Good morning, everybody, and thank you, Kathleen, and thank you, SCCM, for this opportunity to present here today. So I'll be actually taking Ty's work a little further, and as part of the session, talk about the challenges that critical care providers face as they go about managing patients with opioid use disorder in the ICU. A little about myself, I'm an anesthesiologist intensivist. I'm an associate professor at UT Southwestern Medical Center in Dallas, Texas. Here's a list of my disclosures, none of which is relevant to the talk today. Now, during this talk, I would be briefly discussing the epidemiology of opioid use disorder. I know Kathy talked about it, Ty talked about it a little. We'll talk about it just a little bit, just because without mentioning that, the talk seems incomplete. And then we'll talk about some of the common scenarios in which we, as ICU providers, might have to deal with patients who have opioid use disorder in the ICU. We'll talk about acute opioid overdose, managing an opioid-dependent patient, whether it's after a surgery or someone with medical issues, and then we'll briefly talk about acute opioid withdrawal. Now, how do we define opioid use disorder? So it's essentially frequent use of and tolerance to opioids with symptoms of withdrawal upon cessation, unsuccessful efforts to quit or cut down, a failure to fulfill role obligation, and giving up activities for drug use. Now, when we look at the epidemiology of opioid use disorder, it has been estimated that the prevalence is about 2% to 3%. What that means is about six to eight million adults in the United States are currently living with a diagnosis of opioid use disorder. Now, again, I think this was talked about earlier as well. If you look at opioid overdose-related deaths, there has been a 1,000% increase from 2013 to 2019. Just the year 2019 alone, 70,000 patients died of opioid overdose. That contributes to about 20 per 100,000 patient population, and as Tai mentioned, most of them are related to the use of synthetic opioids such as fentanyl. Now, moving on, let's talk about acute opioid toxicity that we might encounter with patients who have opioid use disorder. Now, this was a retrospective cohort study that was published in 2017 looking at ICU admissions across 162 hospitals in 44 states over six years. The overall prevalence throughout these years was about, so for about 10,000 ICU admissions, around 50 or so were related to acute opioid overdose. Now, when you look at the trend over those years, there was a significant increase of about 34% over those seven years. When we look at mortality, again, it showed a trend which was not on the right side, so 7% in 2009 to 10% in 2015, and what the authors estimated was that the monthly mortality increase was about 0.5% per month. The authors also looked at utilization of ICU resources, and as you can see, in 10% of the patients, mechanical ventilation was needed, non-invasive ventilation in 7%, vasopressor use in 4%, and I think Tai mentioned that as well, the average cost per ICU overdose admission increased by about 60% in those years. Now, we're all aware of the signs and symptoms of acute opioid overdose. The ones that we commonly see in our ICU patients are the significant respiratory depression, the hemodynamic collapse, and the alteration in mental status. As far as management is concerned, pharmacologic reversal with Naloxone remains the mainstay of managing these patients, and the figure here kind of illustrates a stepwise increase in dosing that you can use for Naloxone. Gastric decontamination can be useful if you can institute it within one hour of ingestion. A lot of patients might require mechanical ventilation because of the significant respiratory depression, and because of hemodynamic collapse, they might need inotropes and vasopressor infusions. Now, a couple of things about Naloxone. So, in these patients who have opioid use disorder, there's always the risk of acute withdrawal, and the abrupt catecholamine that can happen with that can lead to pulmonary edema, can lead to cardiac arrhythmias. The other thing to consider, which I teach my residents very often, is the duration of action of a single dose of Naloxone is very short. It's much shorter than the regular duration of action of your opioids, let alone the doses used in overdose. So, a lot of times, that one dose is not gonna help. You would need an infusion of Naloxone to treat these patients. Now, moving on, let's talk about a patient population that I think we all have been dealing in an escalating way since the pandemic, and these are patients who are on chronic opioids or opioid-dependent patients. Now, as the prevalence of opioid use disorder has increased in the general population, so has the incidence of these opioid-dependent patients coming to the ICU and getting admitted. These patients tend to have a longer hospital and ICU length of stay. Now, because of this chronic opioid use, a lot of them develop tolerance, central sensitization, opioid-induced hyperalgesia, and are at a risk for acute opioid withdrawal. Now, when we talk about tolerance, it's associated with the long-term use of opioids, and it occurs because of desensitization of receptor-mediated antinosusceptive pathways. These patients tend to have a lesser susceptibility, both through the therapeutic and adverse effects of opioids, and more often than not, they have a very high need for opioids or for their analgesia. Now, you know, Ty mentioned that as well, an opioid-tolerant patient is a person who takes the following medications in the doses that are described for at least a week. Now, moving on to central sensitization, you know, it occurs in patients who are on chronic opioids as well. Now, what happens is that there is an amplification of synaptic transfer of pain signals, which can manifest as hyperalgesia, wherein these patients have a hypersensitivity to pain, or allodynia, where there is an exaggerated response to even non-noxious stimuli. Opioid-induced hyperalgesia is another phenomenon that you might see in patients who take long-term opioids, and this occurs because of nociceptive sensitization. In these patients, opioid administration paradoxically worsens pain. Now, undertreatment of pain is extremely, extremely common in the ICU, and, you know, it's even more common in patients with opioid use disorder, and this occurs because of unfamiliarity with opioid-equivalent dosing. It's always this fear of causing adverse effects when using higher dose of opioids, especially people who are not, you know, used to using high doses of opioids. They get very concerned and scared about using these doses, and oftentimes, there is a difficulty assessing the severity of opioid dependence, and this undertreatment of pain is so common that pain is often the most common memory that patients have of their ICU stay, and it's not a pleasant one at all. So it's extremely important that we appropriately assess and treat pain. As far as assessment is concerned, I think, you know, in patients who can self-report, the numeric rating scale and the visual analog scale can be helpful. For patients who cannot self-report, which is majority of our patients in the ICU, the Society of Critical Care Medicine Guidelines recommend using the Critical Care Pain Observation Tool and the Behavioral Pain Scale. So once you have appropriately assessed pain, the next step is to treat it. I think one of the limitations is we cannot identify these patients most of the time, so the key is to identify these patients who have chronic opioid use, patients who are opioid-dependent. The next step is to calculate their baseline opioid use in oral morphine equivalents, and once you have calculated that, use multimodal analgesia using opioids, opioid-sparing strategies to take care of their pain. Now, here's a table, you know, it's freely available, which kind of helps you figure out how much opioids they are taking at a regular basis at home. So once you have figured that out, again, unfortunately, opioids will remain the mainstay of managing pain in these patients. The first step in that is to calculate how much opioids were they taking at baseline at home and make sure they get those opioids at least, that's the minimum they should get. And then based on what kind of acute pain issues they have, you may have to supplement that with short-acting opioids. And again, please bear in mind that these patients would tend to have a higher opioid requirement. Their need for opioids should be re-evaluated on a regular basis and doses escalated as needed. So let's talk about some of the opioid-sparing strategies that we can use in the ICU on these patients. Now, the non-opioid analgesics that have been used are estaminophen, the non-steroidal anti-inflammatory drugs, the alpha-2 agonist, such as Clonidine, dexmedetomidine, and the NMD antagonist, ketamine. Starting with estaminophen, I think we all are aware it's available in IV, PO, and parectal formulation. There is some controversy about whether the IV formulation is better than the entral formulation. And the company that manufactures that product wants us to think that it is. But unfortunately, there is no data to support that IV formulation of estaminophen is superior to the oral formulation. So if entral access is available, entral formulation should be preferred. There is good data about estaminophen working well in a multimodal regimen for post-surgical patients, and it's also recommended by the SCCM, pain, agitation, delirium guidelines. A couple of things to know about estaminophen is if you give it in an IV formulation, transient hypotension can occur, which may not be well-tolerated in our hemodynamically unstable patients. And of course, in patients with liver injury and liver disease, the doses have to be reduced. In fact, we use estaminophen in our acute liver failure patients who are listed for transplant, but we just reduce the dose. Non-steroidal anti-inflammatory drugs, again, those are great drugs, have been used extensively for post-operative pain control, but the problem with ICU patients is that a lot of our patients have AKI. NSAIDs are not good for those patients. GI bleeding from stress ulcers, it's likely in these patients. NSAIDs can worsen that. So again, not a good indication. Platelet dysfunction can occur with these patients. So although these drugs are good for post-operative surgical patients, their use in non-surgical patients is probably not routinely recommended. Alpha-2 agonists, we know that they reduce the sympathetic flow, cause both analgesia and sedation, tend to have an opioid sparing action, reduce opioid-induced hyperalgesia, and the best part is they cause minimal respiratory depression. Now, the two drugs that we have are dexmetadomidine and clonidine. Dexmetadomidine is highly selective for alpha-2 receptors, has minimal or no respiratory depression, has been found to reduce delirium, but it tends to have a very variable response. I think it works in 50% of the patients, and 50% of the patients, it just doesn't wanna work. Now, clonidine only available in oral and transdermal formulation. The problem is the prolonged onset and the unpredictable absorption. A novel use of clonidine that has been coming up is to transition patients who've been on dexmetadomidine infusions, and weaning them off and starting them on clonidine and getting them out of the ICU faster. Something to worry about is the rebound syndrome, which can happen if you abruptly stop clonidine. Now, let's look at this meta-analysis, which kind of assessed whether dexmetadomidine would be a good agent for its opioid sparing effect, and in this meta-analysis, the authors found that in post-surgical patients, it not only reduced opioid consumption, but also reduced pain scores at six and 24 hours post-surgery. Now, the biggest limitation with the use of these drugs is the bradycardia and hypotension, which, again, may not be well-tolerated in our critically ill patients, so we have to be very careful about their use. Ketamine is an NMDA antagonist. Now, the good part about ketamine is that even at sub-anesthetic doses, it causes profound analgesia. For burn dressings, for your minor procedures at the bedside in the ICU, it's a phenomenal drug. It preserves pharyngeal and aryngeal reflexes, lowers airway resistance, and tends to cause much less respiratory depression than opioids and other sedatives. Now, in this study where the authors looked at mechanically ventilated adult surgical critically ill patients, they found that low-dose ketamine was able to reduce their opioid consumption without any significant hemodynamic effects, and again, the dose has to be on the lower side. In another study, this time looking at traumatic rib fractures in adult patients, again, ketamine as an adjunct was shown to reduce opioid requirements, was shown to provide better pain management. Now, again, problems with ketamine, sympathetic stimulation can occur, which may not be well-tolerated in some subset of our patients. It does cause psychomimetic effects. In fact, the hallucinations that it causes are just very worrisome. Delirium is another risk, nausea and vomiting, and again, there's very limited data in non-surgical patients. The other drugs that have been used, such as intravenous lidocaine, the lidocaine patch, carbapentanoids, there's very limited evidence in critically ill patients, and conflicting evidence in perioperative settings, especially if you start them afresh in this perioperative setting. Now, another modality that can be used to supplement our systemically administered analgesics is regional analgesia. It's been mainly used for surgical pain, and the techniques commonly used are epidural analgesia, the upper and lower extremity blocks, and facial plane blocks. Now, we'll talk briefly about epidural analgesia. We know that it works really well for post-operative pain in our thoracic surgery patients, major abdominal surgery, major vascular surgery. Like for traumatic rib fractures, for a long time, epidural was considered the gold standard for managing pain. Now, a non-surgical indication that has been looked at is acute pancreatitis. In fact, the EpiPan trial that is currently underway will help us decide if this modality is a good way to manage pain in patients with acute pancreatitis. The problems, again, especially for neuroaxial blocks positioning, you have to sit them up, put them on a side. It's challenging. A lot of them receive therapeutic anticoagulation. They are coagulopathic. Neuroaxial block is contraindicated in these patients. The local anesthetic that you give in the neuroaxial space may cause cardiovascular instability, which may not be tolerated in these patients. And again, resources are limited. Not all ICUs, not all institutions have an anesthesia team that would be available to do these procedures for you in the ICU. Now, a technique that has been used in chronic pain setting is opioid rotation, where you switch to another opioid if you have dose-limiting side effects or limited effectiveness. And the premise for its effectiveness is that because of the different interactions of opioids on various opioid receptors. Now, here's a flowchart that we published in the White Journal a few years back, which kind of comprehensively describes managing pain in a patient with opioid use disorder in the ICU. Now, I think a question was asked when Ty was giving his talk on opioid agonist therapy. So let me take some time to talk about opioid agonist therapy, which is commonly prescribed in opioid-dependent patients. Now, it's important to continue their baseline therapy as much as possible. And combine short-acting opioids with that therapy for acute pain management, again bearing in mind that they would need higher and more frequent doses. In case the therapy is interrupted, it is safe to delay its re-interruption until discharge. Use your opioids and non-opioid adjuncts, meanwhile, to treat their pain and watch for acute withdrawal. Another drug combination that is commonly used in these patients is the buprenorphine-naloxone combination. And acute pain management is extremely challenging in these patients, which we commonly see in post-operative patients. They should be continued as much as possible. They require a higher opioid regimen during their treatment. And multimodal pain regimen is the way to go. A couple of slides on acute opioid withdrawal. As we know, their symptoms are irritability, anxiety. They usually begin two to three half-lives after the last opioid dose. Again, so six to 12 hours after morphine or heroin, or 36 to 48 hours after methadone. Treatment is mainly supportive. Alpha-2 agonists, such as clonidine and dexmedidomidine can be used. And NMDA antagonists can also be used. Clonidine has been effectively used in this setting, in this study, looking at ventilated patients with withdrawal symptoms. Clonidine was shown to decrease their hemodynamic, metabolic, and respiratory demands, and causes better ventilator synchrony. NMDA antagonists, again, they block the depolarization of neurons that process the nociceptive information, prevent hyperalgesia. Again, not much evidence in the ICU, but in narcotic-tolerant patients undergoing spine surgery, this drug was associated with reduced opioid consumption and better pain control. So in conclusion, as the prevalence of opioid use disorder has increased and is increasing in our general population, the number of patients with opioid use disorder presenting to the ICU is bound to increase. It is very important we recognize these patients, and then assess and appropriately treat their acute pain on top of their chronic pain. Use multimodal analgesia in the form of opioids, non-opioid adjuncts, and regional analgesia. Thank you so much for your time.

critical care providers

opioid use disorder

ICU

opioid overdose

pain management