Dr. Jess Hawkins joins the show to discuss the literature pertaining to remifentanil and opioid-induced hyperalgesia. Dr. Hawkins is an anesthesia resident at the Massachusetts General Hospital.
This podcast was recorded as part of the Depth of Anesthesia podcast elective.
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Music by Stephen Campbell, MD.
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References
Peter Yi, MD, Peter Pryzbylkowski, MD, Opioid Induced Hyperalgesia, Pain Medicine, Volume 16, Issue suppl_1, October 2015, Pages S32–S36, https://doi.org/10.1111/pme.12914
Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M. Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain. 2003 Nov;106(1-2):49-57. doi: 10.1016/s0304-3959(03)00276-8. PMID: 14581110
Joly V, Richebe P, Guignard B, Fletcher D, Maurette P, Sessler DI, Chauvin M. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005 Jul;103(1):147-55. doi: 10.1097/00000542-200507000-00022. PMID: 15983467
Fletcher D, Martinez V. Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis. Br J Anaesth. 2014 Jun;112(6):991-1004. doi: 10.1093/bja/aeu137. PMID: 24829420
Comelon M, Raeder J, Stuhaug A, et al. Gradual withdrawal of remifentanil infusion may prevent opioid-induced hyperalgesia. Br J Anaesth 2016; 116: 524–30
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David Hao
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 guest today is Dr. Jess Hawkins. Dr. Hawkins is an anesthesia resident at the Massachusetts General Hospital.
She graduated from Stanford Medical School, holds a master’s degree in education from the University of Pennsylvania, and earned her undergraduate degree from Stanford University. Dr. Hawkins, welcome to the show.
Jess Hawkins
Thanks so much for having me. I’m really happy to be here.
David Hao
Our case today is of a 71 year old man with a history of mild intermittent asthma and chronic low back pain who’s presenting for an anterior cervical corpectomy infusion, and the surgical team is requesting neurophysiologic monitoring. The evening before the procedure, the resident reviews her plan with the attending anesthesiologist and suggests using total intravenous anesthesia with propofol and remifentanil. The attending advises the resident to consider using an alternative agent instead of remifentanyl due to a potential concern for increased postoperative pain. Dr. Hawkins, what are some of the claims in this case?
Jess Hawkins
The primary claim here is that remifentanil increases postoperative pain and opioid consumption, specifically through opioid induced hyperalgesia.
David Hao
So here now are two questions for our listeners to think about. What is the level of your agreement with the claim that remifentanyl increases postoperative pain through opioid induced hyperalgesia? And what is the level of evidence for what you believe? Jess, I’m wondering, how did you get interested in exploring the subject?
Jess Hawkins
Well, REMI is a really commonly used drug in our ORs here, especially in cases where neuromuscular blockade is contraindicated because of its ability to provide immobility. In addition to that, it can aid in hemodynamic stability, smooth out emergence, and it’s rapidly titratable. It’s hard to think of a reason not to use REMI except OIH or opioid induced hyperalgesia. And while I knew of OIH before I did this podcast, I felt like I didn’t really have enough information about it to incorporate it into my clinical decision making. For instance, who’s at risk for it? And what remifentanyl doses are we talking about? And maybe most importantly, what do we actually mean when we say hyperalgesia?
David Hao
I think I had many of the same questions when I was in training, and I think for our listeners, it’s important to begin our conversation Just by talking a bit about what exactly opioid. By talking a bit about what exactly opioid induced hyperalgesia is as an entity. So the International association for the Study of Pain, or iasp, defines hyperalgesia as increased pain from a stimulus that normally provokes pain. And opioid induced hyperalgesia, or oih, is a condition of enhanced pain sensitivity in patients on chronic opioid therapy. Interestingly, this is not a new phenomenon. It’s actually been described in the literature. As far back as 1870, there was a physician named Albitt who noted, quote, at such times, I have certainly felt a great responsibility to say that pain, which I know is an evil, is less injurious than morphia, which may be an evil.
Does morphia tend to encourage the very pain it pretends to relieve? And one of the challenges here, I think, is that there’s unfortunately no official criteria or guidelines for diagnosing oih. And as we’ll see, it’s measured and ultimately diagnosed very differently across all these different studies.
Jess Hawkins
Exactly right. One of the challenges is that pain from OH is not necessarily located at the source of injury or disease. It can manifest as generalized pain or diffuse pain.
It’s usually ill defined. So OIH can be confused with tolerance, it can be confused with withdrawal. And because they can exhibit similar symptoms, in addition, allodynia and hyperalgesia can also manifest intolerance and withdrawal, making them difficult to differentiate from oih.
David Hao
So the interesting thing about OIH is the true incidence is really unknown. And that’s, I think, due to a combination of things, including limited literature and some methodological challenges. But there are studies in three distinct patient populations that I think give us some insights. So these populations are one, former opioid abuse patients on methadone maintenance therapy, two, patients administered opioids during the perioperative period, and three, healthy volunteers given opioids acutely followed by pain tolerance testing. Today we’re going to primarily focus on patients in the perioperative period with a little bit of discussion of research involving healthy volunteers. Now, while many studies provide some evidence for this entity of oiha, Angst et al were among the first to prove its existence by demonstrating that it could actually be induced in healthy volunteers exposed to remifentanyl. Jess, can you tell us a little bit more about this study?
Jess Hawkins
Sure. This was a study published in pain in 2003. They studied 10 healthy men. The mean age was 28 years. It was a double blind, randomized crossover Placebo controlled single center study. So all the great things. The subjects, they were randomly allocated to receive a parallel infusion of either S ketamine plus saline placebo, remifentanil plus saline placebo, or S ketamine plus remifentanil and saline placebo plus saline placebo.
All the subjects received all the treatments, but on different occasions. So the minimal inner occasion interval was about three days. They used two mechanically distinct experimental pain models. One was heat pain evoked in normal skin and one was mechanically evoked pain in a hyperalgesic skin lesion. In this study, they were using an infusion rate of remifentanil set to 0.1 mics per kg per minute to achieve a stable plasma concentration ranging between 2.7 and 2.9 nanograms per mil during the infusion.
David Hao
So just to clarify, they’re using two experimental pain models. One is heat pain on normal skin and the second is mechanically evoked pain in a hyperalgesic skin lesion. And you might be wondering how they created this lesion. They used a modified method that was previously published in which current was sent between two wires inserted in parallel into the dermis of the left volar forearm. Now, the reason they used the second model was because they were specifically interested in secondary hyperalgesia, which is hyperalgesia due to enhanced processing of neuronal input at the level of the spinal cord, also known as central sensitization, which is an important characteristic of many clinical pain states. All right, Jess, what were the findings of this study?
Jess Hawkins
Yeah, so what they found was for the secondary mechanical hyperalgesia, an infusion of placebo and remifentanyl administration resulted in a significant reduction of the hyperalgesic area at 75 minutes into the infusion, but not at 115 minutes into the infusion compared with placebo placebo administration. In addition, the infusion of the placebo and remifentanyl combo resulted in a 130% increase of the hyperalgesic area once the infusion of remifentanyl was stopped. That increase, interestingly, wasn’t observed whenever they used esketamine. So if S ketamine was co administered with remifentanil or if S ketamine was administered alone. So, in summary, the study provides some experimental evidence that an area of skin that’s already hyperalgesic to mechanical stimuli before starting the infusion of remifentanil at 0.1 mics per kg per minute in an opioid naive human can increase that hyperalgesic area by as much as 130%.
David Hao
So this study I think is pretty interesting because they actually used skin surface area as a somewhat objective measure of the extent of hyperalgesia. So for primary hyperalgesia, which is fairly locally confined, you can measure things like intensity, stimulus threshold or the extent of the affected area, like this study did. But for something like secondary hyperalgesia, which is more centralized, that’s when you have to rely on things like subjective pain measurements or indirectly measuring pain by collecting data on things like analgesic use. And as we’re going to see, researchers have had to be fairly creative in the different ways that they ultimately use to try to objectively measure hyperalgesia. Given that remifentanyl induced hyperalgesia had been seen in both animals and healthy volunteers, but hadn’t yet been documented in a clinical setting, a research team from France decided to dive in and they wanted to test two key hypotheses. First, that high doses of intraoperative remifentanyl could lead to increased pain sensitivity around the surgical site, and second, that small doses of ketamine might actually be able to prevent this hyperalgesia.
Jess Hawkins
In this study, which was published in anesthesiology in 2005, they recruited adult patients from two different centers. They were ASA 1 to 3. They were scheduled to undergo open colorectal surgery lasting at least two hours. Notable exclusion criteria included those who took analgesics or had opioids within 12 hours of the surgery and those who had contraindications to the self administration of opioids. For example, if they were unable to understand patient controlled analgesia or the PCA device, what they did was they randomly assigned the subjects to three groups. The first group was a small dose remifentanil group, the second was a large dose remifentanyl group and the third was a large dose remifentanylketamine group. In the small group, patients were given an intraoperative infusion of remifentanil at a rate of 0.05 mics per kilogram per minute and that’s been demonstrated to not induce hyperalgesia in volunteers.
In the large dose remifentanyl group, they were given the REMI at a rate of 0.4 mics per kg per minute and then the large dose remifentanylketamine group received the same dose of high dose REMI, so 0.4 mics per kg per minute. They were also given an initial loading dose of ketamine followed by an infusion. The loading dose was 0.5mg per kg and that was followed by a maintenance infusion of 5 mics per kg per minute intraoperatively until skin closure and then after post op by an infusion of 2 mics per kg per minute during the initial 48 hours. Additionally, every patient received 1 mck of remifentanyl with induction and a 0.15 milligram per kg bolus of morphine 30 minutes before the end of the surgery.
David Hao
So before we go a little further, I’m just going to take a quick moment here to pause and talk a bit more about the methods because I think that can be a little bit confusing. So basically, patients were divided into three groups, small dose remifentanyl, large dose remifenil and large dose remifenil with ketamine. They tested thresholds for both mechanical stimuli and for pressure. So the pain threshold for mechanical stimuli was assessed using calibrated Von Frey filaments or hairs. And for the pain pressure threshold, they used a handheld electronic pressure algometer. Both of these thresholds were measured in an area 2-3 cm from the incision at three levels, the top, middle and bottom of the incision as well as on the inner forearm. Now, they also looked at mechanical static hyperalgesia, also with Von Frey hairs, and then dynamic mechanical allodynia using a soft brush.
So just to clarify, again, we’re seeing measurements of pain thresholds as well as measurements of hyperalgesia and allodynia. And all of the protocols are very well described in the paper. But we won’t get too much into the weeds here. Jess, what were the results of the study?
Jess Hawkins
So they found that tactile pain thresholds adjacent to the incision were Significantly less at 24 and 48 hours post op in the large dose remifentanyl group than in the other groups. They also found that there was no significant differences among the groups for the pressure pain threshold at 2-3 cm from the incision. In addition, no clear sensation of pain could be evoked in any of the groups by stroking the skin with a brush for the allodynia measurement. The extent of the hyperalgesia to von Frey hair stimulation proximal to the incision was detected in all patients and was significantly larger at 24 and 48 hours in the large dose remifentanil group versus the other two groups. In addition, the mean time to first morphine administration and the cumulative amount of intravenous morphine given by nurses in the PACU didn’t differ between the three groups. However, post op morphine consumption, including morphine titrated in the PACU, was significantly greater throughout the 48 hours post op in the large dose remifentanil group versus other groups.
David Hao
Got it. So it sounds to me like in this study, adult patients undergoing open colorectal surgery were assigned to these different groups. And the findings were that those who got the large dose of REMY experienced significantly more peri incisional hyperalgesia and allodynia. And this was shown by the lower tactile pain thresholds and a larger area of hyperalgesia. And again, these were effects that were not seen in patients who received either the small dose a REMI or the large dose with ketamine. It sounds like on top of that, patients in the large dose Remy group also needed a lot more morphine after surgery, which I think potentially underscores the role of small dose ketamine in mitigating this hyperalgesia. Now, the studies that we’ve talked about so far have mostly been small and certainly limited to single centers.
And while some of them have looked into postoperative hyperalgesia in surgical patients, the small sample sizes, I think make it pretty tough to draw any solid conclusions about the clinically relevant effects of perioperative remifentanyl. So fortunately, to gain a deeper understanding of OIH in the surgical population, Fletcher et al conducted the largest systematic review and meta analysis to date and published in 2014. Jess, can you walk us through their findings?
Jess Hawkins
Sure. So, as you said, this was a systematic review and meta analysis. It was published in the British Journal of anesthesia in 2014. They looked at 27 randomized controlled trials published between 1994 and 2013, including total of 1,494 participants. The median sample size was about 50 per study. Populations included were adults and children who were undergoing surgery and receiving opioids for analgesia. The interventions included in the study were remifentanil, sufentanil or fentanyl administered during the surgical procedure.
Whatever the timing, the dose or the mode of administration, the comparer arm was a lower dose of the same opioid or a placebo. The exclusion criteria for the study were any analgesia techniques or medication that was not equivalent or comparable between the groups during the intervention or the duration of study being limited to the pacu. What they found was the majority of their randomized controlled trials, 19 of them investigated opioid induced hyperalgesia in patients treated with remifentanil. Three studies explored IV fentanyl, one study looked at sufentanil and four studies looked at intrathecal fentanyl. The remifentanyl administration scheme differed significantly between the trials, but most used a combination of remifentanyl bolus followed by a continuous infusion which varied from.05 to 0.9 mics per kg per minute. Most of the trials looked at pain at rest at 24 hours, at 4 hours and at 1 hour post op, and all of these trials showed significantly higher pain scores in the experimental groups compared to the controls. Pain on movement at 24 hours did not show a significant difference between the groups.
They found that more morphine was used by patients who had received intraoperative opioids versus controls. The estimation of the mean 24 hour morphine consumption was 18 milligrams. Five of the trials looked at primary hyperalgesia and in those trials the reported pain thresholds were significantly lower for experimental groups than the control group, meaning they had more pain. So four of the trials which included 181 patients, explored secondary hyperalgesia and in those trials they found a slight trend for a larger area of secondary hyperalgesia in the experimental groups, but the standardized mean difference of that area wasn’t significantly different from that of the controls. In the remifentanyl subgroup, though, the standardized mean difference for both the primary hyperalgesia and secondary hyperalgesia were significantly different. So from all this, the authors concluded that high intraoperative doses of remifentanil may slightly increase pain intensity at 24 hours and moderately increased morphine use after surgery with no increase in morphine related side effects. In addition, one hour after surgery they concluded that the difference in pain intensity between the remifentanil group and the control group was about 22%.
So in the control group the mean pain at rest was 39 out of 100 on a visual analog scale and the remifentinel group was 22% higher than that. According to a previous study on the clinical significance of differences in pain intensity, this would be considered to be a minimal aggravation of pain. Notably, there was a lot of diversity of research methods in between these randomized controlled trials, so the data was very heterogeneous. Because of that, the authors weren’t really able to define a cutoff value for the remifentanyl cumulative dose, the the infusion rate or the target effect site concentration above which remifentanil might induce hyperalgesia.
David Hao
So this is a really interesting study. And if I were to summarize some of the findings, I’d say that they ultimately looked at 27 RCTs. Most of the studies zeroed in on remifentanyl, and they concluded basically that higher doses of remifentanyl during surgery were linked to significantly more pain at rest for up to 24 hours, hours postoperatively and higher morphine use. But this increase in morphine use didn’t come with more morphine related side effects. And because the studies ultimately used so many different methods, the authors couldn’t pin down a clear dose of Remy that would consistently trigger hyperalgesia. And I appreciate you bringing up the concept of clinical significance of differences in pain intensity, because if we look at the mean difference at 24 hours, 4 hours and 1 hour, you’ll see that the actual numbers are 9.4 centimeters at 1 hour, 7.1 centimeters at 4 hours, and 3 centimeters at 24 hours. And this is on a 100 centimeter visual analog scale.
And so for those of you who are familiar with the concept of minimal clinically important difference, this is a case perhaps of where we reach statistical significance, but not necessarily clinical relevance. An interesting twist also comes from the subgroup analysis here, which suggested that perhaps using propofol for anesthesia might actually help prevent remifentanyl induced hyperalgesia. So in the studies where propofol was used, even high doses of REMI didn’t seem to lead to increased morphine consumption compared to studies that might have used things like inhalational anesthetics or regional anesthesia. So I think this leads us to the question of if we know that this condition potentially is relevant, how can we best mitigate this? And there have been several pharmacologic strategies that have been tested to prevent remifentanyl induced hyperalgesia, including things like perioperative ketamine, magnesium, propofol and nitrous oxide. But one very interesting study that came out in this space actually looks at the potential role of just gradual withdrawal of remifentanyl.
Jess Hawkins
Yeah, so this was another study from the British Journal of Anesthesia and that was published in 2016. In this study, they looked at 19 healthy male volunteers. It was a single center, it was the University of Oslo, and it was a randomized, double blinded, placebo controlled crossover study. Each of the subjects went through three sessions. In one of the sessions, they had an abrupt withdrawal of remifentanil. In another session, they had a gradual withdrawal of remifentanil. And in a third session, they just had a placebo infusion with saline.
They assessed the pain at baseline, during the infusion and then twice after the infusion ended, one at 45 to 50 minutes and another one at 105 to 110 minutes. They used a heat pain test and a cold presser test to measure pain. So when testing the heat pain test, they found that there was development of opioid induced hyperalgesia 45 minutes after the end of the infusion in the abrupt withdrawal session compared to the gradual withdrawal session and the placebo session. There was no indication of opioid induced hyperalgesia in the withdrawal session. In the cold pressor test, however, they did see that there was evidence of opioid induced hyperalgesia in both of the remifentanyl sessions at the final assessment with the heat pain and the cold pressor test. So that was the one at 110ish minutes after the end of the infusion. There weren’t any significant differences between either of the remifentanil sessions compared with placebo.
David Hao
Alright, so it sounds like this study found that abrupt withdrawal of remifentanyl resulted in the development of OIH as indicated by higher pain scores in heat pain tests conducted 45 minutes after the infusion ended. In contrast, when they gradually withdrew the remifentanyl, this did not lead to OIH using heat pain tests. And the pain scores were similar to those in the placebo group. But in the cold presser test, which is the alternative test, OIH was actually observed after both abrupt and gradual withdrawal. But ultimately the duration of hyperalgesia was fairly short lived. And after about 105 minutes after the infusion ended, there was really no significant differences. Is that fair to say about the study?
Jess Hawkins
Yeah, I think that sums it up well.
David Hao
All right, so I think that covers all the major studies that we were planning on talking about today. And Jess, I’m hoping you can actually take our listeners through a little bit of a summary of some of the findings from the primary literature that we just chatted about.
Jess Hawkins
Sure, I’d be happy to. So we talked about quite a bit today on opioid induced hyperalgesia. First, the definition of opioid induced hyperalgesia is a condition where opioid use actually increases pain sensitivity and that pain sensitivity can be localized or more generalized. It’s been shown to occur with high doses of opioids like remifentanil, particularly in the perioperative setting. Opioid induced hyperalgesia is a bit different from acute opioid tolerance or withdrawal. It’s all about an increased sensitivity to pain. So this can show up as primary hyperalgesia, which is localized around the incision site, or as secondary hyperalgesia, which is more widespread in surgical patients, particularly in those who received the high doses of remifentanil during surgery.
We saw a spike in acute pain and that seemed to last about 24 hours after surgery, and that came with higher morphine use in the post op setting. Those patients tended to have a lower pain threshold and a larger area of hyperalgesia near their incisions. One of the key studies we discussed was that one by Angst et al and that provided some of the earliest experimental evidence of opioid induced hyperalgesia in humans. They showed that after stopping a remifentanyl infusion, there was a significant increase in pain sensitivity. And that’s pretty clear proof that we can induce opioid induced hyperalgesia. To measure hyperalgesia, studies have used different things like tactile pain thresholds and the extent of the hyperalgesic area around surgical sites. Jolie et al showed that patients who received higher doses of REMI had a significantly more peri incisional hyperalgesia and they required more opioids postoperatively.
Interestingly, they found that smaller doses of ketamine could prevent these effects. We also looked at a meta analysis by Fletcher et al and that confirmed that high doses of remifentanil are linked to higher pain scores and higher opioid consumption after surgery. However, the data was pretty mixed and they couldn’t pinpoint an exact dose that consistently leads to opioid induced hyperalgesia. Finally, a study by Komelan et al showed that gradually tapering remifentanil rather than stopping it abruptly, might help prevent opioid induced hyperalgesia. Now, I think it’s important to say that the clinical relevance of these findings isn’t entirely clear, especially because different studies use different methods to measure hyperalgesia, which makes comparisons really tricky. The most significant effects of remifentanil seem to pop up right after surgery, with higher doses carrying a greater risk of developing opioid induced hyperalgesia. The numbers are statistically significant, but they may not be clinically relevant, the exact relationship between the dose and the risk of opioid induced hyperalgesia is still a bit murky.
So in summary, while opioid induced hyperalgesia is well documented, its clinical significance, especially in the short term postoperative period, still requires a lot more research, particularly when it comes to prevention strategies like ketamine or gradual opioid withdrawal.
David Hao
Jess, I thought that was an excellent summary and I want to thank you so much for taking the time today. I know we wrote this script a while ago, so I appreciate you hanging in there and dusting this off for us. But fortunately, I think since some of those key studies have come out, there does not seem to have been a lot more movement in this space in terms of new literature. So I think that we ended up covering all of the key studies here.
Jess Hawkins
Thank you so much for having me. It was fun.
David Hao
And lastly, a quick plug for those of you attending the iars meeting in 2025, there actually will be a workshop hosted by the journal Anesthesia and Analgesia titled ANA Journal Club how to Read and Apply Various Types of Papers. So stay on the lookout and I hope to see some of.
