Morphine metabolites as novel analgesic drugs?
OBJECTIVE
Morphine metabolites have attracted continuing interest for their contribution to the desired and unwanted effects of morphine. Among the metabolites of morphine, morphine-6-glucuronide has been given most scientific attention. It accounts for 10% of the morphine metabolism, acts as an agonist at mu-opioid receptors and exerts antinociceptive effects. This review summarizes the recent findings on morphine-6-glucuronide and discusses its potential use as an analgesic.


RESULTS
Morphine-6-glucuronide has a very long delay between the time course of its plasma concentrations and the time course of its central nervous effects, with 6-8 h probably the longest transfer half-life between plasma and effect site of all opioids administered in humans. This complicates the control of morphine-6-glucuronide therapy when used as an intravenous analgesic, and the long duration of action confers no advantage over other opioids because long-lasting opioid analgesia can be readily obtained with sustained release formulations of other opioids. During acute treatment, however, morphine-6-glucuronide appears to be sufficiently potent to exert peripheral analgesic effects, without exerting major central nervous opioid side effects for a short period of time. The side effects profile does not clearly separate morphine-6-glucuronide from morphine, with reports of similar side effects. There are contrasting reports, however, about similar or less respiratory depression and other side effects compared with morphine after systemic injection.


CONCLUSIONS
Morphine-6-glucuronide might qualify as an analgesic but it has several pharmacological properties that make it far from ideal for therapeutic use. Whether it will be a useful addition to the currently established analgesics has yet to be demonstrated.
Lötsch
Jörn
J
Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt, Germany. j.loetsch@em.uni-frankfurt.de