Lack of analgesic activity of morphine-6-glucuronide after short-term intravenous administration in healthy volunteers

Background: The analgesic activity of morphine-6-glucuronide (M-6-G) is well recognized for its contribution to the effects of morphine and its possible use as an oploid analgesic with a wider therapeutic range than morphine. The present study attempted to quantify the relative contribution of M-6-G to analgesia observed after systemic administration of morphine. Methods: In a placebo-controlled sixfold crossover study in 20 healthy men, the effects of M-6-G were assessed at steady-state plasma concentrations of MG-G identical to and two and three times higher than those measured after administration of morphine, Morphine and M-G-G were administered as an intravenous bolus followed by infusion over 4 h, Dosage A was M-6-G-bolus of 0.015 mg/kg plus infusion of 0.0072 mg.kg(-1).h(-1). Dosage B was M-6-G-bolus of 0.029 mg/kg plus infusion of 0.014 mg.kg(-1).h(-1), Dosage C was M-6-G-bolus of 0.044 mg/kg plus infusion of 0.022 mg.kg(-1).h(-1). Dosage D was a morphine bolus of 0.14 mg/kg plus infusion of 0.05 mg.kg(-1).h(-1) for 4 fi. Dosage E was M-6-G combined with morphine (doses A + D). Dosage F mas a placebo. The analgesic effects of M-6-G and morphine were measured before administration of the bolus and after 3.5 h using an experimental pain model based on pain-related cortical potentials and pain ratings after specific stimulation of the nasal nociceptor with short pulses of gaseous carbon dioxide.