There is a new wave of migraine treatments on the horizon, focusing on a previously overlooked neural pathway that may provide relief. Understanding various migraine mechanisms is essential, given that migraines affect over 1 billion people globally, especially those who do not respond to standard therapies.

Despite past failures in drug trials, skepticism about this neural pathway’s significance is fading. Recent placebo-controlled studies call for a reevaluation of earlier assumptions about its role in migraine treatment.

Mehsud Ashina and his team at the University of Copenhagen investigated substance P, a neuropeptide linked to migraines. This crucial molecule, released by the trigeminal nerve, leads to pain through blood vessel dilation and inflammation in the meninges, thus amplifying pain signals.

Recent findings show that substance P injections induce headaches, with 71% of non-migraine individuals exhibiting dilation of the superficial temporal artery, a response similar to that seen in migraine sufferers, validating substance P’s role in these conditions.

Following the late 1990s dismissal of substance P as a viable target for migraine drugs, largely due to previous drug failures, Ashina’s team proposed that simplicistic targeting of a single receptor, the neurokinin-1 receptor (NK1-R), was misguided. It is known now that substance P interacts with multiple receptors, including MRGPRX2, enhancing pain signals.

“Previous trials failed because they targeted NK1-R alone,” Ashina explains. Michael Moskowitz at Harvard recognized the trigeminal nerve’s pivotal role in migraines. “Blocking substance P’s broad effects could open new therapeutic doors. With our evolving knowledge, it’s time to revisit this strategy.”

Current advancements allow for monoclonal antibodies that block substance P directly. These innovations have already proven effective against another migraine target, calcitonin gene-related peptide (CGRP), while also exploring pituitary adenylate cyclase-activating polypeptide (PACAP).

Recently, Danish pharmaceutical company Lundbeck presented initial findings from a randomized controlled trial on an anti-PACAP monoclonal antibody called Bocnevert, which reportedly decreased monthly migraine days compared to a placebo. “This data is a positive development,” says Lars Edvinson from Lund University. Full results are expected to be shared at an upcoming conference.

With this shift in focus, there’s potential to reduce reliance on CGRP inhibitors, which have transformed migraine management since their U.S. approval in 2018, effectively halving migraine days for many. However, 40% of users still struggle.

“While CGRP drugs are effective for many, they are not universal,” says Peter Goadsby from King’s College Hospital, who collaborated on CGRP research in the 1990s. “Finding new solutions for the millions still underserved remains a pressing challenge.”

Further research is expected on the impact of inhibiting these peptides. “Substance P, CGRP, and PACAP interact with the meningeal vessel wall but do so uniquely, so there is room for optimism,” Moskowitz adds. A combination approach targeting multiple pathways may enhance treatment efficacy for non-responders.

However, it is uncertain whether drugs targeting substance P and PACAP will eclipse the effects of CGRP antagonists, which are released in higher quantities from the trigeminal nerve. “I do not believe that these alternatives can fully replace CGRP’s impact,” Edvinsson states.