Current treatment options for cluster headache: limitations and the unmet need for better and specific treatments—a consensus article

Lund et al. The Journal of Headache and Pain https://doi.org/10.1186/s10194-023-01660-8 (2023) 24:121 CONSENSUS ARTICLE The Journal of Headache and Pain Open Access Current treatment options for cluster headache: limitations and the unmet need for better and specific treatments—a consensus article Nunu Laura Timotheussen Lund1,2*, Anja Sofie Petersen1, Rolf Fronczek3,4, Jacob Tfelt‑Hansen5,6, Andrea Carmine Belin7, Tore Meisingset8,9, Erling Tronvik8,9, Anna Steinberg10,11, Charly Gaul12 and Rigmor Højland Jensen1 Abstract Aim Treatment for cluster headache is currently based on a trial-and-error approach. The available preventive treat‑ ment is unspecific and based on few and small studies not adhering to modern standards. Therefore, the authors col‑ laborated to discuss acute and preventive treatment in cluster headache, addressing the unmet need of safe and tol‑ erable preventive medication from the perspectives of people with cluster headache and society, headache specialist and cardiologist. Findings The impact of cluster headache on personal life is substantial. Mean annual direct and indirect costs of cluster headache are more than 11,000 Euros per patient. For acute treatment, the main problems are treatment response, availability, costs and, for triptans, contraindications and the maximum use allowed. Intermediate treatment with steroids and greater occipital nerve blocks are effective but cannot be used continuously. Preventive treatment is sparsely studied and overall limited by relatively low efficacy and side effects. Neurostimulation is a relevant option for treatment-refractory chronic patients. From a cardiologist’s perspective use of verapamil and triptans may be wor‑ risome and regular follow-up is essential when using verapamil and lithium. Conclusion We find that there is a great and unmet need to pursue novel and targeted preventive modalities to sup‑ press the horrific pain attacks for people with cluster headache. Keywords Cluster headache, Treatment, Burden, CGRP, Verapamil, Review *Correspondence: Nunu Laura Timotheussen Lund Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom‑ mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lund et al. The Journal of Headache and Pain (2023) 24:121 Page 2 of 13 Graphical Abstract Introduction Cluster headache (CH) is the most common trigeminoautonomic cephalalgia [1]. The recurrent attacks up to 8 times per day are among the most severe pains described by humans, succeeding gun-shot wounds, giving birth and kidney stones [2]. The life-time prevalence is 1,24/1000 [3] and the typical age of onset is 20–40 years [4]. Existing treatments for CH have originally been developed for other medical conditions and are based on empirical data [5–8]. The three existing European guidelines for the management of CH are based on very few and small studies mostly not fulfilling modern standards: The 2023 European Academy of Neurology Guidelines on Cluster Headache, the 2006 European Federation of Neurological Societies (EFNS) guidelines on the treatment of CH and other Trigemino-autonomic cephalalgias (mainly for Neurologists) and the European Headache Federations (EHF) guidelines for headache disorders (mainly for Primary Care Physicians) [9–11]. In addition, national guidelines exist. Therefore, the aim of this paper is to provide insights into the unmet need for safe and tolerable CH preventive medication from the perspective of people with CH and society, headache specialist and cardiologist. To do this, we review and discuss existing treatment possibilities for CH. Neurostimulation and future perspectives are also discussed in this consensus paper arising from some of the major CH clinics and research centers in Europe. From the perspective of patient and society ”I’d rather give birth than endure a cluster headache attack” CH has an impact on all aspects of peoples’ lives including higher proportions of multimorbidity of somatic and psychiatric diseases [12–14]. In a recent interviewbased Danish study on personal and economic burden, 92% of people with episodic CH (ECH) in bout, 98% of people with chronic CH (CCH) and even 15% people with ECH in remission reported to be restricted in their everyday lives [15]. People with CH do not present with any physical handicaps, hindering understanding from family, friends and colleagues [16]. Overall, the disease mainly affects the younger half of the population where careers and family lives are being established, and in 21% and 48% of people with ECH and CCH, CH led to dependency on family and friends [15]. In clinical experience, family members report feeling helpless and afraid because people with CH may get irritable or aggressive as part of their attacks or might even become self-harming. Lund et al. The Journal of Headache and Pain (2023) 24:121 The mean diagnostic delay, although decreasing, is 6 years, during which patients are therapeutically mismanaged [17]. Misdiagnosis is seen in 49% of people with CH most often with migraine, tension-type headache and sinusitis and removal of a healthy tooth has been reported in 15–43% [18–20]. Females are misdiagnosed more frequently than males with suggested reasons being pre-assumptions of women having migraine, a lower male:female ratio in chronic patients and differences in the clinical presentation [12, 13]. Self-rated health is strongly associated with mortality, making it an important instrument when investigating the burden of a disease [21]. Self-rated health is significantly reduced in ECH and in CCH the odds are tenfold lower of rating their health as ‘good’ or ‘very good’ compared to matched controls [15]. Co-existing depression and anxiety also occur more frequently in people with CH compared to controls [18, 22–24]. Suicidal thoughts are reported by 47–55% and attempts by 1.3–2% of people with CH [18, 24–26]. “Although I’m not in bout, I still fear attacks every (...truncated)