PH2.7 | PH2.7 | Non-Opioid Analgesics and NSAIDs — SDL Guide — Summary & Reflection

KEY TAKEAWAYS

Key takeaways from this module:

1. Pain involves peripheral nociceptor sensitisation (PGE2 lowers threshold) and central sensitisation; prostaglandins from the COX pathway are the critical mediators that NSAIDs target.
2. COX-1 is constitutive (gastric cytoprotection, platelet TXA2); COX-2 is primarily inducible (inflammation, fever) but also constitutive in kidney and endothelium.
3. Non-selective NSAIDs (aspirin, ibuprofen, diclofenac, indomethacin, naproxen, ketorolac, piroxicam, mefenamic acid) inhibit both COX isoforms; aspirin does so irreversibly via acetylation — all others are reversible.
4. Selective COX-2 inhibitors (celecoxib, etoricoxib) spare gastric COX-1 but increase cardiovascular risk (PGI2 suppression without TXA2 suppression). GI advantage lost with co-aspirin.
5. Paracetamol: analgesic and antipyretic; NO anti-inflammatory activity; safe at therapeutic doses; hepatotoxic in overdose (NAPQI exhausts glutathione); antidote = N-acetylcysteine.
6. Triple whammy: NSAID + ACE inhibitor + diuretic = major AKI risk in susceptible patients.
7. Contraindications: NSAIDs contraindicated in peptic ulcer, CKD (eGFR <30), decompensated heart failure, 3rd trimester pregnancy. Aspirin contraindicated in children (Reye's syndrome). Coxibs contraindicated in established CVD.
8. Rofecoxib withdrawal (2004): a landmark pharmacovigilance event demonstrating the cardiovascular hazard of COX-2 selective inhibition without TXA2 suppression.
9. NSAID-exacerbated respiratory disease: ~10–20% of adult asthmatics; mechanism = LOX-shunting of arachidonic acid → excess leukotrienes.

REFLECT

Return to the opening case: the patient who developed GI bleeding on ibuprofen. His GI bleed was a direct consequence of COX-1 inhibition removing gastric mucosal protection — a predictable, mechanistically inevitable consequence of his drug choice without gastroprotection. His colleague on celecoxib avoided this. But consider: if the first patient also had hypertension and ischaemic heart disease, would celecoxib be safe? No — the cardiovascular risk of coxibs would make it dangerous.

Pharmacological reasoning is about trade-offs. Every NSAID choice balances analgesia against GI risk, cardiovascular risk, and renal risk. The 'right' choice depends on which patient is in front of you. As a practitioner, your skill lies in reading that specific risk profile and prescribing accordingly — not in having memorised a single 'safest' drug.