The FDA has advised that for children younger than 12, codeine is now contraindicated for the management of pain or cough, as is tramadol for pain. This is due to the fact that some people have a variation in their CYP2D6 enzymes which makes them metabolise drugs that are substrates of CYP2D6 very rapidly.

As both codeine and tramadol are metabolised by CYP2D6 into active metabolites, ultra-metabolisers are at risk of high levels of these active ingredients with a consequently increased risk of respiratory depression. The prevalence of CYP2D6 ultra-metabolisers varies by race and ethnic group.

Furthermore, tramadol is now also contraindicated post-tonsillectomy/adenoidectomy for pain relief in children aged 12-18. Codeine and tramadol are also not recommended in 12-18 year olds who are obese, have severe lung disease or sleep apnoea.

Finally, the FDA is cautioning nursing mothers about using tramadol, based on the theoretical risk, and codeine, based on documented reports of respiratory depression, in breastfed infants.