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So Many Migraine Therapies, So Many Decisions
Here's How the Experts Choose

Article In Brief

Therapy options for patients with migraines have expanded over the past couple of years, with several new drug classes specific to the disorder. Leading migraine experts discuss how they decide to choose one therapy over another.

Treatment options for migraine have expanded considerably over the past two years, with several new classes of targeted, migraine-specific drugs coming to the market.

The expansion of therapies for acute migraine and migraine prevention is welcome news for migraine sufferers, many of whom do not get adequate relief despite trying multiple treatments.

For neurologists and others who treat migraine patients, the new options may provide a clearer rationale for how to approach treatment because, until recently, most of the drugs used for migraine were developed for other conditions such as epilepsy. The newer medications are designed to target pathophysiologic pathways involved in the migraine process in the hope of achieving better pain relief with fewer side effects.

“For our patients with migraine, we often have to say, ‘I am going to give you this medicine that was originally created to help seizures (or blood pressure, or depression), and it is going to help your headache,’” said Rebecca E. Wells, MD, MPH, associate professor of neurology and founder and director of the Comprehensive Headache Program at Wake Forest Baptist Health.

With the new drugs, she now can tell patients how the drug is different and how it targets the pathophysiology of how migraine is working in their brain.

The CGRP Inhibitors

Among the newer class of preventive drugs generating excitement are calcitonin gene-related peptide (CRGP) inhibitors, monoclonal antibodies that block a pathway involved in the migraine process.

“There are over 30 million people (in the US) with migraine, and yet only about 40 percent of them get adequate treatment,” said Jessica Ailani, MD, FAAN, director of Medstar Georgetown Headache Center and professor of clinical neurology at Medstar Georgetown University Hospital.

She and other migraine experts say the newer migraine drugs aren't a panacea for all patients and don't render obsolete the older, less expensive migraine therapies that work well for many people. But they hope that a broader range of treatments will lead to more people being effectively treated and sticking with their medicines because of fewer side effects.

“We are definitely seeing more patients come back to the practice we haven't seen in a while,” said Dr. Ailani. “Some patients come in saying, ‘I hear there is something new.’”

Erenumab (Aimovig), fremanezumab (Ajovy), and galcanezumab (Emgality) are humanized monoclonal antibodies that block CGRP by either binding to the CGRP receptor (erenumab) or binding to the CGRP ligand (fremanezumab and galcanezumab).

The injectables are administered every one to three months, depending on the drug. Erenumab carries a warning of possible hypersensitivity reactions, and the drug can also cause severe constipation. Galcanezumab is also approved for cluster headaches.

Epitenezumab (Vyepti), which works by binding to the CGRP ligand, is the first approved intravenous treatment for migraine prevention. It is administered via IV infusion at a clinic every three months. Because the drug was approved by the US Food and Drug Administration (FDA) in February just as the pandemic was taking off in the US, doctors say they have minimal experience in prescribing it.


“There are over 30 million people (in the US) with migraine, and yet only about 40 percent of them get adequate treatment.”—DR. JESSICA AILANI

The clinical trial results submitted to the FDA vary for each of the CGRP therapies, though in general, they are effective for about 50 to 60 percent of patients, Dr. Ailani said. While longer-term effects are not known with the newer migraine drugs, “CGRPs come with very few side effects from what we can tell, and they are much better tolerated by patients,” she said.

Newer Acute Therapies

Ubrogepant (Ubrelvy) is the first in a class of oral medications called “gepants,” a small molecule CGRP receptor antagonist. Ubrogepant was approved in December 2019 for the acute treatment of migraine with or without aura. Unlike triptans, the drug works without constricting blood vessels, which means it could be an attractive alternative choice for patients with a history or risk of cardiovascular disease or stroke, Dr. Ailani said.

Rimegepant (Nurtec), another drug in the gepant class—a dissolvable tablet—was approved by the FDA in February for acute treatment of migraine. Like ubrogepant, the drug does not constrict blood vessels and likewise could be useful for migraine patients with a history of high blood pressure or stroke, Dr. Ailani said.

Rimegepant has a long half-life of 11 hours and is prescribed once as needed for migraine, Dr. Ailani said. Both of the gepants are processed through the liver and have specific interactions with certain medications, so this is important to take into account when prescribing, she said.

The ‘Ditans’

Lasmiditan (Reyvow), the first medication in a new class of migraine drugs called “ditans,” is approved for the acute treatment of migraine with or without aura. Ditans do not cause vasoconstriction, so this drug can be an option for patients with vascular disease who need migraine-specific treatment, Dr. Alaini said.

The drug, which is a serotonin (5-HT)1F receptor agonist, can cause dizziness and sedation, and patients are warned not to drive or operate machinery within eight hours of taking it, even if they feel alert. The drug is a controlled substance.

Dr. Ailani said triptans are still her “go-to” generics for acute migraine because they are cheaper than the new drugs, and insurance companies cover them. They also have a known track record. She said that typically insurance companies require that patients fail two triptans before switching to a gepant.

The Guiding Principles

Kathleen B. Digre, MD, FAAN, distinguished professor of neurology at the University of Utah, said that even with the bigger tool chest doctors now have to work with, the basic principles of migraine management should remain key to every patient encounter.

“The first guiding principle is ‘always make a right diagnosis,’” Dr. Digre said. “That means a careful history and exam to make sure I know what the patient has. Then I look for comorbidities, things that run with migraine, like poor sleep, depression and anxiety, obesity, things that can make migraine worse,” she said.

It's also essential to understand patients' expectations, she added. “If I am going to talk with them about treatment options, I need to know where they are in their own minds. Are they willing to try a medication, or do they want to consider neuromodulation or do they want a healthy lifestyle approach? They are not going to take something just because you said so,” Dr. Digre said.

She said many patients “have tried every drug in the book,” and may have mistakenly fallen into the category of being a “non-responder” because they were not on an effective dose of a medicine or only took it on and off as symptoms flared or subsided. Some have experienced intolerable side-effects.

“They might have thrown out drugs that might have helped, just because they didn't take them long enough or at the correct dosage,” she said.


“They might have thrown out drugs that might have helped, just because they didnt take them long enough or at the correct dosage.”—DR. KATHLEEN B. DIGRE


“We are picking up many of the patients who were formally ‘non-responders’ medications are also more tolerable for many of our patients.”—DR. RANDOLPH W. EVANS

Dr. Digre said she tends to start treatment with older drugs such as triptans for acute migraine and antihypertensives, tricyclics, or anticonvulsants for prevention because of their known track record and availability in inexpensive generic forms. She said her practice often faces pushback from insurers to pay for the costlier newer drugs.

“I try to practice cost-effective medicine, and I am always thinking of cost to the patient and cost to the system,” she said. “If patients fail two or three classes of generic medications, I am going to advocate for them to get a new CGRP monoclonal therapy.”

Randolph W. Evans, MD, FAAN, clinical professor of neurology at Baylor College of Medicine, said there has long been an unmet need for migraine drugs.

“We are picking up many of the patients who were formally ‘non- responders,” he said, noting that the “new medications are also more tolerable for many of our patients.”

But even with the new lineup of drugs, “there is nothing close to 100 percent for prevention. We still have people who don't respond, and that is the big mystery,” he said.

Dr. Evans conducts industry-sponsored educational sessions for primary care doctors on the new migraine therapies, and he said they feel comfortable using the new medications. One limitation in explaining the pros and cons of the various drugs is that “we don't have head-to-head studies (of the new migraine drugs) so many times we are driven by insurance coverage,” when picking a treatment, Dr. Evans said.

Dr. Evans said the new drugs might prove effective in combined therapy for prevention, in the same way, that older medications are used in combination.

“We have been combining Botox with a (CGRP) monoclonal antibody and finding additional efficacy in those who are partial responders to one,” he said. There have also been favorable anecdotal reports of rimegepant used in combination with a CGRP monoclonal antibody, he said.

Patient Education Is Important

Dr. Wells, of Wake Forest, said that with the broader array of drugs to now choose from, patient education is more important than ever. She said it is hard to thoroughly discuss the many options during the time allotted for a clinical visit, and the similar-sounding names of drugs can be confusing for patients.

In 2018, when the CGRP medications first came on the market, she initiated separate patient education sessions to introduce patients to their possible treatment choices before their appointments. The sessions were at first held in person, but to increase access and availability, they are now available online.

Surveys before and after the sessions showed that not only were they helpful for improving patient understanding of the new medications, the online format was also as effective as the in-person sessions, Dr. Wells said. She said the separate educational sessions help improve clinic flow.

Dr. Wells said the overall message that she tries to convey to patients, no matter their ultimate treatment choice, is that “migraine is a complex neurologic disease and it's not something that is ‘just in their head.’”

Deborah I. Friedman, MD, MPH, FAAN, professor of neurology and ophthalmology at UT Southwestern Medical Center, said the ability to take migraine prevention medicine with a monthly or quarterly injection or instead of daily oral medication is a welcome switch for some patients.


“We know the adherence rate for oral medications, both preventive and acute, is very poor. Eighty percent of people who get a prescription for a migraine drug are not on it at the end of the year.”—DR. DEBORAH I. FRIEDMAN

“We know the adherence rate for oral medications, both preventive and acute, is very poor,” she said. “Eighty percent of people who get a prescription for a migraine drug are not on it at the end of the year.”

But Dr. Friedman said that one of the things she's gleaned from her clinical practice is that even though migraine therapy overall has benefited from the addition of the CGRPs, patience is still required.

“When these drugs first came out, there was a mistaken impression that they would work very quickly for everyone,” she said. While many patients do report a decline in headache in the first three months, as was shown in clinical testing, “one of the things we've learned is that you have to give patients a five to six-month trial to make sure they have time to respond.”


Dr. Digre had no relevant disclosures. Dr. Ailani has received honoraria from- Allergan/Abbvie, Biohaven, Axsome, Lundbeck, Amgen, Eli Lilly, Teva, Impel, Satsuma, and Revance. Dr. Friedman serves on the advisory board of Allergan, BioBiohaven Pharmaceuticals, Eli Lilly, Impel, Invex, Lundbeck, Merck, Revance, Teva, Theranica, and Zosano. She has received grant support from Allergan and Merck. Dr. Evans has received fees for serving on the speakers' bureau for Allergan, Amgen, Biohaven, Eli Lilly, Novartis, and Teva.