Guest: Dr. Alyson McGregor

View the recording from our Migraine Clinician Masterclass, developed in partnership with IVPN Neuropsychiatry. In this webinar, we hear from Dr. Alyson McGregor, who talks about Migraine in the Emergency Room. Please note that this video is intended for healthcare providers.

TRANSCRIPT

Dr. Alyson McGregor: Who I am and the reason why I’m here is to really sort of give you the perspective of going to the emergency department with headache from the, you know, physician side. How do we triage headaches? And so, I’ve spent my past two decades seeing patients in the emergency department and researching sex and gender differences and being an advocate for it, and I’ve published a couple of lay books as well as a textbook. 

And so you’re right, I can’t do this without talking about sex and gender differences in migraine because that is the new evidence, that’s the new research. So I don’t even need to put it in the title because just by looking at the evidence of migraines and treatments and some of the biases in our screening tools, it’s important to know that there are new research and new evidence base that take this into account. 

So just sort of making sure we’re all on the same page, there was this basic assumption by science, by research, by medicine, that men and women were alike in every way except for the reproductive organs. And so that was something that was why we studied men and we, you know, took that evidence and we applied it to both men and women.

But it doesn’t take long to come into my environment where we see the whole spectrum of disease. And the truth is that men and women do not present the same in many, many diseases and illness. We don’t have the same risk factors. We have metabolism of pharmaceuticals that are different. We have different outcomes of disease. For instance, you know, 90% of all autoimmune disorders are in women. Sudden cardiac death is 30 times more likely in men during exercise than in women. 

And then we have this migraine over here. And migraine has been considered a women’s problem, a women’s disease. And let’s explore that a little bit. So what we, you know, it’s important for me to start by saying that the differences that we now see in men and women are at the cellular level, the DNA. So our steroid chromosomes, sex chromosomes, XX if you’re a female, XY if you’re male, these chromosomes are in every cell in the body. They are not just in the reproductive organs and they’re in the brain and they really impact the way that our brain responds to pain and stimuli. And so that’s really important for us to understand. 

It’s also important for us to understand that every cell in our body also has receptors for estrogen, right? So our hormones. So there are hormone receptors in our brain, in our immune cells, and in our entire milieu. So considering these things is really the new wave of understanding evidence. 

And in the United States, since 2016, our major funding body, our National Institutes of Health, said that you must include sex as a biological variable in your application if you want to even be considered for funding. What that’s done is really open up all this new evidence that we didn’t really know that was there. And so it’s a really exciting time. 

So when we think about coming to the ER with a headache, it’s the fifth leading cause of ED visits. So a nontraumatic headache – so without having trauma, you go in and you complain that you have a headache. That leads to 3.8 million visits a year in the US. And that’s about 2.8% of all visits. So this is not insignificant. 

And so let’s just think about this in terms of primary and secondary. So I know secondary is going to be talked about at a later time. But so when we think about a headache, we’re thinking about the fact that the head is experiencing pain. So the trigeminal neurovascular system is stimulated. And what happens is it releases neuropeptides. And then those activate other neurons down the line. And so that is the primary type of a headache. 

When we are considering a secondary headache, we’re saying that something else has caused that headache. A brain tumor, for instance. What are we going to see with a brain tumor? We’re going to see neurologic dysfunction. We’re going to see acute neuro effects. We’re going to have different pain during the day. 

When there’s an infection source like meningitis, there’s other signs. There’s a fever. If there’s a serious head injury, that’s usually visible. The piece that’s most important is when it is acute, then it’s considered a concern for subarachnoid hemorrhage. So that is not visible from the outside. That is where we have to really distinguish between is this a primary problem or is this a secondary problem? 

And so when we think about migraine, I was asked to focus on migraine, obviously. And so when we think about it’s the most common primary headache, it’s usually associated with other signs and symptoms. The nausea, vomiting, photophobia, phonophobia, exacerbated by physical activity. Most of the time, there is an aura. And if there is one present, it’s visual. And it happens in the temporal regions. It’s usually described as throbbing. And the timeframe is four to 72 hours. And that’s been quite consistent throughout a lot of the guidelines.

And here’s the problem. It can range from several attacks a month to less than one attack per year. And each individual can have many attacks at one point and then very few attacks at another point. The problem with being in the emergency department setting and seeing a patient that the definition requires understanding the episodic nature. And we only have this one point in time that we are assessing that patient. And that patient is describing a very painful process. So that makes it quite challenging. 

And so looking at what a primary headache is, most of the time in the emergency department, it doesn’t always matter to distinguish between the three of them. Because oftentimes they do react to the medications, cross-react to a lot of the same medications.

But I thought it would be really important to just describe, like when we’re talking about migraine, one of the major pieces is that looking at the additional symptoms. There’s usually nausea and vomiting, as I mentioned with the other things, whereas tension headache, there’s really no nausea or vomiting. And a cluster headache, there’s autonomic symptoms. So tearing and rhinorrhea and sweating. So that can be an important clue when you’re seeing a patient. 

Also note that we have considered, like when we look at the incidence and prevalence of disease, we say that women are more likely to have migraines. Women are more likely to have tension headaches and men are more likely to be diagnosed with cluster headaches. So the bottom line is that migraine is more prevalent, it’s more frequent, and it’s more disabling in women versus men by up to three times. This is interesting.

And some of this has to do with obviously the considerations and the different profile of either the DNA sex chromosomes or the hormone profile. And what’s been really studied is the estrogen withdrawal hypothesis that initiates a migraine. But let’s just look at lifespan.

And the blue indicates men and the incidence and prevalence of migraine in men, and the pink are women. And you can see that very early on in childhood, boys tend to be diagnosed with migraine more frequently. As soon as you start getting to the reproductive years, that’s when that incidence and prevalence really increases with women. And that persists throughout the lifetime, the lifespan. 

And you can always see like for both men and women, as our lifespan evolves and our hormone levels change, that that changes the prevalence of migraine. Let’s look at this even closer because when we think about the hormonal milieu and the changes that happen during the menstrual cycle, we have seen this as an endometrial issue, that menstrual cycles give women periods, right? So we’ve looked at it from that perspective.

And when we look at and compare the follicular phase and the luteal phase, if you just focus on the red line above the estrogen levels, you can see as the estrogen levels go up, you have ovulation, and then they have a couple dramatic drops. And what we’ve realized is that it is those drops in estrogen that are stimulating the migraine, stimulating the headache and the neuropeptide release. But the visual that we usually use is looking at the endometrium so we can understand those fluctuations.

But those fluctuations, the blood vessels, the inflammation, the response, the neurovascular cycles are happening in the brain. They’re happening in the heart and in the lungs and all throughout the body. So we have to really embrace this understanding of this fluctuation in all areas of what we study.

So with this estrogen in mind, it’s been thought that migraines are triggered by that rapid decrease during the luteal phase, right? And then what they feel, if you looked at, if you look at women who have migraines compared to women who don’t, and you chart their estrogen level, the faster the decline of estrogen during that luteal phase, the more likely they are to have the migraine. 

It’s been shown that males have migraines also, and that’s another biased issue because we have gendered this to be a problem for women only. But there’s some relationship between the androgen levels and estrogen levels that are important to really embrace when you’re looking at both sexes.

And what’s really interesting is that the number of migraines decreased during two specific times in a woman’s life, during pregnancy when estrogen is high and during menopause when estrogen is low. So let’s look at that. 

This is estrogen levels throughout the trimester. And you can see that just once a woman is pregnant, her estrogen levels increase and increase, and this is where they become migraine-free. They’re feeling good, right? And then what do you have as soon as you give labor, postpartum, that’s when you have that dramatic drop, and that’s when you have higher incidences. 

Let’s look at menopause, right? So reproductive years, cycling, estrogen, cycling, progesterone, perimenopause, very variable, right? So you may have really precipitous drops. You may not. There’s some relief here. And then postmenopausal, your levels stay low, and then there is relief. So really it’s the change instead of, and it’s the lack of having steady state. 

So compared to males, females are more likely to have longer duration of migraines, more likely to have those nausea and vomiting, photophobia. That provides a greater disability because it takes a longer time to recover, and they’re more likely to have recurrence of migraines than men.

Here’s the problem. It’s a clinical diagnosis, and this is challenging to have happen in a quick environment like the emergency department, right? We don’t have specific blood tests that can help us, right? Labs are not really helpful unless, you get a beta HCG. So if you want to look to see if someone’s pregnant, that’s important because that’s going to affect your treatment decisions.

But also because it’s a clinical diagnosis, and we have gendered this as a female’s problem, our data is mostly retrospective, and it’s mostly biased because it has predominantly included women. More women are invited to these studies because they’re figured, oh, it’s a greater incidence. Let me enroll them. And our data is incredibly biased towards women and against men in this particular example. 

And then there’s actually no validated tools to use in the emergency department setting to diagnose a migraine. So the International Classification of Headache Disorders says, okay, you have to have at least five attacks, and that fulfills this criteria. So there’s the time frame, four to 72 hours, and then you have to at least have two unilateral location, pulsating, very severe, physical activity, and then you need at least nausea, vomiting, photophobia, phonophobia. This is really impossible to use in a one-time setting. I could ask them how many attacks they’ve had, but it’s not very accurate.

This is another one that has actually been validated in a primary care setting because it does use a one-time visit. But it has not been validated in acute care setting. So we could look at this in the emergency department but understanding that it has not been validated.

So we could ask our patients during the last three months, do you have any of the following with your headaches? Nausea, does the light bother you? Does it limit your ability? And so response to this are two or three questions. 

In the emergency department, we teach a mnemonic. A mnemonic is not a validated screening tool. However, we do use this, and it’s called a POUNDing headache. So is it pulsatile? Is it the four to 72 hours? Is it unilateral, nauseating, disabling? You start to see some patterns here, but it’s important to know if you’re using these things as a clinical diagnosis, understanding the limitations. 

Why is that critical? Because there is a high risk of death. For instance, like I said, if you mistake a subarachnoid hemorrhage for a migraine headache, that has a much more high risk of death. And neither of them are visible, like trauma is or a fever. Also, it’s a high risk of death because migraines have been associated with cardiovascular disease. They’ve been associated with stroke. So it’s really important to understand that a migraine isn’t just a migraine, that it actually puts that patient at risk of more serious conditions. 

So our biggest decision-making step is when is neuroimaging indicated? And let’s go back and look at this. So we have the primary, we have the secondary. It’s when is it that acute condition, when do we assign it that we think it’s worth to rule out and consider a secondary cause like subarachnoid? 

So the American College of Emergency Physicians has some recommendations. For instance, they have this critical question: In the adult emergency department patient presenting with acute headache, are there risk stratification strategies that reliably identify the need for emergent neuroimaging? And so the level of evidence, just to remember, level A is they reviewed the evidence and it’s excellent. Level B, that it’s good evidence. Level C, you start to get to not a lot of evidence, but expert consensus.

So this is a level B, and the level B is saying that there’s this Ottawa Subarachnoid Hemorrhage Rule. So there’s a rule that was validated and it has a high sensitivity to rule out subarachnoid, a low specificity to rule it in. And that you have to use this if you are seeing the patient within the first hour of pain symptoms. Again, don’t use any one single sign. 

So let’s look at this. It’s the Ottawa Subarachnoid. It’s for adults, anyone over the age of 15. And if you have symptoms of neck pain or stiffness, if you are age 40 or older, if you have a witnessed loss of consciousness, if this happened during exertion, either exercise or sexual intercourse, which I see. Is it thunderclap? Is it peak in intensity? And do you have limited neck flexion? If you have any of these signs, then you cannot rule out subarachnoid hemorrhage, and you would move towards neuroimaging. So that is one step. 

This has been validated in emergency department setting and emergency department patients, and it was found to be highly sensitive for identifying subarachnoid. But again, you cannot rule out subarachnoid with this. 

So another one, in the adult emergency department patient presenting with acute headache, does a normal CT scan performed within six hours preclude the need for further diagnostic workup for subarachnoid? And this is a level B again. And what it’s saying is that if you do a CT scan within six hours of their symptom onset, and it is normal, and they have a normal neurologic exam, then that is sufficient. And then you can consider diagnosing this patient with migraine without moving towards neuroimaging. Of course, you have to make sure you have a more up-to-date CT scanner. 

The other thing we use in the emergency department a lot are red flags. And again, these are things that get passed down. So red flags for headache are thunderclap onset, focal neuro findings, fever, trauma, altered mental status. A lot of these make sense, right? 

And so in the adult emergency department, if still considered to be at risk after that negative CT, is a CT angio as effective as a lumbar puncture? Again, this gets into a later, a more advanced under a workup for subarachnoid. So not my particular focus, but again, shared decision-making, lumbar puncture, CTA are considered as effective. 

So let’s talk about treatment. This is critical. And what’s really important to realize is as we start to think about treatments and medication, let’s just review quickly the Ambien, zolpidem is another word for it. So what we learned from Ambien, Ambien was on the market for 20, 25 years or so, and it’s a sleep aid drug. And it was primarily prescribed to women, even though it was primarily studied in men, because women were more likely to be diagnosed with sleep disorders than men.

So what happened is when you study men and you approve the drug based on those studies, and then now it’s prescribed to women, the only time we can really assess whether that there’s adverse drug reactions is post-market surveillance. And so that’s what we discovered with this. There were lots of post-market surveillance that said women were waking up the morning after taking zolpidem or Ambien and then getting into motor vehicle crashes. Motor vehicle crashes are life and death. And preventing any one of them prevents a crisis. So this prompted another look.

And what they discovered is that when they gave women and men this drug and they waited the same amount of time, they checked the serum concentration of the drug and women had two times the serum concentration compared to men. And so that was related to the fact that they had more concentration of the drug in the morning and then were more likely to have impaired driving. So this was the first Food and Drug Administration in the US sex-based dosing recommendation that men should be prescribed 10 mg and women 5. 

This is one medication. We have 20,000 medications approved for use and prescription in the United States right now. So keep that in mind when we’re thinking about our medication options. A lot of this is going to be new evidence that we’re coming to light.

So let’s look at a quick case. We have Erica who’s a healthy 24-year-old medical student. She presents to the emergency department with severe headache and nausea. She’s had it for the past six hours. She had a similar headache once a term. It keeps her from clinical duties one to two days if untreated.

After a careful history, physical exam, looking for all those things that we talked about, you examine, you decide she has a migraine. Why do you decide that? Because you checked the Ottawa Subarachnoid Hemorrhage Rule and she doesn’t meet any of these criteria. 

You looked at your red flags. She doesn’t have any of these. You’re using your mnemonic for migraine and you’ve discovered that yes, she meets a lot of these criteria. So you’re comfortable saying that this is a migraine headache.

And what is the best ED treatment for her? And so what we want to really consider in the emergency department is a lot of patients have already tried over-the-counter medication. Not only that, if they have migraine, they often will have the nausea and vomiting with it. So a lot of the first-line treatments in the emergency setting are parenteral, meaning bypassing the GI system. So usually IV, subQ, IM, that sort of thing. 

And there’s three main classes that are considered first line. One is NSAIDs, so the nonsteroidal anti-inflammatory drugs, like Ketorolac, which is IV. It has not been very well studied in this particular setting, but it has been found to be very effective, especially when studied even as monotherapy. 

Triptans, very common, are serotonin agonists. This is abortive therapy, and you can use it subQ or nasal. This is contraindicated in those with known cardiovascular disease, if they’re pregnant, or if they have stroke. And it’s less effective if it’s been going on for a long time. This is really good to give in the early stages. Interestingly, and I will bring this up again in a moment, is that the serum concentrations of triptans are higher in women than in men. And this is quite the case for a lot of medications and has to do with the metabolism differences. So keep that in mind. And females are more likely to have increased relapse rates after taking a triptan than men. 

And then you have antidopaminergic ones, so prochlorperazine, metoclopramide. These things are great for that gastroparesis piece, antiemetic, and it’s also antiheadache. It is working on the neurovasculature. Of course, you feel sedated, and you can have extrapyramidal symptoms like akathisia. So they’re very restless. Diphenhydramine will reduce that, especially with prochlorperazine, not as much proven with Reglan. 

So this is really the first line that we have in our bag of tricks. Acetaminophen IV is not readily available. My previous institution, I was there for almost two decades. And as soon as we started having acetaminophen IV, it was really incredible. I found it very, very effective in migraines and many other reasons. However, this is the one that’s most commonly tried before the patients actually arrived to the ED. 

IV fluids, now think about this. If someone’s had a headache and it’s been going on for a while, they’ve been nauseous and vomiting, yes, they’re probably dehydrated. Or if they were dehydrated to begin with, that’s often a trigger for migraines. So IV fluids can be very effective if you feel as though this is part of the patient’s presentation. 

And then there’s Haldol and droperidol. They find that when it’s been looked at in clinical trials, that it’s about as effective as placebo. And placebo is quite effective. So it’s unclear whether it’s related to just a placebo effect. And again, always have to look at risk factor profile, like QT prolongation, which is much more prominent in women. Women have a longer QT interval on average. And then they’re more likely to be on lots of other prescription medications, which continues to increase their QT interval and increase their QT interval. So this is important to really consider, especially in women. 

Third line are opiates. They’re considered less effective. There’s greater disability. It’s not an abortive process. It’s more of a relief of some of the pain, but then there’s somnolence with it. There’s also an increased likelihood of ED recidivism, which means that the patients come back and then come back and then come back. So this may be still, there are circumstances where this could be very helpful. This is up to our judgment. We don’t want patients to be in pain, but we have to also consider with all of these, it’s really considering the benefits and the risk. 

What I think is really interesting now is the addition of steroids, dexamethasone. So there’s an acute inflammatory process, right? You have those neuropeptides that are there. You are having a sort of depressed cortical stimulation. There’s a depolarization, and then there’s this depressant process and all this neuronic activation. And so what’s been happened is this discovery that actually giving dexamethasone does not necessarily help the acute phase of the pain, but it does help reduce the recurrence within that 72-hour period. So that’s been critical. 

And then this is so interesting that we’re having all these new preventive treatments of migraine. Certainly things like estrogen, as I mentioned already, someone can be placed on hormone treatments or birth control pills, oral contraceptive pills, or even other modes of delivery. Because remember, there are receptors for estrogen in the cranial vasculature, in the dura mater, in the different parts of the trigeminal vascular system. And remember, the consistency of estrogen levels reduces the incidence of migraines.

So this is an interesting thing that many can be discussed. Of course, the calcitonin gene-related peptide, the CGRP, is fantastic. And I say fantastic because I’m not a neuroscientist, but I love the fact that we have other options that we’re discovering. And why not affect that period where you have that neuromodulation, where you have the sensitization of the brain and the trigeminal system. And so I think that’s critical. Some things that are also tried are topiramate, some antiepileptics, beta-blockers have been shown to be effective.

So I want to just also say that the guidelines for acute treatment and prophylactic treatment are biased because they really don’t address the sex and gender observed differences. We see these differences in treatments of Ambien as the flagship, and then triptans. So if we consider that there are differences, why don’t we have recommendations for the dosing of these medications based on the biological sex or the gender identity of the patients? The only thing that’s really sex-specific is if it’s considered a menstrual migraine, and then you could use really evening out the estrogen levels as a treatment option.

But with all of those other treatments, it’s not studied and it’s not discussed, but it’s starting to be. Now in the US, the Food and Drug Administration has the drug trial snapshots where you can go online and look up a drug. Newly approved drugs are now being showcased on their website for transparency reasons. So you can say, oh, I was just given this new drug, this Ajovy, which is a new preventative medication. You can see who was enrolled in the study that was used to approve that drug. And you can see that 87% of those that were enrolled were women and 13% were men.

So these are the biases that we are living with and we’re understanding and we’re trying to really illuminate if this matters. What we need to do is make sure that we have sex-specific data so that the data is disaggregated by sex and then compared. Because women, they’re more likely to seek professional medical advice. Women are more likely to encounter with the healthcare system than men. So with that, women are more likely to be prescribed. And so they’re more likely to be prescribed preventive medications like a triptan. And they’re more likely to have pain relief. 

But what’s really interesting is that when you look at the metabolism of the drug, there are sex differences in the pharmacokinetics. What are pharmacokinetics? So it’s how the body deals with the drug and how the drug deals with the body. So it’s really just a movement of that medication. And what has been shown is that both the area under the curve and the total concentration of the drug of triptans are higher in women than in men. 

However, what’s really also interesting is that may not have a lot of clinical importance. It’s not just that. So this was really interesting research, and it looked at non-pharmacokinetic factors of variability of response to triptans. So even if women have higher concentrations, it may not relate to the clinical piece that we’re measuring. But there are other responses that might be happening to the fact that women have higher concentrations. Maybe it’s having a difference in placebo effect by sex or gender. Maybe the course of the migraine is different between men and women and therefore that concentration comes into place.

And thinking about this also, it’s important that we consider, are women taking contraception? Are women wanting to get pregnant? A lot of the medications might be contraindicated, like valproic acid and Depakote are contraindicated in pregnancy. 

So it’s really important to understand what is the biological sex of my patient? What is the gender identity? How does that affect their presentation of disease? How does that affect the response to treatment? 

This was a nice, simple, bold study that said this is a suggested prescription for severe migraine in the emergency department. Saline fluid, prochlorperazine, diphenhydramine, remember those two go together, an NSAID, Ketorolac, and then dexamethasone to prevent return.

So I thought it was worth, it’s hard to come up with, and there’s so many options. Erica got that. She got prochlorperazine, she got diphenhydramine, Ketorolac, and saline, and she got dexamethasone. And she’s doing really well. And she got a family physician referral and some handouts. 

I was asked to just briefly mention status, which is when it lasts greater than 72 hours. Again, this is the art of medicine, right? So we have all of those options and there are no direct standards, and we need to do our own research and to put this together. 

So when it’s long, I did find this. This is a step-by-step suggestion that you can start with a lot of those first-line ones to the second lines, a second dose of some of the first and second lines, maybe consider nerve blocks, and then consider opioids. So again, consider this is the art of the medicine. 

This is a very simple, quick case. 35-year-old male comes in. He said he’s tried over-the-counter stuff. He rarely goes to the doctor. When he does have headaches, he goes to the emergency department, he gets IV Dilaudid, and he feels better. And you look and you saw that he’s gotten that the past couple of times, and he’s starting to present frequently. 

So opiates are not considered a good idea and avoidable when possible. And actually, this study looked at prochlorperazine was more effective than hydromorphone or Dilaudid. So, I think it’s really important. The American College of Emergency Physicians agrees that trying to use preferentially nonopioid medications is critical. 

I just want to point out where I get a lot of this information based on sex and gender. If you go to the website, sexandgenderhealth.org, and you go under the resources section, there’s a validated PubMed search tool that will automatically put search terms into your PubMed. And then you can add whatever field that you want. 

So when I was preparing for this, I used this PubMed search tool. I added the word migraine. And now I have all of this really, if you look at the graph on the left, and you see where the amount of evidence, look at the last five years or so, the amount of evidence that we’re getting of sex- and gender-specific conditions in relation to migraine are increasing and are really interesting. 

And, you know, just a plug for expert to physician is this collaborative effort, OM Health Hub, where we are collecting the experts in migraine. And if, you know, I’m happy to bring some of you in on this, direct to consumer so that throughout the world, internationally, if you want to know sex-specific health conditions, especially related to your migraine, which is very common, as we know, you can go online and actually have a masterclass experience with the expert. 

So a summary, you can use the Ottawa Subarachnoid Rule to rule out the need for a CT scan. Don’t forget the red flags. Try to use non-narcotics. Start incorporating sex and gender evidence into your area of expertise and use shared decision-making.

*The contents of this video are intended for general informational purposes only and does not constitute professional medical advice, diagnosis, or treatment. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition. AMD and the speaker do not recommend or endorse any specific course of treatment, products, procedures, opinions, or other information that may be mentioned. Reliance on any information provided by this content is solely at your own risk.