What are the most effective medications for treating headaches?

Most Effective Headache Medications

For mild to moderate headaches, NSAIDs (ibuprofen 400-800mg, naproxen sodium 275-550mg, or aspirin 650-1000mg) are first-line treatment, while moderate to severe migraines require triptans (sumatriptan, rizatriptan, naratriptan, or zolmitriptan) as first-line therapy. 1

Treatment Algorithm by Headache Severity

Mild to Moderate Headaches

• Start with NSAIDs as first-line therapy 1

  • Ibuprofen 400-800mg every 6 hours (maximum 2.4g/day) 1
  • Naproxen sodium 275-550mg every 2-6 hours (maximum initial dose 825mg, avoid exceeding 1.5g/day) 1
  • Aspirin 650-1000mg every 4-6 hours (maximum 4g/day) 1

• Combination therapy with aspirin-acetaminophen-caffeine is highly effective when NSAIDs alone are insufficient 1

  • Acetaminophen alone is ineffective and should not be used as monotherapy 1

Moderate to Severe Migraines

• Triptans are first-line therapy 1

  • Oral options: sumatriptan 50-100mg, rizatriptan, naratriptan, or zolmitriptan 1
  • Subcutaneous sumatriptan 6mg provides highest efficacy (59% complete pain relief at 2 hours) but with higher adverse event rates 2, 3
  • Intranasal sumatriptan 5-20mg for patients with early nausea/vomiting 2

• Take triptans early in the attack while pain is still mild for maximum effectiveness 2

Severe Migraines Unresponsive to First-Line Therapy

• Parenteral ketorolac 60mg IM has rapid onset (approximately 6 hours duration) with minimal rebound headache risk 1, 2
• Dihydroergotamine (DHE) intranasal spray has good evidence for efficacy and safety 1
• Combination IV therapy: metoclopramide 10mg + ketorolac 30mg for severe attacks requiring emergency treatment 2

Adjunctive Medications

For Nausea and Vomiting

• Metoclopramide 10mg provides synergistic analgesia beyond treating nausea alone 1
• Prochlorperazine 10mg effectively relieves headache pain comparable to metoclopramide 1, 2
• Antiemetics should not be restricted only to vomiting patients—nausea itself is disabling and warrants treatment 1, 2

Route Selection

• Use non-oral routes (intranasal, subcutaneous, or IV) when nausea/vomiting present early in the attack 1

Tension-Type Headaches

• Ibuprofen 400mg or acetaminophen 1000mg for acute treatment 1
• Amitriptyline for prevention of chronic tension-type headaches 1

Critical Medication-Overuse Pitfall

Limit acute headache medications to no more than twice weekly to prevent medication-overuse headache (rebound headache) 1, 2. This applies to:

• Opioids 1
• Triptans 1
• Ergotamine 1
• Caffeine-containing analgesics 1
• Butalbital-containing compounds 1

If using acute medications more than twice weekly, initiate preventive therapy immediately rather than increasing acute medication frequency 2

Preventive Therapy Indications

Consider preventive medications when patients have: 1

• Two or more attacks per month producing disability lasting 3+ days
• Use of acute medications more than twice weekly
• Failure of or contraindications to acute treatments
• Uncommon migraine variants (hemiplegic, prolonged aura, migrainous infarction)

First-Line Preventive Agents

• Propranolol 80-240mg/day 1
• Timolol 20-30mg/day 1
• Amitriptyline 30-150mg/day 1
• Divalproex sodium 500-1500mg/day or sodium valproate 800-1500mg/day 1
• Topiramate 1
• Newer CGRP inhibitors (gepants, eptinezumab, atogepant) for episodic migraines 1
• AbobotulinumtoxinA for chronic migraines only (not episodic) 1

Gabapentin is not recommended for episodic migraine prevention 1

Medications to Avoid or Use Cautiously

Avoid as Routine Therapy

• Opioids (meperidine, butorphanol, hydromorphone) should be reserved only when other medications cannot be used, sedation is acceptable, and abuse risk has been addressed 1, 2

  • Lead to dependency, rebound headaches, and loss of efficacy 1, 2
  • If opioid required, butorphanol nasal spray has better evidence than other opioids 2

• Acetaminophen monotherapy is ineffective for migraine 1

Contraindications for Triptans

Do not use triptans in patients with: 1

• Uncontrolled hypertension
• Basilar or hemiplegic migraine
• Cardiovascular disease or risk factors for heart disease

Newer Treatment Options

CGRP inhibitors (gepants) and eptinezumab represent effective newer options for acute and preventive migraine treatment 1, though the 2002-2003 guidelines 1 predate these agents. The 2024 VA/DoD guideline 1 confirms their efficacy alongside traditional therapies.

Non-Pharmacologic Adjuncts

Aerobic exercise and physical therapy can be used in management of both tension-type headaches and migraines 1, providing additional benefit when combined with pharmacotherapy.