COMMENTARY

New Migraine Treatments: Which Is Right for Your Patients?

Rebecca Burch, MD

Disclosures

July 02, 2021

Editorial Collaboration

Medscape &

It's an exciting time to be treating people with migraine. The past several years have seen a profusion of new migraine treatment options, and clinicians have more choices to offer patients than ever. In addition to acute and preventive therapies targeting calcitonin gene-related peptide (CGRP) receptors — one of the neurotransmitters involved in migraine generation and perpetuation — there are acute treatments in other medication classes as well as a remote electrical neuromodulation (REN) device recently approved by the US Food and Drug Administration (FDA).

With all of these choices, how should clinicians go about determining what's right for their patients? Here's an overview of the latest treatments and what physicians might consider before recommending them.

New Acute Therapies

Several new options for acute treatment have been approved by the FDA in the past few years. These include two small-molecule antagonists to the CGRP receptor (gepants), ubrogepant and rimegepant; a 5-HT1F receptor agonist (ditan), lasmiditan; a liquid formulation of celecoxib (Elyxyb) now FDA-approved specifically for migraine; and a REN device, Nerivio (Theranica; Montclair, New Jersey).

Among the gepant medications, ubrogepant is available as a 50 mg or 100 mg tablet, and a dose may be repeated after 2 hours. Rimegepant is a 75 mg orally disintegrating tablet that can be taken once per 24-hour period. Both medications showed effectiveness for acute treatment of migraine pain and most bothersome symptoms in randomized clinical trials. Roughly 19%-21% of participants who took ubrogepant or rimegepant reported pain freedom at 2 hours compared with 11%-14% of the placebo group. These medications are typically very well tolerated, with nausea, somnolence, and dry mouth being reported by less than 5% of the treatment group. Gepants are not believed to have vasoconstrictive properties, making them a good choice for patients with cardiovascular risk factors who need to avoid triptans (the latter are vasoconstrictive). Rimegepant also has evidence for effectiveness as a preventive as well as an acute treatment, and gepants are, so far, thought not to contribute to medication overuse to the same degree as older treatments, if at all.

Triptans, the longstanding mainstay of acute treatment for migraine, target the 5-HT1B and -D receptors, which are both antinociceptive and vasoconstrictive. In contrast, lasmiditan acts at the 5-HT1F receptor, which has antinociceptive properties but does not cause vasoconstriction. Lasmiditan is therefore another excellent acute treatment choice for patients with cardiac disease or risk factors. Post-hoc analyses of two phase 3 clinical trials that compared treatment of acute migraine with lasmiditan vs placebo found that about 30% of participants who took lasmiditan 100 mg were pain-free at 2 hours compared with just under 17% of the placebo group. Common treatment-emergent adverse events with lasmiditan include dizziness, paresthesia, somnolence, fatigue, nausea, muscular weakness, and hypoesthesia. Patients who take lasmiditan should be counseled not to drive for 8 hours after taking the drug, as safety studies showed impairment even if participants were not fully aware of their deficits.

Celecoxib was initially approved by the FDA in 1998 for treatment of arthritis pain. A recently developed oral solution of celecoxib (Elyxyb) 120 mg was studied for the acute treatment of migraine in two randomized clinical trials and showed 2-hour pain freedom in about 32%-35% of the treatment group compared with 21%-25% of the placebo group. Celecoxib has many previously documented side effects, including black box warnings for increased risk for serious cardiovascular thrombotic events; increased risk for serious gastrointestinal adverse events, including bleeding, ulceration, and perforation; and contraindication in the setting of coronary artery bypass graft surgery.

The REN device Nerivio was FDA approved for use by adults, aged 18 years or older, with acute migraine in 2019, and the clearance was expanded for adolescent use in January. A clinical trial evaluating the REN device found 2-hour pain freedom in about 37% of the group using the active device compared with just over 18% of the sham-device group. The device was generally well tolerated, with a small number of participants using the active device reporting a sensation of warmth, redness, or arm pain. The main barrier to use of the REN device is access, as neuromodulation devices are generally not covered well by insurance and the out-of-pocket cost may be prohibitive for many patients.

When Is It Time to Consider New Acute Treatments?

Although head-to-head comparisons of triptans and newer treatments have not been conducted, available clinical trial data suggest that triptans, on the whole, have a greater therapeutic effect than the newer therapies discussed here. Among all available treatments, triptans still have the largest body of evidence for both efficacy and safety. They should, therefore, continue to be considered first-line treatment in patients who need prescription acute treatment and do not have contraindications to triptans, such as cardiac disease or uncontrolled hypertension. Individual response to triptans can be idiosyncratic; often a patient will respond to a specific triptan after not responding to others. It's therefore reasonable to try two or three different triptans before switching medication classes.

Patients who do not respond to or who do not tolerate triptans, or who are unable to take them due to contraindications, should be considered for one of the newer drugs. Gepants are often the next option considered because of their relatively benign side-effect profile and the early evidence suggesting that they may not cause medication overuse headache. Rimegepant may be particularly useful in patients who prefer to use acute treatment frequently, as a recent clinical trial showed that it has a preventive effect when used every other day, rather than causing headache worsening. Nonsteroidal anti-inflammatory drugs (NSAIDs) also have a wealth of evidence for both efficacy and relative safety, and should be considered a second-line option in patients who do not have gastrointestinal, cardiac, or renal contraindications. Because lasmiditan has a similar mechanism for reducing pain but does not cause vasoconstriction, it is a good alternative to triptans in patients with cardiovascular risk factors. Patients who respond well to triptans but are no longer able to take them due to cardiac disease, or who have not responded to gepants, would be excellent candidates for lasmiditan. The REN device is a good choice for patients who prefer a nonpharmacologic treatment option or who have not responded to other treatments, and who are able to access it affordably. The gepants and lasmiditan should be avoided during pregnancy.

Preventive Drug Options

Several monoclonal antibodies to CGRP or the CGRP receptor have been FDA approved over the past few years. The first to be approved was erenumab, which targets the CGRP receptor; subsequently approved CGRP receptor monoclonal antibodies bind to the CGRP ligand itself. All are given either as subcutaneous injections or intravenously. Erenumab is available as a 70 mg or 140 mg subcutaneous injection given monthly. Fremanezumab can be given either as a 225 mg monthly subcutaneous injection or a 675 mg injection every 3 months, while galcanezumab is given as a monthly 120 mg subcutaneous injection after a 240 mg initial loading dose. Eptinezumab, the most recently approved, is given intravenously every 3 months. All of these treatments are effective for prevention of migraine, with data submitted to the FDA for approval showing a reduction of 3.2-4.7 migraine days per month in the treatment arm (0.7-2 days greater reduction compared with placebo). Approximately, 43%-62% of participants in the active arm of CGRP monoclonal antibodies trials saw a reduction in monthly migraine days of 50% or more, which is about 12%-23% more than the placebo group. CGRP monoclonal antibodies were well tolerated in clinical trials. Adverse effects include injection-site reactions, constipation, muscle aches, nasopharyngitis, and hypersensitivity reactions. The product label for erenumab has also been updated since initial release to reflect the possibility of new or worsened hypertension. Observational reports from use in clinical practice suggest that adverse events associated with CGRP monoclonal antibodies may be more common than was seen in clinical trials.

The Case for CGRP Monoclonal Antibody Therapy

Previously available oral preventive medications with good evidence for safety and effectiveness, such as propranolol, topiramate, and amitriptyline, are still considered first-line preventive treatment for migraine. This is based mostly on the fact that the older treatments have a larger body of long-term safety data, combined with limitations in access to new treatments due to cost and insurance coverage. Current guidance from the American Headache Society recommends that CGRP monoclonal antibodies be considered after two or more older preventive migraine treatments are not effective, are not tolerated, or are contraindicated. CGRP monoclonal antibodies do not interact with other medications and are particularly good choices in patients with polypharmacy. The half-life of CGRP monoclonal antibodies is roughly 1 month on average, which leads to both the benefit of convenient monthly or quarterly dosing and the drawback of potential persistence of adverse effects for some time after stopping treatment. CGRP monoclonal antibodies therefore may be a high-priority choice for patients who do not like to take daily medications, but would rank lower for patients who are concerned about the possibility of prolonged adverse effects. In patients with chronic migraine who have not responded to two or more older preventive treatments, either onabotulinumtoxinA (Botox) or a CGRP monoclonal antibodies can be considered. CGRP monoclonal antibodies tend to be faster in onset than onabotulinumtoxinA and involve fewer injections, but onabotulinumtoxin A has a low likelihood of producing systemic adverse effects. Determining the order in which to try these two treatments often comes down to patient preference. Due to lack of pregnancy safety data and theoretical concerns related to the role of CGRP in preventing gestational hypertensive disorders, CGRP monoclonal antibodies should be avoided during pregnancy and should be stopped within 5 to 6 months (or 5 1/2 half-lives) prior to pregnancy in order to allow a washout period.

While several exciting new options have expanded the treatment landscape for migraine, they do not replace older, established choices. Cost and access are important factors for many patients, and future studies describing long-term safety as well as comparative effectiveness will help guide treatment decision-making in the future.

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