Should We Reconsider Substance P as a Migraine Target After Anti-CGRP Success? | Research

The takeaway

Substance P was previously abandoned as a migraine target, but the success of anti-CGRP and anti-PACAP therapies suggests it deserves renewed investigation using modern methods.

Previously dismissed target
Substance P was abandoned as a migraine target after NK-1 antagonist failures, but this paper argues for re-evaluation using modern methods

What the researchers found

The failure of NK-1 receptor antagonists does not necessarily mean substance P is irrelevant to migraine; a systematic re-evaluation using validated methodologies (like those used for CGRP) is warranted.

Why it matters

If substance P does contribute to migraine, targeting it could provide additional therapeutic options for the many patients who do not fully respond to anti-CGRP drugs.

The numbers in context

Proposes randomized, double-blind, placebo-controlled crossover provocation studies in healthy volunteers and migraine patients, modeled on successful CGRP and PACAP provocation studies.

How the study worked

Methodological proposal for re-evaluating substance P in migraine using randomized, double-blind provocation studies inspired by the anti-CGRP development framework.

Who was studied

People with migraine (proposed studies)

What this study cannot tell us

This is a proposal, not new experimental data. Previous NK-1 antagonist failures suggest substance P may not be a viable target, though the methodology was different.

How to read the evidence

Methodological perspective piece — no new clinical data. The proposal is well-reasoned but its validity depends on future experimental results.

When this study was published

Published in 2025, building on the proven anti-CGRP methodology to propose a systematic re-evaluation.

The bigger picture

Migraine therapy has been transformed by systematically studying neuropeptides. Applying the same rigorous approach to substance P could either validate a new target or definitively close the door.

Questions still open

Would substance P infusion trigger migraine-like attacks in controlled settings?
Could combination therapies targeting both CGRP and substance P benefit treatment-resistant migraine patients?

Common questions

What is substance P and what does it do?

Substance P is a neuropeptide involved in pain transmission and inflammation. It was once thought to play a major role in migraine, but drugs targeting it failed in clinical trials, leading researchers to focus on CGRP instead.

Why revisit a target that previously failed?

The success of anti-CGRP drugs showed that the way you test a migraine target matters. The early substance P studies may have used the wrong approach. This paper proposes using the validated methodology that worked for CGRP to give substance P a fair re-evaluation.

Read the original research

Revisiting substance P in migraine: a methodological approach inspired by anti-CGRP and anti-PACAP success.

The journal of headache and pain, 26(1), 22

View on PubMed ↗Publisher’s paper ↗

Citation

Pellesi, Lanfranco; Edvinsson, Lars. (2025). Revisiting substance P in migraine: a methodological approach inspired by anti-CGRP and anti-PACAP success.. The journal of headache and pain, 26(1), 22. https://doi.org/10.1186/s10194-025-01959-8