Integrating gepants into clinical practice for the acute treatment of migraine

To assess the role of small-molecule calcitonin gene-related peptide receptor antagonists (gepants) in the acute treatment of migraine, particularly in relation to triptan treatments.

Triptans have established efficacy and are widely prescribed for the acute treatment of migraine. However, triptans may not be recommended for some individuals due to cardiovascular contraindications and precautions, as well as other comorbidities, and many may discontinue triptans because of inadequate or inconsistent symptom relief or poor tolerability. Several gepants are also indicated for the treatment of migraine (both acute and preventive), and their demonstrated efficacy and safety may address some challenges associated with triptans.

This narrative review addresses considerations for the acute treatment of migraine through summarizing literature and data from preclinical studies and clinical trials of triptans and gepants.

We consider triptans and gepants, where available, first-line treatment options for the acute treatment of migraine. Triptans may be prescribed in the absence of contraindications, significant risk of cardiovascular disease, or risk for or history of medication-overuse headache. In those who have contraindications or precautions for triptans, those who do not have an adequate response to triptans, and those unable to tolerate them, gepants are often an appropriate option. The efficacy and safety of gepants for the acute treatment of migraine has been established through clinical trials and open-label extension studies and based on real-world evidence. Gepants have demonstrated efficacy and tolerability in triptan insufficient responders, perhaps because of their distinct mechanisms of action. Additionally, the safety of gepants, including relative cardiovascular safety, is supported in pivotal controlled trials and open-label extension trials. In experimental settings and through their use as preventive treatment for migraine, gepants appear unlikely to produce medication-overuse headache. In addition, one gepant (ubrogepant) has demonstrated efficacy in preventing headache onset when given during the prodrome, a finding that has not been demonstrated for triptans. A single-arm, open-label study of naratriptan given during the prodrome suggested fewer subsequent headaches, but interpretation is limited because there was no contemporaneous control group. Limited head-to-head clinical trials comparing gepants and triptans have not demonstrated significant differences. Prescribers of both triptans and gepants should be mindful of potential drug-drug interactions.

Key advantages of gepants include their favorable tolerability, efficacy for the acute treatment of both the prodromal/premonitory phase (ubrogepant) and the headache phase of migraine (ubrogepant, rimegepant, zavegepant), lack of cardiovascular contraindications, and lack of association with medication-overuse headache. Disadvantages include limitations due to cost and access and CYP3A4 drug interactions for most gepants. Together, the advantages may help to optimize patient care and lead to better persistence and effectiveness in a real-world setting. Head-to-head studies are needed to clarify the comparative effectiveness of triptans and gepants.