DurgicalDurgical
EN
Open the app

Pharmacology · Opioids and antagonists

Codeine !

A weak opioid for mild to moderate pain and cough. It is a prodrug: CYP2D6 turns it into morphine, which makes it dangerous in ultra-rapid metabolisers.

Updated 2026-11-01

  • Class: Opioids and antagonists
  • Receptor: μ-opioid receptor (through the morphine it forms)
  • ATC code: R05DA04
  • WHO Model List of Essential Medicines

The figure shows morphine, codeine's active metabolite, in the μ receptor bound to its Gi protein; the viewer crops the image to the receptor.

Target in 3D: μ-opioid receptor (through the morphine it forms). PDB structure 8EF6 (RCSB PDB, public domain). View the structure at RCSB PDB

Mechanism of action

Codeine (3-methylmorphine) has little affinity for the μ receptor. Its pain relief depends on hepatic CYP2D6 O-demethylating it to morphine, which activates the μ receptor. Because of CYP2D6 polymorphisms, poor metabolisers get little analgesia and ultra-rapid metabolisers make too much morphine, with a risk of respiratory depression. It also suppresses the cough reflex in the brainstem.

  1. Hepatic CYP2D6 turns part of the codeine into morphine
  2. Morphine activates the μ receptor in the pain pathway
  3. Less pain transmission and a weaker cough reflex
  4. Ultra-rapid metaboliser: excess morphine and respiratory depression

Pharmacokinetics

Absorption
Well absorbed by mouth.
Metabolism
Liver: mostly glucuronidation to codeine-6-glucuronide; a part becomes morphine (CYP2D6, active) and another norcodeine (CYP3A4).
Elimination
Kidney, as metabolites.

Indications

  • Mild to moderate pain when other analgesics are not enough, often combined with paracetamol
  • Cough (as an antitussive)

Adverse effects

Common

  • Drowsiness, dizziness and sedation
  • Nausea and vomiting
  • Constipation
  • Sweating

Contraindications

  • Children younger than 12 years
  • Postoperative management of tonsillectomy or adenoidectomy in under-18s
  • Significant respiratory depression
  • Acute or severe bronchial asthma without monitoring or resuscitation equipment
  • Known or suspected gastrointestinal obstruction, including paralytic ileus
  • Hypersensitivity to the drug
  • Use of monoamine oxidase inhibitors within the last 14 days

Key interactions

Benzodiazepines, alcohol and other central nervous system depressants
Add up to profound sedation, respiratory depression, coma and death.
CYP3A4 inhibitors
More codeine left for CYP2D6 and more morphine: a stronger or longer effect.
CYP3A4 inducers, or stopping an inhibitor
Less morphine: weaker pain relief or withdrawal.
Monoamine oxidase inhibitors (current or within the last 14 days)
Contraindicated: risk of serotonin syndrome or opioid toxicity.

What is monitored

  • Respiratory rate and sedation level
  • Bowel habits
  • Signs of toxicity in the breastfed infant if the mother receives it

Administration and safety

  • Check whether the product is a combination with paracetamol so that total paracetamol is not exceeded.
  • Not used in children under 12 or after tonsillectomy in under-18s.
  • Controlled medicine: the order is verified, every dose recorded and leftovers kept secure.

Nursing care

  • Before each dose: respiratory rate, oxygen saturation and sedation level; hold the dose and report excessive sedation or slow breathing.
  • Keep naloxone at hand and teach the family to recognise an overdose.
  • Prevent constipation from the start and track bowel habits.
  • Prevent falls: dizziness, drowsiness and orthostatic hypotension.
  • Breastfeeding is not recommended during treatment: an infant can be poisoned if the mother is an ultra-rapid metaboliser.

Pregnancy and breastfeeding

Prolonged use in pregnancy can cause neonatal opioid withdrawal syndrome, which is expected and treatable; the newborn is watched after birth.

Test yourself

Think of the answer, then tap the question to see it.

Why can codeine be fatal in some children?

Ultra-rapid CYP2D6 metabolisers turn more codeine into morphine and can develop severe respiratory depression; so it is contraindicated under 12 and after tonsillectomy in under-18s.

What happens to codeine analgesia in a CYP2D6 poor metaboliser?

Little morphine is formed and pain relief is poor.

How can a CYP3A4 inhibitor increase codeine's effect?

By slowing the route to norcodeine it leaves more codeine for CYP2D6, which makes more morphine.

Add to my cards (3)

← Back to the class: Opioids and antagonists

Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: Codeine: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026); CODEINE SULFATE tablet (DailyMed (U.S. National Library of Medicine), 2026); Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed., ch. 23 (McGraw Hill, 2023); ATCDDD - ATC/DDD Index (WHO Collaborating Centre for Drug Statistics Methodology, 2026).

Spotted a mistake?We are always improving for the community. Tell us what is wrong and our team will review it.Report a mistake

Representative model, for educational purposes only.