Relationships among morphine metabolism, pain and side effects during long-term treatment: an update

The two metabolites of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), have been studied intensively in animals and humans during the past 30 years in order to elucidate their precise action and possible contribution to the desired effects and side effects seen after morphine administration. M3G and M6G are formed by morphine glucuronidation, mainly in the liver, and are excreted by the kidneys. The metabolites are found in the cerebrospinal fluid after single as well as multiple doses of morphine. M6G binds to opioid receptors, and animal studies have demonstrated that M6G may be a more potent analgesic than morphine. Results from human studies regarding the analgesic effect of M6G are not unanimous. The potency ratio between systemic M6G and morphine in humans has not been settled, but is probably lower than previously assumed. Hitherto, only a few studies have found evidence for a contributory effect of M6G to the overall effects observed after morphine administration. Several studies have demonstrated that administration of M6G is accompanied by fewer and a milder degree of opioid-like side effects than observed after morphine administration, but most of the studies have used lower doses of M6G than of morphine. M3G displays very low affinity for opioid receptors and has no analgesic activity. Animal studies have shown that M3G may antagonize the analgesic effect of morphine and M6G, but no human studies have demonstrated this. M3G has also been connected to certain neurotoxic symptoms, such as hyperalgesia, allodynia and myoclonus, which have been observed after administration of M3G or high doses of morphine in animals. The symptoms have been reported sporadically in humans treated primarily with high doses of morphine, but the role of M3G in eliciting the symptoms is not fully elucidated.