If there's something long-acting that targets multiple receptors and has a variable equianalgesic dose ratio in your neighborhood, who you gonna call?
Eduardo Bruera (@edubru) and Kevin Madden (@madden_kevin), of MD Anderson Cancer Center!
Get ready for chills and thrills as they take Sarah and Dan on a haunted tour of that spooky old opioid, methadone, and bust some of the myths about dosing, QT prolongation, and more.
If there's something long-acting that targets multiple receptors and has a variable equianalgesic dose ratio in your neighborhood, who you gonna call?
Eduardo Bruera (@edubru) and Kevin Madden (@madden_kevin), of MD Anderson Cancer Center!
Get ready for chills and thrills as they take Sarah and Dan on a haunted tour of that spooky old opioid, methadone, and bust some of the myths about dosing, QT prolongation, and more.
This is Dan.
Sarah Dabagh:And this is Sarah.
Daniel Eison:And we'd like to welcome you to PediPal.
Sarah Dabagh:A new podcast about all things pediatric palliative care.
Daniel Eison:The views in this podcast are ours alone and do not represent our respective organizations, and they do not constitute medical advice.
Sarah Dabagh:If you're here for spook-tacular PediPal Halloween episode, keep listening because you might be scared of some of the information we're about to share, but we don't think you should be.
Daniel Eison:I'm really excited that we are getting an episode out now in October, especially near the end of October, because as a palliative care doctor, I have been getting all of my costuming and decorating ready well ahead of time and not leaving it to the last minute, because I understand the importance of advance scare planning.
Sarah Dabagh:Ah, pretty good.
Daniel Eison:And I made sure to have a ghouls of care conversation.
Sarah Dabagh:Oh, that's pretty good, too. Not excellent! [laughter]
Daniel Eison: Okay, but I came up with more stuff. Okay, so this episode is about that spine-tingling drug that we are all scared of:methadone. And it's Halloween, so I was workshopping a bunch of potential titles for the episode.
Sarah Dabagh:The problem with methadone is if we try and do like "metha-ween" like Halloween, it just sounds like methamphetamines.
Daniel Eison:Yeah, no, no, no, mine are much better than that. [laughter] So like I said, I didn't sleep last night. I spent a lot of time coming up with titles. So listen, Okay, what about"Metha-dawn of the Dead?"
Sarah Dabagh:Pretty good.
Daniel Eison:Pretty good? Okay, wait I got more.
Sarah Dabagh:It's a little long. But it's pretty good.
Daniel Eison: Oh, don't worry. They get longer. Okay, okay:"Analgesic Activity."
Sarah Dabagh:In context, yes. Out of context. No, You're right, you're right. Okay. "Five to Seven Days Later." That's pretty good!
Daniel Eison: It's a bit of a thinker. Okay. Okay. I got more:"The Blair Switch to Another Opioid Project."
Sarah Dabagh:I hope we're recording these, because these are all... decent. [laughter] "Nightmare on NMDA Street."
Daniel Eison:Yes! That's great!
Sarah Dabagh:Like it's... like we can really make these terrible.
Daniel Eison:Oh, wait, I did. How about "Get Out... your little calipers to measure the QT interval on EKG?"
Sarah Dabagh:That's that's even longer. Dan, there's-- I think there's only so much our listeners can take.
Daniel Eison: One more, one more, one more:"Carrie... an opioid conversion table because methadone is tricky to convert."
Sarah Dabagh:Alright, Nightmare on Podcast Recording Street. [laughter] You've gone too far. So why don't we get into the episode. We have two amazing guests who are here to talk a little bit about the history that they've had with methadone, and how they came to love it and not be scared of it.
Kevin Madden:Hello, my name is Kevin Madden, and I work at MD Anderson Cancer Center in Houston, Texas.
Eduardo Bruera:Hello, my name is Eduardo Bruera, and I'm the Chair of Palliative Care, Rehabilitation and Integrative Medicine at MD Anderson.
Sarah Dabagh:What makes methadone such a good pain medication?
Kevin Madden:I think methadone is an extraordinary medication, especially for pediatric palliative care, even outside of oncology, simply because it's the only long-acting opioid that comes as a liquid. So when I was first introduced to it was during fellowship, and we would use it a lot in our patients who have gastrostomy tubes who don't have the ability to swallow. And it seemed to be kind morphine or long-acting oxycodone was a lot of end-of-dose failure. So the patient's telling us really around eight, nine, ten, eleven hours, I'm really starting to feel this wear off a bit. Methadone has such an extraordinary long half life, that, to me, I tell families that it gives them flexibility in living their lives. They don't need to be tied to 7am and 7pm, if they are out doing things,
Eduardo Bruera:I completely agree. And basically, what brought methadone? Methadone had a bad start, really. And the reason for the bad start was that in studies done in the late 70s, and early 80s, there was this misconception that the eqianalgesic dose ratio, when you compare that with other opioid agonists, was almost one-to-one. And there were even randomized control trials. one done in the
Even better than that, it's a Lamborghini that costs $15 a month. [laughter] I'm curious, you know, it sounds like there are so many advantages, as you're saying:it's flexible, and it's potent, and it targets so many different receptors. At the same time, though, there are some significant disadvantages that you both alluded to, when you pitch this to families, or when you were first picking up potent methadone became. And that was, on one hand, the extraordinary advantage of methadone. On the other hand, that is what made methadone potentially dangerous when it was used by someone who did not have experience. And so what we used to say as an example, and that might help our colleagues: All the other opiates are little Toyotas and Hondas. You get out of one, you go into another, no
Kevin Madden:The answer is absolutely yes. We get back from pharmacists, we get pushback from physicians, we get pushback from families, everyone, and all for different reasons. I became interested in methadone because of that sort of soft pushback that I got, which was hard to argue with. Historically, IV methadone has been associated with a long QT, but they found out that it's really just the Wolff-Parkinson-White, and went to Texas Children's electrophysiology. And I thought, this person has to know exactly what what long QT is, this is their life. And so I asked my daughter's doctor, I said, "What is-- What do you think is a long QT? Because we're getting a lot of pushback nextdoor at MD Anderson." And she said, "Oh, well, you know, it's really interesting. There's one guy at Mayo, after which it becomes exponential. And so you know, a 10 or 20 millisecond increase from 500 to 520 puts you at a much higher risk than 460 to 480. So people usually will ask, "Well, what do you do based on Dr. Ackerman?" whose the cardiologist from Mayo who develops all these, "What do you actually do at 460, 470, 480?" Considering the difficulty in titrating off methadone onto another long acting medication that we have. Then it's very hard. They're like, "Wow, that sounds like the best choice." And then when you tell them the name, even if there's hesitancy, which I get, it's hard for them to go against a recommendation of what might be best for their child.
Sarah Dabagh:It's funny, I actually take the opposite strategy. Sometimes I will tell people the name. I'll say, "You've probably heard about this for this reason." And I'll say "We originally started using the medication for that reason, for addiction. And the reason it works so well for that is because it's so steady in your body, and we want the pain control to be as steady as possible.
Kevin Madden:So I feel like even though methadone is an extraordinary drug, I think, as Dr. Bruera was talking about, what I've actually found now, seven years in, is how you discuss pain and frame pain psychologically has a much bigger difference than any other medication. And so we have a pretty structured way that we go through sort of the day-one talk on pain management, and we address what the parents that report that their children are starting to feel better very quickly, within one to two days. And then of course, I tell them, well, more is to come. This is just the beginning they'll they'll feel even better in a few more days. It's obviously not like any other opioid. We have to counsel parents a lot about that, because they've become sort of accustomed to-- especially if they through the same pathway. We decided to get a methadone level which he had no idea what that even meant, because we don't check methadone levels. But what we decided to do since he was admitted and everything was normal, we hypothesized that CBD was blocking the metabolism of methadone, the level went higher, the kid got really sleepy. We continued him on the same dose of methadone. We told him
Sarah Dabagh:Do you start it as a first-line drug? And how fast do you up-titrate?
Kevin Madden:We did this study where we established what we call the standard of care, so every person started on methadone followed the exact same protocol. So we started with 0.1 milligrams per kilogram BID, we got a baseline ECG, we [inaudible] all their symptoms, at baseline, follow-up one, and follow-up two. What we found was between baseline and follow-up one, the QTc went up slightly,
Daniel Eison:How different is this for the adult world?
Eduardo Bruera:There are good studies in the adult population, including a randomized controlled trial we did with morphine, showing that you can start patients with methadone as your first line opioid, it's a good option to other, you know, opioid agonists in that category. So I would say that, as Kevin was saying, pain is the most important parameter. If the patient is having considerable
Kevin Madden:One time I do get anxious is when we convert from oral to IV, the bioavailability is extraordinary, like 80 to 90% in the stomach, not even in the intestine. And so when we convert, we don't convert, we go one-to-one, because it just doesn't make much sense to multiply your oral dose by point-eight or point-nine, because that's the real conversion. And I think it does two things:
Eduardo Bruera:Initially, the original studies also made a little bit of an error in that opioid ratio from oral to IV, they somehow produced some-- I don't know how much-- data suggesting that you have to double the dose when you went from IV to PO. But we've done some work, and others later, suggesting exactly what Kevin said: the bioavailability PO is very high, it's around 80%. And so
Sarah Dabagh:Do you have a theoretical maximum or a number which makes you nervous?
Eduardo Bruera:I think through that literature, we've learned a little bit of the titration of these agents, and it probably can be titrated into much higher doses for nociception than it is titrated usually, it's just a matter of making sure that the escalation of dose follows the usual rules of any other opioid. Once the patient is stable on methadone, the titration would follow the 20 to 30%
Kevin Madden:Our institution has a preponderance of children with solid tumors compared to leukemias and lymphomas, so tremendous amounts of pain. But the fascinating thing that I've been able to sort of pick up is, in six weeks, if they say they're hurting more, it's not because they're tolerant, it's likely because their disease is starting to progress at a level that other people may not
Eduardo Bruera:I think what Kevin alluded to that I think is of great importance is it doesn't work that we say no, this is not a problem. When you have pain, you're not going to get any opioid use disorder or non-medical opioid use, because we're using it for pain. Patients are smarter than that. And they will figure out that that doesn't make a lot of sense, because a lot of the people who got
Daniel Eison:The things you brought up there-- addressing fears, setting clear expectations from the start, using our words thoughtfully-- these are the core principles of palliative care, right? And these are important things. And so I think it's great that you're bringing them into conversation with prescribing a medication like methadone. It's not about the medication being particularly
Sarah Dabagh:I wanted to touch on, Kevin, you mentioned the bimodal distribution, when you're talking about sort of QTc's and people's opinions on what a long QT is. But I find that I see a bimodal distribution on people checking EKGs, either once a week or never at all; I see a bimodal distribution on people who use methadone as a first line pain medication, and on people who hesitate and wait
Kevin Madden:I think a lot of the not liking it is based in fear, rooted in a lot of misconceptions about the medication, even among providers, right? We all-- I remember going through medical school, I remember going through residency, I remember being a fellow in critical care, and I remember being told we can only give intravenous methadone in the intensive care unit. So the patient has
Daniel Eison:A lot of the things we've talked about today, and I'm sure this is going through Sarah's mind too, are reminded me so much of our episode about ketamine, when we talked about how afraid patients and families can be and how delicate or even frightened institutions are of ketamine. And our guests on that episode, were saying it's really such a safe medication. If I can read between the
Kevin Madden:I think I'm mostly an advocate for my patients more than a drug. And so if I see a drug that I think is superior to others, whatever it is-- for pain, nausea, vomiting, diarrhea, constipation, dyspnea, insomnia-- I'm going to use it or recommended, at least. So I think mostly, as I said earlier, the purpose of pain control is to maximize functionality in your activities of
Sarah Dabagh:So Dan, what are our take home points from this episode?
Daniel Eison:My take home point is that I am going to be even more... what's the word I'm looking for?
Sarah Dabagh:An enthusiast? An advocate?
Daniel Eison:No, I, yeah, all those are true, but I'm going to be even more annoying to people who tell me I need to get an EKG for methadone. Based on the evidence, our guests presented, I think we go way overboard for all of these patients.
Sarah Dabagh:And you know, I really appreciated what Kevin had to say about the doses he starts and how often he feels like he needs to titrate, too. I feel like when I look at a methadone conversion table, and I do the math, no matter where I start, the table is designed to get me to five mg's BID, it's designed to get me there, no matter what my OME is to start! But I really appreciated the
Daniel Eison: Absolutely. Just the idea that, yes, you have to be careful with methadone, but we're careful with everything we do:all of the medications and all of the conversations and all of the interactions. And so methadone isn't really all that different. We just have to think about slightly different cautions, and different things.
Sarah Dabagh:And don't be so cautious that you don't use it, and don't be so cautious that you start as I loved Dr. Bruera, say homeopathic dose.
Daniel Eison:Yes, exactly. I really like his Lamborghini metaphor, too. That stuck with me for sure. I think I only have one other question for you.
Sarah Dabagh:Oh, is it a Halloween question?
Daniel Eison:No...
Sarah Dabagh:Is it a pun?
Daniel Eison:No...
Sarah Dabagh:Is it?
Daniel Eison:Maybe... Um, what do you say to a vampire who is on too much Dilaudid and gets allodynia?
Sarah Dabagh:I don't know.
Daniel Eison:Have a happy 'allo-wean.
Sarah Dabagh:Oh, that's not good. Thanks for listening. Our theme song is provided by Kevin McLeod. You can follow us on Twitter where our username is @PediPal. You can find the notes for this podcast and all of our episodes on pedipal.org. If you'd like to submit thoughts, objections or ideas for future episodes, please reach out via the email on our website. This has been PediPal, we'll see you next month. Two amazing guests who are here to talk a little bit about the history that they've had with methadone and how they came to love it and not be scared of it. So this is more of a Valentine's Day episode disguised as a Halloween episode with lots of QTs involved.
Daniel Eison:No! That was-- [laughter] that was way worse than any of mine!
Sarah Dabagh:Okay, don't put that in!
Daniel Eison:No, I'm gonna put that in! It was so good!