What is the best next‑line medication for an adult with a headache that is not adequately relieved by acetaminophen (Tylenol) and ibuprofen?

Best Next-Line Headache Medication After Tylenol and Ibuprofen Failure

Add a triptan (sumatriptan 50–100 mg) to your current NSAID regimen rather than switching medications entirely, because the combination of triptan plus NSAID provides superior pain relief compared to either agent alone. 1

Evidence-Based Treatment Algorithm

Step 1: Combination Therapy (Strongest Recommendation)

• The combination of sumatriptan 50–100 mg PLUS naproxen 500 mg is the single most effective acute headache treatment, achieving sustained pain relief in 130 additional patients per 1,000 compared to sumatriptan alone at 48 hours. 1
• If you've been using ibuprofen, switch to naproxen 500 mg and add sumatriptan 50–100 mg for maximum benefit. 1
• This combination is superior to acetaminophen plus triptan, which has lower-certainty evidence. 1

Step 2: Timing Is Critical

• Take medication early when pain is still mild, not after it becomes severe—this single factor improves pain-free response from 28% to 50% at 2 hours. 2
• Waiting until pain is moderate or severe significantly reduces treatment effectiveness. 2

Step 3: Alternative Triptan Options If Sumatriptan Fails

• Failure of one triptan does not predict failure of others—if sumatriptan doesn't work after 2–3 headache episodes, try rizatriptan 10 mg (fastest oral triptan, peak in 60–90 minutes) or eletriptan 40 mg. 2, 3
• Naratriptan has the longest half-life and may prevent headache recurrence. 2

Step 4: Non-Oral Routes for Severe Attacks

• Subcutaneous sumatriptan 6 mg provides the highest efficacy (59% pain-free at 2 hours) with onset within 15 minutes, particularly useful when nausea/vomiting is present. 2, 4
• Intranasal sumatriptan 5–20 mg is an alternative when oral medication fails due to nausea. 2, 3

Critical Frequency Limitation to Prevent Medication-Overuse Headache

• Limit ALL acute headache 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 you need acute treatment more than twice weekly, initiate preventive therapy immediately (propranolol, topiramate, or amitriptyline) rather than increasing acute medication frequency. 2, 5

Third-Line Options When Triptans Are Contraindicated or Ineffective

• CGRP antagonists (gepants) such as ubrogepant 50–100 mg or rimegepant are third-line options with no vasoconstriction, making them safe for patients with cardiovascular disease. 2, 3
• Lasmiditan 50–200 mg (ditan) is another non-vasoconstricting alternative, but patients cannot drive for 8 hours after use due to CNS effects. 2

Medications to Absolutely Avoid

• Never use opioids (codeine, hydromorphone, oxycodone) or butalbital-containing compounds for headache treatment—they provide questionable efficacy, cause dependency, trigger rebound headaches, and worsen long-term outcomes. 2, 5, 6
• These agents should be reserved exclusively for cases where every other evidence-based treatment is contraindicated. 2, 5

Contraindications to Triptans

• Triptans are contraindicated in ischemic heart disease, uncontrolled hypertension (>140/90 mmHg), cerebrovascular disease, history of stroke/TIA, basilar or hemiplegic migraine, and within 24 hours of ergotamine use. 2, 3
• In controlled hypertension or sodium-sensitive hypertension without cardiovascular disease, triptans remain safe and appropriate. 2

Red Flags Requiring Urgent Evaluation

• Seek immediate medical attention for thunderclap onset, fever with neck stiffness, progressive worsening pattern, new neurological deficits, or headache that awakens you from sleep. 5

Cost-Effective Over-the-Counter Alternative

• If prescription triptans are unavailable, the combination of aspirin 500 mg + acetaminophen 500 mg + caffeine 130 mg achieves pain reduction to mild or none in 59.3% of patients at 2 hours (vs. 32.8% with placebo), with an excellent safety profile. 5, 7
• This combination is significantly more effective than acetaminophen alone. 5, 7

Common Pitfall to Avoid

• Do not abandon triptan therapy after a single failed attempt—each triptan has different pharmacokinetics, and trying 2–3 different triptans before declaring treatment failure is essential. 2, 3
• Do not increase the frequency of acute medication use in response to treatment failure; instead, transition to preventive therapy. 2, 5