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Cluster headache pathophysiology — insights from current and emerging treatments

Nature Reviews Neurology volume 17, pages 308–324 (2021)Cite this article

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Abstract

Cluster headache is a debilitating primary headache disorder that affects approximately 0.1% of the population worldwide. Cluster headache attacks involve severe unilateral pain in the trigeminal distribution together with ipsilateral cranial autonomic features and a sense of agitation. Acute treatments are available and are effective in just over half of the patients. Until recently, preventive medications were borrowed from non-headache indications, so management of cluster headache is challenging. However, as our understanding of cluster headache pathophysiology has evolved on the basis of key bench and neuroimaging studies, crucial neuropeptides and brain structures have been identified as emerging treatment targets. In this Review, we provide an overview of what is known about the pathophysiology of cluster headache and discuss the existing treatment options and their mechanisms of action. Existing acute treatments include triptans and high-flow oxygen, interim treatment options include corticosteroids in oral form or for greater occipital nerve block, and preventive treatments include verapamil, lithium, melatonin and topiramate. We also consider emerging treatment options, including calcitonin gene-related peptide antibodies, non-invasive vagus nerve stimulation, sphenopalatine ganglion stimulation and somatostatin receptor agonists, discuss how evidence from trials of these emerging treatments provides insights into the pathophysiology of cluster headache and highlight areas for future research.

Key points

  • Cluster headache is a debilitating primary headache disorder with two subtypes — episodic and chronic — that are currently defined according to a temporal cut-off.

  • Cluster headache pathogenesis involves complex interactions between the trigeminovascular pathway, trigeminal autonomic reflex, hypothalamus and the neuropeptides calcitonin gene-related peptide and pituitary adenylate cyclase-activating polypeptide 38.

  • Emerging therapies in cluster headache include calcitonin gene-related peptide monoclonal antibodies, non-invasive vagus nerve stimulation and sphenopalatine ganglion stimulation.

  • Clinical studies of these emerging treatments have highlighted differences between episodic and chronic cluster headache that imply different underlying mechanisms that could be used to distinguish them.

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Fig. 1: The three key components of cluster headache pathophysiology.

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Article 13 January 2022

Michel D. Ferrari, Peter J. Goadsby, … David W. Dodick

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Acknowledgements

The authors are part-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

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Authors and Affiliations

  1. Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    Diana Y. Wei & Peter J. Goadsby

  2. NIHR–Wellcome Trust King’s Clinical Research Facility, King’s College Hospital, London, UK

    Diana Y. Wei & Peter J. Goadsby

  3. Department of Neurology, University of California, Los Angeles, CA, USA

    Peter J. Goadsby

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Correspondence to Peter J. Goadsby.

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Competing interests

P.J.G. reports, over the last 36 months, grants and personal fees from Amgen and Eli-Lilly and Company, grant from Celgene, and personal fees from Alder Biopharmaceuticals, Aeon Biopharma, Allergan, Biohaven Pharmaceuticals Inc., Clexio, Electrocore LLC, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, Lundbeck, MundiPharma, Novartis, Pfizer, Praxis, Sanofi, Santara Therapeutics, Satsuma, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees for advice through Gerson Lehrman Group, LEK and Guidepoint, fees for educational materials from Massachusetts Medical Society, Medery, Medlink, PrimeEd, UptoDate, WebMD, and publishing royalties from Oxford University Press, and Wolters Kluwer, and for medicolegal advice in headache, and a patent magnetic stimulation for headache assigned to eNeura without fee (WO2016090333 A1). D.Y.W. declares no competing interests.

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Wei, D.Y., Goadsby, P.J. Cluster headache pathophysiology — insights from current and emerging treatments. Nat Rev Neurol 17, 308–324 (2021). https://doi.org/10.1038/s41582-021-00477-w

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