Analgesics & Pain Management

Effective pain management requires understanding the mechanisms of nociception and how different drug classes modulate the pain pathway.

Opioids act primarily on mu (μ) opioid receptors in the CNS and peripheral nervous system. Mu receptor activation is Gi protein-coupled, causing hyperpolarisation via increased K+ conductance and decreased Ca2+ entry, inhibiting neuronal firing and neurotransmitter release. This produces analgesia, euphoria, and sedation. Delta (δ) receptors contribute to analgesia and modulation of mu receptor activity, while kappa (κ) receptors mediate spinal analgesia, sedation, and dysphoria.

Morphine is the prototype opioid. It is well absorbed orally but undergoes extensive first-pass metabolism (bioavailability ~35%). Its active metabolite, morphine-6-glucuronide (M6G), accumulates in renal failure and can cause prolonged toxicity. Clinical effects include analgesia, respiratory depression (dose-limiting), constipation (via enteric mu receptors — does not develop tolerance), nausea, urinary retention, and miosis. Codeine is a prodrug requiring CYP2D6 metabolism to morphine for analgesia; poor metabolisers (5–10% of Europeans) receive no benefit, while ultra-rapid metabolisers (common in some African populations) face toxicity risk. Tramadol has a dual mechanism: weak mu agonism plus serotonin-noradrenaline reuptake inhibition. It lowers the seizure threshold and can cause serotonin syndrome when combined with SSRIs.

Opioid overdose is managed with naloxone, a competitive mu antagonist with a short half-life (60–90 min). Repeated dosing or infusion is required for long-acting opioids.

NSAIDs inhibit cyclooxygenase enzymes (COX-1 and COX-2), preventing prostaglandin synthesis from arachidonic acid. COX-1 is constitutively expressed, protecting the gastric mucosa and mediating platelet thromboxane A2 synthesis. COX-2 is inducible at sites of inflammation. Non-selective NSAIDs (ibuprofen, diclofenac, naproxen) inhibit both isoforms — effective anti-inflammatory analgesics but associated with gastric ulceration, platelet inhibition, and renal impairment (particularly in volume-depleted patients). Selective COX-2 inhibitors (celecoxib) reduce GI risk but carry increased cardiovascular thrombotic risk due to unopposed prostacyclin deficiency.

Paracetamol (acetaminophen) has a poorly understood mechanism but likely involves inhibition of a central COX-3 variant and modulation of the endocannabinoid system. It has excellent analgesic and antipyretic properties with minimal anti-inflammatory effect. In overdose, N-acetyl-p-benzoquinone imine (NAPQI) accumulates (glutathione stores depleted) causing hepatocellular necrosis. N-acetylcysteine (NAC) replenishes glutathione and is the antidote.

Adjuvant analgesics include: tricyclic antidepressants (amitriptyline) and SNRIs (duloxetine) for neuropathic pain via monoamine pathway enhancement; gabapentinoids (gabapentin, pregabalin) which block α2δ subunits of voltage-gated calcium channels; and low-dose corticosteroids for inflammatory pain.

The WHO pain ladder guides analgesic prescribing: step 1 (non-opioids for mild pain), step 2 (weak opioids for moderate pain), step 3 (strong opioids for severe pain), with adjuvants at any step.