Published: March 2013


Codeine and Ultra-Rapid Metabolisers

Prescriber Update 34(1):3-4
March 2013

Key Messages

  • Patients may respond differently to codeine and some patients may be at increased risk of serious adverse effects.
  • Symptoms of codeine toxicity or overdose may include somnolence, difficulty waking, confusion, shallow breathing, nausea and vomiting.
  • Treatment of codeine toxicity is most commonly with the opioid antagonist, naloxone.

Prescribers are reminded that patients may respond differently to codeine treatment and are encouraged to educate parents and caregivers of young patients about possible adverse effects associated with codeine use.

Codeine is a widely used opioid analgesic and is sometimes given post-operatively for pain relief in children. Codeine has a very low affinity for opioid receptors and is partially metabolised to morphine in the liver via the cytochrome P450 enzyme 2D6 (CYP2D6).

Genetic differences in the expression of the CYP2D6 enzyme results in differences in the extent to which codeine is metabolised. Patients deficient in or lacking this enzyme cannot convert codeine to morphine and therefore may not obtain adequate analgesic pain relief. Conversely, patients who metabolise codeine very rapidly (ultra-rapid metabolisers) are at increased risk of developing adverse effects of opioid toxicity, even at low doses.

Estimates suggest that up to 10% of the Caucasian population may be poor metabolisers and up to 10% may be ultra-rapid metabolisers1. The prevalence in Maori and Pacific people is not known. Genetic testing to identify ultra-rapid metabolisers prior to prescribing codeine is not currently available in New Zealand.

Recently, cases of respiratory depression and death following the use of codeine for post-surgery analgesia have been reported in the medical literature2. These incidents occurred in children who had evidence of being ultra-rapid metabolisers of codeine. Post-operative codeine use after surgeries such as tonsillectomy or adenoidectomy may increase the risk of breathing difficulties in susceptible children.

Symptoms of codeine toxicity or overdose may include nausea, vomiting, constipation, lack of appetite, somnolence, extreme sleepiness, difficulty waking, confusion, shallow breathing and coma. Caregivers and patients should be advised to immediately discontinue codeine and seek medical attention if these symptoms occur.

Effects can be reversed with naloxone, a narcotic antagonist. Naloxone acts by competing for the same receptor sites as opioids.

  1. de Leon J, Armstrong SC, Cozza KL. 2006. Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics 47(1): 75-85.
  2. Kelly LE, Rieder M, van den Anker J, et al. 2012. More codeine fatalities after tonsillectomy in North American children. Pediatrics 129(5): e1343-1347.


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