High-altitude headache (HAH) is the most common neurological manifestation triggered by hypoxia during rapid ascent above 2500 m, often presenting as an isolated symptom or as part of acute mountain sickness (AMS). HAH shares clinical features with migraine, cluster headache and other primary headache, complicating differential diagnosis. Prevalence varies widely depending on ascent speed and altitude, with higher rates observed in populations ascending rapidly by passive transport and lower rates in those ascending gradually on foot. Controlled normobaric hypoxic chamber studies confirm hypoxia as a potent trigger, with most participants developing HAH within hours. Environmental factors, including fluctuations in barometric pressure, further contribute to headache onset. We propose that the pathophysiology involves activation and sensitization of the trigeminovascular system, with key molecular mediators such as nitric oxide, adenosine, calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) playing central roles. Hypoxia stabilizes hypoxia-inducible factor-1α (HIF-1α), driving transcriptional changes that can prime vascular and neuronal pathways for head pain. Although HAH typically responds to simple analgesics and oxygen, its similarity with migraine suggests that targeted therapies against CGRP and PACAP may offer additional benefits. Future research should clarify the mechanistic continuum between HAH and AMS and evaluate multitarget therapeutic approaches.
Abstract
Journal Article
Review
eng
42231830
Falla, Marika, et al. "High-altitude Headache: Insights Into Pathophysiology and Potential Treatment Implications." The Journal of Physiology, 2026.
Falla M, Frank F, Strapazzon G, et al. High-altitude headache: Insights into pathophysiology and potential treatment implications. J Physiol. 2026.
Falla, M., Frank, F., Strapazzon, G., & Lawley, J. (2026). High-altitude headache: Insights into pathophysiology and potential treatment implications. The Journal of Physiology. https://doi.org/10.1113/JP289704
Falla M, et al. High-altitude Headache: Insights Into Pathophysiology and Potential Treatment Implications. J Physiol. 2026 Jun 3; PubMed PMID: 42231830.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR
T1 - High-altitude headache: Insights into pathophysiology and potential treatment implications.
AU - Falla,Marika,
AU - Frank,Florian,
AU - Strapazzon,Giacomo,
AU - Lawley,Justin,
Y1 - 2026/06/03/
PY - 2025/11/29/received
PY - 2026/05/05/accepted
PY - 2026/6/3/medline
PY - 2026/6/3/pubmed
PY - 2026/6/3/entrez
KW - CGRP
KW - PACAP
KW - altitude
KW - headache
KW - hypoxia
KW - migraine
KW - sensitization
KW - trigeminal system
JF - The Journal of physiology
JO - J Physiol
N2 - High-altitude headache (HAH) is the most common neurological manifestation triggered by hypoxia during rapid ascent above 2500 m, often presenting as an isolated symptom or as part of acute mountain sickness (AMS). HAH shares clinical features with migraine, cluster headache and other primary headache, complicating differential diagnosis. Prevalence varies widely depending on ascent speed and altitude, with higher rates observed in populations ascending rapidly by passive transport and lower rates in those ascending gradually on foot. Controlled normobaric hypoxic chamber studies confirm hypoxia as a potent trigger, with most participants developing HAH within hours. Environmental factors, including fluctuations in barometric pressure, further contribute to headache onset. We propose that the pathophysiology involves activation and sensitization of the trigeminovascular system, with key molecular mediators such as nitric oxide, adenosine, calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) playing central roles. Hypoxia stabilizes hypoxia-inducible factor-1α (HIF-1α), driving transcriptional changes that can prime vascular and neuronal pathways for head pain. Although HAH typically responds to simple analgesics and oxygen, its similarity with migraine suggests that targeted therapies against CGRP and PACAP may offer additional benefits. Future research should clarify the mechanistic continuum between HAH and AMS and evaluate multitarget therapeutic approaches.
SN - 1469-7793
UR - https://www.unboundmedicine.com/prime/citation/42231830/High-altitude_headache:_Insights_into_pathophysiology_and_potential_treatment_implications.
DB - PRIME
DP - Unbound Medicine
ER -
