Opioid analgesics-related pharmacokinetic drug interactions: from the perspectives of evidence based on randomized controlled trials and clinical risk management

Figures & data

Figure 1 Flowchart of literature selection.

Abbreviation: DDIs, drug–drug interactions.

Table 1 Metabolism and transporter profiles of common opioid analgesics

Opioids	Metabolic pathways and metabolites	Metabolizing enzymes	Transporters	Extraction ratio
Morphine	Glucuronidation to inactive metabolite 3-glucuronide (more than 50%) and 6-glucuronide with more potent analgesic action than morphine (approximately 10%)	UGT2B7, OCT1	P-gp	0.76
Tramadol	O-Desmethylation by CYP2D6 to O-desmethylated tramadol (also called M1, the main metabolite of tramadol with a more potent μ-opioid receptor agonist than the parent drug) N-Desmethylation by CYP3A4 and CYP2B6 to N-desmethyl-tramadol (also called M2, the main inactive metabolite of tramadol)	CYP2D6, CYP2B6, CYP3A4, OCT1	NA	NA
Oxycodone	CYP3A4-mediated N-demethylation to inactive metabolite noroxycodone CYP2D6-mediated O-demethylation to active metabolite oxymorphone which must undergo secondary metabolism via glucuronidation by UGT2B7	CYP3A4, CYP2D6, UGT2B7	P-gp	NA
Hydrocodone	CYP3A4-mediated N-demethylation to norhydrocodone (a major inactive metabolite) CYP2D6-mediated O-demethylation to hydromorphone (a minor active metabolite of hydrocodone)	CYP3A4, CYP2D6	NA	NA
Codeine	Glucuronidation mostly by UGT2B7 to codeine-6-glucuronide (approximately 60%–80%) CYP3A4-mediated N-demethylation to norcodeine (approximately 2%–10%) CYP2D6-mediated O-demethylation to morphine (0.5%–10%) Codeine-6-glucuronide and norcodeine have similar affinity to the μ-opioid receptor, whereas morphine has 200-fold greater affinity for the μ-opioid receptor compared to codeine	UGT2B7, CYP3A4, CYP2D6	NA	0.52
Dihydrocodeine	CYP2D6-mediated O-demethylation to dihydromorphine which has a potency similar to morphine and can also undergo glucuronidation to active dihydromorphine-6-O-glucuronide N-Demethylation by CYP3A4 to weakly active metabolite nordihydrocodeine Glucuronidation via UGT2B7 to weakly active metabolite dihydrocodeine-6-glucuronide (25%–30%)	CYP2D6, CYP3A4, UGT2B7	NA	NA
Buprenorphine	Extensive metabolism (N-dealkylation) by CYP3A4 to inactive metabolite norbuprenorphine which can further undergo glucuronidation via UGT1A3 and UGT1A1 Glucuronidation via UGT2B7	CYP3A4, UGT2B7, UGT1A3, UGT1A1	NA	0.6–0.9
Fentanyl	CYP3A4-mediated N-dealkylation to inactive metabolite norfentanyl	CYP3A4	P-gp	0.80–1.0
Tilidine	Extensive first-pass metabolism (N-demethylation) by CYP3A4 and CYP2C19 to active nortilidine and subsequent N-demethylation to bisnortilidine by the same CYP isozymes as the prodrug tilidine	CYP3A4, CYP2C19	NA	NA
Methadone	N-Demethylation to an inactive metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene by CYP3A4 and CYP2B6	CYP3A4, CYP2B6	P-gp	<0.30

Abbreviation: NA, not applicable.

Figure 2 Opioid-related pharmacokinetic drug–drug interaction mechanisms.