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.
Deborah Hay, PhD, of the University of Auckland in New Zealand, presented the plenary lecture. After reminding the audience about the structure and known functions of CGRP, as well as its potential as a treatment for headache, Professor Hay explained that CGRP is a cardiovascular peptide acting as a potent vasodilator and 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 a number of pathologies. For example, in the metabolic system, CGRP is considered to play a role in the development of diabetes, control of body weight and lipid usage. CGRP knockout mice have reduced weight gain and are generally healthier than control animals. CGRP is also found in sensory neurons of the face and head, mostly concentrated in the trigeminal nerve. Studies have shown that CGRP blood levels increase during a migraine attack and that infusing it into migraineurs can bring on a migraine attack. There is also data to suggest that it is associated with cluster headaches.
Available information collectively shows that CGRP is involved in the pathophysiology of migraine, including pain transmission, vasodilation, and neurogenic inflammation. Therefore, it is expected that blocking its activity would help alleviate migraine symptoms. Several medications known to interact with CGRP can be broadly categorized under preventative or acute therapies, and are either anti-CGRP antibodies, anti-CGRP receptor antibodies, or receptor antagonists. So far, all of the CCRP-related clinical trials for migraine have shown positive short-term outcomes.
In the next phase of development, it will be interesting to determine the nature of chronic long-term side effects of such treatments. Also, a subset of patients might not be responsive to those treatments; it will therefore be important to determine the factors distinguishing them from responsive patients. It will also be important to determine if blockade of these receptors leads to compensatory increases in receptor expression and possible rebound effects.
In another plenary presentation, Paul Durham, PhD, of the University of Missouri, spoke about the biology of serotonin (5-HT) and its role in migraine. Serotonin is generated in raphe nuclei and diffuses throughout the brain; it is believed to play a key role in pain modulation. Studies have shown that levels of serotonin are elevated during a migraine attack. There are currently 14 different serotonin receptors that are known, with some of them already targeted in migraine treatment.
For example, triptans, an important abortive treatment, bind to 5HT1B/1D receptors. Other molecules, including HT1F agonists, have also been found to be useful in treating migraine. The 5HT1B/1D receptors which are present in several brain sites, including the trigeminal ganglion and meningeal arteries, are thought to be involved in blocking of vasodilation. Activation of these serotonin receptors inhibits glutamate and CGRP signaling involved in migraine pathogenesis.
Dr Durham recalled a systematic review and network meta-analysis published in Headache in 2015 by Cameron and colleagues1 in which triptans were found to be 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 vs other painful conditions. There are now a number of other delivery methods for triptans devised to overcome the limitations of oral delivery for patients with nausea or to palliate low tolerance of oral intake.
In another important presentation, Amynah Pradhan, PhD, of the University of Illinois at Chicago, covered the issue of long-term opioid use to treat painful conditions in her talk titled “Opioids in General in Migraine.” Of the 4 opioid receptor subtypes, the mu receptor is the one most research efforts focus on. This receptor is activated by opioids, some foods, and sexual activity. Chronic stimulation or overstimulation of the mu-opioid receptor by morphine, hydromorphone, or oxycodone, may lead to euphoria, often resulting in addiction, Dr Pradhan explained. When used for the treatment of migraine, opioids lead to more frequent and severe migraine. Studies have found that the greater number of opioid-use days, the more likely someone is to develop more frequent headaches.
Dr Pradhan’s lab conducted a study to determine why activation of the mu receptor leads to medication overuse, headaches or rebound headaches. They used a known migraine trigger, nitroglycerin, to develop a chronic migraine model in mice, and found the effect of nitroglycerin to be dose-dependent. Mice presenting with headache-like symptoms induced by nitroglycerin and treated with morphine developed an increased basal hypersensitivity.
Dr Pradhan also discussed targeting of the delta receptor, which may have a lower risk of side effects from medication overuse or rebound. The delta receptor, which is mainly active in chronic pain states, has a low potential for addiction and has an overall antidepressant and anxiolytic effect. These receptors are mainly expressed in the cortex and forebrain, as well as amygdala and hippocampus – areas that have been implicated in pain awareness and emotional processing. Delta agonists lead to a reduction in pain levels when activated by acute nitroglycerin, but do not increase basal hypersensitivity, suggesting that they could be a potential target for pain control.
Additional highlights included the Seymour Solomon Lecture Award, which was given to Dawn Buse, PhD, who gave a talk dealing with the relationship between stress and headache. She also warned about the dangers of physician burnout and ways to reduce stress for practitioner and patient alike – a topic that is top-of-mind among many clinicians.
Overall, the American Headache Society put on another educational, informative, and enjoyable meeting for all attendees, both seasoned and new to the profession.
Find additional AHS 2016 coverage here.
1.Cameron C, Kelly S, Hsieh SC, et al. Triptans in the Acute Treatment of Migraine: A Systematic Review and Network Meta-Analysis. Headache. 2015;55 Suppl 4:221-35.
This article originally appeared on Neurology Advisor