Discover the future of migraine management with us in our final episode of Two Docs Talk Migraines. Feel the excitement as Dr. Michael Koren and Dr. Steven Toenjes delve into a world where CGRP antagonists and pharmacogenomics interlace to tailor therapies to individual needs. We're talking about groundbreaking approaches to chronic migraine care, from the FDA-approved botulinum toxin type A, also known as Botox, to the promising horizon of nerve-stimulation devices. This is your ticket to understanding the complexities of migraine pathophysiology and the innovative clinical trials shaping the hope for relief.
Join an enlightening journey through the maze of headache treatment, where we illuminate the nuances of botulinum toxin dosing, the emergence of PACAP inhibitors, and the intriguing potential of prostaglandin-based therapies. With his profound expertise, Dr. Toenjes guides us through the patient selection process for these groundbreaking clinical trials and the profound impact research has on patient care. You're not just listening to another discussion; you're stepping into a realm where the future of migraine treatment unfolds in real-time, offering a beacon of hope to those awaiting new solutions.
Talking Topics:
Exploring Therapeutic Options for Migraine
Updates in Migraine Treatment and Research
Part 1: Breaking Down Headache Myths - Release Date May 15, 2024 Part 2: Treatments and Clinical Research Advancements - Release Date May 22, 2024 Part 3: Breakthroughs in Migraine Research - Release Date May 29, 2024
Discover the future of migraine management with us in our final episode of Two Docs Talk Migraines. Feel the excitement as Dr. Michael Koren and Dr. Steven Toenjes delve into a world where CGRP antagonists and pharmacogenomics interlace to tailor therapies to individual needs. We're talking about groundbreaking approaches to chronic migraine care, from the FDA-approved botulinum toxin type A, also known as Botox, to the promising horizon of nerve-stimulation devices. This is your ticket to understanding the complexities of migraine pathophysiology and the innovative clinical trials shaping the hope for relief.
Join an enlightening journey through the maze of headache treatment, where we illuminate the nuances of botulinum toxin dosing, the emergence of PACAP inhibitors, and the intriguing potential of prostaglandin-based therapies. With his profound expertise, Dr. Toenjes guides us through the patient selection process for these groundbreaking clinical trials and the profound impact research has on patient care. You're not just listening to another discussion; you're stepping into a realm where the future of migraine treatment unfolds in real-time, offering a beacon of hope to those awaiting new solutions.
Talking Topics:
Exploring Therapeutic Options for Migraine
Updates in Migraine Treatment and Research
Part 1: Breaking Down Headache Myths - Release Date May 15, 2024 Part 2: Treatments and Clinical Research Advancements - Release Date May 22, 2024 Part 3: Breakthroughs in Migraine Research - Release Date May 29, 2024
Welcome to MedEvidence, where we help you navigate the truth behind medical research with unbiased, evidence-proven facts, powered by ENCORE Research Group and hosted by cardiologist and top medical researcher, Dr. Michael Koren.
Dr. Koren:
Hello, I'm Dr. Michael Koren, moderating an episode of MedEvidence that involves Dr. Toenjes and our talk about headaches and migraines in particular. This is our third discussion, third session, and we want to talk about research now.
Dr. Koren:
We are research guys. We've been doing this for a long time. You've been very involved here at our research center in Jacksonville, Florida, and we want to know what the latest and greatest is and some of the concepts that are being considered to help people with headaches, particularly migraine headaches, which is a huge source of lost productivity and disability. So we had some interesting discussions in the last session and including the use of Botox for headaches, and we're going to talk a little bit about that because we actually have a clinical trial that's looking at that, and we also talked about the groups of patients that are just not getting where they need to get with current therapeutic modalities. So maybe you can start the conversation by telling us the group of patients that are not getting where they need to get, despite some of the advances we've already made.
Dr. Toenjes:
Well, certainly, our headache clinics have patients that we're having trouble, you know, getting their headaches syndrome under control. You know, that's relatively uncommon. With the mixture of therapeutic options that are available, we generally eventually are very likely to get someone's headaches syndrome under control, whether that be a mixture of things, but it usually happens. But there's still patients that we're not sufficiently successful with, and so there are more things to consider with development of new therapeutics. There are novel approaches that I think it'll be very helpful to see. You know, some of the things that are in the pipeline may have efficacy and safety through the process of clinical trials and then become additional options.
Dr. Koren:
You mentioned in the last segment that the class of CGRP gene-related calcitonin peptide), I think is the acronym are successful up to 50 to 70% in terms of preventing migraine headaches, which would infer to me that there's still a 30 to 50% rate of migraine headaches in some patients. Are there any special characteristics of those people that don't seem to respond to CGRP antagonists?
Dr. Toenjes:
No, I don't think we can really predict that right now. Maybe in the future, if there are some pharmacogenomic-type studies that investigate these sorts of things and there are some early studies I'm not aware of any with CGRP-based drugs but other therapies, there are some pharmacogenomic information that we can in the future perhaps may be able to use. But no, it is a trial and error thing.
Dr. Toenjes:
This calcitonin gene-related peptide, or CGRP, is something that is very central to a lot of what goes on in our brain with the disorder of migraine. It is a neuropeptide that exists in all of the C fiber or pain fibers that are throughout our body, and those very heavily innervate our meninges, the lining of the brain, and the process kicks off a strong CGRP release out at the level of our meninges that stimulates the trigeminal sensory innervation that is alongside to really kick off a lot of what happens in a migraine- the dilation of the vasculature. This is what's responsible largely for the neurogenic inflammation and likely even breakdown in some vascular permeability and mast cell degranulation, all happening largely at the level of our meninges, kicked off by more, and then stimulating more central pain pathways.
Dr. Koren:
So just to get into that a little bit more, particularly from my standpoint as a cardiologist. So this has to do with intracellular calcium regulation. And calcium channel blockers do work to some degree for migraines. Is there any relationship between calcium channel blocker success and CGRP success?
Dr. Toenjes:
Not that I'm aware of, and so we will have some of the calcium channel blockers would be in the category in the previous section we referred to as oldies but goodies that are also cheapies. There actually are some pharmacogenomic data, particularly with Verapamil. You know that sort of stuff is in terms of predicting the likelihood of a response to Verapamil, and that's not really ready for prime time in a clinic. But those sorts of research data are extremely interesting and probably will in part be kind of the future of headache practice, I believe, eventually. So it would be nice to be able to predict what you will respond to and what you will likely have side effects to, but we're not that good at that yet.
Dr. Koren:
What we like to do in MedEvidence is talk about what we know, what we don't know, and how we're going to learn about what we don't know. So one of the things we don't know is predicting who's going to respond to which category of drugs. So let's get to one of the categories, Botox. Botox is not thought of necessarily as a headache drug, but it works, doesn't it?
Dr. Toenjes:
It sure does. It's one of our most effective treatments. Specifically, or currently FDA-approved it's for chronic migraine patients, chronic migraine patients being patients that have headaches on more days than they don't have headaches, and at least eight of them in a month become migrainous. That's really what we mean by chronic migraine, as long as that's gone on for a duration of at least several months. Now we say Botox and everybody knows the name Botox, but Botox is a trade name and so it's onabotulinum toxin A is sort of the name of what Botox is.
Dr. Toenjes:
Once you practice onabotulinum toxin A a few times, you can kind of get it to come out, and so there are numerous botulinum toxins and Botox or onabotulinum toxin A is the one that's FDA approved for chronic migraine, and there are other toxins that have different FDA approvals, and one of the studies that we'll be entering into is a different botulinum toxin and addressing specifically both episodic and chronic migraine patients, and so that's very exciting, I think, as a potential option and a new botulinum toxin therapy that may demonstrate efficacy, safety and hopefully, if so, then be FDA approved.
Dr. Koren:
Okay, so now I call it botulism toxin, Does it really matter if you pronounce it that way or botulinum.
Dr. Toenjes:
I think everybody knows what you're talking about. It is a therapy that is seemingly fairly unconventional.
Dr. Koren:
Do you inject it in the forehead area?
Dr. Toenjes:
It is a procedure, really the protocol for it we would call just named after the clinical studies that demonstrated its efficacy, very specific location and doses of injections. There's actually 31 injection sites in the PREEMPT protocol and generally certainly in the clinic. Kind of that's the way that we start. It is a protocol that's been validated through the years and adjusted and it is one of our most useful go-to therapies for the really challenging migraine patient. Botulinum toxin is taken up by sensory neurons and we believe that it's taken into our brainstem actually, and one of the things that it does is it paralyzes the ability of trigeminal innervation to release CGRP and, other neuropeptides, but one of its likely main mechanisms of action is paralyzing the ability to release that CGRP substance out in our meninges.
Dr. Koren:
Just for the lay audience, trigeminal is the nerve that affects the eyes and the face. And is responsible for all of the sensory innervation of the lining of our brain or the meninges. So how does the protocol differ when using botulism or botulism, however you pronounce it toxin, for cosmetic purposes versus neurological purposes?
Dr. Toenjes:
So botulinum toxins are capable of influencing sensory neurons the way that I just mentioned, but they also weaken muscle. They prevent motor neurons from being capable of stimulating a muscle so it can contract. And it is a way that you can get rid of a wrinkle, you can weaken the muscles that are producing those wrinkles. And that has been something that has been you know, known and done for a very long period of time. And the observation was made with a plastic surgeon who was doing cosmetic botulinum toxin injections and realized, you know, while one in five females is a migraine patient a pretty consistent report that you know. Hey, you know, with this cosmetic stuff, my migraines are really getting better. And then, lo and behold, here come the studies in migraine with demonstrated efficacy. And the protocols are the same for the different indications?
Dr. Toenjes:
No, the doses are going to be much higher for migraine, and so that's an important point. You know, when we're doing cosmetic, we don't do cosmetic injections, but when cosmetic injections are being done, they're done in different locations and generally at a much lower dose than what we are using for migraine treatments.
Dr. Koren:
Is it a problem that people that get prescribed the toxin for neurological purposes use it off-label for other things? Is that an abuse of the therapy?
Dr. Toenjes:
We discourage that, and the main reason that one of the main reasons to discourage that is we need to understand that this is a toxin that it is possible for our immune system to respond to, and so we could develop antibodies to onabotulinum toxin A or any other botulinum toxin, and if our immune system really responds to it and develops high concentrations of antibodies to it, that therapy is not going to work for us because our immune system will gobble it up as soon as we inject it, so undermine your own purposes, correct?
Dr. Toenjes:
And so the protocol of injection every 12 weeks seems to work well at reducing the likelihood of development of antitoxin antibodies, and mixing that up really does run the risk of stimulating our immune system and backfiring on the patient. And so botulinum toxin has a lot of utilities, and there are patients that require it for bladder issues. There are heart-related studies with botulinum toxin. If there is another indication or a person is doing cosmetic injections along with migraine-based injections, we just really strongly encourage them to have those done pretty much on the same day or within a day of each other.
Dr. Koren:
Interesting, very interesting. So let's move to another area of research. What else is going on in terms of treatment for refractory patients that have migraines?
Dr. Toenjes:
There are other novel compounds, PACAP, or pituitary adenylate cyclase protein, that seems to potentially maybe have some significant pathophysiologic relevance to migraine and it is a completely novel therapeutic that we've participated in some of those trials here and there. There are more with various pharmaceuticals planned for the future, and so that's a completely unique mechanism of treatment that may come around the bend.
Dr. Koren:
Nothing on the market yet. Oh, no, no, no.
Dr. Toenjes:
No PACAP inhibitors FDA approved at this time. And then, in terms of relatively unique, I think is one of the studies that we'll be participating with, the therapy that impacts prostaglandin pathways. Prostaglandins are a very important part of inflammation and pain and can influence vascular tone as well, and so there are novel prostaglandin-based preventive therapies that will also be studied here in the near future, and so the general message for the migraine sufferer who has not had a sufficient response to a variety of therapies is to understand that the research world is inventing and continues to address and try to come up with new strategies for those patients that we've not been that successful with in the past.
Dr. Koren:
Sure. So you're a clinical trial guy and you see lots of these patients. When do you approach a patient about getting involved in clinical research? Obviously, I would think that somebody that has a great response to something that's already out there is probably not going to be the best candidate. On the other hand, it sounds like there are people that go through your headache clinic that would be great candidates. So give us a little insight into how you approach that and why you would choose a particular type of patient for this discussion.
Dr. Toenjes:
You know there seems to be a personality type that's interested in investigation and you know patients who understand the landscape of treatments. Then you know pointing out to them that there are newer treatments that you, just like all of our CGRP-based therapies,
Dr. Koren:
We Yes, absolutely. Yeah, even though a lot of these studies are placebo-controlled. Sometimes there's an open label portion of the trial where everybody gets access to it, but it's obvious in some cases who's getting the therapy and who's not. Quite frankly, it is. Especially in something symptomatic, correct Right.
Dr. Toenjes:
One of the things that's true about, and a challenge in the migraine study world, is that looming placebo effect, and so it can be difficult to really tease out, but sometimes therapies are so effective, which is okay.
Dr. Koren:
Again, if the placebo works for you, that's great we love that too.
Dr. Koren:
But in some people it's so profound how much different they feel after they participate in a trial that you have to think the therapy has something to do with it.
Dr. Toenjes:
There was a wise individual who made the statement if you're having trouble getting control of somebody's headaches, one of the best ways to get them under control is enroll them into a clinical trial.
Dr. Koren:
There's no question about that.
Dr. Koren:
Well, there's other parts of it. There's the nurturing part of it, there's reinforcement of dietary issues, of avoiding triggers, all these things that you've already brought up. So the clinical research process is extremely helpful for a lot of people. Absolutely, I think so. So is there anything else out there that we should be aware of, in terms of, maybe, research that is not being done here in Northeast Florida that we should be looking out for, or other things that may be a particular niche for a particular type of headache patient?
Dr. Toenjes:
We always hold the cluster headache patients in a very, you know, specific niche, and so you know I do think that it's you know the cluster headache patients are always waiting for additional studies to come out. And so maybe some word or mention about, y ou know, neuro-stimulation devices and those types of therapies that re not really medicines. You know, I think that you know, unfortunately it's difficult for nerve stimulators, and there are transcranial magnetic stimulators and other types of therapies. Devices to really get traction with insurance coverage.
Dr. Koren:
Are there any devices approved now for migraine headaches? Oh yes, Can you mention those?
Dr. Toenjes:
Sure. So a transcranial magnetic stimulation device . It's approved for both abortive therapy and prevention and has demonstrated efficacy.
Dr. Koren:
Do you wear this, do you have to go to a clinic to get it?
Dr. Toenjes:
That's the problem is you've got to rent it or purchase it and it's generally cost prohibitive. And there are other nerve stimulation devices. A lot of people will have heard of Cefaly, which is just an electric stimulation device that really can help some patients. And so, you know, I think, as the efficacy of these sorts of things becomes increasingly, you know, more and more demonstrated, hopefully coverage will be a little more reasonable. You know it's unfortunate that the transcranial magnetic stimulation device companies have largely kind of given up on the United States at the moment. But it is a safe therapy and it has, you know, good efficacy.
Dr. Koren:
And they've given up on the US because of payment issues.
Dr. Toenjes:
Right. Yes.
Dr. Koren:
Interesting. And how about narcotic avoidance? I know that's a big push by the government and others because of all the side effects of chronic narcotic use. Are there studies that are specifically focused on that?
Dr. Toenjes:
So first, if you're going to a provider and you have a migraine syndrome and what they're prescribing for you is a narcotic, I think that you should maybe seek an additional opinion. Narcotics are almost never appropriate for a migraine patient. Narcotics really don't abort migraines. I say in my opinion. No narcotic has ever aborted a migraine ever. It may allow someone to go to sleep, and then sleep would have then aborted the migraine, but it wasn't the actual narcotic effect. As a matter of fact, narcotics will run a very high rate of backfiring on a migraine patient and producing that medication rebound phenomenon. It's extremely, extremely potent at actually making a migraine patient worse, and so we almost never are prescribing narcotics.
Dr. Koren:
And that's a big change. So when I was a medical resident, I used to be taught to give Demerol in the emergency room. That was supposed to be the best narcotic for migraine patients. Obviously, that turned out to be incorrect.
Dr. Toenjes:
It was very incorrect. Yes, we have learned this for sure over the last 20, 30 years, and we really should be avoiding narcotics, because we understand migraine pathophysiology a lot better now, and these migraine therapies are migraine-specific therapies, I mean, they are directed at the pathophysiology of migraine and that's why they're so much more effective.
Dr. Koren:
But I understand there is still a group of patients that are being prescribed narcotics because of quote headaches and that could be a target maybe for clinical research, I would think.
Dr. Toenjes:
Historically you'll find in many most actually clinical trials that patients who are on frequent doses of narcotics are going to be excluded from those studies and the conventional, you know, consultation, you know, in terms of designing studies would generally suggest that because nothing's going to work in that scenario.
Dr. Toenjes:
The first thing that really needs to happen is the narcotics need to be weaned and so approaches to actually get rid of what's very likely an offending agent worsening a headache syndrome. That's actually what needs to be done. I would be surprised to find pharmaceuticals interested in studying that population.
Dr. Koren:
Unless it can help people get off narcotics more easily.
Dr. Toenjes:
As an end point, for the study, absolutely Very, very useful. Yeah, it is a challenging situation. It's really difficult when the person has another pain condition that really does justify the narcotic use, and so those are some of our most challenging headache patients, for sure.
Dr. Koren:
Well. Thank you, Steve. This has been a fascinating conversation. It's been absolutely fabulous. I've learned a tremendous amount. Hopefully our audience will have learned as well. Thank you for being part of MedEvidence. You're welcome.