Highlights From the 2016 American Headache Society Annual Meeting

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Highlights From the 2016 American Headache Society Annual Meeting
Highlights From the 2016 American Headache Society Annual Meeting

The 58th Annual Scientific Meeting of the American Headache Society took place June 9-12 in San Diego, CA. This year, a highly anticipated plenary session on CGRP antagonists took center stage, while pre-meeting courses and a new patient-submitted video competition helped round out the always-informative meeting.

Professor Deborah Hay, BSc (hons), PhD, of the University of Auckland in New Zealand, presented the plenary session on CGRP and its receptors. Professor Hay laid out the basics about the structure and known functions for this molecule, as well as its future potential as a treatment for headache. Professor Hay explained that CGRP is a cardiovascular peptide that works as a potent vasodilator that is thought to be cardioprotective. There are 2 forms of the CGRP molecule, alpha and beta, which are expressed throughout the central and peripheral nervous system. It was initially identified about 35 years ago and is thought to be active in a range of different systems and involved in many diseases. For example, in the metabolic system, it is considered to play a role in the development of diabetes, control of body weight and lipid usage. In experiments, CGRP knockout mice had reduced weight gain and were generally healthier. CGRP is also found in sensory neurons of the face and head, mostly concentrated in the trigeminal nerve. Studies have shown that CGRP content is higher in the blood during a migraine attack and CGRP infusion into migraineurs can bring on a migraine attack.  There is also data to suggest that it is associated with cluster headaches.

All of the known information collectively shows that the CGRP is involved in the pathophysiology of migraine, including pain transmission, vasodilation, and neurogenic inflammation. Therefore, it makes sense that blocking the activity of CGRP would treat migraine.  There are now a few different types of medications that interact with this molecule that can be broadly categorized as those that are preventative as well as acute therapies, and work either as anti-CGRP antibodies, anti-receptor antibodies, or receptor antagonists. So far, all of the trials for this molecule have been positive in the short-term.

What will be interesting in the next phase of development will be to determine what the chronic long-term side effects will be. Also, it is a given that there will be a subset of patients who do not respond to this treatment, and it will be important to determine the characteristics of those patients. It will also be important to determine if blockade of these receptors leads to compensatory increases in receptor expression leading to possible rebound effects.

In another plenary presentation, Paul Durham, PhD, of the University of Missouri, spoke about the biology of serotonin and its role in migraine. Serotonin is made in raphe nuclei and then distributed throughout the brain, and it is believed to play a key role in pain modulation. Studies have shown that there are elevated levels of serotonin during a migraine attack.  There are currently 14 different serotonin receptors that are known, with some of them already used in treating migraines. For example, triptans, an important abortive treatment, works on 5HT1B/1D receptors. Other molecules, including HT1F agonists, have also been found to be useful in treating migraine. The 5HT1B/1D receptors work on multiple sites in the brain, including trigeminal ganglion and meningeal arteries, thought to be involved in blocking vasodilation. The activation of these serotonin receptors inhibits glutamate and CGRP which is a part of the cascade of events that lead to a migraine. 

Dr Durham recalled a systematic review and network meta-analysis published in Headache in 2015 by Cameron, et al,1 which found that triptans are still the most effective therapy for acute migraine relief – equal or better than NSAIDs or acetaminophen. Triptans are also known to be selective for headache and migraine and do not work in other pain conditions. There are now a number of other delivery methods for triptans to overcome the limitations of oral delivery for patients with nausea or other reasons for being unable to tolerate oral medications. 

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