While a number of neuropeptides have been identified as biomarkers, none as yet is considered to be specific for cluster headaches.19

Calcitonin gene-related peptide (CGRP) has received the most attention (hence the new drug launches), but VIP and pituitary adenylate cyclase-activating peptide are also significant biomarkers.

CGRP and pituitary adenylate cyclase-activating peptide (PACAP) are found in trigeminal sensory fibres. Sympathetic fibres contain neuropeptide Y, norepinephrine and adenosine triphosphate (ATP).

Many of these compounds cause vasodilation, with CGRP considered the most potent neuropeptide. CGRP, which is distributed throughout the central nervous system, also causes plasma to leak from cells (plasma extravasation). When CGRP is released in the trigeminal nervous system, it can initiate a chain reaction, including stimulating nitric oxide production and sensitising neurons further.19,21

For VIP, another potent vasodilator and inflammatory modulator, elevated levels during migraine and cluster headaches points to intense parasympathetic action. However, while CGRP’s vasodilator activity is considered a part of its migraine-trigger activity, VIP does not appear to trigger migraine.6,19

Somatostatin, another neuropeptide released from the hypothalamus, is implicated in migraine (with five receptor subtypes identified), and in cluster headaches. The presence of octreotide, a somatostatin analogue agonist can be effective in treating cluster headache but not migraine.6