Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. Narrator - ? 00:11 This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Speaker 1 00:31 Welcome to HelixTalk. Episode 64 I'm your co host, Dr. Kane. Speaker 2 00:35 I'm Dr. Schuman, and I'm Dr. Patel, and today I'm excited that we're going to be talking about something that I'm really, really passionate about, that's migraine management. So name of this episode, with apologies to the band, The Clash is, should I stay or should ergot and so what we want to do here is go through and talk about the history of ergotamine and its clinical use, something that's really fascinating as it's evolved over time, and they can see it as this important milestone in terms of what we know, not just about migraine management, but about overall, what we know about our alpha and beta receptor pharmacology. Speaker 1 01:08 And I think what's kind of cool about the ergots is kind of how they came about, being a medication to begin with. You know, sometimes we think of medications that are built in a lab and a chemical synthesis kind of standpoint, but these actually have a neat history to them, Speaker 3 01:22 yeah, and now, especially now that we don't get to see a lot of ergotamine medication prescriptions, but then again, it's good to know where they came from and what was its use, and what can we do with them still being in the market. Speaker 2 01:36 All right, so just to start with first, what in the world is this and what is maybe, what is some of that historical significance? So what it is, it's a product that was formed from a fungus known as claviceps Purpurea, and it grows on rye plants in particular. Now they noted it was individuals who had eaten the contaminated plants. They turn a purple color and it may have been associated with witchcraft — possibly the Salem witch trials. One thought is that perhaps individuals had consumed some of this ergot which had led to some of this confusion about some of the psychosis, or some of these unusual things they saw flying around them. And these when they thought were witches, it may have been this ergotism, again, other than hallucinations, other things that could potentially lead to 1000s of deaths through a couple different kinds of this ergotism. So there's a gangrenous ergotism, something called St. Anthony's Fire, or "holy fire", specifically for this burning pain that's associated with it — it does not sound like a fun thing. Speaker 1 02:33 And of course, that burning pain is caused by vasoconstriction, so your tissues don't get enough blood flow, and that essentially leads to things like dry rot and loss of limb because of a lack of blood flow. Speaker 3 02:45 And the other effect of the ergotism were more on convulsive ergotism that included things such as altered mental status, rigid limbs, muscle spasms, diarrhea and seizures. And if you recall or have listened to our previous episode, it sounds very much similar to the serotonin syndrome type Speaker 2 03:04 episode, right? So they talked about with that these medications are not generally believed to cause serotonin syndrome. So if you do recognize these symptoms, be thinking about the differential, which could be, in rare cases, something like an ergotism, that there are overlaps in some of the presentation of these different things. Speaker 3 03:20 And the history seems very similar to how the warfarin discovery had occurred, but out of quality control in farming industry, and you know, looking at the inspection of the crops, and that has resulted into decreased rates of this type of organism in the common public out there, including any type of convulsive organism that was nowhere to be in that in 1920 28 or so, so Speaker 1 03:45 Dr. Sherman, help me understand here, so at least with warfarin, we had cows that ate these Clover patches and bled out. We said, Hey, that looks like a medication that we can use to thin your blood with. How did we go? Then, from Hey, this ride gets moldy, you ingest it, and then you either convulse or your limbs fall off. How did we decide that that was a good thing for our patients? Speaker 2 04:06 What's really interesting is, even before it was used for migraines, ergot itself was used to assess in obstetrics clinics, they found that it constricted uterine blood vessels and thus could even decrease bleeding when you use around childbirth. Even as early as 1100 BC in China, they were using this fairly commonly, and then it was introduced to the US, really in about 1808, and it's really cool as they track the first references to it. There was an Italian medical journal, but really a gentleman by the name of Dr. Edward Woakes. He was a neurologist in England, and really was studying neuralgia itself and some facial paresthesias. He reported that there was this damage to the nerve fibers, either due to a trauma or due to a type of infection, and then there was a loss of sympathetic tone. And after that loss of sympathetic tone, you'd see vasodilation and fluid effusion, and therefore you'd see pain, sensation, sensation. So then what he thought is okay, if this loss of tone leads. To pain, maybe then vasoconstriction or increase in sympathetic tone. We didn't call it sympathetic, as they didn't know that was at the time, but that could lead to vasoconstriction and then treat the source of the pain. Speaker 3 05:10 So that sounds very much similar to the pathophysiology of how migraine comes about. We believe that that's related to the vasodilation. So vasoconstrictors can help relieve some of that pain, right? Speaker 2 05:21 That's what's so interesting, is, again, this is before they even really knew they were what, what it was. So they had five patients with what he called neuralgia, who responded to this ergot administration. One of them was a 35 year old who said, I have this recurrent, episodic nerve pain in my right temple. It comes on. It's really bad. That's, you know, now, we would call a migraine there. There was a lot of overlap, not really being sure what it was. And then by 1878 it was included in textbooks as an acceptable treatment for migraines, both as an abortive and a prophylactic agent. It was a more evidence-based alternative. So some other delightful things they used at the time included chloroform, arsenic, and mercury. So again, other delightful treatments which you could try. Speaker 3 06:03 So I'm assuming there were no such things at medical lawsuits in that time of practice, either, not Speaker 2 06:08 so much. If you could, apparently get your hands on it. It was, it was worth trying. Speaker 1 06:12 So this seems like kind of one of those very old medications that clearly has been around a long time. When was the first time that we actually realized that we're actually giving these patients what we now call ergotamine. Speaker 2 06:23 Means, Well, the interesting part is, in 1918 a man named Arthur Stoll was able to isolate out the out of the Ergo find the active ingredient in something called ergotamine. Structurally, it's actually similar to tryptophan, which we know is serotonergic in nature. And so again, that should give our listeners an idea about the mechanism of action. And then, in total, there are over 80 different ergot alkaloids. Really, there are three different classes: clavines, peptides, and lysergic acid amides. Speaker 1 06:49 So one kind of interesting thing about those lysergic acid amides is that LSD comes from this class, which links back to the idea of hallucinogenic properties. These compounds hit different serotonin receptors — LSD hits 5‑HT2 receptors — and ergot derivatives are purported to hit a number of different receptors. Speaker 3 07:18 so most of these ad identified alkaloids. I mean, if you put it in a more pharmacologic nature, how do they actually work? What is the effect of these agents? Speaker 2 07:29 So this is one that we're not 100% sure exactly what it does, but as we learn more about agonists, we believe it produces partial agonism/functional antagonism of adrenergic, serotonergic, and dopaminergic receptors. And the thing is, the affinities between the different receptors is going to depend upon the particular agent, so whether it's LSD or ergotamine or even some of the newer medications, as well as the synthetics. Speaker 1 07:57 So just to clarify, then, what you're saying is that they're partial agonist. But because your body makes these compounds, like serotonin as an example, functionally, it ends up decreasing the amount. So functionally, it's an antagonist, even though, on a receptor level, it's a partial agonist. Speaker 2 08:14 For some receptors, again, that's going to depend upon the agent — it may be more agonist at serotonergic receptors in some cases. It's kind of, it all depends upon the affinity of the individual agent. But what's really neat is that much of what we know about the entire sympathetic nervous system, this is my own personal geek out alert is that what we know about the sympathetic nervous system really was first hinted at from this from these medications. We give you this medication, and we think it causes, you know, blood to decrease, so we think it vasoconstricts. So what must be in it? This must be the sympathetic system that we're eating. So a lot of what we know was found out decades and decades and decades later about, you know, what we commonly teach in all of our pharmacology and physiology classes was really started here with ergotamine. Speaker 3 08:57 So we're talking about ergotamine and its treatment for migraine, but we do know triptans are also used for migraine. So when you compare the ergotamines with triptans, how are they similar — or are they different? Speaker 2 09:11 Ergotamine is thought to act at 5‑HT1B/1D receptors, similar to triptans, but it is not selective. It also has activity at 5‑HT2 receptors, dopaminergic D2 receptors and alpha‑adrenergic receptors, and it seems to have a longer constricting effect on arteries than on veins. So that's a reason why we need to watch the frequency of dosing, as we'll talk about a little bit later. So are these Speaker 1 09:41 medications actually FDA approved, or these? Are they kind of what we've seen historically, and that led to things like tryptans? Speaker 2 09:49 So these are both. So they actually are FDA approved, both for treating and preventing migraines and cluster headaches. And again, it works via vasoconstriction, decreasing neuroinflammation. There are a number of dosage forms (oral and rectal), but a key point is that ergotamine has low oral bioavailability, so choose the route of administration accordingly. Speaker 3 10:13 So some of the common side effects, if we review them, they seem to be very similar to the episodes of ergotism that we talked about earlier, which can include things such as nausea and vomiting because of the hitting of the serotonin receptors, diarrhea, muscle weakness, paresthesia and chest tightness. We know that prolonged use of ergots or got means can lead to development of fibrosis in the heart valve, and that can lead to things such as arrhythmias, murmurs, abnormal conduction of the impulses in the heart, right? Speaker 2 10:47 And so first, so the paresthesia. That's something when I started teaching migraine, what you think that's kind of a weird side effect to have with this migraine Med, but if you think that it is slowing the conduction of these nerve signals and pain, then it kind of makes sense. You get a paresthesia. But the big thing is — it's contraindicated in disease states where vasoconstriction is dangerous: peripheral vascular disease, coronary artery disease, uncontrolled hypertension, liver disease, renal disease, or anywhere ischemia is a concern. And of note, so are the tryptans as well. So this is something that applies, really, to both classes or both types of medications. Speaker 1 11:24 So then, just to put that kind of in the clinical context, if we have a patient who has a migraine and is also extremely hypertensive, maybe giving either a tryptan or an ergot doesn't make any sense, right? Speaker 2 11:36 Yeah — at the very least we teach in lecture to get cardiology on board and have a clear risk‑versus‑benefit discussion, rather than assuming one option is acceptable. Everyone needs to weigh in: what is the risk, what alternatives exist, and how concerned should we be from a cardiac standpoint? Speaker 3 11:58 are we? And besides, you know, considering the cardiac risk and stuff, what we need to know is some multi migraines and some people can be accompanied with things such as nausea and vomiting. So if they're already experiencing migraines along with nausea and vomiting, then probably ergots is not the best choice, because it can worsen the problem Unknown Speaker 12:15 potentially. Yeah, that's something we need to consider as well. Speaker 1 12:18 So within this class of ergot says, Do we just have ergotamine, or there are other compounds that we've kind of come up with within that drug class? Speaker 2 12:26 The next one that came out was dihydroergotamine (DHE), a semisynthetic derivative. It's available in a whole host of dosage forms — intranasal, intramuscular, IV and subcutaneous — given inconsistent GI absorption. Really, just like with ergotamine, there's inconsistent GI absorption, so oral dosing is unreliable. DHE appears to have somewhat greater alpha‑receptor affinity than ergotamine too, and a slower onset of action compared with triptans. So one important counseling point with these medications, especially DHE, is to set expectations about time to effect. So if you're going to consider this as an abortive, you're not necessarily going to see that immediate response. And that was also something that was noted in some of the trials if you're simply and maybe some of the heterogeneity in these studies is if you're giving the medication and then saying, all right, we're going to check in 10 minutes and see how your migraine is and saying, oh, it's gone. Medicine must have failed. Well, if you wait an hour, and some of these studies they did, you would find that it had an equal advocacy. Speaker 1 13:33 So it sounds like this is very similar to ergotamine, but maybe some downsides in terms of its onset of action, things like that. Are there any upsides besides the dosage forms that are available for dhe? Speaker 2 13:45 Well, one nice thing, though, is, and I'll kind of kind of get into this a little bit later, is it, since it does have a slow onset, there's also a slow offset of action too. And so potentially, if you have someone who does have recurrent migraines, this can be kind of in the middle between an abortive and technically, a little bit of a prophylactic as well. And again, owing to that slow dissociation of receptors. And then it is FDA approved, again, for acute treatment of migraine and cluster headaches. And with with that slow offset, some evidence in migraine prevention side effects, though contraindications are similar, maybe a lower risk of that, ergotism from some of these synthetics, for example. Speaker 3 14:24 So as far as the clinical efficacy of the ergots or ergotamines — or even the semisynthetic versions like dihydroergotamine — what do we know about the clinical trials? What's the evidence? Speaker 2 14:35 So the cool thing is they've done studies dating as far back as the 1930s showing high efficacy. More recent studies most often compared ergot derivatives head‑to‑head with triptans; triptans frequently performed better in acute migraine trials, although ergot derivatives have held their own in some comparisons. Speaker 1 15:04 So highly effective. Of course, when we think about clinical trials we consider both efficacy and safety — because these agents hit many receptors in addition to 5‑HT1B/1D, they carry additional side effects that triptans may not. Speaker 2 15:22 One important safety issue is medication‑overuse headache. Overuse of ergotamine can trigger a cycle of vasoconstriction followed by rebound vasodilation and recurrent headaches — a never‑ending cycle that requires drug withdrawal to resolve. Advise patients to limit use (e.g., <10 days/month or no more than twice weekly) and consider alternatives when headaches are frequent. Speaker 3 16:10 So I'm assuming there's some sort of a limitation on how often patient can use it, in a month and a week, what would be that recommendation? Speaker 2 16:17 And a lot of the time they'll make recommendations as far as per month. So that's one of the ones, for example, with a lot of the trick, Dan is saying, you know, use, for example, in this case, use normally 10 times a month. But there's a number of some papers recently saying, well, more based upon the pharmacodynamics, really, maybe a better way of looking at is more about two times a week. Maybe it's not dosing per month, but how spread out it is within so therefore, you know, if you said, Well, I'm gonna use 10 days straight within a month and none at all the rest of the month. That doesn't suddenly make it less of a problem. So really, it's more about limiting to two days a week and that kind of which should still keep you within that less than 10 a month frame. But it's more about how spread out each dose is, rather than the Speaker 3 16:56 cumulative effect within a month. And I feel like if they need to use it that many times in the month that they definitely need to see the doctor and evaluate any other pathophysiology going behind, consider other options for the treatment. Speaker 2 17:09 Certainly that's where you look at prophylactics, as well as identifying the risk factors. And then Dr. Kane, you know you're one thing to note that's kind of in your wheelhouse is cardiovascular side effects. With this one, it seems to be the significantly greater risk of these effects compared to tryptans. And in fact, many early concerns about ischemia started with the ergot alkaloids; when we review the data there is risk — probably greater with ergotamines than with triptans — so clinicians should be cautious. Speaker 1 17:41 So you're saying is for is for either the ergots or with the triptans, they both carry a risk of cardiovascular complications from that vasoconstriction, but probably the ergots are a little bit worse, but both are still not great, right? For a hypertensive CAD type Speaker 2 17:56 patient again, and that's where it's all hands on deck for a clinical plan — reach out to cardiology, primary care, neurology and pharmacy to ensure the patient's best interests are addressed. Speaker 1 18:12 So we covered initial efficacy versus basically whatever they had in the 1930s we covered the safety. And as you mentioned, Dr. Sherman, you said that when the triptans came out, the ergots were a common comparator. Sometimes, when this happens, we have these non inferiority studies that are simply designed to show that they're just as good. Sometimes we do have superiority studies to demonstrate that this new drug class is better than what has been done in the past. How were the trials rolled out for the triptans, and especially in comparison to the ergots? Some of Speaker 2 18:45 these were actual head to head studies, where they did find that the triptans, again, sometimes they held their own. But a number of these studies, they were inferior. So they compared, for example, sumatriptan 100 mg, rizatriptan 10 mg, and eletriptan 40 mg versus ergotamine; in many head‑to‑head trials triptans were superior acutely. So in those cases, aha, this drug, the ergonomics aren't as effective. But again, recurrence rates were actually lower with ergotamine likely due to the fact, again, mentioned before, that since it binds to the receptor, more slowly, lose the receptor more slowly, the times of the next dose was a little bit less so, and so that if that's the case, you know that may be a reasonable medication if you do continue to have these recurrent migraines, and you can handle the fact that maybe a little bit of a slower onset. Speaker 3 19:32 Do you think some of the effect was also due to the fact that ergotamines are not really readily bioavailable if taken orally, so maybe triptans have different bioavailability compared with ergotamines? If comparable dosage forms had been used, the effect might have differed. Speaker 2 19:52 That's a great point. Dr. Patel, individuals that have reviewed these studies and looked back, especially at those providers that believe strongly in the use of ergot and. And said that, yes, because of the bioavailability, maybe we weren't comparing apples to apples here in terms of our dose, and maybe we were using essentially a too low a dose. So if we were to use an ergotamine with better bioavailability (rectal, higher oral dose, or intramuscular/subcutaneous routes), maybe you would get a better response in the study. However, the other flip side is you would probably see higher side‑effect rates and more dropouts. So we kind of take the good with the bad. But it does come down to ergotamines. Speaker 1 20:30 think also you have to think about from a patient point of view, they're not going to be that concerned about, you know, bioavailability and things like that. They're going to say, Okay, I want to take an oral medication. I don't want to mess around with a rectal suppository. You know, from that standpoint, they're going to just care about what they would actually do in their own practice, in terms of two oral medications and comparing those, for example. Speaker 2 20:52 So then that's where one thing to kind of look at is: does all this information still justify their retention on the market? When triptans came out they largely supplanted use of older ergot products. Do we have a need? Is this one that we're should they kind of go extinct and go out, you know, move out of the way of these newer, better medications, perhaps. But again, given the fact that for some, you know recurrent, you know, frequent migraines, as well as maybe those who have failed something like a trip to perhaps it is considerable to use one of these medications. One analogy is the tricyclic antidepressants: older, 'dirty' agents (e.g., TCAs) were largely supplanted by SSRIs/SNRIs — they are safer, but not always more effective. So maybe then we have to dust off the old medication of these recurrent cases, as long as we monitor carefully for the side effects. And I think it's the same way here. So probably those with frequent recurrent migraines, it's worth considering an ergotamine. The big thing is to like with a consider the route of administration. So rectal routes probably the best if we're going to use them, certainly less convenient, but probably the more Speaker 1 22:04 effective one. And to your point earlier, Dr. Patel, you said, for a patient who is having very frequent migraines, really, that probably prompts a different discussion in terms of prophylactic regimens, like Dr. Schuman mentioned. So certainly, you know this is going to be in this very, very small niche market of migraine treatment, given that if someone is so poorly controlled on triptan, for example, they probably need to be thinking about more chronic therapies to prevent migraines, as opposed to always reaching for their ergot as a triptan failure or, Speaker 3 22:37 yeah, using maybe better bioavailable dosage form, but then exposing patients to higher side effects. Speaker 2 22:43 What's interesting is that there's actually an inhaled form of dihydrogotamine, which is trying to get on the market. I was kind of following. It's been kind of right on the fringes for really, the last few years. And there's also a nasal spray that has been around since 1997, although in this case the efficacy is somewhat unimpressive — inferior to subcutaneous and intranasal sumatriptan. So again, we're mostly looking at some of those direct, you know, subcutaneous or rectal routes. Speaker 3 23:10 So do we still use ergotamines in practice? I mean, you have, you see a lot of patients at the VA — what's your experience? Speaker 2 23:18 Uncommonly — again, because of side effects — most of the time when we're starting somebody on treatment we use one of the newer medications. Maybe we use NSAIDs or combination OTC products — acetaminophen, aspirin, or caffeine — and some of those combination products every now and then; occasionally a patient does very well on them. We continue it. The big thing, though, is monitoring with a lot of these medications. Make sure you are monitoring for cardiovascular risks, paresthesias, and other concerning psychiatric effects, and discuss risks such as ergotism and cardiovascular complications — similar vigilance as for serotonin syndrome. Speaker 1 23:56 At least for me, anytime I've ever seen these in practice — which has been extremely rare — it's in someone who's been on them for a very long time and they don't really see a need to change. A patient newly started on ergotamine yesterday would be very rare in my practice. That would be very rare in my practice, at least. Yeah. So it's Speaker 2 24:17 one that I'll probably keep it, you know, I think I've become a little bit more favorably, especially just in reading extra far, maybe a little more favorable to it. I still probably would not do this first line, but if I've got somebody again that we just haven't gotten any traction with the triptans and nothing else has worked as well outside that family, maybe we go to ergotamine as an abortive agent. Speaker 1 24:37 Well, to kind of wrap up some of the key concepts from this episode, one of my take home points, which I think is fascinating, is kind of the history of ergots and how we discovered them, just kind of like warfarin, you know, in terms of a spoiled plant that caused problems. And it really does represent a huge milestone for our understanding of pharmacology and. How that kind of played a role in something like the tryptans being developed. Speaker 3 25:04 And we commonly try to compare these to another gold standard treatment for migraine, which is the triptans. But something to note that these are very different than tryptans when it comes to the receptor profile, like you said, Dr. Schuman, it kind of takes a while for them to latch onto the receptor, and the same thing when it starts to bear off. And then their pharmacokinetics, mainly their bioavailability. Yeah. Speaker 2 25:28 Again, as I mentioned, I still believe that even though these are not the first thing I'm going to pull out for somebody who has, you know, severe migraines, they're still, I believe, is a niche for them, as long as we do the monitoring and discuss that, maybe it's, you know, again, less than eight to 10 per month. But really, maybe what we should be focusing on is saying that using it more than twice weekly is problematic; advise patients of that potential side‑effect profile, check contraindications (especially cardiovascular), and educate about rebound headaches and the tendency to keep dosing, which worsens the cycle. Speaker 3 26:04 Sure, Patient Decision making is involved when you're choosing what type of dosage form you want to give. You know that oral bioavailability is pretty low with the oral form. But then again, rectal is good in terms of bioavailability, but not always the patient's first choice of, you know, dosage, but hopefully the intranasal route that's coming up that you mentioned, Dr. Shuman, hopefully that holds some grounds for more usability. Speaker 1 26:29 So with that, that wraps up. Today's episode number 64 if you'd like to visit us online, we're at HelixTalk.com we're also on Twitter, at HelixTalk. We love those five star reviews. Keep them coming with that. I'm Dr. Kane, I'm Dr. Shulman, Speaker 3 26:42 and I'm Dr. Patel. And the answer to, should I stay or should I ergot? I guess it's just gonna have to be patient specific. Study hard. Narrator - Dr. Abel 26:51 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there to Narrator - ? 27:02 suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.