Non-opioid Analgesics

Non-opioids: Intro & MOA - The Pain Tamers

• Definition: Diverse drug group for mild-moderate pain & fever; some possess significant anti-inflammatory effects (e.g., NSAIDs). Not structurally related to opioids, generally fewer side effects like dependence.
• Key Classes:
  • NSAIDs (e.g., Ibuprofen, Diclofenac)
  • Paracetamol (Acetaminophen) - analgesic, antipyretic, weak anti-inflammatory.
  • Others (e.g., Nefopam - centrally acting, non-opioid).
• NSAID MOA - Primary Action:
  • Inhibit cyclooxygenase (COX) enzymes (isoforms COX-1 & COX-2).
  • This blocks conversion of arachidonic acid (released by phospholipase A2) to prostaglandins (PGs), prostacyclin (PGI2), & thromboxane A2 (TXA2).
  • PGs: Key mediators of pain, inflammation, fever.
  • 📌 Mnemonic: "NSAIDs knock out COX, PGs can't box!"

⭐ Most NSAIDs non-selectively inhibit COX-1 & COX-2, yielding therapeutic effects but also side effects (e.g., gastric issues via COX-1 inhibition).

NSAIDs: Types & ADRs - COX & Effects

• COX Enzymes & Effects:
  • COX-1 (Constitutive): GI protection (PGE2/PGI2), Platelet aggregation (TXA2), Renal function.
  • COX-2 (Inducible/Constitutive): Inflammation, Pain, Fever. Also renal function, PGI2 (vasodilation, anti-platelet) in endothelium.

• NSAID Classes & Comparative ADRs:

*   **GI:** ↓Protective PGs.
*   **Renal:** ↓PGs → ↓RBF, Na+/H2O retention.
*   **CV (Coxibs/Non-Aspirin NSAIDs):** Unopposed TXA2 or ↓PGI2 → prothrombotic.
*   **AERD:** Leukotriene overproduction.

⭐ Aspirin: Irreversible COX-1 inhibition in platelets (antiplatelet effect for 7-10 days). Low dose (75-150 mg) for cardioprotection.

📌 COX-1 = Gut, Renal, Platelets (GRP). COX-2 = Inflammation, Pain, Fever (IPF).

Paracetamol: The Go-To - Beyond NSAIDs

• Mechanism: Weak COX inhibitor (mainly central); possible effects on COX-3, serotonergic pathways. Analgesic, antipyretic.
  • ⚠️ No significant anti-inflammatory effect.
• Dosing:
  • Adults: 0.5-1g QDS (max 4g/day).
  • Pediatrics: 10-15 mg/kg/dose.
• Hepatotoxicity:
  • Toxic metabolite: NAPQI (N-acetyl-p-benzoquinone imine) via CYP450 (mainly CYP2E1).
  • Overdose depletes glutathione → NAPQI damages hepatocytes.
  • Toxic dose (acute): >150 mg/kg or >7.5-10g.
  • Risk factors: Chronic alcohol, malnutrition, enzyme inducers (e.g., rifampicin, isoniazid).
• Antidote: N-acetylcysteine (NAC).
  • Replenishes glutathione, directly detoxifies NAPQI.
  • Best if given within 8-10 hours post-ingestion.

⭐ Rumack-Matthew nomogram guides NAC therapy based on serum paracetamol levels vs. time post-ingestion.

Paracetamol Poisoning Management Flowchart:

Clinical Use: Smart Choices - Pick Wisely

Choose non-opioids by pain type, severity, patient risks. Paracetamol is cornerstone if NSAIDs risky.

• Paracetamol: Max dose 4g/day (adults). In severe hepatic impairment, limit to <2g/day.
• NSAIDs: Use lowest effective dose, shortest duration. ⚠️ AVOID if GFR <30 mL/min, active PUD, or 3rd trimester pregnancy.
• ⚠️ Interactions: NSAIDs with anticoagulants (↑bleeding); +ACEi/ARBs/diuretics (↑renal toxicity).

⭐ For osteoarthritis in elderly, paracetamol is first-line over NSAIDs due to better safety, despite weaker anti-inflammatory effects.

High‑Yield Points - ⚡ Biggest Takeaways

• Paracetamol: Central COX inhibition; hepatotoxicity (NAPQI) reversed by N-acetylcysteine; max 4g/day.
• NSAIDs: COX-1 & COX-2 inhibition; risks: GIT ulcers, renal impairment, bronchospasm.
• Selective COX-2 inhibitors: ↓ GIT side effects, but ↑ cardiovascular thrombotic risk (e.g., Etoricoxib).
• Nefopam: Centrally acting non-opioid; inhibits monoamine reuptake; causes tachycardia, sweating.
• Low-dose Ketamine: NMDA antagonist; potent analgesic for neuropathic pain, opioid-sparing.
• Gabapentinoids: Target α2δ Ca2+ channel subunit; first-line for neuropathic pain.