CLUSTER HEADACHE: A NARRATIVE REVIEW OF EPIDEMIOLOGY, DIAGNOSIS CRITERIA, RISK FACTORS, PATHOPHYSIOLOGY AND THERAPEUTIC STRATEGIES
DOI:
https://doi.org/10.31435/ijitss.4(48).2025.4322Keywords:
Cluster Headache, Trigeminal Autonomic Cephalalgia, Hypothalamus Dysfunction, CGRP, NeuromodulationAbstract
Introduction: Cluster Headache (CH) is a rare but highly disabling primary headache disorder characterized by unilateral pain and cranial autonomic symptoms. It causes major personal and societal burden due to its impact on patients’ quality of life.
Purpose of the study: The aim of this review is to provide a comprehensive analysis of CH, including its epidemiology, diagnostic criteria, risk factors, pathophysiology, and treatment. Recent advances in neurobiology and targeted therapies are highlighted.
Description of the state of knowledge: Recognized as the most severe of the trigeminal autonomic cephalalgias, CH combines intense head pain with autonomic dysfunction and a distinct circadian pattern. Epidemiological studies report variability in prevalence across regions and demographic groups, with evidence of late-onset and pediatric cases contributing to diagnostic delays.
Several risk factors have been identified, including smoking, alcohol consumption, and disturbances in circadian rhythms. Genetic studies reveal susceptibility loci associated with neurovascular regulation, inflammation, and circadian pathways, suggesting a complex genetic background. Functional and structural neuroimaging consistently implicate hypothalamic dysfunction, which interacts with trigeminovascular and parasympathetic systems. Standard treatment includes acute therapies such as subcutaneous triptans and high-flow oxygen, as well as preventive strategies with verapamil.
Recent advances have introduced CGRP monoclonal antibodies and neuromodulation, providing new options for refractory patients.
Conclusion: Advances in understanding the neurobiological basis and risk factors of CH have enabled more precise diagnostic and therapeutic approaches. However, further research is needed to optimize management and reduce disease burden.
References
Abagnale, C., Di Renzo, A., Giuliani, G., Sebastianelli, G., Casillo, F., Ziccardi, L., Parisi, V., Di Lorenzo, C., Serrao, M., Caramia, F., Di Piero, V., & Coppola, G. (2025). MRI-based analysis of the microstructure of the thalamus and hypothalamus and functional connectivity between cortical networks in episodic cluster headache. The Journal of Headache and Pain, 26(1), 12. https://doi.org/10.1186/s10194-024-01920-1
Allena, M., De Icco, R., Sances, G., Ahmad, L., Putortì, A., Pucci, E., Greco, R., & Tassorelli, C. (2019). Gender Differences in the Clinical Presentation of Cluster Headache: A Role for Sexual Hormones? Frontiers in Neurology, 10. https://doi.org/10.3389/fneur.2019.01220
Barloese, M. (2021). Current understanding of the chronobiology of cluster headache and the role of sleep in its management. Nature and Science of Sleep, 13, 153–162. https://doi.org/10.2147/NSS.S278088
Barloese, M., Jennum, P., Lund, N., Knudsen, S., Gammeltoft, S., & Jensen, R. (2015). Reduced CSF hypocretin-1 levels are associated with cluster headache. Cephalalgia, 35(10), 869–876. https://doi.org/10.1177/0333102414562971
Burish, M. J., Pearson, S. M., Shapiro, R. E., Zhang, W., & Schor, L. I. (2021). Cluster headache is one of the most intensely painful human conditions: Results from the International Cluster Headache Questionnaire. Headache, 61(1), 117–124. https://doi.org/10.1111/head.14021
Buture, A., Gooriah, R., Nimeri, R., & Ahmed, F. (2016). Current understanding on pain mechanism in migraine and cluster headache. In Anesthesiology and Pain Medicine (Vol. 6, Issue 3). Kowsar Medical Institute. https://doi.org/10.5812/aapm.35190
Chong, C. D., Aguilar, M., & Schwedt, T. J. (2020). Altered Hypothalamic Region Covariance in Migraine and Cluster Headache: A Structural MRI Study. Headache, 60(3), 553–563. https://doi.org/10.1111/head.13742
De Pue, A., Lutin, B., & Paemeleire, K. (2016). Chronic cluster headache and the pituitary gland. Journal of Headache and Pain, 17(1). https://doi.org/10.1186/s10194-016-0614-0
Deligianni, C., Pellesi, L., Chaudhry, B. A., Haulund Vollesen, A. L., Snoer, A. H., Hannibal, J., Jensen, R. H., & Ashina, M. (2023). Plasma levels of VIP are not elevated during PACAP- and VIP-induced cluster headache attacks: an exploratory study. Frontiers in Neurology, 14. https://doi.org/10.3389/fneur.2023.1135246
Diener, H. C., & May, A. (2022). Drug Treatment of Cluster Headache. In Drugs (Vol. 82, Issue 1, pp. 33–42). Adis. https://doi.org/10.1007/s40265-021-01658-z
Dirkx, T. H. T., Haane, D. Y. P., & Koehler, P. J. (2018). Oxygen treatment for cluster headache attacks at different flow rates: A double-blind, randomized, crossover study. Journal of Headache and Pain, 19(1). https://doi.org/10.1186/s10194-018-0917-4
Dodick, D. W., Goadsby, P. J., Lucas, C., Jensen, R., Bardos, J. N., Martinez, J. M., Zhou, C., Aurora, S. K., Yang, J. Y., Conley, R. R., & Oakes, T. (2020). Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment. Cephalalgia, 40(9), 935–948. https://doi.org/10.1177/0333102420905321
Fourier, C., Ran, C., Steinberg, A., Sjöstrand, C., Waldenlind, E., & Belin, A. C. (2023). Sex Differences in Clinical Features, Treatment, and Lifestyle Factors in Patients with Cluster Headache. Neurology, 100(12), E1207–E1220. https://doi.org/10.1212/WNL.0000000000201688
Fourier, C., Ran, C., Steinberg, A., Sjöstrand, C., Waldenlind, E., & Carmine Belin, A. (2016). Screening of two ADH4 variations in a Swedish cluster headache case-control material. Headache, 56(5), 835–840. https://doi.org/10.1111/head.12807
Gaul, C., Diener, H. C., Silver, N., Magis, D., Reuter, U., Andersson, A., Liebler, E. J., & Straube, A. (2016). Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): A randomised controlled study. Cephalalgia, 36(6), 534–546. https://doi.org/10.1177/0333102415607070
Giani, L., Cecchini, A. P., Astengo, A., Lauria, G., & Leone, M. (2021). Cluster headache not responsive to sumatriptan: A retrospective study. Cephalalgia, 41(1), 117–121. https://doi.org/10.1177/0333102420956705
Goadsby, P. J. (2018). Cluster headache and the trigeminal-autonomic reflex: Driving or being driven? In Cephalalgia (Vol. 38, Issue 8, pp. 1415–1417). SAGE Publications Ltd. https://doi.org/10.1177/0333102417738252
Goadsby, P. J., Dodick, D. W., Leone, M., Bardos, J. N., Oakes, T. M., Millen, B. A., Zhou, C., Dowsett, S. A., Aurora, S. K., Ahn, A. H., Yang, J.-Y., Conley, R. R., & Martinez, J. M. (2019). Trial of Galcanezumab in Prevention of Episodic Cluster Headache. New England Journal of Medicine, 381(2), 132–141. https://doi.org/10.1056/nejmoa1813440
Göbel, C. H., Karstedt, S., Heinze, A., Koch, B., & Göbel, H. (2021). Phenotype of Cluster Headache: Clinical Variability, Persisting Pain Between Attacks, and Comorbidities—An Observational Cohort Study in 825 Patients. Pain and Therapy, 10(2), 1121–1137. https://doi.org/10.1007/s40122-021-00267-8
Hagen, K. (2024). One-year prevalence of cluster headache, hemicrania continua, paroxysmal hemicrania and SUNCT in Norway: a population-based nationwide registry study. Journal of Headache and Pain, 25(1). https://doi.org/10.1186/s10194-024-01738-x
Imai, N., & Kitamura, E. (2019). Differences in clinical features of cluster headache between drinkers and nondrinkers in Japan. PLoS ONE, 14(11). https://doi.org/10.1371/journal.pone.0224407
Jensen, R. H., Tassorelli, C., Tepper, S. J., Charles, A., Goadsby, P. J., Snoer, A. H., Sperling, B., Krog Josiassen, M., Borgen Linander, C., Ettrup, A., & Boneva, N. (2025). Efficacy and Safety of Eptinezumab in Episodic Cluster Headache: A Randomized Clinical Trial. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2025.1317
Ji Lee, M., Cho, S. J., Wook Park, J., Kyung Chu, M., Moon, H. S., Chung, P. W., Myun Chung, J., Sohn, J. H., Kim, B. K., Kim, B. S., Kim, S. K., Song, T. J., Choi, Y. J., Park, K. Y., Oh, K., Ahn, J. Y., Lee, K. S., Cho, S., & Chung, C. S. (2019). Increased suicidality in patients with cluster headache. Cephalalgia, 39(10), 1249–1256. https://doi.org/10.1177/0333102419845660
Jürgens, T. P., Barloese, M., May, A., Láinez, J. M., Schoenen, J., Gaul, C., Goodman, A. M., Caparso, A., & Jensen, R. H. (2017). Long-term effectiveness of sphenopalatine ganglion stimulation for cluster headache. Cephalalgia, 37(5), 423–434. https://doi.org/10.1177/0333102416649092
Kaddumukasa, M., Mugenyi, L., Kaddumukasa, M. N., Ddumba, E., Devereaux, M., Furlan, A., Sajatovic, M., & Katabira, E. (2016). Prevalence and incidence of neurological disorders among adult Ugandans in rural and urban Mukono district; a cross-sectional study. BMC Neurology, 16(1). https://doi.org/10.1186/s12883-016-0732-y
Kim, S. A., Choi, S. Y., Youn, M. S., Pozo-Rosich, P., & Lee, M. J. (2023). Epidemiology, burden and clinical spectrum of cluster headache: a global update. In Cephalalgia (Vol. 43, Issue 9). SAGE Publications Ltd. https://doi.org/10.1177/03331024231201577
Kollenburg, L., Arnts, H., Heitkamp, M., Geerts, S., Robinson, C., Dominguez, M., Mulleners, W., & Kurt, E. (2024). Occipital nerve stimulation for cluster headache: lessons to learn from the ‘voltage tuners.’ Journal of Headache and Pain, 25(1). https://doi.org/10.1186/s10194-024-01839-7
Koppen, H., Stolwijk, J., Wilms, E. B., Van Driel, V., Ferrari, M. D., & Haan, J. (2016). Cardiac monitoring of high-dose verapamil in cluster headache: An international Delphi study. Cephalalgia, 36(14), 1385–1388. https://doi.org/10.1177/0333102416631968
Law, S., Derry, S., & Moore, R. A. (2013). Triptans for acute cluster headache. In Cochrane Database of Systematic Reviews (Vol. 2013, Issue 7). John Wiley and Sons Ltd. https://doi.org/10.1002/14651858.CD008042.pub3
Liampas, I., Siokas, V., Brotis, A., Aloizou, A. M., Mentis, A. F. A., Vikelis, M., & Dardiotis, E. (2020). Meta-analysis of melatonin levels in cluster headache—Review of clinical implications. In Acta Neurologica Scandinavica (Vol. 142, Issue 4, pp. 356–367). Blackwell Publishing Ltd. https://doi.org/10.1111/ane.13317
Liaw, Y. C., Wang, Y. F., Chen, W. T., Chen, S. P., Wu, J. W., Chen, S. T., Lai, K. L., Fuh, J. L., & Wang, S. J. (2022). Sex-related differences in cluster headache: A hospital-based study in Taiwan. Cephalalgia, 42(14), 1532–1542. https://doi.org/10.1177/03331024221120054
Lund, N., Barloese, M., Petersen, A., Haddock, B., & Jensen, R. (2017). Chronobiology differs between men and women with cluster headache, clinical phenotype does not. https://www.neurology.org
Lund, N. L. T., Petersen, A. S., Fronczek, R., Tfelt-Hansen, J., Belin, A. C., Meisingset, T., Tronvik, E., Steinberg, A., Gaul, C., & Jensen, R. H. (2023). Current treatment options for cluster headache: limitations and the unmet need for better and specific treatments—a consensus article. Journal of Headache and Pain, 24(1). https://doi.org/10.1186/s10194-023-01660-8
Manzoni, G. C., Camarda, C., Genovese, A., Quintana, S., Rausa, F., Taga, A., & Torelli, P. (2019). Cluster headache in relation to different age groups. In Neurological Sciences (Vol. 40, pp. 9–13). Springer-Verlag Italia s.r.l. https://doi.org/10.1007/s10072-019-03767-w
May, A., Evers, S., Goadsby, P. J., Leone, M., Manzoni, G. C., Pascual, J., Carvalho, V., Romoli, M., Aleksovska, K., Pozo-Rosich, P., & Jensen, R. H. (2023a). European Academy of Neurology guidelines on the treatment of cluster headache. European Journal of Neurology, 30(10), 2955–2979. https://doi.org/10.1111/ene.15956
May, A., Evers, S., Goadsby, P. J., Leone, M., Manzoni, G. C., Pascual, J., Carvalho, V., Romoli, M., Aleksovska, K., Pozo-Rosich, P., & Jensen, R. H. (2023b). European Academy of Neurology guidelines on the treatment of cluster headache. European Journal of Neurology, 30(10), 2955–2979. https://doi.org/10.1111/ene.15956
May, A., Evers, S., Goadsby, P. J., Leone, M., Manzoni, G. C., Pascual, J., Carvalho, V., Romoli, M., Aleksovska, K., Pozo-Rosich, P., & Jensen, R. H. (2023c). European Academy of Neurology guidelines on the treatment of cluster headache. European Journal of Neurology, 30(10), 2955–2979. https://doi.org/10.1111/ene.15956
May, A., Schwedt, T. J., Magis, D., Pozo-Rosich, P., Evers, S., & Wang, S. J. (2018). Cluster headache. Nature Reviews Disease Primers, 4. https://doi.org/10.1038/nrdp.2018.6
Moon, H. S., Cho, S. J., Kim, B. K., Lee, M. J., Chung, P. W., Sohn, J. H., Kim, S. K., Choi, Y. J., Song, T. J., Kim, J. M., Park, J. W., Park, K. Y., Chung, J. M., Ahn, J. Y., Kim, B. S., Oh, K., Lee, K. S., Chung, C. S., & Chu, M. K. (2019). Field testing the diagnostic criteria of cluster headache in the third edition of the International Classification of Headache Disorders: A cross-sectional multicentre study. Cephalalgia, 39(7), 900–907. https://doi.org/10.1177/0333102419837159
Obermann, M., Nägel, S., Ose, C., Sonuc, N., Scherag, A., Storch, P., Gaul, C., Böger, A., Kraya, T., Jansen, J. P., Straube, A., Freilinger, T., Kaube, H., Jürgens, T. P., Diener, H. C., Katsarava, Z., Kleinschnitz, C., & Holle, D. (2021). Safety and efficacy of prednisone versus placebo in short-term prevention of episodic cluster headache: a multicentre, double-blind, randomised controlled trial. The Lancet Neurology, 20(1), 29–37. https://doi.org/10.1016/S1474-4422(20)30363-X
O’Connor, E., Nikram, E., Grangeon, L., Danno, D., Houlden, H., & Matharu, M. (2022). The clinical characteristics of familial cluster headache. Cephalalgia, 42(8), 715–721. https://doi.org/10.1177/03331024221076478
Olesen, J. (2018). Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. In Cephalalgia (Vol. 38, Issue 1, pp. 1–211). SAGE Publications Ltd. https://doi.org/10.1177/0333102417738202
Pearson, S. M., Burish, M. J., Shapiro, R. E., Yan, Y., & Schor, L. I. (2019). Effectiveness of Oxygen and Other Acute Treatments for Cluster Headache: Results From the Cluster Headache Questionnaire, an International Survey. Headache, 59(2), 235–249. https://doi.org/10.1111/head.13473
Pellesi, L., Chaudhry, B. A., Vollesen, A. L. H., Snoer, A. H., Baumann, K., Skov, P. S., Jensen, R. H., & Ashina, M. (2022). PACAP38- and VIP-induced cluster headache attacks are not associated with changes of plasma CGRP or markers of mast cell activation. Cephalalgia, 42(8), 687–695. https://doi.org/10.1177/03331024211056248
Petersen, A. S., Lund, N., Jensen, R. H., & Barloese, M. (2021). Real-life treatment of cluster headache in a tertiary headache center – results from the Danish Cluster Headache Survey. Cephalalgia, 41(5), 525–534. https://doi.org/10.1177/0333102420970455
Pilati, L., Torrente, A., Alonge, P., Vassallo, L., Maccora, S., Gagliardo, A., Pignolo, A., Iacono, S., Ferlisi, S., Di Stefano, V., Camarda, C., & Brighina, F. (2023). Sleep and Chronobiology as a Key to Understand Cluster Headache. In Neurology International (Vol. 15, Issue 1, pp. 497–507). MDPI. https://doi.org/10.3390/neurolint15010029
Pineyro, M. M., Sosa, G., Finozzi, M. R., Stecker, N., Pisabarro, R., & Belzarena, M. C. (2017). Chronic cluster‐like headache in a patient with a macroprolactinoma presenting with falsely low prolactin levels: bromocriptine versus cabergoline? Clinical Case Reports, 5(11), 1868–1873. https://doi.org/10.1002/ccr3.1208
Qiu, E., Tian, L., Wang, Y., Ma, L., & Yu, S. (2015). Abnormal coactivation of the hypothalamus and salience network in patients with cluster headache. http://www.fmrib.ox.ac.uk/fsl/
Ran, C., Olofsgård, F. J., Wellfelt, K., Steinberg, A., & Belin, A. C. (2024). Elevated cytokine levels in the central nervous system of cluster headache patients in bout and in remission. Journal of Headache and Pain, 25(1). https://doi.org/10.1186/s10194-024-01829-9
Rubino, E., Roveta, F., Marcinnò, A., Ferrandes, F., Piella, E. M., & Rainero, I. (2024). Intravenous methylprednisolone in patients with episodic cluster headache non-responders to oral steroids: results from an observational, interventional, single-center study. Confinia Cephalalgica et Neurologica, 34(1). https://doi.org/10.4081/cc.2024.15618
Schindler, E. A. D., & Burish, M. J. (2022). Recent advances in the diagnosis and management of cluster headache. In The BMJ. BMJ Publishing Group. https://doi.org/10.1136/bmj-2020-059577
Schor, L. I., Pearson, S. M., Shapiro, R. E., Zhang, W., Miao, H., & Burish, M. J. (2021). Cluster headache epidemiology including pediatric onset, sex, and ICHD criteria: Results from the International Cluster Headache Questionnaire. Headache, 61(10), 1511–1520. https://doi.org/10.1111/head.14237
Schulte, L. H., Haji, A. A., & May, A. (2020). Phase dependent hypothalamic activation following trigeminal input in cluster headache. Journal of Headache and Pain, 21(1). https://doi.org/10.1186/s10194-020-01098-2
Sharaf, J., & Ali, A. (2025). Cluster headache vs. labor: A comparative perspective on acute pain during and after delivery. Headache. https://doi.org/10.1111/head.14976
Snoer, A., Vollesen, A. L. H., Beske, R. P., Guo, S., Hoffmann, J., Fahrenkrug, J., Jørgensen, N. R., Martinussen, T., Jensen, R. H., & Ashina, M. (2019). Calcitonin-gene related peptide and disease activity in cluster headache. Cephalalgia, 39(5), 575–584. https://doi.org/10.1177/0333102419837154
Stanyer, E. C., Hoffmann, J., & Holland, P. R. (2024). Orexins and primary headaches: an overview of the neurobiology and clinical impact. In Expert Review of Neurotherapeutics (Vol. 24, Issue 5, pp. 487–496). Taylor and Francis Ltd. https://doi.org/10.1080/14737175.2024.2328728
Tsai, C.-L., Lin, G.-Y., Wu, S.-K., Yang, F.-C., & Wang, S.-J. (2020). Chronic Cluster Headache Update and East-West Comparisons: Focusing on Clinical Features, Pathophysiology, and Management. https://doi.org/10.1007/s11916-020-00902-7/Published
Vollesen, A. L. H., Snoer, A., Beske, R. P., Guo, S., Hoffmann, J., Jensen, R. H., & Ashina, M. (2018). Effect of Infusion of Calcitonin Gene-Related Peptide on Cluster Headache Attacks: A Randomized Clinical Trial. JAMA Neurology, 75(10), 1187–1197. https://doi.org/10.1001/jamaneurol.2018.1675
Waung, M. W., Taylor, A., Qualmann, K. J., & Burish, M. J. (2020). Family History of Cluster Headache: A Systematic Review. JAMA Neurology, 77(7), 887–896. https://doi.org/10.1001/jamaneurol.2020.0682
Winsvold, B. S., Harder, A. V. E., Ran, C., Chalmer, M. A., Dalmasso, M. C., Ferkingstad, E., Tripathi, K. P., Bacchelli, E., Børte, S., Fourier, C., Petersen, A. S., Vijfhuizen, L. S., Magnusson, S. H., O’Connor, E., Bjornsdottir, G., Häppölä, P., Wang, Y. F., Callesen, I., Kelderman, T., … Zwart, J. A. (2023). Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor. Annals of Neurology, 94(4), 713–726. https://doi.org/10.1002/ana.26743
Downloads
Published
Issue
Section
License
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.

