Naproxen

Naproxen is a propionic acid NSAID with a long half-life that permits twice-daily dosing. It has the lowest arterial thrombotic risk among the commonly used NSAIDs in observational data, but its gastrointestinal bleeding risk is higher than that of ibuprofen.

Class. Nonselective NSAID (propionic acid derivative).

Mechanism. Reversible inhibition of COX-1 and COX-2 with sustained platelet thromboxane suppression at full dose.

Pharmacokinetics. Oral bioavailability about 95%. Peak 2 to 4 hours for naproxen, 1 to 2 hours for naproxen sodium. Protein binding over 99%. Half-life 12 to 17 hours. Hepatic metabolism (O-demethylation and glucuronidation) with renal excretion.

Equivalence. Naproxen sodium 550 mg is equivalent to naproxen 500 mg.

Indications are osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute gout, juvenile idiopathic arthritis, musculoskeletal pain, dysmenorrhoea and acute headache or migraine.

Adults

• Chronic inflammatory conditions: 250 to 500 mg twice daily. Maximum 1 g daily over the long term; up to 1.25 g daily for short courses.
• Acute pain and dysmenorrhoea: 500 mg first dose, then 250 mg every 6 to 8 hours as needed. Maximum 1.25 g on day 1, then 1 g daily.
• Acute gout: 750 mg first dose, then 250 mg every 8 hours until the attack settles.
• No titration is needed beyond adjusting to the lowest effective dose.

Children over 5 years (specialist). Juvenile idiopathic arthritis: 10 mg/kg daily in 2 divided doses.

Gastroprotection. Offer a proton pump inhibitor in older adults and in anyone with ulcer history or on anticoagulant, antiplatelet, corticosteroid or SSRI therapy.

Contraindications. Active or previous gastrointestinal ulcer, bleeding or perforation; severe heart failure; severe renal impairment (creatinine clearance under 30 mL/min); severe hepatic impairment; third trimester; aspirin-exacerbated respiratory disease or other NSAID hypersensitivity; around coronary artery bypass surgery; suspected dengue.

Boxed-warning-level risks. Arterial thrombotic events (lower than diclofenac but not absent); gastrointestinal bleeding, ulceration and perforation.

Adverse effects. Common: dyspepsia, nausea, abdominal pain, headache, dizziness, tinnitus, oedema and raised blood pressure. Serious: gastrointestinal haemorrhage, acute kidney injury, hyperkalaemia, bronchospasm, severe skin reactions, hepatitis, pseudoporphyria and anaphylaxis.

Interactions. Same class pattern: bleeding with anticoagulants, antiplatelets, corticosteroids and SSRIs; kidney injury with ACE inhibitors, angiotensin receptor blockers and diuretics; raised lithium and methotrexate; nephrotoxicity with ciclosporin, tacrolimus and tenofovir disoproxil. Naproxen can blunt the antiplatelet effect of low-dose aspirin.

Common prescribing errors. Duplicate NSAID therapy (including over-the-counter naproxen sodium 220 mg tablets); dosing sodium and base salts interchangeably; continuing a loading-style dose beyond day 1.

Special groups

• Pregnancy: avoid from 20 weeks and absolutely in the third trimester; before 20 weeks, only when needed at the lowest dose.
• Breastfeeding: it enters milk and the infant half-life is long, so prefer ibuprofen. Short courses only if no alternative.
• Older adults: lower dose (250 mg twice daily), gastroprotection, renal checks.
• Kidney impairment: avoid if creatinine clearance is under 30 mL/min; lowest dose in mild to moderate.
• Liver impairment: avoid in severe disease; lower dose in mild to moderate.
• Regional: avoid in dehydration, suspected dengue and in people taking tenofovir disoproxil unless renal function is monitored.

Formulations. Tablets 250 and 500 mg, naproxen sodium 275 and 550 mg, enteric-coated and modified-release forms, suspension 125 mg/5 mL, suppositories 500 mg.

Administration. Oral doses with food or milk. Modified-release forms are swallowed whole. Enteric-coated forms have a delayed onset and are not suitable for acute pain.

Baseline. Blood pressure, creatinine and eGFR, cardiovascular and ulcer history, volume status and concurrent medicines.

Monitoring. Blood pressure, fluid status and creatinine within 1 to 2 weeks in high-risk patients. Haemoglobin if gastrointestinal symptoms develop. Liver enzymes periodically in long-term use.

Therapeutic drug monitoring. Not used.

Stopping thresholds. Stop for gastrointestinal bleeding, creatinine rise of 30% or more, new heart failure or severe hypertension, severe rash or bronchospasm.

Referral and escalation. Melaena, haematemesis, oliguria, chest pain or anaphylaxis needs emergency care. Inadequate control beyond 2 weeks needs specialist review.