5.3 Analgesics: NSAIDs, Opioids & Migraine

The WHO Analgesic Ladder

The WHO analgesic ladder, developed for cancer pain but a useful general framework, escalates therapy in three steps: step 1 non-opioid (paracetamol and/or an NSAID) for mild pain; step 2 adds a weak opioid (codeine, tramadol) for moderate pain; step 3 uses a strong opioid (morphine, oxycodone, fentanyl) for severe pain. Adjuvants - gabapentinoids, antidepressants, corticosteroids - can be added at any step. The guiding principle for chronic pain is "by the clock, by the ladder, by the mouth": scheduled dosing, stepwise escalation, and oral route preferred.

Paracetamol (Acetaminophen)

Paracetamol provides analgesia and antipyresis with no meaningful anti-inflammatory effect and no gastric or platelet toxicity, making it the default first-line analgesic. The maximum adult dose is 4 g per day (1 g four times daily), with lower limits in low body weight, hepatic impairment, and chronic alcohol use. In overdose, the hepatic metabolite N-acetyl-p-benzoquinone imine (NAPQI) depletes glutathione and causes centrilobular hepatotoxicity; patients are often asymptomatic for 24-48 hours before liver failure emerges. The antidote is N-acetylcysteine, which replenishes glutathione and is most effective when started within 8 hours; a paracetamol level is plotted against the Rumack-Matthew nomogram to guide treatment. A classic dispensing error is duplicate paracetamol hidden in combination products (co-codamol, cold-and-flu remedies).

NSAIDs and COX-2 Inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDs) - ibuprofen, diclofenac, naproxen - inhibit cyclo-oxygenase (COX) enzymes, reducing prostaglandin synthesis. This explains both efficacy and the triad of harms:

• Gastrointestinal: dyspepsia, ulceration, and bleeding (loss of protective mucosal prostaglandins).
• Renal: afferent arteriolar vasoconstriction causing acute kidney injury - risk multiplies in the "triple whammy" of NSAID + ACE inhibitor/ARB + diuretic, and in chronic kidney disease NSAIDs are avoided.
• Cardiovascular: increased thrombotic events (MI, stroke) and worsening heart failure through sodium and fluid retention; avoid in established cardiovascular disease where possible.

Other key cautions: avoid NSAIDs in the third trimester of pregnancy (premature closure of the ductus arteriosus, oligohydramnios), in aspirin-exacerbated respiratory disease, and with anticoagulants. Celecoxib, a COX-2 selective inhibitor, spares the GI mucosa and platelets but retains - and may concentrate - cardiovascular risk, so it is contraindicated in ischemic heart disease and cerebrovascular disease. For high-GI-risk patients who genuinely need an NSAID, co-prescribe gastroprotection: a proton pump inhibitor is standard, or misoprostol (a prostaglandin E1 analogue; contraindicated in pregnancy because it is uterotonic).

Opioids

Opioids act at mu, kappa, and delta receptors. Essential exam points by agent:

• Codeine is a prodrug activated by CYP2D6 to morphine. Poor metabolizers (~7-10% of many populations) get no analgesia; ultra-rapid metabolizers convert it dangerously fast - the basis for contraindicating codeine in breastfeeding (morphine toxicity in the infant) and in children.
• Tramadol combines weak mu-agonism with serotonin-norepinephrine reuptake inhibition; it therefore carries serotonin syndrome risk with SSRIs/SNRIs and lowers the seizure threshold.
• Morphine is the reference strong opioid: adverse effects include respiratory depression (the lethal effect in overdose), sedation, nausea (usually settles; give an antiemetic initially), and constipation, which never resolves with tolerance - co-prescribe a stimulant laxative (e.g., senna) from day one. Naloxone, a short-acting competitive antagonist, reverses opioid overdose; repeat dosing or infusion may be needed because naloxone's half-life is shorter than that of most opioids.
• Opioid-induced hyperalgesia is the paradoxical state where escalating opioid doses increase pain sensitivity; the correct response is dose reduction/rotation, not escalation.
• Equianalgesic awareness: know the anchors rather than memorizing tables - oral morphine 10 mg is roughly equivalent to oral oxycodone 5-6.6 mg and to oral codeine 100 mg; transdermal fentanyl is dosed in micrograms and is far more potent. Always reduce the calculated dose (typically by 25-50%) when rotating between opioids to allow for incomplete cross-tolerance.

In the UAE, opioids and tramadol are strictly controlled medicines; prescriptions, quantities, and documentation follow federal controlled-substance regulations - a recurring theme in the pharmacy-practice sections of the DHA assessment.

Neuropathic Pain

First-line agents for neuropathic pain (diabetic neuropathy, post-herpetic neuralgia, radicular pain) are gabapentin and pregabalin (alpha-2-delta calcium-channel ligands; titrate slowly, renal dose adjustment, sedation), duloxetine (SNRI, especially in diabetic neuropathy), and amitriptyline (TCA, typically low doses of 10-25 mg at night; anticholinergic cautions in the elderly). NSAIDs and simple analgesics are generally ineffective for pure neuropathic pain.

Migraine

Acute treatment starts with paracetamol or an NSAID plus an antiemetic such as metoclopramide or prochlorperazine. Triptans (sumatriptan and others) are 5-HT1B/1D receptor agonists that abort attacks by cranial vasoconstriction and inhibiting trigeminal peptide release. The vasoconstrictive mechanism makes them contraindicated in ischemic heart disease, prior MI or stroke, uncontrolled hypertension, and peripheral vascular disease. Combining triptans with SSRIs/SNRIs carries an additive (though uncommon) serotonin syndrome risk. Overuse of any acute migraine drug more than 10-15 days per month causes medication-overuse headache.

CGRP-targeted therapies - monoclonal antibodies (erenumab, galcanezumab, fremanezumab) for prophylaxis and oral gepants (rimegepant, ubrogepant) - block the calcitonin gene-related peptide pathway central to migraine; know them at concept level. Established prophylaxis options (when attacks are frequent or disabling) include propranolol (avoid in asthma), topiramate (teratogenic - cleft lip/palate - and causes cognitive slowing and weight loss), amitriptyline, and candesartan. Valproate is effective but generally avoided in women of childbearing potential for the teratogenicity reasons covered in Section 5.1.