Integrating gepants into clinical practice for the acute treatment of migraine

Abstract

Objective

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.

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Plain Language Summary

Triptans are commonly prescribed and effective for acute migraine treatment, but some medical conditions prevent their use; calcitonin gene–related peptide receptor antagonists (gepants) are newer medications that are effective and well‐tolerated for both acute and preventive migraine treatment. This narrative review examined research on triptans and gepants in acute migraine treatment; gepants offer key advantages including favorable tolerability, effectiveness during both the premonitory and headache phases, no cardiovascular contraindications, and no association with medication‐overuse headache, although they have limitations related to cost, access, and drug interactions. These advantages may help optimize patient care and improve treatment adherence in real‐world settings, although direct comparison studies are needed to clarify how triptans and gepants compare in effectiveness.

Abbreviations

5‐HT

5‐hydroxytryptamine

AE

adverse event

CGRP

calcitonin gene–related peptide

CVD

cardiovascular disease

MBS

most bothersome symptom

MOH

medication overuse headache

NMA

network meta‐analysis

NNT

number needed to treat

PRN

as needed

QALY

quality‐adjusted life year

INTRODUCTION

Acute treatments for migraine aim to relieve pain and symptoms, restore function, reduce disability, and prevent progression; they should be offered to all patients with a confirmed diagnosis of migraine. ¹ Effective options include both nonspecific and specific treatments. Nonspecific acute treatments include certain NSAIDs, simple analgesics (aspirin, acetaminophen), and combination analgesics, among other classes; whereas migraine‐specific treatments include ergot derivatives, triptans, lasmiditan, and gepants (calcitonin gene–related peptide [CGRP] receptor antagonists). ¹ , ² , ³ Although newer medications for the acute treatment of migraine offer safe and effective options for those with the disease, appropriate integration of these new medications into practice remains challenging.

Some NSAIDs have established efficacy and are recommended for the acute treatment of migraine ¹ ; they also carry black box warnings because they increase the risk of cardiovascular events. ⁴ , ⁵ , ⁶ Serious gastrointestinal adverse events (AEs), such as bleeding, perforation, and ulceration, have also been reported with NSAID use. ⁷ Patient history, comorbidities, advanced age, and concomitant medications should be considered when NSAIDs are prescribed in clinical practice. ⁴

Triptans have established efficacy and are widely prescribed for the acute treatment of migraine. ¹ , ⁸ They should be offered as a first‐line treatment when safety and tolerability do not preclude their use. ¹ However, there is limited evidence supporting administration of triptans during the prodrome phase. In a single‐arm, open‐label study, administration of naratriptan during the prodrome phase appeared to reduce the occurrence of subsequent headaches. ⁹ However, the study lacked a placebo control group. Some patients with migraine may discontinue triptans due to inadequate or inconsistent pain relief or due to tolerability issues. ¹ Others may not initiate triptans because of cardiovascular contraindications or precautions. ¹

Ditans, serotonin 5‐HT_1F (5‐hydroxytryptamine) receptor agonists, are a class of neural, non‐vasoconstrictive treatments for migraine, represented in practice by the approved medicine lasmiditan. ¹⁰ Lasmiditan is an option for those who are unable to use triptans due to cardiovascular concerns. ¹¹ , ¹² Lasmiditan is a controlled substance (schedule V) ¹³ and has a warning of driving impairment. ¹⁴ The central nervous system distribution of 5‐HT_1F receptors may explain central nervous system–related AEs, although this may bring added efficacy for some patients. ¹⁵ , ¹⁶ , ¹⁷

Gepants are small‐molecule CGRP receptor antagonists that represent a novel class of migraine medication. ¹⁸ There are four gepants with regulatory approval for the treatment of migraine in the United States. Two are acute treatments only (ubrogepant, the first gepant approved for the acute treatment of migraine, and zavegepant); one is a preventive treatment only (atogepant); and one is both an acute and a preventive treatment (rimegepant). ¹⁹ , ²⁰ , ²¹ , ²² , ²³ Their demonstrated efficacy, tolerability, safety, and lack of cardiovascular contraindications may address some of the management gaps associated with triptans. ²⁴

The objective of this narrative review is to evaluate the emerging role of gepants in the acute migraine treatment landscape by discussing the mechanisms of action and clinical trial data for gepants and triptans and reviewing considerations for clinical decision‐making. We also consider the results of a recent network meta‐analysis summarizing efficacy data for triptans and gepants. ²⁵

MECHANISMS OF ACTION OF GEPANTS AND TRIPTANS

Mechanisms of action

The pathophysiology of migraine is complex; the available evidence implicates altered function in brain sensory processing with involvement of the trigeminal somatosensory system, among other pathways. ²⁶ CGRP, a potent peptide vasodilator and neurotransmitter in the trigeminal sensory system involved in the pathogenesis of migraine, is released by activated trigeminal ganglion cells. ²⁶ The expression of CGRP has been observed in both the central and peripheral nervous systems. Gepants have high affinity for CGRP receptors, lower affinity for the amylin 1 receptor, and still lower affinity for the adrenomedullin 1 and 2 receptors. ¹⁸

In contrast, triptans are agonists of 5‐HT_1B/1D receptors. ²⁷ Many triptans have moderate‐to‐high affinity for 5‐HT_1B receptors found on meningeal, cerebral, and cardiac blood vessels, accounting for their action as vasoconstrictors; some have affinity for 5‐HT_1F receptors. Additionally, the localization of 5‐HT_1B, 5‐HT_1D, and 5‐HT_1F receptors within the trigeminal nerve endings and in the trigeminal cervical complex supports the hypothesis that stimulation of these receptors by triptans inhibits the release of neuropeptides, including CGRP, and consequently reduces nociceptive transmission. ²⁶ , ²⁸

CLINICAL TRIALS OF GEPANTS

Gepants for the acute treatment of migraine

Ubrogepant

ACHIEVE I ²⁹ and ACHIEVE II ³⁰ were pivotal randomized, placebo‐controlled phase 3 trials that evaluated the efficacy and safety of ubrogepant. Participants with moderate‐to‐severe cardiovascular risk factors, as defined by the National Cholesterol Education Program guidelines, were eligible for these trials. Eligible participants were aged 18–75 years with a history of migraine with or without aura for at least 1 year who had experienced two to eight migraine attacks with moderate‐to‐severe headache pain in each of the 3 months prior to screening; randomization was stratified based on previous response to triptans and current use of preventive medications. Data from these studies showed that both the 100‐mg and 50‐mg ubrogepant doses resulted in significant improvements relative to placebo in the coprimary endpoints of pain freedom and freedom from the most bothersome symptom 2 h postdose. ²⁹ , ³⁰ Pain relief rates were also significantly higher for both doses. A pooled analysis of the dose common to these two studies, ubrogepant 50 mg, showed similar statistically significant results on these endpoints. ³¹ Both ACHIEVE I and II allowed patients initially dosed with 50 mg to re‐dose either with another ubrogepant 50 mg tablet or placebo. Of those re‐randomized to a second active dose, a significantly higher proportion became pain‐free 2 h later compared with those who received placebo. ³² Additional results are listed in Table 1. Although the pooled analysis of phase 3 ubrogepant trials focused on the 50 mg dose, similar results were observed with ubrogepant 100 mg in ACHIEVE I. ²⁹ In a separate post hoc analysis of ACHIEVE I and II, proportions of participants with the ability to function normally with no disability were higher with ubrogepant compared with placebo 2 h postdose and at subsequent time points. ³³ In addition, the most common AEs reported in ACHIEVE I and II were nausea (1.9% for ubrogepant vs. 1.8% vs. placebo), dizziness (1.2% vs. 1.1% for ubrogepant vs. placebo), and somnolence (0.7% vs. 0.6% for ubrogepant vs. placebo). ³¹

TABLE 1.

Results from randomized controlled trials of gepants in the acute treatment of migraine attacks. ³¹ , ⁴² , ⁴⁹

Endpoints	Efficacy Endpoints
	Pain freedom at 2 h, %	Absence of MBS at 2 h, %	Pain relief at 2 h, %	Sustained pain freedom (2–24 h), %	Sustained pain relief (2–24 h), %	Absence of associated symptoms at 2 h, %
Ubrogepant (pooled mITT population from 2 RCTs: placebo, n = 912; ubrogepant 50 mg, n = 887)
Ubrogepant 50 mg	20.5	38.7	61.7	13.6	36.5	Photophobia: 42.3 Phonophobia: 55.9 Nausea: 70.8
Placebo	13.0	27.6	48.7	8.4	20.9	Photophobia: 33.4 Phonophobia: 46.7 Nausea: 66.1
p value	<0.001	<0.001	<0.001	<0.001	<0.001	Photophobia: <0.001 Phonophobia: <0.001 Nausea: 0.06
Rimegepant (pooled from 4 RCTs with 3827 participants)
Rimegepant 75 mg	20.6	36.0	58.6	22.1	47.1	Photophobia: 35.5 Phonophobia: 40.1 Nausea: 50.3
Placebo	12.5	25.1	44.6	12.3	29.4	Photophobia: 23.9 Phonophobia: 29.1 Nausea: 44.7
p value	<0.001	<0.001	<0.001	0.001	<0.001	Photophobia: <0.001 Phonophobia: <0.001 Nausea: 0.001
Rimegepant RCT (rimegepant 75 mg, n = 666; placebo, n = 674)
Rimegepant 75 mg	20	50	67	16	NA	NA
Placebo	11	36	49	8	NA	NA
p value	<0.001	<0.001	<0.001	<0.001	NA	NA
Rimegepant RCT (rimegepant 25 mg, n = 238; rimegepant 75 mg, n = 238; placebo, n = 230) a
Rimegepant 75 mg	32.4	65.1	79.0	23.1	63.4	Photophobia: 59.1 Phonophobia: 66.7 Nausea: 73.7
Placebo	13.0	50.4	56.5	6.5	31.7	Photophobia: 49.0 Phonophobia: 50.0 Nausea: 62.6
p value	<0.001	<0.001	<0.001	<0.001	<0.001	Photophobia: 0.071 Phonophobia: 0.011 b Nausea: 0.105 b
Zavegepant (efficacy analysis from 1 RCT: placebo, n = 646; zavegepant, n = 623)
Zavegepant 10 mg	24	40	59	15	41	Photophobia: 37 Phonophobia: 41 Nausea: 52
Placebo	15	31	50	10	33	Photophobia: 29 Phonophobia: 33 Nausea: 51
p value	<0.001	0.0012	NA	NA	NA	NA

Abbreviations: MBS, most bothersome symptom; mITT, modified intent‐to‐treat; NA, not available; RCT, randomized controlled trial.

^a Data for participants receiving 25 mg rimegepant are not shown because formal hypothesis testing for this group was not performed.

^b Indicates nominal p value without formal hypothesis testing.

The efficacy and safety of ubrogepant 100 mg administered during the premonitory phase (prodrome) was assessed in the PRODROME trial. ³⁴ This was a randomized, double‐blind, placebo‐controlled, phase 3 crossover trial. ³⁴ Adult participants aged 18–75 years who had at least a 1‐year history of migraine with or without aura, a history of 2–8 migraine attacks per month, and who could reliably identify prodromal symptoms were eligible for randomization. A higher proportion of qualifying prodromal events treated with ubrogepant 100 mg compared with events treated with placebo were free of moderate or severe headache over 24 h. As in previous studies, the most common AEs were nausea (5% for ubrogepant vs. 3% for placebo), fatigue (3% for ubrogepant vs. 2% for placebo), dizziness (2% for ubrogepant vs. 3% placebo), and somnolence (2% for ubrogepant vs. 1% for placebo).

Rimegepant

In four double‐blind, randomized, placebo‐controlled, phase 3 trials, participants received oral rimegepant 75 mg or placebo for the acute treatment of migraine. ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ Enrolled participants had at least a 1‐year history of migraine, were at least 18 years of age, and had 2‐8 migraine attacks of moderate or severe intensity per month. Participants for whom triptans were contraindicated (e.g., history of coronary artery disease or stroke) were eligible for these trials if they met all other study entry criteria. In all trials, rimegepant was more effective than placebo on the coprimary endpoints of pain freedom and most bothersome symptom (MBS) freedom 2 h post‐treatment. Results from pooled analyses of three of the above trials, ³⁵ , ³⁷ , ³⁸ a dose‐ranging phase 2 trial ⁴⁰ and two additional randomized controlled trials, ³⁶ , ⁴¹ are highlighted in Table 1. Additionally, in phase 3 trials of rimegepant 75 mg, higher proportions of rimegepant‐treated participants had no disability and the ability to function normally as early as 1–2 h postdose compared with placebo‐treated participants. ³⁵ , ³⁶ , ³⁷ , ³⁸ The most common AEs reported among participants who received rimegepant were nausea (1.6% for rimegepant vs. 1.0% for placebo) and urinary tract infection (1.5% for rimegepant vs. 0.8% for placebo). ⁴² Rimegepant was administered either as a tablet or an orally dissolvable tablet in these studies ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ ; these two forms are bioequivalent. ⁴³ In a recent phase 2/3 randomized, double‐blind, placebo‐controlled study of rimegepant in Japanese participants with a ≥ 1‐year history of migraine, acute treatment with rimegepant 75 mg resulted in significantly higher rates of pain freedom at 2 h postdose compared with placebo (Table 1). ⁴¹ At 2 h postdose, significantly higher proportions of participants treated with rimegepant compared with placebo experienced pain relief and return to normal function; most participants (60.5%) treated with rimegepant experienced sustained pain relief for up to 48 h postdose. ⁴¹ All on‐treatment AEs were of mild or moderate severity, and most were deemed unrelated to rimegepant. ⁴¹ The most common on‐treatment AE was nasopharyngitis (1.3% for rimegepant vs. 0.9% for placebo). ⁴¹ In a phase 4 study of rimegepant versus placebo in adults with migraine who were ineligible for triptans, a significantly higher proportion of participants experienced pain relief at 2 h postdose with rimegepant (55.9%) than with placebo (32.7%; p < 0.001). ⁴⁴ The frequency of AEs was similar between the two treatment arms (12.5% for rimegepant vs. 12.1% for placebo), and most were of mild or moderate severity. ⁴⁴

A post hoc analysis of a trial evaluating long‐term treatment with rimegepant demonstrated that as‐needed (PRN) rimegepant was well tolerated. Participants were divided into those with prior triptan failures, those who were currently using triptans, and those who were triptan‐naive. ⁴⁵ Over 52 weeks of treatment, all three groups showed improvements in migraine‐related disability, in quality of life, and in clinical global impression of change scores. At 52 weeks of treatment, high treatment satisfaction rates were observed across all triptan subgroups. ⁴⁵ Long‐term treatment with PRN rimegepant also demonstrated a favorable safety profile in participants who were concomitantly taking preventive medications for migraine; only 4.5% discontinued rimegepant due to AEs. Most AEs were mild or moderate. ⁴⁶ In participants experiencing >6 monthly migraine days at baseline, treatment with PRN rimegepant for 52 weeks resulted in a reduction of 2 monthly migraine days and an assessed benefit of 0.08 quality‐adjusted life years (QALYs). ⁴⁷ The use of rimegepant was stable over time without medication‐associated increases in the frequency of migraine. ⁴⁷ Long‐term treatment with PRN rimegepant was also associated with a reduction in the mean number of days with acute migraine medication use. ⁴⁸

Zavegepant

In a double‐blind, randomized, placebo‐controlled, phase 3 trial, participants were randomized to receive intranasal zavegepant 10 mg or placebo for the acute treatment of migraine. ⁴⁹ Eligible participants were at least 18 years of age, with at least a 1‐year history of migraine with or without aura and 2‐8 migraine attacks of moderate or severe intensity per month. Participants for whom triptans were contraindicated were eligible for this study if they met all other study criteria. A higher proportion of participants who received zavegepant 10 mg were free from pain and from their MBS at 2 h postdose compared with those who received placebo. Additional results are included in Table 1. The most common AEs reported for zavegepant compared with placebo were dysgeusia (21% vs. 5%), nasal discomfort (4% vs. 1%), nausea (3% vs. 1%), vomiting (1% vs. <1%), and throat irritation (1% vs. <1%).

Comparison of triptan and gepant efficacy for the acute treatment of migraine

A recent network meta‐analysis (NMA) of trials evaluating acute treatments for migraine concluded that four triptans had the most favorable efficacy profiles, outperforming newer branded products, including gepants. ²⁵ The fundamental assumption of the NMA was that adjusting for differences in placebo rates controls for differences among studies, an assumption that merits careful scrutiny. ⁵⁰ Firstly, this NMA compared triptans with gepants based on studies that were sometimes conducted decades apart. ⁵⁰ Additionally, individuals who do respond well with triptans may be less likely to participate in current trials, ⁵⁰ potentially changing the nature of the participant population in recent studies versus those from decades ago. Eligibility criteria have also shifted; most triptan trials required only one attack per month, whereas gepant trials required a higher frequency of migraine attacks. ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷ , ⁵⁸ , ⁵⁹ , ⁶⁰ , ⁶¹ , ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸ , ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷² , ⁷³ , ⁷⁴ , ⁷⁵ The primary endpoints specified by regulations also changed from 2‐hour pain relief and freedom from each of three common associated symptoms (photophobia, phonophobia, and nausea) to 2‐hour pain freedom and freedom from the participant‐designated most bothersome of these symptoms. ⁷⁶ Moreover, methods of data collection shifted from paper diaries to electronic diaries; when using an electronic diary, participants look at an illuminated screen, which may cause photophobia‐induced pain, reducing pain‐free rates. ⁵⁰ The passage of time and changes in study methods have the potential to reduce measured estimates of treatment efficacy relative to the triptan studies largely conducted in the 1990s. Under this hypothesis, we would predict that results in more recent studies of triptans would have less favorable results than historical comparisons. This prediction is supported by the development program for the rizatriptan–meloxicam combination product. In a phase 3 study, the 2‐hour pain‐free rate for rizatriptan 10 mg was only 17.4%, ⁷⁷ far lower than the meta‐analytic summary estimate for rizatriptan of 41%. ⁷⁸ Placebo subtracted differences for 2‐hour pain freedom were 10.7% for rizatriptan in recent data ⁷⁷ and 31% in a meta‐analysis of triptan‐era studies. ⁷⁸ This shift in pattern over time supports the hypothesis that older studies may not be comparable to more recent ones.

As an alternative approach to making comparisons across studies, a recent analysis that evaluated the number needed to treat (NNT) for pain freedom at 2 h with ubrogepant, rimegepant, and zavegepant found that the NNTs for gepants ranged from 9 to 12 and were comparable to those for NSAIDs (7–11) but higher than NNTs for triptans (2–8). ⁷⁹ Analysis based on NNT has the same limitations as other meta‐analytic summaries and is based on the hypothesis that correcting for placebo adjusts for differences among studies, an assumption that is at odds with the evidence as outlined above.

Given that head‐to‐head trials are the gold standard for comparative effectiveness, ⁸⁰ we examined three studies that directly compared a triptan and a gepant; two of these studies had a parallel group design, and one study had an adaptive design. All three were conducted 10–15 years ago. ⁴⁰ , ⁷⁴ , ⁷⁵ Only one of these studies evaluated a marketed gepant; this phase 2 dose‐ranging study used an adaptive design, and multiple doses of rimegepant were compared with placebo. ⁴⁰ Sumatriptan 100 mg was included as an active control. Although not designed for this purpose, the study provided an opportunity to compare rimegepant 75 mg with sumatriptan 100 mg (Figure 1). Pain‐free rates at 2 h were 31% for rimegepant 75 mg (N = 86) and 35% for sumatriptan 100 mg (N = 100). Although limited by sample size and the adaptive design, these data showed no differences between rimegepant and sumatriptan in efficacy at 2 h. The most commonly reported AEs with sumatriptan were nausea (2%), dizziness (1%), vomiting (1%), paresthesia (2%), and chest discomfort (2%). With rimegepant 75 mg, the most commonly reported AEs were nausea (3%), dizziness (1%), and vomiting (2%).

FIGURE 1.

Efficacy outcomes for sumatriptan 100 mg and rimegepant 75 mg. ^{40 a}Number of participants who completed the study. Note that this was an adaptive trial, conducted primarily for dose ranging and not to compare efficacy of rimegepant and sumatriptan. [Color figure can be viewed at wileyonlinelibrary.com]

In a phase 3 randomized, double‐blind, placebo‐ and active‐controlled, parallel‐group study, telcagepant 150 mg and 300 mg were compared with placebo and zolmitriptan 5 mg. ⁷⁴ The authors concluded that the “efficacy of telcagepant 300 mg and zolmitriptan 5 mg were much the same. (p. 2115)” Telcagepant 300 mg and zolmitriptan did not differ in any of the primary or secondary endpoints, including pain freedom at 2 h, pain relief at 2 h, no phonophobia at 2 h, no photophobia at 2 h, no nausea at 2 h, and 2–24 h sustained pain freedom. The most commonly reported AEs within 14 days were dizziness (11%), dry mouth (8%), and fatigue (7%) with zolmitriptan; and dry mouth (5%–6%), somnolence (4%–5%), and dizziness (4%–5%) with telcagepant.

In a phase 2 randomized, double‐blind, double‐dummy, placebo‐ and active‐controlled, parallel‐group, dose‐finding study, the safety and efficacy of three doses of BI 44370 TA, an orally available CGRP antagonist that was previously in development, were assessed. ⁷⁵ Eletriptan 40 mg was included in the study as an active comparator. Pain‐free response at 2 h was 27% for BI 44370 TA 400 mg and 35% for eletriptan. The most common AEs reported were fatigue (4%) and oropharyngeal pain (3%) with eletriptan, and diarrhea (1%–3%) and influenza (2%–3%) with BI 44370 TA.

For the available head‐to‐head trials, triptans were included as an active comparator to establish that the trial design was sensitive to treatment effects of a known, effective active treatment (the triptan), usually in the context of dose optimization. They were not designed to test the comparative effectiveness of a gepant versus a triptan.

Nonetheless, taken together, the studies suggest at most modest differences in efficacy between triptans and gepants. While awaiting adequately powered, specifically designed comparative effectiveness trials, clinicians must formulate treatment recommendations based on available data.

CONSIDERATIONS FOR CLINICAL DECISION‐MAKING

For optimal acute treatment of migraine, an accurate diagnosis must be established. ¹ Treatment choice is then informed by the patient's migraine symptom profile, preferences for treatment attributes including efficacy and tolerability, cardiovascular risk factors, risk for medication‐overuse headache, and prior experience with acute treatments.

Safety

Despite their efficacy, real‐world evidence from the US Food and Drug Administration Adverse Event Reporting System database documents side effects associated with triptans involving gastrointestinal, cardiac, respiratory, and nervous systems. ⁸¹ Triptans are associated with vasoconstriction, albeit they were developed to be “cerebroselective” and have been associated with adverse cardiovascular events. ⁸² Therefore, triptans are contraindicated in those with symptomatic cardiovascular disease (CVD), including coronary artery disease, history of stroke or transient ischemic attack, peripheral vascular disease, and uncontrolled hypertension. ⁸³ , ⁸⁴ In the American Migraine Prevalence and Prevention study, 13.1% of respondents with episodic migraine reported at least one cardiovascular event, condition, or procedure that would contraindicate triptan use. ⁸⁵ Additionally, certain triptans have been associated with an unfavorable tolerability profile. Common, but usually mild and brief acute AEs associated with triptans include paraesthesia, flushing, and palpitations. ³ In a claims database analysis of more than 230,000 individuals with migraine, more than 20% of commercially‐insured patients with migraine had a cardiovascular condition that contraindicates the use of a triptan, and an additional 25% had at least two cardiovascular risk factors identified as warnings and precautions to triptans. ⁸⁶ In contrast, gepants are not associated with the constriction of blood vessels and, therefore, CVD is not a contraindication and CVD risk factors are not a precaution. ⁸⁷ Although transaminitis and hepatotoxicity were reported with first‐generation gepants, these have not been an issue with the currently approved later‐generation gepants. ⁸⁸ Rimegepant, ubrogepant, and zavegepant are contraindicated in individuals with a history of hypersensitivity to the treatment or any of its components. ¹⁹ , ²⁰ , ²² Ubrogepant and rimegepant are also contraindicated or advised to avoid concomitant use with strong CYP3A4 inhibitors. ¹⁹ , ²⁰ Moreover, new onset or worsening of preexisting hypertension or Raynaud's phenomenon may occur with gepants. ¹⁹ , ²⁰ , ²² In a network meta‐analysis of 76 studies of acute migraine therapies, triptans were associated with a higher incidence of AEs than gepants. ⁸⁹ As such, a study of the number needed to harm comparing triptans with other acute migraine therapies may provide additional guidance on treatment selection. Direct comparisons of tolerability and safety in head‐to‐head studies are also preferred.

Medication‐overuse headache

It is believed that pronociceptive neuroadaptive changes may be caused by prolonged exposure to some receptor agonists. ⁹⁰ These changes include receptor desensitization and downregulation of functional receptors, as well as increased expression of CGRP. ⁹⁰ , ⁹¹ These phenomena are linked especially to agonists of G‐protein–coupled receptors such as triptans. ⁹⁰ , ⁹² The resulting alterations in neural processing may contribute to the development of medication‐overuse headache (MOH) by heightening hypersensitivity in brain circuits implicated in migraine. ⁹¹ , ⁹³ Animal studies have been valuable in understanding MOH. ⁹⁴ , ⁹⁵ , ⁹⁶ , ⁹⁷ In rats, prolonged exposure to a high dose of sumatriptan followed by an acute noxious stimulus resulted in long‐lasting changes in descending pain modulation. Some migraine treatments may increase the risk of MOH via this, or other mechanisms linked to central sensitization. Repeated dosing of lasmiditan induced cutaneous allodynia in a rodent model of MOH, a finding consistent with peripheral and central sensitization mechanisms of MOH. ⁹⁵ , ⁹⁷ Another rodent study showed that receptor antagonists do not appear to induce MOH‐like hypersensitivity. ⁹⁶ The study also demonstrated that repeated treatment with ubrogepant did not induce latent sensitization or cutaneous allodynia. However, findings in rodent models are imperfect in predicting responses in humans.

Reduction in monthly migraine days in humans has been observed with frequent acute dosing with rimegepant once daily as needed for up to 52 weeks ⁴⁷ and demonstrated with every other day use of rimegepant and once‐daily use of atogepant, suggesting that gepants are not associated with MOH. ⁴⁷ , ⁹⁸ Additionally, in studies of preventive treatment of migraine with CGRP receptor‐targeting monoclonal antibodies, prolonged CGRP antagonism was associated with a reduction in migraine and in headache days, not an increase as would be predicted if these agents caused MOH. ⁹⁹ , ¹⁰⁰ , ¹⁰¹ Overall, the available evidence does not indicate that gepants induce MOH. Real‐world evidence suggests that initiation of rimegepant therapy may reduce opioid and barbiturate use, both of which are associated with MOH. ¹⁰² , ¹⁰³ A US insurance claims database analysis conducted from September 2019 through March 2023 demonstrated a significant reduction in opioid use following initiation of treatment with rimegepant, as indexed by the number of prescription refills and average dispensed morphine milligram equivalents, with approximately 38% of patients discontinuing opioid therapy. ¹⁰² Significant reductions in the utilization of butalbital were observed as measured by the number of prescription refills, quantity of medication dispensed, and duration of use; approximately 48% of butalbital users discontinued opioid therapy. ¹⁰² However, additional longitudinal studies are required to validate these findings.

Consideration of vascular risk

Because gepants block CGRP, a potent vasodilator, a potential risk for cardiovascular events was proposed. ¹⁰⁴ This notion was supported by a study of cerebral blood flow in individuals with episodic or chronic migraine being treated with CGRP monoclonal antibodies. In responders, cerebral blood flow velocity was reduced, suggesting an increased risk for developing stroke. ¹⁰⁵ In a mouse model of cerebral ischemia, single and chronic doses of olcegepant appeared to inhibit cerebral blood flow. ¹⁰⁴ In addition, trigeminovascular dilation, which is partially mediated by CGRP, plays an essential role in acute stroke. ¹⁰⁵ However, CGRP‐targeted agents do not appear to affect cerebral hemodynamics in humans ¹⁰⁶ ; there is no evidence that gepants cross the blood–brain barrier to a significant extent, and their impact on cerebrovascular function is unknown. ¹⁰⁵ Randomized controlled trials of gepants did not demonstrate elevated risk for cardiovascular events. In a phase 2/3 open‐label study of rimegepant in participants with cardiovascular risk factors, rimegepant was shown to be safe over a 1‐year period, even in participants with moderate or high cardiovascular risk. ¹⁰⁷ The incidence of hypertension was low (0.8%–1.8%) across all cardiovascular risk subgroups and there were no cases of myocardial infarction. ¹⁰⁷ Cardiovascular events (angina pectoris, hemiplegia, hemiparesis, and ischemic colitis) occurred in four participants. In a participant who developed ischemic colitis, the investigator thought the event was possibly related to rimegepant leading to treatment discontinuation. ¹⁰⁷ Real‐world evidence from the VigiAccess and US Food and Drug Administration Adverse Event Reporting System databases indicated the occurrence of cardiac events with rimegepant, ubrogepant, and atogepant, with the strongest signal for atogepant. ¹⁰⁸ Although pretreatment levels of cardiovascular risk factors, reporting bias, and polypharmacy may be confounding factors in real‐world analyses, additional long‐term studies and continual monitoring for cardiovascular events in patients prescribed gepants for migraine are warranted. ¹⁰⁸ It is recommended that gepants should be avoided in the setting of acute stroke and for a period of time thereafter; restarting gepant therapy can be considered for an individual after a thorough risk–benefit assessment. ¹⁰⁵ The use of gepants should also be avoided in those with small vessel disease or distal/intracerebral stenosis. ¹⁰⁵ In individuals with migraine aged 65 years or older who have a history of stroke, restarting gepant therapy should be approached with caution. ¹⁰⁵ Gepants may not be suitable for individuals aged 65 years or older with hypertension, although this requires a judgment about risk and benefits. ¹⁰⁵ However, if deemed necessary, the use of gepants with shorter half‐lives is recommended. ¹⁰⁵

Economic considerations and healthcare barriers to the use of gepants

Although the cost of gepants is markedly higher than the cost of triptans, acute treatment with gepants is warranted for patients with migraine who do not respond to triptans. ¹⁰⁹ , ¹¹⁰ A systematic literature review conducted by the Institute for Clinical and Economic Review (ICER) found that ubrogepant and rimegepant were more effective and cost less than lasmiditan for patients who were ineligible for triptan therapy. Another analysis found that zavegepant was more cost‐effective than rimegepant for acute migraine treatment, with an incremental cost‐effectiveness ratio of $67,914 per QALY gained, which was below the incremental cost‐effectiveness ratio threshold of $100,000 per QALY gained. ¹¹¹ In light of the higher costs of gepants versus triptans, efforts should be made to increase access to and lower the costs of gepants for patients with migraine for whom triptans are ineffective or are contraindicated. ¹⁰⁹ Furthermore, for patients with chronic migraine, the direct costs of CGRP‐targeted therapies should be considered in the context of reducing overall healthcare resource utilization and improving treatment adherence. ¹¹²

The role of gepants in the migraine treatment landscape

For individuals with migraine who are naive to triptans and gepants, triptans are a first‐line treatment option in the absence of contraindications or concerns about medication‐overuse headache. In those with CVD contraindications, a gepant or lasmiditan may be a better acute treatment option. The medium‐term safety of gepants, including cardiovascular safety, has been supported in extension trials. ¹¹³ , ¹¹⁴

Among triptan‐exposed patients with migraine, some may discontinue triptans due to lack of efficacy or tolerability concerns. ⁸ Globally, triptan discontinuation rates range from approximately 44% to 66%. ¹¹⁵ Of those who use triptans, approximately 18% to 44% discontinue treatment due to a lack of effect or an insufficient response. ¹¹⁵ Compared with those who have a response to triptans, those who have an insufficient response have higher migraine‐related healthcare resource use and costs, worse health‐related quality of life, and higher work productivity burden. ¹¹⁶ The American Headache Society consensus statement recommends trying ≥2 oral triptans before switching to a different medication class. ¹ However, findings from a claims study suggest that a second triptan is rarely tried after inadequate response to initial triptan treatment in real‐world clinical practice; over 12 months, only 9.3% of patients with migraine received a second triptan, and this number rose to only 13.2% over 24 months. ¹¹⁷ Despite guidelines recommending against the use of opioids for the treatment of migraine, ¹¹⁸ 53% of patients who did not refill their initial triptan prescription filled ≥1 opioid prescription over the subsequent 24 months. Together, these results highlight the lack of efficacy and tolerability concerns that may be associated with triptans.

Because triptans and gepants have distinct mechanisms of action, ¹¹⁹ , ¹²⁰ responses to these medication classes are somewhat independent. A post hoc analysis of pooled data from the two pivotal trials of ubrogepant evaluated the efficacy and safety of ubrogepant 50 mg in participants with triptan failures. ¹²¹ Within the subgroup of participants who reported insufficient efficacy with previous triptan use, ubrogepant demonstrated significant benefits versus placebo in rates of pain freedom (15% vs. 6%; p = 0.011), absence of MBS (35% vs. 21%; p = 0.005), and pain relief (55% vs. 40%; p = 0.015) at 2 h. Another analysis of pooled data from three clinical trials demonstrated rimegepant 75 mg was efficacious in achieving pain freedom and absence of MBS in participant subgroups with and without previous triptan treatment failure. ¹²² These findings demonstrate that gepants can be effective for those who have experienced inadequate efficacy from triptans. Finally, notably, there is no contraindication to combining gepants with other classes of acute medications for migraine. ¹⁹ , ²⁰ , ²²

The standard of care for acute treatment is to treat early in the attack while pain is mild. ¹²³ Data for the treatment of mild pain with ubrogepant comes from post hoc analyses of long‐term open‐label studies. ¹²⁴ Ubrogepant has demonstrated higher 2‐hour pain freedom rates for the treatment of attacks with mild pain (47% for ubrogepant 50 mg and 55% for ubrogepant 100 mg) versus treatment of attacks with moderate or severe pain (24% for ubrogepant 50 mg and 26% for ubrogepant 100 mg). ¹²⁴ Higher pain‐free rates occurred within person for attacks treated when pain was mild versus those treated when pain was moderate or severe (50% vs. 26% for ubrogepant 50 mg and 58% vs. 33% for ubrogepant 100 mg). ¹²⁴ Additionally, ubrogepant treatment during the prodromal phase of a migraine attack may effectively relieve prodromal symptoms and has been shown to prevent the development of headache. ³⁴ , ¹²⁵ Moreover, medications with nonoral routes of administration, such as zavegepant, sumatriptan, or zolmitriptan, may particularly benefit those whose needs are not met by oral medications ⁴⁹ , ¹²⁶ , ¹²⁷ ; these groups include patients whose migraine attacks rapidly accelerate in pain intensity, those with prominent nausea or vomiting, and those who have an inadequate response to oral treatments. ¹

Preventive treatment should be considered for individuals with migraine receiving acute treatment who still have ≥4 headache days per month (regardless of disability) or who are overly reliant on acute treatments. ¹ The specific preventive treatment recommended for migraine is very individualized and dependent on several factors, including the individual's comorbidities, contraindications or allergies, individual preference, and concomitant medications. ¹ There are no contraindications to using triptans or gepants for the acute treatment of migraine in combination with the medications generally used for the preventative treatment of migraine. ¹ , ¹⁹ , ²⁰ , ²² , ¹²⁸ Notably, combining ubrogepant with atogepant or monoclonal antibodies targeting the CGRP receptor or ligand did not lead to clinically meaningful changes in the pharmacokinetic profile of ubrogepant and has been demonstrated to be safe. ¹²⁹ , ¹³⁰ , ¹³¹ Moreover, the TANDEM study showed that once‐daily atogepant for the preventive treatment of episodic migraine taken concomitantly with ubrogepant as needed for the acute treatment of migraine is safe and tolerable. ¹³² Topline results from the COURAGE II study, which evaluated the real‐world effectiveness of ubrogepant for the acute treatment of migraine when used concomitantly with atogepant, demonstrated high rates of meaningful pain relief within 2 h (57.5%) and within 4 h (73.4%) of treatment of acute migraine attacks with ubrogepant. ¹³³ In addition, a significant association with acute treatment optimization, high rates of treatment satisfaction (92%), and safety outcomes consistent with the known safety profiles of atogepant and ubrogepant were also reported. ¹³³ Further evaluation of combination treatment with preventive and acute gepants in large‐scale clinical trials is warranted.

CONCLUSIONS AND FUTURE DIRECTIONS

Gepants represent a novel treatment option with demonstrated clinical efficacy for the treatment of migraine. Gepants are particularly appropriate for patients who cannot use triptans as acute treatment because of contraindications, safety, or tolerability concerns; lack of triptan efficacy; or for those at risk for MOH. Due to the favorable tolerability profile of gepants, those with migraine may be more willing to treat an attack early in its course while pain is mild or during prodromes that are reliably associated with the onset of migraine headaches.

Although efficacy comparisons across clinical trials of existing acute treatment options for migraine are of clinical interest, caution should be used when comparing the results of clinical trials conducted decades apart and with extensive differences in methodology. Additionally, these comparisons exclude participants who have cardiovascular or other contraindications or poor tolerability with triptans. Key advantages of gepants include their efficacy, favorable tolerability profile, and reduced potential to produce MOH. In appropriately selected patients, these advantages may optimize patient care and lead to better persistence and efficacy outcomes in a real‐world setting. Specifically designed head‐to‐head studies are recommended to assess the comparative effectiveness of triptans and gepants.

AUTHOR CONTRIBUTIONS

Richard B. Lipton: Conceptualization; writing – original draft; writing – review and editing. David W. Dodick: Conceptualization; writing – original draft; writing – review and editing. Linda Davis: Conceptualization; writing – original draft; writing – review and editing. Stephanie J. Nahas: Conceptualization; writing – original draft; writing – review and editing. Peter J. Goadsby: Conceptualization; writing – original draft; writing – review and editing.

FUNDING INFORMATION

AbbVie funded this study and contributed to the study design; collection, analysis, and interpretation of data; and the review and approval of the final manuscript for publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.

CONFLICT OF INTEREST STATEMENT

Richard B. Lipton reports support for the present study from AbbVie; research support paid to his institution from the Czap Foundation, the National Institutes of Health, the S&L Marx Foundation, and the US Food and Drug Administration; and personal fees from AbbVie/Allergan, American Academy of Neurology, American Headache Society, Amgen, Axsome, Biohaven, Eli Lilly, GlaxoSmithKline, Grifols, Lundbeck, Merck, Pfizer, Teva, Vector, and Vedanta Research. He holds stock/options in Biohaven, CoolTech, and NuvieBio. David W. Dodick reports consulting for AbbVie, Genentech, Nocira, and Vedana; honoraria for Cambridge University Press, Oxford University Press, and Wolters Kluwer; stock options for Atria Health, AYYA Biosciences, Cephalgia Group, EigenLyfe, Epien, ExSano, Healint, Keimon Medical, King‐Devick Technologies, Man and Science, Matterhorn, Nocira, NuvieBio, Palion, and Theranica; is a shareholder in Ontologics; serves on the board of directors for Atrial Health, Cephalgia Group, EigenLyfe, King‐Devick Technologies, MigraHealth, and NuvieBio; is an employee of Atria Health; and holds the non‐royalty–bearing patent 17189376.1‐1466:vTitle: Onabotulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis. Linda Davis is a consultant and speaker for AbbVie and Eli Lilly. Stephanie J. Nahas has received honoraria for consulting from AbbVie, Amneal, Axsome, Bausch Health, Eli Lilly, Ipsen, and Pfizer; and has received honoraria for work in education or publishing from American Academy of Neurology, American Headache Society, Diamond Headache Clinic Research and Educational Foundation, MedLink Neurology, Springer, WebMD/Medscape, and Wolters‐Kluwer. Peter J. Goadsby reports consulting fees from AbbVie and, over the past 36 months, Eon Biopharma, Aurene, CoolTech LLC, Dr. Reddy's, Eli‐Lilly and Company, Epalex, Kallyope, Linpharma, Lundbeck, Orion Pharma, Pfizer, PureTech Health LLC, Satsuma, Shiratronics, and Teva Pharmaceuticals; personal fees for advice through Gerson Lehrman Group, Guidepoint, SAI Med Partners, and Vector Metric; fees for educational materials from CME Outfitters and WebMD; and publishing royalties or fees from Massachusetts Medical Society, Oxford University Press, UpToDate, and Wolters Kluwer.