Thank you for joining the Migraine Education Series. I'm Brittany Mays, a Headache Specialist at Vanderbilt University Medical Center, and I also serve as a Headache Specialist at our Headache Center of Excellence at our Nashville VA. And I'm going to be presenting to you the pharmacologic approach to migraine treatment. We will go ahead and get started. I do not have any disclosures pertinent to this presentation. At the end of this lecture, I hope that we'll be able to review the preventive and acute treatment options for migraine, and that you'll be able to understand first and second line pharmacologic treatment options for migraine that are available. Now, this is my favorite way to start this lecture is how do we approach migraine treatment? And I think sports, they bring us all together. This is probably the best analogy I give my patients. So we approach migraine management with the two-pronged approach, preventive and acute treatment. So I want you to think of preventive treatment like it's the defensive line here in the soccer field, or like you're building a fence for the patient, right? The purpose of prevention or the purpose of your defensive line is to reduce the migraine frequency as well as reducing the migraine intensity. And so just like with a true defensive line in soccer, there are multiple different players coming together to form that defensive line and to build that strong force. And similarly, with pharmacologic approaches to prevention, sometimes we'll use small doses of multiple pharmacologics to really work together and try to slow the frequency of migraine down. But with even the most proper preventive treatment in place or the most sound defensive line in soccer available, we know that there's those awesome players, I'm a fan of Killian Mbappe, that can break through the defensive line and they are gonna score. So we know that with a proper preventive plan in place, breakthrough migraines can still happen. And that's when the acute treatment or the goalie comes in. And so the goalie or acute treatment is the last ditch effort to try to make migraine headache and migraine associated bothersome symptoms more manageable. And so just like with a true goalie, at some point, if he's taking a lot of, he or she's taking a lot of shots, they're ultimately gonna miss and the ball's gonna go on the goal. Same thing with the acute treatment approach is that if it gets used too frequently, it's probably gonna lose its effectiveness with time. And more worrisome is that it may cause rebound headache or medication overuse headache, which is more refractory. So that's why it's more important if you hear that patients are using their acute treatment options quite often, it's probably a preventative problem, not as much as an acute treatment problem. So when do we start preventive treatment? Now I operate clinically using the American Headache Society consensus statement on preventive and acute treatment. So right now there's no definitive rule of thumb. So in my clinical practice, if patients have less than four migraine days per month, I typically do not start preventive treatment because at that point, I would feel that the risks are outweighing the true benefits. But if patients are progressing to maybe four to eight migraine days per month, I may or may not start preventive treatment. And that's where we truly use an individualized treatment approach in talking with our patients. Some may wanna be more aggressive versus others. And there are alternative options that we could consider if they wanna be a little bit less aggressive. So I let the patients guide me and we work as a team when it's kind of that gray zone number of headache days per month. But if patients are presenting with more than eight migraine days per month, I for sure am going to educate them about starting pharmacologic preventive treatment because at this time, I'm really worried about that evolution into chronic migraine, which is more, it happens more readily and it's way more difficult to transition from chronic migraine to episodic versus transitioning from episodic to chronic. So we'll talk about prevention. Another question I get from my patients is how long do we have to be on preventive treatment for? And that's reasonable, right? A lot of patients with migraine are younger. They don't wanna commit to lifelong medication. And so I'll educate my patients that we want to achieve stability. And stability can mean a variety of things for each patient. That could mean for some patients that maybe their headache frequency reduced by 50% and that's stability. For some patients that might mean that, oh, I have one to two migraine days per month, that could be stability. But we wanna achieve that stability for six months to a year. And at that point, we'll discuss weaning the pharmacologic preventive treatments. Alternatively, when do we start acute treatment? If patients are seeking care for headache, arguably all of them should be started on acute treatment for migraine. What's important though, is the education regarding medication overuse headache. And so oral analgesics, especially those insets are the most common overuse medication for migraine. And we have data now to support that too frequent use can contribute to medication overuse headache or rebound headache that tends to be more refractory to treatment. So in essence, we want them to limit their acute treatment to no more than two times per week on average throughout the month to help prevent this and to prevent complications from this. And how do you assess though that an acute treatment is actually working for a patient? My rule of thumb is that, as we've discussed on the other lectures, migraine is such a complex presentation and a multi-phasic syndrome that typically by the time that the headache appears in phase three, everything biochemically has already been activated in the brain. And so the goal really is to make things more tolerable. If it takes it away, fantastic. But the goal is to make migraine and migraine symptoms more tolerable so that patients can continue about their day and function as they need to. So ideally an acute treatment should be more than 75% effective in making symptoms more tolerable or completely alleviating migraine. Now we'll transition into discussing pharmacologic acute treatments for migraine. And so we have our two gold stars here, and those are to indicate that these are current first-line treatments or first-line acute treatments for migraine. So we'll start on the left-hand side and review triptans and ditans. So triptans are serotonin 1B1D agonists. The serotonin 1B agonism causes potent vasoconstriction, which helps to eliminate and reduce the amount of free and free flow, truly, of the excitatory neuropeptides that are being released with that serotonin 1D agonism. So there are seven different triptan formulations, and there are nine total formulations based on the route that are available. So we have oral route, there's intranasal, and there's injectable formulations. But with that serotonin 1B agonism, with that potent vasoconstriction, that means for a lot of patients with medical comorbidities that triptans are contraindicated. And so a new class of medications have been brought to market, which are these ditans, which are serotonin 1F agonists that don't have that potent vasoconstrictive activity. And so this could be a great option for patients that do not or have contraindications to triptans. So our gold standard really is to use triptans in combination with NSAID if there's not a contraindication, and then we'll use anti-emetics as well. And so we're gonna slide over to the right-hand side of the screen where we see this gold star and it says the analgesics. So as I discussed previously, the NSAIDs are the most commonly overused acute treatment medications when we're treating headache. And so we often need to counsel regarding the risk of medication overuse with these. And if patients are presenting with medication overuse, how to reduce the frequency of their NSAID intake. But as combination therapy with triptans on an as-needed basis, no more than two times per week, these are quite effective. And the anti-emetics that we tend to prefer really are Reglan, Phenergan, and Compazine, all have potential sedation risk. And then they have also those extraperimental side effect risk. And so sometimes we'll co-administer it with Benadryl to avoid those side effects. I want to draw your attention to the bottom here where in headache medicine now, we are truly avoiding barbiturates and opiates. We have data to say that these medications for acute treatment of migraine really don't have a place and can lead to worsening headachronicity, can lead to central sensitization, dependence, and horrible withdrawal. So in my practice, I do not prescribe these medications for acute treatment of migraine. So let's start reviewing the triptans a little bit more in detail. So again, there's seven different triptan medications and nine different formulations, and they all vary based on formulation, half-life, bioavailability, my apologies, and tolerability. As far as the clinical side effects we see with triptans, about 20 to 30% of patients will present with triptan tightness with the short-acting triptans. And what is that? So triptan tightness often gets mistaken for anaphylaxis as patients will experience tightening in the jaw, neck, and chest that can be really off-putting. So it's really important to counsel your patients about this before implementing the triptans. Triptans can also cause nausea, emesis, flushing, and dizziness. Then we have to be mindful of patients with sulfa allergy. There are a couple of triptans that are safe in those with sulfa allergy, including frovatriptan, rizotriptan, and zolmatriptan. And then because of that serotonin 1B agonism, the potent vasoconstriction, triptans are contraindicated in those with a coexisting history of coronary artery disease, peripheral vascular disease, Raynaud's surprisingly as well, which is quite common, and cerebrovascular disease. Now, I wanted to highlight a couple. We have two long-acting triptans. And the reason why I wanted to take a second to highlight these is that with these triptans, if patients say that they're not able to tolerate triptans due to triptan tightness, I tend to find that the longer-acting triptans have less of that triptan tightness because they take a little bit longer to work, but cover for the patients for a longer period of time. As such, sometimes I'll take advantage of those properties and actually schedule these long-acting triptans if patients present with menstrual migraine or strong hormonally-related migraine. So these long-acting triptans can be a really great tool in your toolkit if patients really are presenting with migraine only around their menstrual cycle. Now, let's say that patients have contraindications to triptans, or they've tried a couple and they haven't been effective. We do have the second-line treatment options, which are the small-molecule CGRP antagonists. And CGRP, that calcitonin gene-related peptide, is an excitatory protein that we know is intricately involved in migraine pathophysiology, which my colleague eloquently highlighted in his lecture. And so we do have some options available for acute treatment. At present, we have two oral formulations available, which are ubrogepant and remegepant. And we have one intranasal formulation, which is zevegepant, which we had FDA approval for last year in 2023. CGRP receptors, there's a high density of them along the GI tract. Namely, this is why we see mostly predominant GI side effects. So that includes nausea, indigestion, constipation. These agents can cause fatigue, dry mouth, as well as dysgousia, which is more common in zevegepant, that intranasal formulation. But I've been using these quite often in my clinical practice, and they have been a game changer. Patients love not experiencing that tryptant tightness, and they've been really effective in making migraine symptoms more tolerable so that patients continue to function. Now let's discuss the preventive treatment for migraine. And as you can see here, at present, we have three gold standard pharmacologic classes for treatment of migraine. And these are considered first-line for now. Exciting news is that the American Headache Society recently released a consensus guideline to support the use of these CGRP antagonists as first-line treatment. So I'm excited as a headache specialist to see if now we can start using these as first-line agents. But for the education in this talk, we will highlight the first-line agents that are the antihypertensives, the anti-anxiety depression medications, as well as the anti-epileptics. So we'll start with the antihypertensives. The first-line antihypertensive class of medication that we prefer to use are beta blockers. And so beta blockers help to prevent that vasodilation, and it helps to decrease the release of those excitatory neuropeptides. Propranolol has the strongest body of evidence to support its use. And this is my preference in clinical practice as well, as propranolol does cross the blood-brain barrier and can not only be helpful for headache, but can also be helpful in patients that have coexisting anxiety or if they have coexisting POTS. But if you don't want to use propranolol, you can consider metobrol, temolol, tenolol as well. You want to be mindful of avoiding these agents in patients with asthma history or that have baseline bradycardia or hypotension. And then for considerations for use, like I said, specifically with propranolol, it can double as an anxiolytic, and it's great with patients with coexisting history of POTS because it can kind of treat both. And then this class of medication is helpful for those with hypertension. And side effects include, but are not limited to orthostatic hypotension, bradycardia, depression, decreased exercise tolerance. Now let's transition to the anxiety depression medications. So the first line anti-anxiety antidepressant agents that we use are tricyclic antidepressants. This we think helps to limit the central sensitization that's caused during migraine and also helps to limit that sympathetic activity. Amitriptyline has the strongest body of evidence to support its use, But clinically, I tend to favor nortriptyline because, in my experience, this has less of those anticholinergic side effects. But you can also consider protriptyline as an alternative. With this class of medication, there are contraindications. In the psychiatry world, there is an ongoing discussion whether TCA's lower seizure threshold. And a couple of papers that I reviewed recently have shown that this is actually being called into question and may be considered safe at the small dosages that we use to treat headache. If patients have history of urinary retention, you would not want to use these agents. If they have significant dry eye at baseline, the TCA's can definitely exacerbate that. But considerations for use. So these are great in patients with coexisting history of anxiety, depression, or those patients that have nighttime awakenings because of urinary frequency. It can be helpful for patients with urinary incontinence and insomnia. But namely, the side effects that we see are the sedation, dry mouth, dry eye, constipation, all those anticholinergic side effects. I put an asterisk next to appetite stimulation because oftentimes patients will say this specifically is causing weight gain. But truly, it's that appetite stimulation. And I find that if you counsel your patient about it ahead of time, it causes less of those challenges as far as weight gain. And then serotonin syndrome, if you're using this in combination therapy with their prior psychiatric medications. And then for patients who are trying to conceive, there is this potential risk of neonatal withdrawal. So you want to be mindful with using this in patients who are trying to conceive or are currently pregnant. Moving to the antiepileptics. So the first line antiepileptic options that we use are topiramate. It has the strongest body of evidence. And so with the antiepileptics, we suspect that this helps to prevent cortical spreading and depression that happens throughout the brain during migraine. Topiramate, because it has the strongest body of evidence, we typically start there. But all alternatives that we could consider include Depakote, Zanisamide, Gabapentin, Lamictal. With topiramate specifically, you want to be mindful and avoid this medication in patients who have pre-existing history of kidney stones. And then for truly all of these, if patients are of childbearing age, you probably want to avoid these because of teratogenic risk. But considerations for use, especially with topiramate in particular, it could be helpful in patients who may want to lose weight because topiramate can cause appetite suppression. As far as side effects go with this class of medication, sedation, brain fog, particularly with topiramate paresthesias, I've had a couple of cases of scary interior uveitis that require treatment. Weight loss, which could be seen potentially as a positive or negative side effect, as well as kidney stones. Zanisamide is actually a great suitable alternative to topiramate. So let's say someone's been responsive to topiramate, but they started having significant paresthesias or cognitive side effects. I will actually transition patients to zanisamide and I find quite equitable efficacy and then more minimal cognitive side effects. So you can keep that in mind to use. Moving on to the second line agents, which again, hopefully in the future, these will be first line agents, the CGRP antagonists that we have available. So for prevention, we have three injectables that are once for once monthly administration. We have a renumab that comes in 7,840 milligram dose formulations. We unfortunately have to avoid this medication in those that have poorly controlled hypertension at baseline. We have freminizumab and galconizumab. Galconizumab does require a loading dose. So just be mindful of that. Similarly to the small molecule CGRP antagonists that we discussed for acute treatment, these injectables, the biggest side effect profile we see with them really are injection site pain reaction, those GI side effects that we saw with those G-PANS, and then the hypertension, potential for hypertension exacerbation with a renumab. At present, we would say that these are contraindicated in pregnancy, but there are clinical trials looking into using these agents throughout pregnancy and lactation, which I'm excited about. And then consideration. So these are currently second line agents for those patients with episodic or chronic migraine. So for review, episodic migraine, less than 15 headache days or migraine days per month, chronic migraine, 15 or more migraine days per month. So they have indications for both. We have one infusion that's available that is administered every three months, and that's eptinizumab. Contraindications, again, currently pregnancy, hope to be studied in the future. This specific indication for eptinizumab is for chronic migraine only, and this has a similar side effect profile as those once-monthly injectables. Now for the G-PANS or the small molecule CGRP antagonists, we have two that are available for preventive use. So Atojapant considerations, if patients just prefer oral options, this can be a great alternative to the once-monthly injectable. And it does have FDA clearance or indication for episodic or chronic migraine use. And then the side effect profile, again, as we discussed previously. And Remedjapant is unique in that it has an FDA indication specifically for preventive and acute treatment of episodic or chronic migraine. And so this is important to think about if you've had patients that find it helpful for acute treatment. Maybe you consider every other day dosing specifically for prevention purposes. But you have plenty of options. I share with my patients, sometimes we just plug and chug and try to figure out what's most effective for them. And then, of course, insurance may be a driving factor as well. But great options. All of these classes have been working really well, and I've been thankful to be a headache practitioner during the time of implementing CGRP antagonists into practice. Another second-line option for migraine prevention is onabotulinumtoxin A. And this has an indication specifically for chronic migraine, and it is considered as a second-line preventive. So patients must be unsuccessfully treated with at least two oral preventive trials for at least three months, and then the patients must meet the ICHD-3 criteria for chronic migraine. So this is a series of 31 injection sites, and a total of 155 units divided in these sites are administered. Now, I wanted to discuss briefly special populations or special considerations for specific patient populations. So oftentimes in my practice, I'm getting referrals for preconception counseling and what happens to migraine during pregnancy and lactation and what treatment options are available. So I like to counsel my patients that during pregnancy and lactation, so specifically during pregnancy, the anticipated course of migraine is that it may worsen during the first trimester, but migraine tends to improve during the second and third trimester, as well as lactation. So we tend to say that pregnancy may be protective against migraine in some ways. Now, when it comes to acute treatment use with triptans, there has been ongoing controversy about this for many, many years. But fortunately, we have a 2015 meta-analysis from Scandinavia where they were following outcomes for those patients exposed to triptans during pregnancy. And through this meta-analysis, there was no significant increase in major congenital malformations, premature birth, or spontaneous abortions among triptan users. And interestingly, we have been using for years prior to using triptans for acute treatment during pregnancy, butabletol-containing medications have been the preference. But we have now more data to support that butabletol may increase the risk of congenital heart defects with use during the first trimester. So I tend to avoid butabletol altogether in my practice, and I will favor a triptan for acute treatment use of migraine during pregnancy over butabletol-containing compounds. As far as prevention goes, as we'll review here in a second, there are some pharmacologics to consider, but what's gaining traction in the headache medicine space? Is there a potential role specifically for onabotulinum toxin A? We think that this is such a large protein that not only should it really not cross into the placenta, but we're hopeful that it doesn't cross into the breast milk at a really high dosage. So this is going to be a great source of studies and research in the future. There have been several case theories so far saying that this may be safe or supporting that this may be safe. There also may be a role for neuromodulation. So if you stay tuned for the next lecture by my colleague, she will be reviewing options that are non-pharmacologic for migraine. And so most recently, a couple of my colleagues have been studying this remote electrical neuromodulation device, specifically in patients who are pregnant and using it on an as-needed basis. And they found that this was a safe option for acute treatment. There were no adverse outcomes. So this is, again, an exciting time that we have options for this patient population. So one of my colleagues, Dr. Rahill, wrote a great article truly summarizing our current guidelines for preventive and acute treatment options during pregnancy and lactation. So I just wanted to draw your attention to a couple. In my clinical practice, I tend to favor using propranolol and magnesium for prevention, let's say if the patients don't follow that typical pattern of migraine improving throughout the pregnancy. So we can consider starting propranolol, magnesium. Propranolol, there have been very few case reports of renal agenesis and fetal bradycardia. But in general, when I've been working with the pediatric team, as well as my colleagues in OB-GYN, we have a consensus that propranolol, a small dose for headache prevention, may be helpful. Nutraceuticals, so magnesium, coenzyme Q10, riboflavin, they haven't been studied extensively but could have a role for use. And oftentimes, patients feel more comfortable in using nutraceuticals versus prescribed pharmacologics. As we just discussed, onobotulinumtoxin A may have a role. I actually use onobotulinumtoxin A routinely in my practice for patients who are pregnant and has been working very well. So I'm excited to see the data come out on this and safety data come out on this in the future. And then, as I mentioned, the CGRP antagonists are relatively new. So several of my colleagues are conducting great clinical trials of safety during pregnancy. So we'll hopefully compile some safety data in the future. And hopefully, we'll be able to use these agents and continue these agents during pregnancy. But for right now, the current guidelines are to allow for a five to six-month washout period if patients are using those once-monthly injectables prior to trying to conceive. As far as acute treatment of migraine during pregnancy, there are a couple of options that I'll draw your attention to. So metoclopramide is usually my go-to for anti-nausea. Orazofran is an alternative option. I prefer to use intranasal lidocaine. But then I'll also use lidocaine in the form of a procedure. So I'll do trigeminal branch blocks and occipital nerve blocks with lidocaine only. And those can be effective, especially if patients are presenting with status migranosis, to help break that cycle. But intranasal lidocaine can be a great substitute. As we discuss tryptans, lots of controversy surrounding this. But through education, I've been able to work with my OB-GYN colleagues. And we've been starting to incorporate tryptans at really low doses during pregnancy. So I'm excited to see this paradigm shift. And then GPANs. So when it comes to the GPANs, we do have one safety study looking specifically at remedjupant. And so with remedjupant, this one was looking at specifically during lactate. This study was looking specifically during lactation. There was very, very little amount excreted in breast milk. So this may have a role potentially for use during pregnancy and with lactation. And this is the study. It was Baker et al. in 2022. And it was less than 1% of the relative infant dose was found in the human breast milk. And so I just wanted to end with highlighting, you know, you started these pharmacologics. How do you really follow up with these clinically when you see a patient for follow-up? And so just to review, for preventive treatment, when you ask about this in follow-up, you want to ask about the duration of the treatment, the efficacy. Was there any change in the frequency, intensity, or duration of their migraine? Asking, of course, about adverse effects. And then just be mindful. In the past, if patients say they weren't successfully treated with something, is it because it was given as monotherapy or was it actually given as combination therapy? Because again, building that defensive line, sometimes some polypharmacy may be effective. For acute treatment, you always want to ask about the efficacy. Again, for me, the goal would be at least 75% or more effective in reducing and consistently reducing migraine frequency. I'm sorry, migraine intensity and most intensity of most bothersome symptoms, as well as the time to onset. So how long is it taking to kick in? Are the patients repeating the dose? If they are repeating the dose, especially with a tryptan, that may indicate that they need a longer acting tryptan. The time to onset that's important to remember, because we do have some parental options available that will have the quicker onset. The usage frequency, highlighting the point about medication overuse headaches. So how often are they using their acute treatments? And please make sure to ask about the NSAIDs, because oftentimes patients think of these as benign, because you can purchase them over the counter. So make sure to always ask about the NSAID use, as well as the acute treatments that you've prescribed, and then any adverse effects. In conclusion, I hope that you've been able to understand that implementing pharmacologic preventive and acute treatments should be reviewed on a case-by-case basis. And so what I like to share with my patients is, hey, I don't have the magic wand. What I enjoy with working with you is that we're putting the pieces of the puzzle together. So what may work specifically for you may not work as well for the next patient. And so it's truly creating that individual individualized treatment plan. And so we reviewed current first-line preventive options. As I discussed, this may evolve given this recent consensus guideline that was released by the American Headache Society. But current first-line preventive options include antihypertensives, antiepileptics, as well as antidepressants. First-line acute options include the tryptan plus NSAID combination, as long as there's no contraindication. Second-line preventive and acute options include the CGRP antagonist, as well as on a botulinum toxin A that I did not include there. And then just be mindful of special consideration populations, such as those who are trying to conceive who are pregnant and lactating. Thank you for listening. And please continue on in this migraine education series with my colleague to learn about non-pharmacologic options for treatment of migraine. Thank you.

migraine treatment

preventive treatments

acute treatments

pharmacologic approaches

CGRP antagonists

individualized treatment

medication overuse