The codeine lesson: how one safety signal changed paediatric prescribing
A painkiller given to children for decades turned out to be dangerous for a genetically identifiable minority. The response remains a model for pharmacogenomic safety.
In brief
How CYP2D6 ultra-rapid metabolism made codeine dangerous for some children, and why the FDA and EMA restricted its use in children from 2013.
- Codeine is converted to morphine by the enzyme CYP2D6, whose activity varies widely between people.
- Ultra-rapid metabolisers can produce dangerous morphine levels from standard doses.
- US and EU regulators restricted codeine in children between 2013 and 2017.
Codeine was for decades a standard choice for pain and cough in children. It is cheap, familiar and was widely seen as gentler than stronger opioids. That perception turned out to be wrong for some children.
The mechanism
Codeine itself has little painkilling effect. It works because the liver enzyme CYP2D6 converts part of it into morphine. CYP2D6 activity is genetically determined and varies enormously. Poor metabolisers get little benefit. Ultra-rapid metabolisers, who carry extra functional copies of the gene, convert codeine quickly and can reach high morphine levels from a normal dose.
The proportion of ultra-rapid metabolisers varies between populations, from a few per cent in some to considerably more in others.
The signal
Reports emerged of children who suffered life-threatening breathing problems or died after receiving codeine, many after tonsillectomy or adenoidectomy for obstructive sleep apnoea. Children with sleep-disordered breathing were particularly vulnerable to opioid-induced respiratory depression. In several cases, testing showed the child was an ultra-rapid metaboliser.
The response
In 2013 the FDA added a boxed warning against codeine for pain after tonsillectomy or adenoidectomy in children. The same year, the EMA restricted codeine for pain to children over 12 and contraindicated it after these operations in under-18s. In 2017 the FDA went further, contraindicating codeine, and tramadol, for children under 12.
Why it still matters
The codeine story shaped how regulators think about pharmacogenomics: a drug can be safe on average and dangerous for an identifiable subgroup. It also showed how long a familiar medicine can be used in children before its risks are properly understood.
