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Drug Reference

codeine

opioid analgesic· Brands: Codeine Phosphate, Panadeine, Nurofen Plus, Solpadeine, Tylenol No. 3PO

Mechanism of action
Codeine is a prodrug converted to morphine in the body. It acts as a weak agonist at mu-opioid receptors in the central nervous system, producing analgesia, cough suppression, and sedation. The analgesic effect is mainly mediated by its active metabolite morphine, which binds to mu-opioid receptors and inhibits ascending pain pathways.
Pharmacokinetics
Codeine is well absorbed after oral administration and undergoes extensive first-pass hepatic metabolism. It is O-demethylated to morphine by CYP2D6 and N-demethylated to norcodeine by CYP3A4. Analgesic efficacy depends on CYP2D6 activity, which is genetically variable. Peak plasma concentrations occur within 1 hour. The elimination half-life is about 3 hours. Excretion is mainly renal as inactive metabolites and unchanged drug.
Indications & dosing

Mild to moderate pain

Short-term use for acute pain. Response varies due to CYP2D6 metabolism; avoid in children under 12 years.

  • adult · PO: 30–60 mg every 4-6 hours · Short-term use for acute pain. Response varies due to CYP2D6 metabolism; avoid in children under 12 years.

Non-productive cough

Only for dry, non-productive cough. Avoid in productive cough and in children under 12 years.

  • adult · PO: 15–30 mg every 4-6 hours · Only for dry, non-productive cough. Avoid in productive cough and in children under 12 years.
Contraindications & precautions
  • Respiratory depression · Codeine is contraindicated in patients with respiratory depression or who are in a state where respiratory depression is a risk.
  • Acute severe asthma · Opioids can exacerbate asthma and cause fatal respiratory depression.
  • Paralytic ileus · Opioids increase gastrointestinal smooth muscle tone, potentially worsening ileus.
  • Children under 12 years · Risk of life-threatening respiratory depression. Codeine is contraindicated in children under 12.
  • Severe hepatic impairment · Hepatically metabolised; severe disease may lead to unpredictable effects.
  • Pregnancy · Codeine crosses the placenta; use only if benefits outweigh risks, as it can cause neonatal respiratory depression.
  • Breastfeeding · Codeine passes into breast milk; particularly risky in ultra-rapid CYP2D6 metabolisers.
  • Use with caution in patients with decreased respiratory reserve, including COPD, severe asthma, or other conditions that predispose to respiratory depression.
  • Use with caution in renal impairment, as codeine metabolites may accumulate and increase the risk of adverse effects.
  • Use with caution in hepatic impairment, as codeine is metabolised in the liver; consider alternative analgesia.
  • Use with caution in the elderly, as they are more susceptible to opioid adverse effects such as drowsiness and hypotension.
  • Use with caution in patients with a history of drug misuse or dependence; codeine has the potential for abuse.
  • Avoid concurrent use with other CNS depressants (e.g. alcohol, benzodiazepines) due to additive sedative and respiratory depressant effects.
Adverse effects
  • Constipation
  • Nausea and vomiting
  • Drowsiness
  • Dizziness
  • Dry mouth
  • Respiratory depressionserious
  • Hypotensionserious
  • Dependence and toleranceserious
Renal & hepatic adjustment
  • eGFR 30–59: Use with caution; consider dose reduction to reduce risk of accumulation.
  • eGFR 0–29: Avoid; risk of accumulation of active metabolites and respiratory depression. (avoid)
  • Hepatic impairment (mild): Use with caution; monitor for increased sensitivity to opioid effects.
  • Hepatic impairment (moderate): Consider dose reduction; monitor closely for adverse effects.
  • Hepatic impairment (severe): Avoid; contraindicated due to risk of toxicity and unpredictable metabolism. (avoid)
Monitoring, pregnancy & toxicity
  • Pain relief · Assess regularly
  • Respiratory rate · Especially in high-risk patients
  • Constipation · Monitor and prophylaxis if needed
  • Signs of dependence or abuse · Throughout therapy
  • Pregnancy: Use not recommended during pregnancy; if required, use lowest effective dose for shortest duration. Avoid in third trimester due to risk of neonatal respiratory depression and withdrawal.
  • Toxicity: Respiratory depression · Administer naloxone; provide supportive care including oxygen and ventilation.
  • Toxicity: Pinpoint pupils (miosis) · Supportive care; naloxone if respiratory depression is present.
  • Toxicity: Sedation and CNS depression · Supportive care; naloxone; consider activated charcoal if recent ingestion.
  • Toxicity: Hypotension and bradycardia · Fluid resuscitation; atropine for bradycardia; naloxone may reverse.
Antidotes & reversal
  • Naloxone · Reverses respiratory depression; repeated doses may be needed.
Clinical notes
Codeine is used for mild to moderate pain and as a cough suppressant. It is often combined with paracetamol or aspirin. Use with caution in patients with respiratory depression, asthma, or severe hepatic impairment. Common adverse effects include constipation, nausea, and sedation. There is a risk of dependence and tolerance with prolonged use. Because CYP2D6 metabolism varies, some patients may experience reduced or enhanced effects. Codeine should be avoided in children under 12 years and in breastfeeding mothers due to the risk of serious adverse effects.

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BNF; local formulary