SYSTEMATIC REVIEW OF FACTORS AFFECTING THE RATIOS OF MORPHINE AND ITSMAJOR METABOLITES

In a systematic review of 57 studies with information on 1232 patients we examined the effect of age, renal impairment, route of administrat ion, and method of analysis on the ratios of morphine-3-glucuronide:mo rphine (M3G:M) and morphine-6-glucuronide:morphine (M6G:M) and the rel ative concentrations of M3G and M6G. Across all studies the range of t he ratios of metabolites to morphine was wide (0.001-504 for M3G:M, an d 0-97 for M6G:M). Neonates produced morphine glucuronides at a lower rate than older children or adults. Metabolite ratios were higher in r enal impairment. Routes of administration which avoided first pass met abolism (intravenous, transdermal, rectal, intramuscular, epidural and intrathecal) resulted in lower metabolite production than oral, bucca l or sublingual. Metabolite production was similar for single and mult iple dosing. There was no evidence of differences between methods of a ssay. There was a high correlation between the two glucuronide metabol ites in spite of the different situations studied, supporting a single glucuronidating enzyme. Morphine was present in CSF at a fourfold hig her concentration than the glucuronide metabolites. (C) 1998 Internati onal Association for the Study of Pain. Published by Elsevier Science B.V.