Analgesics and NSAIDs

Pain assessment and the analgesic ladder

• Alert adults on surgical wards are assessed regularly with a numerical rating scale (0–10).
• WHO ladder: non-opioid (paracetamol, NSAID), then weak opioid (codeine, tramadol), then strong opioid (morphine, oxycodone, fentanyl), each with adjuvants.
• Neuropathic pain adjuvants: amitriptyline, duloxetine, gabapentin and pregabalin (bind the α2δ subunit of voltage-gated calcium channels, reducing transmitter release). Combined with opioids they add to respiratory depression.
• Ketamine (NMDA antagonist) is a useful adjunct in opioid-tolerant patients because it blocks NMDA-driven central sensitisation (wind-up).
• Nitrous oxide supplies analgesia that potent but poorly analgesic volatile agents such as halothane lack.

Opioids: receptors and effects

• Endogenous opioid peptides are endorphins, enkephalins and dynorphins. Opioid receptors (μ, κ, δ) are Gi-coupled: they close presynaptic Ca2+ channels and open postsynaptic K+ channels.
• μ effects: analgesia, euphoria, respiratory depression (reduced CO2 sensitivity), miosis, constipation (no tolerance, so always prescribe a laxative), nausea (chemoreceptor trigger zone), urinary retention, pruritus, cough suppression, sphincter of Oddi spasm.
• In biliary colic, morphine is combined with an antispasmodic or replaced by an NSAID; in renal colic an NSAID (diclofenac) is first line. For opioid-induced vomiting, cyclizine is a suitable antiemetic. In cancer pain, morphine is given with a laxative and an antiemetic.

• Naloxone is a competitive μ antagonist with a short half-life (about 1 hour). After a heroin or long-acting opioid overdose the patient may wake, then become drowsy again as naloxone wears off before the opioid: observe and use repeated doses or an infusion.
• After surgery, give naloxone in small titrated IV doses; a large bolus reverses analgesia and causes severe pain, agitation and hypertension.
• Opioid dependence: methadone or buprenorphine maintenance. Urine screening detects opioid use; withdrawal features are yawning, rhinorrhoea, dilated pupils, piloerection, diarrhoea.

Exam trap The earliest warning of opioid respiratory depression is increasing sedation; supplemental oxygen keeps saturation normal while CO2 rises, so count the breaths.

Patient-controlled analgesia and regional techniques

• PCA has a lockout interval so that a new dose cannot be given before the previous one has had time to act; this prevents stacking. Relatives pressing the button defeats the safety mechanism.
• A patient pressing often but still in severe pain: assess the pain, cause (compartment syndrome, a complication) and pump settings before increasing the dose.
• Epidural hypotension after a bupivacaine top-up is the commonest immediate complication: sympathetic block causes vasodilatation (warm periphery). Always exclude bleeding.
• Intrathecal morphine is hydrophilic: it stays in the CSF and spreads up to the brainstem slowly, so respiratory depression can appear many hours later. Lipophilic fentanyl is taken up locally and acts briefly.
• Rib fractures with poor cough: thoracic epidural or paravertebral block. Femoral fracture: fascia iliaca or femoral nerve block.

NSAIDs and aspirin

NSAIDs inhibit cyclooxygenase, reducing prostaglandin synthesis from arachidonic acid. COX-1 is constitutive (gastric mucosa, platelets, kidney); COX-2 is induced in inflammation and also makes endothelial prostacyclin.

• Aspirin irreversibly acetylates COX-1 (serine 530). Platelets have no nucleus and cannot make new enzyme, so the antiplatelet effect lasts the platelet lifespan (7–10 days) though aspirin is cleared in hours. Stop about a week before surgery if needed. Reye syndrome under 16. Overdose: respiratory alkalosis then metabolic acidosis; no antidote; urinary alkalinisation with sodium bicarbonate, haemodialysis if severe.
• Aspirin 30 minutes before niacin reduces its prostaglandin-mediated flushing.
• Ibuprofen or indomethacin closes a PDA in preterm babies, the deliberate use of the same mechanism.
• Ibuprofen is the preferred anti-inflammatory analgesic in breastfeeding; NSAIDs are a problem in late pregnancy, not lactation.
• Mefenamic acid or another NSAID is first line for primary dysmenorrhoea (prostaglandin-driven uterine contractions).
• Ketorolac can be given IV or IM; short courses only because of renal and GI risk. Celecoxib and etoricoxib are selective COX-2 inhibitors.
• Paracetamol is the safest analgesic after dental extraction in someone with a gastric ulcer, and post-operatively in asthma.

Paracetamol

• Central analgesic and antipyretic; not anti-inflammatory. Adults 1 g six-hourly, maximum 4 g/day; under 50 kg use 15 mg/kg (a 40 kg woman: 600 mg IV six-hourly). Confusing mg with mL has caused tenfold infant overdoses.
• Overdose: CYP2E1 converts excess drug to NAPQI, normally detoxified by glutathione. When glutathione is exhausted, NAPQI binds liver proteins: centrilobular (zone 3) necrosis, peaking at 72–96 hours.
• N-acetylcysteine replenishes glutathione (supplies cysteine) so NAPQI is detoxified. Use the nomogram from 4 hours; treat at once if staggered, presentation over 8 hours, or level uncertain.
• Chronic heavy drinkers and malnourished patients are more vulnerable: alcohol induces CYP2E1 and poor nutrition lowers glutathione.

Remember Paracetamol kills through NAPQI; acetylcysteine saves through glutathione.

DMARDs for rheumatoid arthritis

• Methotrexate overdose (daily instead of weekly): pancytopenia and mucositis. The antidote is folinic acid (leucovorin), which is already reduced and bypasses the blocked DHFR; folic acid cannot.
• Leflunomide before pregnancy: colestyramine washout, then confirm undetectable levels.

Gout

• Gout with stones and developmental delay in a child with enzyme overactivity suggests PRPP synthetase superactivity; deficiency of HGPRT is Lesch–Nyhan syndrome.

Exam trap Probenecid and rasburicase lower urate by opposite routes: one increases excretion, the other destroys urate.

Migraine and cluster headache

• Acute: paracetamol or NSAID with an antiemetic; triptans (5-HT1B/1D agonists) are contraindicated in ischaemic heart disease and uncontrolled hypertension.
• Prevention: propranolol, topiramate, amitriptyline, candesartan, CGRP antibodies. Medication overuse headache needs withdrawal.
• Cluster: high-flow oxygen, SC sumatriptan; verapamil prevention.

How FCPS asks about this

• Patient drowsy again an hour after naloxone: naloxone wears off before the opioid.
• Baby apnoeic while mother takes codeine: ultra-rapid CYP2D6 metabolism.
• Why aspirin acts for the platelet's life: irreversible acetylation of COX-1.
• How acetylcysteine works: replenishes glutathione to detoxify NAPQI.
• Wheeze after diclofenac with nasal polyps: arachidonic acid shunted to leukotrienes.
• Methotrexate overdose antidote: folinic acid; methotrexate is a competitive DHFR inhibitor.
• Late respiratory depression after intrathecal morphine: hydrophilic drug spreads rostrally in CSF.