Table 1. Factors contributing to opioid toxicity in CKD.

Factors contributing to opioid toxicity in chronic kidney disease
Patient factors		Exogenous factors
Independent of kidney function • Age – extremes of age, increases sensitivity • Gender – women more sensitive • Genetic – absence of A118G SNP* • Route of administration§ • Enterohepatic circulation • Hypoalbuminemia • Concomitant illness(es) – Sepsis, liver disease	Dependent on kidney function • Decreased clearance – accumulation of parent drug and active metabolites • Decreased threshold • Change in volume of distribution (V d) • Change in protein binding • Impaired ventilatory response to carbon dioxide in CKD	Drug-drug interactions • Cytochrome P450 2D6 system @ • P-glycoprotein inhibitors¶ • Concomitant antibiotic useº

* A118G polymorphism protects against M6G-related opioid toxicity ²⁸.

§ Routes that use first pass metabolism results in higher production of metabolites than those that bypass it.

¶ P-glycoprotein inhibitors increase uptake of M6G across blood brain barrier ^{16, 17}.

º Concomitant antibiotics by altering bacterial flora reduces bacterial glucuronidase, resulting in reabsorption of M6G.

^@ Extensive 2D6 metabolism may occur in up to 1/3 ^rd of patients of east African heritage – increasing the risk of opioid overdose from codeine.