Migraine Treatments: Past, Present, and Future

What is a migraine? If you’ve ever experienced intense throbbing on the side of your head and felt that every small sound or bright light was forcing daggers into your skull, then you’re probably 1 of approximately 39 million Americans who have suffered from a migraine headache in the past year. According to the CDC, women are nearly twice as likely to have migraine compared with men (20.1% vs 10.6%), with ages 18-44 at highest risk.¹

Migraine is a brain disorder that produces a wide array of neurological and systemic symptoms, commonly including severe head pain; sensitivity to lights, sounds, and smells; neck or shoulder pain; ringing in the ears; nausea and vomiting; and irritability. Migraines can be a primary diagnosis or a symptom of an underlying medical (meningitis, hormone changes) or psychological (depression, anxiety disorder, post-traumatic stress disorder) condition. For more than 90% of sufferers, migraines interfere with education, work, or social activities.²

PAST: Trepanning, Leeches, and Eels

Migraines are not a modern phenomenon. People have always suffered from severe, debilitating headaches and employed various remedies to alleviate the pain.

Credit: Damir Khabirov - stock.adobe.com

Trepanning, the process of drilling holes into the skull to alleviate pressure and pain, dates as far back as 7000 B.C. and continued into the 1600s. Other treatments included burning the head, applying leeches to the forehead, and bathing with eels.

Other not so drastic, but equally ineffective, remedies included soaking feet in hot water to draw blood from the head; running around the house 3 times; rubbing the head with a stone containing iron ore; or wrapping damp cloths around the head and burning scented wood.

It wasn’t until 1926 that ergotamine became the first medicinal treatment available for the treatment of migraines. Ergotamine and its derivatives work by activating the 5-HT1D receptors, causing vasoconstriction of intracranial blood vessels and inhibiting the release of inflammatory neuropeptides. Available in multiple formulations, ergotamine has remained a commonly prescribed option due to its efficacy and low cost.

It wasn’t until 40 years later that another class of medications was discovered to reduce migraine frequency. Propranolol, a nonselective beta blocker used for the treatment of hypertension, led the way as the first approved prevention treatment for migraines.

Propranolol, amitriptyline, valproic acid, and topiramate, which exert their effects by targeting various neurotransmitter sites in the brain, have been used for decades for the prevention of migraines. Though considered safe and effective, their use is often limited due to adverse effects (AEs) and patient intolerance.

PRESENT: Many Migraine Therapy Options, But No Perfect Treatment

Today, multiple medications are used for acute treatment as well as migraine prophylaxis. According to the American Headache Society, some of the goals of acute migraine treatment include:

• Rapid and consistent freedom from pain and associated symptoms, especially the most bothersome symptom, without recurrence.
• Restored ability to function.
• Optimal self-care and reduced subsequent use of resources (e.g., emergency department visits, diagnostic imaging, clinician and ambulatory infusion center visits).

Treatment options can include triptans, ergotamine derivatives, “gepants,” “ditans,” non-steroidal anti-inflammatory drugs (NSAIDs), and combination analgesics. Choice of therapies depends on the patient’s chronic medical conditions, past efficacy, and tolerability.

Triptans

Triptans sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan, and frovatriptan are selective serotonin agonists binding at the 5-HT1B/1D receptor.

This class of medications is available in several different formulations, with onset of action ranging from 10-15 minutes for subcutaneous/intranasal administration to 30-60 minutes for oral/sublingual tablets. Triptans are considered safe and effective for most patients with migraine but should be avoided in patients with cardiovascular risks such as ischemic heart disease, stroke, angina, and uncontrolled hypertension.

Ditans

Ditans are a new class of abortive medications targeting the serotonin 5-HT1F receptors, which are found in the brain, uterine, and mesenteric tissue, but not in the heart.³ Lasmiditan is the first 5-HT1F agonist approved for the treatment of migraine attack.

Available as an oral tablet, it differs from triptans primarily in its lack of vasoconstrictive effects and is thereby safer for patients with uncontrolled hypertension and other cardiovascular risks.⁴ AEs are comparable to triptans but tend to have higher incidence of CNS-related AEs, including dizziness, nausea, and fatigue.

NSAIDs, Combination Analgesics, and Others

Dihydroergotamine, NSAIDs, acetaminophen, and other combination analgesics are available by prescription or OTC for as-needed management of migraines. Often used as first-line therapies, these medications can be overused and lead to rebound migraines. When patients have 4 or more headaches or at least 8 headache days, regardless of severity, per month, they should be evaluated for prevention therapy.

The goals of therapy for migraine prevention, as outlined by the American Headache Society include:

• Reduce attack frequency, severity, duration, and disability.
• Improve responsiveness to and avoid escalation in use of acute treatment.
• Improve function and reduce disability.
• Enable patients to manage their own disease to enhance a sense of personal control.
• Improve health-related quality of life (HRQoL).
• Reduce headache-related distress and psychological symptoms.

Treatment options include both pharmacological and non-pharmacological therapies.

Non-Pharmacological and Pharmacological Approaches to Prevention

Non-pharmacological approaches to migraine management include lifestyle modifications aimed at reducing triggers that are responsible for headache onset. Common triggers include stress, sleep changes, diet, weather changes, and hormonal changes. Although not all triggers are easily modifiable, dietary changes, regular exercise, and adequate hydration can improve headaches without the need for medication.

Behavioral therapies also play a role in prevention and may include relaxation training and cognitive behavioral therapy (CBT) for stress management and electromyographic (EMG) biofeedback for muscle tension reduction. Other interventions can include acupuncture, chiropractic therapy, hypnosis, and physical therapy. Migraine journals may help patients pinpoint specific triggers and make appropriate lifestyle modifications to reduce headache frequency.

Pharmacological options include antiepileptic drugs (divalproex sodium, topiramate); beta blockers (propranolol, metoprolol, timolol); angiotensin receptor blockers (candesartan); and newer agents such as calcitonin gene-related peptide(CGRP) antagonists (monoclonal antibodies and gepants) andOnabotulinumtoxinA (Botox). As with acute therapies, the choice of medication is based on patient preference and history of efficacy and tolerability.

CGRP Receptor Antagonists

CGRP is produced in both the central and peripheral nervous systems and is thought to trigger migraines due to its effects on vasodilation, neurogenic inflammation, and peripheral sensitization. CGRP increases during migraine attacks and is correlated with headache intensity.⁵

Currently there are 8 CGRP antagonists approved in the United States—4 monoclonal antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab) indicated for migraine prophylaxis and 4 small molecule antagonists (atogepant for prophylaxis; ubrogepant, zavegepant for acute treatment; and rimegepant with approval for both prophylaxis and treatment).

Monoclonal antibodies are administered subcutaneously by self-injection monthly, with fremanezumab having the option for injection every 3 months. The newest monoclonal antibody, eptinezumab, is administered intravenously by a health care provider and is also dosed every 3 months. Generally well tolerated, the most commonly reported AEs include injection site reactions, nausea, headache, and constipation.

Small molecule antagonists, or gepants, are orally administered CGRP antagonists, with the exception of zavegepant, which is given intranasally. Like their monoclonal antibody counterparts, gepants are generally well tolerated but produce similar AEs, including nausea, headache, and constipation.

OnabotulinumtoxinA

Botox is the only neurotoxin currently approved for the treatment of migraines. It works by preventing calcium-dependent release of neurotransmitters from nerve fibers that are involved in pain signaling and is administered by a health care provider. The effects of OnabotulinumtoxinA last for approximately 10-12 weeks.

FUTURE: Novel Therapies and Innovative Delivery Systems

According to market research trends, $4.34 billion was spent on migraine drugs worldwide in 2021, with the number projected to rise to $8.79 billion by 2030.⁶ The migraine pipeline looks to take advantage of the ever-growing need for novel therapies, as well as innovative delivery systems.

Several old drugs are being reworked into new formulations to decrease time to onset, provide localized treatment, and extend duration of action. Dihydroergotamine derivatives for nasal and subcutaneous injection; zucapsaicin, currently available as a topical agent for pain relief, for intranasal administration; and a novel botulinum containing neurotoxin, daxibotulinumtoxinA, whose effects last up to 6 months, are just some of the medications in the migraine pipeline.

Research is also being conducted into novel therapeutic targets, including pituitary adenylate cyclase-activating polypeptide, adenosine, δ-opioid receptors, potassium channels, transient receptor potential ion channels, and acid-sensing ion channels.

The perfect migraine treatment has yet to be discovered. Medication AEs often limit long-term use, and medications are not always able to provide complete relief.

The effects of chronic migraine are so debilitating that combination therapies are often employed, using both pharmacological and non-pharmacological measures, to decrease morbidity and increase the patient’s quality of life.

With millions of migraine sufferers and billions of potential dollars at stake, the future of migraine treatment lies in the medication that can decrease migraine frequency, duration, and severity while minimizing AEs and the need for redosing.

References

1. QuickStats: Percentage of Adults Who Had a Severe Headache or Migraine in the Past 3 Months, by Sex and Age Group – National Health Interview Survey, United States, 2018. MMWR Morb Morta; Wkly Rep 2020;69:359. DOI: http://dx.doi.org/10.15585/mmwr.mm6912a8
2. Estave P.M., Beeghly S., Anderson R., Margol C., Shakir M., George G., et al. Learning the full impact of migraine through patient voices: A qualitative study. Headache. 2021;61(7):1004–1020. [PMC free article] [PubMed] [Google Scholar]
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4. Clemow DB, Johnson KW, Hochstetler HM, Ossipov MH, Hake AM, Blumenfeld AM. Lasmiditan mechanism of action - review of a selective 5-HT1F agonist. J Headache Pain. 2020 Jun 10;21(1):71. doi: 10.1186/s10194-020-01132-3. PMID: 32522164; PMCID: PMC7288483.
5. Edvinsson, L. (2018), The CGRP Pathway in Migraine as a Viable Target for Therapies. Headache: The Journal of Head and Face Pain, 58: 33-47. https://doi.org/10.1111/head.13305
6. Polaris Market Research. Migraine Drugs Market Size Global Report, 2022 – 2030. https://www.polarismarketresearch.com/industry-analysis/migraine-drugs-market