M6G - post-operative pain

Morphine formulations are currently the gold standard treatment for the relief of moderate to severe post-operative pain. A limitation of morphine treatment is often the unpleasant side effects experienced, of which nausea and vomiting are the most common. An active potent metabolite of morphine, morphine-6-glucuronide (M6G), may offer therapeutic advantages over morphine in having an equivalent analgesic effect, but with a reduced tendency to cause nausea, vomiting and respiratory depression.

Phase I and II clinical trials have shown that M6G given intravenously can induce analgesia equivalent to morphine in the treatment of moderate to severe post-operative pain. These studies, along with those published in the scientific literature, suggest that M6G can also reduce post operative nausea and vomiting compared with morphine, as well as inducing less sedation and respiratory depression.

Two Phase III trials have now been completed with M6G. The first recruited 167 patients in three European countries, suffering from post-operative pain following knee surgery carried out under spinal anaesthesia. The study confirmed an effective single dose of M6G and demonstrated nausea levels similar to placebo.

Results from a second Phase III trial have now been reported, in which 517 patients suffering from moderate to severe post-operative pain following major abdominal surgery received either M6G or morphine. The study demonstrated that M6G controlled analgesia as well as morphine, with a reduction in nausea and vomiting by several measures. There also appeared to be a reduction in sedation with M6G during the early hours following surgery.

M6G was added to PAION’s portfolio by way of the acquisition of CeNeS. Following the transaction PAION initiated a meta-analysis of the clinical data in order to reevaluate the study results obtained so far, and to gain a clearer view of the status of the M6G program. The combined data analysis based on 769 patients has now been completed. The results confirm the analgesic effect of M6G and also reveal significant reductions in both vomiting and nausea, the pre-specified parameters of the meta-analysis, compared with patients treated with morphine.

In parallel, modelling analyses have been conducted to simulate dose response relationships and pharmacodynamic effects. The results support the product profile of M6G, both in terms of its analgesic properties and side-effect profile, and in addition reproduce the previously observed longer duration of action of M6G compared to morphine. Based on this model, PAION believes that even at increased doses M6G may be better tolerated than equianalgesic doses of morphine.