Why Anti-CGRP Drugs Work for Migraine But Anti-Substance P Drugs Failed | Research

The takeaway

Substance P is released in much smaller quantities than CGRP from migraine-relevant brain structures, explaining why blocking substance P receptors failed in clinical trials while anti-CGRP drugs succeeded.

SP << CGRP release
Substance P release was comparatively minor versus CGRP from all migraine-relevant structures, explaining the failure of NK1R antagonists in clinical trials

What the researchers found

Substance P release from stimulated dura mater, trigeminal ganglion neurons, and fibers was comparatively minor compared to CGRP release, explaining the clinical failure of NK1R antagonists for migraine while validating CGRP as the primary target.

Why it matters

This resolves a decades-old mystery in migraine research: why blocking substance P didn't work. It validates the scientific rationale behind current anti-CGRP migraine drugs and clarifies substance P's limited role in migraine pain.

The numbers in context

SP co-localizes with CGRP in C-fibers; SP release minor vs CGRP from dura, TG, and fibers; NKA in some C-fibers; NKB in large/medium neurons and A-delta fibers

How the study worked

Animal study using immunohistochemistry and semi-quantitative cell counts in rat trigeminal ganglia. Functional neuropeptide release measured by ELISA after stimulation with 60 mM potassium or 100 nM capsaicin.

Who was studied

Rat trigeminal ganglion and dura mater tissue

What this study cannot tell us

Rat model — human trigeminal physiology may differ. In vitro stimulation conditions may not replicate natural migraine triggers. Release measurements are relative comparisons, not absolute quantification.

How to read the evidence

Moderate evidence: well-designed mechanistic animal study with functional release data, but uses rat tissue and in vitro stimulation rather than human or in vivo measurements.

When this study was published

Published in 2021. Anti-CGRP drugs have continued to show clinical success, further supporting this study's conclusions about CGRP dominance in migraine.

The bigger picture

Understanding the relative contributions of different neuropeptides to migraine helps explain why CGRP-targeting drugs (gepants and anti-CGRP antibodies) have been so successful. It also suggests that substance P might still play a role in migraine as a secondary amplifier, potentially relevant for treatment-resistant cases.

Questions still open

Could targeting both CGRP and substance P simultaneously help patients who don't respond to anti-CGRP drugs alone?
Does the substance P/CGRP release ratio differ in human trigeminal tissue compared to rats?
What role does neurokinin B play in migraine given its different localization pattern?

Common questions

Why do anti-CGRP drugs work for migraine but substance P blockers don't?

This study shows that CGRP is released in much larger quantities than substance P from the nerves involved in migraine. Since CGRP is the dominant pain signal, blocking it is effective. Substance P plays only a minor supporting role, so blocking it alone doesn't provide meaningful relief.

Does substance P play any role in migraine?

Yes, but a secondary one. Substance P co-exists with CGRP in the same nerve fibers and may amplify pain signals. However, its release is much smaller than CGRP, which is why targeting substance P alone was insufficient for migraine treatment.

Read the original research

Neurokinins and their receptors in the rat trigeminal system: Differential localization and release with implications for migraine pain.

Molecular pain, 17, 17448069211059400

View on PubMed ↗Publisher’s paper ↗

Citation

Edvinsson, Jacob Ca; Reducha, Philip V; Sheykhzade, Majid; Warfvinge, Karin; Haanes, Kristian A; Edvinsson, Lars. (2021). Neurokinins and their receptors in the rat trigeminal system: Differential localization and release with implications for migraine pain.. Molecular pain, 17, 17448069211059400. https://doi.org/10.1177/17448069211059400