What are the recommended first‑line preventive medications, dosing, and safety considerations for an adult with episodic migraine?

First-Line Preventive Medications for Episodic Migraine

For episodic migraine prevention in adults, start with candesartan 16 mg daily or propranolol 80–240 mg daily as first-line oral agents, or use CGRP monoclonal antibodies (erenumab, fremanezumab, or galcanezumab) if oral agents fail or are not tolerated. 1

Recommended First-Line Agents

Angiotensin Receptor Blockers (Strongest Recommendation)

• Candesartan 16 mg once daily or telmisartan 80 mg once daily receive strong recommendations from the 2024 VA/DoD guidelines for episodic migraine prevention. 1
• Candesartan is particularly useful when hypertension coexists, providing dual therapeutic benefit. 1, 2

Beta-Blockers (Established Efficacy)

• Propranolol 80–240 mg daily (most commonly 160 mg once daily) is FDA-approved with strong evidence from multiple randomized trials. 1, 3
• Timolol 20–30 mg daily also has strong evidence for migraine prophylaxis. 1
• Metoprolol is supported by moderate-quality evidence as an alternative beta-blocker. 1, 3
• Only beta-blockers without intrinsic sympathomimetic activity are effective; avoid acebutolol. 3, 4

CGRP Monoclonal Antibodies (Highest Efficacy, Highest Cost)

• Erenumab, fremanezumab, or galcanezumab receive strong recommendations from the 2024 VA/DoD guidelines for both episodic and chronic migraine. 1, 2
• These agents reduce monthly migraine days by 3.2–4.4 days with favorable tolerability profiles. 5
• The 2025 American College of Physicians guideline positions CGRP therapies as second-line after failure of beta-blockers, valproate, venlafaxine, or amitriptyline. 1
• Eptinezumab IV receives a weak recommendation for episodic or chronic migraine. 1

Oral CGRP Antagonists (Gepants)

• Atogepant 10 mg, 30 mg, or 60 mg once daily is FDA-approved for episodic migraine prevention (60 mg for chronic migraine). 1, 6
• Rimegepant has insufficient evidence per the 2024 VA/DoD guidelines but receives a weak recommendation from the 2025 ACP guideline. 1

Second-Line Agents

Antiepileptic Drugs

• Topiramate 50–100 mg daily (typically 50 mg twice daily) receives weak recommendations for both episodic and chronic migraine. 1, 3
• Topiramate is preferred in patients with obesity because it promotes weight loss. 3, 4
• Valproate 800–1500 mg daily or divalproex sodium 500–1500 mg daily receive weak recommendations but are strictly contraindicated in women of childbearing potential due to teratogenic risk. 1, 3

Tricyclic Antidepressants

• Amitriptyline 30–150 mg daily is preferred when comorbid depression, anxiety, or sleep disturbances exist. 1, 3, 4
• Evidence for amitriptyline is stronger for episodic migraine than chronic migraine. 3, 4

Other Agents with Weak Evidence

• Lisinopril receives a weak recommendation for episodic migraine. 1, 2
• Oral magnesium receives a weak recommendation for migraine prevention. 1, 2
• Memantine receives a weak recommendation for episodic migraine. 1, 2

Dosing and Administration

Beta-Blocker Dosing

• Propranolol: Start 80 mg daily, titrate to 160–240 mg daily (most patients require ≥160 mg for efficacy). 1, 3
• Timolol: 20–30 mg daily. 1
• Metoprolol: Typical effective doses range from 100–200 mg daily. 3

CGRP Monoclonal Antibody Dosing

• Erenumab: 70 mg or 140 mg subcutaneous monthly. 7
• Fremanezumab: 225 mg subcutaneous monthly or 675 mg quarterly. 7
• Galcanezumab: 240 mg loading dose, then 120 mg subcutaneous monthly. 7
• Eptinezumab: 100 mg IV every 3 months. 1

Atogepant Dosing

• Episodic migraine: 10 mg, 30 mg, or 60 mg once daily. 6
• Chronic migraine: 60 mg once daily. 6
• Severe renal impairment: 10 mg once daily for episodic migraine; avoid in chronic migraine. 6
• Strong CYP3A4 inhibitors: 10 mg once daily for episodic migraine; avoid in chronic migraine. 6
• OATP inhibitors: 10–30 mg once daily for episodic migraine; 30 mg once daily for chronic migraine. 6

Topiramate Dosing

• Start 25 mg daily, titrate by 25 mg weekly to target dose of 50–100 mg daily (divided twice daily). 3, 4

Safety Considerations

Contraindications

• Beta-blockers: Avoid in asthma, severe bradycardia, heart block, or decompensated heart failure. 3
• Valproate/divalproex: Absolutely contraindicated in women of childbearing potential due to teratogenic effects (neural tube defects, developmental delays). 1
• Atogepant: Contraindicated in patients with hypersensitivity to atogepant; severe hypersensitivity reactions including anaphylaxis and dyspnea can occur days after administration. 6

Common Adverse Effects

• Propranolol: Fatigue, bradycardia, hypotension, depression, sexual dysfunction. 3
• Topiramate: Paresthesias, cognitive slowing, weight loss, kidney stones, metabolic acidosis. 3, 4
• Amitriptyline: Sedation, dry mouth, constipation, weight gain, orthostatic hypotension. 3, 4
• CGRP monoclonal antibodies: Injection-site reactions, constipation (generally well-tolerated). 7, 5
• Atogepant: Nausea (≥4%), constipation (≥4%), fatigue/somnolence (≥4%). 6

Treatment Algorithm

Step 1: Assess Indications for Preventive Therapy

• ≥2 migraine attacks per month with disability lasting ≥3 days. 1, 3
• Acute medication use >2 days per week (risk of medication-overuse headache). 1
• Contraindication to or failure of acute treatments. 1, 3
• Patient preference for prevention over frequent acute treatment. 3, 8

Step 2: Select First-Line Agent Based on Comorbidities

• Hypertension present → candesartan 16 mg daily. 1, 2
• No contraindications to beta-blockers → propranolol 80–240 mg daily. 1
• Obesity present → topiramate 50–100 mg daily (promotes weight loss). 3
• Depression, anxiety, or insomnia present → amitriptyline 30–150 mg daily. 3, 4
• Failure of oral agents or intolerance → CGRP monoclonal antibodies. 1, 7

Step 3: Titrate to Effective Dose

• Start low and titrate slowly over 2–4 weeks to minimize side effects. 3, 8
• Allow 2–3 months at target dose before judging efficacy. 3, 8
• For CGRP monoclonal antibodies, assess efficacy after 3–6 months. 7, 8

Step 4: Escalate if First-Line Fails

• After failure of two oral preventives (e.g., propranolol and topiramate), escalate to CGRP monoclonal antibodies or atogepant. 1, 7
• The 2025 ACP guideline recommends trying beta-blockers, valproate, venlafaxine, or amitriptyline before CGRP therapies. 1

Critical Pitfalls to Avoid

• Do not use sub-therapeutic doses: Propranolol <160 mg or amitriptyline <30 mg are generally ineffective. 3
• Do not abandon therapy prematurely: Allow 2–3 months at target dose before declaring failure. 3, 8
• Do not prescribe valproate to women of childbearing potential without absolute contraception and informed consent about teratogenic risk. 1
• Do not use gabapentin: The 2024 VA/DoD guidelines recommend against gabapentin for episodic migraine prevention. 1
• Do not use botulinum toxin for episodic migraine: OnabotulinumtoxinA is recommended only for chronic migraine (≥15 headache days/month), not episodic migraine. 1, 2
• Limit acute medication use to ≤2 days per week to prevent medication-overuse headache, which can increase headache frequency and lead to daily headaches. 1

Duration of Preventive Therapy

• After 6–12 months of successful prevention (≥50% reduction in monthly migraine days), consider tapering or discontinuing preventive therapy to determine if it can be stopped. 3, 8
• Use a headache diary to track attack frequency, severity, and acute medication use throughout treatment. 3, 8