Stepping wisely for migraine relief
ACP recently published a clinical guideline on prevention of episodic migraine, suggesting a stairstep prescribing approach in nonpregnant adults.
Preventing migraine can sometimes be difficult, but internal medicine physicians can better assist patients with time and patience using a stairstep approach, including the consideration of newer therapies.
In 2018, nearly 16% of U.S. adults reported experiencing migraine or severe headaches, including one out of every five women, according to data published in 2021 in Headache. Migraine also accounted for more than 4.3 million office visits and roughly 4 million visits to the emergency department in 2016, the study found.
But too often, people miss out on the benefits of prevention, studies have shown. A 2018 survey, published in 2022 by Headache, found that 40% of U.S. adults with migraine met the eligibility criteria for preventive medication based on the frequency and severity of their symptoms, but fewer than half that number, 16.8%, were currently taking a preventive drug.
Various factors contribute to gaps in migraine relief, starting with delays in diagnosing the condition, said Richard B. Lipton, MD, the study's lead author, who directs the Montefiore Headache Center at Albert Einstein College of Medicine in Bronx, N.Y. But even when patients are diagnosed correctly, they might not stick with preventive medication, he said.
“They cite two main reasons,” he said. “One is that the medication caused too many side effects, and the other is that the medication didn't work that well. I think really what people do when they decide, ‘Should I stay on my migraine medicine or not?’ is to make a judgment that overall the aggregate benefits are not worth the aggregate costs, in terms of side effects or the cost of medication out of pocket and so forth.”
Earlier this year, ACP published a clinical guideline about prescribing for prevention of episodic migraine, by far the most common form, in nonpregnant patients. The guideline noted that episodic migraine is defined as one to 14 headache days per month.
In the guideline, published online on Feb. 4 by Annals of Internal Medicine, the authors suggest a stairstep prescribing approach in nonpregnant adults with three recommendations.
- As an initial step, prescribe one of five oral medications: a beta-blocker, either metoprolol or propranolol; the antiseizure medication valproate; the serotonin and norepinephrine reuptake inhibitor venlafaxine; or the tricyclic antidepressant amitriptyline.
- For next-step treatment, they suggest one of the newer therapies that target calcitonin gene-related peptide (CGRP) in patients who can't tolerate or don't adequately respond to one or more trials of the older therapies suggested as an initial step.
- When none of those prior therapies work or none can be tolerated, the antiseizure medication topiramate is suggested.
With newer therapies emerging, the guideline is designed to provide physicians with prescribing guidance based on high-quality studies, said Carolyn Crandall, MD, MS, MACP, Chair of ACP's Clinical Guidelines Committee. “How do we place these newer medications in the context with the ones that were already available?”
First-line differences
One hurdle in developing the ACP guideline was the lack of “high-certainty evidence” in favoring one therapy over another for prevention, wrote the authors of an accompanying systematic review and network meta-analysis, which was published simultaneously in Annals. “Evidence was mostly insufficient or of low certainty,” they added.
Most of the drugs were compared against placebos, and there were a limited number of head-to-head studies comparing different medications that also included data on key patient outcomes, such as frequency and duration of migraine, said Dr. Crandall, a professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles. “It makes this guideline quite challenging,” she said.
Along with focusing on high-quality studies, the committee weighed relative benefits and harms, Dr. Crandall said. Regarding the newer CGRP therapies, she said, “The reason that they're listed as the second step essentially is because given that they have a similar balance of net benefit to the older drugs, what we had to do was look further at different things to help distinguish them.” To that end, the committee weighed drug cost and patient preference as well, she said.
The CGRP therapies, the first of which was approved by the FDA in 2018, directly target migraine by blocking the activity of calcitonin gene-related peptide, a molecule that is involved in migraine attacks. But the drugs are pricey.
The median cost for annual treatment with one of the six CGRP therapies ranged from $7,071 to $22,790, according to data published in the guideline. For the older drugs, the median cost ranged from $67 to $393 annually. In addition, patients prefer oral drugs over injections or infusions, according to an accompanying research review looking at patient values, also published Feb. 4 in Annals.
The guideline authors considered those additional factors in developing the recommendations, Dr. Crandall said. “Given similar net benefit, they [the CGRP therapies] are much more expensive and the injectable route is probably less preferred by patients than those suggested as initial (step) treatment,” she said. While some CGRP therapies are oral drugs, there remains a lack of clear evidence for net benefit compared with the older drugs, she noted.
The American Headache Society (AHS) has adopted a different position, listing CGRP therapies as another first-line option to consider in a position statement published in the April 2024 Headache.
“The data indicates that the efficacy and tolerability of CGRP-targeting therapies are equal to or greater than those of previous first-line therapies” and that serious adverse events are rare, the authors wrote. They acknowledged that CGRP-targeting therapies are significantly more expensive than most previously established therapies but argued that cost-benefit considerations should include not just the direct cost of the medication but also indirect cost savings, including reduced health care use and improved productivity in patients.
The AHS position statement cited one head-to-head study, published in 2022 in Cephalalgia, that compared a monoclonal antibody CGRP inhibitor (erenumab) to topiramate in 777 patients randomized to either drug for six months. A higher percentage, 38.9%, discontinued topiramate due to adverse events compared to 10.6% in the erenumab group. In the erenumab group, 55.4% of patients reported at least a 50% reduction in migraine days compared with 31.2% in the topiramate group.
Good candidates for the CGRP drugs include patients who experience frequent episodic migraine, 10 or more a month, as they are less likely to respond to other therapies, said Andrew Charles, MD, lead author on the AHS position statement and professor of neurology and director of the UCLA Goldberg Migraine Program in California. Another example is a patient who wants to avoid potential side effects of an older therapy, such as a male patient worried about the risk of erectile dysfunction or exercise intolerance when taking a beta-blocker, he said.
Regarding the CGRP therapies, “we're saying that they are a first-line option,” not the only one, Dr. Charles said. “And their use shouldn't require prior treatment with another therapy.”
The drawback of the stairstep prescribing approach is that an older migraine medication might require at least three months to determine whether it works, Dr. Charles said. “What happens is oftentimes people will try something, it will not work or will be poorly tolerated, and then they just give up.”
Tailoring the approach
The underlying mechanisms for migraine vary from patient to patient, which makes it more challenging to reduce the number and severity, said Juliana H. VanderPluym, MD, a headache specialist and associate professor of neurology at the Mayo Clinic College of Medicine and Science, based in Scottsdale, Ariz.
“That's why we end up with these long lists of various therapies that are targeted at different underlying pathophysiological mechanisms,” Dr. VanderPluym said. “No two people with migraine are going to look exactly the same.”
In making an initial prescribing recommendation, a patient's other medical issues might play a role, Dr. Crandall said. In patients with certain cardiovascular risk factors, physicians could start with metoprolol or propranolol. In patients with major depression, venlafaxine might be a good option, she said.
Sometimes patients struggle to remain on the drugs due to side effects or difficulties with dosing, such as multiple doses each day, said Dr. VanderPluym, who has received research support from Patient-Centered Outcomes Research Institute. She cited one analysis, based on Canadian claims data and published in 2022 in the Journal of Pharmacy & Pharmaceutical Sciences, which showed that half of patients discontinued their initial treatment within four months.
To boost adherence, physicians should place a strong emphasis on patient preference along with weighing a drug's effectiveness, side effects, and cost-related issues, Dr. Crandall and Dr. VanderPluym agreed.
As one example, Dr. VanderPluym said, “I have many patients that do not like the idea of being on antidepressant medication. They have concerns that they feel like it's going to change who they are as a person. They have concerns about potential withdrawal from the medication when they're able to stop the medicine one day.”
A physician can counsel patients that a drug is not being prescribed because the physician believes they have another medical condition, such as depression or seizures, Dr. VanderPluym said, and that drugs are often started at lower dosages for migraine prevention and then titrated up slowly. “That often helps people understand that we're trying to use these medicines in a different way,” she said.
Regarding the ACP guideline recommendations, Dr. VanderPluym raised concerns about the inclusion of valproate. While the guideline specifies that its recommendations are for nonpregnant adults, she cautioned against using the drug in women of child-bearing age given its teratogenic properties. “We know that many pregnancies happen unplanned,” she said.
Dr. Crandall pointed out that there are five drug options listed in the guideline's first recommendation, and physicians can discuss them with patients, including valproate, using a shared decision-making approach. If a woman of childbearing age is still interested in valproate, she could wait to start it until beginning contraception, such as an intrauterine device, Dr. Crandall said.
Providing reassurance
While the newer CGRP therapies are costly, more insurers have been moving to cover them as a first-line option since the AHS position statement, Dr. Charles said. He shared AHS data showing that by October 2024, nearly half of patients with coverage through a commercial insurer had access to at least some of the CGRP therapies without a requirement to try other preventive medications first. In May 2024, 22% of commercially insured patients had first-line coverage.
The CGRP-targeted therapies are “more effective and have fewer side effects than the traditional oral generics,” Dr. Lipton said, noting that their main drawback is the higher cost. But, he added, “if someone is worried about side effects, if someone has a lot of medical contraindications to other medications, it makes sense to start with a CGRP-targeted therapy.”
Given the numerous variables to weigh in prescribing for migraine prevention, including cost, it might require more than one drug trial to identify optimal treatment for a specific patient, Dr. VanderPluym said. She recommended that internal medicine physicians consider referring patients to a neurologist or headache specialist if they've tried at least two classes of preventive drugs without achieving migraine relief.
However, she stressed, “it's not that the patient failed the medicine. It's just that it wasn't the right match. I view migraine as a disease that is not one shoe fits all, nor is it going to be for treatment.”
It's an exciting time for prevention, with these newer, more targeted therapies and other drugs in the works, Dr. VanderPluym said.
“That does make the process of treating migraine complicated,” she said. “But that's what we're here for as medical professionals is to engage in those complex medical decisions and help guide and navigate our patients through those.”
