The Brain Chemistry Behind Tension-Type Headache: What We Know and What We Do Not | Research

The takeaway

Neurotransmitter and neuropeptide changes in tension-type headache are reported but inconsistent, with key therapeutic targets still unconfirmed.

Most common headache worldwide
Despite affecting more people than any other headache disorder, tension-type headache lacks targeted treatments due to poorly understood neurochemistry

What the researchers found

Peripheral and central neurotransmitter alterations are present in tension-type headache but evidence remains inconsistent across studies, limiting therapeutic target identification.

Why it matters

TTH affects more people than any other headache disorder, yet treatment options are largely limited to generic painkillers. Understanding the specific neurochemical drivers could enable targeted therapies like those developed for migraine.

The numbers in context

30 studies included from PubMed and Embase. Substance P elevated in salivary and platelet samples. Beta-endorphins often reduced. Mixed findings for CGRP, serotonin, and other mediators.

How the study worked

Systematic review of PubMed and Embase for studies reporting neurotransmitter or neuropeptide levels in tension-type headache patients.

Who was studied

People with tension-type headache

What this study cannot tell us

Inconsistent findings across studies, likely due to methodological differences and small sample sizes. TTH subtypes may have different neurochemical profiles.

How to read the evidence

Systematic review of observational studies. While methodologically sound, the underlying evidence is inconsistent and limited by small study sizes.

When this study was published

Published in 2025, providing the most current synthesis of TTH neurochemistry.

The bigger picture

While migraine has benefited from targeted peptide therapies (anti-CGRP drugs), TTH lags behind. This review aims to catch up by mapping the neurochemical landscape for TTH-specific drug development.

Questions still open

Could CGRP-targeted therapies that work for migraine also help with tension-type headache?
Which neurotransmitter pathways are most consistently altered in chronic versus episodic TTH?

Common questions

Why do we not have targeted drugs for tension-type headache like we do for migraine?

Unlike migraine where CGRP was identified as a key target, tension-type headache neurochemistry is less clearly defined. This review shows that while neurotransmitter changes exist, studies do not consistently agree on which changes matter most.

What neurotransmitters are involved in tension-type headache?

Multiple neurotransmitters and neuropeptides have been implicated, but no single one has emerged as a clear therapeutic target. The inconsistency across studies suggests the condition may involve complex interactions between multiple neurochemical systems.

Read the original research

Neurotransmitter Imbalance in Tension-Type Headache: A Systematic Review of Mechanisms and Therapeutic Targets.

Pain and therapy, 14(4), 1279-1291

View on PubMed ↗Publisher’s paper ↗

Citation

Pellesi, Lanfranco; Yangjeh, Aidin; Hajjaj, Ibrahim; Lababidi, Mousbah; Sarwar, Fezan; Wang, Wei; Martelletti, Paolo. (2025). Neurotransmitter Imbalance in Tension-Type Headache: A Systematic Review of Mechanisms and Therapeutic Targets.. Pain and therapy, 14(4), 1279-1291. https://doi.org/10.1007/s40122-025-00761-3