# Migraine Prevention: Oral Agents and CGRP-Targeted Therapies

## Introduction

Preventive therapy is indicated when migraine attacks are frequent, disabling, or refractory to acute treatment. The landscape has been transformed by CGRP-targeted therapies, which offer the first mechanism-specific preventive treatments for migraine. This lecture reviews indications, traditional oral agents, and the newer monoclonal antibodies and gepants.

## Indications for Preventive Therapy

Preventive therapy should be considered when patients have 4 or more migraine days per month (or fewer if attacks are severe, prolonged, or poorly responsive to acute therapy), when significant disability persists despite optimized acute treatment, when there are contraindications to or overuse of acute medications, based on patient preference, or for special migraine subtypes such as hemiplegic migraine, brainstem aura, or migrainous infarction. The goal is to reduce attack frequency by 50% or more and improve quality of life.

## Traditional Oral Preventive Agents

### Beta-Blockers

Propranolol (80-240 mg/day) and metoprolol (50-200 mg/day) have the strongest evidence (Level A). Their mechanism involves central beta-adrenergic blockade, though the exact migraine mechanism remains unclear. Side effects include fatigue, exercise intolerance, depression, and bradycardia. They should be avoided in asthma, decompensated heart failure, and diabetes with frequent hypoglycemia.

### Antiepileptic Drugs

Topiramate (50-200 mg/day) has Level A evidence and also promotes weight loss. Side effects include cognitive slowing (earning it the nickname "dopamax"), paresthesias, nephrolithiasis, acute angle-closure glaucoma, and teratogenicity. Valproate/divalproex (500-1500 mg/day) also has Level A evidence and is effective but limited by weight gain, tremor, hair loss, hepatotoxicity, and teratogenicity (Category X).

### Antidepressants

Amitriptyline (25-75 mg/day) has Level B evidence and is particularly useful for comorbid insomnia, tension-type headache, or depression. Side effects include sedation, weight gain, dry mouth, constipation, and cardiac conduction effects. Venlafaxine (150 mg/day) has Level B evidence and is useful for comorbid anxiety or depression.

### Other Oral Agents

Candesartan (16 mg/day) is an angiotensin receptor blocker with Level B evidence that is well tolerated. Lisinopril (20 mg/day) is an ACE inhibitor with limited evidence. Magnesium (400-600 mg/day) has Level B evidence for migraine with aura and is safe and inexpensive. Riboflavin (400 mg/day) has Level B evidence with minimal side effects and is a reasonable first-line option for patients preferring nutraceuticals.

## CGRP-Targeted Monoclonal Antibodies

### Overview

CGRP-targeted monoclonal antibodies represent the first mechanism-specific preventive treatments for migraine. They target either the CGRP ligand or receptor and are administered monthly or quarterly via subcutaneous or intravenous injection. They offer rapid onset of action (often within the first month), a favorable side-effect profile compared to traditional oral agents, and minimal drug interactions.

### Individual Agents

| Agent | Target | Route/Frequency | Special Notes |
|---|---|---|---|
| Erenumab | CGRP receptor | SC monthly (70–140 mg) | Only receptor-targeting mAb; constipation |
| Fremanezumab | CGRP ligand | SC monthly or quarterly | Quarterly dosing option |
| Galcanezumab | CGRP ligand | SC monthly (120 mg after 240 mg load) | Also approved for episodic cluster headache |
| Eptinezumab | CGRP ligand | IV quarterly (100–300 mg) | Fastest onset; infusion center required |
| Atogepant (gepant) | CGRP receptor | PO daily (60 mg) | Oral prevention option |
| Rimegepant (gepant) | CGRP receptor | PO every other day (75 mg) | Dual acute + preventive approval |

Erenumab (70-140 mg subcutaneously monthly) is a human monoclonal antibody targeting the CGRP receptor, FDA-approved for episodic and chronic migraine. Fremanezumab (225 mg subcutaneously monthly or 675 mg subcutaneously quarterly) is a humanized antibody targeting the CGRP ligand. Galcanezumab (240 mg loading dose, then 120 mg subcutaneously monthly) is a humanized antibody targeting the CGRP ligand, also approved for episodic cluster headache. Eptinezumab (100-300 mg intravenously quarterly) is a humanized antibody targeting the CGRP ligand with the fastest onset, administered in an infusion center.

### Efficacy Data

All CGRP monoclonal antibodies demonstrate a 50% or greater reduction in monthly migraine days in approximately 50% of episodic migraine patients and 25-30% of chronic migraine patients. They produce significant improvement in disability scores (MIDAS, HIT-6), show consistent efficacy in patients who have failed 2-4 prior preventive classes, and have low discontinuation rates due to adverse effects.

### Safety and Side Effects

The most common side effect is injection site reactions (erythema, pain). Constipation is reported with erenumab (the CGRP receptor antagonist). Although there is a theoretical cardiovascular concern (CGRP is a vasodilator), no signal of increased cardiovascular events has appeared in trials or post-marketing surveillance. Importantly, there is no hepatotoxicity, no CNS side effects, and no drug interactions. These agents are not recommended in pregnancy due to insufficient data, and the long half-life requires a washout period.

## Oral CGRP Receptor Antagonists (Gepants) for Prevention

Atogepant (60 mg daily) is FDA-approved for episodic migraine prevention as an oral small-molecule CGRP receptor antagonist. Rimegepant (75 mg every other day) is approved for both acute treatment and prevention. Advantages include oral administration, no injection, and flexible dosing. Side effects are generally mild (nausea, constipation), and hepatotoxicity monitoring is recommended.

## OnabotulinumtoxinA

OnabotulinumtoxinA (Botox) is approved for chronic migraine (15 or more headache days per month with 8 or more being migraine days). The PREEMPT protocol involves 155-195 units injected across 31-39 sites in the head and neck every 12 weeks. Its mechanism involves inhibiting CGRP and substance P release from trigeminal afferents and blocking peripheral sensitization. Efficacy improves with repeated treatment cycles, and assessment should be made after 2-3 cycles before deeming failure. It is not effective for episodic migraine.

## Neuromodulation

Non-invasive vagus nerve stimulation (nVNS) is FDA-cleared for migraine and cluster headache. Single-pulse transcranial magnetic stimulation (sTMS) is FDA-cleared for migraine with aura. External trigeminal nerve stimulation (eTNS) using the Cefaly device is available for migraine prevention. Remote electrical neuromodulation (REN) uses an upper arm device for acute migraine. These devices are generally safe and well-tolerated, and are useful as adjunctive therapy or for patients averse to medications.

## Clinical Pearls

Traditional oral agents should be started first when comorbidities align (beta-blocker for hypertension, topiramate for obesity, amitriptyline for insomnia). CGRP-targeted therapies are first-line options for patients who fail, are intolerant of, or have contraindications to traditional preventives. Realistic expectations should be set: a 50% reduction in migraine days is considered a therapeutic success. OnabotulinumtoxinA is indicated only for chronic migraine and requires 2-3 cycles to assess efficacy.

## References
- 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.
- Dodick DW, Ashina M, Brandes JL, et al. ARISE: a phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia. 2018;38(6):1026-1037.
- Ailani J, Lipton RB, Goadsby PJ, et al. Atogepant for the preventive treatment of migraine. N Engl J Med. 2021;385(8):695-706.
- 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.