What is the safety of naproxen (nonsteroidal anti-inflammatory drug (NSAID)) for headache relief?

Safety of Naproxen for Headache

Naproxen is generally safe and well-tolerated for acute headache treatment when used appropriately, but carries significant cardiovascular and gastrointestinal risks that require careful patient selection and dosing limits. 1

Critical Safety Warnings

Cardiovascular Risks

• NSAIDs including naproxen may cause serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal, with risk increasing with duration of use 1
• Patients with existing cardiovascular disease or risk factors face greater risk and require careful evaluation before prescribing 1
• Naproxen is absolutely contraindicated for peri-operative pain in coronary artery bypass graft (CABG) surgery 1

Gastrointestinal Risks

• NSAIDs cause serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal 1
• These events can occur at any time during use without warning symptoms 1
• Elderly patients are at substantially greater risk for serious gastrointestinal events 1
• Consider adding proton pump inhibitor (omeprazole 20-40 mg daily) for gastroprotection if regular NSAID use is necessary 2

Medication Overuse Headache Risk

• Limit acute headache medication use to ≤2 days per week to prevent medication overuse headache, which worsens migraine frequency and creates a rebound cycle 2
• Weekly use of acute headache medications (≥2 days per week) places patients at high risk for medication overuse headache 2
• The threshold for medication overuse headache is ≥15 days per month with NSAIDs 3

Efficacy and Safety Profile in Clinical Trials

Demonstrated Efficacy

• Naproxen (500 mg and 825 mg) demonstrates moderate efficacy with NNT of 11 for pain-free response at 2 hours (17% response vs 8% with placebo) and NNT of 6.0 for headache relief (45% response vs 29% with placebo) 3, 4
• The combination of sumatriptan and naproxen has the greatest net benefit compared to naproxen monotherapy, with high-certainty evidence 3
• Naproxen is effective in reducing headache intensity and improving migraine-associated symptoms (nausea, photophobia, phonophobia) 5

Adverse Event Profile

• Adverse events with naproxen are mostly mild or moderate in severity and rarely lead to withdrawal 3, 4
• Common adverse events include nausea, dizziness, dyspepsia, and abdominal pain 5
• The risk of any adverse event is greater with naproxen than placebo (pooled risk ratio 1.29,95% CI 1.04-1.60) 5
• When naproxen 500 mg alone was analyzed, adverse events were not significantly more common than placebo 4

Hepatic and Renal Safety Considerations

• Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) occur in approximately 1% of patients 1
• Rare cases of severe hepatic reactions including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure (some fatal) have been reported 1
• Discontinue naproxen if clinical signs of liver disease develop or if systemic manifestations occur (eosinophilia, rash) 1
• Chronic alcoholic liver disease reduces total plasma concentration but increases unbound naproxen concentration, requiring dose adjustment 1

Hematological Safety

• NSAIDs inhibit platelet aggregation and prolong bleeding time, though the effect is quantitatively less and shorter duration than aspirin 1
• Patients with coagulation disorders or receiving anticoagulants require careful monitoring 1
• Monitor hemoglobin or hematocrit in patients on long-term NSAID therapy who exhibit signs of anemia 1

Contraindications and Special Populations

Absolute Contraindications

• Aspirin-sensitive asthma (cross-reactivity can cause severe bronchospasm, which can be fatal) 1
• Peri-operative CABG surgery 1

Use with Caution

• Patients with cardiovascular disease or risk factors 1
• Elderly patients (greater risk for serious GI events) 1
• Patients with preexisting asthma 1
• Pregnancy (avoid in late pregnancy due to risk of premature ductus arteriosus closure) 1
• Patients with hepatic or renal impairment 1

Recommended Dosing for Safety

• Maximum single dose: 825 mg initially, followed by 550 mg one hour later if needed 6
• Standard dosing: 500 mg as initial dose 3, 4
• Do not exceed recommended maximum daily doses 2
• Use the lowest effective dose to minimize risks 1

Clinical Monitoring Requirements

• Monitor for signs of GI bleeding (epigastric pain, dyspepsia, melena, hematemesis) 1
• Check CBC and chemistry profile periodically in patients on long-term treatment 1
• Monitor liver function tests if clinical signs of hepatotoxicity develop (nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness) 1
• Assess for unexplained weight gain or edema 1

Key Safety Pitfalls to Avoid

• Do not combine naproxen with aspirin, as aspirin increases naproxen excretion rate and the combination results in higher frequency of adverse events 1
• Do not use naproxen as monotherapy when combination with triptan would be more effective and appropriate 3
• Do not exceed 2 days per week of use to prevent medication overuse headache 2
• Do not ignore warning signs of serious adverse events (chest pain, shortness of breath, GI bleeding symptoms, skin rash) 1