Nonselective NSAIDs

Nonselective NSAIDs inhibit both COX-1 and COX-2 at therapeutic doses. Their effects therefore combine analgesia and anti-inflammatory action with predictable gastric mucosal injury, platelet inhibition and renal prostaglandin loss. The members differ in potency, half-life, cardiovascular and gastric risk, and licensed use.

Mechanism. Reversible competitive inhibition of cyclo-oxygenase (aspirin is irreversible), lowering prostaglandin E2, prostacyclin and thromboxane A2. Platelet inhibition lasts the life of the platelet for aspirin and only while the drug is present for the others.

Pharmacokinetics. Ibuprofen: half-life 2 hours; naproxen 12 to 17 hours; diclofenac 1 to 2 hours (effect lasts longer in joint fluid); indometacin 4 to 5 hours; piroxicam about 50 hours; ketorolac 5 to 6 hours (longer in older adults and renal impairment). Taking with food lowers gastric irritation and delays peak.

Ibuprofen. 200 to 400 mg orally every 6 to 8 hours; up to 600 mg every 8 hours for inflammatory conditions; maximum 2.4 g daily. Child 5 to 10 mg/kg every 6 to 8 hours, maximum 30 mg/kg daily. Lowest gastric risk at analgesic doses.

Naproxen. 250 to 500 mg orally twice daily; usual maximum 1 g, 1.25 g for short courses. Gout 750 mg first, then 250 mg every 8 hours. Longer half-life allows twice-daily dosing and carries lower cardiovascular risk.

Diclofenac. 50 mg orally every 8 hours or 75 mg modified-release twice daily; 100 mg rectally; 75 mg intramuscularly once or twice daily for up to 2 days; maximum 150 mg daily. Hepatotoxicity in a small minority; higher thrombotic risk.

Ketorolac. 15 to 30 mg intravenously or intramuscularly every 6 hours; maximum 120 mg daily and 5 days in total; 15 mg every 6 hours (maximum 60 mg daily) if over 65 years, under 50 kg or renal impairment. Oral continuation 10 mg every 4 to 6 hours, maximum 40 mg daily. Not for use before major surgery with bleeding risk.

Indometacin. 25 to 50 mg two to three times daily with food, maximum 200 mg; suppository 100 mg at night. Used for gout, ankylosing spondylitis, pericarditis and neonatal ductus arteriosus (specialist dosing). Frequent headache and confusion.

Piroxicam, meloxicam and mefenamic acid. Piroxicam 20 mg daily (highest gastric risk and cutaneous reactions; use restricted in many countries); meloxicam 7.5 to 15 mg daily; mefenamic acid 500 mg three times daily for dysmenorrhoea (seizures in overdose).

Aspirin. Analgesic and antipyretic dose 300 to 900 mg every 4 to 6 hours, maximum 4 g; not for children under 16 because of Reye syndrome. Antiplatelet use at 75 to 100 mg daily is a separate indication.

• First-line. Ibuprofen or naproxen for acute musculoskeletal pain, dysmenorrhoea, dental pain and mild to moderate postoperative pain.
• Alternative. Diclofenac when higher potency is needed and cardiovascular risk is low; meloxicam for once-daily dosing in chronic arthritis.
• Specialist. Indometacin for gout, ankylosing spondylitis and neonatal ductus arteriosus; piroxicam only where other options have failed.
• Emergency. Diclofenac 75 mg intramuscularly or ketorolac 15 to 30 mg intravenously for renal colic and severe acute pain when oral dosing is not possible.

Choice by risk. High cardiovascular risk: naproxen or low-dose ibuprofen with a proton pump inhibitor. High gastric risk: add omeprazole 20 mg daily, or switch to a COX-2 inhibitor. Renal impairment: avoid.

Contraindications. Active gastrointestinal bleeding or ulcer; severe heart failure; eGFR under 30 mL/min; aspirin-sensitive asthma or NSAID hypersensitivity; third trimester; perioperative coronary bypass; diclofenac in established cardiovascular disease; ketorolac in bleeding diathesis and labour.

Serious adverse effects. Gastrointestinal bleeding and perforation; acute kidney injury and hyperkalaemia; hypertension and fluid retention; thrombotic events (boxed-warning-level risk); bronchospasm; hepatotoxicity (diclofenac); central nervous system effects (indometacin); severe skin reactions (piroxicam).

Major interactions. Anticoagulants, antiplatelets, SSRIs and corticosteroids (bleeding); ACE inhibitors, ARBs and diuretics (kidney injury); lithium, methotrexate, ciclosporin (toxicity); ibuprofen with low-dose aspirin (reduced antiplatelet effect).

Common prescribing errors.

• Duplicate NSAIDs.
• Ketorolac beyond 5 days or at full dose in frail patients.
• Long-term piroxicam.
• NSAID in dehydration.
• Missing gastroprotection.

Special groups.

• Pregnancy: avoid from 20 weeks; contraindicated in the third trimester.
• Breastfeeding: ibuprofen and diclofenac acceptable.
• Children: ibuprofen only; avoid aspirin under 16.
• Older adults: lowest dose, gastroprotection, ketorolac 15 mg.
• Kidney and liver: avoid in eGFR under 30 mL/min and in cirrhosis with ascites.
• East Africa: avoid when dengue is suspected, in dehydration from gastroenteritis, and in sickle cell patients with renal impairment.

Monitoring. Blood pressure, creatinine and potassium at 1 to 2 weeks in those at renal risk, then every 3 to 6 months; haemoglobin if gastric symptoms; liver enzymes on diclofenac if treatment exceeds 4 weeks.

Referral and escalation. Gastrointestinal bleeding, acute kidney injury, angioedema or cardiovascular event.

Comparison with alternative classes. Compared with COX-2 inhibitors, nonselective agents cause more gastric injury and impair platelet function; compared with paracetamol they treat inflammation but carry more organ risk.