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Opioid Analgesic — Weak (Prodrug) Pregnancy: Avoid near term — neonatal withdrawal syndrome; use paracetamol as first-line in pregnancy

Codeine Phosphate (Orthopaedic — Mild-Moderate Pain)

Brand names: Codeine Phosphate Tablets, Codeine Linctus

Adult dose

Dose: 30–60 mg every 4–6 hours
Route: Oral
Frequency: Every 4–6 hours
Max: 240 mg/day
WHO analgesic ladder Step 2. Usually combined with paracetamol (co-codamol 30/500). Codeine is a prodrug — converted to morphine by CYP2D6. Ultra-rapid metabolisers (CYP2D6 gene duplication — more common in North African, Ethiopian, Saudi Arabian populations) convert codeine to morphine rapidly — risk of respiratory depression at standard doses.

Paediatric dose

Route:
CONTRAINDICATED in children under 18 years following MHRA 2013 safety review — risk of respiratory depression and death in children with CYP2D6 ultra-rapid metaboliser genotype, and in children post-adenotonsillectomy for obstructive sleep apnoea

Dose adjustments

Renal

Avoid in severe renal impairment — morphine metabolites accumulate; use paracetamol ± NSAID instead

Hepatic

Reduce dose in hepatic impairment — reduced CYP2D6 activity; unpredictable morphine conversion

Clinical pearls

  • MHRA 2013: Codeine contraindicated in under-18s — following reports of morphine toxicity deaths in children with CYP2D6 ultra-rapid metaboliser genotype; particularly high risk in children with adenotonsillectomy for obstructive sleep apnoea (hypoxic vulnerability)
  • CYP2D6 ultra-rapid metabolisers: approximately 1–2% of UK population, but 6–10% of North African, Ethiopian, and Saudi Arabian populations — these patients convert codeine to morphine 10× faster; risk of fatal respiratory depression at standard doses
  • CYP2D6 poor metabolisers (~10% white Caucasians): codeine has minimal analgesic effect — no morphine conversion; explains why some patients report codeine does not work for them
  • Codeine in post-operative orthopaedic care: increasingly being replaced by tramadol or dihydrocodeine as second-step opioid — codeine's analgesic effect is entirely dependent on CYP2D6 conversion to morphine
  • MHRA 2015: Restriction to breastfeeding — if codeine must be used, limit to lowest dose, shortest course; advise mothers to monitor neonates for drowsiness, poor feeding, limpness, breathing changes

Contraindications

  • Children under 18 years — MHRA 2013 absolute contraindication
  • Breastfeeding — neonatal morphine toxicity if mother is CYP2D6 ultra-rapid metaboliser
  • Acute respiratory depression
  • Known CYP2D6 ultra-rapid metaboliser phenotype
  • Paralytic ileus

Side effects

  • Constipation — universal; co-prescribe laxative
  • Nausea and vomiting
  • Sedation
  • Respiratory depression — rare at standard doses in normal metabolisers; significant risk in ultra-rapid metabolisers
  • Dependence potential

Interactions

  • CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion) — reduce conversion of codeine to morphine; reduced analgesia
  • CYP2D6 inducers — increase morphine conversion; toxicity risk
  • CNS depressants — additive sedation and respiratory depression
  • MAO inhibitors — avoid within 14 days

Monitoring

  • Respiratory rate and sedation
  • Bowel function
  • Pain response (poor response may indicate CYP2D6 poor metaboliser)

Reference: BNFc; BNF 90; MHRA DSU 2013 (Children Under 18); MHRA DSU 2015 (Breastfeeding); EMA Codeine Review 2013; SPC Codeine Phosphate Tablets. Verify against your local formulary and the latest BNF before prescribing.

Related

Curated clinical cross-links plus same-class fallbacks.

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