Cluster headache pathophysiology — insights from current and emerging treatments

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. In this Review, Wei and Goadsby discuss the pathophysiology of cluster headache, the treatments available and their mechanisms, and the insights being provided by results from trials of emerging treatments, which indicate mechanistic differences between episodic and chronic cluster headache. 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. 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.