Codeine Poisoning

Codeine poisoning causes opioid toxicity, with sedation, respiratory depression and constipation. Severity depends on CYP2D6 conversion to morphine, so ultra-rapid metabolisers are at risk of life threatening effects at normal doses, particularly children and breastfed infants.

Codeine is common in over-the-counter and prescribed combination products with paracetamol or ibuprofen, so co-ingested drugs are a frequent concern. Severe toxicity is unusual under 5 mg/kg and likely above 10 mg/kg in the opioid naive; children under 12 years should not receive codeine.

Risk factors for harm. CYP2D6 ultra-rapid metaboliser genotype (about 1 to 2% in Northern Europeans and up to 10 to 30% in North African and Ethiopian populations), renal impairment, breastfeeding mothers on codeine, and sleep apnoea.

Course. Peak effects in 1 to 2 hours, lasting 4 to 6 hours (longer in renal failure or modified release products).

Pathophysiology.

Codeine is a prodrug converted by CYP2D6 to morphine, which activates mu opioid receptors and suppresses respiration.

Poor metabolisers produce less morphine, and ultra-rapid metabolisers produce toxic levels.

• Drowsiness, miosis, nausea, vomiting, itching and constipation.
• Respiratory depression, hypoxia and coma.
• Hypotension, bradycardia, pulmonary oedema and seizures in large doses or in children.
• Features of paracetamol or ibuprofen toxicity in combination products.

Red flags.

• Respiratory rate under 10 breaths/minute or hypoxia.
• Infant or child with sedation or poor feeding (maternal use while breastfeeding).
• Co-ingested paracetamol over 150 mg/kg.

• History of dose, product (single or combination) and time; paracetamol and salicylate levels at 4 hours.
• Clinical triad of reduced consciousness, miosis and respiratory depression; response to naloxone supports the diagnosis.
• Glucose, electrolytes, renal and liver function, venous gas and ECG.
• Genotype testing for CYP2D6 where toxicity occurs at therapeutic doses.

Differential diagnosis. Other opioid overdose, benzodiazepine or barbiturate overdose, alcohol intoxication, hypoglycaemia and neonatal sepsis.

• Airway protection, oxygen and ventilation as needed.
• Naloxone 0.4 mg intravenously, repeated every 2 to 3 minutes and increased up to 2 mg for each dose until the respiratory rate is over 10 breaths/minute and breathing is adequate (intramuscular 0.4 to 2 mg, or intranasal 4 mg). Maximum 10 mg before reviewing the diagnosis. Monitor respiratory rate, oxygen saturation, withdrawal (agitation, vomiting, pulmonary oedema) and re-sedation. In opioid dependent patients, titrate in 0.04 to 0.1 mg steps; no renal or hepatic adjustment; acceptable in pregnancy.
• Children: naloxone 10 micrograms/kg intravenously, repeated up to 100 micrograms/kg if no response. Maximum 2 mg for each dose. Monitor respiratory rate and re-sedation.
• Activated charcoal 50 g orally once (1 g/kg, maximum 50 g, in children) within 1 hour of a significant ingestion if the airway is protected. Monitor the airway for aspiration. Avoid with reduced consciousness, ileus or gastrointestinal obstruction; no renal or hepatic adjustment; acceptable in pregnancy.
• Combination products: measure paracetamol at 4 hours and give acetylcysteine intravenously, by weight (maximum 110 kg), if over the treatment line: 150 mg/kg in 200 mL of 5% glucose over 1 hour, then 50 mg/kg in 500 mL over 4 hours, then 100 mg/kg in 1000 mL over 16 hours. Maximum 33 g in total. Monitor for anaphylactoid reaction, ALT, INR and creatinine; no dose reduction in liver or renal impairment; give in pregnancy.
• Observe for at least 6 hours (12 hours for modified release or children); admit for any child with symptoms.
• Breastfed infant with sedation: stop maternal codeine, and use an alternative analgesic.
• Psychiatric assessment in intentional ingestion.

Monitoring. Respiratory rate, oxygen saturation and conscious level hourly; ALT and INR after combination overdoses.

Referral and escalation. Poisons information centre; paediatric service for children; intensive care for hypoventilation.

Special groups. Children under 12 years and breastfeeding mothers: avoid codeine. Renal impairment: accumulation of active metabolites.