relief, mostly in the first 24 hours. If you really look at this one, this is from the Canadian Journal of Anesthesiology, 2011, where they looked at this, and you can see that first 24 hours, pretty good. Pretty good confidence interval, though right at 24 hours, we start to see some crossover. And even with coughing, pain during coughing, which is a big thing that we have to deal with, especially if they've had a large surgical incision, this can also be something that we see. So really, with lidocaine, it's that first 24 hours where you probably get your biggest bang for the buck. It can definitely help opioid spare, which is good. But in terms of an equally analgesic and used as a sole analgesic, absolutely not. But it can definitely be one more analgesic that you can probably safely add with a fairly moderate evidence base to support it. One other thing to show here is really highlighting that post-operative morphine administration. Abdominal surgery and non-abdominal, well mostly in abdominal surgery, is the point that we're making here. You can see a pretty big reduction there, but for other types of surgery, not so much. So if you've got a patient with abdominal surgery, if you're looking to spare opioids, lidocaine infusion may be your best bet. Some other systematic reviews that have looked at this, smaller ones, not as rigorous as Cochrane, but they did show some effects, shorter length of stay, less pain intensity. That was the Merritt trial. McCarthy also looked at this. 16 trials with over 700 patients. They found more significant reductions in pain intensity. All these studies have tended to show lower opioid consumption, which again is a really good effect, earlier return of bowel function. So what kind of dosing are we talking about here? Well this is what's described in the literature. A lot of wide-ranging doses. Most of the doses are less than 5 milligrams per kilogram per hour. In fact, most of the time when we use this, we usually set it at a range of between 0.5 to 3 milligrams per kilogram per hour. And you can see several studies here that have looked at this. Chronic pain uncontrolled by opioids, that's there's a suggested dose that showed improved pain scores. Complex spine surgery can be a very painful surgery. Also showed significant health related quality of life, as evidenced by SF-12 scores at a dose of 2 mg per kg per hour. Open radical cystectomy and off-pump coronary artery bypass surgery also showed some positive effects. Interesting that the troponin elevations tended to be lower in a lidocaine group for off-pump coronary bypass. So some places will use it for that reason. So this gives you a sense of the dosing. I think the conclusion here would be, you know, think about this as an adjunct. It's safe. You have to be careful if you're giving another regional anesthetic because this drug will get you into trouble if you're giving other local anesthetics, such as bupivacaine or ropivacaine, or even just other doses of lidocaine for other blocks, or an epidural catheter, or a paravertebral catheter. So really, if you're going to use this, you want to make sure they probably don't have any of the regional blocks going on that can cause that local anesthetic toxicity. But at these doses, you're going to wind up safe with a potential for some benefit. So where do I land on lidocaine? I think it's useful. It is an evidence-based adjunct. The evidence is not as strong as we'd like it to be, but in the first 24 hours when a patient tends to be in a lot of pain, especially if it's a surgical patient, this is definitely something to think about if you want an opioid spare and add that as an adjunct to your overall analgesic plan. Okay, I just want to talk really briefly about another opioid. I know the topic of this is non-opioids, but it's worth mentioning remifentanil because I get asked a lot of questions about this, and I do use this drug occasionally. It is clearly an opioid, but the question is, if we're going to use an opioid, what about one that goes away really quickly? That way it's not staying around causing all the bad side effects. What if we just need some short, intense burst of analgesia? Can we use a drug like remifentanil? Well, here's some of the data on this. First, remifentanil is a very potent opioid. It's 200 more times potent than morphine. It's metabolized by nonspecific esterases, so therefore it does not accumulate in organ failure, and that's a really good thing. Clearance is reduced a bit in renal failure, but overall this drug is taken out by these nonspecific esterases, and that's really good. Therefore, it has a very predictable onset and offset. The contact-sensitive halftime is around 3 to 4 minutes, which really buys you an elimination half-life of less than 10 minutes. This drug is gone in less than 10 minutes, so even if you're on an infusion, if you don't have any renal failure and you shut it off, that patient will wake up. So that's a good and bad thing. It's a good thing if you just needed some really short, intense analgesia, maybe for a bedside procedure. Not a good thing if you are worried about hyperalgesia and you don't have something in the background to cover that analgesia. The half-life again, first-order kinetics, contact-sensitive halftime, this is just a review of what that context-sensitive halftime, how that's defined, and when we show that graphically, this is really a classic graph that we talk about in anesthesiology. Other opioids like fentanyl, even L-fentanyl and su-fentanyl, they also have favorable pharmacokinetics initially. They have rapid onset, rapid dissociation, but then they stay around for a long time. I'm sure you've seen this if you've had patients on high-dose fentanyl infusions. They sometimes don't wake up for a day if they've been on that for a long time. Remifentanil has the advantage of just going away. You can see it's a flat line in terms of the contact-sensitive halftime, so that's a very favorable aspect of this. There are multiple randomized studies that have looked at remifentanil with mixed results. Some have shown a reduction in ventilator days when this is used as a component of anal-ghost sedation. There may be a role in neurocritical care patients when you want to get a fast neurologic exam, but the thing you have to watch out for is that hyperalgesia. In 2009, which is kind of a while ago, they looked at this in a meta-analysis and they didn't really find any difference in outcomes. What can we say about remifentanil other than it's pretty expensive? This is some 2021 cost data that I found. Fentanyl is really cheap. You can get a 20 mil syringe or vial for $22, whereas remifentanil is many orders of magnitude more expensive. I think that I just put this out here because this is important to know again for that short and tense burst when you don't want to commit someone to a longer-dosed opioid. I thought it's worth mentioning. When you intubate, it's actually a pretty good drug for intubation. There's some good data on that, but we have a lot of other choices that are potentially cheaper. In terms of the acute opioid tolerance and opioid-induced hyperalgesia, this is a systematic review that came out in 2015. They did see that when you push up the dosage to greater than one microgram per kilogram per minute, you can see some pretty severe and consistent hyperalgesia. That's not a good thing. You can block some of that with propofol, at least the hemodynamic effects. You're not blocking the pain with propofol. There may be a modulatory effect due to the GABA-A receptor blockade that you get with propofol, but I just put this out here as another adjunct to add in. Think about remifentanil if you've got a really need of just a short burst of analgesia for a painful bedside procedure, but you don't need to commit them to a really long opioid. What are some examples of this? Maybe a chest tube insertion. Maybe you're doing another bedside procedure addressing change. We do see this sometimes used in burn patients for addressing changes as a part of an opioid rotation scheme. These are some of the roles, some of the clinical scenarios rather, where you might find remifentanil to be helpful even though it is an opioid. All right, let's get back to non-opioids. That's the whole reason we're here today. What about this? 44-year-old man, nurses come to us. This guy is just a beast. He's alcoholic pancreatitis. His RAS is consistently positive for. He's hitting, kicking nurses. He's self-extubated twice. He's tachycardic. We've got him on propofol, which at our institution we cap that off at 75 mikes per kilogram per minute, and he's also on a really hefty dose of fentanyl, 200 mikes per hour. That's a really high dose of fentanyl. So what can we do? How can we attenuate this? Is there anything else we can add in our anal go sedation plan? You know, pain is certainly a component here. There's probably also some withdrawal going on, but this is also just a young patient who's just not happy to be strapped down into a bed, and he's pretty sick. So what can we do to help with this? What is the role of dexmedetomidine in terms of opioid sparing, in terms of non-opioid analgesia? This drug comes up a lot, and we use it a lot. So what do we what do we really get out of the analgesic aspects? So we know all this works, or as a review, I know everyone probably remembers how this works. It's activation of the alpha-2 receptors in the locus coriolis. Good intranasal and buccal absorption, actually, so he doesn't have to always be given IV. I think we forget that sometimes. Most of us will use it as an infusion. It has a pretty good elimination half-life, maybe a little bit longer in ICU patients. Clearance does depend on hepatic blood flow, and the alpha-2 to alpha-1 ratio is 1600 to 1. So that puts it at a range of 7 to 8 times higher than clonidine. So that's why, if you might say to yourself, well, clonidine is a lot cheaper, let's just use that. Just keep in mind that clonidine doesn't have the same central alpha-2 receptor blockade density that you get with dexmedetomidine. This drug actually does resemble natural sleep more so than propofol. It can mimic deep recovery sleep after sleep deprivation. That's been shown in several studies. Pain transmission suppressed. Now this is where we get into the analgesic effects. Is it a true analgesic? Well, that's unclear, but we do know that it does reduce substance P and glutamate. It may have minimal effects on respiratory function, so those are all favorable things. This drug can, in fact, have some opioid sparing effects, and that's why we mention it. But to think that it's a pure analgesic is probably not right. Keep in mind, and this is really for more of our learners that are coming up the ranks, when you first start using this drug, you do have to be cognizant that when you bolus this drug, and we're seeing a lot more boluses, especially for surgical patients that are getting bolused in the operating room, you can get hypertension because the peripheral alphas will be activated first, causing vasoconstriction, and that can lead to a baroreceptor effect, which causes bradycardia. This is balanced out by the vasodilatory, the overall vasodilatory effect of the central alpha 2a receptors, but just keep this in mind when you push it. We usually start patients with maybe a bolus, but a lot of us will just start them on a patient on an infusion, and this is the typical dosing that's recommended by the manufacturer in the package insert, 0.2 up to 1.5. Doses higher than 1.5 are probably not effective. Many of us have done this, but the literature, and I have a paper that's listed in the comments of these slides that talks about that from Venitol 2003, we've known that this probably is not very effective. We probably saturated most of the receptors at that dose, so going higher is not going to really get you much more. You really have to watch the heart rate with dexmedetomidine, as I'm sure many of you know, and then when we look at just a review of how this has been used for sedation, the MENS 1 trial, which is 106 patients, there were more patients alive in the dex group, but more bradycardic. This was followed by MENS 2, which again was an adult study with several important patients that were excluded. Pregnant patients, heart blocks, patients with baseline cognitive impairment were excluded, but it did have a larger N, and they didn't find any difference in ventilator-free days, death, or global cognition at six months. They concluded this didn't really lead to better outcomes. Nevertheless, it's still a very good sedative. This is the New England Journal paper that I think a lot of folks are familiar with. Not a lot on the analgesic effects in this. And then, can we use it to prevent delirium? Well, this was looked at in a two-center double-blind RCT, nocturnal dex versus placebo, and they found a pretty large difference with delirium. So, that's one thing. We use this occasionally for nocturnal sedation or to help with patients who are really having some problems at night. But nevertheless, when we talk about the opioid sparing, that's probably the best we get with it. It's not a pure analgesic. There are other effects. It could be neuroprotective, may help with some cardiovascular and ventilatory outcomes. There's a whole bunch of purported effects, such as enhancement of the immune system and maybe some beneficial micro circulatory effects, which are very interesting, as well as some of the other neuroprotective effects that are listed here. But the bottom line is, once again, it's not a pure analgesic. It does have some mechanisms that help decrease pain transmission. So, it could be part of a multimodal strategy, but it's not in and of itself an analgesic. And that's the whole point I'm trying to make here with dexmedetomidine. It has some other good effects, some other equivocal effects, but it's not a pure analgesic. All right, let's just talk about one last medication here, olaceridine. So, this is a newer drug that's a selective mu-opioid receptor binder, and this drug just was approved in 2020. We don't have it at our institution yet, and this is maybe something we see a lot more. The mechanism here is reduced beta-arrestin activity. It may have more selective activity for analgesia. Let me show you how that may work. So, you can see in this diagram here, there's an analgesic response via the G-protein coupled pathway at the mu-receptor. And what you see with this particular agent is more of an analgesic effect and less adverse effects because this drug is really targeting that G-protein pathway. So, that's a very novel mechanism that really arrests that beta-arrestin recruitment, which is thought to be responsible for most opioid-related adverse events. So, potentially an opioid. I know we said we weren't going to talk about opioids much, but this is an opioid that may be a little bit more beneficial, something just to keep your eyes open for. The dosing for this, 1.5 IV, and you can repeat that with half the dose an hour after the initial dose. There is a PCA demand dose of much lower, 0.35, so you can make this a patient-controlled analgesic. And the interesting thing is here is they're they're telling us is this really doesn't require any dose adjustment for patients with hepatic or renal impairment. There's a phase 3 studies, Apollo 1 and 2, more responders compared with morphine. They looked at some high-risk patients in Athena. They didn't see any higher risk of respiratory depression in patients who are at risk for respiratory depression. It seems similar or less than morphine in terms of the respiratory depression. You still get the respiratory depression, but fewer dose interruptions. There are some reports of QT prolongation, and it can, like all opioids, still cause physical dependence. So it's not any better of an opioid in terms of the dependence, and it's still an opioid, but I mentioned it because I felt that this is a newer drug that we probably should be aware of because it may show up in our ICUs. And maybe there are some patients that this could be more beneficial with, but nevertheless, more to come, more to follow with this drug. So in summary, this is a bit of a busy slide, and I would hope that many of your hospitals have a similar algorithm. This looks very similar to what was published in the 2018 PADIS guidelines from SCCM. I think when you start to take a look at a patient, and I won't walk through the entire chart here, but I leave this for your review, you know, you always want to do, you do want to start with analgesia first, if you can. You make sure that you've got good analgesic coverage, and then as you move down into this, some of the agents that we've talked about here, such as dexmedetomidine, ketamine, think about using them maybe a little earlier. You can see in our own institution, ketamine doesn't come in until we get to refractory agitation, but many of us have bumped this up a little bit higher to a second line, maybe a third line agent to help that opioid reduction. So this is just something to think about in terms of how you can integrate this into your own institutional pain, agitation, delirium, and mobility guidelines. I want to just highlight, you know, two other things we didn't talk about much, acetaminophen and tramadol. Tramadol is certainly another option. You have to watch out for seizure disorders. There's a dose adjustment required in renal failure, but it is yet another good option if you want to avoid the pure mu agonists. Methadone is also an opioid, but it does have some opioid sparing effects, mainly because it has another mechanism. It also has some NMDA inhibition. So a commonly used dose, starting low, if you want to, you know, knock down that gigantic fentanyl dose you've got that you're trying to wean the patient down off, or perhaps your oxycodone dose, which may be too high. Think about maybe another dose of methadone, adding that in every eight hours or so. A very low dose, 2.5 to 5. Keep in mind, this is clearly an opioid, and the half-life for methadone is very long. So that will be a drug that you're going to want to think about as the patient's getting better, but it may help you in the short term come down off your really high doses of fentanyl. And then there's always acetaminophen, and we usually recommend keeping under 4 grams, and more frail patients will even go lower than that, less than 3 grams a day. The rectal suppository versus IV. IV is great. Most of your institutions, at least ours, is restricted by pharmacy because, you know, we just really don't want to have a cost. It's really costly. So it's not as bad as it used to be, but I will tell you that the last cost data that I received was it's about $19 a dose versus a rectal suppository, which is less than a dollar, about 66 cents. The nurses won't like you because anytime we have to give something rectal, it's a lot easier to give an IV, and some of our patients may not be able to receive it rectally. But think about rectal acetaminophen if your patient is not able to take any oral acetaminophen. Always think regional. That's a whole other talk. Maybe we can talk about that another day, but if you've got a chance to do a regional or a peripheral block or a neuroaxial block, always think about that. That can really help with all the opioids, avoiding them, and we really try, we're trying to do a much better job of that at our institution. I would encourage you to do the same. I thank you for your time. Sorry this had to be virtual this year, but I look forward to seeing everybody in person next year. Thank you.

multimodal analgesia

ketamine

lidocaine

pain assessment

non-opioid options

surgical patients

dexmedetomidine

olaseridine