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Morphine and its major metabolites

Clinical bottom line

The effects of age, renal impairment, route of administration and method of analysis were examined for their effects on the ratio in plasma between morphine and its major metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Neonates produced less glucuronide than children or adults. Metabolite ratios were higher in renal impairment. Routes of administration that avoided first pass metabolism (intravenous, transdermal, rectal, intramuscular) resulted in lower metabolite production than oral, buccal or sublingual. Metabolite production was similar for single or multiple dosing.

Morphine is an old established and very effective drug. In some ways it is simple to use and there are good guidelines about how to use it effectively in particular situations. It's mechanism of action is complicated by the fact that it has an active metabolite, morphine-6-glucuronide (M6G), and that there is suspicion (on no good evidence) that the other metabolite morphine-3-glucuronide (M3G) can act as an antagonist at high concentrations. Clearly there is a need to understand those circumstances where the relationship between morphine and its metabolites is deranged, and that could affect the effect obtained from a given dose.


CC Faura et al. Systematic review of factors affecting the ratios of morphine and its major metabolites. Pain 1998 74:43-53.


The review sought reports of plasma concentrations of morphine and its metabolites in human subjects, using a number of electronic databases. The date of the last search was March 1997. Neonates were defined as children within one month of birth, children as defined by the original authors. Molar ratios of morphine to M3G, morphine to M6G and M3G to M6G were calculated. The mean results were weighted by the size of the study.


There were 57 studies with 1232 patients in 91 clinical groups.

Effect of age

Neonates had low ratios of morphine glucuronides to morphine. This was higher in children, and higher again in adults.

Effect of renal impairment

With impaired renal function the ratios of morphine glucuronides to morphine increased significantly, whether the morphine was given by oral or intravenous route of administration.

Single or multiple doses

For oral administration there was no difference in ratios between single and multiple dosing.

Method of analysis

Similar results were obtained for chromatographic and immunological methods of analysis.

Ratio of M3G to M6G

This ratio remained constant in all subgroups analysed. This suggests that morphine glucuronidation is predominantly under the control of a single enzyme system.


These results are useful in understanding some of the background to using morphine in clinical situations. Active metabolites will be higher in patients with impaired renal function, and lower in children and especially neonates.