Best Medications for Headache When NSAIDs Are Ineffective
For patients with headaches that do not respond to NSAIDs, the recommended first-line treatment is a triptan (such as sumatriptan) combined with acetaminophen. 1
Treatment Algorithm Based on Headache Type and Severity
For Migraine Headaches
- If NSAIDs have failed, add a triptan to an NSAID or to acetaminophen (when NSAIDs are contraindicated) 1
- Choice of specific triptan (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, or zolmitriptan) should be based on route of administration and cost 1
- Begin treatment as soon as possible after headache onset for improved efficacy 1
When Triptans Are Contraindicated or Ineffective
- CGRP antagonists (gepants) such as rimegepant, ubrogepant, or zavegepant are recommended for moderate to severe acute episodic migraine 1, 2
- Dihydroergotamine (DHE), particularly in intranasal formulation, shows good efficacy for acute migraine attacks 2, 3
- Lasmiditan (a ditan) can be considered for moderate to severe acute migraine when other options fail 2
For Headaches with Significant Nausea/Vomiting
- Select a non-oral route of administration (nasal spray, injection) 1, 4
- Add an antiemetic such as metoclopramide or prochlorperazine, which can also provide synergistic analgesia 2, 3
- Combination of acetaminophen (1000 mg) plus metoclopramide (10 mg) has shown efficacy equivalent to oral sumatriptan 100 mg 5
Specific Medication Evidence and Considerations
Triptans
- Oral sumatriptan 50-100 mg provides significant headache relief at 2 hours (50-62% response rate) compared to placebo (17-27%) 6
- Subcutaneous and intranasal sumatriptan are particularly useful for patients with nausea and vomiting 3
- Contraindicated in patients with uncontrolled hypertension, coronary artery disease, and basilar or hemiplegic migraine 4
CGRP Antagonists (Gepants)
- Rimegepant, ubrogepant, and zavegepant are effective for moderate to severe migraine attacks 2
- Particularly valuable for patients who cannot take triptans due to cardiovascular contraindications 7
- Generally well-tolerated with fewer cardiovascular concerns than triptans 8
Other Options
- Dihydroergotamine nasal spray has good evidence for efficacy and safety 1, 2
- Acetaminophen alone is ineffective for most migraines but may be combined with caffeine for mild to moderate attacks 4, 5
- Antiemetics like metoclopramide or prochlorperazine can be effective both for nausea and as primary headache treatment 3
Important Cautions
- Avoid opioids and butalbital-containing medications for routine headache treatment as they can lead to dependency, rebound headaches, and eventual loss of efficacy 1, 2, 9
- Be aware of medication overuse headache, which can occur with frequent use of acute medications (≥15 days per month with most medications; ≥10 days per month with triptans) 1, 2
- If episodic migraine occurs frequently or treatment doesn't provide adequate response, consider preventive medications 1
- Patients who don't respond to one triptan may respond to another within the same drug class 1