Should buprenorphine be discontinued preoperatively?

Welcome back to Depth of Anesthesia. This is a podcast that critically exactly the first time. I'm David Hao, and I'm an anesthesia resident at the Massachusetts General Hospital. And I'm Ashwini Joshi. I'm an incoming anesthesia resident at MGH as well.

This week's episode will be available on anesthesiologynews.com. They have two ongoing podcast series currently available through their channel. The latest episode explores a rare crisis of malignant hyperthermia in a pediatric patient. Our guest today is Dr. Tony Anderson. Dr. Anderson completed his anesthesia residency at the University of California, San Francisco. and his Pediatric Anesthesia Fellowship at Boston Children's Hospital.

He's currently an assistant editor for anesthesia and analgesia And his research interests focus on the use of focused ultrasound for peripheral nerve neuromodulation and pediatric perioperative outcomes. Dr. Anderson, welcome to the show. Thank you very much for the invitation to be here. This is wonderful and a great topic. Thank you.

This is a topic that we've been curious about exploring for almost more than a year now, so I'm very grateful to have you join the show. So let's get started with our case for today. Our case today is that of a thirty five year old woman who is being evaluated in the preoperative clinic. The resident notices that the patient has a history of substance use disorder and is on a combination of buprenorphine and naloxone. also known as Suboxone. The resident recalls the drug's mechanism of action and then suggests to the attending that the patient should probably discontinue the medication prior to the day of surgery to improve perioperative pain management.

Dr. Anderson, what are some of the claims here in this case? Well buprenorphine's mechanism of action may inhibit the analgesic actions of traditional opioids or full mu opioid receptor agonist, and patients on buprenorphine may experience uncontrolled postoperative pain, which may be difficult to control with the traditional opioids. Here now are two questions for our listeners to consider. What is the level of your agreement with the claim that buprenorphine inhibits the analgesic actions of traditional opioids? and patients may therefore experience uncontrolled postoperative pain. And what is the level of evidence for what you believe?

Dr. Anderson, how did you get interested in exploring this subject? I became interested when I was a faculty at the Massachusetts General Hospital. I became more and more the go-to anesthesiologists for patients with a history of chronic pain and or substance use disorder who are taking buprenorphine, methadone. or uh other treatment for substance use disorder who traditionally had difficult to control postoperative pain So the surgeons would speak with me about the best way to manage the patient's pain, especially postoperatively. And more and more patients began to come for surgery who were taking ruprenorphine. It was interesting that many of the specialists at the time were recommending discontinuation of buprenorphine pre-operatively, but the evidence was somewhat controversial.

And additionally, I spoke with some of the psychiatrists who took care of patients with substance use disorder. And they were quite concerned about the potential for substance use disorder, opioid use disorder, relapse. if these patients were taken off of the buprenorphine or methadone. And you know, given that we're supposed to be um and should be and and are increasingly being taught to be perioperative physicians as anesthesiologists. I thought this was a really important point. To explore, given that the risk of death if patients relapse with substance use disorder is quite high And we had had to balance that with the risk, the potential risk.

At the time there wasn't a lot of evidence, but the potential risk for poorly controlled postoperative pain. As I was listening to you talk about your experiences, I think it's pretty easy to see how this has developed into the controversy that it has. My own understanding is that some of the basis for concerns around continuing buprenorphine perioperatively relates to its unique mechanism of action. Can you tell us a little bit about this mechanism? Sure.

So buprenorphine 's a partial agonist at the mu receptor, which means that it only partially activates the receptors. It's a weak kappa receptor antagonist, but it is a potent analgesic in the acting on the central nervous system And the partial agonism at the mu receptor is unique to buprenorphine and gives it many of its important um properties. specifically that it its analgesic effect plateaus at higher doses and buprenorphine very importantly exhibits ceiling effects on respiratory depression meaning that it's considered and has been shown to be safer than methadone for treating substance use or opioid use disorder. It has quite high affinity to the muopioid receptor and slow disassociation kinetics. So in that way it differs from other full opioid agonists such as morphine or fecum.

Got it. So it sounds like some of the pharmacologic basis for these claims is that because buprenorphine has high receptor binding affinity. a long half-life and only partial agonism, there's a thought that buprenorphee may therefore inhibit uh some of the traditional opioids in terms of their actions. Is that right? Correct. That that was the concerns and I I think it's logical when this was a new uh medication to think that this may be an an issue if patients continued on reprenorphine I think that the vast majority of patients I've encountered have been on suboxone, which is a combination of buprenorphine and naloxone, specifically formulated as a sublingual film.

Dr. Anderson, why is it formulated that way and are there any other formulations of buprenorphine that we should be aware of? Yes. has poor bioavailability because of the first pass effect, the majority of the drug is broken down in the liver and intestine. So sublingual administration is the preferred route It has a slow onset when taken sublingually, and the peak effect occurs in three to four hours. But the other formulations include parental formulations, implants, extended release injections transmucosal films, sublingual tablets, and transdermal patches? So definitely quite a few formulations of buprenorphine.

And as I mentioned before, I suspect most of us will see it in the form of a transmucosal film. lexaboxone or sublingual tablet, also known as subutex. And these are often related to opioid detox, addiction therapy, or chronic pain treatment Heading now into the evidence, we'll start with two studies that dive into some of these claims and then we'll discuss the results of a systematic review that incorporates those two studies. We'll then move from there into chatting about some of the recent findings from two new studies that were published after the systematic review. So first up is a prospective matched cohort study from 2016. Dr. Anderson, what can you tell us about this study?

So this is a paper by Hansen et al. The title is Total Joint Arthroplasty in Patients Taking Methadone. or the combination of ruprinorphine and daloxone preoperatively for prior heroin addiction, a prospective match cohort study. This was published in 2016 in the Journal of Arthroplasty. So these were patients undergoing total joint arthoprasty with documented preoperative treatment for a history of drug addiction. It's a small study. There were only 17 st um subjects in the methadone or buprenorphine naloxone groups with 34 matched controls.

Six weeks after surgery, there was no significant difference between the study and control groups with respect to clinical outcomes, pain control. Function, there was no difference in pain score observed at one year. The length of hospital stay was similar between groups, and there was no difference in post-operative complications between the groups either. And the take-home point from this study is that equivalent pain control and successful clinical outcomes were demonstrated in patients undergoing elective total joint arthroplasty. while being treated with methadone or the buprenorphine meloxone combination for prior heroin addiction compared with a matched control group. So it sounds like in this population, patients who were continued on opioid replacement therapy did not show a significant difference in pain or function when compared with their matched counterparts.

I will point out, though, that there was a difference in terms of referrals to pain service and the dose of oral narcotics given at discharge. Nine patients in the study group were referred to the pain service for intractable pain, compared to only one in the control group. And the dose of oral narcotics prescribed at discharge was about eight times higher in terms of morphine equivalence for the study group. But as you alluded to, all of these findings have to be considered in the context of the very small sample size Our next study examines pain and opioid requirements in the first 24 hours in a slightly different patient population. What can you tell us about this paper?

This is a study by McIntyre et al. titled Pain Relief and Opioid Requirements in the First 24 Hours After Surgery in Patients Taking Buprenorphine and Methadone Opioid Substitution Therapy This is a 2013 article in anesthesia intensive care. So there were 51 patients on methadone and buprenorphine opioid substitution therapy in this study 29 on methadone, 22 on buprenorphine. Patients were included if they required IBPCA without concurrent regional or epidural analgesia or local anesthetic wound infusions. While the guidelines that were current during the study period recommended that both methanone and buprenorphine be given on the day of surgery as well as continued after surgery, this didn't occur in all of the patients in both groups although no reason was given um for why it was not um continued.

But there was no statistical significant correlation be f between the first 24 hour PCA opioid requirements and preoperative buprenorphine or methadone doses in the patient groups. Patients on buprenorphine who were not given buprenorphine the day after surgery had significantly higher PCA morphine equivalent requirements in the first twenty-four hours after surgery compared with those who were given their usual dose. There was no significant difference. in pain scores at rest or movement on the first day after surgery in the buprenorphine group compared with the methadone group or with the inage group, depending on whether patients have been given uh had been continued with methadone or rufrenorphine on the day after surgery. So it sounds like there are two key takeaways from this study.

First, it looks like similar to the Hanson study we just talked about, there were no significant differences between pain scores between the buprenorphine or methadone groups, but more importantly, there was no difference within each group. depending on whether the patient had been given buprenorphine or methadone on the day after surgery. I also want to emphasize the point you brought up that patients who were not given buprenorphine the day after surgery actually had significantly higher PCA morphine equivalent requirements in the first 24 hours after surgery compared with those who are given their usual dose. Again, the total number of patients in this study is quite small. The groups are fairly heterogeneous. So We have to be cautious about interpreting those results.

Ashwini, as I understand it, the systematic review from 2019 included both of these studies, amongst others. What were some of the findings from this review? Yeah, so we did look at the systematic review. This one is by Goal et al. titled The Perioperative Patient on Buprenorphine, a systematic review of perioperative management strategies and patient outcomes. This was published in 2019 in the Canadian Journal of Anesthesia.

The systematic review included 18 studies through June 2017, including four observational studies and one control. study and as David mentioned we've already discussed two of these papers in depth. The remaining 13 studies were case reports. The authors included patients of all ages undergoing surgery who were on buprenorphine for either chronic pain or addiction management. Putting together the evidence from the cohort studies, the authors highlight a Meyer et al. case control study of 63 women undergoing vaginal or caesarean delivery, which showed that patients who continued buprenorphine had similar pain and analgesic requirements during labor, but experienced more postpartum pain compared to age-matched controls not taking buprenorphine. And importantly, there was no comparison to buprenorphine discontinuation in those patients who were taking buprenorphine.

Another study that they looked at in the review by Gupta et al. which was a retrospective cohort study, did not report analgesic or relapse outcomes, but the patients in this study who were on buprenorphine were continued on this medication. And another study did not necessarily stratify patients who were continued on buprenorphine versus methadone but found that women who were on either of these medications received significantly less opioid and more NSAT for pain control following cesarean delivery. And again, pain scores and relapse rates were not reported. Looking at some of the higher quality evidence included in the systematic review We can see that there's quite a bit of data that we'd like to see actually missing from these studies, but the authors conclude that of the observational studies, Authors showed equivalent peri and postoperative pain control among buprenorphine continued patients.

So consistent with our earlier discussion, it seems like perioperative and post-operative pain was equivalent in the buprenorphine continued patients across these observational studies. A number of case reports were also included in this review, certainly lower quality evidence, but were there any notable findings? Yeah, so you know, 13 out of the 18 studies included in the systematic review were from case reports And all except one of the cases were on sublingual buprenorphine. However, there was significant variation between patients in the dose that they took daily, ranging from zero milligrams in a patient who had previously taken buprenorphine and was now tapered down for several years to 32 milligrams daily. And there was also variation in whether the patient's buprenorpine dose was adjusted perioperatively, again ranging from weaning down to 2 milligrams postoperatively to actually increasing the dose to 72 milligrams post-operatively.

Of the patients who continued buprenorphine postoperatively, pain was well controlled in 9 and poorly controlled in 2. And in both of these patients, buprenorphine was tapered prior to surgery. And of the patients who discontinue, pain was well controlled in two patients and poorly controlled in five. And unfortunately, long-term outcomes were infrequently reported in the studies included here. And actually only three out of the 13 case reports even included any long-term data.

And so the authors correctly conclude that the current evidence is low quality and limited, but from the studies that they looked at here, insufficient to recommend discontinuing buprenorphine The authors of the review also highlighted the importance of incorporating harm reduction into the plans for patients on buprenorphine as discontinuation can lead to relapse. And they highlighted that we should be looking at long-term outcomes in these patients. Thanks, Ashweeney. Now, since the systematic review by Goal et al. was published in 2019, there have been some additional studies looking at this topic. Dr. Anderson, how do these studies add to what we know so far?

Yeah, so the outcomes of these studies are pretty similar to the ones that we've talked about. There seems to be growing evidence. that continuing buprenorphine perioperatively does not result in poor perioperative pain control One of the more recent studies is by Lee et al. Evidence for continuing buprenorphine in the periopter period from the Clinical Journal of Pain in 2020. And this is a retrospective cohort study of 50 patients undergoing elective surgery at Stanford that compared postoperative changes in pain score and opioid prescriptions. The majority of patients were on buprenorphine for chronic pain. Day surgery and private patients were excluded, and patients on buprenorphine for cancer-related pain and cardiac surgery patients were also excluded The primary outcome was a change in pain score perioperatively.

Pre-operative pain score on the 10-point scale was subtracted from the mean pain score on the first 24 hours post-operatively. And the results are stratified by transdermal versus sublinqual bruprinorphe. So in the transdermal group, 62% Patients continued buprenorphine and those who continued had a significantly lower change in pain score postoperatively than those who discontinued buprenorphine. And that change in pain score was 0.6 versus 4.8. So a rather big difference.

In other words, patients who continued to be prenorphine had better postoperative pain control In the sublingual group, whose average dose was 36 times the transdermal dose, there was no difference in pain score, but patients were discharged on fewer scheduled opioid prescriptions There is no difference in maximum PRN opioid dose or non-buprenorphine opioid requirements in the first 24 hours postoperatively, and there is no difference in the change in pain score across surgery types. So it sounds like this retrospective cohort study did not seem to suggest that continuing buprenorphine worsens post-operative pain control. In fact, continuing buprenorphine may actually have been associated with improved pain control for patients at least on the transdermal formulations. And for the sublingual group in which there were no differences in pain scores, the study at least observed fewer scheduled opioid prescriptions on discharge.

Were there any notable limitations of this study? Sure, so certainly. So the study population is only patients who were admitted after surgery, and that excludes about 50% of the surgical patients on buprenorphine as they were discharged in less than 24 hours. There is a wide range of baseline buprenorphine doses, though the authors did not find dose to be a confounding factor. It was unclear why the sublingual group did not see a difference in PENE score, but the transgress.

And another recent retrospective cohort study came out of 55 patients by K and all out of MGH. And all of the patients here were enrolled on buprenorphine for opioid use disorder specifically as opposed to chronic pain. The authors compared pain scores in the PACU and postoperative opioid prescriptions Dr. Anderson, what were some of the findings from this study? So this study is by Quay et al. titled Perioperative Continuation of Buprenorphine at Low to Moderate Doses. was associated with lower postoper pain scores and decreased outpatient opioid dispensing compared with buprenorphine discontinuation. This was published in Pain Medicine Journal in 2020.

So this is a, as you pointed out, a 55-patient study. 38 of those patients continued sublingual buprenorphine and 17 had it held. Both groups were on similar doses of buprenorphine at baseline. The guidelines at that time at Massachusetts General Hospital was for buprenorphine to be continued. The patients underwent a variety of surgeries with half of the patients undergoing orthopedic surgery The primary outcome was opioid prescriptions and mean morphine equivalents dispensed in an outpatient setting. There was a significant difference in post-operative Opioid prescription and PACU pain scores, the morphine milligram equivalents of full opioid agonists dispensed were 229 in the continuation group versus 529. in the group that had buprenorphine held, so stopped.

Patients were more likely to have an opioid prescription dispensed if buprenorphine was discontinued. 53 % in the continued group versus 82% in the discontinued group. The mean pain score was 2.9. In the group where buprenorphine was continued peroperatively, and 7.6 in the group where buprenorphine was discontinued There is no difference in treatment adherence as measured by buprenorphine prescriptions filled up to 60 days postoperatively. So if I'm understanding these results correctly, continuation of buprenorphine in these patients who are taking it for opioid use disorder resulted in both better pain control and fewer opioids needed postoperatively without actually affecting treatment and adherence, which is certainly a concern that clinicians may have when caring for patients on buprenorphine Correct.

And there were certainly some potential issues with the study. Again, this is a heterogeneous population, so it's difficult to control for all these things. Decisions to continue or discontinue buprenorphine could have introduced selection bias. Given that the hospital's guideline was to continue buprenorphine, there could have been a reason why buprenorphine was discontinued that may also predispose these patients to more difficult post-operative pain control. And there was significant heterogeneity in the surgeries limitations in the use of prescriptions filled as a proxy for medications taken, of course, and a lack of data regarding regional anesthesia and inpatient opioid requirements.

So it seems like based on these two retrospective cohort studies, buprenorphine continuation was not associated with worse pain control post-operatively. And for patients on the lower doses, continuation was actually associated with decreased postoperative pain. What I think is still not clear though, and where certainly higher quality randomized controlled trials could be helpful is what factors lead to buprenorphine continuation or discontinuation and if there's something different about the patients who fall into either group. I also want to briefly touch on a clinical practice advisory that was published in the British Journal of Anesthesia by many of the same authors who conducted the systematic review that we discussed. These were guidelines derived from expert consensus, and they tried to address some of the key questions with respect to optimal pre-intra and post-operative management strategies for buprenorphine.

The authors in general are quick to acknowledge the limited and overall low quality of evidence. For example, their primary recommendation to continue buprenorphine at preoperative doses was based on level five evidence. So case series or studies with no controls. We'll link this clinical advisory to the show notes, but I wanted to discuss this paper because I think that many current hospital guidelines may be based on these recommendations. Dr. Anderson, would you be able to summarize some of the evidence that we've discussed today on this topic?

Sure. Most of the evidence we have around pain control in patients taking buprenorphine comes from retrospective and observational studies which showed different results. Several studies suggest higher opioid requirements and or postoperative pain levels and others show no difference. The newer retrospective cohort studies we discuss show either no difference or improve postoperative pain control for patients who continue buprenorphine perioperatively. Our highest quality evidence by Hoflick et al. showed that patients undergoing cesarean delivery who continued buprenorphine or methadone required fewer opioids More NSAIDs than non-opioid dependent women, but pain scores were not measured.

There is, however, significant heterogeneity in the population studied surgeries included in the studies and type of opioid replacement therapy both between and within these studies. It is also possible that the variability and results of these papers reflect true variability in patient outcomes on buprenorphine given its known interpatient variability for half-life. Dr. Anderson, thank you again for this wonderful discussion. Let's return now to the two questions at the top of our show for our listeners to consider. What is the level of your agreement with the claim that buprenorphine inhibits the analgesic actions of traditional opioids, and patients may therefore experience uncontrolled postoperative pain?

And what is the level of evidence for what you believe? Dr. Anderson, thank you again for joining us today. I think this discussion will provide a lot of insights for our listeners into the latest evidence around the perioperative management of buprenorphine. Yeah, thank you very much again for the invitation to participate. Again, this is really an an interesting and I think important topic.

And Ashwini, thank you for joining us on the show and for all your help with putting this episode together. Yeah, of course. Thanks so much for having me. I really learned a lot On behalf of the Depth of Anesthesia team, thank you for joining us. I know everyone listening to this show is plenty busy, and it means a lot to me that you chose to spend some time with us today.

A big thank you also to our patrons. Your generosity is greatly appreciated. Stay hungry and keep asking questions.