Morphine-6-glucuronide: morphine's successor for postoperative pain relief?

In searching for an analgesic with fewer side effects than morphine, examination of morphine's active metabolite, morphine-6-glucuronide (M6G), suggests that M6G is possibly such a drug. In contrast to morphine, M6G is not metabolized but excreted via the kidneys and exhibits enterohepatic cycling, as it is a substrate for multidrug resistance transporter proteins in the liver and intestines. M6G exhibits a delay in its analgesic effect (blood-effect site equilibration half-life 4-8 h), which is partly related to slow passage through the blood-brain barrier and distribution within the brain compartment. In humans, M6G's potency is just half of that of morphine. In clinical studies, M6G is well tolerated and produces adequate and long lasting postoperative analgesia. At analgesic doses, M6G causes similar reduction of the ventilatory response to CO2 as an equianalgesic dose of morphine but significantly less depression of the hypoxic ventilatory response. Preliminary data indicate that M6G is associated less than morphine with nausea and vomiting, causing 50% and 75% less nausea in postoperative and experimental settings, respectively. Although the data from the literature are very promising, we believe that more studies are necessary before we may conclude that M6G is superior to morphine for postoperative analgesia.