Opioids · Pain & inflammation
Codeine
Tylenol No. 3 (with acetaminophen)®(brand names vary by market)
A prodrug whose effect depends on an enzyme nobody has measured.
Also: oral liquid
Mechanism
Weak mu agonist itself; its analgesia comes almost entirely from CYP2D6 conversion to morphine. That enzyme's activity varies enormously between people and is affected by other drugs.
Indications
- Mild to moderate pain
- Cough suppression
- Diarrhoea, historically
Formulations
Dosing concepts
Genetic variability
Poor metabolisers get almost no analgesia. Ultra-rapid metabolisers convert far more than expected and can develop opioid toxicity at ordinary doses.
Falling out of use
Its unpredictability has moved many guidelines away from it entirely, in favour of a low dose of a predictable opioid.
Concepts, not prescribing instructions. Practice numbers live in current references and local protocols.
Pharmacokinetics
- Bioavailability
- ~50%
- Half-life
- 2 to 4 h
- Elimination
- hepatic: CYP2D6 to morphine; inhibited by fluoxetine, paroxetine and bupropion
- Protein binding
- ~7%
Adverse effects
- ConstipationcommonProminent even at analgesic doses.
- Nausea and drowsinesscommon
- No analgesia at all in poor metaboliserscommonAn adverse outcome even though it is not an adverse effect.
- Opioid toxicity in ultra-rapid metabolisersseriousIncluding deaths in children and in breastfed infants.
Contraindications & precautions
Contraindications
- Children under 12
- After tonsillectomy or adenoidectomy in children
- Breastfeeding
- Known CYP2D6 ultra-rapid metaboliser status
Precautions
- Concurrent CYP2D6 inhibitors
- Renal impairment
- Older adults
Interactions
No curated interaction entries yet for this agent.
Monitoring
Whether it is actually working
A substantial minority get nothing from it, and that is worth recognising rather than escalating
Sedation, especially in children and breastfeeding mothers
Where the fatal cases have occurred
Total acetaminophen from combination products
Same trap as oxycodone combinations
Counselling points
- If this does not help your pain at all, tell us; some people cannot convert it into its active form.
- Not to be taken while breastfeeding.
- It causes constipation; take a laxative if needed.
- Check whether your tablets also contain acetaminophen.
Clinical pearls
- Fluoxetine, paroxetine and bupropion all block CYP2D6, so a patient on any of them gets little or no analgesia from codeine. It is an interaction of absence, and nobody notices it as an interaction.
- The paediatric contraindications came from deaths in ultra-rapid metabolisers after tonsillectomy, and they are absolute.
References & review
- Codeine product monograph (consult the current version for your market) (monograph)
- Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed. (reference-work)
Last reviewed 2026-08-16 · jurisdiction: global · drug information changes; verify against current references before practice use.