Introduction: Although it causes a huge burden to sufferers, cluster headache (CH), remains an undertreated condition, partly due to the absence of established acute and prophylactic treatment options. New therapeutic approaches providing fast and safe relief from CH are needed. Areas covered: A systematic review was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendation on recently published (last 5 years) papers on CH treatment. The authors also collected preliminary results from ongoing trials on emerging therapeutic/preventive pharmacological and interventional approaches for CH. Studies and results are reviewed and discussed. Expert opinion: The complexity of CH pathophysiology prevents the definition of reliable acute and preventive treatments. In the real-world clinical setting, several treatments are combined to provide relief to patients and increase their quality of life. Drugs targeting neuropeptides or their receptors within the trigeminovascular network are of particular interest to prevent CH attacks. Calcitonin gene-related peptide (CGRP) blockade seems attractive and promising, but studies on anti-CGRP monoclonal antibodies indicated rather modest or even absence of a prophylactic effect. A deeper insight into CH pathophysiology, and combined approaches may lead the path to new, more effective and personalized CH therapies.
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