Testing a Combination Therapy for Migraine: Anti-CGRP Antibodies Plus Neuromodulation

A new, small randomized trial suggests that transcranial direct current stimulation may provide added benefit to those taking CGRP-targeted therapies. But definitive conclusions await further studies.

Migraine is a complex condition in which both the peripheral and central nervous system play a role. Because of that complexity, many people with migraine don’t experience relief from only a single treatment.

Now, a new randomized clinical trial suggests that combining treatments – one that targets central migraine mechanisms with another that affects peripheral mechanisms –  could help some patients in the future.

The research, from co-first authors Raffaele Ornello and Aurora D’Atri, University of L’Aquila, Italy, and colleagues, showed that a small cohort of patients who didn’t fully respond to anti-calcitonin gene-related peptide (CGRP) antibody therapies reported fewer migraine days after receiving a short course of transcranial direct current stimulation (tDCS), a type of neuromodulation.

While ample caution is warranted – the new research included just 30 participants and did not meet its primary outcome of the number of headache days – the trial is nonetheless the first of its kind to study the combination of anti-CGRP antibodies, which primarily target the peripheral nervous system, with tDCS, which directly targets the brain. It suggests that tDCS could be an avenue for treating patients who don’t fully respond to the antibodies.

The study “reinforces what we know” about how migraines work, said Shivang Joshi, a neurologist and headache specialist at Community Neuroscience Services, Westborough, US, who was not involved in the study. “There’s probably a combination of central and peripheral processes that are involved in [migraine] pathophysiology. So having a ‘dual attack mode,’ so to speak, is probably beneficial.”

The “study undoubtedly opens new hope for combination treatment strategies in migraine care, as demonstrated through rigorous and robust study designs,” wrote Antonio Russo and Uwe Reuter, in a related editorial.

The study and editorial appeared in the May 2025 issue of Cephalalgia.

Setting up a study
Anti-CGRP antibodies have transformed the treatment of migraine. Unfortunately, not all people with migraine respond to them, while others experience only a minimal reduction in migraine days. For these patients, additional treatments that directly target migraine mechanisms in the central nervous system might provide some relief.

However, researchers aren’t sure whether combining therapies that work via different mechanisms will help patients.

“The question is, How do [migraine therapies targeting the central nervous system] exert their action, and how do [anti-CGRP antibodies] interact with treatments aimed to treat migraine from within the brain?” said Ornello.

Ornello and his colleagues wanted to know whether patients taking anti-CGRP antibodies could further benefit from an additional migraine therapy directly targeting brain activity – in this case tDCS.

tDCS is a type of neuromodulation that delivers a weak current through the scalp, with the goal of modulating neural activity. A common protocol testing this procedure in the migraine field is to use tDCS to excite frontal cortical areas, which could affect activity in thalamocortical circuits linked to migraine, but also to use it to inhibit occipital areas that may play a role in cortical spreading depression.

In the new study, the researchers included 30 patients from two migraine centers in Italy. These patients had shown a partial response to anti-CGRP antibodies, experiencing a reduction in migraine days but still reporting eight or more migraine days in the past 30 days. The study only included patients who had received the antibodies for at least 90 days. The final cohort was 80% female, and roughly 80% of patients were previously diagnosed with chronic migraine (six patients had episodic migraine).

The 30 patients were randomized to receive either active tDCS or sham tDCS. They tracked their symptoms by filling out a headache diary for 28 days prior to the start of treatment, during five days of tDCS, and during a 28-day follow-up period.

During the trial, members of the active group received five daily 20-minute sessions of bilateral cathodal (inhibitory) tDCS stimulation on the occipital area, and anodal (excitatory) stimulation on the M1 area (primary motor cortex), a common target in studies of tDCS that is involved in pain. The control group received sham tDCS.

Equivocal findings
The results of the study were mixed. The team didn’t find any difference between the active and sham groups in the number of headache days – the study’s primary endpoint – in the 28-day follow-up period. However, patients who received active tDCS did report fewer migraine days during follow-up compared to the sham tDCS group (9.2 migraine days/month vs. 16.6 migraine days/month, respectively), and also showed fewer migraine days compared to baseline.

In terms of neurophysiological endpoints, electroencephalogram (EEG) recordings revealed that active tDCS led to a widespread decrease in delta power (referring to low-frequency activity) at frontal regions of the brain compared to sham tDCS. However, the researchers could not detect a significant correlation between the EEG neurophysiological effect and the study’s clinical endpoints in the active tDCS subjects.

Previous tDCS trials that targeted migraine have had mixed results. But the new findings “provided proof that [tDCS is] actually doing something in the brain,” Ornello said.

The new results will need to be verified in a larger sample of migraine patients. “I’d be compelled to see more, longer, and larger studies,” Joshi said. Research like this study “might inspire someone to do a larger trial.”

And there are other wrinkles that need to be ironed out. For instance, patients in the study needed to travel daily to centers where they could receive the neurostimulation. That can put both a financial and practical burden on patients, said co-first author Aurora D’Atri, a neuropsychologist and cognitive scientist.

Researchers will also need to work out the best way to deliver tDCS. They have used divergent parameters, targeting different brain areas and using different levels of stimulation. If investigators can determine what approach works best, ultimately “the idea is that [tDCS] is a technique that could be delivered at home,” D’Atri said.

Freda Kreier is a freelance science journalist based in Washington, DC.

Image credit: 123RF Stock Photo.

References
Effectiveness of transcranial direct current stimulation and monoclonal antibodies acting on the CGRP as a combined treatment for migraine (TACTIC): Results of a randomized controlled trial.
Ornello et al.
Cephalalgia. 2025 May;45(5):3331024251325567.

Raising the bar in migraine prevention: Toward freedom and optimal control.
Russo A, Reuter U.
Cephalalgia. 2025 May;45(5):3331024251331198.