High-altitude headache pathophysiology involves trigeminovascular system, CGRP, and PACAP, suggesting targeted treatments.

High-altitude headache (HAH) is the most prevalent neurological symptom triggered by hypoxia during rapid ascent above 2500 m, often presenting as an isolated symptom or part of acute mountain sickness (AMS). Its clinical features overlap significantly with migraine and cluster headache, complicating accurate differential diagnosis. Current standard-of-care primarily relies on simple analgesics and oxygen, which often provide symptomatic relief but do not address the underlying molecular mechanisms. Understanding the specific pathways involved could lead to more effective, targeted interventions.

This comprehensive review synthesized current literature on High-altitude headache (HAH), examining its clinical presentation, prevalence, and proposed pathophysiology. Researchers analyzed findings from controlled normobaric hypoxic chamber studies and observational data, focusing on molecular mediators and neurological pathways involved in headache onset. The work aimed to integrate diverse insights to propose a unified mechanistic model and identify novel therapeutic avenues beyond standard care, particularly by drawing parallels with other primary headache disorders.

Prevalence of HAH varies widely, with higher rates observed in populations ascending rapidly by passive transport. Controlled normobaric hypoxic chamber studies confirmed hypoxia as a potent trigger, with most participants developing HAH within hours. The review proposes that HAH pathophysiology involves activation and sensitization of the trigeminovascular system. Key molecular mediators playing central roles include nitric oxide, adenosine, calcitonin gene-related peptide (CGRP), and pituitary adenylate cyclase-activating polypeptide (PACAP). Hypoxia stabilizes hypoxia-inducible factor-1α (HIF-1α), which drives transcriptional changes that can prime vascular and neuronal pathways for head pain. This mechanistic understanding suggests a continuum with other primary headaches.

The similarity of HAH with migraine strongly suggests that targeted therapies against CGRP and PACAP may offer additional benefits beyond traditional analgesics.