Some patients tolerate codeine very poorly and become nauseous on small doses, while others may fail to get pain relief at even high doses. 

Codeine is an opioid pro-drug that is converted to its active form, morphine, by the liver. The enzyme in the liver responsible for this metabolism is part of the CYP2D6 pathway of cytochrome P450 enzymes. 

There are over 100 genetic variants of CYP2D6, of which several result in ultra-rapid, high activity and some in reduced or no enzyme activity. Those with ultra-rapid activity (one to two per cent of the population) tolerate the drug poorly as they get a morphine ‘overdose’.

At the other extreme, in patients who are ‘poor’ or ‘intermediate’ metabolisers (as many as five to 10 per cent of the population), the analgesic effects of codeine may be inadequate due to lower levels of active morphine. In these patients, dihydrocodeine may prove to be effective, or the use of low-dose morphine may be required. 

Warfarin is another example where some people require very low doses to achieve anticoagulation, while others need extremely high doses.