Codeine for analgesia: restricted use in children because of reports of morphine toxicity

Codeine should only be used to relieve acute moderate pain in children older than 12 years and only if it cannot be relieved by other painkillers such as paracetamol or ibuprofen alone. Furthermore, a significant risk of serious and life-threatening adverse reactions has been identified in children with obstructive sleep apnoea who received codeine after tonsillectomy or adenoidectomy (or both). Codeine is now contraindicated in all children younger than 18 years who undergo these procedures for obstructive sleep apnoea

• From: Medicines and Healthcare products Regulatory Agency
• Published: 11 December 2014

• Therapeutic area: Anaesthesia and intensive care, Dentistry, Ear, nose and throat, Paediatrics and neonatology and Pain management and palliation

Article date: July 2013

Codeine is used for pain relief in adults and children and is considered to be suitable for persistent pain of up to moderate intensity. It is commonly used in combination with other drugs—mainly paracetamol, but also aspirin, caffeine, or ibuprofen. However, despite its established use, there remains substantial lack of knowledge about its safety and efficacy—particularly in the paediatric population.

Metabolism

Codeine is converted to morphine in the liver by the CYP2D6 enzyme. There are many genetic variations of CYP2D6, which affect the extent of this conversion in individuals. People can be classified as: poor; intermediate; extensive; or ultra-rapid metabolisers. Different plasma morphine concentrations in patients’ blood lead not only to different levels of pain relief, but also to a variable and unpredictable risk of side effects due to morphine’s action on the brain and respiratory centre.

Poor metabolisers convert very little codeine into morphine and therefore have little or no pain relief. 7–10% of Caucasians are poor metabolisers, but this proportion varies with ethnic origin.

Individuals who are ultra-rapid metabolisers or extensive metabolisers have an excessive amount of morphine in their blood, which can lead to severe side effects due to its effects on the brain and on breathing. Prevalence of ultra-rapid metabolisers also varies by ethnic origin: it is less common in northern European countries (including the UK) and is more common in Spain, Italy, Greece, Africa, and the Middle East (see table).

African or Ethiopian

Prevalence of ultra-rapid metabolisers: 29.0%

African American

Prevalence of ultra-rapid metabolisers:3.4–6.5%

Asian

Prevalence of ultra-rapid metabolisers: 1.2–2.0%

Caucasian

Prevalence of ultra-rapid metabolisers: 3.6–6.5%

Greek

Prevalence of ultra-rapid metabolisers: 6.0%

Hungarian

Prevalence of ultra-rapid metabolisers: 1.9%

Northern European

Prevalence of ultra-rapid metabolisers: 1.0–2.0%

European review

A European review of the safety of codeine-containing medicines licensed for pain relief in children (age 0–18 years) began in October 2012. This review was triggered by concerns of an increased risk of morphine toxicity when susceptible children receive codeine for pain after surgery. These concerns follow the reporting of three fatalities and one life-threatening case of respiratory depression in children given codeine after tonsillectomy or adenoidectomy in the treatment of obstructive sleep apnoea.^{[footnote 1] [footnote 2]}

Conclusions of the review

The review concluded that codeine-containing medicines for the management of pain should only be used to treat acute moderate pain in children older than age 12 years and only if it cannot be relieved by other painkillers such as paracetamol or ibuprofen alone.

Furthermore, a significant risk was identified in children with obstructive sleep apnoea who received codeine after tonsillectomy or adenoidectomy (or both) irrespective of CYP2D6 status. Codeine is now contraindicated in all children younger than 18 years who undergo these procedures for sleep apnoea. This is because of an increased risk of serious and life-threatening adverse reactions, including loss of consciousness and respiratory arrest.

The review also concluded that codeine should be contraindicated in all patients known to be CYP2D6 ultra-rapid metabolisers. Codeine should also not be used by breastfeeding mothers because it can pass to the baby through breast milk and potentially cause harm.

Advice for healthcare professionals:

• Codeine should only be used to relieve acute moderate pain in children older than 12 years and only if it cannot be relieved by other painkillers such as paracetamol or ibuprofen
• Codeine is contraindicated in all children (ie, younger than 18 years) who undergo tonsillectomy or adenoidectomy (or both) for obstructive sleep apnoea
• Codeine is not recommended for use in children whose breathing might be compromised, including those with: neuromuscular disorders; severe cardiac or respiratory conditions; upper respiratory or lung infections; multiple trauma; or extensive surgical procedures. The symptoms of morphine toxicity may be increased in these settings
• In children age 12–18 years, the maximum daily dose should not exceed 240 mg. This may be taken in divided doses, up to four times a day at intervals of no less than 6 hours. It should be used at the lowest effective dose for the shortest period. Duration of treatment should be limited to 3 days and if no effective pain relief is achieved, treatment should be reviewed by a physician
• Information should be given to parents and caregivers on how to recognise the signs of morphine toxicity, and advice should be given to stop giving the child codeine and to seek medical attention immediately if their child is showing these signs or symptoms
• Symptoms of codeine toxicity include: reduced levels of consciousness; lack of appetite; somnolence; constipation; respiratory depression; ‘pin-point’ pupils; or nausea and vomiting
• Codeine is contraindicated in all patients of any age known to be CYP2D6 ultra-rapid metabolisers
• Codeine should not be used by breastfeeding mothers because it can pass to the baby through breast milk and potentially cause harm

Please note that this advice applies only to codeine-containing products; it does not apply to dihydrocodeine because this medicine was not included in the review.

Further Information

European Medicines Agency announcement

US Food and Drug Administration information

Health Canada information

British National Formulary

Article citation: Drug Safety Update vol 6 issue 12, July 2013: A1.

1. Ciszkowski C, et al. N Engl J Med 2009; 361: 827–28. ↩

2. Kelly LE, et al. Pediatrics 2012; 129: 1343–47. ↩

Published 11 December 2014