Randomized placebo-controlled trial of the activity of the morphine glucuronides

Background: Morphine-6-glucuronide (M6G) is an active metabolite of morphin e with potent analgesic activity Morphine-3-glucuronide (M3G), the most pre valent metabolite, has minimal affinity for opioid receptors. It has been s uggested from animal model data and by examination of metabolite ratios in humans that M3G may functionally antagonize the respiratory depressant and analgesic actions of morphine and M6G. Methods: We performed a double-blind placebo-controlled trial with 10 healt hy volunteers. The trial had 6 arms: (1) placebo, (2) 10 mg/70 kg of morphi ne, (3) 3.3 mg/70 kg of M6G, (4) 30.6 mg/70 kg of M3G, (5) 30.6 mg/70 kg of M3G with 10 mg/70 kg of morphine, and (6) 30.6 mg/70 kg of M3G with 3.3 mg /70 kg of M6G; all were give by slow intravenous bolus. Analgesia was asses sed with the use of the submaximal ischemic pain model. The effects were qu antified on numerical and visual analogue scales. Respiratory parameters an d response to steady state 5% carbon dioxide challenge were assessed with s pirometry, mass spectroscopy, and earlobe blood gas analysis. Results: Morphine and M6G produced significant pain relief compared with pl acebo (morphine, P < .0001; M6G, P = .033). Pain relief after M6G was less than after morphine (P = .009) and M3G was no better than placebo (P = .26) . Pain relief with morphine and M6G were not significantly altered by M3G ( P = .59 and P = .28, respectively). Significant and similar dysphoria and s edation occurred with both morphine (P < .002) and M6G (P < .016) but were absent with both M3G and placebo. Respiratory parameters suggested that M6G produced less respiratory depression than morphine. Both morphine and M6G caused a significant reduction in respiratory drive compared with placebo ( morphine, P = .002; M6G, P = .013); this effect was not reversed by M3G (P = .35 and P = .83, respectively). Conclusions: M3G appears to be devoid of significant activity; in these cir cumstances and at these doses, it does not antagonize either the analgesic or respiratory depressant effects of M6G or morphine.