David Kudrow, MD

 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.

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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.

David Kudrow, MD

Articles

Ubrogepant for Acute Migraine Treatment

The Impact of CGRP Antagonists on Chronic Migraine

Deciding on Acute and Preventative Treatment Options for Migraine

The Difference Between Episodic and Chronic Migraine