What is the recommended dosage and safety precautions for using a combination of aspirin (acetylsalicylic acid), caffeine, and paracetamol (acetaminophen) for headache treatment?

Aspirin + Caffeine + Paracetamol (Acetaminophen) Combination Therapy

The combination of aspirin 250-500 mg + paracetamol 200-500 mg + caffeine 50-100 mg is strongly recommended as first-line treatment for acute migraine and tension-type headache, with superior efficacy compared to single agents or dual combinations. 1, 2

Recommended Dosage

Standard dosing is two tablets of the fixed combination (typically 250 mg aspirin + 200 mg paracetamol + 50 mg caffeine per tablet) at headache onset, with one additional tablet every 30 minutes as needed, up to a maximum of 6 tablets per attack. 3

• Treatment should be initiated as early as possible during the attack while pain is still mild to maximize efficacy 1, 2
• Maximum weekly limit is 10 tablets to prevent medication-overuse headache 3
• The combination achieves 50% pain relief significantly faster than placebo (p = 0.0008) and outperforms all single components 4, 5

Evidence for Superior Efficacy

The triple combination demonstrates statistically significant superiority over dual combinations and monotherapy across all efficacy endpoints. 5

• Time to 50% pain relief is significantly better than aspirin + paracetamol without caffeine (p = 0.0181), aspirin alone (p = 0.0398), and paracetamol alone (p = 0.0016) 5
• Effective across the full spectrum from mild to severe headache intensity, with consistent efficacy regardless of baseline pain severity 4, 6
• The combination provides synergistic analgesia, with caffeine enhancing absorption and efficacy of the analgesic components 2, 7

Safety Precautions and Contraindications

Limit use to no more than 2 days per week (or 10 tablets per week) to prevent medication-overuse headache, which develops with frequent use and leads to daily chronic headaches. 1, 3

• Standard NSAID contraindications apply: active GI bleeding, severe renal impairment (creatinine clearance <30 mL/min), aspirin/NSAID-induced asthma 2, 3
• Monitor total daily acetaminophen intake to ensure it does not exceed 4000 mg per day from all sources 2
• Avoid in pregnancy (particularly third trimester due to aspirin), lactation, and children under 12 years due to aspirin content 3

Adjunctive Therapy for Enhanced Efficacy

Adding metoclopramide 10 mg or prochlorperazine 25 mg orally 20-30 minutes before the combination provides synergistic analgesia and treats associated nausea. 2, 3

• Metoclopramide improves gastric motility impaired during migraine attacks, enhancing medication absorption 1, 2
• Prochlorperazine has direct analgesic effects for headache pain in addition to antiemetic properties 1, 2
• Non-oral routes (IV, rectal) should be considered when significant nausea or vomiting is present early in the attack 1, 2

When to Escalate Treatment

If the combination fails after 2-3 headache episodes, escalate to triptan therapy (sumatriptan, rizatriptan, or zolmitriptan) for moderate-to-severe attacks. 1, 2

• The combination is most appropriate for mild-to-moderate migraine or tension-type headache 1
• For severe migraine with rapid onset or vomiting, consider subcutaneous sumatriptan 6 mg as first-line instead 1, 2
• If headaches occur more than 2 days per week despite optimized acute treatment, initiate preventive therapy rather than increasing acute medication frequency 2, 3

Critical Pitfalls to Avoid

Never allow patients to exceed the 2-days-per-week frequency limit, as this creates a vicious cycle of medication-overuse headache requiring withdrawal and preventive therapy. 1, 2

• Overuse of caffeine-containing analgesics specifically leads to rebound headaches upon withdrawal 1, 7
• Do not combine with ergotamine-containing medications within 24 hours due to additive vasoconstriction risk 3
• Avoid establishing patterns of daily or near-daily use, which transforms episodic headache into chronic daily headache 1

Tolerability Profile

The combination is well-tolerated with adverse event rates similar to placebo (13.4-18.9%), consisting primarily of mild, transient gastrointestinal symptoms. 4, 6, 5

• No serious adverse events have been reported with the combination in clinical trials 4, 5
• The safety profile is superior to triptans, which have higher rates of serious/severe adverse events (NNH 32 for sumatriptan vs. combination therapy) 8
• Long-term safety concerns relate to medication-overuse headache rather than direct toxicity when used within recommended frequency limits 1