Two Docs Talk: Migraines

Two Docs Talk: Migraines
Part 1: Breaking Down Headache Myths


Created by AI

Narrator: 0:01

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. Michael Koren: 0:17

Hello, I'm Dr. Michael Koren and I'm delighted to be here with a great colleague, Steven Toenjes, and we're going to talk about headaches. A s a physician, as a clinical researcher and as somebody that runs a business, I have a lot of headaches, so I'm hoping that in this MedEvidence Hour, you're going to help us understand headaches and maybe help me and a lot of other people with your knowledge.

Dr. Steven Toenjes: 0:41

Well, that would certainly be the goal and I'm delighted at the opportunity. I'm Steven Toenjes. I'm a neurologist in Jacksonville. We do general neurology and certainly have a subspecialty niche of headache medicine for sure, and this is basically what we do.

Dr. Michael Koren: 1:03

So, first of all, Steve is an amazing neurologist. He's fabulous and he's a go-to guy in this area in northeast Florida. So thank you for what you do for our patients and thank you for what you do for research, and you also have taught me a lot over the years and you've been involved in clinical research here. So let's help everybody else understand what it is that you do, what it is that you know, and let's start with the basic concept about what is a headache. What are the different types of headaches? Obviously, I alluded to some headaches of what I have to do day to day, and we all have those in our lives, but those are fundamentally different type of headaches compared to cluster headaches or migraine headaches. So there's a lot of terminology out there that people really don't understand quite that well in my experience. So why don't you start by telling us what is a headache and what are the types?

Dr. Michael Koren: 1:51

and why they're important to have different types.

Dr. Steven Toenjes: 1:53

So there are a lot of misconceptions about what types of headaches people experience specifically with migraine. I'll sort of focus in on or pay attention specifically to migraine, because there are a lot of misconceptions.

Dr. Michael Koren: 2:14

Are migraines the worst kind of headaches or different categories are equally bad?

Dr. Steven Toenjes: 2:20

So therein lies some of the uncertainty. There are diagnostic criteria for all of the headache disorders that humans experience. It's called the International Classification of Headache Disorders. It's on its third revision and it's very easy to access online, and so those are a very well thought out and validated through the years and then thus revised set of diagnostic criteria. And so, with our migraine criteria, we really think of headaches that have a couple of particular types of characteristics. There's four main characteristics to consider them being unilateral, them being pulsating or throbbing,

Dr. Michael Koren: 3:05

On one side of the head being pulsating or throbbing on one side of the head being pulsating or throbbing in character. Does that mean they're vascular because they're pulsating? Sometimes people have that. Not necessarily. Okay, not necessarily. Sorry to interrupt you.

Dr. Steven Toenjes: 3:17

No, you're good. So unilateral, pulsating, moderate or severe in intensity. And so, yes, migraines are often moderate or severe in intensity. And so, yes, migraines are often moderate or severe in intensity. And then the fourth one is aggravated by or requires avoidance of routine physical activity. You really just need two of those characteristics, and so if you had a unilateral or one-sided headache that was throbbing, it wouldn't need to be severe. As a matter of fact, it could be mild.

Dr. Steven Toenjes: 3:46

Now, most migraines are going to be moderate or severe, but it can be misleading, because the headache does not need to be moderate or severe. As a matter of fact, it's even possible to have a migraine and have no pain. And so, along with the other four characteristics of migrainous headaches, you know the criteria would require light and sound sensitivity or nausea. The person does not need to have nausea. You don't need to have light and sound sensitivity. If you have nausea and you can still satisfy the diagnostic criteria.

Dr. Steven Toenjes: 4:22

It's important to understand that the light sensitivity and sound sensitivity that can come with migraines does not need to be severe. A lot of times, patients are confused by the fact that light will bother them. It's just not that bad. They will turn the lights off and if they've got a migraine. The radio or the TV are not on, and that counts. That behavior is there because they are light and sound sensitive, and so the photo and photosensitivity can be relatively mild. It does not need to be severe. That's a very common reason why someone is confused about a diagnosis of migraine.

Narrator: 5:03

Okay, so before we get more into migraines, we're going to spend a lot of time on that, since we do the research in that Sure.

Dr. Michael Koren: 5:10

But just for the audience. People talk about tension headaches, they talk about sinus headaches, they talk about cluster headaches. Yes, do they really have the same type of specific diagnostic criteria, or are they just general terms?

Dr. Steven Toenjes: 5:22

Absolutely. They're definitely defined very specifically. I think a lot of the confusion comes with tension and migraine, tension being the most common primary headache disorder that humans experience, migraine being the most common severe primary headache disorder that humans experience. I think it's interesting to look actually at the diagnostic criteria and if you do and you read migraine's criteria and tension headaches criteria, you'll notice that the generators of the criteria just took migraine diagnostic criteria and put the word not in front of each of the criteria, and that is tension headaches criteria.

Dr. Steven Toenjes: 6:09

So they're not unilateral, they're not throbbing, they're not moderate or severe and they're not exacerbated by routine physical activity. That's literally the tension criteria.

Dr. Michael Koren: 6:20

How about cluster? Does that mean anything?

Dr. Steven Toenjes: 6:22

Absolutely so. Cluster is very different and mentioning cluster does bring up a very useful aspect of diagnostic criteria. Duration of a headache is a very, very important piece of the puzzle. Migraines untreated or unsuccessfully treated last between four and 72 hours. They don't last 30 minutes. Cluster headaches are generally fairly easily differentiated from migraines based on simply the duration of the headache. A cluster headache really does not last more than 180 minutes.

Dr. Steven Toenjes: 7:01

So it's not up to three hours and usually it's down around 30 minutes, maybe an hour, and cluster headache is severe or very severe. And so cluster headaches are quite different and have a lot of automatic.

Dr. Michael Koren: 7:16

They hit you hard and they hit you quickly.

Dr. Steven Toenjes: 7:17

They do. They do and they're not nearly as common as migraine. You mentioned one sinus headache and that is something that is often confused with migraine, because migraine can hurt in the region of our sinuses and the vast majority of what is even diagnosed by physicians as a sinus headache is migraine. The statistics are 85% of what a physician diagnoses as a sinus headache is migraine, and so almost all sinus headache is migraine.

Dr. Michael Koren: 7:53

Interesting? Yes, and is there any way to distinguish that? If they respond to antihistamines it's more sinus or

Dr. Steven Toenjes: 8:01

The diagnostic criteria. Okay, gotcha.

Dr. Michael Koren: 8:02

And then you know, I'm sure there are other categories and others post-concussive headaches and others. Are there any other major ones that you want to bring to the fore?

Dr. Steven Toenjes: 8:10

You know, we do see a lot of post-traumatic, post-concussive headache syndromes. A significant percentage of the time I would say a majority of the time when we're seeing these patients in clinic, they are actually a migraine patient whose headaches have increased in severity after the putative trauma, and so sometimes it's difficult to really decipher the difference between a post-traumatic headache syndrome and a migraine syndrome. Post-traumatic headaches are often migrainous. They often have very typical migrainous characters, and when we look at studies on efficacy, it is migraine-based therapies that wind up demonstrating efficacy.

Dr. Steven Toenjes: 8:59

Limited studies.

Dr. Michael Koren: 9:01

Any other major categories to throw out there?

Dr. Steven Toenjes: 9:06

I don't think so. I think those are, you know, it's really. You know, migraine is just such a common issue. You know, one in five females, one in 10 males, have migraine.

Dr. Michael Koren: 9:18

So, yeah, that brings up an interesting issue. So headaches is a big problem in terms of workplace productivity, among other things. Obviously, we like to relieve people's symptoms, but it's interesting from what I've heard, insurers are actually very positive about paying for migraine treatments and other headache treatments because of the productivity issues at the workplace. So you may want to comment on that.

Dr. Steven Toenjes: 9:41

So in global burden of disease studies, where we're really assessing the impact of a particular syndrome on essentially disability or the ability to function in life and at work. In the Global Burden of Disease Studies, migraine is number two in the list of most disabling conditions in women of childbearing ages. It's clearly number one, and so it is by far one of our top most disabled.

Dr. Michael Koren: 10:18

Number one would be heart disease, I assume.

Dr. Steven Toenjes: 10:20

No, number one is lower back pain.

Dr. Michael Koren: 10:22

Really yes, low back pain.

Dr. Steven Toenjes: 10:25

And so there are different ways to sort of slice up the disability with migraine. There is, of course, what we refer to as absenteeism, right, so someone's missing work because they have a bad migraine or unable to function for that day. There's also what we term presenteeism, meaning the person stays at work.

Dr. Michael Koren: 10:50

It is worthless. It is basically worthless headaches and two are the triggering elements of headaches.

Dr. Steven Toenjes: 11:14

You know, in terms of genetics, I think that the genetic stuff is not really ready for prime time in terms of we're not regularly doing any kind of genetic assessments in clinics. I do believe that that is the future to come.

Dr. Michael Koren: 11:31

Do migraines run in families?

Dr. Steven Toenjes: 11:37

Oh definitely, there's no question about that. There is a genetic component. We just don't understand it well. You would term it a polygenetic disease. And yes, if a parent one parent, is a migraineur, the likelihood of any individual offspring being a migraine patient is 80%.

Dr. Michael Koren: 11:54

Wow, and if both parents are migraine patients.

Dr. Steven Toenjes: 11:57

It's 95%.

Dr. Michael Koren: 11:58

Okay, so that's not Mendelian, but there's something going on there.

Dr. Steven Toenjes: 12:02

Clearly interesting.

Dr. Michael Koren: 12:03

Yes, and then talk about triggers. I know that's a huge discussion point from parents for people that have headaches.

Dr. Steven Toenjes: 12:10

I would tie trigger discussions up with lifestyle suggestions. We often are not aware of the impact of our sleep habits on various things. Definitely, migraine is extremely sensitive, often to derangements in our circadian rhythm, certain food-related triggers. Generally those tend to be pretty obvious to a person. I mean, if somebody drinks a glass of red wine and a high percentage of the time they are vomiting in the bathroom with a severe pounding headache when they do that they figure that out very, very easily.

Dr. Michael Koren: 12:51

Or they're on a GLP-1 angonist.

Dr. Steven Toenjes: 12:53

Correct, and so the dietary and behavioral triggers are often pretty well known to a patient. Most of the time that's something I ask the patient and they tell me. I don't tell them. But there are triggers like dehydration, ie you should drink water and stay hydrated.

Dr. Steven Toenjes: 13:17

Prolonged fasting, skipping meals, is actually often a prominent migraine trigger. So we should eat regular, healthy meals. Altering circadian rhythms, bed and wake time sleeping enough. And then the last behavioral approach we would say is exercise. Exercise is actually very useful. Exercise causes headaches or relieves them? No it's very beneficial to have regular exercise.

Dr. Steven Toenjes: 13:46

One special trigger that I would point out is something that is just extremely potent would actually be musculoskeletal neck pain. Pain in our mid and upper cervical spine is very commonly really the trigger or culprit that ends up with a patient, you know, needing to come to our clinic. Yeah, it is, and it's very useful to identify that, because there really are some special physical therapists in the community who are capable of impacting the neck pain-related trigger and thereby the headache syndrome with essentially exercise, stretching and careful strengthening, and that's not a medicine.

Dr. Michael Koren: 14:33

Very interesting. So a little bit more clarity on the amount of time from trigger to symptoms, that would be typical. I know some people aren't 100% sure if something caused it and what that time course should be.

Dr. Steven Toenjes: 14:47

I would say it's variable because a migraine event remember the pain part of it I alluded to being a four to 72 hour window event. There are different phases of migraine. There is the painfully obvious pain phase.

Dr. Michael Koren: 15:06


Dr. Steven Toenjes: 15:07

But there's a prodromal phase that can last hours to a full day or so before a migraine, and then there can be a post-drome or a quote-unquote migraine hangover after the pain is over, and so it could be difficult for someone to identify that a trigger tipped them off into a prodromal phase that may last as much as a day, but usually, I mean, our brains are very good at figuring out what kind of stuff is making us hurt, and so a person usually will figure that out Pretty quickly.

Dr. Michael Koren: 15:42

So it's not usually necessary to do sort of trial and error with regard to different substances and see what causes problems and what isn't. Challenges very specific types of challenges per se.

Dr. Steven Toenjes: 15:55

I think that a person can't, you know, if somebody is having a difficult time with their migraines. There is some utility to focusing on potential dietary and behavioral triggers, with filling out diaries and keeping track of things in that manner and most of the time they're going to be, you know, capable of identifying them. Some triggers are amazingly impressive, particularly smell-related triggers. I mean, there are a high percentage of patients who, if they smell a particular perfume or a particular smell, will instantaneously have a migraine.

Dr. Michael Koren: 16:37

Instantaneously, isn't that ?

Dr. Steven Toenjes: 16:38

craz High percentage. Very, very interesting, often very disabling, especially if you're a teacher and you're a migraine with aura and your aura includes expressive aphasia and your teenage kids figure out that they can trigger a migraine in you and you can't talk.

Dr. Michael Koren: 16:56

Isn't that crazy.

Dr. Steven Toenjes: 16:59

She had to quit her job.

Dr. Michael Koren: 17:00

Oh, my goodness, yeah, huh. And that brings up another point. So do you need to have headaches and get the diagnosis of migraines? You hear about these other type of symptoms associated with migrainous problems. So do you need pain as part of that

Dr. Steven Toenjes: 17:16

Oh, that's a great question. The answer is no, and so one of the phases that about a quarter of migraine patients are capable of having is the aura phase. A lot of people have generally heard of visual aura. You can get funny visual phenomena that can occur. Generally, a person will see something like a scintillation, a light or a kaleidoscope that sort of grows and spreads across visual space. Generally, a visual or any other aura symptom is going to be something that will evolve over minutes, last less than an hour, typically 20 to 30 minutes and then go away, most commonly then being followed by the pain phase or the headache. But you can have aura and not have a headache. True, aophagic migraine or no, head pain, migraine or the official term.

Dr. Steven Toenjes: 18:17

In the international classification of migraine disorders, I would point out, the most common migraine aura symptom is a visual one. The second most common is an evolution of hemibody numbness and the third is an expressive aphasia body numbness. Oftentimes these will come one, two, three the visual aura, then the sensory aura, then aphasia, and that lands patients in the emergency room.

Dr. Michael Koren: 18:41

Right. So aphasia just for people's knowledge means you can't speak.

Dr. Steven Toenjes: 18:45

Yes, you know what you want to say, but you can't get your words out Exactly, and so one of our more common clinical scenarios is where we see people with one of their first aura events that include aphasia or numbness in the emergency room for suspected stroke.

Dr. Michael Koren: 19:01

So in our next segment, I want to talk about the treatments, and I'm going to give a little tease for that. It's anywhere from caffeine to Botox, to a bunch of other things.

Narrator: 19:18

Thanks for joining the MedEvidence podcast. To learn more, head over to or subscribe to our podcast on your favorite podcast platform.

Part 2 Treatments and Clinical Research Advancements


Created by AI

Narrator: 0:01

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. Michael Koren: 0:17

Hello, I'm Dr. Michael Koren and I'm moderating another session of MedEvidence with Dr. Steven Toenjes, who is a fabulous neurologist. This is our second discussion about headaches in general and migraines specifically, and we had a fabulous conversation just now about the epidemiology of migraines, about the things that causes migraines, the different types of migraines and some really interesting cases about triggers for migraine. I was especially fascinated about the teacher who had a migraine reaction to smell to the extent that they couldn't do their profession anymore because they became aphasic, meaning they couldn't speak if the migraine was triggered by that smell.

Dr. Steven Toenjes: 1:01

Isn't that crazy?

Dr. Michael Koren: 1:02

And it was perfume, if I remember correctly, it was yeah. So migraines can have many type of manifestations and they're the second most disabling thing for our general patient population. So pretty interesting stuff. So let's get now into the treatment of migraines, and obviously you're our expert on it, so kind of run us through the gamut you mentioned some things in the first session but kind of break it down for people from non-pharmacological things, first line, second line, prevention versus acute treatment.

Dr. Steven Toenjes: 1:38

First understand that the goals of treatment and I do believe it should be viewed in this manner both from the provider and the patient is that what we're trying to do with treatments is mitigate that disability. We're trying to mitigate the person's you know, trouble they're having functioning at work in their personal lives, and that's a good thing to try to do.

Dr. Michael Koren: 2:08

So just before we get into that, out of curiosity as a neurologist, do people come to you directly? Are you getting more referrals for people that have failed other things and have preconceived notions about what works and what doesn't work?

Dr. Steven Toenjes: 2:19

It's a mix. It's absolutely a mix. We see it all for sure. So just in general, we mentioned in the last session some behavioral approaches. Those are always important to make sure that a migraineur is pursuing.

Dr. Steven Toenjes: 2:40

But in terms of medication options you know we do I think it's helpful to split medications really more into three categories. We'll say acute or abortive therapy. Those are medications that you're going to take when you have a headache and you're trying to abort that headache. One of our very important categories of treatments is preventive therapy. These are therapies that we have either sustained exposures to or daily therapies, and they have as their goal reducing the frequency and overall severity of the headache syndrome.

Dr. Steven Toenjes: 3:20

I include a third category where we really use the term rescue therapy. Oftentimes rescue will be used to describe abortive therapies, but in our clinic our rescue therapies are really you know, keep me out of the emergency room therapies. I've got an extremely severe headache and you know the person may just be profusely vomiting up everything that we're trying to give to them at that point, and so something to sort of end that when things have gotten a little too far. You know I keep that sort of as a special category on its own. And so our patients. We do differentiate abortive therapy and rescue therapies. It's very helpful with, just in a general sense. When we're talking about success with various therapies. What do we mean by success?

Dr. Steven Toenjes: 4:22

If we're talking about abortive therapies, we mean that the person gets relief from the abortive therapy meaning in the goals and an acceptable goal is within a relatively short period of time.

Dr. Steven Toenjes: 4:36

Within a yeah hour or two to get to either no pain that's the best obviously and then remain pain-free, sustain pain freedom or minimal pain, so mild or no pain, and then without significant side effects. Through the years, you know, patients will often report that a medication works very well for them, but the medication also produces some disability, ie sedation, and then the person is out of commission because they're basically put to sleep by the medicine that they're taking. And so what we really mean by success is, the vast majority of the time with an abortive therapy, pain-free or minimal to no pain, and the person is returning to function, not having to sleep for the rest of the day. Gotcha Preventive therapies we usually will set as a goal at least a 50% reduction in frequency. That often comes with a reduction in overall severity, and so that's kind of how we define what we mean by success tolerating a therapy either no or minimal side effects and then also achieving the 50% reduction.

Dr. Michael Koren: 5:58

So just Is that something achievable for most patients, or can you get to zero or give us a little bit of sense for where we are in terms of current therapies?

Dr. Steven Toenjes: 6:07

Sure, speaking specifically about preventive therapies, we break them up into our conventional oral therapies that we've had for a number of years. Really, when we say that, we're referring to several specific medicines beta blocker, blood pressure medicines and some other blood pressure medicines like verapamil and other calcium channel blockers. Seizure medicines mainly topiramate, although there are others and then medicines in the antidepressant class, mainly the tricyclic antidepressants like amitriptyline or Elavil, although SNRIs like venlafaxine also do have some efficacy. There are other oral conventional therapies as well, but those are sort of the main three categories.

Dr. Michael Koren: 7:02

For prevention?

Dr. Steven Toenjes: 7:03

For prevention. Well, if you look at and you're seeing, say, a chronic migraine patient in clinic and you grab from either one of those three categories, the likelihood that you'll get success with what you grab is in the range of around 30%, and so most people are not going to either tolerate the therapy or be successful.

Dr. Michael Koren: 7:31

So even just for my knowledge, so even the simpler things that are non-prescription treatments like aspirin or caffeine, do they have preventative effects or they just use for abortive reasons?

Dr. Steven Toenjes: 7:44

So caffeine should be viewed as an abortive therapy. It's not going to be a preventive therapy and it's an important one to understand. It is often very successful at aborting a migraine.

Dr. Steven Toenjes: 7:58

If you look at any over-the-counter formulation and it says migraine formulation on it the thing that's in there that's been added is caffeine, for a reason, but most abortive approaches we have to understand can backfire on a migraine patient. Most abortive therapies, if they are taken too frequently, will actually do the opposite of a preventive therapy and will increase the frequency and severity of the headache syndrome, and caffeine will definitely do that.

Dr. Steven Toenjes: 8:29

So will aspirin. Most abortive therapies will do that. We do have abortive approaches that do not produce medication overuse, headache or rebound phenomenon. Some of our newer medicines in the GPANT class, medicines like Eptinezumap or Vyepti, Rimegepant, which is Nurtec that people see commercials for there's also a nasal spray named Zavzpret that's in the GPANT class. These medicines blur the distinction between preventive and abortive therapy. They are effective as abortive agents and they don't cause medication overuse, and so if taken frequently they don't backfire and produce a rebound phenomenon. They actually do the opposite. They're effective in prevention, and so that's why the Nurtec commercials mention this therapy can relieve and prevent migraines, and the FDA lets them say that in the commercial because it does have efficacy.

Dr. Michael Koren: 9:29

Dual role, dual role. W hereas a beta blocker is not going to work for an acute migraine.

Dr. Steven Toenjes: 9:34

That would be unusual there are. The only scenario that I can think of is there are some beta blocker eye drops that lower intraocular pressure, that actually have a couple of studies demonstrating some efficacy in abortive relief.

Narrator: 9:56


Dr. Steven Toenjes: 9:57

And so, but for the most part no.

Dr. Steven Toenjes: 10:01

And so now in the migraine world, there's really been two major, really advanced or really explosions in therapies of just a tremendous expansion in what's available.

Dr. Steven Toenjes: 10:17

In the 1990s, with the first FDA approval of sumatriptan or Imitrex there are seven triptans they're all seven generic now. That happened through the 90s and 2000s, and then in 2018, was the first FDA approval of our CGRP-based therapies, or therapies that are directed at impacting calcitonin gene-related peptide signaling within our brain, with the approval of Aimovig in 2018, and then several other CGRP-based therapies that followed shortly thereafter and are in widespread use now. If you look at the success rate that success rate as we defined it and you look at our CGRP-based therapies, you look at our CGRP-based therapies, you'll find numbers more like 50, 60 in some studies getting as good as 70% success. And so it's nice to be able to take patients who feel defeated, feel as though they have lost hope, feel as though that they have attempted so many things throughout their life, and point out to them that since the advent of our CGRP-based therapies in 2018, now we have therapies that most people get to success as we have defined it.

Dr. Michael Koren: 11:46

And we have been part of that clinical trial experience. I know that you've been involved in these studies. We'll talk more specifically about clinical trials in our next segment. That you've been involved in these studies We'll talk more specifically about clinical trials in our next segment. But it's satisfying when you see a concept that started in its infancy, that was developed in clinical trials and now is something that you can tell your patients works up to 70% of the time. That's pretty cool.

Dr. Steven Toenjes: 12:03

You mentioned, can I have no headaches? It is the CGRP-based class that we do. It's kind of a marketing thing. I think that does get pulled out of research trials. But a number of the therapies do have patients that can get a whole month where they actually don't have a migraine. Most people are not going to achieve migraine freedom, but the name of the game is to try to reduce frequency as much as possible and really to try to get the frequency down to where abortive medications are not being used, with a frequency that may be capable of building rebound and really trying to mitigate the migraines that they do get. And so if somebody still has one or two migraines in a week but they can be successful with an abortive agent that we find for them, then you've really started to impact the headache related disability at that point.

Dr. Michael Koren: 13:15

And you mentioned the triptans, which are now generic and less expensive. How do they fit in terms of efficacy between those and the first class of beta blockers and amitriptyline-type class?

Dr. Steven Toenjes: 13:23

So triptans are abortive and the beta blockers are preventive. You know we are in, I think, an evolution of behavior over the last, you know, six or seven years. What we used to have mainly was largely triptans and its parent compound, dihydroergotamine, and NSAIDs and nausea medicines. We always need to remember nausea is very important to treat in a migraine patient and the neuroleptic antiemetics are often capable of aborting the migraine, not just the nausea. And so through the Neuroleptic, meaning a seizure medication, no, no, no. The neuroleptic antiemetics like Promethazine, Phenergan.

Dr. Steven Toenjes: 14:11

Compazine, Reglan, metoclopramide as opposed to Ondansetron, which is not in a neuroleptic category.

Dr. Steven Toenjes: 14:20

So while mainly what we have been trying to treat migraines with abortively is triptans, we've essentially kind of been shoving these things down patients' throats for the last 20, 30 years, including patients who have significant sedation with or other side effects from triptans, and with the invention of the GPANT class, which tend to be very, very well tolerated, you know, we're sort of, I think, and I myself have even noticed that you know you really got to talk to patients about what happens when they use a medicine that they are saying works for them, because some of our newer medicines just seem to be so much better tolerated that they may be capable of getting the same response that they're getting, but not the sedation or other side effects that they've just been accepting as being better than having the headache.

Dr. Steven Toenjes: 15:22

And so you know, I think, that triptans are amazing medicines and for many, many patients probably in the range of a third or so are going to do very well with a triptan, and while they're generic, we often will start with those, unless there are reasons to not use them for sure.

Dr. Michael Koren: 15:42

Interesting, Interesting so, and there's a lot of new things that we're starting to contemplate that are either a progression from previous knowledge or something that's brand new, and we'd like to discuss that in some of the clinical trials that are ongoing and where the gaps are in our next segment. But thank you for that fabulous run through the pharmacology. It gets a little bit complicated, it does, but you're allowed to go back to the beginning of the talk and listen to it again.

Dr. Steven Toenjes: 16:09


Dr. Michael Koren: 16:09

And realize that polypharmacy in this area is probably something that you use frequently. Often it's not just one product. It may require several.

Dr. Steven Toenjes: 16:19

And I would point out that I'm kind of skimming the surface here, like we're not really diving into this. There are therapies that I haven't even mentioned, you know, like Botox. We haven't. We'll get there Now, I mentioned it, yes and so, but there are a number of things that haven't even been mentioned and it is sort of a surface view of headache medicine, I think.

Dr. Michael Koren: 16:42

And just the last thing in terms of the polypharmacy elements, do you always build from the first class or is it OK to just jump to the more advanced recent therapies?

Dr. Steven Toenjes: 16:53

So it is welcome that the American Headache Society has changed their stance on the CGRP-based therapies, particularly preventive therapies, and have pointed out that they are medically appropriate first line, for mainly the reasons that we've mentioned. The difference in likelihood of success. Most of the time how we behave or what we can do in clinic is certainly influenced by the overlay of insurance payers, and insurance payers generally require starting with the oldies, but goodies that are also cheapies, right, right. And so variable requirements dependent on certain medicines, whether there's one treatment that needed to be pursued with a conventional therapy, oral or two or three, and different plans have different rules.

Dr. Michael Koren: 17:49

Is that a big problem with insurance? I know in cardiology I deal with it all the time, but I don't know if that was as big of an issue in the headache world.

Dr. Steven Toenjes: 17:57

It's an extremely severe problem. It's a headache. It's a headache, yes.

Dr. Michael Koren: 18:01

Well, with that we're going to end this session of MedEvidence and we're going to jump into some of the things people should look forward to, and also opportunities for people to get involved in clinical research.If they're still struggling with headaches.

Narrator: 18:16

Thanks for joining the MedEvidence podcast. To learn more, head over to or subscribe to our podcast on your favorite podcast platform.

Part 3 - Breakthroughs in Migraine Research


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Narrator: 0:01

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: 0:17

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: 0:34

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: 1:30

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: 2:31

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: 2:59

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: 3:34

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: 4:51

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: 5:11

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: 6:05

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: 6:28

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: 7:05

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: 7:52

Okay, so now I call it botulism toxin, Does it really matter if you pronounce it that way or botulinum.

Dr. Toenjes: 7:59

I think everybody knows what you're talking about. It is a therapy that is seemingly fairly unconventional.

Dr. Koren: 8:11

Do you inject it in the forehead area?

Dr. Toenjes: 8:16

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: 9:41

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: 10:03

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: 11:11

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: 11:35

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: 11:47

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: 12:24

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: 13:11

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: 13:47

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: 14:15

Nothing on the market yet. Oh, no, no, no.

Dr. Toenjes: 14:17

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: 15:20

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: 15:46

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: 16:13

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: 16:38

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: 16:56

Again, if the placebo works for you, that's great we love that too.

Dr. Koren: 17:01

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: 17:08

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: 17:19

There's no question about that.

Dr. Koren: 17:21

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: 17:53

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: 18:44

Are there any devices approved now for migraine headaches? Oh yes, Can you mention those?

Dr. Toenjes: 18:49

Sure. So a transcranial magnetic stimulation device . It's approved for both abortive therapy and prevention and has demonstrated efficacy.

Dr. Koren: 19:04

Do you wear this, do you have to go to a clinic to get it?

Dr. Toenjes: 19:07

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: 20:08

And they've given up on the US because of payment issues.

Dr. Toenjes: 20:10

Right. Yes.

Dr. Koren: 20:11

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: 20:25

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: 21:27

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: 21:39

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: 22:09

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: 22:19

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: 22:47

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: 23:11

Unless it can help people get off narcotics more easily.

Dr. Toenjes: 23:14

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: 23:36

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.

Dr. Toenjes:

You're welcome.

Narrator: 23:48

Thanks for joining MedEvidence.

Ever found yourself crippled by a headache, unsure if it's the stress of the day or something more? Dr. Michael Koren sits down with renowned neurologist Steven Toenjes in a three-part series to shed light on the shadowy world of headaches and migraines. In our enlightening conversation, we deconstruct the various headache types and clarify the often confounding diagnostic criteria. With Dr. Toenjes' expertise, we navigate through the maze of migraine myths, laying out the reality of their diverse manifestations, from the classic debilitating pain to the lesser-known painless forms. Whether you're a migraine veteran or just curious about that throbbing in your temples, this talk is packed with insights that promise to transform your understanding of this widespread condition.

Headaches are more than just a personal nuisance; they're a global health titan, especially impacting women in their prime. In this gripping discussion, we examine the staggering disability caused by migraines, which stealthily infiltrate both personal and professional spheres through missed days and muted productivity. The genetic lottery of migraines is laid bare, along with a toolkit for managing the lifestyle factors that poke the migraine bear. We also pull back the curtain on migraine aura symptoms—those disconcerting visual and speech disturbances that mimic a stroke—and preview a trove of treatment strategies awaiting in the wings. From homegrown hacks to high-tech treatments, this episode is an indispensable guide for anyone ready to reclaim their life from the clutches of chronic headaches.

Talking Topics:

  1. Understanding Different Types of Headaches
  2. Migraine Aura Symptoms and Treatments
  3. Treatment Migraines
  4. Clinical Research and Headache Management

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

Recording Date: May 13, 2024

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Recording Date: May 13, 2024
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