Eric: Welcome to the GeriPal podcast. This is Eric Widera.
Alex: This is Alex Smith.
Eric: And Alex, I have a feeling I’m going to love this podcast. Who do we have with us today?
Alex: We’ve got an all-star lineup. We have Drew Rosielle, who is a palliative care doctor at the University of Minnesota. He’s the editor of Fast Facts. He’s the founder of Pallimed and the author of two recent posts on Pallimed titled, “Simplifying Opioid Conversions and Opioid Equianalgesic Tables are Broken”. Welcome to the GeriPal podcast, Drew.
Drew: Yeah. Thank you. Yeah. Delighted to be here.
Alex: And we’re delighted to welcome back to the GeriPal podcast, Mary Lynn McPherson, who is professor and executive director of advanced postgraduate education and palliative care at the University of Maryland Baltimore School of Pharmacy and author of “Demystifying Opioid Conversion Calculations”, second edition, which we discussed on a prior podcast. Welcome back to the GeriPal podcast. Mary Lynn.
Mary Lynn: Thank you. It’s a pleasure to be here.
Eric: Before we get into the topic of, rethinking opioid conversions, Drew, I think you have a song request for Alex.
Drew: Yeah. My request is, Unsatisfied by The Replacements. I chose this because Replacements are a legendary Minneapolis band. And because I’m unsatisfied with equianalgesic tables and other aspects of how we talk about opioid conversions.
Eric: Let’s hit it. Alex.
Eric: Drew, you are not satisfied with equianalgesic tables or in your Pallimed post calling them EATs, which is…
Drew: That was pure laziness. I just didn’t want to write equianalgesic tables 50 times, so I just said EATs and please let’s not call them EATs.
Eric: Why are you so dissatisfied equianalgesic tables?
Eric: Wait. Actually, for those who don’t, what is an equianalgesic table? Mary Lynn. I see you holding up a… what are you holding up? It looks like a Excel sheet.
Mary Lynn: No, no. It’s an equivalency table on a laminated card.
Eric: What’s an equivalency table?
Mary Lynn: It is how you go from one opioid to a different opioid, depending on the opioid and the route of administration looking at, you could call it equivalency, you could just call it a conversion, also. It depends on the clinical situation.
Eric: All right. We want to switch from, let’s say morphine to Dilaudid. We pull up our handy dandy equianalgesic table or conversion table. It tells us roughly how much one drug is comparable to another drug. We do a conversion. We may account for things like cross-tolerance and dose reduction. And it gives us a number. Is that right?
Mary Lynn: That’s correct. They put you in the ballpark at least.
Eric: Marilyn, you’ve been doing this for a long time. How long have you been using these equianalgesic tables, conversion tables?
Mary Lynn: I think the first one I saw, came out in New England Journal, probably 30, 35 years ago from Michael Levy. They have changed a little bit since then. The first one that came out said that 10 milligrams of parenteral morphine was 60 milligrams oral, until we quickly figured out with chronic dosing, we have to account for the therapeutic effect of the morphine-6-glucuronide. That did adjust that variable. But since then, it’s been pretty constant. Until the second edition of my book, that is.
Alex: Is there another-
Eric: So, 10 milligrams of IV morphine is 30 milligrams of PO, which is 1.5 of IV Dilaudid, which is… I got that table memorized, burnt into my head. I’ve started to hear a lot of people using opioid kites before now, Drew.
Drew: I just enter, there’s more to equianalgesic tables because what’s… and this is important to my discussion of them. Is that the way the tables are structured? Every single a quantity in those cells, on that table are considered equianalgesic. So, every single [inaudible 00:05:10] there is per the table, in an equianalgesic relationship to one another. That’s one aspect of it. And then going along with that-
Eric: When you say equianalgesic, that 10 milligrams gives you the same analgesia of IV morphine as 30 milligrams of PO morphine, that’s equally-
Drew: That’s the idea. Yeah. Yeah. That’s the idea behind equianalgesia.
Alex: Before we get into Drew’s issues with equianalgesic tables, I think there’s another reason for the existence of equianalgesic tables, at least to my mind and the way I use them. And that is to try and figure out is this patient on a little bit of opioid, a medium amount of opioid or a lot of opioid. So, when I see a patient and they’re on like three different opioids, I’m trying to figure out, okay, is this a little bit, or is this a lot, then I can convert it all to oral morphine, equivalence or OME as it’s commonly referred to. I have a sense, I have a gauge in my mind of what, a little bit of OME, opioid oral morphine equivalence is. And I have a sense of what a lot is. That’s another way in which I use equianalgesic tables. Does that sound right?
Mary Lynn: I think being sensitive to that very fact is the whole crux of what we’re talking about here. I don’t care whether you use an equianalgesic chart or a multiplier, or a divisor really, as I said to begin with, this kind of a calculation just gets you in the ballpark. The whole shooting match is using a process. I advocate a five-step process, which is assessing your patient, calculating the total daily dose, doing, pulling the trigger on the actual math, whether it’s a ratio or a multiplier or a divisor or an app or whatever. Step four is adjusting it for your patient. And step five is the most important, monitoring the patient. So, when I say this literally gets you in the ballpark, I don’t know which of the 40,000 seats is yours. This just gets you admission to the ballpark.
Alex: All right. Maybe we should turn it over to Drew now, I think, Eric.
Eric: All right, Drew. You say opioid equianalgesic tables are broken. Why is this broken?
Drew: Yeah. I think the there’s, it’s a long answer, I have. So, hopefully it’ll tolerate me. I was trained in how to use them in the early 2000s. And I’ve been teaching them for years, myself. Over the years, I’ve realized that I stopped using them because I didn’t like the way the math that equianalgesic tables encourages people to use. It would involve cross multiplication, which I think scares a lot of people and it’s easy to mess up. I realized over the years, I had most of my fellows and residents just… I would teach them these things and they would not use them. They would go to online calculators because they were too… were scared of the math and making mistakes. As I’ve been blogging about this for a couple months now, I’m really trying to find anyone who loves these things. And is like, dang, like this… yeah, yeah, yeah. Well, yeah, Dr. McPherson, aside.
Drew: That this is like really a superior way of talking about how to calculate opioid conversions. I think part of it’s the math, but I think what really happened is, I think the story here is that in 2018, MD Anderson published this really landmark study by Dr. Reddy and her colleagues about going from IV Dilaudid to other to oral Dilaudid, oral hydromorphone, I should say, oral morphine and oral oxycodone. Landmark study. And really, the best that had ever been looked at, especially in our population and sort of a cancer serious illness population. Those conversion ratios that came out of that study were substantially different than what the conversion ratios that had been in the, in what I call the classic equianalgesic table.
Drew: Just to take one example, the table that says 1.5 milligrams of IV Dilaudid is equianalgesic to 30 milligrams of oral morphine. I think most of us are familiar with that table. That’s a 20 to one ratio. What MD Anderson found was really more of a 10 ratio. So, the oral morphine dose would be about 10 times the IV Dilaudid dose, not 20 times the IV Dilaudid dose. So, there’s no big differences. So, Dr. McPherson, as far as I can tell, she’s really the only person in our professional community who in any sort of serious public way said, folks we need to do something about this. We need to respond to this really good data because, as Dr. McPherson is, in other venues have talked about extensively. The whole thing is based on sort of flimsy data anyway, but this Dilaudid, IV Dilaudid data, is really in some ways the best data we’ve got.
Drew: She updated an equianalgesic table and published that in the second edition of her book. But there was all sorts of fallout from that, that me and many of my colleagues experienced. I know this is like, we’re talking about math and so that makes it all a little complicated, but think about it this way. The old table, 1.5 milligrams of Dilaudid times 20, to get the oral morphine dose. The new table, you’d multiply it by 10, maybe it’s 12 on your table, but it’s something much smaller. That was good. I think that was a good, conservative change, based on science and everyone were like, yes, good.
Drew: The problem with equianalgesic tables is that every one of those relationships is fixed and bidirectional. If you make one conversion twice as conservative, going from IV Dilaudid to morphine, you make the reverse conversion going from oral morphine to IV hydromorphone. You make that twice as aggressive. So, you can’t change it in one direction, without having this mirror image change on the other direction. A lot of people were like, gosh, this new table, this wants me to put people on twice the amount of IV hydromorphone that I was used to. I’m not comfortable with that. Right. That was a big part of it. And the other part of it, was…
Eric: Wait, wait, wait … I’m going to hold right there. I love your thoughts on this too, Lynn, because I think, when we think about some other tables, like a fentanyl conversion chart, we usually think about, that’s a unidirectional table. You don’t go the other way because incomplete cross-tolerance is already built into that. We’ll talk about cross-tolerance, but there’s some dose reduction. How should we think about some of this new data around these conversions, like from IV Dilaudid to PO? Your thoughts on that.
Mary Lynn: I think the bi-directionality question is a very valid question. I think the whole thing we’re talking about here is process versus content. So, let’s talk about the content Dr. Rosielle just mentioned. We’re all believers in evidence-based practice. Which of course, is the three-legged stool of the patient’s wishes and beliefs, the clinicians experience, this is how we’ve always done it and evidence. I don’t think the patient’s got a big dog in this fight about saying how we should do these conversions, which brings us down to we’ve always done it this way, which I can accept unless we have evidence. As Dr. Rosielle just pointed out, Dr. Reddy did the wonderful study transitioning off of IV Dilaudid to the oral opioids.
Mary Lynn: I saved it just for you, Dr. Widera and Dr. Smith. I actually reached out to my girl, Dr. Reddy, I said, “Girl, you got to bail me out here.” I know that MD Anderson has, the way we’ve always done it, is a 10 to one. They take 10 times the oral morphine, one 10th of that is the IV hydromorphone. I said, “We need to do the study in reverse.” She said, “Okay.” She pulled 22 charts and she actually did it. It’s just a pilot. And the median conversion, hold onto your head, is 12.5, which is exactly what I have on the chart. So, it is bidirectional.
Mary Lynn: Now, is that an office little pilot project? Of course not, we’re talking about doing a multicenter trial. But MD Anderson for decades, has used the 10 to one. And this 22-chart audit has shown the median conversion was 12.5 and the mean was 10.5. So, it’s exactly what I have in the chart. I see you inhaling, let me finish. Really, the best chart would be 10 milligrams of IV morphine is 20 to 30 of oral morphine. But I think people would have an embolic event if you gave them a flipping range. So, I was not fond of doing the range idea. The chart that I have in my book and that I use in practice and so many healthcare systems have adopted already, is the very best, cutting edge data we have. But we still, regardless of how you do this calculation have to temper it with clinical judgment.
Eric: I got two questions. First is, if you do a study looking at your standard of care, which is 10 to one and the results turn out to be 10 to one. How important is that, versus if you looked at a lot of different solutions, with a lot of different standards, some using 20 to one, some using 10 to one and seeing what the average is there? Because I’ve been using the classic, 1.5 to the 30 PO morphine. Got to say over probably nearly 20 years of use, I’ve never really run into big issues with that conversion. Thoughts on that.
Mary Lynn: I’m willing to bet that you temper that calculation with your clinical judgment though.
Eric: Yeah. I usually do a 25 to 50% dose reduction, which gives me 10 to one. But if I use the 10 to one and then I dose reduce by 50%, I’d probably be significantly under dosing.
Mary Lynn: Think about why we’re doing these conversions. I know it’s not a hundred percent, but when you look at switching somebody from oral morphine to IV Dilaudid, it’s usually because their pain is not well controlled. That is not an equivalent conversion. That is just rotating. When you look at somebody who’s on IV Dilaudid and you’re going to send them home now with oral morphine, that’s more of an equivalency because their pain has been controlled. You see what I’m saying?
Drew: I guess my perspective is, if we just had simple conversion tables, which had, when going from IV Dilaudid to morphine, do this one. When going from morphine to IV hydromorphone, use this one. And those ratios can be different. There’s a whole edifice that we’ve created of doing these workarounds for these equianalgesic tables that are forced into ranges that all of us are uncomfortable with. Even though I worked for 20 years, like you did Eric, with the 20 to one IV Hydromorphone to morphine ratio, I always radically dose reduced. And that was my practice. My point is that’s unnecessary. It’s unnecessary because we can have our cake and eat it too. We can have conversion tables, which use evidence-based ratios as much as we can find them. And those conversion tables don’t have to have bidirectional ratios. They can have conservative ratios every single way.
Drew: Instead of saying, we have one ratio and it goes in both directions, but everyone knows wink, wink, read this book. Everyone knows that in this way, you just have to really, really dose reduce. And my proposal is that, that workaround is not very necessary. Nuance is always going to be needed. Clinician judgment is always going to be needed about patient mental status, patient frailty, the circumstances of the conversion. But that a lot of this extra work that we ask interns to do, we ask hospitalists who don’t know what’s what to do.
Drew: All of this could be, it’s not going to be taken away entirely, but would be mitigated if we had conversion tables that weren’t fixed and bidirectional. Because the other thing I’ll add is that if you change on that equianalgesic table, if you’ve gotten your data and you change morphine and hydromorphone, and you change the number for morphine there, all of a sudden, you’ve now changed the morphine ratio between oral morphine and oral oxycodone, oral morphine and oral IV morphine. These tables, because the format of them is that everything is in fixed relationship with each other, you can’t just nudge one thing based on a new study. Everything crumbles and why? What I asked was why? We can just do it easier. It’s easy.
Eric: What does easier look like to you, Drew? Because having 20, 30, 40 different tables…
Mary Lynn: Oh, no. It’s more than that. If you look at the 10 drugs I have in the chart and you do every possible calculation, I calculated this last night. It would be 560 lines of data. I hope you got a really big lab coat pocket to fit that in.
Eric: How would that look in your eyes, Drew?
Mary Lynn: Every box in my table is defensible with data to back it up.
Eric: How would that look like to you, Drew?
Drew: I’ve published a draft version of it on the blog. Yeah. It’s compacted. There’s more cells in it than the average equianalgesic table, but there’s not 500 cells. You can add them up.
Mary Lynn: Include them all. Include them all, it would be.
Drew: My table has the vast… it has all of the conversions that would happen between various formulations of morphine, oxycodone and hydromorphone that are available in the U.S. It’s like 18 entries long, and it’s compact. I’m not sure that it would, I don’t understand the 500-entry thing.
Mary Lynn: I have 10 opioids in the chart, then you’ve got an oral column and a parenteral column. If you took opioid number one and went to opioid number two and then one to three and then one to four and so forth. Honestly, I can calculate that. It was it’s like five or 600 lines. But more importantly, when I looked at your appendix, Dr. Rosielle the Institute of Safe Medication Practices says, you should never have order sets or charts or anything where one drug name is very close in proximity to another drug name, particularly if they sound alike. Hydrocodone and hydromorphone, ISMP recommends using tall man lettering because it’s so confusing. Even in your chart on one line, even within the same line, you’ve got one multiplier and one divisor, I personally find your chart way more confusing. As a matter of fact, one point you and I agree on, is opioid conversion calculators are probably the work of Satan.
Mary Lynn: I would actually rather somebody use an on my calculator because then at least I don’t have to worry about them using the wrong line, picking up the wrong line. And to your point that you and your fellows have difficulty doing a ratio calculation. This reminds me of Dr. Meyer’s a very famous video about people are not born knowing how to intubate somebody, nor are they born knowing how to break bad news or have a goals of care conversation. They weren’t born learning how to knowing how to do a ratio conversion, but they did learn in third grade. If they’ve forgotten what Miss Peach taught them in third grade, it’s literally would take you 15 minutes to walk them through that. I really am not buying that it’s too complicated to do A over B, equal C over D, if you know three of the four variables. Come on.
Eric: Drew, what I’m also hearing from you though in your post is maybe there’s something different about people doing primary palliative care and pain management versus specialty palliative care. And the level of knowledge they need to know. Is that right?
Drew: Of course, yeah. I think part of my argument, again, for people who are listening, they can look at the conversion table, which I would really want point out was just a proof-of-concept draft that I put out there.
Eric: We’ll have links to Drew post, which also has the Dropbox version of his table and box version.
Drew: Yeah. There’s an annotated version as well, that I put on there with just why I chose those numbers. There’s nothing remarkable, just ready data and stuff like that. I want my fellows to have read Dr. McPherson’s book and to know the content really well. I expect my colleagues to know that there’s a large amount of sophisticated, nuanced knowledge that all of us who do high risk pain management for seriously ill patients need to be aware of. But I just don’t expect my medical students, residents and generalist colleagues to do that and to have that. Part of my proposal is, again, that we can actually use very similar information. That’s what’s on the equianalgesic tables. We can put it in a format that the math is a single multiplication or division calculation, not several. You can make your own judgements about whether it’s compact or not. I guess I’m not putting in tramadol and meperidine, but I feel okay about that.
Eric: Alex, I see you got a question.
Alex: I want to come to Drew’s defense a little bit here. I think Mary Lynn, there may be some agreement here. We went through a little bit of this with ePrognosis, our online prognostic calculators. The idea was, why in this day and age have… So, in a prognostic calculator, you take all these potential elements of risk. You take somebody’s has disability. You take their age, their gender, you take their chronic conditions. Maybe they have heart failure. You take their function. You take some lab values. All those things are related to risk and you could put them together in an equation. The old way of doing this is that there would be pencil and paper, like an equianalgesic table. And you’d see, okay, you get so many points for being male. So many points for having heart failure. So many points for having disability. And then you’d add it all up. And then you’d go to a risk score sheet, said, if you have this many points that corresponds to this mortality risk.
Alex: We realized, you know what? We should just put this on the web because why have people get out their pencil and paper do all these calculations. We should just have all the calculations hidden and that people can just enter their values and then they get the result. So, why not do what Drew’s suggesting? And just say… and I think I heard you say Mary Lynn earlier, that you’d rather they go to the web and do this. Why not have one place on the web? And if the con conversions are complicated, just take that away, remove that element of error.
Mary Lynn: I can tell you why.
Alex: And have it all online, easy to use-
Drew: Not boxed.
Alex: … no algebra necessary.
Mary Lynn: I wish that I, with all my heart that I could tell you, whether you use Dr. Rosielle’s approach or my approach, or the man on the moons approach, that this is a cookbook approach and that your mother could do it, but that’s not the case. I have very good research. We’ve done several projects, looking at people using these online calculators. The disparity in resolution to hypothetical cases is so disparate, it would knock your hat in the creek. From between program to program, to program, and between users. The problem with an online calculator, is people put in the numbers, they crunch through it and say, eureka, I’ve got the answer. And they just turn off their brain. I actually had a student once who did a calculation online after he did it. He’s like, “Wow.” I said “What?” He said, “It’s like a million milligrams of morphine.” I said, “Well, what do you think of that?” He said, “Well, we’re going to have to order more morphine.” I was like, oh… [laughter]
Mary Lynn: Yeah. We all agree, that’s not a good look. So, I think people tend to turn off their brain with those online apps. And they don’t think about, that’s why I like the five steps because was the patient in pain with the patient and not in pain. To your point, was the patient on 30 milligrams of morphine a day or 300 milligrams or morphine a day. Dr. Rosielle and I agree that fentanyl is a hot mess when it comes to doing the conversions. What’s the patient’s body habitus. There’s so many variables that go into this. And I think we do our learners a disservice, even if they’re not going to be a palliative care person when they grow up. Even primary palliative care skills when it comes to conversion calculations. I think they need to understand these basic concepts or, you know what? They should not be in the game and they should call us instead.
Eric: Drew, thoughts on that?
Drew: I agree in part. I think that I want my residents and medical students and colleagues to do more than a math calculation. Obviously, there’s no like between me and Dr. McPherson on that. And I think probably almost everyone who does this work. But fundamentally, I think we have structured this as, we’ve made it harder than is necessary. Really because of the structure and the nature of equianalgesic tables, similar information with simpler math, can easily be presented to our colleagues. I think it’s time to do that. Especially, because I am hoping, there will be additional data that comes forward, which will help us make these tables better. And every single time, however, that data comes forward and we have to adjust one value on that table, it’s going to mess up everything else. And it just seems to me like we don’t have to do that. If we didn’t structure the information as analgesic table, and instead just had it as a simple conversion table off oral morphine conversion. Conversion table off oral hydromorphone in a simple, compact way…It’s just easier.
Mary Lynn: I think another benefit of looking at an equivalency table is it allows the learner to gain a deeper appreciation of the relative potencies, which you’re not going to get with a multiplier or a divisor. For example, it shocks me how many people don’t know when there’s a medication where the dose is different, whether it’s oral or parenteral, they have to really think a long time, which is the higher, and which is the lower number. That’s pretty straightforward, if it’s IV, you’re putting it in the systemic circulation. We don’t have to worry about bio availability. But if I can look at a chart and see, okay, 20 milligrams of oral oxycodone, is about 25 or 30 of oral morphine. Oh, oxycodone is actually a little more potent than morphine. What the heck? And Hydrocodone is about the same as oral morphine. So, I think that visual really helps people understand these concepts better.
Eric: How much of this debate is really just about processes and you end up in the same value anyway. For example, I use the traditional opioid conversion table, equianalgesic table. Probably for the vast majority of… and my process is, A, I’ll find out if they’re pain or not. I will look up their total doses. I will convert using the table. And then I’ll usually do a 25 to 50% dose reduction. And then again, individualizing it to the patient. How much pain they’re in, thinking about either we’re switching different types of drugs. Am I switching from morphine to morphine or morphine to Dilaudid. And then I’ll evaluate. That sounds very similar to Lynn. Lynn, that’s basically your five steps right there, right?
Mary Lynn: That’s the process. Exactly. Is the patient possibly experiencing hyperalgesia? Simply reducing and taking away the old drug is a therapeutic intervention. I think the key is being, doing this safely and effectively.
Eric: I bet that if I worked at MD Anderson, I’d probably get the same amount as they did using their 10 to one… wait, yeah. 10 to one instead of 20, one ratio. Not too far off.
Mary Lynn: They adjust it too.
Drew: Thy didn’t.
Mary Lynn: They do also adjust it, depending on the situation. If the patient’s been screaming, it depends, you’re right. If you’re switching opioids, there is going to be a difference in cross-tolerance, despite what Dr. Rosielle said his in second post, so we can talk about that. But if you’re on the same opioid, morphine is morphine, is morphine. Once it gets absorbed and gets to the receptor, but then is the patient in pain or not. If you’re switching opioids, I would reduce, because of lack of cross-tolerance. And yes, I do believe in that. But if they’re in pain, maybe I would not have reduced as much.
Eric: Drew, both of our fourth step is individualizing it. Thinking about incomplete cross-tolerance, sounds like you don’t buy that. Tell me your thoughts.
Drew: From a pedagogical standpoint, you’re teaching residents. I have decided at some point a while back, I was done having a five minute aside in my precious time with the residents explaining to them this baroque and confusing term, incomplete cross-tolerance, that I wasn’t sure was a relevant concept when it comes to opioid switching. I really want to emphasize that adjusting the dose after the calculation for a patient, for safety, for knowing that there’s a broad inter individual variability and how people respond to opioids. I think that practice, reducing for safety, reducing for inter individual variability, is very important, especially if you’re using equianalgesic tables, which, depending which way you’re going, prompt us to put people on too much, regularly. So, the practice is fine. I think from a pedagogical standpoint, incomplete cross-tolerance is a distraction.
Eric: So, from a teaching standpoint, let me get this straight, it may be confusing. It sounds like you’re also focusing more on the safe conversion. What’s the term that you used again, in Pallimed post?
Drew: What I talked about was, we should be using the language of, safe and effective opioid conversions, opioid switching. I just want to observe that, I think, there’s a field that’s been heading this way anyway really, when you look at methadone and buprenorphine. And maybe to an extent fentanyl, but, especially methadone and buprenorphine. It’s been years since I had a thought in my mind, one my patient, let’s say he was on 15 BID of oral methadone. How much morphine is that equivalent to? I don’t even think in those terms. Most of my colleagues, I know, don’t think in those terms either. They don’t find it a helpful question.
Drew: There are parallel questions, which is, again, what’s a safe amount of oral morphine [inaudible 00:33:46] to put this patient on, if I was taking them off methadone or putting them on methadone. What is a safe and effective method of doing that? I’m not asking myself what’s equivalent. And again, I would say that the whole idea in complete cross-tolerance is really contingent on the idea that there exists out there, some sort of equivalent dose. And I think we can move on from that.
Eric: Mary Lynn, I saw that look.
Mary Lynn: Your assertion that we should all raise our right hand and swear to the deities, we shall never utter the word cross-tolerance again is… it reminds me of that TV commercial, the guy with the fungal toenail infection, where he says, it’s nothing. And then the doctor says, it’s a thing. It’s an infection. And you’re going to give it to other people which creeps out the kid. This is a thing. My God, Gavril Pasternak is rolling in his grave right now. This is 30, 40-year-old data. When I say I bought a new pair of shoes, okay, maybe they were Keds sneakers. Maybe they were Jimmy Choos. All shoes are not the same. Just because morphine binds to the new receptor and oxycodone binds the new receptor. We know we have minimally, three different variants in the new receptor. Pasternak would say 25.
Mary Lynn: And then when you look at the intracellular mechanisms of how an opioid works and the Beta-Arrestin signaling, which is dramatically different. Buprenorphine, not at all. Fentanyl is a strong Beta-Arrestin signaler. I think to say that the consideration of cross-tolerance is a baroque and outdated and fuddy-duddy concept is… I think, if you can’t run with the big dogs, you should stay on the porch. I think this is an important concept. I think we can simplify it for our learners, but they do need to understand it. It is a thing. It’s a thing. Go get some fluconazole. It’s a thing
Eric: I wish I had all those phrases of Mary Lynn McPherson in my head. [laughter]
Mary Lynn: Feel free to borrow.
Eric: But I also hear Drew’s point though, that it’s more about how do you teach these concepts. If you have, which most of us have, a limited amount of time to do teaching around pain management, how much do we want to focus on concepts of new opioid receptors and all these things versus actually just simplifying into five steps. And saying, that fourth step is really about individualizing and making it a safe switch. Am I hearing you correct, Drew, that’s part of this?
Drew: I’m going to stick by my position that I’m not going to regularly introduce Beta-Arrestin, molecular biology into my lectures on opioid switching. I feel very sincerely about that. I think we are obliged, and speaking as a clinician educator here. I think we are obliged to teach our colleagues and our students in a way that’s going to work for them. And my goal is not for them to understand the molecular biology of opioids. My goal is how do I help them convert and switch between opioids in a safe way, that’s not going to harm my patients. I think that five minutes that I spend explaining things like incomplete cross-tolerance, is time that I can just say, 10 seconds. Then we reduce it further because there’s a broad inter individual variation between how they respond, the opioids. I think that’s factually accurate. And that’s my major point.
Alex: I have a question. I love the challenging of established practice. We love that on GeriPal. I love that Mary Lynn McPherson came up with a new opioid equianalgesic table. And I love that Drew is talking about throwing out the table altogether and coming up with a new formulation and also new way of teaching. Yet part of me wonders, this is, so I’m a clinician researcher. I mostly do research. Is there any reason to suspect that there isn’t… what is truth? That’s a lot of what research is trying to get to, what is the truth? Is there any reason to suspect that there isn’t actually some equianalgesic table that is like on average what we would expect for people. And that ratio going from one, say oral morphine to IV Dilaudid or hydromorphone, and going from IV hydromorphone, Dilaudid back to morphine. Is it some reasonable, fixed relationship that on average we can say, okay, we go in one direction, it’s this way. And we go the other direction, it’s the same way. Same ratio.
Drew: Hypothetically, with broad, perfect knowledge, we could talk about… We could hypothetically have perfect knowledge of, in a population, what the average or median equianalgesic ratios would be. Sure. I guess one of my major arguments is that, that knowledge is not the same thing, necessarily. Obviously, that knowledge is important and foundational. But it’s not the same thing from a practical standpoint, necessarily. And how we teach people how to safely convert. Because again, the whole thing with reducing for individual variation is based in part, because of the idea that we may know, like the MD Anderson data. Going from IV hydromorphone to, let’s say, to oral morphine and showing a 10 times conversion factor.
Drew: That was a population average, or maybe median, for those, whatever it was, 5,000 patients.
Eric: Based on a standard that they have of 10 to one.
Drew: Yeah. Yeah. Right. It was reflective of their practice. But let’s just take that on face value. It’s the best data we’ve got. My argument is that all of us are used to, and then we have these very common standard practices of knocking part of that off for safety, for individual variation. For the incomplete cross-tolerance. So, our method, the actual method of switching between those things is, while it’s founded on that data, it’s not a one-to-one ratio. So, my idea is, let’s cut out the middle stuff and just present people a simple way of doing it, or at least simpler. There’s always needs to be room for new ones on patient specifics about how they’re doing and how much pain they’re in and how frail they are, and their mental status. There’s no doubt about that, but I think we can make it easier. I don’t know.
Mary Lynn: Dr. Rosielle, I’m concerned about oversimplification, for example. The lines, line, line, lines that you have, some is from the old table, some is from the new. Some is stuff that you particularly like yourself. My chart and granted, maybe somebody can come up with a better idea, but mine is based on the very best population-based data in print, as of today. I was just looking at a study, looking at fentanyl to hydromorphone, which comes out to closer to 0.2. I have 0.15 in the chart. You have 0.1 in your chart, probably, if you’re using the old chart. I don’t think you’re-
Drew: There’s no fentanyl in my chart.
Mary Lynn: It’s not really data-based. So, I don’t think we should oversimplify this to that degree. If you’re going to oversimplify that much, you might as well use an online calculator and just adjust and cross your fingers.
Eric: Mary Lynn, I’d love your thoughts about Alex’s question. Is there something as close to a truth as we can get with these tables?
Mary Lynn: Excuse my humility, but I think I did it already. It’s the chart that I published. It is referenced out the wazoo. I don’t know how anybody could find any better data to substantiated it. Is it a moving target? Yes. Dr. Rosielle’s correct. Something could be published tomorrow to say, y’all are nuts, that throws a wrinkle into things. How are we going to address this? But I think-
Alex: But Mary Lynn, if I could just interrupt. I don’t understand scientifically, how they determine an equianalgesic dose.
Mary Lynn: That’s the thing.
Alex: How do you determine what the equi… let’s talk about morphine to hydromorphone because we’ve talked about that quite a bit. How would you determine what that equianalgesic ratio is?
Mary Lynn: Dr. Reddy’s methodology was all one, you do the conversion, you do the switch. And when the dust settles, what was the median conversion, to either get that patient comfortable or keep them comfortable? That’s why we had the 10 to 60 back in the old days, because they said, let’s take Dr. Smith and I’ll ride my car over his foot. How much morphine does he need to get comfortable? 10 milligrams IV. Great. Let’s come back next week and I’ll ride over the other foot. How much oral morphine does it need 60. Great. But if we had left you morphine 10 Q4, around the clock IV, your morphine-6-glucuronide would’ve kicked in and it’s only three to one. So, we have to look after the fact and say, from a population perspective, what got the job done?
Mary Lynn: It did not make the patient toxic. And I got them in the ballpark. But because of this variability, even when you look across a line on my chart, looking at hydromorphone. When you look at IV to oral, that is entirely driven by bio availability. And we have data from 1987 showing it’s about 50%, but there’s a very wide range. It could be anywhere from 30% to 70%. When you look at the four of us, there is an 11-fold difference in our guts, cytochrome p450 enzyme activity and a 30-fold difference quantitatively in our liver. There’s a huge variability from patient to patient, to patient. Regardless of which conversion scheme you use, the most important thing is to follow a process. And I think our learners must understand that process, or frankly, I think they’re dangerous.
Alex: I think Eric made a good point earlier about how at MD Anderson, that starting dose is going to bias the data in one direction. If the starting dose is 10 to one, then you’re more likely to find that, hey, 10 to one works, than if you start with 20 to one. I worry that this isn’t a true experiment. As you were saying, where we can have a laboratory and we can subject people to pain and we can try various doses. It’s anchored, so to speak, to that initial ratio with which they start.
Mary Lynn: But we are-
Drew: I think that’s right.
Mary Lynn: But we’re looking at people and we’re looking at what works. That’s why we look at the median conversion or whatever number you want to call a multiplier, divisor, as opposed to… why would we start from ground zero? It’s like an antihypertensive, you’re going to compare it to the gold standard, for example. It’s not just going to be against placebo. They have to wait until the dust settles to say, okay, when we look at 22 patients, the median number most often out of these patients that did the trick, was a 12.5 conversion. Now of course, they’re going to start with their 10 to one because that’s what they’ve done for 30 years. Why would they say, let’s start with 30 for one just for giggles and see how that works out. I see your point, but I think looking at the median outcome is the best indicator of where our best shot is.
Drew: Alex, to your point again, I think, just reflecting about our experience, the last couple of decades with methadone and now with buprenorphine. It’s been, I think, a really eye-opening experience for many of us and realizing that the exactness of this dose may not really matter that much, to an extent. And putting people on methadone. I got these patients. I could put them on five milligrams BID. I could put them on 7.5 milligrams BID you know. As far as I can tell, it doesn’t matter hugely.
Eric: But is that just something special about methadone and buprenorphine?
Drew: I don’t know. I think the same is true with buprenorphine, so it’s not unique to methadone. I would argue the same is true from buprenorphine. I also think that… and this is again, one of the points I made in the blog post, that especially when we’re talking about the low to moderate doses, 30, 50 milligrams a day of oral morphine, 60 milligrams, a day of oral morphine. It doesn’t matter that much. I think these things are, to an extent, more forgiving. And to that point, I think what Alex is saying probably makes, an extent. If you’re a culture that takes the IV hydromorphone dose and divides it by 20 and puts them on oral morphine, and that works just fine. You’re going to find that works okay. And if you’re on a culture that divides it at by 10, and then maybe knocks a little bit more off, you’re probably going to find that works okay, too.
Drew: One of the final points that I was trying to make in my blog post, which we don’t have time to talk about today, but is that the other skeleton in our closet here, is that all of these, all of these tables that are out there they don’t have these, this huge asterisk and caveat saying, none of this should apply at very high doses. We present them like these ratios are linear across all doses. And that converting someone off 40 milligrams of morphine, we should put them on the same ratio of hydromorphone as 400 milligrams of morphine or 800 milligrams of morphine. I don’t think that’s right.
Eric: In her process, the fourth step is about individualizing. Mary Lynn, your thoughts on the higher doses, lower doses, what do you think?
Mary Lynn: If somebody’s on a Godzilla dose of morphine, maybe they’re having some hyperalgesia and we shouldn’t give him full credit for that dose. I agree.
Eric: Last question for both of you, we meet again in 10 years to do another equianalgesic talk. What do you think we’re going to be doing in 10 years, Drew?
Drew: My hope is that in the next five years, additional reasonably good clinical data emerge about this. And people are going to try to smash that data into equianalgesic table. And realize, oh my God, I’m adjusting the morphine thing here, but now it’s… and realizing that all these problems that EATs caused by having fixed and bidirectional things. There’s going to be more appreciation, so…
Eric: After 10 years, are we going to be using an app that does that for us?
Drew: We’re going to be using Dr. McPherson’s data and using a conversion, a more simplified, streamlined conversion table.
Eric: Ok. Lynn, 10 years from now.
Mary Lynn: 10 years from now, the fourth-
Eric: We’re still using your book.
Mary Lynn: The fourth edition of my book will be out. I think we’ll still have equianalgesic conversion table that we will continue to refine with better population-based data. And whether you use that, or you do use an app, the app will hold your hand better through the process and not just plug and chug.
Eric: Great. And maybe teach you what it’s doing behind the scenes.
Mary Lynn: That would be lovely.
Alex: Can I answer?
Eric: Yeah, Alex.
Alex: Here’s my answer. We’ll be using buprenorphine because it’s a much better medication with less addiction potential and a ceiling effect on side effects. Because we’ll be using that almost exclusively, there’ll be much less need for opioid equianalgesic tables.
Eric: And my answer-
Drew: Buprenorphine just can’t go on a table.
Eric: My answer is, at 10 years we’re going to have the exact, same, spirited discussion about what’s wrong.
Alex: We will reconvene.
Eric: What’s should we do?
Mary Lynn: On my calendar.
Drew: We’ll have a thousand dollars a month Beta-Arrestin modulator. And it’ll be a whole new world.
Eric: With that, maybe we’re going to all end this podcast dissatisfied. Alex, do you want to do a little bit more of that song?
Eric: I love it when the song perfectly encapsulates the podcast. I honestly really want to thank both Lynn and Drew for being on this podcast, sharing their opinions. I agree with what Alex said earlier. The only way that as a field we move forward, is if we think about where our dogma comes from. Thinking about does it need to change. Lynn, love your book. We’ll have a link to it on our show notes. Everybody who hasn’t read it should buy the book. If you read it before, read it again. Drew, really want to thank you again for stimulating this really interesting discussion about EATS, equianalgesic tables. I just wanted to see Lynn’s face, right when I said EATs.
Mary Lynn: I’m going to go eat cookie now, I think.
Drew: Thanks for having me.
Eric: As always, thank you, Archstone Foundation for your continued support and to all of our listeners.