On today's podcast we go deep into the mind of one of the most brilliant and respected palliative care pharmacists, Mary Lynn McPherson, to ask all the questions we've had about opioids but were too afraid to ask. There isn't really a better person to do this with, as she also just released her second edition of her book: Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing. This is the go-to guide for not only learning how to calculate opioid conversions, but also gives great tips for those who have been doing this for a while (I learned a ton from it).
In today's podcast we talk about specific aspects of her book including questions about:
- Whether is is time to update equianalgesic tables
- The usefulness of opioid conversion calculations
- Tips and tricks on methadone dosing
- Fentanyl and cachexia
- Sublingual morphine - does it work?
- What to use in liver and renal failure (and why it may not be hydromorphone)
- Titrating PCAs and drips
- and so much more...
So take a listen to the podcast and pick yourself up a copy of Lynn's book. You can find Lynn's book at the following sites:
by: Eric Widera (@ewidera)
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Eric: Welcome to the GeriPal podcast. This is Eric Widera.
Alex: This is Alex Smith.
Eric: And, Alex, who is our guest today?
Alex: Today, we have a palliative care superstar.
Alex: Guru, superstar on the line. All of her sessions at the annual academy meeting, AAHPM HPNA are packed, sold out, standing room only. Welcome to GeriPal Podcast, Lynn McPherson. Lynn is a Professor at the University of Maryland, School of Pharmacy and Program Director of the Masters of Science in Palliative Care at The University Of Maryland. Thank you so much for joining.
Lynn: Thank you for having me. It's a pleasure to join you two rock stars.
Eric: I am so excited about this podcast. I love going to every one of your sessions. I learn a ton.
Lynn: Thank you, especially good jokes, right?
Eric: I'm actually really excited because I just finished reading your book, Demystifying Opioid Conversion Calculations: A Guide For Affective Dosing, that just came out. Is that right, Lynn?
Lynn: It did about a week ago.
Eric: Wonderful. So, we'll talk a little bit about the book, but before we go into the meat of this podcast, Lynn, do you have a song request for Alex?
Lynn: Well, I'm a big fan of Huey Lewis and the News, I Want A New Drug.
Alex: Good choice. [Singing]
Eric: Alex, alone with his opioids.
Lynn: Wow. Move over Huey, you nailed it.
Eric: That was great, Alex. Well done.
Lynn: Very good.
Alex: Thank you.
Eric: I'm always impressed, every time. Another new drug, or another new song.
Alex: It's a good challenge.
Eric: Good challenge.
Alex: So fun.
Eric: Well Lynn, a very big thank you for coming on. We're going to be talking a little bit about opioids during this time and opioid conversion calculations, and a little bit about your book. Before we jump into this, let's talk for a second about your book. I can only imagine the amount of work you put into this book. Why did you do it?
Lynn: Well, probably, there's a psychopathology at work here but the whole thing started about 10 years ago when I was searching for a good resource on opioid conversion calculations and I kept beating my head on the table saying there's got to be something out there and there wasn't. So I thought, "Well, you know what, maybe I'll just do it." So, I spent a year, every time I gave a lecture, I'll do a little survey instrument and I would give it to the audience saying, "Do you think this is a great idea?" "What would you like to see included?"
And then, coincidentally, an editor from the American Society of Health-System Pharmacists had emailed all the faculty at my school right before the holiday break and said, "Look, I'm going to be in your building. Does anyone have any good ideas for a book?" So, I wrote back and said, "I do. Why don't you contact me in January?" So, she called me within about 15 seconds and said, "You can't do that to an acquisitions editor." And that's what got the whole thing started.
Eric: How long did it take you to write the book?
Lynn: Way longer than the publisher would have liked. The first edition took about two years, I would say, because I have a lot else going. This was really hard to do because as you very well know, there's very little consensus, and then, with the second edition, and that I was longer getting that done that they would have liked as well, but to my benefit I think and to the benefit of the book, we're finally getting better data about doing these calculations. So, I think it significantly better informed the second edition so I was really pleased with it.
Alex: That's wonderful. I wonder if you could tell us what's the number one most common question that you get about opioid conversions?
Lynn: Well, I think there are always questions about methadone dosing, that's probably the drug that scares people the most, but other than that, it's kind of all over the place. I was just in Texas at MD Anderson giving a lecture on opioid conversations and one of the physicians asked about now that we're getting better data looking at steady state conversions as opposed to single dose cross-over trials in healthy normal people, do you still have to reduce cross-tolerance? And you don't, but that raises the question how do you know from those equianalgesic tables when you do have to reduce and when you should don't need to reduce, so I think people are very confused about that. When do I need to reduce for lack of cross tolerance? It's a much more complicated question. Is the patient in pain, is the patient not in pain, what's their clinical situation?
So, this is why I rabidly despise apps for opioid conversion calculations because it lets you shut off your brain and you just don't even question the number and you just roll with it, and people tend to make egregious errors by using an app.
Eric: That was actually one of our questions. Can't we just use an app?
Eric: It sounds like you just answered that for us.
Lynn: You cannot. You'll be in big trouble. A pharmacist student wants once on rotation and a nurse asked me to do a conversion, so I turned to junior and I said, "Hey, this is great. You do the calculation for the nurse," he said, "Oh, I got an app for that," I said, "Of course, you do". He whips out his phone, he does the calculation and he goes, "Wow," I said, "What wow?" He said, "It came out to like 5,000 milligrams of morphine," so I said, "Well, what do you think of that?" He said, "Well, we're going to have to order more morphine." What a monkey.
Eric: Going back to how you've outlined this book, the very first chapter is if we're not going to use an app, we go to our handy dandy trusty opioid conversion tables, equianalgesic tables. What are the issues that you have with opioid conversion tables? And yours looks a little different too than the ones I've seen.
Lynn: Very much is different, yes it is. I think the bigger issue is, with the first edition of this book, my table looked very similar to the tables that are still out there today where you would say, for example, that one and a half milligrams of IV hydromorphone is seven and a half milligrams oral, which is 30 milligrams of oral morphine. So, if you went from IV Dilaudid to oral morphine, you would multiply by 20. That was based on single dose acute pain cross over trials mostly in healthy, normal people. Most of the tables that out there do not account for the patient is young, the patient is old, the patient's in the pink of health, the patient is sick, they're skinny, they're fluffy. It takes no account of patient specific variables, I would say. But now, we do have some data that's starting to emerge.
Dr. Akhila Reddy from MD Anderson has done several studies looking at IV hydromorphone to oral opioid. She's looked at hydrocodone to morphine more carefully, transdermal fentanyl, so this data is finally starting to come out, but it still requires caution in using these charts. If you read the book, you remember the line where I said, "Using one of these charts is like giving you a ticket to the ballpark, but you still don't know exactly which of the 40,000 seats is your seat. You still have to use your brain and your clinical acumen to decide how to go with this."
And I am a board-certified card carrying wennie when it comes to the scheduled around the clock dose of the opioid that I've just calculated, but I'm insanely generous with the breakthrough because I don't want anyone to suffer because I'm a big wennie.
Eric: All right. Wait, I'm just going to step back, I shouldn't be using 1.5 of hydromorphone to 7.5 of hydromorphone?
Lynn: No. Because if you look at data that's actually quite old, the bioavailability is about 50%. So, you're right, my new chart, I think, is going to cause quite a stir because I have that, for hydromorphone 2 milligrams IV is 5 milligrams oral, which is much closer to the numerous studies we have showing the bioavailability really is about 50%, although there is quite a wide range. Also, I lowered the equivalent to oral morphine from 30 to 25 because Dr. Reddy's data showed that it's about 10 or 11, 12 times the potency of IV Dilaudid when you're switching to oral morphine. So, the chart still works. Everybody's got their own chart, but frankly, my chart is based on the very, very latest, best evidence available.
Eric: Okay. So, this is my challenge with looking at all of these new data because most of the new random trials of this is looking at going from let's say hydromorphone IV to PO but not the other way around. And same thing with when we're looking at morphine or morphine to something else. Is the equianalgesic table, has it lost its time? Should we move on to something else because going from one drug to another drug in one direction may not be the same as going from the new drug back to the old drug.
Lynn: Right. So, you're questioning bidirectionality?
Lynn: And in fact, with the IV hydromorphone to oral morphine, Dr. Reddy did look at that and she did show bidirectionality, but when you look at data looking at IV or subcu morphine to IV or subcu hydromorphone or oral morphine or hydromorphone, those old studies showed that it's not quite as bidirectional as you would think. In the charts, what people have done is kind of split the difference. I know my pharmacy students, when they see a chart like this and we talk about drug math, they get very excited because they think there's one right answer, but that's the whole point. I actually flirted with doing away with the chart as you just suggested or instead of putting a number in there, putting in a range like well, 1, 2 milligrams of IV Dilaudid is somewhere between 20 and 30 milligrams of oral morphine. But I think that will confuse people even more, so I chose to stick with the very best number from the data that I could find and come up with the five-step process that I strongly advocate which calls for people to use their brain and interpret that number.
When you calculate a number, you can either go with that number, reduce it or increase it. That's where the thought process comes in.
Eric: I was told I did not have to use my brain in medicine.
Lynn: I heard that, but they were wrong, they pulled your good leg there, dude.
Eric: At least math. So, can you just briefly go over what are the five steps that you're advocating?
Lynn: Sure. The first step, and this makes nurses crazy when they call me, they say, "Why can't you just answer the question instead of asking me all these questions?" The first step is to carefully assess the complaint of pain. Because sometimes, the answer is not to switch opioids, sometimes, the answer is you just need to increase the opioid they're on or maybe you need to add a coanalgesic. So, it is doing a complete assessment of the pain and you're going to need that data in step number four, so stay tuned on that. Step number-
Alex: Wait, wait. Can I stop ... Hold on. Along the lines of that first step there, when you say coanalgesic, are you talking about a second opioid or are you talking about adding adjuvant analgesic?
Lynn: Adding an adjuvant drug, yes.
Lynn: So ...
Alex: So you do not advocate ... for example, I know several clinicians who swear by having people on multiple different long-acting opioids.
Lynn: No. I don't buy that at all. We had data to support that looking at the way different ligands ends bind. I don't think we're there right now. The only time I would ever recommend using an opioid adjunctively is perhaps using baby low dose methadone on top of a more complex regimen. It seems sometimes, and the data ... again, it's not very thick on the ground there either, that adding a little baby low dose methadone on top of the whole red hot mess due to NMDA-receptor antagonism can be a beautiful thing, but no, I don't agree with using too long actings. I think you're just looking for trouble.
Alex: Great. Sorry, I interrupted you. Step one is consider increasing the opioid you're on rather than switching or adding a co-
Lynn: Right, making sure that doing the conversion is the correct therapeutic thing to do. So, let's say you decide, "Yep, that's the right course of action." Step number two is to calculate the total daily dose of what the patient is currently getting. So, if they're getting oral long-acting plus breakthrough, and you got to be careful there because often, people will tell me, "Oh, they're on MS Contin 30 q12 with Roxanol 10 q2 prn," and also how much are they using on the prn, "I just told you, 10 q2," I said, "No. You told me the order. You didn't tell me how much the patient is getting." If you don't know how much the patient is getting, just leave it out of the equation.
So, you want to really be comfortable with the total daily dose of the current opioid the patient is receiving. Then-
Eric: And I love ... in your book, you also said, "Just because somebody says they're using q2 hours, that prn, doesn't mean they're actually using it because they may be sleeping."
Eric: And so, really, thinking about using diaries to help document when they're using these prns instead of just saying, "Oh, they're using q2 so that's 12 doses a day," but probably, they're sleeping at some point.
Lynn: Absolutely. So, if you do have the luxury of, in a nursing home or assisted living looking at an MAR, a medication administration record or if the patient is at home, if they're keeping any diaries themselves, that's very beneficial. But if it looks a little fishy, don't even include it. Very important.
Then step three is the one that makes everybody want to have a seizure, which is the actual ratio. The way I set up this equation is I put my ... everything on the left side of the ratio is real time data. I put my unknown in the numerator, x milligrams of my new opioid by their preferred route of administration over the current opioid by whatever route of administration the patient is getting it. Everything from the right hand side comes from the equianalgesic table. You will see the same opioid with the same route in the numerator on both sides and similarly, in the denominator on both sides. You cross-multiply, you solve for x. That's step three, you've got this number. And now, what do you do with this number? That's for step-
Alex: Wait, wait. So, on step three ... sorry to interrupt ... you do not advocate converting to morphine equivalents and then, converting from morphine equivalents to the new opioid every time?
Lynn: I do not.
Alex: You do not?
Lynn: No, I never do that. But if you are a doubting Thomas, you can certainly do that to prove to yourself you'll get the same number.
Eric: Or likely that you'll just mess up on the additional math steps.
Alex: Well, I’ll tell you why I do that, I was trained to do that. And it's largely because I think in morphine equivalents. Like if I need to know is that a lot or a little, I can't answer that question as well with the other opioids, but I can answer that with morphine.
Lynn: That's fair. That's fair, but check your math and make sure you're doing the direct conversion appropriately too. I do think that increases the margin of error but fair point. All right. So now, you've got the number, the magic number. Step four is to revisit what was going on in step one, is the patient in pain at the time ... why are we switching? Are we switching because they were having uncontrolled pain, but yet, you continue to believe an opioid is appropriate therapy. Maybe you need to be a little more aggressive. Maybe you're switching because now the patient can't swallow tablets or capsules anymore, but they were very, very comfortable. Maybe you're switching for whatever the reason may be. So then, you have to take in to consideration what am I going to do with this number.
Generally, you don't roll with that number. For one thing, it's probably a goofy number that you can actually do with tablets and capsules that are commercially available if it's the oral route of administration. If a patient was switching because of a side effect and their pain was well controlled, another important consideration is, are you switching from one opioid to a different opioid? So, if you're going to a different molecule, they will be more sensitive to the new molecule so you probably should reduce it.
Now, as I said earlier, what's confounding the situation is we have steady state data looking at going from IV Dilaudid to oral morphine, for example, which kind of took in to consideration that lack of complete cross tolerance. So, I probably would not cut back as much, but this is where you have to put on your thinking cap. Sometimes I'll reduce that by 50%. Sometimes, I'll reduce it by maybe 15%. Rule of thumb, it's about a third. And then I'm-
Eric: Wait, going back to steady state. Let's say somebody's gotten more than five doses ... Wait, I'm trying to think back. So steady state happens after ...
Lynn: Five half lives.
Eric: ... five half lives. So, it's been passed by the half lives, their conversion's going to be different than somebody who is-
Lynn: No. No, that's not what I mean.
Lynn: I'm talking about the evidence that we have. When those clinical trials were done on patients who were at steady state, that data is more reliable in terms of how much do I really need the dose reduce. But if it's not and if we're looking at data, for example, conversions where we don't have that kind of data, I would tend to cut back even more.
Alex: Well, this is wonderful. On the same note here, how long is the issue that they've achieved steady state with the opioid and at that point we should be thinking about dose reducing for incomplete cross-tolerance, like immediately after they've had five doses or is it something about the chronicity of they've been taking it for weeks or days or months and we should have greater consideration for incomplete cross tolerance?
Lynn: Well, I think one thing you have to be concerned about is that they've been on the same opioid regimen for a good while, and now, they're not responding as well. You have to give some thought about tolerance. That's why when you switch to a different molecule, you really do need to cut back because they're going to be more sensitive to the new molecule despite doing the math correctly.
Alex: Right. So, the incomplete tolerance, cross-tolerance issue only comes up once they're tolerant which is something that happens over the course of weeks to months, right, not necessarily days?
Lynn: No, I don't think we can necessarily say that either. The current thinking is we have 25 different kinds of mu receptors, which is crazypants, but maybe a new oxycodone binds a little bit differently than morphine or than hydromorphone or than hydrocodone. So, it could be after one dose, for example, or two doses. You could be short of steady state and still, you could have binding differences when you're switching opioids. All I'm saying is when you're switching from one opioid to another, it's a muddier picture than if you're going from IV hydromorphone to oral hydromorphone because once you get the drug into the systemic circulation, hydromorphone is hydromorphone whether you put it in rectally or IV or orally. See what I mean?
Alex: Yeah. That's terrific. This is so good. This is ...
Eric: All right. Wait. Wait. I want to go back, because I don’t want to forget the steps. So we're going to asses the patient, step one.
Eric: Two, we're going to determine the total daily dose of the current opioid.
Eric: Three, we're going to decide which opioid analgesic to use.
Lynn: And do your ratio.
Eric: And do our ratios, and we're going to individualize the dosing based on what we gathered in step one. That's step four, right?
Lynn: Right. Let me tell one more thing about four, and then, we'll do five.
Lynn: So, let's say you're switching from Dilaudid to morphine, for example. So you want to cut back because of lack of cross tolerance but the patient was in a ton of pain. I think that also factors in to your decision. While you might cut back some, you wouldn't cut back as much than if the patient were very, very well-controlled and in fact, they're a little bit sedated. So, you have to take all that into consideration.
And step five is the most important step of all. It is monitoring your patient like nobody's business, because you probably will be off a seat or two in the ballpark, so you can't just do this and walk away. So, you have to be very careful to ... like I'm very fond of asking patients to rate their pain before they take a dose of breakthrough and one hour later, because you peak when your morphine or oxycodone or hydromorphone by about 40-45 minutes. So, at one hour, that's as good as it's going to get. And then, I watch how they do over the next 12 to 24 hours, maybe 48, and then, I can adjust things. So, the patient can take the fewest doses of breakthrough possible.
Eric: All right. When you said the most important step, I thought it was billing, but no.
Alex: Step six is billing.
Lynn: That's step six. That'll be in edition three.
Eric: Okay. Going back. Going back to like when we're deciding to which opioid to choose like for folks with liver failure, let's say, are there any preferences in individuals with liver failure?
Lynn: Nope. All the opioids are handled by the liver, so I think I would be very, very leery about methadone particularly if it's somebody with end stage cirrhosis because that's going to take a long time to get to steady state, but all the opioids are handled by the liver. I think you have a little more flexibility in making better choices when the person has renal impairment because methadone, we believe its main metabolite is largely pharmacologically-inactive. Although there's a hint of data now that perhaps that metabolite may be the culpable agent with QTc prolongation but for intents and purposes, let's say they're pharmacologically-inactive as are the metabolites of fentanyl.
So, those would be better choices of people with significant renal impairment.
Eric: Okay. We're avoiding morphine, hydrocodone and codeine.
Alex: We're talking about in renal failure.
Eric: In renal failure.
Alex: We've gone from liver ... Liver ...
Eric: Yeah. We've switched on to ...
Alex: So liver, it's just backing up. I just want to clarify. Liver, avoiding methadone but all others start low, go slow?
Lynn: All of them, absolutely. So, all of the opioids are handled by the liver. The most problematic in my mind has got to be the methadone because it could take you two weeks to get to steady state with an incompetent liver.
Alex: Got it. And then, when we move on, talk about the kidneys and renal issues, people with chronic renal disease, acute renal issues, then, we're talking about avoiding ... You were just going to say, Eric, you're going to ask?
Eric: I always was taught like morphine and similar things like hydrocodone and codeine, we just avoid all the time. We had a great episode on Tramadol or Tramadon’t that our listeners listened to.
Lynn: Yeah, love it
Alex: But in terms of other opioids ...
Eric: Yeah. What about oxycodone and hydromorphone? I know we use a lot of that in ...
Alex: Yeah. Fentanyl.
Eric: Well, fentanyl, we just heard that fentanyl and methadone are the safest probably but this middle ground.
Lynn: Correct. Yeah.
Eric: What are your thoughts about those?
Lynn: I'll tell you, I think the naughtiest kittens are clearly morphine, but I think hydromorphone is almost just as bad, and I know prescribers think that hydromorphone is such a clean drug, but both morphine and hydromorphone are metabolized to a 3-glucuronide metabolite, and that's the bad boy that accumulates and can cause opioid-induced hyperalgesia.
Alex: Metabolizing the kidneys?
Lynn: By the liver. The liver. And then, it's a pharmacologically-active metabolite that relies on renal excretion. So, if you have bad kidneys, that sucker is going to accumulate and can cause hyperalgesia. There's muscle twitching, seizures, coma and even death, not a good look. I think the best are going to be the fentanyl and the methadone, and frankly the rest, the hydrocodone and the oxycodone are in the middle. They're in the middle of the pack. That's what I think.
Alex: We're going to need a second podcast. So many questions. This is great.
Eric: So, eould you advocate for avoiding hydromorphone like we avoid morphine in renal failure?
Lynn: You know, I do think it's almost as bad as morphine. I think morphine is still the worst. And people, you'll see on listservs like what the creatinine clearance cut off for using morphine or hydromorphone, and I think that's kind of a subjective question because it's like a three-sided graph because it depends on how much of the opioid they're getting for a day and how bad the renal function is.
For example, if I have a really bad renal function but I only took morphine 5 milligrams orally once a day, that's not that big of a deal because even if it takes 24 hours to get them metabolites out of my body, it's okay. But if I was taking a higher dose and taking it more frequently, then, it becomes more of an issue. And the same with hydromorphone.
Alex: This is terrific. We talked about opioids and liver disease, opioids and renal disease, could we talk about opioids and older adults?
Lynn: Of course. We do know that older adults, when you look at differences between older adults and younger people, there is a pharmaco-dynamic difference. So, older adults are more sensitive overall to the effects of the opioid. Just last week, a physician asked me for a starting dose of methadone in a opioid-naïve patient which we actually do in hospice that makes a lot of people uncomfortable. And this doctor started the patient on methadone, 0.5 milligrams q12, and I wrote back and I said, "I think we can be a little more aggressive and do one q12." They emailed me back day two and said, "Oh my gosh, it's a miracle. She's completely pain-free."
Lynn: That's not a good look either though. With methadone, you don't want to be rock star on day two. You don't want to be a rock star until day four or five, so I was like, "Wow. Now, we have to watch her for accumulating sedation."
Alex: Right. That is amazing.
Lynn: It was amazing.
Alex: Such a low dose.
Lynn: I know, it’s like licking the bottle. You know what I mean.
Eric: Okay. I'd like to ask you a little bit more, sticking on this drug. Actually, moving away, types of drugs to administration of drugs. We use a lot of sublingual morphine, Roxanol, the version that we have here. Does it get absorbed sublingually? Or is that an old wives' tale and it just drops down in the gut and you absorb it usually?
Lynn: It's a fabulous question. When I think about the most important drugs in hospice and palliative care, I always talk about my six pack which are the intensols. So, an Intensol is a high-concentrate oral solution of a medication. So, we have morphine and oxycodone 20 to one. We have methadone 10 to one. We have Haloperidol, we have Alprazolam, Prednisone, Dexamethasone. These are the drugs we use over and over again, and I see patients who are no longer cognitively-intact or they're unable to swallow, even if someone is completely unconscious, you can prop their body up 30 degrees and put up to 1 ml in the buccal cavity. So what happens? That's a great question. It depends on how water or fat-soluble the drug is.
For example, morphine is the most water-soluble of all the opioids. So only about 20% of that dose gets transmucosally-absorbed, but that's okay. Kind of hangs in the buccal cavity there and trickles down the throat very slowly just like they had swallowed it, which is fine, it's perfectly fine. You look at a drug like Fentanyl which is one of the most lipid-soluble drugs, probably closer to 50% of that drug gets absorbed transmucosally, which is why we have six transmucosal Fentanyl products on the market, because you have better absorption, because of the lipid solubility.
Eric: I got another question based on that. Because we're talking about lipids, Fentanyl transmucosal, and "Oh my God, they have no subcutaneous fat, we can't give it to them because it won't be absorbed." Thoughts on that statement.
Lynn: What we do know clinically and anecdotally, the people who are very wasted and cachectic, if you use transdermal fentanyl, they really don't seem to get the bang for the buck that you would expect. There's some data from Norwegian country, for example, why is this? We're not 100% sure. It could be that being a very fat soluble drug, if somebody is skin and bones, literally, can you find a little fat to apply the patch? That maybe part of it, it may be partly the drug. What does gets absorb kind of looks around and sees, it's got no where to hang, it says, "Well, I guess I'll get out of dodge now." But we also know, for example, that cancer patients, Fentanyl is pretty highly bound to albumin, and with cancer, the Fentanyl albumin combination goes into the extra vascular space and hangs, so it's not in the central circulation available to bind to the mu receptor in the central nervous system. So, I think there's a lot going on.
I think the biggest admonition that I would share is if you have someone on transdermal Fentanyl and you know in your heart this is just not working out, you don't go from 25 to 50 to 75 to 100 and say, "Well, this isn't working. I better take that 100 of my patch, and I know that's equivalent to 200 of oral morphine, I'm just going to switch to oral morphine." You should never do that. Go back to the last strength that worked, and if you can't find any strength that worked, pretend they're opioid-naïve and start from scratch.
Eric: I really liked the figure in your book too because in the chapter about fentanyl, it clearly shows, it's the micro circulation in the upper dermis, the micro circulation in the cutaneous area that matters. It's not that deep fat pad area where it's going to be absorbed.
Alex: So, it leads me to another question about fentanyl. I was taught that in setting a person who's on a Fentanyl patch who's getting a fever, you should rip off the patch because that Fentanyl is going to be absorbed more rapidly and not in a reliable way.
Lynn: Well, we do know if somebody has a fever about 104 or so, you can increase Fentanyl absorption by 30%. I think the biggest point to take home from that is, I took care of a gentleman who is a construction worker and had a concrete ceiling collapse on him and obliterate his right hip, so it was rebuilt but it left him with horrible pain. So, he was on transdermal Fentanyl for his pain which he insisted on putting on the hip because I could not disavow him of the notion that the drug didn't actually get sucked right in to his hip. But the third day, he ran out of steam, so he said, "Don't worry about it though. I just put a heating pad over it and it all works out." Well, I almost had a stroke. So, we do know that about 20% of people can't go 72 hours, so 20% of folks who got to go q48.
Eric: And I also loved in your book, you also talked about not just our cautions with putting fentanyl patches but taking them off and how to dispose them.
What do you teach people how to get rid of a fentanyl patch?
Lynn: Well, you're still supposed to give it a burial at sea, you're still supposed to hold the two together, sticky sides together and dispose it by flushing, although I know hospices are using different techniques, putting in a sharps container or something like that, but you got to be so careful because if a child or a small pet got a hold of a used transdermal fentanyl patch, it could be a fatal event.
Alex: Yeah. Speaking of the dosing- are we off fentanyl?
Eric: Yeah. We can move on.
Alex: I want to ask about oxycodone, OxyContin in particular, is it a BID drug or should it be a TID drug?
Lynn: I think OxyContin in the most part is a twice a day drug. I do want to caution people not to say BID. Even though you are saying BID, you are thinking q12, but don't forget in the hospital, if you say BID or TID, that's different from q8 to q12.
Lynn: But I think for most patients, it really is a twice a day drug. Whenever we're in that situation, it doesn't seem to be lasting. My first inclination is to try and increase the dose a little bit to see if I can maintain that q12 hour dosing but sometimes, you just can't and you have to go to q8. Same with MS Contin.
Eric: I'm going to go back to routes of administration now because we're jumping all over the place. I loved your comment on IM, oxymorons, you want to repeat that for us?
Lynn: Yes. An IM opioid is an oxymoron like jumbo shrimp or plastic silver ware. So, here, we're going to give you something to relieve the pain, but it's really going to hurt. So I don't think it's a good look
Eric: Do you ever use IM?
Lynn: We try very hard not to. Maybe once a year but maybe not even that often. I mean I think subcu is a beautiful route of administration and when you look at an equianalgesic chart, subcu and IV are close enough for government work given all the variables that affect that equianalgesic chart that I think subcu is a beautiful thing. The only thing to remember with subcu is don't exceed your volume. So, people say 1 milliliter an hour is the upper limit, certainly, you can push it to 2-2 and a half but you risk blowing your sight, but boy, any hospice nurse in the country will tell you if somebody blows their access in the middle of the night, sometimes, you can talk a family member through reestablishing subcu access and not even have to make a visit, but certainly not with IV.
Eric: So, which of the IV pain meds can we give subcu?
Lynn: Pretty much all of them.
Lynn: Yeah. We have pretty wide acceptance there. I worked with a resident to come up with a guide for parenteral administration of the top 50 drugs we use in hospice and palliative care, so I'd be happy to share that with you.
Eric: Oh, that'd be wonderful.
Alex: Any new opioids coming down the pipeline in development that we should be aware of that may be game-changers?
Lynn: I think it'll be interesting to see what happens with the kappa agonists. So stay tuned on that. I mean I've not heard of anything else that's like hold the presses but we'll see with the kappa agonists how that pans out.
Eric: All right. I got buprenorphine. Should we use it?
Lynn: You know, I think the United States is in some ways behind the rest of the world in using buprenorphine as an analgesic. Certainly, we have Butrans and we have Belbuca, they're both branded products, they're fairly expensive and there's a pretty significant level of discomfort among practitioners with buprenorphine. It is a partial agonist, but it's got a higher affinity for the mu receptor than the traditional opioid such as morphine and hydrocodone and oxycodone, for example. So, you got to be very careful.
If someone is on a traditional opioid, you can't just throw buprenorphine on top of it because you could throw the patient into withdrawal because the mu receptor is far more attracted to buprenorphine than the morphine oxycodone crew. But you could use any opioid and add it to buprenorphine. So, I do think we have some work there. I think it'd be nice, I heard that California just came out with a buprenorphine generic that we can start to use for pain that is very cost-effective. So, I think we're very close to that point and I would like to see us explore that.
Eric: And remind me, partial agonists, what does that mean again?
Lynn: It means it doesn't bind fully to the receptor. People say "Is there or idsn't there a ceiling effect in analgesia where if you're looking at an XY axis there, the more you give the drug, the more pain relief you get, you go up, up, up." But at a certain point, that line's going to level off that even if you continue to give more and more drug, you don't get any additional pain relief. But now, people are arguing that's a pretty high limit where you start to see that.
The good news is that buprenorphine is we'd probably see a bit less respiratory depression because of this pharmacologic property. My good friend, Dr. Mel Davis is a huge buprenorphine fan. He wrote a wonderful article about 12 things everybody should know about buprenorphine. It's worth a quick read. I think it's a very interesting molecule, and I think we are on a cusp of learning to use it more effectively in clinical practice. And an oldie but a goodie is Nalbuphine. And we are seeing people use Nalbuphine now for acute pain in the face of the IV morphine, hydromorphone, fentanyl shortage. So, it's something to learn.
Eric: So, do you think buprenorphine is going to be the new methadone where palces are going to like it if it's the cheap generic?
Lynn: I think there's some hope for using it more routinely in clinical practice. I'm disappointed that Levorphanol is so expensive because Levorphanol is very similar to methadone in terms of the properties that make methadone a favorable drug an NMDA-receptor antagonism, twice a day dosing, but it is a branded product right now and it's obscenely expensive. It will be nice if we have a generic formulation of that.
Alex: Speaking of methadone, I know our listeners and readers probably have a number of questions. Feel free to send them to us and maybe we'll have a second podcast, if you're willing, Lynn. This is so terrific, there's so many questions. Your book is fantastic and we hope that people go to that as a resource as well. We'll have a link to it on the blog associated with this podcast. But on the topic of methadone, you have a table in the book with six different methods of converting to or starting methadone. Is there a way to simplify it for our listeners and readers? Is there one method that you would elevate above the others?
Lynn: Sure. The methods that I have at that table are evidence-based methods. Some better than others. I just worked with a group where we came up with a physician paper looking at the American Pain Society Guidelines for the safe and effective use of methadone, and we applied that to hospice and palliative care and they came up with a very simple strategy that, frankly, was based more on safety than anything. Anybody on up to 60 milligrams of oral morphine a day, we consider along with opioid-naïve patients, and we would start anywhere from 2 to 5 or maybe 7 and a half milligrams a day if it's a pretty robust patient. If it's greater than 60 milligrams of oral morphine equivalent and they're under 65 years old, we do a 10 to one conversion. So, every 10 milligrams of oral morphine is 1 milligram of oral methadone. If they are on greater than 200 milligrams of oral morphine equivalent or they're over 65 years old, we do a 20 to 1 conversion. But we do recognize the discontinuous nature of this approach.
If you go to bed 64 years old and you wake up 65, I mean your organs didn't shut down automatically. So, I'm always asking nurses is the patient a young or an old 63 or a young or an old 67, and the nurses, boy, they are all over that. They completely get it and give me an accurate answer. So, I do think this is an approach that I've used this for a long time. It's a very safe way to go, and then, we're crazy generous with breakthrough and we don't use methadone for breakthrough. That's the important thing.
Eric: No methadone for breakthrough. Because I've heard some people advocate for that, which all seems very scary to me.
Lynn: Me to. So, I would much rather use a linear drug like morphine, for example. I'm not at all a fan of the method where they say, "Pick a dose of methadone like 5 milligrams and tell the patient take it every three hours as much as you need and then, in a week, we'll see how much you need," I think that's just looking for trouble. And another important part of that is no matter how much a patient is on, we never start at higher than 30, maybe 40 milligrams of oral methadone a day, and at home, I would not exceed 30. And increasing the dose of methadone, a total daily dose, if they're on less than 30 milligrams a day, we increase by no more than 5 milligrams in total per day and no sooner than five to seven days.
Eric: In total, not going from 5 TID to 10 ... or q8 hours.
Eric: You're going up by 2 milligrams with each dose?
Lynn: Yes. I'm a big fan of the 10 milligram per ml solution. And don't forget, you can go from three times a day to a larger dose twice a day and get the job done. Most of the time, we can get away with q12 hour dosing with methadone.
Eric: I got a question on bidirectionality, like this dose 20 to 1. Am I using this 20 to 1 ratio to go back?
Lynn: No. Not unless you're looking for trouble. There's only one paper that's really been looked at and that's by Walker, and they looked at switching off of methadone to oral morphine and it worked out to be 4.7. But again, I’m a card-carrying wennie, so what I do is triple it. I take the methadone dose, multiply it by three and that's your oral morphine dose. The reason I don't do 4.7 is it still going to take days to get that methadone out of the body.
Eric: Oh yeah.
Lynn: I'm conservative, I'm very generous with the breakthrough and patients get this. If you explain it to them, it's going to take five days to get the full effect, it's going to take five days to get the drug out of your body, hang with me, use the breakthrough, they get it and they're willing to be your partner in this.
Alex: When we're talking about generous with breakthrough and you said that several times, do you have a recommendation in terms of the total daily opioid dose? Because I was trained 10 to 20%. I know here at UCSF, they generally teach 5 to 15%, what is very generous with breakthrough?
Lynn: Well, the rule I use is 10 to 15%, but I do think sometimes, and often, I will recommend this, when our nurse calls me, I'll say so when you call the prescriber, here's what you should do. So, let's say somebody was on MS-Contin 30 q12 that's 60. Ten percent will be six, 15% would be nine, they're both goofy numbers. So often, I will ask the nurse to ask the prescriber for two orders, morphine 5 milligrams q2 prn moderate pain or morphine 10 milligrams q2 prn severe pain, gives the patient a little latitude there. And often, we'll have two strengths of breakthrough dosing available depending on what they're going to do. If they have idiopathic breakthrough pain, maybe the 5 milligrams will get the job done. But when the nurse comes to the wound care, maybe you need the 10 milligrams an hour before the nurse comes.
And I think if we are seeing a lot of idiopathic breakthrough pains, not incident pain, it's not end of dose deterioration, much of that is neuropathic. So, if you're seeing that a lot, maybe, that's the time also to add one of those adjuvant drugs.
Eric: All right. So, maybe for the breakthroughs, having one for moderate, one for severe especially those goofy numbers, they're also on a drip of morphine in the ICU, should we just put a big range one to 10, like knock yourself out nurses with going up on it over the next 10 hours?
Lynn: No. Oh my gosh. That's just looking for trouble there. I have a whole presentation on how to adjust drip. So, if you think about it, the three of us-
Eric: The whole chapter in the book of how to do it.
Lynn: I know.
Eric: With good figures too.
Lynn: It's an important point, and people mess this up a lot, is you know, hopefully, the three of us have a normal half life of morphine which is about two to three hours. So, if one of us was on a morphine infusion, it's going to take eight to 12 hours to get 87 to 90% of the way to steady state. So, you never want to write an order nurse to titrate to comfort because if you keep increasing and increasing it, you're doing some serious dose stacking and it's all going to hit steady state at 3 in the morning when the patient is asleep and nobody's really got eyes on the patient.
You can give the nurse the latitude to increase the bolus dose, the clinician dose that the nurse is in charge of because the nurse has to do a clinical assessment prior to giving that. But if you do have someone with advanced illness and on an continuous infusion of an opioid, the bolus dose that is the pca that the patient can give, there is a pretty wide range there, anywhere from 50 to even 150% of the hourly infusion. So, if somebody's on 5 milligrams an hour of IV morphine, let's just say, the bolus give you anywhere from 2 and a half to 7 and a half milligrams. I know that sounds a little crazy, but you would only use that crazy dose if you had cut way, way, way back on the continuous infusion because you're really felt like you're kind of shooting in the dark.
We often have that in a hospice patient. They're admitted to us. They're on some crazy regimen of maybe transdermal fentanyl and they're cachectic and they're on MS-Contin and they're using Vicodin out the kazoo, we'll put him in patient, we'll add it all together but then, we cut way back on the continuous infusion, but we're generous with the bolus and we can sort that out within about 12 to 18-24 hours. So, that's, again conservative with the standing and generous with the breakthrough.
Alex: That's terrific. Okay, I got a question here. When we're talking about intensols, we're talking about liquid concentrations of opioids. Eric and I have wanted to do a taste test about these for a long time. Eric knows that I'm going for this, because we’ve heard from our patients that some of these don't taste very good.
Alex: But we've been unable to figure out how to do, actually do a taste test ethically and practically.
Eric: Without being thrown in jail.
Alex: Right, right. It would be swish and spit, just to be clear, we just want to taste. But what do you know about the taste of these different liquid opioid preparations?
Lynn: I know several things. I know that the opioid liquids all are very, very bitter and research has shown that the best flavors to mask that bitter are things like raspberry or tutti frutti, and pharmacists routinely have a whole kit called FlavoRX, other brands available too where they can flavor like antibiotics for kids, they can flavor these opioids so it's really important to ask that because often patients will say, "I'm not taking this stuff because it tastes so horrible," so that is an important consideration.
Compounding pharmacists are worth their weight in gold. They often do compounding even for pets. They'll have tuna fish flavor for cats and chicken liver flavor for the dogs. They really help you quite a bit in this area.
Alex: That's terrific.
Eric: Well, I think that's fabulous. There is a lot more to learn from Lynn, so she has a great book again, Demystifying Opioid Conversion Calculations. Lynn, where can we buy this book?
Lynn: Either on Amazon or ASHP.org which is the publisher, the American Society of Health-Systems Pharmacists.
Eric: And we will have a link to it on our GeriPal podcast. Lynn, again, a huge thank you for coming on.
Alex: Huge thank you.
Eric: We have a ton more questions for you so we'd love to have you on. We haven't even talked about things like PCAs and all that other fun stuff, but I think now is the time to end. Alex, would you like to sing a little bit more.
Eric: That sounds like kappa-agonist is going to be our new drug.
Alex: That's right.
Lynn: We’ll need a song for that too.
Eric: Or buprenorphine, we'll see. It's going to be a race. I want to thank all of our listeners for joining us this week. We will look forward to our next podcast next week, it's with Guy Micco. Do us a favor, if you’re listening to this podcast, take a very brief second and rate us on your favorite podcasting software whether it be iTunes or anything else. Give us a quick shout out. And Lynn, a very big thank you for joining us.
Alex: Thank you so much, Lynn.
Lynn: Thank you both. Take care. Bye-bye.