Figure 2.

Genes involved in opioids’ action, metabolism, and transport. CYP2D6 metabolizes tramadol, codeine, hydrocodone and oxycodone to their more active metabolites, O-desmethyltramadol, morphine, hydromorphone and oxymorphone, respectively. Morphine is further metabolized by UGT2B7 to M3G and M6G (which has pharmacological activity). Fentanyl is metabolized by both CYP3A4 and CYP3A5 to an inactive metabolite, norfentanyl. Methadone is mainly metabolized by CYP2B6, with little contribution from CYP3A4, CYP2D6, or CYP2C19, to form an inactive metabolite, EDDP. Several opioids are substrates of the P-glycoprotein transporter, encoded by the ABCB1 gene, which is located in various locations in the body, including the liver and intestine and at the blood–brain barrier. In the brain, opioids bind and activate the mu-opioid receptor encoded by the OPRM1 gene. The COMT gene may also affect the opioid’s action. ABCB1 = P-glycoprotein encoding gene; COMT = catechol-o-methyltransferase encoding gene; DRD2 = dopamine receptor D2 subtype encoding gene; EDDP = 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine; M3G = morphine-3-glucuronide; M6G = morphine-6-glucuronide; OCT1 = organic cation transporter 1 encoding gene; OPRM1 = mu-opioid receptor encoding gene; UGT2B7 = UDP-glucuronosyltransferase 2B7.