Gianluca Coppola, Marco A. Arruda, Messoud Ashina, Mads Barloese, Andrea Carmine Belin, Sara Bottiroli, Debashish Chowdhury, Roberto De Icco, Cherubino Di Lorenzo, Giulia Di Stefano, Jacob C. A. Edvinsson, Stefan Evers, Stefania Ferraro, Rolf Fronczek, David García‐Azorín, Peter J. Goadsby, Licia Grazzi, Dagny Holle, Julia J. Jansen, Raquel Gil‐Gouveia, Giorgio Lambru, Michel Lantéri‐Minet, Marco Lisicki, Dimos D. Mitsikostas, Teshamae Monteith, Danilo Antonio Montisano, Mark Obermann, Li‐Ling Hope Pan, Kuan‐Po Peng, Mário Fernando Prieto Peres, Igor Petrušić, Alberto Proietti Cecchini, Marta Vila‐Pueyo, Alberto Raggi, Innocenzo Rainero, Giorgio Sandrini, Gabriele Sebastianelli, Tsubasa Takizawa, Surat Tanprawate, Cristina Tassorelli, Andrea Truini, Massimiliano Valeriani, Doğa Vurallı, Marta Waliszewska‐Prosół, Shuu-Jiun Wang, Yonggang Wang, Tissa Wijeratne, Paolo Martelletti
BACKGROUND: Cluster headache (CH) is a rare primary headache disorder characterized by recurrent episodes of strictly unilateral excruciating pain accompanied by trigemino-autonomic signs, which significantly impacts the quality of life, social interactions, and occupational functioning of those who are affected. To promote a better understanding of this disabling condition and to foster research on the topic, this review provides a comprehensive description of the hallmarks of CH, including its clinical presentation, diagnostic challenges, pathophysiology, and current and novel therapeutic targets. It concludes by describing the disease burden and advocating for significant improvements in healthcare systems, and promoting health equity, as well as reducing stigma. PRINCIPAL FINDINGS: Despite its distinctive clinical and chronobiological features, CH may be mistaken for other primary headache disorders or different types of orofacial pain. Key pathogenic characteristics include the activation of the trigeminal-autonomic system with the release of several neuropeptides, the involvement of the hypothalamus in regulating the circadian rhythm, genetic variants, and the mesolimbic system. Both invasive and non-invasive neuromodulation treatments have been used to target the trigemino-cervical, parasympathetic, and hypothalamic systems. Additionally, novel therapeutic targets are currently being study. Alongside canonical therapies, several complementary approaches have been explored over the years, with most evidence deriving from uncontrolled research involving individuals who do not respond to standard pharmacological treatments. Despite advancements in our understanding of this complex disease, CH continues to pose considerable social, economic, and psychological challenges. Advocacy is essential and should prioritize early diagnosis, alleviate stigma, provide specialized training for healthcare professionals, and offer support to and through patient associations. CONCLUSIONS: CH is characterised by a complex, multifactorial, pathophysiology that is still not fully understood. Precise diagnosis, additional research studies, and robust psychosocial and institutional support are necessary to improve the quality of life for individuals affected by this debilitating condition.