Morphine-6-glucuronide study

In an in-vitro study ketoconazole inhibited morphine glucuronidation to morphine-3-glucuronide and morphine-6-glucuronide. The clinical relevance of this is unknown. 

Quinidine sulfate 600 mg, given one hour before intravenous morphine sulfate 150 mierograms/kg, did not alter morphine-induced miosis in healthy subjects. However, the same dose of quinidine given before oral morphine sulfate 30 mg (with ondansetron as an antiemetic) increased morphine-induced miosis by 56%. This increase was considered proportionate to the increase in morphine AUC (60%) and maximum level (88%). There was no change in the elimination half-life of morphine. Similarly, in another study in healthy subjects, quinidine 800 mg, given one hour before intravenous morphine 7.5 mg did not alter the respiratory depressant nor mitotic effects of morphine, and there was no change in plasma morphine or morphine glucuronide levels. ... 

Olson RJ, Justice JB (1993) Quantitative microdialysis under transient conditions. Anal Chem 65 1017-1022 Stain-Texier F, Boschi G, Sandouk P et al. (1999) Elevated concentrations of morphine 6-beta-D-glucuronide in brain extracellular fluid despite low blood-brain barrier permeability. Br J Pharmacol 128 917-924 Ungerstedt U (1991) Microdialysis - principles and applications for studies in animals and man. J Intern Med 230 365-373... 

Normorphine has been found(436) to be excreted as normorphine-3-glucuronide (32%) in dogs. In addition, small amounts of dihydronormorphine (TMS derivative) and 15-dehydronormorphine (TFA derivative) were detected in extracts of dog urine by gc/ms. Dehydration of TV-hydroxy normorphine, not detected during this study, was proposed, tentatively, as the source of the latter. The presence of dihydronormorphine was suspected from the isolation of dihydromorphine as a minor metabolite of morphine/437 ... 

Romberg R, van Dorp E, Hollander J, Kmit M, Binning A, Smith T, Dahan A (2007) A randomized, double-blind, placebo-controlled pilot study of IV morphine-6-glucuronide for postoperative pain relief after knee replacement surgery. Clin J Pain 23 197-203... 

Several phase II enzymes may also be expressed as a function of age. Studies of paracetamol (acetaminophen) suggest that sulfation is the major metabolic pathway during the neonatal period and early infancy, changing to glucuronidation over several months (Miller et ai, 1976). The increase in morphine clearance due to glucuronidation is related to postconceptional age (Scott et ai, 1999). 

A single 50-mg dose of diclofenac sodium did not have an important effect on the pharmacokinetics of a single 100-mg dose of codeine phosphate in a placebo-controlled crossover study in 12 healthy subjects. There was no effect on the metabolic clearance of morphine, and only a slight (about 5% to 10%) increase in the levels of glucuronide metabolites. In addition, diclofenac did not alter the analgesic effects of codeine as assessed in a cold pressor test (a test in which opioids, but not NSAIDs, are effective). ... 

However, in eontrast to these reports, a study in 7 patients on the first postoperative day after spinal surgery found that, although diclofenac 100 mg rectally reduced patient-controlled morphine consumption by 20%, respiratory rates were significantly lower after the diclofenac, and minimal at about 200 minutes. Levels of an active metabolite, morphine-6-glucuronide did not significantly decrease until 420 minutes. ... 

NSAIDs are frequently used with opioids because of their lack of respiratory depression and opioid-sparing effects. However, this study demonstrates that there may be a risk of respiratory depression and other adverse effects due to persistently high levels of morphine-6-glucuronide for a number of hours after receiving an NSAID. During this time period, patients should be more closely monitored. ... 

---