Headache Horizons: The Promise of Dual Treatment for Migraine

Traditionally, migraine therapies have been categorized as acute or preventive. Acute treatments are taken after a migraine attack begins to relieve pain, mitigate associated symptoms, and restore function. Preventive treatments are taken whether or not a migraine attack is present to reduce the frequency and the severity of attacks.^1,2 This paradigm is now shifting with the expanded indication, in May 2021, of rimegepant for preventive migraine treatment, making it the first drug approved by the Food and Drug Administration (FDA) for both preventive and acute migraine treatment. Eptinezumab, another recently approved preventive migraine treatment, relieves acute attacks, suggesting it may also be effective for both acute treatment and prevention.³ Both rimegepant and eptinezumab target calcitonin gene-related peptide (CGRP), known to play a key role in both the acute and preventive treatment of migraine.^4,5 To understand what such a paradigm shift might mean for people with migraine and the clinicians treating them, this brief review covers acute and preventive treatment and then the emerging options of pre-emptive and dual treatment of migraine.

Acute Treatments

Virtually everyone with migraine takes an acute treatment whether or not they are taking preventive treatment.⁶ Nonsteroidal anti-inflammatory drugs (NSAIDs) have established efficacy for mild-to-moderate attacks, and triptans have been first-line treatment for moderate-to-severe attacks.² When orally administered, acute migraine treatments take 1 to 2 hours to become effective, leaving individuals with pain and inability to function for that time. NSAIDs have gastrointestinal side effects, especially with long-term frequent use. With triptans, some people have sweating, chest pressure, flushing, and tingling, making these less tolerable. Triptans are also contraindicated in individuals with cardiovascular disease and require precautions in those with cardiovascular risk factors.⁷

Most acute treatments may make headaches worse if taken too often.⁸ Excessive use of acute medications may give rise to medication-overuse headache (MOH), a secondary headache disorder.¹ The risk of headache exacerbation and the development of MOH effectively limits the number of migraine attacks a person can treat each month with many acute medications.^1,2

Ubrogepant (also a CGRP inhibitor) and rimegepant are new treatments, approved at the end of 2019 and the beginning of 2020, respectively, as acute treatments. Neither carry the risk of MOH, and both have high tolerability with somnolence (ubrogepant only) and nausea the adverse events seen most often in clinical trials. Although neither is contraindicated in those with cardiovascular risk factors, both interact with other medications, particularly inhibitors of the cytochrome P450 3A4 (CYP3A4) pathway or P-glycoprotein (P-GP) or breast cancer resistance protein (BRCP).^9,10

Preventive Treatment

Usual criteria for preventive treatment depend on multiple factors, including the frequency and disability of migraine attacks.² As many as 38% of people with migraine may need preventive treatment, but far fewer receive it.¹¹

Underutilization of preventive treatment has stemmed partly from reluctance to take daily medication for a problem that doesn’t occur daily. In addition, before 2018, all preventive treatments had been developed for conditions other than migraine (eg, beta blockers, antiseizure medications, and antidepressants). Although these agents improve the lives of people with migraine, they all also have issues of tolerability with side effects ranging from weight gain to dizziness, agitation, and cognitive dysfunction. Onabotulinum toxin A is also effective preventive treatment for chronic migraine, has few side effects, but must be administered by an experienced practitioner and requires 31 injections every 3 months.

In 2018 and 2019, the first agents developed specifically for preventive treatment were approved by the FDA. These are the monoclonal antibodies (MAbs) that inhibit CGRP, binding the receptor (like the gepants) or the CGRP ligand itself. CGRP-targeted MAbs are effective preventive treatments for many, with very few side effects (as per package inserts, injection site reactions, hypersensitivity, and occasionally, constipation or hypertension [erenumab]). They are given monthly or quarterly.

Gepants are effective as preventive treatments, with rimegepant approved as a dual treatment (see below),¹² and atogepant found effective in a clinical trial and being reviewed by the FDA for this use.¹³

Pre-emptive Treatment

Although people with migraine may be ambivalent about taking medicine on days when they do not have an active migraine, many would like a treatment to take pre-emptively—in anticipation of a likely migraine attack.^16,17 Although no pre-emptive treatment was ever approved by the FDA, this area of has been well developed for people with menstrual migraine.¹⁶ Those who have regular menstrual periods accompanied by regular migraine attacks can be pre-emptively treated from a couple of days before menstrual flow begins to a few days after. Some individuals also seek treatment prior to potentially stressful or important events (eg, a family wedding or a potentially stressful meeting)—this can be thought of as “special-occasion” treatment. In these cases, physicians sometimes prescribe treatment a day or so before and on the day of the event to reduce the probability of migraine. These pre-emptive strategies are intermediate between acute and preventive treatment. Like acute treatment, this is a when-needed approach. Like prevention, treatment is taken outside the context of an attack that has already began and may eliminate the period of discomfort while awaiting the onset of treatment effects. This is an area of promise that requires additional investigation. In particular, the use of headache apps may improve the predictability of attacks and increase the opportunity for pre-emptive intervention.^12,17

Dual Treatment

To date, only rimegepant is approved by the FDA as a dual agent for both acute and preventive treatment. As of this writing CGRP-targeted therapies are the best candidates for dual therapy. Most oral preventive treatments take time to reach efficacy, as discussed, and people using those for prevention still need a separate acute treatment for breakthrough migraine attacks.¹⁸ The converse is also true; people using certain acute treatments will need separate preventive treatment to reduce attack frequency and severity and avoid the risk of MOH.¹

With dual treatment, instead of prescribing 2 drugs, 1 as an acute treatment and another as a preventive, patients can use 1 drug in at least 2 ways. It can be used as a preventive treatment and if breakthrough migraine attacks occur, an additional dose can be taken to relieve the pain and other symptoms of that attack. For those using it as acute treatment, the conversation about overuse changes to a conversation about potentially reducing migraine attack frequency with every acute treatment. If headaches increase in frequency, for example in a period of stress, a patient may switch from acute to acute and preventive use of rimegepant for a time and switch back as the stress lifts.

Although studies are still needed, dual treatment may also improve prospects for preemptive therapy. Considering that the preventive dose is every other day but can be taken up to 18 times per month, taking a dose the day before and the day of a special occasion will make migraine attacks much less likely. The 11-hour half-life of rimegepant also supports that possibility of taking it preemptively,⁹ because it will still be present for a longer time than other acute treatments, such as triptans that have a half-life closer to 2 hours.⁷

Summary

The development of CGRP targeted therapies that are effective with very few side effects or contraindications and multiple modes of administration opened a new era for migraine with more options for people with migraine than ever before. This latest development of a dual treatment that can be used acutely when a migraine attack occurs and for reducing frequency and potentially pre-empting an attack has the potential to be a watershed moment for what is among the most prevalent neurologic conditions.