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Peer-reviewedCC BY 4.0Frontiers in Neurology

From past to present and toward the future: a mechanism-informed clinical framework for COVID-19-associated headache and post-viral pain

  • Cheng He1,2
  • Yan Xue3
  • Yao Liu4
  • Zhou-Can Xu1,2
  • Rui-Qi Zhao3
  • Jia-Yi Sun3
  • Jian-Feng Meng1
  • Meng-Ruo Song1
  • Zhi-Jun Zhang1,2,5
  • Qun-Feng Gui1
5 affiliations
  1. 1Department of Neurosurgery, The Sixth Affiliated Hospital of Nantong University, Yancheng Third People's Hospital
  2. 2Department of Human Anatomy, Medical School of Nantong University
  3. 3Nantong University, Nantong
  4. 4Department of Implantology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration
  5. 5Jiangsu Province Key Laboratory in University for Inflammation and Molecular Drug Target, Nantong University, Nantong
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Abstract

Headache is a prominent acute and persistent neurological manifestation of COVID-19, representing both as a significant clinical challenge and a valuable model for understanding the neurotropic effects of SARS-CoV-2. This review synthesizes evidence showing that the epidemiology of COVID-19 headache is distinctly shaped by younger age, female sex, and a prior history of headache disorders; its clinical phenotypes are diverse, strongly associating with chemosensory dysfunctions such as anosmia; and its core pathophysiology involves neuroinflammation (e.g., cytokine-mediated pathways), trigeminovascular activation, and sex-specific neuroendocrine-immune interactions. Although acute headache often responds to conventional analgesics, persistent cases—a major component of Post-Acute Sequelae of COVID-19 (PASC)—necessitate a multidisciplinary management approach. This contrasts with the typically self-limiting headache following vaccination. Future research should prioritize longitudinal studies to define chronicity, mechanistic investigations into sex-specific pathways, and the development of phenotype-specific, personalized therapeutic strategies.

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Cite

BibTeXRIS
BibTeX
@article{he2026from,
  title = {{From past to present and toward the future: a mechanism-informed clinical framework for COVID-19-associated headache and post-viral pain}},
  author = {Cheng He and Yan Xue and Yao Liu and Zhou-Can Xu and Rui-Qi Zhao and Jia-Yi Sun and Jian-Feng Meng and Meng-Ruo Song and Zhi-Jun Zhang and Qun-Feng Gui},
  journal = {Frontiers in Neurology},
  year = {2026},
  month = oct,
  doi = {10.3389/fneur.2026.1937278},
  url = {https://www.frontiersin.org/articles/10.3389/fneur.2026.1937278/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - From past to present and toward the future: a mechanism-informed clinical framework for COVID-19-associated headache and post-viral pain
AU  - Cheng He
AU  - Yan Xue
AU  - Yao Liu
AU  - Zhou-Can Xu
AU  - Rui-Qi Zhao
AU  - Jia-Yi Sun
AU  - Jian-Feng Meng
AU  - Meng-Ruo Song
AU  - Zhi-Jun Zhang
AU  - Qun-Feng Gui
PY  - 2026
DA  - 2026/10/13
JO  - Frontiers in Neurology
DO  - 10.3389/fneur.2026.1937278
UR  - https://www.frontiersin.org/articles/10.3389/fneur.2026.1937278/full
AB  - Headache is a prominent acute and persistent neurological manifestation of COVID-19, representing both as a significant clinical challenge and a valuable model for understanding the neurotropic effects of SARS-CoV-2. This review synthesizes evidence showing that the epidemiology of COVID-19 headache is distinctly shaped by younger age, female sex, and a prior history of headache disorders; its clinical phenotypes are diverse, strongly associating with chemosensory dysfunctions such as anosmia; and its core pathophysiology involves neuroinflammation (e.g., cytokine-mediated pathways), trigeminovascular activation, and sex-specific neuroendocrine-immune interactions. Although acute headache often responds to conventional analgesics, persistent cases—a major component of Post-Acute Sequelae of COVID-19 (PASC)—necessitate a multidisciplinary management approach. This contrasts with the typically self-limiting headache following vaccination. Future research should prioritize longitudinal studies to define chronicity, mechanistic investigations into sex-specific pathways, and the development of phenotype-specific, personalized therapeutic strategies.
SN  - 1664-2295
ER  -