Codeine for Cough

Codeine is an opioid antitussive reserved for distressing dry cough when other measures have failed, for example in advanced lung disease. Evidence of cough benefit is limited. Its place is narrow because of respiratory depression, dependence and variable CYP2D6 metabolism.

Classification. Opioid analgesic and antitussive, schedule-controlled in many regions.

Mechanism. Acts on mu opioid receptors in the brainstem to suppress the cough reflex. Part of the effect is due to conversion to morphine.

Pharmacokinetics. About 10% is converted to morphine by CYP2D6. The rest is metabolised by glucuronidation and CYP3A4. Half-life 3 to 4 hours. Active metabolites are renally cleared.

Alternative, short-term, distressing dry cough in adults. 15 to 30 mg every 4 to 6 hours as needed. Maximum 120 mg daily. Typical linctus 15 mg/5 mL, 5 to 10 mL three or four times daily.

Specialist, palliative cough. Same doses, reviewed regularly. Titrate to the lowest effective dose and add a laxative.

Children and adolescents. Contraindicated under 12 years. Not advised from 12 to 18 years if breathing is compromised.

Emergency. Not used.

Loading and titration. No loading dose. Start at 15 mg and increase only if needed.

Boxed-warning-level risk. Life-threatening respiratory depression and death in children, especially after tonsillectomy or adenoidectomy, and in ultra-rapid CYP2D6 metabolisers. Addiction, abuse and misuse. Concurrent benzodiazepines or other central nervous system depressants. Neonatal opioid withdrawal after prolonged use in pregnancy.

Contraindications. Respiratory depression, acute asthma or COPD exacerbation, children under 12 years, breastfeeding, known ultra-rapid CYP2D6 metabolism, acute abdomen, paralytic ileus, raised intracranial pressure, concurrent monoamine oxidase inhibitor.

Serious adverse effects. Respiratory depression, dependence, biliary spasm, paralytic ileus, serotonin toxicity in rare cases, severe hypotension.

Common adverse effects. Constipation, drowsiness, nausea, dizziness.

Interactions. Benzodiazepines, alcohol and other sedatives add respiratory depression. Strong CYP3A4 inhibitors, including ritonavir, raise exposure. CYP2D6 inhibitors reduce morphine formation and so may reduce effect. Monoamine oxidase inhibitors are contraindicated.

Common prescribing errors. Prescribing to children. Combining with another codeine-containing product (for example codeine with paracetamol). Exceeding 120 mg daily. Using it for productive cough.

Special groups.

• Pregnancy: avoid prolonged use and near term. Breastfeeding: avoid, because infants have died of morphine toxicity.

• Older adults: start at 15 mg; watch sedation and constipation.

• Kidney impairment: avoid or halve the dose when GFR is under 30 mL/min. Liver impairment: use lower doses and longer intervals.

• East Africa: ultra-rapid CYP2D6 metabolism is more common in some East and North African populations, which raises the risk of morphine toxicity in children and breastfed infants. Exclude tuberculosis before treating a persistent cough.

Formulations. Linctus 15 mg/5 mL, tablets 15 mg and 30 mg, combination products (avoid for cough).

Baseline. Cough duration, respiratory reserve, sedatives, kidney and liver function, pregnancy and breastfeeding status.

Monitoring. Cough, sedation, respiratory rate, bowel function. Review within 1 week.

Stop and reduce rules. Stop or reduce for sedation, slow breathing or confusion. Taper if used for over 2 weeks. Therapeutic drug monitoring is not used.

Referral and escalation. Refer for persistent cough without a cause, haemoptysis or palliative symptom control.