DearR Mayo Clinic: I am a 30-year-old woman who has had migraines since I was a teenager. My paediatrician said it was likely hormonal since they often occurred during my menstrual cycle. Over the years, I have tried various prescription and over-the-counter medications to treat migraines, as well as preventive therapies, but I continue to struggle. I feel as if my headache days are increasing. I often miss work and cannot participate in activities with friends and family. I'm wondering if any new advances have been made in migraine medications.

Answer: Migraine is a common and potentially disabling disorder. Migraine attacks can cause severe throbbing head pain or pulsing sensations, as well as nausea, vomiting and sensitivity to light and sound. It is estimated that migraines affect almost 40 million people in the U.S.

For many years, patients were limited in treatments that would stop symptoms of a migraine. Most relied on either over-the-counter pain medications or a class of prescription drugs known as triptans, which were available as pills, injections and nasal sprays. Research, though, has shown that if taken too frequently, both the nonprescription and prescription acute medications may worsen the headache disorder. This is known as a "medication-overuse headache."

To decrease the frequency and severity of migraine attacks, many people have used long-term preventive treatments, though most were medications that had originally been intended to treat other conditions, such as drugs to lower blood pressure, antidepressants and anti-seizure drugs. In addition, these drugs can cause side effects, such as nausea and dizziness that can make sticking to treatment difficult.

As knowledge has grown about what is happening in the brain when a migraine attack occurs, the list of available treatments is expanding.

Scientists studying migraine found a specific protein — calcitonin gene-related peptide — that was released during a migraine attack. When a migraine attack was stopped, say with a medication like sumatriptan, the blood level of the calcitonin gene-related peptide protein would go down. This led to the advent of targeted preventive treatment options specifically designed for migraine.

The first calcitonin gene-related peptide monoclonal antibody to prevent migraine was approved in 2018.

Today, four drugs have been approved:

• Eptinezumab (Vyepti).
• Erenumab (Aimovig).
• Fremanezumab (Ajovy).
• Galcanezumab (Emgality).

They're designed to find calcitonin gene-related peptide proteins or calcitonin gene-related peptide receptors and basically hug them so that they are inactive.

Two calcitonin gene-related peptide receptor antagonists also prevent migraine and reduce calcitonin gene-related peptide receptor activity:

• Atogepant (Qulipta).
• Rimegepant (Nurtec ODT).

As with the earlier therapies, there are positives and negatives to the new calcitonin gene-related peptide medications. Not every medicine will work for each person. Some of the newer drugs are not well-covered by insurance so you will want to speak with your health care professional about the best options. And while these new medications offer fewer side effects, the long-term side effects are still not known.

As-needed migraine medications

Based on an understanding of the calcitonin gene-related peptide protein, new as-needed migraine medications also target calcitonin gene-related peptides.

That is good news for about 30%–40% of people living with migraine who found triptan-based medications didn't work for them or were not well-tolerated. Also, triptans can potentially narrow blood vessels, so people with a history of stroke, heart attack, ministrokes or uncontrolled hypertension were advised not to take triptans.

Now two new calcitonin gene-related peptide receptor antagonists are available for as-needed treatment of migraine — and they don't narrow blood vessels. They are ubrogepant (Ubrelvy) and rimegepant, which is also approved to prevent migraine. These are oral medications that block the calcitonin gene-related peptide receptor to hopefully stop a migraine attack while it's happening. More research is needed, but these drugs don't appear to have the same risk of medication overuse headache that some other as-needed migraine treatments do.

Another new as-needed medication that's not related to calcitonin gene-related peptide is available. Known as lasmiditan (Reyvow), this drug works on serotonin receptors. But it works on a different subtype of these receptors so it does not narrow blood vessels. This is great for people who had success using triptans but had to stop using them after having a heart attack or stroke.

Even with the plethora of options now available, some people may still need a combination of treatments. It can feel hopeless some days. Rest assured that scientists are working to identify other targets that trigger migraine attacks. For example, another protein that's called pituitary adenylate cyclase-activating peptide is under investigation.

At Mayo Clinic, several focused efforts are underway, including a Migraine Research Program that is studying the role of genetics and the environment in migraine. Also, a Neuroimaging of Headache Disorders Lab is focused on trying to better understand the neurobehavioral complexities of migraine and other headache disorders. Teams of experts are dedicated to research to identify additional molecules and proteins, and then develop new treatment options for every person with migraine.

I always recommend patients maintain an annual visit with a neurologist or headache specialist. Discuss your current situation, what you think is working and whether the new medications may offer relief. It is not uncommon to try different therapies until you find the one that works.

— Dr. Amaal Starling, Neurology, Mayo Clinic, Phoenix