Clinical Guide · 13 min read
Pain management pharmacology
WHO analgesic ladder, NSAIDs and COX selectivity, opioid equianalgesic dosing, neuropathic pain adjuvants, and opioid-induced hyperalgesia — a clinical reference for managing acute and chronic pain.
AnalgesiaNSAIDsOpioidsNeuropathic painWHO ladder
Analgesic drug classes at a glance
| Class | Examples | Mechanism | Pain type | Key cautions |
|---|---|---|---|---|
| Non-opioid (centrally acting) | Paracetamol (acetaminophen) | COX-3 inhibition (CNS), endocannabinoid modulation | Mild–moderate nociceptive | Hepatotoxicity ≥4 g/day; NAPQI metabolite; active metabolite |
| Non-selective NSAIDs | Ibuprofen, naproxen, diclofenac, ketorolac | COX-1 + COX-2 inhibition → ↓prostaglandins | Mild–moderate; inflammatory; musculoskeletal | GI bleeding, renal impairment, CV risk, avoid in CKD |
| COX-2 selective (coxibs) | Celecoxib, etoricoxib | Selective COX-2 inhibition | Inflammatory, OA, RA, post-op | Lower GI risk but higher CV thrombotic risk; avoid in CV disease |
| Weak opioids | Codeine, tramadol, dihydrocodeine | Mu opioid receptor agonism (often pro-drug activation) | Mild–moderate nociceptive | CYP2D6 variability (codeine/tramadol); abuse potential |
| Strong opioids | Morphine, oxycodone, fentanyl, hydromorphone, buprenorphine | Mu (±kappa, delta) opioid receptor agonism | Moderate–severe; cancer pain; post-op | Respiratory depression, constipation, tolerance, OIH, dependence |
| Gabapentinoids | Gabapentin, pregabalin | Alpha-2-delta subunit of voltage-gated Ca²⁺ channels → ↓neurotransmitter release | Neuropathic; fibromyalgia; post-op (opioid-sparing) | Sedation, dizziness; renal dose adjustment; abuse potential |
| TCAs | Amitriptyline, nortriptyline | Serotonin + noradrenaline reuptake inhibition; Na channel blockade | Neuropathic; fibromyalgia; migraine prophylaxis | Anticholinergic effects; QTc prolongation; sedation; overdose risk |
| SNRIs | Duloxetine, venlafaxine | Serotonin + noradrenaline reuptake inhibition → ↑descending inhibition | Neuropathic; fibromyalgia; musculoskeletal | Nausea at initiation; hypertension (venlafaxine); SSRI interactions |
| NMDA antagonists | Ketamine (sub-anaesthetic), memantine | NMDA glutamate receptor antagonism → central sensitisation ↓ | OIH; refractory neuropathic; opioid-sparing post-op | Psychomimetic effects; dose-dependent dissociation; abuse potential |
WHO analgesic ladder
Step 1 — Mild pain
Paracetamol ± NSAID
+ adjuvant if appropriate (e.g., gabapentin for neuropathic component)
↑ if pain persists or increases
Step 2 — Mild to moderate pain
Codeine / tramadol ± paracetamol ± NSAID
Note: CYP2D6 poor metabolisers have reduced codeine efficacy; ultrarapid metabolisers at toxicity risk
↑ if pain persists or increases
Step 3 — Moderate to severe pain
Morphine / oxycodone / fentanyl / hydromorphone ± non-opioid
+ adjuvant at each step: antidepressants, anticonvulsants, corticosteroids, bisphosphonates
↑ if inadequate
Step 4 (2018 update) — Interventional
Nerve blocks, epidural, intrathecal opioids, neuromodulation
For refractory cancer pain or complex chronic pain unresponsive to systemic therapy
Opioid equianalgesic doses
Approximate equianalgesic doses to oral morphine 30 mg. Reduce calculated dose by 25–50% when rotating opioids to account for incomplete cross-tolerance. Always verify with local formulary and specialist guidance.
| Opioid | Route | Equianalgesic dose | t½ (approx) | Notes |
|---|---|---|---|---|
| Morphine | Oral | 30 mg | 2–4 h | Reference standard |
| Morphine | IV/SC | 10 mg | 2–4 h | Oral:IV ratio ~3:1 |
| Oxycodone | Oral | 20 mg | 3–5 h | Prodrug → oxymorphone (minor); CYP3A4/2D6 |
| Hydromorphone | Oral | 7.5 mg | 2–3 h | Active M6G metabolite accumulates in renal impairment |
| Hydromorphone | IV | 1.5 mg | 2–3 h | ~7× more potent than IV morphine |
| Fentanyl | TD patch | 12–25 mcg/h | 17–27 h (patch) | For patients on stable ≥60 mg/day OME; 72 h patch |
| Codeine | Oral | 200 mg | 2–3 h | Prodrug → morphine via CYP2D6; poor/URM variable response |
| Tramadol | Oral | 300 mg | 5–7 h | Weak mu agonist + SNRI; CYP2D6 metaboliser variability; serotonin syndrome risk |
| Buprenorphine | SL/TD | 0.4 mg SL ≈ 30 mg oral morphine | 24–42 h | Partial mu agonist; ceiling for respiratory depression; ceiling not for analgesia |
Frequently asked questions
What is the WHO analgesic ladder and how is it used today?
The WHO analgesic ladder ↗ provides three steps: (1) mild pain — paracetamol ↗/NSAIDs; (2) mild-moderate — weak opioids (codeine, tramadol) ± non-opioids; (3) moderate-severe — strong opioids (morphine ↗, oxycodone, fentanyl) ± adjuvants. Adjuvant analgesics (antidepressants, anticonvulsants, corticosteroids) apply at every step for specific pain types. See opioid safety guide for overdose management.
How do NSAIDs work and what are the main safety concerns?
NSAIDs inhibit cyclooxygenase (COX-1/COX-2) ↗, reducing prostaglandins. COX-1 loss → GI ulceration (mitigate with PPI co-prescription ↗). COX-2 selective agents (celecoxib) have lower GI risk but higher CV risk — the PRECISION trial ↗ showed celecoxib non-inferior to ibuprofen/naproxen for CV outcomes. NSAIDs reduce renal prostaglandins → ↓GFR, Na/water retention; avoid in eGFR <30 mL/min. See renal dosing guide.
What is equianalgesic dosing and how are opioids converted?
Equianalgesic reference: oral morphine 30 mg = oral oxycodone 20 mg = oral hydromorphone 7.5 mg = fentanyl patch 12–25 mcg/h (for 60 mg/day oral morphine equivalent, OME). When rotating, reduce calculated dose by 25–50% for incomplete cross-tolerance. IV morphine is approximately 3× more potent than oral (oral:IV ratio 3:1). Use validated tables — e.g., NHS opioid guidance ↗ or GlobalRPh converter ↗. See also the DrugTheGuide dose converter.
When are adjuvant analgesics used for neuropathic pain?
For neuropathic pain, IASP ↗-endorsed first-line agents are: TCAs (amitriptyline, nortriptyline — NNT ~2–4); SNRIs (duloxetine ↗, venlafaxine); gabapentinoids (gabapentin, pregabalin — NNT ~4–7). Topicals: lidocaine 5% patches ↗ (post-herpetic neuralgia), capsaicin 8% patch (qutenza). See NeuPSIG guidelines ↗ and pharmacogenomics guide for CYP2D6 impact on TCA/tramadol metabolism.
What is opioid-induced hyperalgesia and how is it managed?
Opioid-induced hyperalgesia (OIH) is a paradoxical pain sensitisation caused by opioids — distinct from opioid tolerance ↗. It presents as diffuse, allodynic pain worsening with dose escalation. NMDA receptor activation and central sensitisation are key mechanisms. Management: opioid rotation (different receptor binding profile may reset sensitisation), sub-anaesthetic ketamine ↗ (NMDA antagonism), low-dose methadone (weak NMDA antagonist + mu agonist), and non-opioid adjuvants. See opioid safety guide.