Nonsteroidal Anti Inflammatory Drugs

Nonsteroidal anti-inflammatory drugs inhibit cyclo-oxygenase and are used for pain, inflammation and fever. They are the most widely prescribed analgesic class after paracetamol and the class with the greatest burden of avoidable harm: gastrointestinal bleeding, acute kidney injury and cardiovascular events, each preventable largely by case selection, dose and duration.

Mechanism. COX-1 is constitutive and supports gastric mucosal protection, platelet thromboxane A2 production and renal perfusion. COX-2 is induced in inflammation, but is also constitutive in kidney and vascular endothelium (prostacyclin). Blocking COX-1 explains gastric injury and bleeding; blocking COX-2 explains the anti-inflammatory effect and also renal, hypertensive and thrombotic harm.

Chemical classes. Propionic acids (ibuprofen, naproxen, ketoprofen); acetic acids (diclofenac, indometacin, ketorolac); oxicams (piroxicam, meloxicam); fenamates (mefenamic acid); selective COX-2 inhibitors (celecoxib, etoricoxib); aspirin acts by irreversible acetylation.

Pharmacokinetics. Well absorbed orally, highly protein bound, hepatic metabolism, renal excretion of metabolites. Rapid onset (30 to 60 minutes); anti-inflammatory benefit takes 1 to 2 weeks at regular dosing.

Relative gastrointestinal risk. Highest with piroxicam and ketorolac; intermediate with naproxen and diclofenac; lowest with low-dose ibuprofen and COX-2 inhibitors.

Relative cardiovascular risk. Diclofenac and COX-2 inhibitors carry the highest thrombotic risk; naproxen and low-dose ibuprofen the lowest.

• First-line. Inflammatory musculoskeletal pain, osteoarthritis flares, acute gout, dysmenorrhoea, renal colic, postoperative pain and acute migraine.
• Alternative. Topical NSAID for localised osteoarthritis when systemic risk is high.
• Specialist. Indometacin or ibuprofen for patent ductus arteriosus in neonates; ibuprofen 600 mg every 8 hours for acute pericarditis; NSAIDs for axial spondyloarthritis.
• Emergency. Diclofenac 75 mg intramuscularly for renal colic.

Gastroprotection. Offer a proton pump inhibitor (omeprazole 20 mg daily) to patients over 65, those with previous ulcer or bleeding, and those taking a corticosteroid, anticoagulant, antiplatelet or SSRI. Misoprostol 200 micrograms four times daily is an alternative but causes diarrhoea. Test for and treat Helicobacter pylori in patients with ulcer history.

Selection. Choose naproxen or low-dose ibuprofen if cardiovascular risk is raised; a COX-2 inhibitor with a proton pump inhibitor if gastric risk is high; avoid all NSAIDs when both are high.

Contraindications. Active gastrointestinal bleeding or ulcer; severe heart failure; eGFR under 30 mL/min; hypersensitivity to aspirin or NSAIDs; third trimester; coronary bypass perioperatively; ischaemic heart disease, stroke or peripheral arterial disease for diclofenac and COX-2 inhibitors.

Serious adverse effects.

• Gastrointestinal ulceration, bleeding, perforation.
• Acute kidney injury from loss of afferent vasodilation; hyperkalaemia; papillary necrosis and chronic kidney disease with long use.
• Hypertension, heart failure, myocardial infarction, stroke (boxed-warning-level risk).
• Aspirin-exacerbated respiratory disease, angioedema, anaphylaxis.
• Hepatotoxicity (diclofenac), aseptic meningitis (ibuprofen), severe skin reactions.

Major interactions.

• Anticoagulants, antiplatelets, SSRIs, corticosteroids: bleeding.
• ACE inhibitors or ARBs with diuretics: acute kidney injury (triple whammy).
• Lithium, methotrexate, ciclosporin, tacrolimus, digoxin: raised levels or toxicity.
• Quinolones: seizure risk.
• Antihypertensives: blunted effect.

Common prescribing errors.

• Two NSAIDs together, including over-the-counter use.
• Continuing during dehydration, sepsis or vomiting.
• No review of duration.
• Ketorolac beyond 5 days.
• Missing gastroprotection.

Special groups.

• Pregnancy: avoid from 20 weeks; contraindicated in the third trimester.
• Breastfeeding: ibuprofen preferred; avoid indometacin and long-acting agents.
• Children: ibuprofen 5 to 10 mg/kg every 6 to 8 hours, maximum 30 mg/kg daily; avoid under 3 months.
• Older adults: lowest dose, shortest course, with gastroprotection.
• Kidney: avoid at eGFR under 30 mL/min and use paracetamol instead.
• Liver: avoid in cirrhosis with ascites.
• East Africa: avoid in suspected dengue, severe malaria with dehydration and sickle cell crisis with renal impairment.

Monitoring. Blood pressure; creatinine and potassium at 1 to 2 weeks in those at renal risk and every 3 to 6 months on long-term use; haemoglobin if gastric symptoms; liver enzymes with diclofenac.

Referral and escalation. Haematemesis, melaena or perforation; acute kidney injury; bronchospasm or angioedema; cardiovascular event; need for NSAID beyond 3 months in a high-risk patient.

Comparison with alternative classes. NSAIDs outperform paracetamol for inflammatory pain and avoid opioid harm, but carry gastric, renal and cardiovascular risk that grows with dose and duration.