Morphine-6-glucuronide (M6G) appears to show equivalent
analgesia to
morphine but to have a superior side-effect profile in terms of reduced liability to induce
nausea and
vomiting and
respiratory depression. The purpose of this review is to examine the evidence behind this statement and to identify the possible reasons that may contribute to the profile of M6G. The vast majority of available data supports the notion that both M6G and
morphine mediate their effects by activating the micro-
opioid receptor. The differences for which there is a reasonable consensus in the literature can be summarized as: (1)
Morphine has a slightly higher affinity for the micro-
opioid receptor than M6G, (2) M6G shows a slightly higher efficacy at the micro-
opioid receptor, (3) M6G has a lower affinity for the
kappa-opioid receptor than
morphine, and (4) M6G has a very different absorption, distribution, metabolism, and excretion (ADME) profile from
morphine. However, none of these are adequate alone to explain the clinical differences between M6G and
morphine. The ADME differences are perhaps most likely to explain some of the differences but seem unlikely to be the whole story. Further work is required to examine further the profile of M6G, notably whether M6G penetrates differentially to areas of the brain involved in
pain and those involved in
nausea,
vomiting, and respiratory control or whether micro-
opioid receptors in these brain areas differ in either their regulation or pharmacology.