**3.1. Conventional opioids**

The conventional opioids most commonly used for chronic pain management are morphine, oxycodone and codeine. These agents are all primarily μ‐opioid receptor agonists. Opioid analgesia is mediated not only via its central effects but also via its peripheral action. For individuals with moderate‐to‐severe pain, a stronger opioid (such as morphine or oxycodone) should be chosen in the first place, and codeine is not recommended.

It is important to take into account that codeine depends on conversion to morphine for its analgesic effect. As O‐demethylation of codeine to morphine is dependent on cytochrome CYP2D6 isoenzyme, which is known to exhibit genetic polymorphism, there is significant variation in the metabolism of codeine [9, 10]. Moreover, if another drug inhibits that isoen‐ zyme, less formation of morphine will lead to a poor analgesic effect. This could be the case with some SSRIs such as fluoxetine.

Oxycodone undergoes N‐demethylation to noroxycodone and O‐demethylation to oxymor‐ phone. CYP3A4 and CYP3A5 displayed the highest activity for oxycodone N‐demethylation. CYP2D6 had the highest activity for O‐demethylation. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug‐drug interactions is well established and can cause insufficient pain relief or adverse effects [11].
