Modern Approaches to Migraine Treatment: From Triptans to CGRP-Targeted Therapy and Botox

A comprehensive yet patient-friendly overview of modern migraine management: acute treatments, preventive medications, gepants, CGRP-targeted monoclonal antibodies, and botulinum toxin therapy for chronic migraine (PREEMPT protocol). The text combines clinical accuracy with accessible language.

What Migraine Is and Why It Happens

Migraine is a chronic neurovascular disorder characterized by recurrent episodes of headache accompanied by nausea, photophobia, phonophobia, and sensory hypersensitivity. The key molecular driver of migraine attacks is the calcitonin gene-related peptide (CGRP). CGRP dilates meningeal vessels, activates trigeminal nociceptive pathways, and contributes to neurogenic inflammation that maintains the migraine cascade. Understanding the CGRP pathway has led to innovative and highly effective treatments: CGRP monoclonal antibodies and gepants.

Acute Migraine Treatment: How to Stop an Attack Effectively

The goal of acute therapy is complete resolution of pain and major symptoms within 2 hours. The optimal choice depends on the severity of the attack.

Mild and Moderate Attacks: NSAIDs and Analgesics

• Ibuprofen 400 mg
• Naproxen 500–550 mg
• Acetaminophen 1000 mg
• Aspirin 500–1000 mg
• Combination: acetaminophen + aspirin + caffeine

These agents have strong evidence and remain first-line therapy for less severe, infrequent attacks. Monitoring frequency is important to avoid medication-overuse headache.

Moderate and Severe Attacks: Specific Antimigraine Therapy

Triptans

Triptans (sumatriptan, rizatriptan, zolmitriptan, eletriptan, and others) are selective 5-HT_1B/1D agonists. They inhibit CGRP release and cause cranial vasoconstriction.

• 37–50% achieve pain freedom at 2 hours.
• Most effective when taken early.
• Available in oral, ODT, nasal spray, and injectable forms.

Limitations: contraindicated in patients with ischemic heart disease, stroke, uncontrolled hypertension, and significant vascular disorders.

Gepants for Acute Treatment

Gepants (ubrogepant, rimegepant) are small-molecule CGRP receptor antagonists. Unlike triptans, they do not cause vasoconstriction.

• Used at the onset of an attack.
• 20% achieve pain freedom at 2 hours; 35–40% freedom from the most bothersome symptom.
• Suitable for patients with cardiovascular risk factors.
• Do not cause medication-overuse headache.

Lasmiditan

A selective 5-HT_1F agonist with no vasoconstrictive activity — useful when triptans are contraindicated. However, it may cause sedation; driving is prohibited for at least 8 hours after dosing.

Additional Acute Options

• Antiemetics (metoclopramide, prochlorperazine)
• Non-oral formulations — nasal sprays, injections, suppositories
• Neuromodulation devices — non-invasive vagal nerve stimulation, supraorbital stimulation

Preventive Treatment: Reducing Frequency and Severity

Prevention is recommended when:

• ≥4–5 migraine days per month,
• attacks cause marked disability,
• acute medications are insufficient or overused,
• risk of chronification is present.

Traditional Preventive Medications

• Beta-blockers: propranolol, metoprolol
• Antidepressants: amitriptyline
• Anticonvulsants: topiramate

These options are effective but can be limited by side effects (sedation, weight changes, cognitive slowing).

CGRP-Targeted Therapy: Monoclonal Antibodies and Gepants

Why CGRP Is a Key Target

• Vasodilation of meningeal vessels
• Activation and sensitization of trigeminal pathways
• Amplification of neurogenic inflammation
• Maintenance of the migraine pain cascade

Monoclonal Antibodies (mAbs) Against CGRP

Monoclonal antibodies block either CGRP itself or its receptor:

• Erenumab — CGRP receptor blocker
• Galcanezumab, Fremanezumab, Eptinezumab — CGRP ligand blockers

Mechanism: mAbs prevent activation of the trigeminovascular system, interrupting the molecular cascade before attacks develop.

Indications:

• Frequent episodic migraine (≥4 days/month)
• Chronic migraine (≥15 headache days/month)
• Failure or intolerance of ≥2 traditional preventive medications
• Marked migraine-related disability

Key features:

• Used only for prevention
• Monthly or quarterly dosing
• Onset of effect often within 1–2 weeks
• High tolerability (common: injection-site reactions, constipation)

Gepants: Dual Role — Acute and Preventive

Gepants (atogepant, rimegepant, ubrogepant) block the CGRP receptor and can be used both for acute treatment and prevention.

Gepants for prevention:

• Atogepant — daily
• Rimegepant — every other day

• Reduce migraine frequency by 40–60%.
• Well tolerated (mild nausea, fatigue in some cases).
• Oral dosing — preferred by patients who dislike injections.

Ideal for patients:

• with contraindications to triptans,
• with cardiovascular risk factors,
• preferring oral preventive therapy.

Botulinum Toxin for Chronic Migraine (PREEMPT Protocol)

OnabotulinumtoxinA is approved for chronic migraine (≥15 headache days/month). The PREEMPT protocol involves 31 injection sites (155 units, with optional “follow-the-pain” dosing).

Long-term studies show a 40–60% reduction in headache days, improved quality of life, and decreased need for acute medications. Botox is often combined with CGRP-targeted therapies in refractory chronic migraine.

Choosing the Optimal Treatment Strategy

• Up to 4 attacks/month: optimized acute therapy (NSAIDs, triptan, or gepant)
• 4–8 attacks/month: add preventive therapy (traditional or gepants)
• Chronic migraine: botulinum toxin ± CGRP-mAbs or gepants
• Cardiovascular risk: gepants preferred, triptans limited
• No daily pills preferred: CGRP-mAbs or Botox
• Triptan non-responders: gepants or lasmiditan

Comparison Table

References