Role of morphine's metabolites in analgesia: concepts and controversies.

The metabolites of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G), have been extensively studied for their contribution to clinical effects following administration of morphine. Those contributions to both the desired effect (ie, analgesia) and the undesired effects (eg, nausea, respiratory depression) are the subject of clinical controversy. Much attention and effort have been directed at investigating the properties of M6G because of interest in this substance as a possible substitute for morphine. It exhibits increased potency and the possibility of a better side effect profile compared with morphine, although the reported relative benefits vary widely. M3G is not analgesic, but its role in producing side effects, including the development of clinical tolerance, has been proposed. This review is focused on M6G and the factors that contribute to its clinical utility. The formation and distribution of M6G are presented, as are the analgesic effect and the onset of this effect. The impact of genetics, age, and gender on M6G and its effects is also reviewed.