Noradrenergic system involvement as a major driver of tension-type headache: a systematic review of the current evidence

BACKGROUND: Tension-type headache (TTH) is the most prevalent primary headache disorder, affecting individuals of all ages and imposing a substantial global burden. While traditionally considered a peripheral skeletomuscular condition, current evidence suggests a prominent role for central mechanisms and neurotransmitter dysregulation. In this context, growing evidence highlights the noradrenergic system as a key contributor, both for the TTH genesis and maintenance. METHODS: A systematic literature search was performed according to PRISMA guidelines. A comprehensive search of PubMed/MEDLINE and EMBASE via Scopus up to March 2024 identified studies examining the relationship between TTH and the noradrenergic system. RESULTS: Forty-three eligible studies were included and categorized according to their focus on pathophysiology or treatment. Biochemical studies consistently reported reduced noradrenergic activity, including reduced plasma norepinephrine/epinephrine levels and dopamine-β-hydroxylase activity in TTH patients, often correlating with headache severity and chronicity. Neurophysiological and autonomic investigations further supported noradrenergic involvement, revealing altered reflex suppression, impaired sympathetic habituation, and reduced central autonomic responsiveness in TTH. Pharmacological studies indicated that medication enhancing noradrenergic transmission achieved superior clinical efficacy compared to those acting on the serotonergic system only. DISCUSSION: Overall, the body of evidence underscores the noradrenergic system’s integral role in TTH. The dysregulated noradrenergic system appears to contribute to central sensitization and impaired pain inhibition. These findings, along with the consistent efficacy of noradrenergic-targeting treatments, support a shift towards a more mechanistically specific and personalized approaches. Future research is needed to clarify the specific noradrenergic pathways implicated in TTH, in order to refine treatment strategies and enhance efficacy through precision medicine.