Introduction
Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) widely used for its analgesic, anti-inflammatory, and antipyretic properties. First approved by the FDA in 1976, it remains a cornerstone therapy for various pain and inflammatory conditions. As a propionic acid derivative, naproxen is available in both prescription and over-the-counter formulations under various brand names, including Naprosyn®, Aleve®, and Anaprox®.
Mechanism of Action
Naproxen exerts its therapeutic effects through nonselective inhibition of cyclooxygenase (COX) enzymes, primarily COX-1 and COX-2. These enzymes catalyze the conversion of arachidonic acid to prostaglandins, thromboxanes, and prostacyclins. By inhibiting prostaglandin synthesis, naproxen reduces inflammation, pain, and fever. Unlike selective COX-2 inhibitors, naproxen's nonselective inhibition affects both inflammatory pathways (via COX-2) and protective gastric prostaglandins (via COX-1), explaining its gastrointestinal side effect profile.
Indications
FDA-approved indications include:
- Osteoarthritis
- Rheumatoid arthritis
- Ankylosing spondylitis
- Tendinitis
- Bursitis
- Acute gout
- Primary dysmenorrhea
- Mild to moderate pain
- Fever reduction (OTC formulation)
Off-label uses may include migraine prophylaxis and pediatric arthritis (with specific formulations).
Dosage and Administration
Adults:- Pain/fever: 200-400 mg every 8-12 hours (max 1200 mg/day)
- Rheumatoid arthritis: 250-500 mg twice daily (max 1500 mg/day)
- Osteoarthritis: 250-500 mg twice daily
- Acute gout: 750 mg initially, then 250 mg every 8 hours
- Renal impairment: Avoid in severe renal impairment (CrCl <30 mL/min)
- Hepatic impairment: Use with caution; consider reduced dosing
- Elderly: Start with lowest effective dose due to increased NSAID sensitivity
- Pediatrics: 5-7 mg/kg/dose twice daily (max 15 mg/kg/day)
- Take with food or milk to minimize GI upset
- Immediate-release tablets: May be crushed if needed
- Delayed-release tablets: Swallow whole
- Suspension: Shake well before use
Pharmacokinetics
Absorption: Rapid and complete oral absorption with 95% bioavailability. Peak plasma concentrations reached within 2-4 hours. Food may delay absorption but does not affect extent. Distribution: Volume of distribution approximately 0.16 L/kg. Highly protein-bound (>99%), primarily to albumin. Crosses placenta and enters breast milk. Metabolism: Primarily hepatic via cytochrome P450 system (CYP1A2 and CYP2C9). Metabolites include 6-O-desmethyl naproxen (inactive). Elimination: Elimination half-life 12-17 hours. Renal excretion is primary route (95% as metabolites, <1% unchanged). Urinary alkalinization increases excretion.Contraindications
- Hypersensitivity to naproxen, aspirin, or other NSAIDs
- History of asthma, urticaria, or allergic-type reactions after taking aspirin or NSAIDs
- Perioperative pain in coronary artery bypass graft (CABG) surgery
- Third trimester of pregnancy
Warnings and Precautions
Cardiovascular Risk: NSAIDs may increase risk of serious cardiovascular thrombotic events, including MI and stroke. Risk may increase with duration of use. GI Risk: NSAIDs cause increased risk of serious GI adverse events including bleeding, ulceration, and perforation, which can be fatal. Renal Effects: Long-term NSAID use may result in renal papillary necrosis and other renal injury. Risk increased in elderly, those with renal impairment, heart failure, or volume depletion. Hepatic Effects: May cause hepatic injury; monitor patients for symptoms of liver dysfunction. Hypertension: NSAIDs may lead to new hypertension or worsening of existing hypertension. Anemia: May occur due to GI blood loss or fluid retention.Drug Interactions
Anticoagulants: Increased risk of bleeding with warfarin (monitor INR closely) ACE inhibitors/ARBs: Reduced antihypertensive effect; possible renal function deterioration Diuretics: Reduced diuretic and antihypertensive effects Lithium: Increased lithium levels (monitor serum concentrations) Methotrexate: Increased methotrexate toxicity risk SSRIs/SNRIs: Increased risk of GI bleeding Cyclosporine: Increased nephrotoxicity risk Corticosteroids: Increased GI ulcer riskAdverse Effects
Common (≥1%):- Dyspepsia (10-15%)
- Heartburn (10-12%)
- Nausea (5-10%)
- Headache (5-10%)
- Dizziness (3-5%)
- Rash (3-5%)
- GI bleeding/perforation
- Cardiovascular thrombotic events
- Renal impairment/failure
- Hepatic failure
- Severe skin reactions (SJS, TEN)
- Anaphylaxis
- Fluid retention/edema
- Hypertension exacerbation
Monitoring Parameters
- Efficacy: Pain scales, inflammatory markers, functional assessment
- Renal function: Serum creatinine, BUN at baseline and periodically
- Hepatic function: LFTs at baseline and periodically
- CBC: For anemia due to occult blood loss
- Blood pressure: Regular monitoring
- GI symptoms: Monitor for bleeding, ulceration
- Signs of hypersensitivity reactions
Patient Education
- Take with food or milk to reduce stomach upset
- Do not crush or chew delayed-release tablets
- Report any signs of GI bleeding (black stools, coffee-ground emesis)
- Report chest pain, shortness of breath, weakness, slurred speech
- Avoid concurrent aspirin use unless directed by physician
- Limit alcohol consumption during therapy
- Be aware of potential dizziness/drowsiness
- Use sun protection due to photosensitivity risk
- Do not use during third trimester of pregnancy
- OTC formulations: Do not exceed recommended dosage/duration
References
1. FDA prescribing information for Naproxen. (2023). AccessFDA. 2. Grosser T, Smyth E, FitzGerald GA. Anti-inflammatory, Antipyretic, and Analgesic Agents; Pharmacotherapy of Gout. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics. 13th ed. McGraw Hill; 2017. 3. Solomon DH, et al. The comparative safety of analgesics in older adults with arthritis. Arch Intern Med. 2010;170(22):1968-1976. 4. Trelle S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086. 5. American College of Rheumatology. Guidelines for the Management of Osteoarthritis. Arthritis Care Res. 2019;71(1):2-32. 6. Laine L, et al. Strategies to reduce the GI risks of NSAIDs. Am J Gastroenterol. 2015;110(2):262-268. 7. UpToDate. Naproxen: Drug information. Accessed January 2024.