Should opioid-free anesthesia be implemented? A pro-con debate

Welcome back to Depth of Anesthesia. This is a podcast that critically explores Our clinical practices. I'm David Hao and I'm an anesthesiologist at the Massachusetts General Hospital. Our first guest today is Dr. Scott Cow. Dr. Cow is currently a chief resident at the Massachusetts General Hospital, and he's a graduate of the University of Colorado School of Medicine.

Dr. Cow, welcome to the show. Thanks, David. Really happy to be here. And our second guest is Dr. Mary Daniels. Dr. Daniels is a graduate of Harvard Medical School, and she's originally from Tennessee.

Dr. Daniels, welcome to the show. Thanks for having me. So I'm really excited because today's episode introduces a new format for our episodes. It is a pro-con style discussion. And Dr. Cow, Dr. Daniels, and I, we recently had the privilege of presenting this at a grand rounds at the MGH.

And I thought it was really nice because it sparked a pretty lively and insightful discussion around the topic. So what we're going to do is Dr. Cal will present the proposition, and then Dr. Daniels will offer the con perspective They'll each argue their points of view, drawing of course on primary literature for support, and then following their perspectives, they'll come together to synthesize the evidence and share some of their reflections on the current state of the literature The topic today is the concept of opioid-free anesthesia and analgesia. And the reason we're talking about this is because Well when I conducted a PubMed search in preparation for this grand rounds, I found five hundred and sixty-three publications on this subject in the past five years alone.

So clearly there's growing interest in this space and let me just share some of the editorial titles that stood out to me. Opioid-free anesthesia, should we all adopt it? An overview of current evidence. Opioid-free anesthesia in research and practice, so near yet so far. And opioid-free anesthesia, time to regain our balance.

My perspective is there's clearly a lot of momentum here, and it definitely feels like the right time to explore some of the different perspectives around this approach. So some of you might be wondering, I always use opioids for my anesthetics. Why would this ever matter to me? Well The American Society for Enhanced Recovery and Perioperative Quality Institute put out a joint consensus statement on opioid minimization in opioid naive patients. And they suggested that opioid-free anesthesia and analgesia protocols are not only feasible, but also recommended as a valid perioperative strategy.

And just as ERAS protocols have made their way into the OR, I think you might soon face the question, is opioid-free the right approach for this patient? Before we get too deep into the conversation here, I think it's worth clarifying that there's a lot of confusion around definitions in this space. So moving forward, here's how we'll clarify. Opioid-free analgesia refers to managing pain without opioids throughout the entire perioperative journey And opioid-free anesthesia focused specifically on avoiding opioids during the surgical period. So that's induction, maintenance, and emergence.

So with those distinctions in mind, let's dive a little bit deeper into this conversation. Scott, I'm gonna have you start with talking a little bit about some rationales that you have in support of opioid-free anesthesia and analgesia practices. Absolutely. And thank you again, David, for having me on the show. I think the strongest signal that we've found for opiate-free anesthesia is that it significantly reduces postoperative nausea and vomiting So what does the evidence say?

Between 2019 and 2021, three major meta-analyses came out looking at this concept of opioid-free anesthesia practices. In one editorial, uh, used this tool called ANSTR2, which critically evaluates meta-analyses. And of the three that they analyzed, The highest rated was a 2021 study by Ulassen. And this study specifically focused on randomized controlled trials comparing completely opiate-free anesthesias to that of opiate-based anesthesias in adult patients undergoing general or regional anesthesia And the outcomes that they looked at were important. They looked at adverse events, including things like vomiting and nausea, as well as things like quality of recovery. package discharge times, postoperative pain, and postoperative opioid consumption.

Of these adverse events, the one notable finding that stood out was the reduction in post-operative nausea and vomiting. In the opioid-free anesthesia group. Specifically, nausea outcomes reported in 20 different studies, 17 of them were included in the analysis. From the pooled results The authors showed that there was an odds ratio of 0.27 for nausea and an odds ratio of 0.22 for vomiting, indicating a significant reduction in PONB after surgery. And for cases that weren't specified as nausea or vomiting, they were listed as unspecified PONB, which had an odds ratio of 0.38.

Got it. So we have a meta-analysis highlighting that opioid-free anesthesia significantly reduced PONV with pooled odds ratios of 0.27 for nausea. 0.22 for vomiting and 0.38 for unspecified PONV. And one thing that I'll mention is that as you might expect, there is some substantial heterogeneity seen within these studies. So in the opioid-based anesthesia groups, you have a lot of different medications being used from morphine to remifentanil to fentanyl hydromorphone. And for the opioid-free groups, the variability was even greater.

So despite all this variability, we still see some signal. And Dr. Cow, I think it'd be worthwhile for you to just describe to our listeners how do we how to actually think about an odds ratio like 0.27 that we saw for Nausea? Absolutely. An odds ratio compares the odds of an event occurring in one group to the odds of it occurring in another. An odds ratio less than that of one indicates that the event is less likely in a treatment group.

So using the numbers that we had just talked about. An odds ratio of 0.27 for nausea means that the nausea in the opiate-free anesthesia group is 73% less likely to occur compared to that of opiate-based anesthesia. These reductions in PONV highlight the advantages of opioid-free approaches, despite the variability in regimens that we had just talked about. Awesome. So while it seems that the reduced odds of PONV highlight definitely a key benefit of opioid-free anesthesia.

I am curious how these approaches impact the other parameters that you talked about, like PACU discharge times, postoperative pain levels, and opioid consumption after surgery. Yeah, of course. And actually interestingly, when looking at key outcomes like package discharge times and all the other factors that you had listed. The findings in the study suggest really minimal clinical impact from opioid-free anesthesia. For instance, Time to PACU discharge was unchanged.

In the 10 studies that this study looked at, there was no significant difference in mean discharge time. Similarly, post-operative pain, which I might argue is the elephant in the room, right, when we choose to use a protocol that doesn't have opioids. One of the kind of knee-jerk reactions that people have is a patient comfortable after an operation. In this study, 21 different studies that they analyzed showed no difference in overall mean pain scores in the posto-operative phase. Matter of fact, there was probably a slight signal, although I wouldn't say it's clinically significant, but statistically significant, a slight reduction in actually pain scores in the first zero to two hours in patients.

Who had underwent opioid-free anesthesia. And lastly, as far as post-operative opioid consumption goes, while the opioid-free group did have significantly lower morphine equivalent usage, They had actually a reduction of four milligrams of morphine. The clinical relevance of the small reduction, I would argue, is debatable. Alright, so it seems like while the findings suggest that opioid-free anesthesia does not significantly impact PACU discharge times. Post-operative pain or opioid consumption.

And importantly, as you mentioned, does not worsen pain control. I think it does raise the question of what types of surgeries were actually looked at in these meta-analyses. And That was a question raised by a member of the audience when we gave this grand rounds. And I think it's fair to say, yeah, the expectations for pain management recovery are gonna be pretty different for a large open thorachotomy. compared to something like a skin biopsy. What can you tell us about that?

Of course. That's such a crucial question to ask when we when whenever we appraise medical literature and in determining whether or not findings in the study applies to the patients that we treat. Data from the meta -analysis from the OLAWSIN study, as well as another one that we'll talk about in just a sec here, those were heavily represented by patients who underwent laparoscopic gyne surgery, as well as breast surgery. And David, actually, one of the randomized controlled trials was by Feng. The authors of that study demonstrated similar findings in thoroscopic lung resections where the opioid-free anesthesia patients actually had lower pain scores without increased rescue analgesia in the postoperative phase.

And Scott, you had mentioned earlier there there was actually one other systematic review in meta-analysis that has some additional information. Is that correct? Yeah, absolutely. And this was a study done by Zhang, and it was actually a study that was done more recently than the Lawson study And it was a systematic review and analysis that reaffirmed a lot of the key findings from the Lawson study This study specifically focused on randomized control trials comparing opiate-free anesthesia with that of traditional opiate-based anesthesia in adults undergoing general anesthesia. Their primary outcome was PONV within 24 hours of surgery.

Their secondary outcomes were some interesting things like time to excavation. time to first post-operatives rescue analgesia and pain scores at 24 hours. And so what did they find? They also found that POMB was significantly reduced in the opioid-free anesthesia group. In fact, across 14 studies and 1,300 patients, they found the relative risk score of PONV was 0.41 So another clear and significant reduction in POMB in patients who undergo opioid-free anesthesia. Pain scores at 24 hours were statistically lower as well in the opioid-free group. with a mean difference of negative 0.72.

So, in summary, opioid-free strategies appear to be really effective at reducing PONB without really impacting pain control and the need for rescue angesia in the pacchi Awesome, Dr. Cow. Thank you for sharing your position. And uh let's go on now to the con position. Dr. Daniels, what are some of your thoughts about opioid-free anesthesia? Of course.

So opioid-free protocols have been gaining popularity, but they're not without significant risk There was a multi-center randomized controlled trial by Bilal in 2021 that compared dexmedetomidine to Remifentanil infusions. The result of this study showed that there was a higher rate of their composite adverse outcomes in the dexmenatomidine group. It was 78% in that group compared to 67% in the Remyfentinal group. The composite outcome that they were looking at was a combination of hypoxemia, ileus, and cognitive dysfunction, which were side effects that they deemed related to opioid use They looked at other differences in the Dexmedetomidine group, such as prolonged extirbation times, increased PACU stays, and higher incidences of brachardia and hypotension. One big takeaway from this study was that it was terminated early for a severe safety signal in the dexmedatomidine group.

There were five cases of patients who had severe bradycardia with three cases of patients who had a systole, one patient who required resuscitative efforts, the termination of the surgery, and transfer to the ICU. Importantly, the protocol was adjusted throughout the study such that the anesthesiologist was not blinded to the regimen and they were able to titrate the they were able to titrate the infusion rate of dexmenatomidine and remifentanil. to patient effect and to side effects. However, we noticed that in this study at least there were significant risks that persisted, including the brachycardia I think that's an important perspective to have because when we think about opioid free protocols, we're typically replacing the opioid with something else.

We're seeing here, as you mentioned, that there's certainly some potential adverse effects from medications like dexmedetomidine And to add some perspective, when we were doing this lit search, we found a study in 2024 conducted by Chassery looking at opioid-free versus opioid-based protocols. And They actually omitted patients who had a heart rate under 60 beats per minute. And I think that just highlights how strict exclusion criteria like that can limit generalizability to real-world clinical settings And this means that sometimes the safety of these protocols in broader populations is still unknown. Absolutely, David. It's clear while some of these opioid-free anesthesia protocols have benefits that may be purported.

It's crucial to evaluate the patients that we're using them in and the associated risks that they may have. And one other thing I think to consider is the clinical comp complexity that these protocols introduce. Managing things like bradycardia and hypotension often add a whole series of additional things that need to be considered. And so certainly there might be a question of whether we're trading one set of issues for another. That's a great point.

It underscores the importance of balancing the risk of using alternative reg regimens as well as the benefits, especially in vulnerable populations, that these medications may have exaggerated side effects, such as the elderly or those with underlying cardiovascular conditions Another challenge about opioid-free protocols is that there's a lack of standardization in these regimens. This makes it challenging to interpret the evidence. In some cases, definitions of opioid-free vary widely. For example, some studies permit rescue opioids, others exclude them entirely. Some protocols are described as opioid-free, yet they include opioids for the induction of anesthesia, such as fentanyl.

Additionally, induction and maintenance regimens can differ significantly. This may include incorporating agents like dexmedetomidine, ketamine, lidocaine, or regional techniques in addition to the opioids or opioid-free protocols that are used. There was a systematic review by Fro and Connect et al. in 2019. This included a variety of trials, but there were two trials in particular, Anu et al. and Song et al. which upon closer examination of the methods of these studies, they did not adhere to specific strict opioid-free criteria, despite being deemed an opioid-free regimen In both of these studies, there were groups that received opioids. In the ANU trial, all the patients received fentanyl, and all groups in the Song trial were administered remifentanil.

So you can see how it makes it challenging when there is a lack of standardization on what opioid-free really means And I think this highlights really the critical importance of having to read individual studies yourself sometimes. I think time and time again from our podcast, we've seen how crucial details in some of these individual trials can really change your interpretation of the broader evidence base. I think this is a great example, right? You have a review that ostensibly evaluates opioid-free. You look closer and you see a deviation, a fundamental deviation.

And I think without this scrutiny, there's a good chance that the review's findings might be misinterpreted. Exactly. Adding to this complexity is the limited timeframe over which many of these outcomes are assessed. Most studies focus on short-term metrics like pain scores, opioid consumption, or PO and B within the first 24 hours. But these don't tell us very much about long-term recovery, functional outcomes, or healthcare utilization, all of which are very important to both patients and providers.

Without this robust long-term data, we're left questioning whether or not the benefits of opioid-free anesthesia really outright outweigh the risk and challenges. Let's talk about another critical consideration. Does opioid-free anesthesia really reduce opioid prescribing at discharge? When we looked at this specifically, the evidence suggests otherwise. There was a study completed on enhanced recovery after surgery protocols in colorectal surgery patients.

And in this study, they found that there was no significant difference in the discharge opioid prescriptions for patients who had opioid-free versus conventional opioid strategies. I think this really highlights that despite our best efforts to minimize opioids, the impact that we're hoping to have may not be as significant on discharge opioid prescribing. There was another study by Carash in 2021 that showed total perioperative opioid consumption doesn't really predict reliably the discharge prescribing patterns of opioids. This disconnect highlights how there's a need for comprehensive strategies, including clinician education and institutional guidelines, rather than relying solely on our intraoperative interventions as the focus I think that's a reasonable point and I think a lot of the conversation around opioid-free protocols was driven by the concern over opioids in the context of the opioid epidemic.

And I think also tying into this discussion is the concept of persistent post-operative opioid use, which is another layer of complexity and certainly something that many of our colleagues and surgical colleagues are looking to avoid. And persistent postoperative opioid use refers to patients continuing to use opioids after the quote expected recovery period. So I'm just curious, what do we know about this condition and risk factors and how that ties into opioid-free techniques? Exactly, David. So persistent postoperative opioid use, as you said, is opioid use that persists beyond three months after surgery.

There's a concern, I think, in our community that the use of intraoperative opioids may be contributing to persistent opioid use and potentially the opioid epidemic as well. There was a study from REMO and really didn't show that this was the case. This study looked at the predictors associated with persistent postoperative opioid use and did not find that intraoperative opioid use was associated, but found other patient factors were, including prior substance use or misuse, chronic back pain, as well as concomitant mental health disorders that patients may have. There's also the contributor of chronic post-surgical pain, and this is pain that persists for three months after surgery. It's closely related to but different from persistent opioid use.

And we know that acute postoperative pain is a risk factor for chronic post-surgical pain. And as we've described throughout this podcast, we know that opioids are potent analgesic agents that could potentially mitigate acute postoperative pain. So I think based on all of the data and especially this study looking at contributing factors for persistent opioid use Our efforts are better focused at addressing these other patient-specific factors rather than intraoperative opioid use. All right, Dr. Daniels, thank you so much for presenting your position. I want to finish up our episode today by just having you both give our listeners a summary of your points today as we close out this discussion.

So we'll start with Dr. Cow. Of course. Meta-analyses consistently demonstrate that opioid-free anesthesia significantly reduces post-operative nausea and vomiting while still providing effective analgesia. When we look at outcomes like packet discharge times, postoperative pain, opiate consumption, the impact is minimal In fact, discharge times and overall pain scores show no significant differences. So the critical takeaways is that these strategies do not worsen pain control And the consistent reduction in PONB remains a clear benefit without introducing clinically meaningful differences in other key outcomes.

Thank you, Scott. Opioid-free antiseizure protocols are certainly gaining traction, but I would say they come with significant risk, as highlighted by the Below trial. Which reported higher adverse events, particularly bradycardia, hypotension, and even cases of asystole, leading to early termination of this clinical trial. Other things to consider include a lack of standardization that further complicates the implementation of opioid-free regimens, with varying definitions making it difficult to draw consistent conclusions from meta-analysis. Additionally, these protocols have not demonstrated reductions in discharge opioid prescribing, underscoring the need for broader strategies like clinician education, institutional guidelines as well Without robust long-term data, it makes it challenging and uncertain whether or not the potential benefits outweigh the risk and challenges of opioid-free anesthesia.

All right. Thank you both for all your efforts today, not only for recording this podcast, but for all the work that you guys put into the Grand Rounds presentation. So thank you both for all your work. Thank you for the opportunity. Thanks again.

Happy to be here. All right. So to our listeners, I hope today's episode offered some valuable insights into the potential benefits. Risks and complexities surrounding opioid-free protocols. And as always, our goal is to foster thoughtful, evidence-based conversations that ultimately challenge our assumptions and inform clinical practice.

So we encourage you to share your thoughts, continue the dialogue with colleagues, and join us next time as we deep dive important topics shaping the field of anesthesia. And until then, stay hungry and keep asking questions. It's a waste of things and choice.