In addition to drug-drug interactions, there is an abundance of evidence showing that genetic variants and drug-gene interactions may also influence opioid response.
17,23,31 Variants in genes encoding for opioid-metabolizing CYP isoenzymes (eg,
CYP2D6), opioid-sensitive transporters (eg,
ABCB1), and opioid-target receptors (eg,
OPRM1) can alter opioid-related analgesia and side effects.
17,23,49 For example, variants in the
CYP2D6 gene result in several phenotypes: poor metabolizer, intermediate metabolizer, and ultra-rapid metabolizer; these are in addition to the nonvariant (ie, wild type) phenotype, normal metabolizer. The poor metabolizer phenotype results in the inability to convert prodrug opioids to their active metabolites, thus making pain relief negligible. In contrast, the ultra-rapid metabolizer phenotype results in increased conversion of prodrug opioids to active metabolites, resulting in higher plasma concentrations of the active opioid.
18,25 Superimposed on genetic variants, multidrug interactions can change the genetically encoded CYP metabolic status (eg, normal metabolizer to poor metabolizer); a process known as
phenoconversion.
12,31 Multidrug interactions resulting in phenoconversion of the CYP2D6 isoenzyme commonly occur in populations with complex medical conditions, such as those with chronic pain and depression.
50 Therefore, it may be useful for health care professionals to know a patient's genotype and phenotype to avoid prescribing an opioid that likely is ineffective or unsafe.