Exploration of Migraine Therapies Through the Ages
Evolution of Migraine Treatments: From Ergot Alkaloids to Modern Therapies
Migraine treatment has come a long way since the introduction of ergot alkaloids in the early 20th century. This journey, spanning nearly a century, has seen significant milestones that have transformed the way migraines are managed.
1920s–1930s: Introduction of Ergot Alkaloids
Ergotamine, derived from the ergot fungus Claviceps purpurea, was identified and used for migraine treatment due to its vasoconstrictive properties affecting central nervous system receptors. Ergotamine's use for acute migraine began in the early 20th century and became a mainstay in migraine therapy [2][3]. Dihydroergotamine, a derivative with fewer side effects, followed later for acute migraine treatment and remains available in nasal spray form [1][5].
1960s–1970s: Use of Beta-Blockers for Prophylaxis
Beta-adrenergic blockers like propranolol were found effective for migraine prevention. These drugs reduce the frequency and severity of migraine attacks by modulating vascular tone and neuronal excitability [3]. This marked the start of migraine prophylactic therapy.
1990s: Introduction of Triptans
Sumatriptan, the first selective serotonin 5-HT1B/1D receptor agonist, was introduced in the early 1990s. Triptans revolutionized acute migraine treatment by specifically targeting migraine pathophysiology, providing rapid relief with fewer side effects than ergots [3]. Multiple triptans with various pharmacokinetic profiles have since been developed.
2000s: Botox (OnabotulinumtoxinA) for Chronic Migraine
Botox injections gained FDA approval for the treatment of chronic migraine in 2010. Botox reduces muscle tension and modulates sensory nerve activity, benefiting patients with frequent migraines resistant to other treatments.
2010s: Calcitonin Gene-Related Peptide (CGRP) Therapies
Monoclonal antibodies targeting CGRP or its receptor (e.g., erenumab, fremanezumab) were approved in the late 2010s, offering effective prophylactic treatment by inhibiting the neuropeptide CGRP, pivotal in migraine pathophysiology. Small-molecule CGRP receptor antagonists (gepants) for acute treatment (ubrogepant, rimegepant) also emerged recently [3].
Recent Advances: Non-Invasive Neuromodulation
Transcranial magnetic stimulators and other neuromodulation devices have been developed as non-drug options for migraine. They modulate neural circuits involved in migraine, offering alternative or adjunctive therapies, especially for patients intolerant to medications.
Notable Developments in the 21st Century
- The FDA approved rimegepant (Nurtec) for acute migraine treatment in 2020.
- Researchers published the first proof-of-concept study of IV anti-CGRP therapy in 2004. The first preventive IV migraine treatment, eptinezumab-jjmr (Vyepti), received FDA approval in 2021.
- The first CGRP monoclonal antibody, erenumab-aooe (Aimovig), received FDA approval in 2018.
- The FDA approved Botox injections in 2010 to prevent chronic migraines.
- The FDA approved the first ditan drug, lasmiditan (Reyvow), in 2019.
- The FDA approved zavegepant (Zavzpret) for acute migraine treatment in 2021.
- The FDA approved ubrogepant (Ubrelvy) for acute migraine treatment in 2019.
- In phase 3 clinical trials, eptinezumab-jjmr significantly reduced the number of headache days per month.
- The FDA approved Atogepant (Qulipta) for preventive migraine treatment in 2021.
Different types of migraine drugs, including CGRP antibodies and CGRP gepants, have been developed based on anti-CGRP therapy. Anti-CGRP therapy targets the nerves that transmit pain sensations between the face and brain and the signaling molecule CGRP, which plays a crucial role in migraine. Ergots, while among the first drugs used to treat acute migraines, with ergotamine being introduced in 1926, are unsuitable for people with certain conditions, such as uncontrolled hypertension.
In summary, migraine treatment evolved from nonspecific ergot alkaloids in the early 20th century to targeted therapies like triptans in the 1990s, followed by Botox for chronic migraine and novel preventive approaches targeting CGRP in the last decade. Modern advances also include neuromodulation devices providing drug-free options for migraine management [1][2][3][5].
[1] Mayo Clinic. (2019). Migraine Treatment. [online] Available at: https://www.mayoclinic.org/diseases-conditions/migraine-headache/diagnosis-treatment/drc-20355813
[2] American Migraine Foundation. (2021). Migraine History: Timeline & Evolution of Treatments. [online] Available at: https://americanmigrainefoundation.org/resource-library/migraine-history-timeline-evolution-of-treatments/
[3] National Institute of Neurological Disorders and Stroke. (2021). Migraine Fact Sheet. [online] Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Migraine-Fact-Sheet
[4] National Library of Medicine. (2021). Migraine: Overview. [online] Available at: https://medlineplus.gov/migraine.html
[5] American Academy of Neurology. (2021). Migraine. [online] Available at: https://www.aan.com/patients/disease-information/migraine-headache
- In the early 20th century, the introduction of ergot alkaloids, such as ergotamine and dihydroergotamine, marked the beginning of migraine treatment, utilizing the vasoconstrictive properties of the ergot fungus to impact central nervous system receptors.
- During the 1960s and 1970s, beta-adrenergic blockers like propranolol became effective for migraine prevention, reducing the frequency and severity of migraine attacks by modulating vascular tone and neuronal excitability.
- Sumatriptan, the first selective serotonin 5-HT1B/1D receptor agonist, was introduced in the 1990s, revolutionizing acute migraine treatment by targeting migraine pathophysiology and providing rapid relief with fewer side effects compared to ergots.
- Botox injections gained FDA approval in 2010 for treating chronic migraines, as they reduce muscle tension and modulate sensory nerve activity, benefiting patients with frequent migraines resistant to other treatments.
- In the late 2010s, monoclonal antibodies targeting Calcitonin Gene-Related Peptide (CGRP) or its receptor (e.g., erenumab, fremanezumab) were approved, offering effective prophylactic treatment by inhibiting the neuropeptide CGRP, which plays a crucial role in migraine pathophysiology.
- By the 2010s, calcitonin gene-related peptide therapies expanded to include both preventive and acute treatments, with the addition of small-molecule CGRP receptor antagonists (gepants) like ubrogepant and rimegepant, and the development of non-invasive neuromodulation devices, providing drug-free options for migraine management.
- In the 21st century, notable developments in migraine treatment include the FDA approval of Qulipta (Atogepant) for preventive migraine treatment in 2021, zavegepant for acute migraine treatment in 2021, rimegepant and ubrogepant for acute migraine treatment in 2019, the first CGRP monoclonal antibody (erenumab-aooe) in 2018, and the first ditan drug (lasmiditan) in 2019. These advancements target the nerves transmitting pain between the face and brain and the signaling molecule CGRP, providing specialized treatments for various types of migraines.
