Since first introduced, anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies and CGRP antagonists (gepants) have had a transformative impact on migraine management, both preventive and abortive.

“CGRP-targeted therapies represent one of the strongest biologically precise additions to the migraine toolbox in decades,” Shaheen Lakhan, MD, PhD, a neurologist and researcher based in Miami, told Medscape Medical News.

“They have not been a universal or magical fix, but they have meaningfully improved outcomes for many patients who previously cycled through nonspecific preventives with poor tolerability. Just as important, they have reinvigorated mechanism-driven migraine care and accelerated a new wave of targeted therapeutic development,” Lakhan said.

As use of CGRP-targeted therapies expand, the clinically important remaining uncertainties are about safety and efficacy in special populations such as children and pregnant or lactating women, sequence and switching strategies after one agent fails, and postmarketing pharmacovigilance signals.

Are CGRP Agents Safe and Effective in Pediatric Patients?

With CGRP-targeted therapy now an established option in adults with migraine, research is underway to determine their safety and efficacy in children, with some reassuring readouts.

In an open-label pharmacokinetics clinical trial, 28 children and adolescents aged 6-17 years with migraine received weight-adjusted intravenous infusions of eptinezumab at doses designed to match the exposure from a 300-mg dose in adults.

Eptinezumab was generally well tolerated, with no new safety signals observed relative to those observed in adults. The most common treatment-related adverse event was orthostatic hypotension, reported in three adolescents (11%). Improvement in migraine-associated disability was observed after a single infusion in both the age groups (6-11 years and 12-17 years).

Last August, the FDA expanded the indication for fremanezumab to include pediatric patients aged 6-17 years with episodic migraine, a decision based on early results from the phase 3 SPACE trial.

In the trial, fremanezumab 120 mg and 220 mg monthly led to greater reductions in monthly migraine days and higher response rates among patients aged 6-17 years than placebo. Treatment for 3 months was also associated with fewer days of moderate-to-severe headache and a decreased use of acute migraine medication, as reported by Medscape Medical News.

Ongoing randomized, placebo-controlled trials for several CGRP pathway treatments in patients younger than 18 years will provide more data on safety and efficacy.

Lakhan told Medscape Medical News that pediatric adoption of CGRP-targeted therapies is “progressing in a careful, data-led way, which is exactly how it should unfold for a newer biologic pathway.”

“Early approvals and trial results are encouraging, particularly for patients with substantial disease burden, but we still want deeper longitudinal safety and developmental data,” Lakhan said.

He expects labeling to continue expanding as more pediatric trials report out and regulators gain confidence with longer follow-up. “The direction is forward, but appropriately measured rather than rushed,” Lakhan said.

Are CGRP Inhibitors Safe for Pre- and Postnatal Use?

Pregnant and lactating women were often excluded from pivotal migraine trials — which is a limitation given that migraine is significantly more common in women than in men.

In terms of pregnancy exposure, a global pharmacovigilance analysis of erenumab, galcanezumab, and fremanezumab did not identify signals for specific maternal toxicities, major birth defects, or disproportionate reporting of spontaneous abortion. The authors cautioned, however, that report counts are limited and surveillance must continue.

As for lactating women, a recent pharmacokinetics study of ubrogepant in human breast milk also provided a reassuring signal of safety. Researchers enrolled 12 adult women who were 1-6 months postpartum and gave each a single 100-mg dose of oral ubrogepant.

Results showed < 0.02 mg of ubrogepant was excreted in breast milk over a 24-hour period. The minimal transfer into breast milk was not considered clinically relevant according to the authors, but they cautioned that because “only a single dose of ubrogepant was tested, no definite conclusions can be drawn about the impact of repeated dosing on milk transmission,” and that the limited sample size may not have adequately captured interindividual variability.

If One CGRP Agent Fails, Should You Try Another?

A common question in tertiary headache clinics is what to do in the case of nonresponse or loss of response to the first CGRP pathway monoclonal antibody.

A recent retrospective cohort study found that switching to another CGRP monoclonal antibody helped at least some patients, with median monthly headache days improving from 27 at baseline to 21 at month 3 on the second agent. Changing the target (CGRP vs the receptor) did not seem to matter, nor did the number of previous doses of the first monoclonal antibody.

The FINESSE trial evaluated the real-world efficacy of fremanezumab in patients with prior treatment failure with another monoclonal antibody targeting CGRP. In 153 patients who did not see relief with erenumab or galcanezumab, switching to fremanezumab led to a 50% or greater reduction in the number of days with migraine per month in 43% of patients.

“Switching is often clinically reasonable and can be productive,” Lakhan told Medscape Medical News.

“Even though these drugs sit under the same CGRP umbrella, they differ in target, structure, pharmacokinetics, delivery, and patient tolerability. Clinical response is not uniform across the class. It is very similar to how we manage antidepressants, where multiple agents act on serotonergic systems but individual patients respond quite differently. A thoughtful within-class switch, after an adequate trial, is consistent with current real-world practice,” Lakhan noted.

How long to wait before switching? Three-month evaluation points have typically been used in retrospective and real-world studies to assess response after switching. However, formal evidence to define an optimal trial duration before switching is lacking or heterogeneous, and some experts advocate waiting longer (roughly 6 months) in some cases before concluding lack of efficacy.

Are There Any New Postmarketing Safety Signals?

CGRP-targeted therapies are still relatively new, making postmarketing safety surveillance critically important.

In general, postmarketing studies have reported adverse event profiles largely consistent with the clinical trials, although a number of “disproportionality” signals for certain events have been noted. One is Raynaud phenomenon, a vascular condition characterized by episodic vasoconstriction.

A 2025 analysis using the FDA’s Adverse Event Reporting System revealed “significant signals of disproportionate reporting” for Raynaud phenomenon in association with CGRP agents approved for migraine treatment or prevention, including fremanezumab, galcanezumab, erenumab, rimegepant, ubrogepant, and atogepant. Triptans, such as sumatriptan, zolmitriptan, rizatriptan, and eletriptan, along with propranolol hydrochloride and celecoxib, also exhibited significant signals of disproportionate reporting.

The authors cautioned that further study is needed to validate this signal and determine whether the association is causal or due to confounding factors.

Previous case reports have also described new-onset or worsening Raynaud phenomenon with CGRP monoclonal antibodies. In one report, a 45-year-old woman with chronic daily headache with migraine features developed Raynaud phenomenon after receiving treatment with a CGRP receptor antagonist.

A separate report described two patients with migraine who experienced an exacerbation of Raynaud phenomenon while taking CGRP monoclonal antibodies (fremanezumab and galcanezumab) and one case of new-onset Raynaud phenomenon while taking the CGRP receptor antagonist erenumab.

And in a cohort study of 169 adults with Raynaud phenomenon, nine patients had microvascular complications after CGRP antagonist use. Two of the nine patients had severe adverse events, including digital autonecrosis that required distal amputation.

The authors advised that while microvascular complications are “uncommon” in patients with Raynaud phenomenon who are taking CGRP antagonists, “the incidence of adverse microvascular events with high morbidity warrants caution in prescribing CGRP antagonists in these patients.”

Given that CGRP is a potent, protective vasodilator that helps regulate blood pressure and protects against ischemic damage, blocking this pathway may carry cardiovascular risk. However, real-world data on potential cardiovascular events with CGRP agents have been reassuring.

A large Medicare-based cohort study found no increased risk for heart attack, stroke, hypertensive crisis, or peripheral revascularization (or Raynaud phenomenon) when anti-CGRP monoclonal antibodies were compared with onabotulinumtoxinA.

Additional real-world data in older populations suggested no meaningful change in blood pressure over 12 months in patients aged 60 years or older receiving CGRP monoclonal antibodies.

What Mechanistic and Other Questions Remain?

While CGRP-targeted therapies have been transformative in migraine care, Lakhan told Medscape Medical News, “Long-term safety in special populations, including pediatrics, pregnancy, and high vascular risk groups, also remains an important area for continued surveillance and study.”

In Lakhan’s view, “the biggest unanswered question is whether CGRP-pathway therapies are purely symptomatic controllers or whether some may be disease modifying and capable of altering migraine trajectory over time.”

“We also need better predictive tools to match the right agent or combination to the right patient rather than relying on sequential trial and error. Another frontier is state-dependent response, understanding which therapies work best at different phases of a patient’s life, comorbidity profile, or migraine cycle,” Lakhan said.