Should We Reconsider Substance P as a Migraine Target After Anti-CGRP Success?
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.
Quick Facts
What This Study 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.
Key Numbers
Proposes randomized, double-blind, placebo-controlled crossover provocation studies in healthy volunteers and migraine patients, modeled on successful CGRP and PACAP provocation studies.
How They Did This
Methodological proposal for re-evaluating substance P in migraine using randomized, double-blind provocation studies inspired by the anti-CGRP development framework.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- 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
- Evidence Grade:
- Methodological perspective piece — no new clinical data. The proposal is well-reasoned but its validity depends on future experimental results.
- Study Age:
- Published in 2025, building on the proven anti-CGRP methodology to propose a systematic re-evaluation.
- Original Title:
- Revisiting substance P in migraine: a methodological approach inspired by anti-CGRP and anti-PACAP success.
- Published In:
- The journal of headache and pain, 26(1), 22 (2025)
- Authors:
- Pellesi, Lanfranco(10), Edvinsson, Lars(6)
- Database ID:
- RPEP-13006
Evidence Hierarchy
Summarizes existing research without a strict systematic method.
What do these levels mean? →Frequently Asked 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 More on RethinkPeptides
Cite This Study
https://rethinkpeptides.com/research/RPEP-13006APA
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
MLA
Pellesi, Lanfranco, et al. "Revisiting substance P in migraine: a methodological approach inspired by anti-CGRP and anti-PACAP success.." The journal of headache and pain, 2025. https://doi.org/10.1186/s10194-025-01959-8
RethinkPeptides
RethinkPeptides Research Database. "Revisiting substance P in migraine: a methodological approac..." RPEP-13006. Retrieved from https://rethinkpeptides.com/research/pellesi-2025-revisiting-substance-p-in
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.