What Will Be the Next Big Breakthrough in Migraine Research?

According to Dr. Ailani, there are many neuropeptides (chemical messengers in nerve cells) involved in migraine but most recently, researchers have focused on two that get released in the brain and cause migraine: calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP). Research on CGRP is more advanced. In the last five years, several drugs that block CGRP receptors (known as CGRP antagonists) have been approved by the FDA, some of which are taken orally when a migraine strikes and some of which are self-injected monthly or quarterly to prevent migraine attacks from happening in the first place.“PACAP is the next molecule that’s closest to nearing the finish line in clinical trials,” says Dr. Ailani. “It’s the next big thing we have our eye on.” Danish researchers have found that the neuropeptide PACAP-38 is a key player in migraine pathophysiology: A clinical trial1 showed that an infusion of PACAP-38 increases plasma levels of the neuropeptide and leads to migraine attacks. In a small study published in Brain2, when the neuropeptide PACAP-38 was injected into people–12 with a history of migraine and 12 without–the majority of people experienced a migraine attack.Now, drug companies are trying to create antibodies that specifically target PACAP receptors. A 2020 clinical trial tested a drug that targets one receptor called PAC13. It, unfortunately, didn’t improve migraine compared to the placebo. Researchers suggest a number of explanations, among them, that the concentration of the drug wasn’t high enough to have an effect, or that perhaps a different PAC receptor needs to be targeted instead of or in addition to PAC1. The good news, according to Dr. Silberstein, is that trials like this teach us more and more about the chemistry of migraine, bringing us closer to finding answers.Once an effective PACAP inhibitor is found, people with migraine will have yet another drug to add to their arsenal of migraine treatments. “There are different pathways for migraine,” notes Dr. Silberstein. “One pathway is CGRP; another is PACAP. When we get a good PACAP drug, I suspect that nonresponders to the CGRP drug will respond to PACAP drugs.”Another promising area of research is the study of how oxytocin (the “love hormone”) may play a role in inhibiting migraine. In 2017, Stanford researchers4 showed that when given as a nasal spray, oxytocin can significantly decrease migraine pain. More research is needed but so far the data has been positive, notes Dr. Ailani.New Drug-Free Ways to Treat MigraineThe thing about targeted migraine medications is that they often cause unpleasant side effects, like tingling or prickling of the skin, dizziness, dry mouth, and nausea, among others. And if you’re pregnant or have a health condition like coronary artery disease, you may not be able to take certain migraine drugs. In these instances, non-drug treatment options are crucial—and fortunately, more and more are becoming available.“An exciting area in the field of migraine is the development of wearable devices that can treat and prevent migraine,” Dr. Silberstein says. In the last five years, the FDA has approved four migraine devices that are worn on different areas of the body: the forehead, neck, arm, or head. Each device works in a slightly different way but they all deliver electrical pulses to nerves that can cause migraine.

According to Dr. Ailani, there are many neuropeptides (chemical messengers in nerve cells) involved in migraine but most recently, researchers have focused on two that get released in the brain and cause migraine: calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP). Research on CGRP is more advanced. In the last five years, several drugs that block CGRP receptors (known as CGRP antagonists) have been approved by the FDA, some of which are taken orally when a migraine strikes and some of which are self-injected monthly or quarterly to prevent migraine attacks from happening in the first place.

“PACAP is the next molecule that’s closest to nearing the finish line in clinical trials,” says Dr. Ailani. “It’s the next big thing we have our eye on.” Danish researchers have found that the neuropeptide PACAP-38 is a key player in migraine pathophysiology: A clinical trial1 showed that an infusion of PACAP-38 increases plasma levels of the neuropeptide and leads to migraine attacks. In a small study published in Brain2, when the neuropeptide PACAP-38 was injected into people–12 with a history of migraine and 12 without–the majority of people experienced a migraine attack.

Now, drug companies are trying to create antibodies that specifically target PACAP receptors. A 2020 clinical trial tested a drug that targets one receptor called PAC13. It, unfortunately, didn’t improve migraine compared to the placebo. Researchers suggest a number of explanations, among them, that the concentration of the drug wasn’t high enough to have an effect, or that perhaps a different PAC receptor needs to be targeted instead of or in addition to PAC1. The good news, according to Dr. Silberstein, is that trials like this teach us more and more about the chemistry of migraine, bringing us closer to finding answers.

Once an effective PACAP inhibitor is found, people with migraine will have yet another drug to add to their arsenal of migraine treatments. “There are different pathways for migraine,” notes Dr. Silberstein. “One pathway is CGRP; another is PACAP. When we get a good PACAP drug, I suspect that nonresponders to the CGRP drug will respond to PACAP drugs.”

Another promising area of research is the study of how oxytocin (the “love hormone”) may play a role in inhibiting migraine. In 2017, Stanford researchers4 showed that when given as a nasal spray, oxytocin can significantly decrease migraine pain. More research is needed but so far the data has been positive, notes Dr. Ailani.

New Drug-Free Ways to Treat Migraine

The thing about targeted migraine medications is that they often cause unpleasant side effects, like tingling or prickling of the skin, dizziness, dry mouth, and nausea, among others. And if you’re pregnant or have a health condition like coronary artery disease, you may not be able to take certain migraine drugs. In these instances, non-drug treatment options are crucial—and fortunately, more and more are becoming available.

“An exciting area in the field of migraine is the development of wearable devices that can treat and prevent migraine,” Dr. Silberstein says. In the last five years, the FDA has approved four migraine devices that are worn on different areas of the body: the forehead, neck, arm, or head. Each device works in a slightly different way but they all deliver electrical pulses to nerves that can cause migraine.

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