Headache Horizons: New and Emerging Acute Migraine Treatments

The Voice of Acute Migraine Attacks

If you have never seen a migraine patient in the throes of a severe acute attack, I encourage you to do so immediately—it is awful. What stands out most to me, as they limp into our drop-in headache clinic, wilted and lifeless, for intravenous treatments,—beyond their dark glasses, their makeshift emesis basins tightly clutched, and the worried look of their accompanying caregivers—are their voices: slight, distant, whispered fractions of their headache-free volume and cadence. This withered tonal expression is all I need to hear to know that this attack is bad, and they are here at my center because their acute treatment, taken before they arrived here, has failed them miserably. These suffering patients—my patients—whom I respectively submit, have honed their acute treatment chops at a facility that knows what it’s doing (we are a tertiary care clinical and research facility), still had to come in, deflated and in pain because their usual at-home remedies failed them.

Migraine Is a Play in 3 or 4 Acts

The performance, if you will, that is a migraine attack begins in the central nervous system (CNS), specifically the brain, with Act 1—the prodrome, characterized by variable combinations of fatigue, mental fogginess, food cravings, and increased yawning. For the approximately 30% of people with migraine who manifest Act 2 with aura—visual, sensory, motor, or vestibular—this also emanates from within the CNS. As you would expect, Acts 1 and 2 give rise to Act 3. Activation of trigeminocervical sensory nociceptors in the peripheral nervous system (PNS) give rise to the crushing pain, nausea, and sensitivity to light and sound. These nociceptors are small, unmyelinated (c-fibers) or sparsely myelinated (a-delta fiber) projections in the meninges, upper neck, and facial structures (eg, eyes, sinuses, and teeth. Once activated, these fibers take center stage and begin firing relentlessly. This merciless neuronal misconduct releases multiple inflammatory mediators—calcitonin gene related peptide (CGRP) plays the role of principle migraine-driving villain. These angry inflammatory mediators travel inward, back to the CNS, with first-order fibers synapsing in the trigeminal nucleus caudalis (TNC) and later-order projections heading to the thalamus, and then cortex, where the signal is interpreted as pain. Following this impressive dénouement comes the final Act 4—the postdrome, a worn-out dish-rag state of CNS ennui lasting hours to several days. Migraine then, may be thought of as both a play and a round; it is a
3- or 4- act (depending on aura) performance with a looping circle from CNS to PNS and back.

How to Stop the Show?

A generation ago the serotonin 5HT-1_b/d receptor agonists, or triptans, revolutionized the landscape for acute migraine treatment. For the first time, we had acute treatments specific for migraine resulting from rigorous double-blind placebo-controlled studies with reasonable efficacy and acceptable safety and tolerability profiles. In the heady early days of triptan launch after triptan launch, backed by the marketing might of pharmaceutical giants, many thought triptans would be the acute treatment answers to our prayers.

Except they weren’t. Accumulating literature suggested triptans, as perhaps could have been expected, worked for some, but not all, people with migraine. Although generally well tolerated, some found triptans to have intolerable side-effects or relative contraindications and others developed medication-overuse issues. When asked whether they would be willing to give up their triptan for a new medicine, a large portion of patients sampled responded with a resounding “Yes!”

Bring in the New Players

Now, as those new medicines begin to arrive, some wonder why it took so long. The short answer is, there were stumbles, mishaps, and bad luck for the better part of a decade. In 2009 a diclofenac potassium in powdered form was approved for acute treatment of migraine in adults, based on 2 randomized double-blind placebo-controlled studies that demonstrated 2-hour pain relief of 24% vs 13% with placebo, 2 to 24 hour sustained freedom from pain for 22% vs 10% with placebo, and 2-hour pain relief for 48% vs 13% with placebo. Powdered diclofenac remains on the market but limitations of insurance coverage limit access to this treatment. In 2011 clinical trials showed an inhaled form of dihydroergotamine (DHE) provided pain relief for 59% of trial participants treated and had statistical superiority to placebo in 4 coprimary outcome measures with a favorable safety and tolerability profile. So, what happened? Problems with the manufacturing plant meant development was stopped before FDA approval, and this formulation never saw the light of day.

Around this time, early work on small-molecule CGRP receptor blockers, the -gepants began and telcagepant was found superiority to placebo with comparable efficacy to rizatriptan and zolmitriptan. However, elevations in serum transaminases in several clinical trial participants led to scrapping the telcagepant and other small molecule CGRP blockers. It wasn’t until 2014 that studies began on the next wave of gepants, including ubrogepant and rimegepant, which were approved and released in late 2019 and 2020, respectively. At the same time, a novel 5HT-1_f product, lasmiditan was developed, tested, and approved in October, 2019.

Finding Your Way to the Best Show in Town

The question is: what is a headache practitioner to do, given this embarrassment of riches (Table), this bonanza of acute treatment options? As a roadmap to navigate the acute migraine care landscape, I offer the following 6 observations, gleaned from many years as both a clinical trialist and clinician.

Triptans Remain the Mainstay

The triptans, serotonin 5HT-1_b/1d receptor agonists, have made countless lives less painful, more predictable, and happier. There are 7—or as the late great Fred Sheftell used to say, 1 for every day of the week (in song, no less, for CME credit: Triptan Du Jour). But just as there is no free lunch, there is no perfect acute migraine class. As noted, nonresponsiveness, side-effects, and relative contraindications mean triptans do not fully meet the need for acute treatment.

DHE Is Underutilized for a Reason and This May Change

Intravenous or subcutaneous DHE is a mainstay in headache infusion clinics and emergency rooms. The nasal preparation, however, has issue that include product assembly, poor absorption (requiring 2 sprays, waiting, and repeating), and cost. The good news is that 2 new formulations that deliver DHE to the nasal mucosa are in development. This is welcome because DHE has characteristics that differentiate it from triptans (efficacy late in an attack).

Rapidly Absorbed NSAIDS Are Effective With More Coming

Diclofenac potassium powder, available since 2009, demonstrated good efficacy and an enviable safety/tolerability profile. For some of my patients (particularly those not enamored of triptans), this is their go-to acute treatment. Unfortunately, it can be difficult to get insurance coverage, which limits access. Liquid celecoxib was approved in May 2020 based on 2 double-blind, placebo-controlled studies of 600 participants. Diclofenac and celecoxib have low side-effects, but carry boxed warnings, for gastrointestinal and cardiovascular issues, making proper patient selection important.

Gepants Have Placebo-Like Side-Effects

Ubrogepant and rimegepant provide pain-freedom, pain reduction, and freedom from most bothersome symptom, but it is the extraordinarily benign side-effect profile that really stands out. Although some patients report lack of efficacy, none are bothered by these -gepants. More gepants are on the way, including a new product delivered in a nasal spray.

Lasmiditan has Good Efficacy and Some Issues

The sole representative of the 5HT-1_f agonist -ditan class, was safe and effective in large blinded studies involving over 4,400 people, including some with stable cardiovascular risk factors). This small, lipophilic molecule crosses the blood-brain barrier (BBB) to hit the many pain receptors in the CNS but also brings side-effects of dizziness and sedation. There is a driving prohibition for 8 hours after dosing and Schedule V designation based on a small study in which recreational drug-users liked lasmiditan more than placebo (but less than alprazolam).

Neurostimulators Are Underused

There are 4 neurostimulators approved for acute treatment of migraine. Of these, 2 stimulate the supraorbital and vagus nerves, and a third sends a pulsed electromagnetic wave through the skull to the occipital cortex. Each has demonstrated efficacy in small sham-controlled trials. Skepticism on the part of prescribers, limited marketing, and relatively high device price tags have limited widespread use, although in my experience patients seem very interested, at least conceptually, in acute treatment without risking systemic side effects.

The fourth neurostimulator approved for acute migraine treatment is a battery-powered arm band that sends a nonpainful stimulus up the musculocutaneous nerve to the brainstem. The proposed mechanism for this is conditioned pain modulation that diminishes the magnitude of the electrical signals generated by migraine. An advantage over other stimulators is lower cost, at about $8.00 per migraine attack.

Summary

It is a great time to be in headache medicine. As neurologists, even if treating this most common, disabling neurologic condition is not your primary thing, we are all headache specialists. Our primary care colleagues and our patients look to our guidance on comprehensive treatment of this disorder. Optimized acute treatment is a pillar of migraine care, along with life-style modification, and preventive therapy. In the past, we languished with no migraine-specific acute care options, then had the triptans, and now have even more tools. Another quote I remember from Fred Sheftell, “If you’ve seen 1 person with migraine, you’ve seen 1 person with migraine.” Sage words, even when our go-to option was a different triptan for each day of the week. For the sake of your patients, get out there, get familiar with these new products, and stay tuned, because more help is one the way.