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Voice-over: Welcome to Spotlight on Migraine, the Professional Series, a podcast hosted by the Association of Migraine Disorders. In the Professional Series, we dive deeper into migraine-related topics with the help of guests from the medical field. The content of these episodes is intended for medical professionals but may be useful or interesting for patients as well. 

 

This episode is brought to you in part by our generous sponsors, Amgen, Novartis, and Alder BioPharmaceuticals.

 

This extended episode features three lectures on the relationship between hormones and migraine. First, Dr. Julie Roth, a women’s neurologist, provides an overview of the difference in migraine manifestation in men versus women and an explanation on the cause of these differences. In section 2, neurologist Dr. Amy Hessler discusses menstrual migraine. She explains the timing of migraine during the menstrual cycle and an assessment of current treatment options for menstrual migraine. Lastly, Dr. Renee Eger, an OB-GYN, summarizes contraceptive options and hormonal management for premenopausal women with migraine, including risks and benefits.

 

Since 2015, Amgen and Novartis have been working together to develop pioneering therapies in Alzheimer’s disease and migraine. Together, Amgen and Novartis share in a mission to fight migraine and the stereotypes and misconceptions surrounding this debilitating disease.

 

Dr. Julie Roth: Thanks very much, and thank you again to Dr. Godley for organizing this wonderful and informative and very educational day for neurologists, I think, learning a lot about ENT, which is a field I don’t necessarily overlap with as much as I do with OB-GYN in my field of women’s neurology. And over the next hour or so, we’ll hear more from OB-GYN and also from this growing field of women’s neurology. And the reality is that you really can’t practice women’s neurology without seeing quite a bit of migraine, because far and away, it is probably the most prevalent neurological condition that we see in women and it is greatly impacted by hormones.

 

So global estimates of primary headache disorders in general — migraine is definitely — we all know it’s a very prevalent neurological disorder in the general population; otherwise, we wouldn’t be here. These are estimates from over 10 years ago, and you can tell that this is an older estimate because chronic daily headache — a lot of these patients have now been reclassified into chronic migraine or new daily persistent headache. Primary headache disorders tend to be more common in women than men, with the exception of the trigeminal autonomic cephalalgias. These are rarer disorders. We do see them as neurologists, but again, they’re not very prevalent among the general population. And cluster headache, which is more prevalent in men, leads the pack among the rarer disorders.

 

This is another more recent breakdown about migraine prevalence by country, and it’s maybe hard to see the countries, but rather than the takeaway message being that there’s a disparity in true migraine among different countries, what I think we should be thinking of from this slide is more about migraine education. So anecdotally, it is extremely common for me both as a clinician and just as a human being to hear stories where people say, “You know, I get these migraines.” 

 

Well, what do you mean? 

 

“Well, I feel like my head is throbbing, and it’s killing me, and all I want to do is go and lie in a dark room, and I’m sick to my stomach. It’s a migraine.” 

 

And of these patients and people that we all know, roughly 100% of them are right. They didn’t need a doctor to tell them they had migraines. If they tell you they have migraines, they are usually right. 

 

On the other hand, we’ve heard a lot today about sinus headache — people saying, “Look, I have a sinus headache,” but in fact, you really have a migraine. And so there’s a tip-of-the-iceberg phenomenon not just in our country but worldwide. I see many patients who thought it was normal to always get a headache that was throbbing around their periods. They didn’t know that wasn’t part of their menstrual period. They didn’t know that that actually has a name, and that’s migraine.

 

As you can imagine, migraine affects more women than men, but it’s a little more complicated than that. It peaks within the childbearing years, and during those years, the ratio between female migraineurs and male migraineurs is the greatest: 3 to 1, sometimes 4 to 1. As Dr. Eger mentioned, up to 25% of women during their childbearing years will report migraines. But on the low end and the higher end of the age spectrum, that ratio diminishes to roughly 2 to 1, but not 1 to 1, so there might be more to it than just the hormones.

 

This is another breakdown. This was done in a prospective study by Dr. Dawn Buse at Montefiore Hospital, and this was a very, very large survey trying to explore that ratio. They also looked at probable migraine, which is defined as not meeting all of the checkboxes in the International Headache Society criteria, and the ratio was still a bit higher in women than men. What Dr. Buse also looked at — and I realize that you won’t be able to see the details of the slide from in the back, but I’ll tell you. She looked at the difference between what migraine looks like among women versus men, and these chunks roughly translate to the associated symptoms of migraine, the frequency of migraine, and the pain of migraine. And while they were roughly similar with the frequency and the pain, a lot of the associated symptoms of migraine — the nausea, the light sensitivity, the blurred vision — seem to be more common in women than men. 

 

Furthermore, disability was higher among female migraineurs compared to male migraineurs. The MIDAS test has been referenced earlier. The MIDAS is a validated inventory that assesses disability from migraine, and women scored higher on the MIDAS. They also reported higher rates of ER utilization, urgent care utilization. Interestingly, women were more likely to receive a diagnosis of migraine from their primary care or specialist provider, but they were also more likely to receive another diagnosis — among those, sinus headache, which we’ve talked about at length today, and also stress headache, which to me is also, “What is that?” I’m not really sure as a neurologist.

 

But another question arises. Are there maybe structural brain differences between male and female migraineurs, men and women in general? So epidemiologic studies are very large. Scientific studies are often much smaller, so we can’t really give you definitive information about these studies. But in one study, a volumetric MRI study and also fMRI study, researchers looked at female and male migraineurs and female and male controls, and what they found on volume measurements of areas of the brain, and this — so I’m actually an epilepsy specialist, and so I’m very interested in the neuroanatomy and what the cortex is doing and what these structures are doing and how they may be connected. So female migraineurs but not male migraineurs and not the healthy controls of either sex — these female migraineurs had thickening in two major areas of the brain, the posterior insula and the precuneus. The posterior insula is a major hub. These are both hubs, so a lot of epilepsy now, it has to do with nodes or hubs and how these nodes are connected with one another. The posterior insula plays a big role in pain. It plays a big role in the autonomic system. The precuneus is a little more of a mysterious structure we’re still learning about, and I asked a few neuroanatomy specialists, scientists, and I looked it up, and the precuneus actually plays an interesting role in our sense of self and where we are in the world in relation to other people and our environment. 

 

So when I think about migraine, I think about triggers, the stress — “What do people think of me? Did I stay up late? What’s going on in the weather? What’s going on in my environment?” — and how this might impact migraine. These are women that maybe these structures are not just thicker but hyperfunctioning.

 

The second part of this study, they applied a noxious thermal stimulation — which sounds like torture, and maybe it is — but you can actually use very, very icy, cold water to stimulate pain receptors, and it’s not harmful to tissue — it’s not destructive to tissue — and that’s one way to test pain. And the women migraineurs, on fMRI — they had stronger responses in their limbic system — the amygdala, the parahippocampal gyrus — and these are structures that have a lot to do with our emotions and our memory and our cognition and our concentration. So I think we should all be thinking about how that may play a role in migraine. When you’re in the throes of migraine, what is your emotional state like? What is your concentration like?

 

Another way to study hormones is to look at men and men’s hormones, because we’ve taken away possible structural or DNA differences, chromosomal differences. And it turns out someone did study this, and about a year ago in our green — we call it the green journal too, our neurology journal, and OB-GYN has their own green journal, but they’re both the green journal. So men with migraine actually had higher levels of circulating estrogen and slightly lower androgens compared to men without migraine. So that’s very interesting.

 

So what do these hormones do on the brain? The brain has hormone receptors, as you can imagine. We know this in epilepsy because estrogen is epileptogenic, or it makes seizures. It makes excitable — hyperexcitable brain structures and progesterone can be anticonvulsive and inhibitory. How might that translate to migraines? Well, it’s interesting, and it’s probably a bit complicated. In animal models that have looked at this — there’s one animal model, a mouse model of migraine, the CACNA1a mutant mouse, which is thought to be a model for familial hemiplegic migraine. These mice, when they were given female hormones at high levels, particularly estrogens, it enhanced cortical spreading depression, which is thought to be responsible for the aura of migraine, while male hormones actually protected against it. So that’s interesting. Another tidbit: sex hormones may regulate nociception, the enhancement of the trigeminal vascular system, which has to do with the pain of migraine and the autonomic dysfunction of migraine. 

 

How does this relate to people? What we know, and what we’ll learn about in the next few talks, is that these fluctuations can play a role on female migraineurs, who are already at risk for migraines. We know that migraine aura is actually more prevalent in the higher-estrogen state, and we may hear a little bit more about that today. However, there’s often a very complex and unpredictable relationship. What we think might be helping our female migraineurs when we start making suggestions about hormones, sometimes, it actually has a different effect than what we expected. I’ve had patients who had the Mirena IUD and then their migraines cleared up, and I have no explanation. That progesterone’s supposed to act locally. I don’t know what happened. So it’s very interesting.

 

We do know about the stroke risk that’s higher among migraineurs with frequent aura, but I’ll say one more thing. There’s a third wheel to this that I’m very interested in, which is preeclampsia and the hypertensive disorders of pregnancy. Migraine’s a risk factor for preeclampsia, specifically migraine with aura. Preeclampsia is a risk factor for stroke and cerebrovascular disease and cardiovascular disease. Migraine with aura is a risk factor for stroke, so how do these little bubbles kind of fit in with each other? And this is something that we really need to learn more about.

 

So in the end, I’d like to see more research in this area, and I think that’s the purpose of this symposium. But I’m all set, and I’d like to turn over the podium. 

 

[pause]

 

Dr. Amy Hessler: I’ve been the clerkship director for eight years, and I want to leave people with useful information as they leave my talks. So the objectives here — that I was asked by Dr. Godley, who kindly invited me to speak today — was to review terminology of headaches, to explore the menstrual cycle and the timing of menstrual migraines, and then to assess the treatment option for menstrual migraines. And by this picture, I’m sure there’s some of you in the audience who are migraineurs yourselves. I am not a migraineur, but my patients do tell me that it feels as if their brain is being pulled out of their head, so this is probably an accurate description, probably drawn by a migraineur.

 

So in discussing primary headache disorders versus secondary headache disorders, amongst us as neurologists, we decided that it’s good just to make sure everyone understands these basic definitions. So the International Classification of Headache Disorders is our go-to place when we as neurologists define migraines and different types of headache disorders. So primary headache disorders is the disease itself. So this encompasses migraine; tension-type headaches; the cephalgias — the trigeminal autonomic cephalgias, of which Dr. Roth had mentioned cluster being the most famous of that; and then the other primary headache disorders. 

 

And then when it comes to the secondary headache disorders, there are actually seven categories, all with subcategories. So this is actually an interesting paper that Dr. David Dodick had published in Seminars in Neurology in 2010, and it’s a mnemonic that I teach to my medical students, but I think it’s helpful to kind of conceptualize “How do I think about secondary headache disorders?” And the SNOOPPPP — with four Ps — SNOOPPPP mnemonic is one that’s popularly thought of, so looking for systemic symptoms, neurologic symptoms lasting greater than an hour, onset of a thunderclap in nature, onset over the age of 50, a pulsatile tinnitus, postural aggravation, papilledema on exam of the fundus, and then precipitating events. I ask my patients, “When you sneeze, cough, bear down to have a bowel movement, does your head pain worsen?”

 

So again, instead of getting caught up in all the details of this subclassification, that SNOOPPPPs mnemonic is kind of interesting when you’re thinking about secondary headache disorders. And as I use with my medical students, you don’t want to see a patient in your clinic, or I don’t want to see my patient in the clinic. Or oftentimes, they’re going to the emergency room after my rotation, and it’d be a migraineur, and you don’t take a careful enough history, and this headache is different. And they’ve had a sentinel bleed, and then they drop dead of a subarachnoid hemorrhage in the parking lot. Not a good thing, even if — so taking a careful history is the key. And then this little cartoon, I actually borrowed from one of my colleagues, because if you’re typing a status report on your Facebook page, you’re probably not having a migraine.

 

So when we talk about the International Classification of Headache Disorders, we talk about migraine with aura. And this has always seemed to me when we look at these diagnostic criteria, kind of like a Chinese fast-food menu. So do you have an A? And then in B, you have to have a reversible aura. And then in C, you have to have at least three out of six. So it’s a little bit confusing. So migraine with aura, most of the time, it’s — 90% of the time, it’s going to be a visual aura, so — then followed by a sensory aura or a speech and language difficulty. So sometimes, people actually have a cluster of aura symptomatology, and it usually follows that trajectory, that it’s visual followed by sensory followed by speech. 

 

So the interesting thing, however, is that you only need two lifetime episodes of aura to be classified as migraine with aura. And as Dr. Eger was talking about, this is important when you’re thinking about, in a woman, as far as, “Can I give her oral contraception or not with the stroke risk factors?” So instead of just asking, “With your headache, do you have a visual aura?” because that’s the most common, you want to say, “Have you ever had an aura?” So only two lifetime episodes — because I’ve actually when I’ve phrased it differently, had colleagues that — or, had patients that have said, “Yes, I’ve had that, but just a couple of times. Most of the time, I don’t have it.” And then three of the six criteria below, that it spreads over time.

 

And then migraine without aura — so interestingly, in migraine with aura, you only need two of those attacks. Migraine without aura, you need five attacks, and the pain should be unilateral, pulsating. I like to say to patients, “If you couldn’t use the word pain, how would you describe your headache? Is it throbbing, is it sharpshooting, is it stabbing?” just to get a characteristic of the pain that they’re experiencing. And then either nausea or vomiting or photo- or phonophobia. 

 

Now, moving to the topic that Dr. Godley had tasked me with, the menstrual migraine — and it’s already been touched on a little bit in the earlier talk — but pure menstrual migraine is just a migraine that is around the time of a woman’s menses, versus menstrually related migraine is around the time of the menses plus other times during the month. So it’s kind of important to differentiate that in optimizing our treatment for our patients. So I am not going to get into the complicated — in the setting of have gynecologists in the audience — the complicated menstrual cycle. What’s important in understanding menstrual migraines is that day 1 is the beginning, or when a woman menstruates; and really, as Dr. Roth — and prior to that, what we were speaking of is that drop-off in estradiol level that, really, we have to be concerned of as far as precipitating migraines or menstrual migraines. So in pure menstrual migraines, it can be two days prior to their menses or three days into their menses, whereas menstrually related migraines, it’s that same time period but also other times during their menstruation period. 

 

So it’s really that estrogen withdrawal effect. So I found this was fascinating that in neurology in the early 70s, they recognized this when they looked at these headaches and when these women were having these headaches, that actually, estradiol prior to menses delayed menstrual migraines. And then artificially raising this level by giving that woman external estrogen supplementing, that could actually — the migraines were not provoked. And then some further studies in the late 90s looked at GnRH alone or with estrogen and progesterone. Then skipping to 2003, it was — GnRH alone was not adequate, but then adding that the transdermal estradiol, could be helpful. And then Calhoun in Cephalalgia in 2011 [sic] is adding estrogen back throughout the cycle or is potentially decreasing that placebo week or decreasing that period of time could be beneficial. And that’s actually what was done in this last study in 2011, where they went from that placebo week of being seven days in duration to being only four days in duration, and there was a statistically significant reduction in intensity and duration of the menstrual migraine. So estrogen is — I came up with this — is “estrogen is egg-celent.” It’s “egg-celent” in — you’ll hear about it when Dr. Waters speaks next. It’s good because you’re not having those circulating estrogen levels, and when you have this drop-off, this is where the woman with menstrual migraines is most vulnerable to have those attacks. 

 

So now, importantly, treatment options. So treatment options — so this is — Dr. Tepper, who’s a headache expert, looked at treatment options, so how can we treat these women with their menstrual migraines? Should we treat them acutely? Should we give them short-term prophylaxis or daily preventatives? So for acute treatments, if they’re infrequent — their migraines are infrequent, we can give them an abortive therapy. If they have predictable menses and menstrual migraines, then we can give them a triptan or a non-triptan; or if they’re not predictable and they have the menstrually related migraines, then we might want to consider a daily preventative medication.

 

So as far as the acute treatments, the triptans were looked at in randomized placebo-controlled trials. Various triptans were looked at. Most of them that were looked at had the longer half-lifes, so actually, rizatriptan had the best evidence for acute treatment. So their criteria was pain-free intervals at 2 hours, which was between 33 and 73%, and then pain relief from 2 to 24 hours, so sustaining pain relief was 63% in sumatrip — I’m sorry, rizatriptan. And then sumatriptan came in second. Pain-free response at 2 hours was 61 to 63%. 

 

So as far as the short-term prophylactics, again, the longer-acting triptans have been looked at. There’s been various randomized controlled trials with frovitriptan, zolmitriptan, naratriptan, and then actually comparing them head to head, which I think is interesting. And what they found was, actually, zolmitriptan dosed more frequently and frovitriptan dosed BID rather than QD was more effective, but then they realized that TID dosing was better than BID. BID was better than Q day, so more frequent — obviously, the point being where frequent dosing was beneficial. And then non-triptans that were used as preventatives were magnesium, naproxen, DHE, and then also estrogens, as was previously talked about.

 

And then lastly, the daily preventatives. So you need to be cautious with the daily preventatives because it can interact with their oral contraception, so topiramate increases the rate of oral estrogen metabolism at doses — so this is an interesting drug, and we’ve learned this in epilepsy studies — at doses higher than 200 mg a day. But if you stay at 100 mg a day, you’re not going to interfere with estradiol metabolism. So it’s category D in pregnancy. Now, we move to category D based on the North American epilepsy registries. In 2011, they were noticing that when women took this for their epilepsy, they were having a higher rate of cleft lip and cleft palate, and so that’s why it moved from a category C to a category D.

 

Lamotrigine has limited data for migraine prophylaxis, but there’s an interesting relationship that — Dr. Roth and I and us as women neurologists struggle with this because it’s challenging to use because the levels fluctuate when we use this with our pregnant patients with epilepsy throughout the course of their pregnancy. But the estradiol lowers the Lamictal concentration — probably not quite as important in headache as it is in epilepsy, when you want to have a consistent level. And it’s category C in pregnancy. 

 

And then valproate, the interesting story — hopefully everyone in the room is aware that valproate is the one that we stay away from because it’s associated with neural tube defects. So it’s the only drug that is interesting. Depending on disease state, it has a different pregnancy category. So in migraine, it has it a category X, and I teach my residents, my medical students: women of childbearing age, I don’t use it in migraine, whereas in epilepsy, it’s category D. But Herzog showed that there’s minimal interaction between valproate and oral contraception.

 

And then gabapentin has mixed data, but it doesn’t affect your OCPs. And then it’s category C in pregnancy.

 

So in conclusion, menstrual migraines are severe, have longer duration, more resistant to treatment than non-menstrual migraines. “Estrogen is egg-celent”; hopefully, I can leave you with that. But as one of my stroke colleagues says, “It’s not so good in stroke,” when I show her this slide, so got to be cautious. So it’s good for pregnancy and in decreasing that fluctuation of estrogen levels and, again, probably why most migraines improve during pregnancy, as you’ll hear next from Dr. Waters. And then menstrual migraines usually improve during pregnancy. And then treatment strategies to think about, acute versus short-term prophylaxis versus preventatives. And for acute treatment, the best evidence is rizatriptan followed by sumatriptan. And then short-term prophylactics are frovitriptan dosed twice a day and — or, and then zolmitriptan dosed three times a day. And then long-term preventatives, we just have to be cautious with the interaction with OCPs. 

 

And with that, I’d like to thank you for your attention.

 

[applause]

 

[pause]

 

Dr. Renee Eger: Thank you everybody. After such an interesting scientific session prior to this, I think that you’re going to find this pretty easy to understand and an interesting topic for an OB-GYN to be talking about because — I want to thank Dr. Godley for the invitation, but I have to say, when I received the invitation, I was asking myself, “What in the world can an OB-GYN tell otolaryngologists and neurologists and other migraine specialists about headaches?” because in my world, we don’t think about that so much. And in fact, I probably can tell you more about all of my favorite athletes than I can about headaches. So instead, I think I’m actually going to focus on what it is that I do every day as an OB-GYN and how our specialty actually looks at headaches. I have no financial disclosures.

 

So my learning objectives are to define the American College of Obstetrics and Gynecology’s recommendations for contraceptive options for patients with migraines and the U.S. Medical Eligibility Criteria for Contraceptive Use as it relates to migraines and migraines with aura. And then finally, I’m going to review the options for hormonal manipulation, as you refer to it, for premenopausal patients who have menstrual migraine headaches.

 

So as a gynecologist, many of my patient visits center around attempts to either get pregnant or to avoid pregnancy, and there are essentially three clinical scenarios I address with sexually active, reproductive-aged women. So the first is women who actually want to get pregnant, so in these instances, my objectives are to optimize a woman’s care to keep her and her fetus safe both during — before, really, and during pregnancy. And preconceptual counseling in these patients includes assessment and treatment of medical problems. With respect to migraine headache management, patients are often treated with NSAIDs, triptans, and ergot derivatives. In pregnancy — and that will probably be addressed later in this session — first-line therapy is usually acetaminophen. NSAIDs and triptans are typically used as second- and third-line treatments and are reserved for use in the second and the third trimesters. Triptans in particular pose the risk of vasoconstriction of the placental blood supply, with sumatriptan having the best safety profile. Ergotamine is actually absolutely contraindicated in pregnancy due to the potential to induce hypertonic uterine contractions and vasospasm or vasoconstriction.

 

So the second answer is for women who want to avoid pregnancy. A typical woman spends approximately 5 years of her reproductive life trying to get pregnant and the other 30 years trying to avoid it. So in fact, data fairly consistently shows that approximately half of all pregnancies are actually unintended. So we generally want to choose a contraceptive method that a patient is likely to be the most compliant with, is the most effective, and would be the safest for her.

 

Sterilization and long-acting but reversable forms of contraception, which are commonly referred to as lark methods, such as IUDs and implants, are the most effective forms of contraception, with less than 1% of patients experiencing an unintended pregnancy within one year of use. Spoiler alert: these forms of contraception, even the progestin-secreting IUDs, have proven safety in patients who experience migraine headaches with or without aura and in patients who have menstrual migraines.

 

The next most effective forms of birth control include estrogen progestin–containing pills, which are often referred to as combined oral contraceptives. This also includes transdermal patches and vaginal rings, as well as intramuscular long-acting Depo-Provera. And these are methods with one-year typical-use failure rates of anywhere from 6 to 9%.

 

So approximately 28% of U.S. women use some form of hormonal contraception. Up to 25% of U.S. women are affected by migraines, largely during the reproductive years. So the question we are often asked is whether estrogen-containing contraception is safe for women who have migraine headaches. This shows the one-year prevalence of migraine headaches by age and gender. Close to 25% of reproductive-age women have regular migraines, and the peak prevalence is in women who are of reproductive age, so finding a birth control method that is safe and is effective for these women is vitally important.

 

One commonly recognized risk for migraine patients is the risk of ischemic stroke. In this survey by Beck showed that the overall stroke risk increases with age. The risk is 2 per 100,000 in 20-year-olds and 11 per 100,000 in 40-year-olds. This risk increases in the setting of migraine headaches, up to 8 per 100,000 in 20-year-olds and 70 per 100,000 for 40-year-olds. The risk increases further with combined oral contraceptive use, up to 280 per 100,000 women who are 40-year-olds who are using combined oral contraceptives are at risk for stroke. 40-year-olds who take combined oral contraceptives who have migraines with aura have 1 additional stroke per 500 patients.

 

Further evidence for this was published in 2017. These are the results of a national healthcare claims nested case-control study of over 25,000 ischemic strokes among reproductive-aged females. And just the use of estrogen-containing pills showed an increase in a woman’s risk of ischemic stroke. A history of a migraine headache without aura and without the use of estrogen-containing pills also increase the risk of stroke. But it was really the presence of migraine with aura that tilted the scale in terms of stroke risk. The risk of stroke was highest, with an odds ratio of over 6, in patients with migraine with aura on estrogen-containing oral contraceptives. So I think you are getting the picture here.

 

So when discussing a hormonal contraception, I think it’s also important to acknowledge the role that progesterone can play. Second- and third-generation progestins were developed to actually provide less androgenic properties than first-generation progestins did. The third-generation progestins in particular have this advantage; however, early studies suggested an increased risk of venous thromboembolic events, particularly with the third-generation progestins. A number of other factors, which we’re not going to discuss today, may influence this risk as well. Levonorgestrel is a second-generation progestin and is considered the progestin with the lowest VTE risk. But the important thing is that second- or third-generation progestins do not seem to impact the risk of ischemic stroke, regardless of what dose of ethinyl estradiol they are combined with as a combined oral contraceptive. This was based on a 2016 systemic review of 26 articles, which showed that progestin-only pills, injectables, implants, and levonorgestrel — which is a progesterone-secreting IUDs — were not associated with an increased risk for any venous or arterial events. So progestin-only contraceptive formulations — even oral ones, which may not actually be as effective as those that contain estrogen — are considered generally safe, even in patients with a history of migraine with aura.

 

So how do we determine eligibility for various contraceptive methods? The U.S. Medical Eligibility Criteria for Contraceptive Use and the U.S. Selected Practice Recommendations for Contraceptive Use are guidelines which have been adapted by the CDC from the World Health Organization. They provide recommendations on the safe use of contraceptive methods for women with various medical conditions. This is actually an app that you can get on your phone, and if you don’t already have it, you should consider downloading it. The data is updated every five years and was last updated in 2016. 

 

The recommendations are divided into four categories. So categories 1 and 2 are conditions where either no restrictions exist or the method can generally be used safely with appropriate follow-up. Categories 3 and 4 indicate the contraceptive choice poses potentially health risks to a patient and are generally not recommended. 

 

So ACOG, or the American College of OB-GYN, recommends that at the time of contraceptive initiation, the diagnosis of migraine with or without aura should be carefully considered in all women who present with a history of headache. Combined hormonal contraception can be used in women who have migraine without aura and no other risk factors for stroke with a U.S. MEC category of 2, whereas estrogen-containing contraceptives are not recommended for women who have a migraine with aura because of the increased risk of stroke with an MEC category of 4.

 

So the third and the final reason we prescribe contraception is as an adjunct in the treatment of disease. Examples of this would include women who use combined oral contraceptives as a way to decrease monthly menstrual period when they have symptomatic anemia or women who use progestin-secreting IUDs to help prevent the risk of the development of endometrial hyperplasia, for example, if they have polycystic ovarian syndrome. And menstrual migraines, in my estimation, actually falls in this type of category. 

 

So menstrual associated migraines affect approximately 8 to 14% of women. These are headaches that typically occur within two days before the onset of menses and last through the third day of menstruation. They’re almost invariably migraines without aura. Fluctuations in normal cycling estrogen and progesterone levels appears to be the trigger in the initiation of these headaches, although I look forward to what my neurology colleagues have to say about that. In particular, menstrual migraines appear to be triggered by a physiologic drop in progesterone levels at the time of menstruation — well, progesterone and estrogen both.

 

So menstrual migraines can be treated with NSAIDs, triptans, and ergot derivatives. In fact, a small placebo-controlled trial published in 1990 showed that prophylactic naproxen given twice daily beginning seven days before the onset of menses will significantly decrease the frequency, severity, and the duration of a menstrual migraine when compared with placebo. So the goal of hormonal treatment regimens for menstrual migraine is to minimize estrogen and progesterone fluctuation. Most combined hormonal contraceptives allow for a drop in the ethinyl estradiol concentration during a placebo week, which can trigger the menstrual migraine. So the extended use of hormonal contraception is an effective and safe way of minimizing endogenous hormonal fluctuation, and by this, I mean using a particular hormonal contraceptive in a continuous, uninterrupted fashion.

 

For patients with menstrual migraines, the use of continuous combined oral contraceptives, rings, or progestin-only oral pills, Depo-Provera, and even subdural progestin-secreting implants are all ways of eliminating normal hormonal estrogen and progesterone cycling. So rather than being contraindicated, these methods offer ways to improve headache severity and frequency. And when using oral contraceptives this way, eliminating the pill-free or placebo week is not only safe, but it also preserves a stable hormonal environment. And while progestin-secreting IUDs are safe for women who have migraines, they really are not particularly helpful in the treatment of the menstrual associated headaches.

 

So to summarize, ACOG and the U.S. MEC classify non-estrogen-containing contraceptive methods safe for women with migraines with or without aura. The ischemic stroke risk associated with estrogen-containing contraceptives is unacceptably high for women with migraine with aura, and effective alternatives exist for these patients desiring reliable contraception. For patients with menstrual migraines, the use of hormonal methods that allow for steady-state estradiol levels appears to be effective in mitigating and in some cases eliminating menstrual migraine altogether.

 

Thank you for your time.

 

[music]

 

Voice-over: Since 2015, Amgen and Novartis have been working together to develop pioneering therapies in Alzheimer’s disease and migraine. Together, Amgen and Novartis share in a mission to fight migraine and the stereotypes and misconceptions surrounding this debilitating disease.

 

Thank you for tuning in to Spotlight on Migraine. For more information on migraine disease, please visit MigraineDisorders.org.

 


This podcast is sponsored in part by Amgen/Novartis and Alder BioPharmaceuticals.

*The contents of this podcast/video are intended for general informational purposes only and do not constitute medical or legal advice; the content is not intended to be a substitute for 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. The speaker does 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.