Table 1.

Pharmacology of Opioids for Chronic Pain Management39,40

Opioid	Physico-Chemical Properties 40			Metabolism 39	Elimination 39
	Vd (L/kg)	PPB (%)	MW (g/mol)
Buprenorphine	8.3	96	467.6	Extensive first-pass hepatic metabolism. Phase 1 metabolism via CYP3A4 and CYP3A5 to norbuprenorphine. Phase 2 metabolism via glucuronidation to the inactive compounds B3G and N3G	Metabolites are primarily eliminated via feces. Only 10–30% of the dose is excreted in urine.
Fentanyl citrate	4	80–85	336.5	Extensive hepatic metabolism into inactive metabolites. Phase 1 metabolism via CYP3A4 to norfentanyl (99%)	<7% excreted unchanged in the urine. <1% excreted unchanged in the feces.
Hydromorphone hydrochloride	1.22	7.1	321.8	Extensive first-pass hepatic metabolism (62%) Phase 2 metabolism: Glucuronidation via UGT2B7 to H3G with no analgesic activity (possibly causes neuroexcitation, agitation, and confusion) Minor Phase 1 metabolism via CYP3A4 and CYP2C9 to norhydromorphone	Mainly eliminated through the urine as H3G. 7% excreted unchanged in the urine. 1% excreted unchanged in the feces.
Oxycodone hydrochloride	2.6	45	405.9	Phase 1 metabolism: -via CYP3A4 and CYP3A5 (N-demethylation) to noroxycodone, and then via CYP2D6 to noroxymorphone -via CYP2D6 (O-demethylation) to oxymorphone, and then via CYP3A4 to noroxymorphone	Mainly eliminated through the urine: 23% unbound noroxycodone 10% conjugated oxymorphone 9% free and conjugated oxycodone <1% oxymorphone
Tramadol	3	20	299.8	Extensive first-pass hepatic metabolism Phase 1 metabolism: -via CYP3A4 and CYP2B6 (N-demethylation) to N-desmethyl-tramadol (M2) -via CYP2D6 (O-demethylation) to O-desmethyltramadol (M1)	90% excreted in the urine (30% as unchanged drug) 10% excreted in the feces
Tapentadol hydrochloride	6.7	20	221.3	Phase 2 metabolism via glucuronidation (97%). Minor contribution of Phase 1 metabolism via CYP2C9 (13%) to N-desmethyl tapentadol and CYP2D6 (2%) to hydroxyl tapentadol. All metabolites are inactive.	99% renal excretion of tapentadol and its metabolites. 3% excreted in urine as unchanged drug.
Methadone	2–6	60–90	309.5	Extensive first-pass hepatic metabolism into inactive metabolites. N-demethylation Metabolism by different CYP450 enzymes: CYP2C19, CYP3A7, and CYP2C8 preferentially metabolize (R)-methadone; CYP2B6, CYP2D6, and CYP2C18 preferentially metabolize (S)-methadone; CYP3A4 does not have an enantiomer preference	Excreted in the feces and urine after extensive biotransformation. 20% excreted unchanged in the urine.
Morphine sulphate	3.2	35	758.8	Phase 2 metabolism via glucuronidation by UGT2B7 (90%) to: -M3G without analgesic activity, but possibly neurotoxic -M6G with analgesic activity. Minor conversion to normorphine.	70–80% excreted in the urine 10% excreted in the feces <10% excreted in urine as unchanged drug.
Codeine	2.6	7	406.4	Phase 2 metabolism via glucuronidation by UGT2B7 and UGT2B4 (80%) to C6G Phase 1 metabolism: -via CYP3A4 (N-demethylation) to norcodeine (10%) without analgesic properties -via CYP2D6 (O-demethylation) to morphine (5–10%)	90% excreted by kidneys 10% excreted in urine as unchanged drug.

Abbreviations: Vd, volume of distribution; PPB, plasma protein binding; WS, water solubility; MW, molecular weight; B3G, buprenorphine-3-glucuronide; N3G, norbuprenorphine-3-glucuronide; H3G, hydromorphone-3-glucuronide; H6G, hydromorphone-6-glucuronide; C6G, codeine-6-glucuronide.

Notes: Green: safe use in CKD; Yellow: use with caution in CKD; Orange: not recommended in CKD