The sphenopalatine (pterygopalatine) ganglion [
42,
43] is a major outflow pathway for the facial (VIIth) nerve cranial dilator system [
44,
45], which is the efferent portion of the trigeminal-autonomic reflex [
46]. This system arises from neurons in the superior salivatory nucleus [
47] that receive inputs from trigeminal nucleus caudalis [
48]. The SPG is a hexamethonium-sensitive nicotinic ganglion [
21] containing vasoactive intestinal polypeptide (VIP) [
49,
50], pituitary adenylate cyclase-activating peptide (PACAP) [
51] and nitric oxide synthase [
52]. This pathway is the basis for canonical cranial autonomic symptoms such as lacrimation, conjunctival injection, nasal symptoms, aural symptoms and periorbital oedema, when activated typically by trigeminal nociceptive afferents [
53•]. Thus, experimentally induced pain [
54], migraine [
55,
56] and the trigeminal autonomic cephalalgias (TACs) [
46] all share expression of the pathway, with a remarkable differentiation in prominence, reproducibility and lateralization of the symptoms in TACs [
57].
Maizels [
58,
59] demonstrated the effectiveness of nasal lidocaine-induced SPG block in reducing pain during migraine attacks. The first trial to attempt SPG stimulation for migraine treatment was a small pilot study performed by Tepper and colleagues [
60], who applied electrical stimulation via a needle inserted in the sphenopalatine fossa through an infrazygomatic approach in 11 patients with refractory migraine. Induced attacks were aborted (
n = 2) or relieved (
n = 3) in only five patients, although the authors discuss that this relatively low response could be due to incorrect lead placement or concomitant medication overuse headache in most patients. At the moment, an RCT is testing the efficacy of an implanted microstimulator in migraine (NCT01540799), and another trial for the acute treatment of episodic migraine (NCT01294046) has been completed and not reported. A single case report of intractable facial pain presenting some migrainous features and treated with SPG modulation has also been published [
61].