Safety of CGRP Receptor Antagonists vs 5-HT1F Agonists


Assessing the differences in dosing and adverse-effect profiles when using small-molecule CGRP receptor antagonists rimegepant and ubrogepant vs lasmiditan.

Peter J. Goadsby, MD, PhD: Wade, contrast for us the small-molecule CGRP receptor antagonist with the gepants. In any 1 year, just 1 development would be great. It’s fantastic to have a second. 

Wade M. Cooper, DO: You’re referring to ubrogepant and rimegepant. Both are FDA approved here in the United States for acute treatment of migraine. What’s cool about these medicines is that they work mostly in the periphery, and they block that inflammatory signal coming from the pain-sensitive nerves. They suppress inflammation of the meninges when they’re effective. 

What’s also cool about these is that they tend to work relatively quickly. Most remarkable from my perspective is their almost complete lack of adverse effects. When you compare the gepants class medicines with the triptan adverse effects, it’s quite phenomenal. Nausea seems to be a reported adverse effect in the clinical trials. If you talked to me 2 weeks ago, I would have told you I hadn’t seen much of that from my patient profile. I’ve had 1 or 2 people with some pretty severe nausea from it, but as a whole, it’s really well tolerated. 

As Paul was saying earlier, because they work on a different mechanism of action than triptans, just like the ditans, these pick on receptors that the triptans just don’t focus on. These medications can be really helpful for people who haven’t responded previously to acute triptan therapy.

Peter J. Goadsby, MD, PhD: We have the new medicines, and they have a range of doses. There are choices in the ditan dosing and ubrogepant dosing. Let’s talk about dosing for a moment. Jelena, tell me about how you see the dosing choices and what your experience has been with lasmiditan dosing. 

Jelena Pavlovic, MD, PhD: It’s 50, 100, and 200 mg, right? They’re comparable in terms of efficacy. We see that they work at 1 hour post-treatment, but they all work better and have better separation from placebo at 2 hours post-treatment. At this point, because of the associated CNS [central nervous system] effects with ditans and with lasmiditan specifically, I like to start low and go slow. 

I start at 50 mg in patients who feel relief and may have a lower adverse-effect profile. If they can’t achieve pain freedom completely, then because there is an additive effect to a higher dose, I will increase the dose at that point.

Peter J. Goadsby, MD, PhD: Wade, where are you with dosing with ubrogepant, for example?

Wade M. Cooper, DO: First, let’s go back to lasmiditan. When it came out, I was so geeked about this. I went to pretty high dosing, and it worked really well for some people. The problem was, I had some people tell me it made them feel a bit spacey and weird. Just as you heard earlier, I’m using lower doses to start. As people do well with it and as we show some efficacy, I’m willing to expand into the 100- or 200-mg doses. 

For the gepants class medicines, you have rimegepant, which has 1 set dose at 75 mg. Ubrogepant has some dosing selections to choose from. What’s interesting, from my perspective, is that unlike with the lasmiditan, where I have to go a bit slower because I want to make sure I don’t make someone feel sick and write an angry email to me, the gepants are just so gosh darn well tolerated, so I tend to use the top-end dosing with them. That’s where the most efficacy has been with those.

Paul G. Mathew, MD: I’ll try to avoid using inappropriate language like “gosh darn,” but just to punctuate those points, I actually do the same thing. I’ll also give patients the instruction that if they tolerate lasmiditan 50 mg just fine and find it partially effective, they should try taking 2 of them. If that works, they can call my office and leave a message, and I’ll call in a prescription for the 100 mg. Similarly, I will do the same thing with ubrogepant with the instructions that if they tolerate the 50 mg just fine and find it partially effective, try taking 2 of them, then let my office know, and I’ll call in a refill for the 100 mg of that medication as well.

Peter J. Goadsby, MD, PhD: While you’re talking about ditans, I wanted to pick that up, and then we’ll swing to others. Tell me about how you see the adverse-effect profile and the safety issues when you contrast ditans or gepants with the older medicines.

Paul G. Mathew, MD: I agree with Jelena and Wade. I found them to be really well tolerated. I find the gepants to be better tolerated than lasmiditan, so that might push my hand a bit. The other thing that will push me in 1 direction or the other is if the person is on a CGRP antibody. In clinical practice, I have yet to see any issues with people who are on a CGRP antibody and also on a gepant. But if they are on an antibody, my preference, at least initially, is to try them on lasmiditan first. 

Why not take advantage of a different mechanism for abortive therapy than what they’re on for prevention when 1 is available? Again, that doesn’t prevent me from using a gepant in those patients if they can’t tolerate lasmiditan or if some other issue arises.

Peter J. Goadsby, MD, PhD: It’s certainly mechanistically attractive to think that if you have a CGRP blockade, the ditan will come along and block other things that are prejunctionally and presynaptically released. Glutamate is the obvious thing, and perhaps it blocks other peptides that are for another day. The multimechanistic side is useful. Colleagues are also finding that there’s room still to push on the CGRP mechanism, even in people with monoclonal antibodies. We have a lot of things to learn practically. 

Paul G. Mathew, MD: The way I describe it to patients is, the antibody is lowering your overall level of CGRP, and if you happen to have a migraine, you’ll have an episodic burst of CGRP, which will then be suppressed by the gepant. That’s how I explain it to patients. If they have a better understanding, even if it’s simplistic, they’re more likely to be compliant. 

Jelena Pavlovic, MD, PhD: That’s in line with the theoretical model.

Peter J. Goadsby, MD, PhD: It’s good basic science evidence. What we’re talking about has a very good laboratory base. For example, take glutamatergic transmission across the trigeminal cervical complex. You can certainly alter that whole transmission with the 1F agonists in the lab. There’s so much to be understood.

Dawn C. Buse, PhD: Paul, I like the way you described that, because these are 2 whole new classes. These are complex with many neurotransmitters involved, and when someone knows a bit of what is going on, they’re going to be more comfortable. They’re going to tolerate any adverse effects that might arise early a bit better, and they’re going to tend to be more adherent. They’re also going to have more comfort with their provider when they’re told in advance what to expect. All of us as humans like to know what to expect, so I like the explanation you just gave with your visuals too. That was helpful.

Paul G. Mathew, MD: It’s not the macarena, OK? 

Wade M. Cooper, DO: One of the nice things about using ditans is you can tell the patients, “You’re going to F migraine.” By that I mean, we’ll affect it in multiple areas. Sometimes, I’ll even share with our patients that we believe their light and sound sensitivity relates to thalamic processing, and we have a receptor there that a ditan might be effective on. 

When we talk about allodynia, or the shutoff switch of migraine, we have F receptors in those regions too. Those become delicious targets. To Paul’s point, the idea of inflammation in the lining of the brain resonates really well with our patients. Using gepants or CGRP-targeted therapies to lower that inflammatory cascade and shut off migraine works really well.

Jelena Pavlovic, MD, PhD: That’s a wonderful way to express it to patients, Wade. I really like that. May I borrow that?

Wade M. Cooper, DO: I got it from Paul, so yes, you can. 

Paul G. Mathew, MD: The other thing I’ll sometimes say is that triptans and ditans are preventing the inflammatory soup. Once the inflammatory soup has started, an NSAID [nonsteroidal anti-inflammatory drug] can help curb that inflammation that’s already started. Again, teaching these very simplistic mechanisms can really educate patients and make them appreciate why combination therapy in certain situations is an advantage.

Jelena Pavlovic, MD, PhD: Peter, I wanted to add another comment to your question about dosing. We did not mention rimegepant, which comes in 1 dose currently and is an ODT, an orally disintegrating tablet, of 75 mg. There isn’t much of a debate of what to do other than give it. It tastes little like licorice, but most patients seem to really like it. The ease of administration—of being in a meeting, turning around, and treating one’s migraine—is really appealing.

Paul G. Mathew, MD: This might be excessive salesmanship, but I also tell patients that because of the rapid-dissolving technology, if you have a sweaty palm, it might actually dissolve in your palm. That’s true, and it accentuates just how rapidly it can dissolve. That it’s rapidly acting further encourages patients to take it soon.

Peter J. Goadsby, MD, PhD: With the consideration that they washed their hands already and all good hygiene has been accepted. I tend to tell patients that the CGRP drugs like ubrogepant or rimegepant block the effect of this chemical we know is in migraine, and that the 1F drug turns the pathways off. I’m completely agnostic about inflammation as a cause of migraine. 

As you probably know, I sail in my own little sea around that. I am prepared to say to patients sometimes that it’s a really complex problem, and it’s really a devastating problem. That means part of the honesty of it is that we don’t understand precisely how these things work. We don’t understand precisely how triptans work 25 years later, but that has not stopped 10 million people from taking and benefiting from them. It’s an evolving process.

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