What Migraine Treatments Are on the Horizon?

New knowledge about the biology behind migraine attacks means improved therapies

migraine
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Migraine is a complex neurological disease that leaves even brilliant scientists and neurologists sometimes scratching their heads. Unlike many other medical conditions, the biology of migraine attacks has not been all figured out yet.

The good news is that researchers are finally getting closer to understanding the "how" behind migraine attacks—meaning their pathophysiology, or how they manifest. It's this knowledge that has revolutionized migraine therapies, setting off a barrage of promising studies and new emerging treatments.

The three big advances in migraine therapy include:

  1. Unique ways to administer triptans, an already well-established anti-migraine drug.
  2. Novel anti-migraine medications for both acute treatment and prevention.
  3. Medical devices to treat and prevent migraines.

Triptans Delivered Uniquely

Triptans bind to serotonin receptors in the brain and are commonly used to treat moderate-to-severe migraine attacks. They are also used to treat mild-to-moderate migraines that do not ease up with an NSAID.

The beauty of triptans is that they can be delivered a number of different ways—tablets, oral disintegrating tablets (wafer), nasal spray, subcutaneous injection (beneath the skin), and a suppository.

With all these options, a person with migraines and his or her doctor can choose a triptan, based on his or her unique preference and needs. These considerations may include:

  • Side effects
  • Onset of action
  • Appeal to certain populations of migrauneurs—for example, those who experience nausea and vomiting with their migraines and cannot tolerate medications by mouth
  • Cost
  • Convenience

It's also exciting to learn that triptans may be administered in even more unique ways in the future. For instance, a sumatriptan lingual spray is currently being developed, as is a zolmitriptan inhaler and rizatriptan mouth dissolving film.

Keep in mind that new formulations don't always work out well.

For instance, sumatriptan used to be available as a battery-powered transdermal patch (called Zecuity) that was applied to the upper arm or thigh. It penetrated the skin using an electric gradient system, delivering 6.5mg of sumatriptan over a period of four hours. However, it is currently off the market due to reports of burns and scars associated with it.

The big picture here is that with new medications and formulations come promise, but also some hesitancy as the nuances get teased out.

Remember too, that the formulation that works for one person may not work for another—so talk with your personal doctor to sort out the pluses and minuses of your migraine therapy options.

Novel Anti-Migraine Medications

As scientists unveil the biology behind how migraine attacks develop in the brain, they are able to target new pathways and receptors. Three advances in migraine drugs include:

  1. Lasmiditan: A medication similar to other triptans but with greater affinity for a specific serotonin receptor.
  2. Medications targeting Calcitonin Gene-Related Peptide (CGRP)
  3. Medications targeting Glutamate

Lasmiditan: A Serotonin 5-HT1F Agonist

Lasmiditan is being developed as an alternative medication to triptans.

Why is an alternative needed? There are three reasons:

  1. Research shows that approximately 35 percent of people do not get migraine relief from oral triptans.
  2. A good number of people cannot take triptans because they may cause blood vessel constriction (vasoconstriction)—so, triptans are contraindicated in those with a history of heart disease, stroke, peripheral vascular disease, uncontrolled high blood pressure, and/or certain types of migraine like a hemiplegic or a basilar migraine. 
  3. Some people simply do not like how triptans make them feel, as they can cause uncomfortable side effects like jaw, neck, and chest tightness, numbness, and tingling (especially of the face).

    The promising news about lasmiditan is that it selectively binds to specific serotonin receptors in the brain, having much less affinity for other serotonin receptors that when bound, can lead to unwanted vasoconstriction.

    The good news is that in a phase 2 study, lasmiditan taken at various doses was found to improve pain from a moderate-to-severe migraine headache to none (or mild) at two hours. The improvement in pain was dose-dependent, meaning the higher the dose, the greater the pain relief.

    The main side effects were dizziness (occurring in 38 percent of the participants) followed by vertigo and fatigue.

    So, unlike current triptans, the precise binding of lasmiditan may avoid vasoconstrictive side effects, but can lead to more nervous system affects, which could be limiting for some people. Overall, larger studies and a clearer picture of the mechanism behind lasmiditan are needed.

    Calcitonin Gene-Related Peptide (CGRP)

    Calcitonin gene-related peptide (CGRP) plays a vital role in migraine pathogenesis. More specifically, research suggests that during a migraine attack, the trigeminal system is activated, leading to release of CGRP from trigeminal nerve endings. CGRP then works to dilate blood vessels around the brain and trigger a phenomenon called neurogenic inflammation, and it's these two steps that then generate a migraine headache.

    So, medications that can block either CGRP itself or the receptors (the docking site in the brain) of CGRP are currently being studied. Unfortunately, some studies examining CGRP-receptor antagonists (medications that block the action of CGRP) have been discontinued early for a number of reasons, including a concern over liver toxicity. But one medication, ubrogepant, was well-tolerated and effective in a phase 2 study

    Three anti-CGRP antibodies (drugs that bind to the protein CGRP and block or inactivate it) have also been developed to prevent migraines, with the idea of removing excess CGRP released by trigeminal nerve endings during a migraine attack. These drugs show promising results in early phase 1 and 2 trials.

    Finally, erenumab is a monoclonal antibody that binds not to CGRP, but to its receptor, and is given underneath the skin (a subcutaneous injection). By binding to the receptor, erenumab blocks it from signaling. It has been studied as a migraine preventive medication and appears well-tolerated in a phase 2 study.

    Overall, targeting the CGRP pathways appears to be a promising therapeutic option for those with either an episodic or chronic migraine disorder.

    Glutamate Receptor Antagonists

    Glutamate is a neurotransmitter, or chemical in the brain, that according to both animal and human studies, appears to play a key role in how migraines manifest. A number of medications related to blocking or altering glutamate receptors have been studied, some for treating acute migraine attacks and others for preventing migraines.

    You may even be taking or are familiar with a preventive medication like topamax (topiramate) and botulinum toxin A that blocks glutamate release, along with other chemicals.

    Interestingly, ketamine (an anesthetic drug), which blocks a receptor of glutamate in the brain called the NMDA receptor, has been found to treat migraine aura—possibly by suppressing cortical spreading depression, a wave of depressed nerve activity that sweeps across the cortex of the brain.

    In a small, double-blind study of people with prolonged migraine aura, 25mg of intranasal ketamine (given through the nose) was compared to intranasal versed (midazolam), which is a sedative. The study found that ketamine reduced the severity but not the duration of the aura. Side effects included:

    • Feelings of unreality
    • Euphoria
    • Temporary mild giddiness

    These effects subsided within 30 to 45 minutes. Overall, the role of glutamate and its pathways in chronic migraine and migraine aura continues to be a source of research, and with that, a hope for newer therapies.

    Revolutionary FDA-Approved Devices for Migraine Therapy

    The creation of devices to treat and prevent migraines has revolutionized migraine therapy. These devices are for the most part easy to use, convenient, and linked to minimal adverse effects. The downsides are the cost and the fact that some devices do not work for everyone.

    Still, investing in a device may be a reasonable option for some migraineurs, especially if medications are not working, or for people who are prone to medication overuse headaches.

    One migraine-preventing device called Cefaly targets the supraorbital nerve (tSNS) which innervates part of the forehead, scalp and upper eyelid. It is a battery-operated device worn like a headband that is used daily for twenty minute sessions.

    It is a safe, well-tolerated, and user-friendly device according to a large study in the Journal of Headache and Pain, with less than five percent of people reporting minor adverse effects. It may be a good option for people who cannot tolerate or do not want to take oral migraine preventive medications.

    Another device is a non-invasive vagus nerve stimulation (nVNS) device (called GammaCore) that can be used to both prevent and treat acute migraine attacks. It works by stimulating the vagus nerve—so it's held against the side of the neck for approximately two minutes after applying a conductive gel. It is believed to work by suppressing high levels of glutamate levels in the trigeminal system.

    In a study in the Journal of Headache and Pain, results showed improvement in the number of headaches per month, as well as pain intensity, in participants with either an episodic or chronic migraine disorder. Few adverse effects were reported and none were serious. These side effects included skin irritation and neck twitching.

    A third device called the Spring transcranial magnetic stimulator (sTMS) is FDA-approved for treating migraine with aura. It is used by applying the device to the back of your head and pressing a button, which releases stimulating magnetic energy into the brain. It can only be used once every 24 hours as treatment. It is believed to work by suppressed cortical spreading depression, the wave of electrical activity that sweeps across the brain.

    A Word From Verywell

    While the culmination of new migraine therapies and devices is exciting and promising, remember that treating and preventing your migraine attacks can be a tedious and malleable process—one of trial and error that will change as your migraines, lifestyle, and/or preferences change. 

    Remain proactive by following up with your neurologist regularly and staying up to date on migraine news, without getting too bogged down on the technical terms of emerging therapies. Let's be hopeful that this debilitating disease may be unburdened a bit more soon for you or your loved one.

    Sources:

    Antonaci F, Ghiotto N, Wu S, Pucci E, Costa A. Recent advances in migraine therapy.Springplus. 2016 May 17;5:637.

    Chan K, MaassenVanDenBrink A. Glutamate receptor antagonists in the management of migraine. Drugs. 2014 Jul;74(11):1165-76.

    Färkkilä M et al. Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) receptor agonist, for the acute treatment of migraine: a phase 2 randomised placebo-controlled, parallel-group, dose-ranging study. Lancet Neurol. 2012 May;11(5):405-13.

    Magis D, Sava S, d/Elia TS, Baschi R, Schoenen J. Safety and patients' satisfaction of transcutaneous supraorbital neurostimulation (tSNS) with the Cefaly device in headache treatment: a survey of 2,313 headache sufferers in the general population. J Headache Pain. 2013 Dec 1;14:95.

    Sun H et al. Safety and efficacy of AMG 334 for prevention of an episodic migraine: a randomized, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(4):382-90.

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