Migraine Treatment Options: From Triptans to CGRP Drugs

Migraines Disable One Billion People Worldwide

The Global Burden of Disease study ranks migraine as the second leading cause of disability globally, affecting roughly 15% of the population at any given time. Women are three times more likely than men to experience them. For decades, treatment relied on medications with significant side effects. The past decade, however, has produced a wave of mechanism-specific drugs that have fundamentally changed care.

How Triptans Work — and Why They Sometimes Fail

Triptans, introduced in the early 1990s, remain first-line acute therapy. They are selective agonists at serotonin receptors 5-HT1B and 5-HT1D. The 5-HT1B action causes vasoconstriction of cranial blood vessels; the 5-HT1D action inhibits trigeminal nerve firing and reduces the release of calcitonin gene-related peptide (CGRP), the neuropeptide now understood as central to migraine pain.

Seven triptans are available. Sumatriptan, the original, reaches peak plasma concentration in 2 hours orally but faster as a nasal spray or subcutaneous injection. Rizatriptan and eletriptan have faster onset and higher oral bioavailability. Response rates vary: roughly 60–70% of patients achieve pain relief at 2 hours with the best-matched triptan, but only 20–30% achieve complete pain freedom.

• Contraindications: triptans are contraindicated in patients with coronary artery disease, uncontrolled hypertension, and history of stroke due to their vasoconstrictive mechanism.
• Medication overuse: using triptans more than 10 days per month risks rebound headache (medication-overuse headache).
• Non-responders: approximately 30% of migraineurs fail two or more triptans.

CGRP Antagonists — A Mechanistic Leap

The identification of CGRP as a key mediator of migraine pain opened a new therapeutic front. Two drug classes emerged: small-molecule CGRP receptor antagonists ("gepants") for acute treatment, and anti-CGRP monoclonal antibodies for prevention.

Ubrogepant (Ubrelvy, FDA approved December 2019) and rimegepant (Nurtec ODT, FDA approved February 2020) are the leading oral gepants. In phase 3 trials, ubrogepant 100 mg achieved pain freedom at 2 hours in 21.2% of patients versus 11.8% for placebo — a clinically meaningful but modest advantage. Rimegepant's key differentiator is dual approval: it is approved both as an acute treatment and as a preventive when taken every other day. Unlike triptans, gepants carry no vasoconstriction risk, making them suitable for patients with cardiovascular contraindications.

The Ditan Class — Targeting a Different Receptor

Lasmiditan (Reyvow, FDA approved October 2019) belongs to the ditan class — selective agonists at the 5-HT1F receptor. This receptor is expressed on trigeminal neurons but not on blood vessels, so lasmiditan has no vasoconstrictive action. In the SAMURAI and SPARTAN trials, lasmiditan 200 mg achieved pain freedom at 2 hours in 32.2% of patients.

The critical caveat: lasmiditan crosses the blood-brain barrier readily and causes central nervous system side effects — dizziness (15–17%), somnolence, and paresthesia. Patients must not drive for at least 8 hours after taking a dose. It is a Schedule V controlled substance in the United States.

Preventive Therapies — Who Needs Them

Prevention is warranted when a patient has four or more migraine days per month, migraines lasting more than 12 hours, inadequate acute therapy response, or medication-overuse risk. Traditional preventives include:

• Topiramate: reduces migraine frequency by approximately 50% in roughly 50% of patients; cognitive side effects ("topamax fog") limit tolerability.
• Propranolol / metoprolol: beta-blockers with approximately 50% responder rates; contraindicated in asthma.
• Amitriptyline: tricyclic antidepressant, effective but heavy sedation and weight gain limit use.
• OnabotulinumtoxinA (Botox): FDA approved for chronic migraine (≥15 headache days/month). The PREEMPT trial showed a 8–9 headache day reduction versus 6–7 for placebo. Administered as 155–195 units across 31 injection sites every 12 weeks.

Anti-CGRP Monoclonal Antibodies — Preventive Revolution

Four anti-CGRP monoclonal antibodies are now approved for migraine prevention. Erenumab (Aimovig) targets the CGRP receptor; fremanezumab (Ajovy), galcanezumab (Emgality), and eptinezumab (Vyepti) target the CGRP ligand directly.

Approximately 50% of patients on anti-CGRP antibodies achieve a ≥50% reduction in monthly migraine days. Constipation is the most reported side effect with erenumab. These agents cost $600–$900 per month without insurance, a significant access barrier.

Prodrome and Aura — Clinical Significance

Migraine unfolds in up to four phases. The prodrome — occurring 6–48 hours before head pain — includes yawning, food cravings, neck stiffness, and mood changes. Recognizing prodrome allows earlier treatment. Aura affects roughly 25–30% of migraineurs: visual phenomena (scintillating scotoma), sensory changes, or speech disturbance lasting 5–60 minutes. Migraine with aura carries a modestly elevated stroke risk, particularly in women who smoke and use combined oral contraceptives — a combination warranting avoidance.

This article is for informational purposes only. Consult a qualified healthcare professional.