EAN 2026 | Combination therapy for migraine: anti-CGRP, anti-PACAP, and onabotulinumtoxinA

I’m going to discuss the role of combination therapy in the management of migraine. One of the big advances in the management of chronic migraine has been the availability of onabotulinum toxin A, which is approved as an evidence-based treatment for chronic migraine, but not for episodic migraine. In addition, over the last eight years, a new class of migraine preventive treatments has emerged, and that class of treatments is often referred to as calcitonin gene-related peptide-targeted medications or CGRP-targeted medications. Of the CGRP-targeted medications for prevention, there are four monoclonal antibodies that are currently available, at least in the U.S., and two gepants, which are currently available. So the monoclonal antibodies are injectables. Three of them are given subcutaneously, usually once a month. One of them is given intravenously, and that drug is given every three months. Of the gepants, which are small molecule CGRP receptor blockers, those drugs are usually given daily or every other day as preventive treatments for migraine. In addition, a new class of medications that is still in relatively early-stage testing targets PACAP. And there is already published evidence that at least one PACAP-targeted medication is effective for the preventive treatment of migraine. So in current practice, the question is, when should we give monotherapy? When should we give combination therapy? And how should treatments be combined? And are there safety problems with combining treatment? So for the combination of onabotulinum toxin A and CGRP-targeted therapies, there is evidence from real-world studies that the combination is effective. In my center, we did a study of people who were on onabotulinum toxin A who had a partial but inadequate response and looked at whether there was an incremental benefit of adding a monoclonal antibody. And there have been many similar studies from other centers. In our study, people prior to Botox had an average of 24 monthly migraine days. After taking Botox, they had an average of 12 monthly migraine days. And the point here is that there is a group of people who, when treated with monotherapy, get striking reductions in migraine days, but reductions that may not be good enough. So in that group, when we then added in open-label fashion, various CGRP-targeted monoclonal antibodies, we found that on average their headache frequency was cut in half, once again demonstrating, at least in a real-world setting, that the combination of Botox and a monoclonal antibody delivers greater treatment effects than Botox alone, and that the combination is safe. And there have now been multiple observational studies that report reductions in monthly headache days, reductions in disability, and higher continuation rates when CGRP monoclonal antibodies are added to Botox. There is a smaller but significant body of evidence that we can add gepants to Botox, add small molecules, the small molecule CGRP inhibitors to Botox as well. And incidentally, there is laboratory evidence that suggests that these drugs should be synergistic because they act differently on unmyelinated C-fibers versus the small myelinated A-delta fibers that are involved in mediating pain in the trigeminovascular system. The guidelines from the American Headache Society support combining preventive treatments from different classes when response to monotherapy is inadequate. And I would say, you know, in the U.S., in refractory patients, combination therapy is the norm. Combination therapy with onabotulinum toxin A and a CGRP therapy is particularly useful in people who have chronic migraine, that is to say 15 or more headache days per month. In partial responders to either onabotulinum toxin A alone or to a CGRP medication, in people who have high levels of disability, and in people who have failed multiple other treatments as well.

The newer set of drugs are antibodies that are PACAP-targeted. And these are early days in exploring CGRP-targeted therapies in combination with PACAP-targeted therapies. And as of now, there are no PACAP-targeted therapies that have received regulatory approval anywhere in the world. PACAP, or pituitary adenylate cyclase activating polypeptide, is another vasodilator neuropeptide which has similarities to CGRP but acts through mechanisms that are independent with it. Preclinical studies show that CGRP and PACAP can induce similar migraine-like symptoms in rodents, but they differ in terms of the intercellular signaling pathways in which they are activated. There are studies and antibodies or blockers in development that target both CGRP and PACAP. And these are early days, but my hope is that we’ll be able to help the most refractory patients with migraine using various combinations of preventive medications. It is common clinical practice in the U.S. to combine onabotulinum toxin A with oral generic medications like beta blockers, antidepressants, and so forth. It’s also common practice to combine the CGRP-targeted therapies with oral generic medications. And the hope is that by combining medications, we’ll be able to deliver the benefits our patients are looking for when monotherapy proves to be inadequate.

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