How do genetic polymorphisms in CYP2D6 affect the analgesic response to codeine?

Genetic polymorphisms in CYP2D6 significantly affect the analgesic response to codeine because CYP2D6 is the primary enzyme responsible for converting codeine into its active metabolite, morphine. Codeine itself has low affinity for opioid receptors and is considered a prodrug, requiring metabolic activation to exert its analgesic effects. CYP2D6 performs O-demethylation of codeine, transforming it into morphine, which has a much higher affinity for the mu (μ) opioid receptor and provides significant pain relief. Individuals with different CYP2D6 genotypes exhibit varying levels of enzyme activity. 'Poor metabolizers' have reduced or absent CYP2D6 activity, leading to minimal conversion of codeine to morphine. As a result, these individuals experience little to no pain relief from codeine. 'Intermediate metabolizers' have moderately reduced CYP2D6 activity and may experience some pain relief from codeine, but it is typically less effective than in individuals with normal CYP2D6 activity. 'Extensive metabolizers' have normal CYP2D6 activity and convert codeine to morphine at a typical rate, resulting in expected analgesic effects. 'Ultrarapid metabolizers' have increased CYP2D6 activity and convert codeine to morphine very rapidly. This can lead to enhanced analgesic effects but also increases the risk of adverse effects, such as respiratory depression, especially in children. Due to these significant differences in analgesic response based on CYP2D6 genotype, codeine is generally not recommended for individuals known to be poor or ultrarapid metabolizers.