Cluster headache pathophysiology - insights from current and emerging treatments

Nat Rev Neurol. 2021 May;17(5):308-324. doi: 10.1038/s41582-021-00477-w. Epub 2021 Mar 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adrenal Cortex Hormones / administration & dosage
  • Antibodies, Monoclonal / administration & dosage
  • Biomarkers / blood
  • Brain / drug effects
  • Brain / physiopathology*
  • Cluster Headache / blood
  • Cluster Headache / physiopathology*
  • Cluster Headache / therapy*
  • Electric Stimulation Therapy / trends
  • Humans
  • Oxygen Inhalation Therapy / trends
  • Tryptamines / administration & dosage
  • Vagus Nerve Stimulation / trends


  • Adrenal Cortex Hormones
  • Antibodies, Monoclonal
  • Biomarkers
  • Tryptamines