Dr. Kendal Williams (Host): Welcome everyone to the Penn Primary Care podcast. I'm your host, Dr. Kendal Williams. Headaches are very common in primary care and very confusing because we don't fully understand why they come on, but they can be disabling for many patients. And sorting through the best ways to both diagnose the type of headache you're dealing with and also to treat it is increasingly complicated. We have a lot of new medications for migraines in particular,= that are now available for us to use, and I think many of us would enjoy a primer on how to use those medications.

So in order to accomplish that, I asked two experts at Penn to come on the podcast to talk about that. So, Dr. Seniha Ozudogru is the Director of the Headache Division at Penn. She's the chief of the Headache and Facial Pain Division in the Department of Neurology, and she is the Director of the Headache and Facial Pain Fellowship at Penn. Seniha, thank you so much for coming on.

Dr. Seniha Ozudogru: Thank you for inviting us. Excited to be here.

Host: Dr. Eric Kaiser comes at headache from a different perspective. He's an MD-PhD. He is the Co-Director of the Fellowship of the Headache Fellowship at Penn, and his focus is on research as well as the clinical side as well. Eric, thanks for coming.

Dr. Eric Kaiser: Thanks so much for having us. It's an absolute pleasure.

Host: So, you know, I think the focus of this will primarily be on some of the newer medications, particularly for migraine because that's what we're hearing about, we're seeing advertised on TV. If we're not prescribing them ourselves, our patients are coming in on them. And for those of us who were trained in more of the triptan era, which would be me, these are kind of new and we're not sure how to manage them. So, I would definitely want to make sure we get to all that. But we wanted to start today to just talk about the various categories of headache, how we should think about them in primary care, and then go into migraines more specifically.

So, Seniha, I'm going to start with you. I mean, when I think about a headache, patient comes in to see me and has a headache complaint, the first thing I'm thinking is it secondary to something else, right? Do they have some other aspect of their care? Do they have, you know, patients are always worried about brain tumors and other things, carbon monoxide poisoning, things that can cause a headache or sinus headache, other things. And then, if that's not it, then I focus on sort of the primary headache categories. But Seniha, is that how you start out with this?

Dr. Seniha Ozudogru: Correct. Yes, that's the most important part. So when we see a patient with headache, the first thing we think about, is this a primary versus a secondary headache disorder? And the first question, is this a new-onset headache or this is a progression of an ongoing headache for a while? If this is a new headache disorder, then we'll look into the other demographics of the patient. So if this is an elderly patient, new-onset headache, then we have to focus on cerebrovascular disease, tumor. If this is a patient with some immune deficiency, then maybe meningitis, encephalitis. If this is a patient who is pregnant, then we have to think about preeclampsia, venous sinus thrombosis. And when it comes to primary headache disorder, it's also important, these demographics, like elderly patient, they can have primary headache disorders like hypnic headache, which we don't see on the younger patients.

And then, we move into the headache characteristics. Is this a side-locked headache or it's a shifting headache? Like unilateral shifting headache for migraine diagnosis, whereas if this is a side-locked headache that it's not shifting, it's always on one side, then we ask about the autonomic symptoms to consider trigeminal autonomic cephalalgia, like cluster headache or paroxysmal hemicrania. So then, we move into the other associated symptoms.

So for migraine, headaches started around puberty and then progressively changed throughout the years, and for some reasons with the change in the life, that it became more chronic, we like to be able to say what caused the chronicity if it was a life-changing event, it was hormonal changes, patient got pregnant, patient went through menopause, and then it became chronic. Then, we can focus on the chronic migraine treatment.

Host: So, I wanted to go back to the sidedness that you referenced. So if it's locked onto one side, you think about trigeminal neuralgia and hemicranial headaches. But I gather migraines can be on both sides, right?

Dr. Seniha Ozudogru: Correct. So for migraine, it should be unilateral shifting. Rarely, migraine can be side-locked. But if a person presents with a side-locked headache, it's always on one side. We first have to rule out secondary causes and we have to think about trigeminal autonomic cephalalgia. This trigeminal autonomic cephalalgia is the big title of this group of headaches, there are three of them, the cluster headache, paroxysmal hemicrania, and then we have SUNCT and SUNA, based on the duration of the headaches, and then some other characteristic we differentiate in those group.

Host: Would trigeminal neuralgia be in that category or is that a separate?

Dr. Seniha Ozudogru: Trigeminal neuralgia is separate. It's more like facial pain. We call this trigeminal autonomic cephalalgias, mostly pain around the eye and temporal area. We call them headache disorders. Sometimes patients, they show up in the ophthalmological clinic with the eye pain. But if the pain is around the eye and temporal area, we call it headache if there is no primary ophthalmological disease. Trigeminal neuralgia, more like a facial pain on the V2-V3 distribution of the trigeminal nerve, whereas trigeminal autonomic cephalalgia is mostly V1 ophthalmic branch distribution.

Host: That's very interesting. So, you mentioned one of the three is cluster headaches, which is the one I'm more familiar with. My understanding is cluster headaches have the name because they come in a cluster where you have them for a few weeks, it's quite severe, and then you might not have them for months or even years, and then they come back. Do those other headaches in that category share that same characteristic, or are they different?

Dr. Seniha Ozudogru: There are differences. So, all these trigeminal autonomic cephalalgias, they are side-locked headache with autonomic symptoms. Autonomic symptoms are tearing of the eye, redness of the eye, ptosis, maybe swelling of the face, sometimes fullness sensation in the ear, and they can have runny nose or congestion on that same side.

So when a patient presents with side-locked headache, then we ask about autonomic symptoms. Autonomic symptoms are redness of the eye, tearing of the eye, causes swelling of the face, runny nose or congestion on the same side of the nostril on that same side of the headache, sometimes fullness sensation in the ear.

Then, we move to the duration. For cluster headache, it's usually 30 minutes up to three hours of headache. For paroxysmal hemicrania, shorter, two minutes to up to 30 minutes. And then, we have SUNCT and SUNA, they are more seconds lasting headaches, they're less than two minutes. Based on this differential, then we make the treatment plan. Because even though they're all called trigeminal autonomic cephalalgias, treatment plans are totally different.

So, paroxysmal hemicrania or  SUNCT and SUNA, are different than cluster headache. Cluster headache usually comes in spring and fall. It's more seasonal. And cluster headache usually comes around a specific timing of the day. Patients can tell you that the headache attack comes around, let's say 10:00 AM, 2:00 PM, and they have one attack at night that wakes them up. Sometimes they can only have night attacks or they can have up to five, 10 attacks a day.  SUNCT and SUNA, they are spontaneous attacks. They can have hundreds of them a day. they come and go, spontaneous, second lasting to less than two minutes attacks. And then, paroxysmal hemicrania again up to 30 minutes of attacks. It can happen multiple times a day. It doesn't have to cluster when it comes to paroxysmal or  SUNCT and SUNA during that season. It can be throughout the year. And paroxysmal hemicrania can turn into a more chronic, continuous version, then we call it hemicrania continua.

Host: How do you treat those? Do you treat those in a similar way to where-- do you treat them like migraines or do you have other strategies?

Dr. Seniha Ozudogru: We have other strategies. For cluster headache, so first thing is for cluster headache, after we make the diagnosis-- for all this headache actually, for proximal hemicrania cluster headache, SUNCT and SUNA, even though these are primary headache disorders, these are rare headache disorders. They are side-locked headache disorders. They're required to have neuroimaging. So, we order MRI with and without contrast for these headache disorders to rule out secondary causes. That's first thing. And then, we start a treatment plan.

For cluster headache, we have a plan for acute treatment. We have a plan, we call it bridging treatment. And then, we have plan for chronic treatment. If it turns into a chronic headache, rarely cluster headache can turn into a chronic one. So, acute treatment is the treatment plan when the patient has the attack, to take the treatment to stop it. So, it has to be quick onset, right? Because the attack itself can be like four to five minutes. If you are prescribing an oral sumatriptan, it takes 20, 30 minutes to kick in. It might not be good enough. So, we prefer sumatriptan injection or sumatriptan nasal spray. And the other treatment is the high-flow oxygen with non-rebreather mask. So, please do not order oxygen with nasal cannula. It is non-rebreather mask, a 100% oxygen, 10 to 15 liters, so it is high flow, or sumatriptan 6 milligram subQ injections. That's for acute treatment to stop the attack when it comes on.

Bridging treatment is the treatment we order, we plan to stop the attack during that season. It's usually high-dose steroid, prednisone 60 to 80 milligram and titrated down over two weeks, or we start them right away on verapamil 120 milligram extended release. It can be increased up to 480 milligram a day. And then, we also have now galcanezumab, one of the CGRP inhibitors, the monoclonal antibody.

Host: That's Emgality, right?

Dr. Seniha Ozudogru: Emgality, yes, it's actually approved for cluster headache too, but the dosing is different. For cluster headache, Emgality 300 milligram, one injection at the onset, and then repeated every month, as long as the cluster attack continues.

Host: So, that's very interesting. I would imagine you don't have a lot of people at home with oxygen that can reach that kind of flow. So, that's mostly in emergency departments, I would assume.

Dr. Seniha Ozudogru: Correct. Correct. Unfortunately, we are having trouble to get those oxygen tanks. So, we have been using sumatriptan injections or nasal sprays more often.

Host: So, I know those headache syndromes are relatively rare, although I think I have two patients in my practice that fall into these categories. And I suppose you see a fair amount of patients with these types of headaches, right?

Dr. Seniha Ozudogru: Correct. Being a tertiary center, we see more patients than in general population, even in general neurologic clinics, still rare headache syndrome, but they are very devastating. They cause significant disability. So, it is important to recognize these headache disorders. 

Host: So, let's talk about migraines and the pattern there. Eric, I'm going to bring you in here. They're not side-locked as you noted, right? That was the term you were using. So, they can be general, but you know, we have migraine with aura, migraine without aura. But what distinguishes a migraine, say, from just a tension headache?

Dr. Eric Kaiser: In comparison to tension headache, I think the distinguishing features are typically associated features. Tension type headache is typically a featureless headache. And so, these headaches that are going to have other associated symptoms. This can include things like sensitivity to light or sound, which we refer to as photophobia or phonophobia. My research really focuses on trying to better understand the mechanisms of photophobia, for instance.

But other associated features can include nausea and vomiting, which is quite common. So if present, oftentimes it's going to immediately move you into a migraine category. But there can be other less common features too. This can include things like sensitivity to smells or osmophobia. Dizziness and vertigo can be common symptoms associated with migraine. And so, in many perspectives, it's something that goes beyond just your typical headache that most patients complain of. And so, these other neurologic phenomenons that really distinguish it.

Another unique feature to migraine can certainly be aura. This can present in a number of different ways. By far, the vast majority of folks with migraine with aura include those with visual aura. That should affect about 90% of folks with migraine with aura. But there can be other neurologic deficits or positive phenomenon that can happen with aura. This can include things like sensory symptoms, numbness or tingling. It can also include things like language deficits where people have a difficulty understanding or even being able to speak during an attack. Less commonly, you can have motor deficits as well. And so, in many cases, sometimes at least for a first presentation, this can very much mimic a TIA or a stroke. And in certain cases, it's appropriate to work that up. And so, you may see this in your emergency rooms, or if you have a patient calling with these symptoms, you should probably send them to the emergency room, especially if this is their first presentation. and so, there's a wide range of symptoms that really kind of will cue you into migraine as being a key feature here.

Other things that may help you distinguish migraine from other mimics can include things like most people with migraine will want to go to a dark room and lay down. Movement aggravates the pain. And so, that's very much distinguishable tension type headache. In other ways, if you are somehow considering differential between cluster and migraine, those with cluster often feel a sense of restlessness. They're unable to stand still. With those with migraine, the movement really aggravates things. They're going to want to rest. They're not going to want to move.

Host: I had Mindy Ganguly, who is in your department. Dr. Ganguly, who is the seizure specialist, epileptic specialist. And she made a comment that oftentimes there's some overlap in terms of migraine features and seizure features. And it's not always clear. You know, obviously, patients who have more migraines are having headaches. But if headache is not a prominent feature of the migraine, it can get a little confusing, right?

Dr. Eric Kaiser: Yeah. This can be certainly sometimes a challenging area. So, we talked about aura. Aura can present without headache following, Classically, we think of aura, starting before a migraine attack. But for some folks, especially those as we age, things can change with time. And so, in this case, you can have the presentation of aura, for instance, a visual aura, but then not go on to have a migraine attack.

The complexity between kind of the neurologic phenomenon of aura and whether that be in the context of seizure or in migraine, can certainly sometimes make things a little bit fuzzier. Also with the fact that seizures can sometimes lead to migraine-like attacks afterwards. So, there can be some overlap that's there. In very rare cases, there's some thought of the concept of migralepsy, for instance, in which migraine can actually induce a seizure. It's a little bit of a controversial topic. I think I've had one or two cases where I've convinced myself that it is a legitimate phenomenon, but I will acknowledge the fact that this is still kind of a controversial diagnosis.

Host: So, I want to come back to migraine in a bit, but probably the most common headaches in the world are tension headaches. And I do want to take a pause and talk about them, because they probably deserve their own space other than they're not this, right? They're not migraine, they're not cluster. So, let's talk about tension headaches. Seniha, I assume tension headaches can be daily in a same way that migraines can, they can be quite disabling as well.

Dr. Seniha Ozudogru: Correct. So, tension type headaches, they can turn into a chronic, and we call it chronic tension type headache. They have been ignored in Neurology and headache worlds such a long time. And there are few recent review of articles on them. We are trying to pay attention more to those.

When it comes to treatment, we don't have much on tension type headache. We know that tension type headaches are less disabling than migraine. They're not as severe. They do not cause nausea. But they can cause either photophobia or phonophobia, one of them, not both of them at the same time. But they can turn into chronic tension type headache. When that happens, first-line, we treat them with medications like amitriptyline, nortriptyline, the tricyclic antidepressants. And then, mirtazapine has been mentioned, but it's not an easy medication to use in the clinic. It causes significant sedation and weight gain. We start with tricyclic antidepressants usually. And if it doesn't get better, then we go back to chronic migraine treatments and try those medications because we don't know any better.

One thing that's challenging when it comes to tension diabetic, differentiating between how much musculoskeletal effect is there, like how much the muscle tightness is contributing to this tension type headache? Physical therapy is really important. We prioritize physical therapy for our patients when we diagnose tension type headache. It's also important to be able to differentiate with cervicogenic headache. If patient has significant restricted range of motion, they have trigger points, they have those tender spots on their neck, on their shoulder area, you might want to consider a cervical x-ray to see if they have significant cervical arthritis, cervical spine disease that might be contributing. So, they might have cervicogenic headache, not only a tension type headache.

Host: And I assume those are due to arthritis in the spine, not specifically a radiculopathy that may be high up, but rather just arthritis in the spine that is somehow radiating into the head. Are they in the occiput when it's cervicogenic?

Dr. Seniha Ozudogru: Cervicogenic headache is usually unilateral, sometimes can be bilateral. It can present like a neck pain, radiating up, and kind of wrapping around the head. And when we press those areas, the patient says that, "Hey, this pain is starting right there." Then, we can precipitate that pain, radiation, and it can associate with radiculopathy symptoms, like patients can have shoulder pain or numbness, tingling on their arms that, I guess, help us to consider cervicogenic headache when that happens. But it is most of the time in that occiput area.

Host: So, physical therapy is your approach there for most of those types of headaches in addition to tension generally, right?

Dr. Seniha Ozudogru: For cervicogenic headache, we like to do occipital nerve blocks and trigger point injections. They can be pretty effective. We have seen patients that they have been having chronic everyday headache for many months and then when we do a nerve block with a specific trigger point injection, it can fix the problem within hours. It can be pretty effective.

Host: That's terrific. Let's talk about migraines, because that's where most of the agents are used for the treatment of headache. We should talk about the non-migraine-specific medications first, right? So, Tylenol, NSAIDs, various caffeine-based agents. Fioricet was very popular when I was in training. And their role, both in migraine and in tension. And then, of course, you can overuse them and you get what's called a medication overuse headache, which can be associated, as I understand it, with any of those agents that are used too often. So, let's start with just the non-migraine-specific medications. So, not triptans, not CGRPs, and how you use those now. 

Dr. Seniha Ozudogru: So, Tylenol, ibuprofen, as long as they help, we offer those medications to our patients. It's important to explain patient what is the expectations from a rescue medication. So, we assess the benefit of rescue medication by two things. One, how soon the medication stops the migraine attack? We like it to stop the migraine attack less than two hours. And two is the recurrences. If the medication causes recurrences, meaning that if the medication stops the headache, stops the migraine attack less than two hours, but the migraine comes back the next day, within 24 to 48 hours, it's a recurrence of the same migraine. So, that means that that rescue medication wasn't effective. So then, we failed that rescue.

The other thing is with these over-the-counter medications, the dosing, we like to hit it hard and stop it. I personally do at least. So instead of one over-the-counter Advil, I like them to try 600 to 800 milligram Advil first, and a combination with an anti-nausea medication. So, ibuprofen by itself might not be very effective. But if you combine ibuprofen with Zofran or Compazine or Reglan, it can be effective to stop the migraine attack or tension type attack. Combinations of Tylenol and ibuprofen, and I guess when you add caffeine that it becomes Excedrin.

The important part with Excedrin, sleep is really important. We like our patients to be able to sleep when they have a migraine attack. So if the headache is a late-onset headache afternoon, we do not want them to take Excedrin. The caffeine affects their sleep and they go into this recurrence of migraine days. So, for Excedrin or any caffeine-including medications, combination of analgesic, we don't want them to take it later in the afternoon.

When it comes to Fioricet, Fiorinal, we try not to prescribe them unless patients have some contraindications for triptans or gepants. So,  Fioricet, Fiorinal is never our priority. We prefer triptans or gepants. If patients cannot be on them, then we can consider  Fioricet, Fiorinal rarely because of their high tendency to cause medication overuse and habituation.

Host: That's interesting. That's a change from when I trained. It was usually the first thing you would try. And when I trained, triptans were new. And so, obviously it's advanced beyond that. That's great. Eric, are there any pearls that feel like maybe you share with the residents and others that you teach about these sort of non-specific migraine therapies?

Dr. Eric Kaiser: Some pearls to kind of think about here would be sometimes there can be advantage of using longer acting NSAIDs. Things like naproxen, which most patients can get over-the-counter, but other prescribed ones can include nabumetone. And these provide an advantage because they're less likely to lead to that rebound effect. And they can be sometimes a little bit more potent, and so have a better ability to terminate the headache and keep the headache away. And so, this can be an advantage compared to ibuprofen, which is shorter acting, or Tylenol, which is also shorter acting. And so, it avoids this or at least decreases the potential for medication overuse headache.

Host: Caffeine does play a role here. I mean, Seniha said not to use it later in the day, but patients do seem to have effect-- you know, I have several patients who say, "Well, I just take four ibuprofen and a cup of coffee and it goes away." I guess that's a common therapy out there.

Dr. Eric Kaiser: The addition of caffeine can be quite helpful. And I think, again, it does pose the potential risk for medication overuse headaches. You have to be cautious there and identify how frequently they're depending on caffeine to be able to terminate their headache. But it can be a very effective addition to many over-the-counter approaches.

And so, if those approaches are effective and working well and meeting the criteria that we just discussed, it can be an effective approach for patients. But you also have to consider how frequently they're using NSAIDs as a whole and discuss those potential systemic side effects as well.

Host: I want to just talk about medication overuse headache for a minute here. You have patients who come in, maybe they're using NSAIDs every day. How do you know it's medication overuse or maybe there's their headaches out of control and they're not getting appropriate treatment? How do you know it's causing the headache versus a symptom of the headache that's not being effectively treated?

Dr. Eric Kaiser: I think oftentimes we don't know specifically, and it's difficult to really be able to distinguish between the two. And this is often why in my notation I say probable medication overuse headache, because there isn't really a clear way to be able to distinguish between the two. I think it's important to be able to identify when you're concerned about how frequently folks are using short-acting analgesics or acute medications for treatment of their headaches, and discuss those potential risks in terms of the potential for systemic side effects as well as for the risk for rebound headache, because it's important for patients to feel empowered and understand what those risks are.

But really then that's leading you to a discussion about the need for preventive medication, to be able to effectively reduce their dependence on these acute medications. And so, that leads you then into kind of a discussion for the importance of that. And clinical trials have also shown that effective preventive treatments are really the key way of decreasing that use of acute medications.

Host: So, let's start there with migraine, and I think maybe with tension to some degree too, because Seniha had said that they're similarly approached. When you think about preventive medications, I mean, I think of propanolol, beta-blockers. I think of anti-seizure medications that can be used as well. But what are the modern preventative drugs that are used?

Dr. Eric Kaiser: Yeah. Let's talk first about what's considered classical, preventative treatments or what's been used historically, partly because we need to do trials of those medications before we can get to some of these newer options that are available on the market now.

So, broad categories of medications that we have historically borrowed from include, as you mentioned, antihypertensives, the antidepressants, and then the anti-seizure medications. If we go into each of those three categories, so first talking about the anti-hypertensives, you mentioned propranolol, beta-blockers as a whole are considered first-line therapy. This include beta-blockers such as propranolol, metoprolol, and then nadolol and atenolol. And these can all be quite effective options at reducing headache frequency and severity. Obviously, you have to think about what are the potential side effects and risks for that individual patient? And so, if you're concerned about an individual with asthma or COPD, this may not be the category to use. Folks that are particularly at risk for hypotension or syncope, you would want to avoid here as well.

Other things to think about sometimes beta-blockers, particularly propranolol, may not be a great option for folks with depression because it can exacerbate those symptoms as well. So, it's all about trying to kind of figure out what is the best match for that individual patient and kind of tick a good survey of the kind of overall health to figure out what the most best preventive option could be. So if it's not an antihypertensive, antidepressants can be good options. And specifically, this includes the tricyclic antidepressants. As Dr. Ozudogru mentioned, this includes amitriptyline and nortriptyline. These can be very effective options. You might consider this, especially in individuals with other comorbid chronic pain because that can also be a helpful treatment option and help manage that. For folks with issues with sleeping, this can also be advantageous because they are sedating.

So again, it becomes figuring out things that might be advantageous in their management as well as not potentially the side effects that can be problematic. This might be not a great option for folks that are sometimes greater than 65. Folks maybe with a prior history of suicidal ideation might avoid due to the risk for potential overdose, folks that you're concerned about potential weight gain. So, all special considerations for each individual patient. But this can be very effective options that I use very frequently in my own clinic.

Other antidepressants, the SNRIs such as duloxetine and venlafaxine can be good options. I would consider these as more second-line antidepressants to reach for, probably not first-line, first-line being most tricyclic antidepressants. But these can be great options as well. The SSRIs really don't have as much strong research in this area. So really, it kind of falls down to the TCAs and the SNRIs.

Host: You know, I recently came upon again this study that was done on antidepressants, looking at the effectiveness and the tricyclics were really effective antidepressants, and they fell out of favor because the SSRIs were so well tolerated. But they still have a role in medicine nowadays for depression.

And so, as you were saying, Eric, sometimes we're trying to solve two problems at once, you know, sleep and headache, and headache and depression, and so forth. But they actually are very effective antidepressants still.

Dr. Eric Kaiser: Yeah. Admittedly, oftentimes with tricylic antidepressants, we find that much lower doses are very effective for migraine management. And so, in many cases, we're able to minimize the potential side effect profile by utilizing low doses of medications. Typically when starting a preventive medication like tricyclic antidepressants, really this goes for any of the preventive medications, whether for all three categories, but starting at low doses and slowly titrating up over time based off of need and tolerance, and can be really an important way of trying to minimize the potential dose and reduce the risk for side effects.

Host: So, as I feel our time moving away, I can feel the listeners already getting upset because I teased them that we were going to talk about all these new medications, and I don't want to miss the opportunity to do that. So, let's briefly touch on triptan specifically. Actually, Eric, I want to ask you, and you're on the research side, and maybe the physiology side. I really don't understand what causes migraines. When it was explained to me as a medical student, it was a vascular phenomenon. And I remember thinking to myself, "Huh, it seemed like it was a lot of hand waving." But these drugs have targeted vascular aspects, right? Each of them, and they seem to work so clearly that I think makes us feel better that the mechanism has something to do with vasoconstriction and dilation and maybe how those alter.

Dr. Eric Kaiser: So, let's clarify a few of those points. I would still argue the pathophysiology of migraine. there are many things that we have yet to understand. But I would say we have really moved past and, in many perspectives, have dismissed the vascular theory of migraine. And research has really suggested that a vasodilation of the cranial arteries is not really the underlying pathophysiology.

And as we've talked about previously in the way that migraine presents, this is a neurologic phenomenon. We talk about this as being a neurovascular theory of migraine and, in many perspectives, still overweighed the role of the vascular component to migraine. Vascular elements are really an epiphenomenon. They do happen, particularly in migraine with aura. But really, this is a neurologic disease, and a disorder of the brain. We're still trying to understand really where a migraine starts and kind of being able to kind of put together kind of a full beginning-to-end mechanism that's there.

Things that we think that are happening, we think to a certain extent, this is a result of polygenetic risk for developing migraine. This is a familial disorder that is a result of numerous small changes within one's genetic code that predisposes of them to developing migraine attacks. And as a result of it, there is an alteration in how the brain responds to various external stimuli. And this leads to hyperreactivity or hypersensitivity within the cortex. But also, we think there's probably a dysmodulation of the brain. And as a result of that, this leads to changes in descending pain pathways in the brain. And so as a result of that, they are more likely to develop migraine attacks or be sensitized to various external stimuli.

Host: So, these newer drugs target this system, calcium gene-related peptide receptors, right? And so, CGRP. And the drugs that we're going to talk about here are all antagonists to that system. Do we know what that system does?

Dr. Eric Kaiser: Yeah. So, let's talk about CGRP. I've been thinking about this since I was a graduate student. So, CGRP is a critical neuropeptide involved in migraine, but certainly involved in other physiologic process. So, CGRP plays a role in pain perception, both for migraine as well as other pain disorders. And particularly, it's widely expressed throughout the trigeminal system. And it's also involved in neurogenic inflammation. And so, both of those are really key aspects to migraine pathophysiology. It's also a potent vasodilator. As I just talked about, we said the vascular theory of migraine is dead, but I will acknowledge the fact that CGRPs is also involved in vasodilation as well. And so, it plays a key role then in mitigating migraine attacks.

From a physiological perspective as it relates to migraine, in folks who are experiencing migraine attacks, studies have observed that there's increased CGRP in folks having an attack. If you inject CGRP into folks who experience migraine, they can actually induce a delayed migraine like attack several hours after the injection of CGRP. If you inject folks who don't get migraine, they may get an initial fullness of head, but don't get that delayed migraine attack later on. This suggests that folks with migraine for some reason are sensitized to CGRP.

And now, we've seen that there are numerous, numerous clinical studies that have shown this is a very effective target for migraine treatment. This includes effectiveness for preventative therapies, both for episodic as well as for chronic migraine, including for those with medication overuse headache, but also as effective acutely, treating both migraine with and without aura.

Host: So, there seem to be two categories of medications that target the CGRP. And CGRP is what we're trying to antagonize here. We're trying to block it, right? So, you have what effectively seem to be monoclonal antibodies, right? So, Vyepti, Ajovy, Emgality that Seniha had mentioned before. And then, you have the gepants. And here, I'm going to mess up how you say these, but atogepant, rimegepant, ubrogepant. So, you're talking about Qulipta, Nurtec, and Ubrelvy, right? So, those are the meds that are out there now. Can we just roughly distinguish those two, how they work, I suppose, and how they're used?

Dr. Eric Kaiser: Yeah, absolutely. So, first, let's talk about the monoclonal antibodies. There are four different agents, as we mentioned, that are on the market. Three of those are monoclonal antibodies that bind a CGRP as a ligand. So, you can think of it as going through and just kind of sopping off any extra CGRP that's in the peripheral circulation. And then, specifically erenumab or Aimovig binds to the CGRP receptor and blocks CGRP actions by binding to the receptor.

Then, on the flip side of things, you have the gepants. So, these are small molecular antagonists that block the CGRP receptor in this case. So, they're most similar to erenumab in terms of the monoclonal antibodies. There are agents then that are effective for the acute treatment, but then also agents that are preventative. On the preventative side, you have atogepant, and then you have rimegepant. And then, rimegepant is also effective for acute treatments, the one agent on the market for migraine that is approved by the FDA for both the acute and preventative treatment of migraine. And then, the other acute agents that are on the market for the acute treatment of migraine, include ubrogepant and then zavegepant.

Host: Okay. I want to go back with those and put the trade names in there too. Because unfortunately, this is often how we know these. So, atogepant is Qulipta. rimegepant is Nurtec and let's say Ubrelvy. Which of those is preventative? Which of those is--

Dr. Eric Kaiser: yep, let's go through this again. So, for the gepants, you have the preventative agents, which is Qulipta or atogepant, and then Nurtec or rimegepant, are the two agents that are preventative. For acute medications, in addition to Nurtec, you also have Ubrelvy, which is ubrogepant. And then, you have Zavzpret, which is a nasal spray.

Host: Yeah. And then, all of the mabs, we talked about, Ajovy, Emgality, and so forth, those are all injectable, right?

Dr. Eric Kaiser: So, three of the agents are injectables, and one of them is intravenous. So, that's Vyepti. Vyepti is an intravenous infusion that is done either in an infusion center or at home. And I would say, probably from a primary care perspective, not something that needs to be utilized there, and usually that requires prescription from a neurologist having failed two other monoclonal antibodies. So, I think the focus really should be on the three subQ monoclonal antibodies, which includes Aimovig, Emgality, and Ajovy.

Host: They're all preventative.

Dr. Eric Kaiser: They're all preventative. Yes. And so the, subQ injections are administered once a month. In clinical trials as a whole, all of them were effective. both for, episodic as well as for chronic migraine.

I would say the best summary of the clinical trials was about 50% of people got at least a 50% reduction in their migraine frequency. And so, they saw a reduction in number of migraine days each month as a result of it. That reduction was continued month after month during the first six-month period.

And in addition to not only reduction in number of migraine days, there was also an improvement in quality of life markers as well in those clinical trials. And so, for many folks, this can be a huge game-changer and lead to really a significant effect in their overall quality of life and changes really how they experience their migraine attacks as a result. Many folks also report that their migraines are easier to treat as a result of it and are more likely to respond to acute treatments.

Host: I assume we don't have a lot of comparative effectiveness data on this. By that, I mean comparing these infusions or subQ injections monthly versus the traditional classical agents. We talked about propanolol, the anti-seizure medications, antidepressants, and so forth. I imagine those are still very much cheaper. And so, in many cases, you're forced to use those classical agents and fail them before you can use one of these therapies, right?

Dr. Eric Kaiser: Yeah. Currently, in the insurance situation standard, at least here in Pennsylvania is a requirement that you fail two different preventive medications, each of those being from one of the three categories that we talked about. So if you have one that failed in the anti-hypertensive, then you need to fail either in anti-seizure or an antidepressant medication. And then if you fail those, then we can move on to these newer CGRP agents.

A similar concept would be for folks with chronic migraine for Botox. And so, we do need to try these classical migraine preventative treatments first. Currently, the American Headache Society was advocating that these are should be considered first-line agents, because they are more effective and safer than even the classical preventative medications. And so, there haven't been specifically head-to-head trials. But a meta-analysis that have looked at both the efficacy of these medications as well as the safety profile overall, they outcompete the other classical preventive medications.

Host: I remember, you know, I'll just tell this quick story. I was a Penn medical student and I was doing Dermatology at Hop. And I presented a case to the attending, and he looked at me and he said, "Well, we've got a lot of different options on how to treat this." He said, "And I'm going to teach you something. When there are a lot of options for something, it means that nothing works very well." And it was a really good teaching point. And it seems though that now these agents for prevention are replacing sort of other ones, as the price comes down, they may just replace the other ones because they're much more effective, right?

Dr. Eric Kaiser: Yeah. I think that these will, in time, really become the first-line agents because they are so effective and safe options for most patients. And so, yeah, I think this is really going to be probably the mainstay of migraine treatment moving forward. Not to say that we don't necessarily need newer therapies that are out there. Not all folks respond to these treatment options. I would argue the more options we have, the better because not everyone responds to each of these treatment options. And so, having a variety of options available for patients really is going to be more likely then to find a treatment option that works best for them.

Host: So Seniha, I'm going to throw it back to you because I want to talk about the gepants. These are the ones that we in primary care may actually prescribe because they don't require, infusion, and so forth. And we talked about Qulipta, Nurtec and Ubrelvy, Nurtec being the one that can both be preventative and abortive. So, how are you thinking about these medications and how are you using them? Let me just throw that out as a broad question.

Dr. Seniha Ozudogru: Sure. Before we start talking about the gepants, I want to touch base on the triptans. Yes, gepants are safer when it comes to cardiovascular, cerebrovascular diseases patients with those risk factors. But triptans still has a role in treatment of migraine. Even though triptans has been out there for a long time, that is something we really like our primary care physicians to be more comfortable prescribing.

Triptans are contraindicated in patients with uncontrolled hypertension, patients with history of coronary artery disease, peripheral artery disease, carotid artery disease. But if you are able to control the patient's blood pressure, they do not have any other risk factors, please do not hesitate to prescribe triptans.

One thing Eric mentioned about the pathophysiology of migraine, how we applied that in clinical picture is we used to say like basilar migraine, right? So if patient has a vertigo and migraine with it, then because we were thinking about basilar artery vasoconstriction, we wouldn't prescribe them triptans. We will be worrying about vasoconstriction after, and we wouldn't prescribe them triptans. Now, we think that it's the brainstem, hyperactivity of the brainstem. So then, it's not a basilar migraine anymore. It's a migraine with vertigo. So, triptans are safe. So, these are important to consider in the clinical picture.

So if you are seeing young patients without any other comorbid illnesses, they do not have high risk for cardiovascular and cerebrovascular disease, you can prescribe triptans. And we have seven different triptans. Sumatriptan, rizatriptan, naratriptan, and eletriptan, which are Imitrex, Maxalt, Amerge, and Relpax. These are generic and you do not have to worry about insurance companies. So, you can prescribe these medications. When you're prescribing triptans, you can go ahead and prescribe their full dose. For Imitrex for adults, it's a 100 milligram. For Maxalt for adult, 10 milligram. For Amerge, naratriptan for adult, it's 2.5 milligram. For Relpax for adult, it's 40 milligram. And the prescription is take one tablet at the onset. You can repeat after two hours, except naratriptan, it's long-acting, so it's after four hours. And they can take usually two tablets, maximum for 24 hours. You try two different triptans, they do not help, then we move on to gepants. That's insurance requirements as well. Or if they have cardiovascular, cerebrovascular disease, then we specify patient cannot be on this because it's contraindicated, they cannot be on triptans, then we move to a gepant.

So, I like Nurtec, rimegepant if patient has high episodic migraine attacks, and they are hesitant to be on preventive medications, but I am worried about medication overuse. So then, I prefer Nurtec because Nurtec has both use, right? It can be used for acute treatment. It can be used for preventive treatment. So if they're having good months, they're only needing it three times a month, they take it as needed. And if they're having few bad months, weather changes, some significant stress, they can take it every other day for prevention for few months, and they can go back to using it as needed. So, Nurtec has that advantage. Ubrelvy, ubrogepant, it's a 100 milligram, it can be prescribed 50 milligram as well. There isn't any significant side effect changes with the dose, 50 versus 100. So, I would like to go ahead and prescribe the 100 milligram. Take one at the onset, can repeat after two hours, maximum dose of 200 milligram. The gepant's most common side effects are nausea and constipation. Very well tolerated. That's the advantage of CGRP inhibitors. They are well tolerated medication, less side effect profile. The patients, they like them.

And then, we have Zavzpret or zavegepant. It's a nasal spray, came out recently. It's not very famous yet. For patients with GI problems or they have significant nausea, throwing up with the migraine, you might consider Zavzpret or zavegepant instead of an oral agent, so they don't throw up their medications.

Host: It was like an ocean of pearls. You know, that's the part of this podcast I think we're going to be going back to and listening to again. So, I'm just going to repeat a couple of things that you said that were very valuable. A, triptans still have a role clearly and often are, I imagine, first-line given the expense of the other agents. They come in multiple different forms. You can give them by mouth, injectables, sublingual nasal sprays. So, triptans really can be very helpful. All generic as you said.

And then, when it comes to the gepants, you mentioned Nurtec, as both preventative and as an agent, as an abortive medication, and it has that flexibility. What was the dose of the Nurtec again and how did you do that?

Dr. Seniha Ozudogru: Seventy-five milligram. Nurtec has a long half life. That's why it's only once-a-day dosing, 75 milligram sublingual. It's once a day. It has like a mint taste. Some patients really like that. And they like that they don't have to worry about drinking it with water. So, they put it under their tongue, it dissolves and it is easy to tolerate.

Host: Gepants, are they better than the triptans or...?

Dr. Seniha Ozudogru: We cannot really say better. So, migraine is a very complex disease. And as Eric tried to explain, the pathophysiological mechanism of migraine is very complex. There are still migraine phenotyping studies. We are trying to see if this is like one disease. It's multiple different presentation. It changes patient to patient. Whatever their dominant mechanism of their migraine, that medication group works for them. So for one patient, it's the CGRP and CGRP inhibitors work for them. But for others, it might not be that. We have patients that they do not respond to CGRP inhibitors. And sometimes it's shocking, they do respond to our old topiramate, our topamax or verapamil, which we don't really talk about it much because it has very low level of proof. So based on patient's dominant mechanism of their migraine, the medication group that works for them changes.

And the other thing is the combination. So, we have patients that CGRP works, but it helps 50% and they have chronic everyday migraines. So then, we have to combine it with Botox or we have to combine it with topiramate, or they have an underlying depression, then we like to combine their Botox treatment with an SNRI medication, so the combination works for them.

What we do is, or I like to do, is when I start with an oral non-specific medication, if it works 20%, I do not stop and move on to next one. I continue and add on the next medication. If it is 0% benefit and side effects only, then I move on to next when I stopped that medication. So, we have to be clever with the combination of treatment. So, that's why we think about, "Okay, what is the pharmacological mechanism of this medication? So, how can we combine with another one so patient get full benefit from it?"

So, for young patients, they have fatigue, they have trouble with school focusing, cognitive decline with their migraine, I like to combine their  venlafaxine with Botox, so they can have a significant benefit with their focusing on attention problem with venlafaxine. And then, Botox kicks in with their migraine so they can have a good relief with that.

And one gepant we forgot to mention, atogepant and Qulipta. Qulipta is the preventive gepant. It comes in 10, 30 and 60 milligram. Ten milligram, we almost never use. Thirty milligram and 60 milligram are good dosing. Sixty milligram is the one shown to cause weight loss. So for patients who are willing to lose weight, that can be an additional benefit for them. Same side effects, nausea and constipation. Qulipta and atogepant can be considered for prevention as well.

Host: So, you mentioned Botox. And so, what is the role of Botox in modern headache management now?

Dr. Seniha Ozudogru: Botox is an underutilized treatment for chronic migraine. It's FDA approved treatment for chronic migraine since 2010. A big part I guess, we are responsible as a neurologist because we don't train our residents to be able to do Botox. Every general neurologist should be trained to do Botox, and we are trying to achieve that with our residency program here at Penn.

So, in 2010, based on the PREEMPT study, Botox is approved for chronic migraine treatment. In real life with the insurance requirements, if the patients try and fail three different non-specific oral medication groups, then they have chronic migraine, meaning that they have migraine headaches more than 15 days a month, over three months, they do qualify for Botox. It's one of the safest option. It doesn't cause any systemic side effects. It is 155 units with 31 injections. There is a migraine protocol that we follow. So, it is a standard internationally. We all do the same injections on the same locations. It can cause maybe droopy eyelids, maybe neck weakness. Other than that, pretty safe treatment. And when those complications happens, they do not last over two weeks.

Nowadays, we are discussing if Botox is a safe option during pregnancy, and we do have patients that they do continue their Botox treatment during pregnancy. And it has, so far, shown non-teratogenic and a safe option. It's not finalized yet. But it seems like it is a safe option.

Host: So, you said it's sort of with chronic migraines, people who have failed multiple other agents, right?

Dr. Seniha Ozudogru: Correct. Correct. So, after those topiramate amitriptyline, beta-blockers, then they do qualify for Botox.

Host: It's preventative.

Dr. Seniha Ozudogru: It is for prevention. Correct. And we repeat it every three months.

Host: We're running a little long. I'm just really curious. Where do you inject in the head?

Dr. Seniha Ozudogru: We do injections on the forehead. There are seven spots on the forehead. There are four spots on the temporalis muscles, three spots on the occipitalis muscles to each side of suboccipitalis, and then three injections on the trapezius muscles.

Host: Eric, is there anything you want to add before we sign off, just on those topics that Seniha just really brilliantly covered for us?

Dr. Eric Kaiser: Yeah. Particularly considering Botox for certain patients, sometimes things that I'm thinking about, I think it's a really attractive option for folks who are more elderly and maybe have other chronic comorbidities that may prevent you from thinking about other preventive treatment options.

It could be also helpful for folks who have a lot of maybe cervical myofascial pain, because it does provide a little bit of muscle relaxation, particularly within the paraspinal muscles as well as the trapezius muscles. Folks perhaps with some comorbid bruxism or TMJ disorder, sometimes adding a little bit of injections into the masseter can be helpful, as well as just the kind of standard temporalis injections can complement some of those other treatment options that you're considering for patients. And so, sometimes those can be good things to think about when picking candidates to start Botox with.

Host: Well, I want to thank you both of you. This has been terrific. I've learned a ton and I think I had a lot to learn because I really didn't fully understand these newer medications other than what I'd read. But that's different from actually talking to somebody who's using them every day. So, this has been immensely helpful. Is there anything else you just want to add before we sign off?

Dr. Seniha Ozudogru: Thank you. It has been great to be here. Migraine is a very common disorder and we are happy to help.

Host: And Seniha, you have headache practices now within your division. I know out at Penn at Valley Forge, I believe you have somebody, and I think you are in New Jersey as well, of course down at Perelman. Are there any other places we should mention where you have headache specialists?

Dr. Seniha Ozudogru: We have a new headache specialist started at Presby and VA and the veteran hospital here in Philadelphia and Pennsylvania Hospital. And our new provider is joining us in August at the Radnor location.

Host: Oh, Radnor. Oh, that's great. Well, I'm at Radnor, so that's terrific. I'm really thrilled. Eric, any closing thoughts?

Dr. Eric Kaiser: I think we are in an exciting place in terms of migraine treatment. I think these CGRP treatments have really revolutionized the field. And I think in time will have other new options down the road. And I think we've gotten to a place that we can really make a big impact on folks' quality of life. And so, we're in a new era. 

Host: Great. Thank you both again for coming. This has been very educational. I'm sure everyone's going to appreciate it. And I want to thank the audience for joining the Penn Primary Care podcast. Please join us again next time.