Systematic review of factors affecting the ratios of morphine and its major metabolites

Abstract

In a systematic review of 57 studies with information on 1232 patients we examined the effect of age, renal impairment, route of administration, and method of analysis on the ratios of morphine-3-glucuronide:morphine (M3G:M) and morphine-6-glucuronide:morphine (M6G:M) and the relative concentrations of M3G and M6G. Across all studies the range of the ratios of metabolites to morphine was wide (0.001-504 for M3G:M, and 0-97 for M6G:M). Neonates produced morphine glucuronides at a lower rate than older children or adults. Metabolite ratios were higher in renal impairment. Routes of administration which avoided first pass metabolism (intravenous, transdermal, rectal, intramuscular, epidural and intrathecal) resulted in lower metabolite production than oral, buccal or sublingual. Metabolite production was similar for single and multiple dosing. There was no evidence of differences between methods of assay. There was a high correlation between the two glucuronide metabolites in spite of the different situations studied, supporting a single glucuronidating enzyme. Morphine was present in CSF at a fourfold higher concentration than the glucuronide metabolites.

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“…The ratio of morphine to M6G concentrations ranged from 1 : 5.5 to 1 : 6.7, which is in agreement with previous studies (15,16).The high number of patients with undetectable plasma morphine concentrations prior to the morning drug dosing is probably due to the low daily CR opioid dose in these patients (mean daily morphine dose 75 mg) since three of these patients had very low oxycodone concentrations, too. In previous clinical studies of cancer patients, it has been found that even low daily doses of CR morphine have resulted in measurable plasma morphine concentrations (17,18) but the assay limit for morphine has been lower (1 ng:ml) (19) than in the present study (5 ng:ml).…”

“…In cancer patients, no simple correlation between opioid and metabolite concentrations and pain relief has been found (19), although Faura et al (16) have reported a tendency towards greater stable phase morphine concentrations in cancer patients with optimal pain control.…”

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“…The liver is the major organ involved in the glucuronidation of morphine [31]. Morphine-3-gluronide (M3G) is the major metabolite (M6G/ M3G ratio approximately 0.15) [35]. Morphine-glucuronides are hydrophylic compounds, that are mainly excreted in urine, and in minor quantities in bile.…”

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“…These studies have consistently demonstrated elevated metabolite levels 88,89,92,[101][102][103][104][105][106] when measured in renal impairment. They also have suggested a frequent association between renal impairment and opioid toxicity.…”