David Kudrow, MD

 What advice would I have for community neurologists for acute and preventive treatment of migraine? It has become easier to treat patients who have migraine. We have a new class of medications that has a very favorable safety profile, a favorable tolerability profile, and a favorable efficacy profile. The biggest barrier to using these new therapeutics is who’s going to pay for them, like the insurance. For patients who don’t have insurance, these medications can be phenomenally expensive.

For patients who have insurance, fortunately, a lot of the companies that make these medications are offering them at deep discounts, at least for a year or perhaps a little longer. But not all patients are eligible for those discounts. They’re typically $0 or low co-pay amounts the patients have to pay. But ultimately, many insurance companies are going to ask physicians, “Have patients tried traditional oral preventive medications,” before putting them on the preventive anti-CGRP monoclonal antibodies or small-molecule antagonists. In many cases, physicians are going to have to step through those options before being able to use these medications.

My attitude is a little different. We’ve come a long way. Great scientific thinkers have introduced these therapies that are disease-specific, migraine-specific, effective, and better tolerated. Why would we need to jump through hoops and try things that are less effective, during which time patients continue to suffer from migraine attacks, disability, and affected quality of life? My hope is that these medications would be available in the future for patients who need them. I wouldn’t be afraid of using this class of medications, either monoclonal antibodies or small-molecule antagonists, because the adverse effect profile and tolerability profile have proven to be quite favorable.

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Dr David Kudrow shares some advice for community neurologists on the acute and preventive treatment of migraine.

Acute and Preventative Migraine Treatment: Advice for Neurologists

 How would I expect the recent approval of rimegepant for the preventive treatment of episodic migraine to change the treatment landscape? This is an interesting question. For decades, we’ve been thinking about migraine therapeutics in terms of acute and preventive migraine treatment. Those 2 concepts never converged until recently. As we all know, rimegepant was approved by the FDA for the treatment of acute migraine about a year ago. I may be off a little, because the pandemic has thrown off my sense of time. In any case, it was initially approved for the acute treatment of migraine in patients with and without aura.

As an investigator involved in those clinical trials, in the long-term safety studies, patients would be given a bottle of 30 rimegepant and told, “Use it on an as-needed basis, provided you don’t take it more than once per day.” Patients would come back for their study visits monthly and say, “It’s interesting. It works very well for my acute migraine, but I’m also having fewer migraines or fewer migraine days.” A study was subsequently done looking at rimegepant 75 mg for the preventive treatment of migraine, and the dosing schedule was every other day. Why? Because in the acute studies, it showed a pretty good, sustained pain relief or pain freedom from 2 hours to 24 and even 48 hours. It also has a relatively long half-life for an acute migraine treatment of up to about 11 or 12 hours. That’s the reason for the dosing schedule. Subsequently, a double-blind placebo-controlled preventive study was done with rimegepant, and it showed efficacy vs placebo in reducing migraine days over 12 weeks.

The interesting concept that we’re now dealing with is that we’re using an acute medication for both the acute treatment of migraine and also the preventive treatment of migraine. That throws us off or blurs the lines between our traditional thinking about migraine therapeutics. In terms of reduction in mean monthly migraine days, a greater proportion of patients on rimegepant had 50% or better reduction in monthly migraine days as well. But as a specialist, it’s making me think, “How do I use this medication?” Another interesting attribute of the CGRP antagonist class is that they don’t seem to cause medication overuse or rebound headaches, which means the patients could theoretically use them on an as-needed basis without having to worry about precipitating medication overuse headache.

I’m now thinking about where the medication is appropriate. If patients want to use it on an as-needed basis as much as they want, that should be OK. If patients want to use it on a preventive basis to ensure that they don’t have migraine attacks, or at least have a reduction in the frequency of migraine attacks, that’s OK, too. If they want to use it on a preemptive basis, such as for an anticipated event that they know will trigger a migraine—perhaps menstrual migraine—then they can use it preemptively as well. The introduction of rimegepant as an acute and preventive treatment for migraine has changed the way we see migraine therapeutics, or at least the way we’ve traditionally looked at migraine therapeutics.

Another aspect that’s important is that we now have injectable monoclonal antibodies among this large class of CGRP antagonist medications, and we have the small-molecule CGRP antagonists. The monoclonal antibodies have a very long half-life of 27 to 31 days. In a population of patients with migraine who are predominantly female and of child-bearing potential, we have to be cautious about using drugs that have very long half-lives, particularly in women who aren’t committed to not becoming pregnant while on the medication.

We don’t know what the effect is on pregnancy or the developing uterus. We have to be cautious. I’m very cautious about using those medications in women of childbearing potential and want to make sure there’s a strategy or commitment to not become pregnant while they’re on the medication because of the long half-life. Traditionally, we say patients should wash out the medications, and it should take 5 half-lives. That’s 5 or 6 months. On the other hand, ubrogepant, a small-molecule CGRP antagonist similar to rimegepant, has a much lower half-life. In 2 days or 2 and a half days, the medication should be entirely out of their system. In that population of patients, it’s a consideration that a medication with a shorter half-life might be a reasonable option in someone who may become pregnant while on the medication. They can wash out the medication very quickly if necessary.

A key opinion leader illustrates how recently approved rimegepant for preventive episodic migraine treatment could change the treatment landscape.

Rimegepant for Preventative Migraine Treatment

 Let’s talk about the injectable CGRP antagonists for migraine prevention. We’ll touch a little on their efficacy, safety, and dosing. The idea is that all of these injectable CGRP antagonist medications are monoclonal antibodies. The safety and efficacy have all been established with these medications in phase 2 and phase 3 clinical trials. The clinical trials were designed pretty much the same. The inclusion and exclusion criteria were pretty much the same. In the end, efficacy, as defined by reduction in mean monthly migraine days, a 50% responder rate, and quality-of-life improvement in both episodic and chronic migraine were pretty similar across the board. The adverse effect profiles differed a little. The pharmacology differs a little from one monoclonal antibody to the next.

With that respect, I’ll say a little about each of them. First, eptinezumab is a monoclonal antibody and the only one administered by intravenous infusion of the 4 in the class. It’s dosed at 100 or 300 mg infused over 30 minutes quarterly, so once every 3 months. Patients get 4 doses per year. The most common adverse events reported with eptinezumab seem to be hypersensitivity reactions.

Erenumab is another medication. This was the first drug approved in the class in May of 2018. It’s a subcutaneous injection that is done monthly by the patient. It’s an autoinjector of either 70 or 140 mg per month. The most common adverse events in clinical trials included injection site reactions, which typically means pain, redness, or swelling. There could be a localized hypersensitivity reaction. In clinical trials, about 3% of patients on the 140-mg dose experienced constipation. Two percent of patients had muscle spasm.

In post-marketing surveillance, there have been reports of more severe cases of constipation, in some cases requiring hospitalization, and even a handful of cases requiring surgical intervention. That’s pretty rare. Also in post-marketing surveillance, there have been some reports of hypertension that we didn’t see in any of the clinical trials. All of the phase 2 and phase 3 studies were looked at for cardiovascular safety, and hypertension didn’t come up as an event occurring more often than with the placebo in any of the trials or with any of the doses. It’s unclear how or why some of these cases are popping up, and it’s actively being looked at. In some cases, patients have a history of hypertension. Otherwise, it’s unknown who might be at risk. In any case, it’s recommended that patients be followed. Blood pressure should be followed after they’re started on medication, at least initially.

Fremanezumab, another of the monoclonal antibodies, is also a monthly subcutaneous injection that’s available by autoinjector. The dose can be either 225 mg per month or 675 mg every 3 months, or quarterly. The most common adverse events occurring in clinical trials with fremanezumab are injection site reactions. Galcanezumab, another monoclonal antibody directed against CGRP, is another monthly subcutaneous injection with initially a loading dose of 240 mg, which is 2 injections of 120 mg, followed by monthly injections of 120 mg. That’s the only one of the medications that has a loading dose.

I should go back and add that the mechanistic difference between these medications is that erenumab is the only one of the monoclonal antibodies that is directed against the CGRP receptor, while eptinezumab, fremanezumab, and galcanezumab are monoclonal antibodies directed against the CGRP ligand. That may be important to remember while considering mechanistic differences between these medications. Why might that be important? CGRP is a ubiquitous potent vasodilator that exists in the central nervous system, the peripheral nervous system, and the enteric nervous system. It obviously binds to its own CGRP receptor, but it also binds to 2 other receptors: the amylin and adrenomedullin receptors. From a mechanistic standpoint, erenumab, which is a receptor blocker, will only block CGRP at the CGRP receptor and not at the other 2 receptors, while the ligand-directed monoclonal antibodies will prevent CGRP from binding to any of the receptors, including the CGRP receptor, amylin receptor, and adrenomedullin receptor.

David Kudrow, MD, reviews the available FDA-approved injectable CGRP antagonists for preventive migraine treatment.

Preventative Migraine Treatment: Injectable CGRP Antagonists

 Ubrogepant is a small molecule CGRP [calcitonin gene-related peptide] antagonist. It binds to the CGRP receptor and prevents CGRP from acting its biological activity. What does that mean? That means CGRP is a potent vasodilator, so it mediates the vasodilatation in the meningeal vessels. CGRP mediates a neuroinflammatory reaction. CGRP also mediates transmission of pain impulses from the periphery, which is the trigeminal nerve into the central nervous system. By blocking those receptors, we can affect migraine at any of those touch points.

Ubrogepant was shown to be effective for the acute treatment of episodic migraine in at least 2—maybe even 3—pivotal single-attack, phase 3 studies. Patients were randomized to either 50 or 100 mg of ubrogepant vs placebo. The primary end point was pain freedom at 2 hours. As I recall, 21% of patients on ubrogepant were pain-free at 2 hours vs about 11% of patients on placebo. A secondary end point was pain relief, which is defined as patients going from moderate or severe pain intensity when they take the dose of study medication to mild pain or no pain at 2 hours. Over 60% of patients randomized to ubrogepant achieved pain relief at 2 hours vs placebo as well.

Other end points included patients who were able to return to normal function, and statistical superiority over placebo in that regard. Patients on ubrogepant also had a greater reduction in non–pain migraine related symptoms, meaning nausea, light sensitivity, or sound sensitivity. It proved to be an effective treatment for acute migraine. It’s available as a 50 and 100 mg tablet. Patients can take a dose 2 hours later if necessary. The maximum daily dose is 200 mg per day. The most common adverse events in ubrogepant studies were nausea in about 4% of patients and somnolence in a small number of patients.

A migraine specialist examines the efficacy and safety of oral CGRP antagonist ubrogepant for the acute treatment of migraine.

Ubrogepant for Acute Migraine Treatment

 How has the introduction of CGRP [calcitonin gene-related peptide] antagonists affected the treatment of chronic migraine? In my experience, vastly. I was a principal investigator in many of the phase 2 and phase 3 clinical trials that evaluated both monoclonal antibodies against CGRP and the small molecule antagonist studies. I had a pretty early view of what these medications were doing in patients with both episodic and chronic migraine. I wouldn’t limit the discussion to chronic migraine.

My practice is a headache specialty practice. Many of my patients have been on preventive medications in the past that they couldn’t tolerate or weren’t very effective for them. We had many patients who initially responded well to the anti-CGRP monoclonal antibodies for migraine prevention. Not only did they respond by having a reduced frequency of monthly migraines, but they also reported that they had an improved quality of life. They were no longer feeling anxious about having migraine, when they were going to have another migraine, how they had to plan their day, or whether they were going to have enough acute medication to last them a month for their migraines. From that perspective, I was very impressed early on with how initially the monoclonal antibodies and all 4 of them were very effective in helping reduce pain and suffering due to migraine.

What has been the effect of the introduction of CGRP antagonists on patients’ quality of life? A lot of the time, the top-line results reported for these clinical trials is reduction in frequency of migraine, which is reduction in the mean monthly migraine days compared with placebo, or the proportion of patients who achieve a 50% or better reduction in monthly migraine days. Traditionally, the metrics of success are reduction of migraine days and, conversely, an increase in migraine-free days. But from a more patient-centric perspective, what do the patients really care about? They care about less disability, not having to miss days at work, and not having to miss days with their family or social events or occasions. They care about quality of life and not having to worry about having migraine or having enough medication.

In many of the phase 2 and phase 3 clinical trials, not only did we see that patients were having a reduction in the frequency in their migraine days, but they also had an improved quality of life. We use the Migraine-Specific Quality of Life Questionnaire and the Migraine Disability Assessment scale to look at those things. In each case of these new therapeutics, patients are also recording improvements in their quality of life. On a daily basis, patients say to me, “I’m doing so much better than I was before. I feel much better.” I attribute that to the introduction of an effective therapy with a good adverse effect profile for them.

Another question is, what about reversion from chronic to episodic migraine? There was a paper published in 2019 looking specifically at that question. We looked at patients who had chronic migraine and, over the course of a 12-week double-blind, placebo-controlled study, looked at what proportion of those patients reverted to episodic migraine, meaning going from at least 15 headache days per month to below 15 headache days per month. The post hoc analysis showed that better than 50% of patients went from chronic migraine to episodic migraine. What was really interesting about that analysis was that patients who we’ve always regarded as the most intractable patients—patients who had prior preventive treatment failures and patients who were also experiencing medication overuse—showed a greater rate of reversion from chronic to episodic in comparison with patients who were on placebo.

Dr David Kudrow discusses how CGRP antagonist treatments have affected chronic migraine, including the effect on quality of life.

The Impact of CGRP Antagonists on Chronic Migraine

 How would I decide on treatment? How do I decide when to introduce preventive treatment for migraine? When do I use acute treatment for migraine? And is that a shared discussion with the patient? Let me start by saying that whether I’m prescribing an acute pharmacotherapy or a preventive therapy for migraine, it’s always a discussion with the patient. First, I find that patients who are informed are usually more compliant with the medication regimen. More information is better for everybody involved.

With respect to acute treatment for migraine, there are patients who have varying intensities or severities of migraine. Some patients can get away with using an over-the-counter medication for some of their migraines, or the same patient may have more severe migraines that require a more migraine-specific abortive agent. Everybody who has migraine should be armed with an acute migraine medication. With respect to preventive treatment, the bar is changing, which has to do with the recent introduction of migraine-specific, mechanism-specific medications that have a better adverse-effect profile and better efficacy. The American Headache Society is now recommending that patients who have even as few as 2 migraine days per month should be considered for preventive treatment if those migraine days are accompanied by significant disability, and any patient who has at least 4 migraine days per month, irrespective of the degree of disability, should be considered for migraine preventive therapy.

In my own practice, it’s a sliding scale. I have patients who may have 4 to 6 migraine days per month, and they’ve been using a triptan that works very effectively for them without much in the way of adverse events. They don’t want to take preventive medication and want to just keep using their acute medication. That’s a reasonable choice. On the other hand, there are patients who have 1 or 2 severe migraine days per month and are debilitated by them. Even if they use their acute medication, that medication may help the headache but then has adverse effects that incapacitate the patient or prevent them from working. Not many patients can tolerate losing 1 or 2 days of work per month without getting fired. If we can’t get those headaches under control with a good acute treatment, then even those patients should be considered for preventive therapy.

It’s always a discussion. Medications have adverse effects. I dread patients calling me and saying, “You didn’t tell me that I wasn’t going to be able to remember my kid’s name or that I was going to gain 20 pounds in the first month of taking this medication.” The discussion of when and whether to start a preventive treatment and which treatment that’s going to be is critical for the success of the therapeutic regimen.

An expert neurologist explains how to decide on migraine treatment with a patient and when to consider preventive treatment.

Deciding on Acute and Preventative Treatment Options for Migraine

 What’s the difference between episodic migraine and chronic migraine? We’ve been using these terms separately for the past couple of decades. Chronic migraine is defined as headache frequency of at least 15 days per month, with at least 8 of those being migraine days. Episodic migraine is everything else, so anything up to 14 headache days per month. But I find that 15-day limit between the 2 diagnostic categories to be rather arbitrary.

Three percent of patients who have episodic migraine will become chronic over the course of a year, and about 25% of patients who have chronic migraine may revert to episodic migraine over the course of a year. More recently, a very important paper from the American Headache Society Wolff Award, which is very prestigious recognized research, showed that an examination of a large database of patients with migraine showed that with respect to the degree of disability that patients experience, patients who have 8 to 14 migraine days per month vs patients who have 15 to 23 migraine days per month are virtually the same. Their degree of disability is about the same, and people who have 24 or more headache days per month have the greatest degree of disability.

That traditional arbitrary boundary between chronic and episodic is in flux at this point. Why is that important? Because there are some medications that we use for patients who have chronic migraine that may be beneficial for patients who have less than chronic migraine. It’s important to understand and recognize that those diagnostic categories are relatively fluid.

Let me also add that with respect to the migraine attack itself, there’s no difference between an acute migraine in a patient who has episodic migraine and an acute migraine that occurs in a patient with chronic migraine. As the frequency of migraine increases, conversely, the frequency of headache-free days decreases. Migraine is a long-lasting phenomenon. We recognize the acute attack as the most obvious clinical observation in a patient that has migraine, but there’s a prodrome to the attack that can be several hours to days in duration. There’s also a postdrome to the attack that can be several hours to days in duration, which prolongs the time of the acute migraine attack. The more frequent migraine becomes, the fewer headache-free days a patient has. That’s important to point out in recognizing how increasing frequency of migraine contributes to disability of the patient’s experience and the need for effective acute and preventive therapeutics.

Is there a difference in the symptoms of migraine in patients who have episodic or chronic migraine? No. The migraine attack is defined as moderate to severe headache. It’s usually unilateral and doesn’t have to be associated with nausea, light sensitivity, or sound sensitivity. The patient doesn’t want to move, it worsens with exertion, and it can occur with a visual aura. Those characteristics are the same, whether a patient has episodic or chronic migraine. Chronic migraine is defined clinically as that frequency of over 14 headache days per month.

David Kudrow, MD, defines episodic and chronic migraine and details how symptoms differ.