Morphine-6-glucuronide: an analgesic of the future?

Morphine-6-beta-glucuronide (M6G) is an opioid agonist that plays a role in the clinical effects of morphine. Although M6G probably crosses the blood-brain barrier with difficulty, during long term morphine administration it may reach sufficiently high CNS concentrations to exert clinically relevant opioid effects. As a consequence of its almost exclusive renal elimination, M6G may accumulate in the body of patients with impaired renal function and cause severe opioid adverse effects with insidious onset and long persistence. Its profile of receptor affinities, however, gives reason to speculate that M6G may exhibit analgesic effects while causing fewer adverse effects than morphine. This is supported by reports of the good tolerability of intrathecal and intravenous injections of M6G in humans with intact renal function. M6G may thus be contemplated as an analgesic for short term postoperative analgesia, especially for intrathecal analgesic therapy. In addition, its possibly higher potency than morphine makes M6G a candidate opioid for local or peripheral analgesic therapy. However, current knowledge is too incomplete to finally judge the clinical usefulness of M6G. The next topics for clinical research on M6G should include: (i) a comparison of the potencies of M6G and morphine to cause wanted and unwanted clinical effects; (ii) development of a predictive population pharmacokinetic-pharmacodynamic model of M6G with calculation of the transfer half-life between plasma and effect site; and (iii) identification of cofactors influencing the action of M6G that can serve as predictors for the clinical outcome of morphine/M6G therapy in an individual including the pharmacogenetics of M6G.