The trigeminovascular pathway provides the anatomical and physiological substrate for migraine headache, and activation of trigeminal nociceptive pathways and the trigeminocervical complex (TCC) may trigger a migraine. Furthermore, chronic activation of these pathways leads to peripheral and central sensitization, contributing to the chronification of migraine.

 A Phenome-Wide Association Study (PheWAS) analysis has identified an association between single-nucleotide variants in the ADRA2 subtype B, a G protein-coupled receptor expressed on peripheral and central presynaptic terminals, and an increased risk for trigeminal nerve disorders.

The ADRA2B gene, encoding the Alpha 2B receptor, is expressed on the trigeminal ganglion.

Recently, it was shown that adding guanfacine, an ADRA2 agonist, to local anesthetic enhanced analgesia compared to local anesthetic alone for trigeminal nerve blocks for the treatment of trigeminal neuralgia and painful trigeminal neuropathy.

Currently some alpha 2 agonists have been shown to mitigate neuropathic pain, and guanfacine may have a role in treating opioid-induced hyperalgesia. However, guanfacine is used clinically only for the treatment of hypertension in adults and attention deficit hyperactivity disorders in children.

There are several reasons  to hypothesize that guanfacine can play a therapeutic role in the treatment of chronic migraine. Stimulation of the ADRA2 suppresses calcium entry into the nerve terminal and inhibits release if neurotransmitter such as CGRP, nitric oxide, substance P, etc. Suppressed pain propagating neurotransmitter release from trigeminal afferents into the TCC may limit activation of sensory, affective, and autonomic symptoms associated with migraine.

Furthermore, chronic treatment with guanfacine may reversing peripheral and central sensitization of trigeminal nerves, as well as pain pathways mediated by the TCC, via a decrease in neurotransmitter release.

Guanfacine should be studied for the treatment of acute and chronic migraine.