morphine-3-glucuronide and Seizures

Morphine-6-glucuronide (M6G), an active metabolite of morphine has been shown to produce analgesia and fewer side effects than morphine, and the introduction of M6G as a new drug for treatment of postoperative pain is planned in 2007. Following morphine intake in humans, the metabolites morphine-3-glucuronide (M3G) and M6G are present in substantial concentrations and for longer periods than the parent drug. The possible reward effects of the morphine glucuronides have previously not been well studied. In the present study, conditioned place preference (CPP) was recorded after conditioning with subcutaneous injections of 5, 10, 20, 30 or 50 micromol/kg morphine or M6G, or 240 or 500 micromol/kg M3G in C57BL/6J-Bom mice, using a biased two compartment ("closed" and "open") counterbalanced paradigm. CPP was induced after treatment with both morphine and M6G with dose dependent increase up to 30 micromol/kg after treatment in the "closed" compartment. No dose response was observed in the "open" compartment, with maximal CPP after 10 micromol/kg morphine or M6G. M3G caused a tendency of condition place aversion (CPA), although not statistically significant. In the present study morphine and M6G demonstrated comparable reward effects, at doses that differed depending on which compartment the mice were conditioned in. M3G showed a tendency to exhibit aversive properties.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Conditioning, Operant; Male; Mice; Mice, Inbred C57BL; Morphine; Morphine Derivatives; Motor Activity; Seizures

A 46-year-old woman suffering from a reactive depression was admitted to the emergency room in coma and with severe respiratory failure. She later developed cardiovascular instability and general convulsions. Two days following admission the patient had no respiratory effort but was able to communicate in writing that she had ingested a large amount of controlled-release morphine tablets. Following treatment with naloxone she was successfully weaned from the respirator the next day.. Sampling for determination of plasma and urine concentrations of morphine and its metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was started 60 h after the presumed time of intake and continued up to 8 days after admission.. The initial plasma concentrations of morphine, M3G and M6G were 2160, 13100 and 2330 nM, respectively, compatible with a lethal dose in an opioid-naive patient. The urinary recovery of morphine, M3G and M6G corresponded to 6.8 mmol, equivalent to an oral intake of at least 2500 mg.. The plasma concentrations of morphine and morphine metabolites documented in this case, indicative of considerable absorption of drug, demonstrate that prolonged observation is necessary following intoxications with controlled-release morphine tablets. This case also highlights the importance of continuous follow-up of oral morphine therapy, so that unused drug is not left unaccounted for in the patient's home.

Topics: Absorption; Analgesics, Opioid; Coma; Delayed-Action Preparations; Depression; Female; Follow-Up Studies; Humans; Middle Aged; Morphine; Morphine Derivatives; Respiratory Insufficiency; Seizures; Suicide, Attempted; Tablets