Migraine Treatment: Medications, Preventives, and Regenerative Options

Acute Treatment: Stopping an Attack

The goal of acute treatment is to make the migraine go away within 2 hours and keep it from coming back within 24 hours. Timing matters enormously: treating early (within the first hour of headache onset) dramatically improves response rates for nearly every medication class [1].

Triptans

Triptans are serotonin 5-HT1B/1D agonists that work by constricting dilated blood vessels and blocking pain signal transmission in the trigeminovascular system. Seven triptans are available, and they are not interchangeable: patients who fail one may respond well to another [2].

Triptans are contraindicated in uncontrolled hypertension, coronary artery disease, history of stroke, and hemiplegic migraine. These contraindications exclude a significant number of patients, which is where gepants fill the gap.

Gepants (CGRP Receptor Antagonists)

Small-molecule CGRP antagonists that block the same pathway as anti-CGRP monoclonal antibodies but in oral form for acute use.

• Ubrogepant (Ubrelvy): 50-100 mg oral. 2-hour pain freedom in 19-22% (vs. 12% placebo). No cardiovascular contraindications [3].
• Rimegepant (Nurtec ODT): 75 mg orally dissolving tablet. Dual-approved for both acute treatment and prevention (every other day dosing). 2-hour pain freedom in 21%.
• Zavegepant (Zavzpret): 10 mg nasal spray. Fastest onset gepant. 2-hour pain freedom in 24%. Good option when nausea prevents oral medication.

Gepants lack the vasoconstrictor properties of triptans, making them safe for patients with cardiovascular disease. They also do not appear to cause medication overuse headache with regular use.

Ditans (5-HT1F Agonists)

• Lasmiditan (Reyvow): 50-200 mg oral. Works on the same serotonin pathway family as triptans but without vasoconstriction. Effective for triptan non-responders. Main limitation: CNS side effects (dizziness, sedation). Classified as Schedule V; patients cannot drive for 8 hours after dosing [4].

NSAIDs and Combination Analgesics

For mild-to-moderate migraines:

• Ibuprofen 400-800 mg: Effective for mild attacks; best taken at onset
• Naproxen 500-750 mg: Longer half-life provides sustained relief
• Aspirin-acetaminophen-caffeine (Excedrin Migraine): OTC combination with good evidence for mild-moderate attacks. Caffeine enhances absorption and has independent analgesic properties
• Diclofenac potassium 50 mg: Faster absorption than diclofenac sodium; good migraine-specific evidence

Anti-Emetics

Nausea and vomiting accompany many migraine attacks and impair oral medication absorption. Metoclopramide (10 mg) or prochlorperazine (10 mg) given IV or IM are effective both as anti-emetics and as migraine-specific treatments in the emergency department. Ondansetron (Zofran) addresses nausea but lacks direct migraine efficacy.

Preventive Treatment: Reducing Attack Frequency

Prevention is recommended when [5]:

• Migraines occur 4 or more days per month
• Acute treatments are ineffective or poorly tolerated
• Acute medication use exceeds 10-15 days per month (medication overuse threshold)
• Attacks are severely debilitating regardless of frequency
• Hemiplegic migraine, brainstem aura, or prolonged aura is present

Anti-CGRP Monoclonal Antibodies

The most significant advance in migraine prevention in decades. These injectable antibodies target CGRP or its receptor, providing sustained prevention with monthly or quarterly dosing.

• Erenumab (Aimovig): 70-140 mg SC monthly. Targets the CGRP receptor. 50% migraine day reduction in 43-50% of patients. Most common side effect: constipation [6].
• Fremanezumab (Ajovy): 225 mg monthly or 675 mg quarterly. Targets CGRP ligand. Quarterly option is unique to this agent.
• Galcanezumab (Emgality): 240 mg loading dose, then 120 mg monthly. Targets CGRP ligand. Also approved for episodic cluster headache.
• Eptinezumab (Vyepti): 100-300 mg IV quarterly. Fastest onset of any preventive (effect detectable on day 1 after infusion). The only IV anti-CGRP option.

These agents have minimal systemic side effects and no drug interactions. They are not hepatotoxic and do not require blood monitoring. The main barrier is cost: $600-800/month without insurance, though manufacturer patient assistance programs cover many patients.

Oral Preventives (First-Generation)

OnabotulinumtoxinA (Botox)

Approved for chronic migraine (15+ headache days/month). Thirty-one fixed-site injections across the head and neck every 12 weeks. Reduces headache days by an average of 8-9 per month. Takes 2-3 treatment cycles to reach full effect. Well tolerated; main side effects are injection site pain and neck weakness [7].

Neuromodulation Devices

FDA-cleared devices that modulate pain pathways without drugs:

• Cefaly (external trigeminal nerve stimulation): Worn on the forehead; approved for both acute and preventive use. Reduces migraine days by 2-3 per month.
• SpringTMS/sTMS (single-pulse transcranial magnetic stimulation): Handheld device applied to the back of the head. Can abort aura and treat acute attacks.
• gammaCore (non-invasive vagus nerve stimulation): Applied to the neck; approved for cluster headache and migraine. Modulates trigeminal pain processing.
• Nerivio: Remote electrical neuromodulation worn on the upper arm; controlled via smartphone app. FDA-cleared for acute and preventive use.

Supplements with Evidence

Several supplements have level B evidence (probably effective) from the American Academy of Neurology [8]:

• Magnesium: 400-600 mg/day of glycinate, citrate, or oxide. Reduces cortical excitability. Particularly helpful in menstrual migraine and migraine with aura.
• Riboflavin (B2): 400 mg/day. Improves mitochondrial energy metabolism. Takes 3 months for full effect.
• CoQ10: 100 mg three times daily. Mitochondrial cofactor. Evidence from a 2005 RCT showing 48% reduction in attack frequency.
• Feverfew: 50-300 mg/day of standardized extract. Anti-inflammatory via inhibition of prostaglandin synthesis. Mixed evidence but generally safe.
• Butterbur (Petasites): Previously recommended but withdrawn in many markets due to hepatotoxicity concerns from PA (pyrrolizidine alkaloid) contamination. Only use PA-free certified products if considering.

Medication Overuse Headache: The Hidden Trap

Using acute migraine medications more than 10-15 days per month causes a paradoxical increase in headache frequency called medication overuse headache (MOH). All acute medications can cause it, but opioids and combination analgesics (butalbital) have the highest risk [9].

Treatment requires withdrawal of the overused medication, which causes a temporary worsening (1-2 weeks of increased headaches) before improvement. Bridge therapy with a short course of corticosteroids, naproxen, or gepants helps manage the withdrawal period. Simultaneously starting a preventive medication is essential.

Emerging and Regenerative Approaches

• Nerve blocks: Greater occipital nerve (GON) blocks with local anesthetic and corticosteroid provide 2-4 weeks of relief. Useful as a bridge while preventive medications take effect.
• Trigger point injections: Targeting myofascial trigger points in the cervical and trapezius musculature can reduce migraine frequency in patients with cervicogenic components.
• Sphenopalatine ganglion (SPG) blocks: Intranasal lidocaine applied to the SPG can abort acute attacks. SPG stimulation devices are in clinical trials for cluster headache and migraine.
• Psilocybin: Phase 2 clinical trials are investigating psilocybin for cluster headache and intractable migraine. Preliminary data suggests potential disease-modifying effects through serotonergic pathway modulation [10].
• Ketamine: IV ketamine infusions are being explored for refractory chronic migraine, targeting NMDA receptor-mediated central sensitization.

Building a Treatment Plan

1. Track first: Keep a headache diary for 1-2 months to establish baseline frequency, severity, and triggers
2. Optimize acute treatment: Find an effective acute medication and take it early. Avoid opioids and butalbital.
3. Start prevention if indicated: Choose based on comorbidities, side effect profile, and patient preference
4. Add supplements: Magnesium + riboflavin + CoQ10 as adjuncts
5. Address lifestyle factors: Regular sleep, exercise, hydration, stress management, trigger avoidance
6. Reassess every 3 months: Adjust or escalate as needed. Success = 50%+ reduction in migraine days.

Related Reading

• Migraine: The Evidence-Based Guide (Pillar)
• Migraine with Aura: What It Looks Like and When to Worry
• Vestibular Migraine: The Dizziness-Migraine Connection

References

1. Lipton RB, Stewart WF. Acute migraine therapy: do doctors understand what patients with migraine want from therapy? Headache. 1999;39(Suppl 2):S20-S26. doi:10.1111/j.1526-4610.1999.00006.x
2. Ferrari MD, Goadsby PJ, Roon KI, et al. Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis. Cephalalgia. 2002;22(8):633-658. doi:10.1046/j.1468-2982.2002.00404.x
3. Dodick DW, Lipton RB, Ailani J, et al. Ubrogepant for the treatment of migraine. N Engl J Med. 2019;381(23):2230-2241. doi:10.1056/NEJMoa1813049
4. Goadsby PJ, Wietecha LA, Dennehy EB, et al. Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine. Brain. 2019;142(7):1894-1904. doi:10.1093/brain/awz134
5. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults. Neurology. 2012;78(17):1337-1345. doi:10.1212/WNL.0b013e3182535d20
6. Goadsby PJ, Reuter U, Hallstrom Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377(22):2123-2132. doi:10.1056/NEJMoa1705848
7. Aurora SK, Dodick DW, Turkel CC, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia. 2010;30(7):793-803. doi:10.1177/0333102410364676
8. Holland S, Silberstein SD, Freitag F, et al. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults. Neurology. 2012;78(17):1346-1353. doi:10.1212/WNL.0b013e3182535d0c
9. Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology. 2008;71(22):1821-1828. doi:10.1212/01.wnl.0000335946.53860.1d
10. Schindler EAD, Sewell RA, Gottschalk CH, et al. Exploratory controlled study of the migraine-suppressing effects of psilocybin. Neurotherapeutics. 2021;18(1):534-543. doi:10.1007/s13311-020-00962-y