Oxytocin and Migraine Headache

Abstract

This article reviews material presented at the 2016 Scottsdale Headache Symposium. This presentation provided scientific results and rationale for the use of intranasal oxytocin for the treatment of migraine headache. Results from preclinical experiments are reviewed, including in vitro experiments demonstrating that trigeminal ganglia neurons possess oxytocin receptors and are inhibited by oxytocin. Furthermore, most of these same neurons contain CGRP, the release of which is inhibited by oxytocin. Results are also presented which demonstrate that nasal oxytocin inhibits responses of trigeminal nucleus caudalis neurons to noxious stimulation using either noxious facial shock or nitroglycerin infusion. These studies led to testing the analgesic effect of intranasal oxytocin in episodic migraineurs-studies which did not meet their primary endpoint of pain relief at 2 h, but which were highly informative and led to additional rat studies wherein inflammation was found to dramatically upregulate the number of oxytocin receptors available on trigeminal neurons. This importance of inflammation was supported by a series of in vivo rat behavioral studies, which demonstrated a clear craniofacial analgesic effect when a pre-existing inflammatory injury was present. The significance of inflammation was further solidified by a small single-dose clinical study, which showed analgesic efficacy that was substantially stronger in chronic migraine patients that had not taken an anti-inflammatory drug within 24 h of oxytocin dosing. A follow-on open label study examining effects of one month of intranasal oxytocin dosing did show a reduction in pain, but a more impressive decrease in the frequency of headaches in both chronic and high frequency episodic migraineurs. This study led to a multicountry double blind, placebo controlled study studying whether, over 2 months of dosing, "as needed" dosing of intranasal oxytocin by chronic and high frequency migraineurs would reduce the frequency of their headaches compared to a 1-month baseline period. This study failed to meet its primary endpoint, due to an extraordinarily high placebo rate in the country of most of the patients (Chile), but was also highly informative, showing strong results in other countries and strong post hoc indications of efficacy. The results provide a strong argument for further development of intranasal oxytocin for migraine prophylaxis.

Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans

“…Harnessing the central OT system has been identified as a promising strategy in translational neuroscience for the development of targeted pharmacological interventions to improve outcome in several conditions currently lacking efficacious treatments (e.g. autism spectrum disorder 7 , schizophrenia 8 , migrain 9 , stroke 6 , obesity 10 , Prader-Willi 11 ).…”

Intranasal Oxytocin Attenuates Reactive and Ongoing, Chronic Pain in a Model of Mild Traumatic Brain Injury

“…Neumann et al 30 recently demonstrated an uptake of OT in the brain after intranasal administration by way of microdialysis. Similarly, we have recently demonstrated that nasally applied radiolabeled oxyocin concentrates in the brain, but mainly in the trigeminal system of rats . There are three proposed ways how intranasally administered OT reaches its target areas: (1) intra‐axonal transport mechanisms, (2) via the peripheral blood stream and the unexpected crossing blood brain barrier, and (3) perineurally along peripheral nerve bundles to reach the CNS.…”

“…Similarly, we have recently demonstrated that nasally applied radiolabeled oxyocin concentrates in the brain, but mainly in the trigeminal system of rats. 31 There are three proposed ways how intranasally administered OT reaches its target areas: (1) intra-axonal transport mechanisms, (2) via the peripheral blood stream and the unexpected crossing blood brain barrier, and (3) perineurally along peripheral nerve bundles to reach the CNS. In a review of the existing literature it is concluded that the perineural mechanism is the most likely.…”

Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans

“…Robust evidence from studies in preclinical models has demonstrated the importance of the central OT system in the development (3) and regulation of complex social behaviours (4,5), the modulation of pain processing (6), feeding behaviour (7) and neuroinflammation after brain ischemia (8). Harnessing the central OT system has been identified as a potential strategy for the development of targeted pharmacological interventions to help to improve outcome in several conditions for which efficacious treatments do not currently exist (e.g autism spectrum disorder (9), schizophrenia (10), migraine (11), stroke (8), obesity (12), Prader-Willi (13)).…”