What are the most effective first‑line migraine medications and are they covered by insurance when prescribed?

Most Effective First-Line Migraine Medications and Insurance Coverage

For acute migraine treatment, the combination of a triptan (sumatriptan 50-100 mg) plus an NSAID (naproxen 500 mg) is the most effective first-line therapy and is universally covered by insurance; for preventive therapy, propranolol (80-240 mg/day) is the most effective first-line medication and is also universally covered. 1, 2

Acute Migraine Treatment: First-Line Medications

Mild to Moderate Attacks

• NSAIDs are the initial first-line choice, with the strongest evidence supporting ibuprofen 400-800 mg, naproxen sodium 500-825 mg, or aspirin 1000 mg 2
• Acetaminophen 1000 mg combined with aspirin 500-1000 mg plus caffeine 130 mg achieves pain reduction in 59.3% of patients at 2 hours 2
• Insurance coverage: NSAIDs and acetaminophen combinations are universally covered as over-the-counter or generic medications with minimal to no cost 2

Moderate to Severe Attacks or NSAID Failure

• Triptan + NSAID combination is superior to either agent alone, with 130 additional patients per 1,000 achieving sustained pain relief at 48 hours compared to triptan monotherapy 2
• Sumatriptan 50-100 mg plus naproxen 500 mg has the strongest evidence, with a number-needed-to-treat of 3.5 for headache relief at 2 hours 2
• Alternative oral triptans include rizatriptan 10 mg (fastest oral triptan, reaching peak in 60-90 minutes), eletriptan 40 mg, or zolmitriptan 2.5-5 mg 2
• Insurance coverage: Generic triptans (sumatriptan, rizatriptan, naratriptan) are universally covered as first-line agents with typical generic copays ($10-30) 2, 3

Route Selection Based on Severity

• Subcutaneous sumatriptan 6 mg provides the highest efficacy (59% complete pain relief at 2 hours) with onset within 15 minutes, indicated when oral routes fail or rapid progression occurs 2
• Intranasal sumatriptan 5-20 mg is appropriate when significant nausea or vomiting prevents oral administration 2
• Insurance coverage: Injectable and intranasal formulations require prior authorization in some plans but are covered as first-line when medically justified 2

Critical Frequency Limitation

• Limit all acute medications to ≤2 days per week (≤10 days per month) to prevent medication-overuse headache, which paradoxically increases headache frequency and can lead to daily headaches 1, 2
• If acute treatment is needed more than twice weekly, initiate preventive therapy immediately 1, 2

Preventive Migraine Treatment: First-Line Medications

Indications for Preventive Therapy

• ≥2 migraine attacks per month producing disability lasting ≥3 days 1
• Acute medication use >2 days per week 1
• Contraindication to or failure of acute treatments 1
• Patient preference for prevention 1

First-Line Preventive Agents

Propranolol (Beta-Blocker)

• Propranolol 80-240 mg/day is the single most effective first-line preventive medication, with FDA approval, strongest evidence base, and most favorable cost-benefit profile 1, 4
• Start at 80 mg daily and titrate to target range, with most patients achieving control at 160 mg daily 4
• Insurance coverage: Propranolol is universally covered as a generic first-line agent with minimal copay ($4-10 per month) and requires no prior authorization 4, 3
• Contraindications include asthma, bradycardia, second or third-degree heart block, and uncontrolled diabetes 4
• Alternative beta-blockers with strong evidence include timolol 20-30 mg/day and metoprolol 1, 3

Topiramate (Anticonvulsant)

• Topiramate 50-100 mg/day (typically 50 mg twice daily) is first-line with strong RCT evidence for both episodic and chronic migraine 1
• Preferred when obesity is present due to associated weight loss benefits 1
• Insurance coverage: Generic topiramate is universally covered as first-line with typical generic copay, no prior authorization required 1, 3
• Common side effects include cognitive slowing, paresthesias, and kidney stones 1

Candesartan (ARB)

• Candesartan is first-line, particularly useful for patients with comorbid hypertension 1
• Insurance coverage: Covered as first-line when hypertension is documented; may require step therapy (trying propranolol or topiramate first) in some plans 1

Second-Line Preventive Agents

Amitriptyline

• Amitriptyline 30-150 mg/day is second-line, preferred when comorbid depression, anxiety, or sleep disturbances are present 1
• Lacks robust RCT evidence for chronic migraine; efficacy is mainly demonstrated in episodic migraine and mixed headache patterns 1
• Insurance coverage: Generic amitriptyline is universally covered with minimal copay, no prior authorization required 1, 3

Valproate/Divalproex

• Sodium valproate 800-1500 mg/day or divalproex sodium 500-1500 mg/day are second-line options 1
• Strictly contraindicated in women of childbearing potential due to teratogenic effects 1
• Insurance coverage: Covered as second-line; may require documentation of first-line failure 1

Third-Line Preventive Agents (When First-Line Fails)

CGRP Monoclonal Antibodies

• Erenumab, fremanezumab, galcanezumab, or eptinezumab should be considered only after failure of 2-3 oral preventive medications 1
• Administered monthly via subcutaneous injection, with efficacy assessment requiring 3-6 months 1
• Insurance coverage: CGRP antibodies are significantly more expensive ($5,000-$6,000 annually) and universally require prior authorization demonstrating failure of at least two first-line oral agents (typically propranolol and topiramate) 1
• Most plans require documentation of inadequate response to propranolol, topiramate, and one additional agent before approval 1

OnabotulinumtoxinA (Botox)

• Only FDA-approved therapy specifically for chronic migraine (≥15 headache days per month), not episodic migraine 1
• Administered as 155-195 units across 31-39 sites every 12 weeks 1
• Insurance coverage: Requires prior authorization with documentation of chronic migraine diagnosis and failure of at least three oral preventives; universally covered for chronic migraine when criteria are met 1

Duration of Adequate Trial

• Allow 2-3 months at therapeutic dose for oral preventives before declaring treatment failure 1, 4
• Allow 3-6 months for CGRP monoclonal antibodies 1
• Allow 6-9 months for onabotulinumtoxinA 1

Insurance Coverage Summary

Universally Covered as First-Line (No Prior Authorization)

• Generic NSAIDs (ibuprofen, naproxen) 2
• Generic triptans (sumatriptan, rizatriptan, naratriptan) 2, 3
• Propranolol 4, 3
• Topiramate 1, 3
• Amitriptyline 1, 3

Require Prior Authorization or Step Therapy

• CGRP monoclonal antibodies (require failure of ≥2 oral preventives) 1
• OnabotulinumtoxinA (require chronic migraine diagnosis and failure of ≥3 oral preventives) 1
• Candesartan (may require documented hypertension or first-line failure) 1
• Brand-name triptans (require generic trial first) 2

Common Pitfalls to Avoid

• Do not prescribe opioids or butalbital-containing compounds for migraine; they have questionable efficacy, lead to dependency, cause rebound headaches, and result in loss of efficacy over time 2
• Do not allow patients to use acute medications more than 2 days per week; this creates medication-overuse headache and requires transition to preventive therapy 1, 2
• Do not start preventive medications at full dose; begin low and titrate slowly over 2-3 months to minimize side effects and improve tolerability 1
• Do not declare preventive treatment failure before 2-3 months at therapeutic dose; clinical benefits may not become apparent immediately 1, 4
• Do not use valproate in women of childbearing potential due to teratogenic risk 1