Morphine/Dextromethorphan - Endo: E 3231, Morphidex

Drugs R D 2003;4(1):55-56


Adis CommentsEndo is developing a fixed 1 : 1 combination of morphine and dextromethorphan [EN 3231, MorphiDex((R))] for the treatment of chronic pain, particularly chronic cancer pain. The product was originally being developed by Algos Pharmaceutical. In July 2000, Algos Pharmaceutical was acquired by Endo Pharmaceuticals Holdings and was renamed Endo Inc. Dextromethorphan is a NMDA antagonist that appears to block the tolerance that otherwise develops with long-term morphine therapy. Development: Endo received a non-approvable letter from the US FDA for use of MorphiDex((R)) for the treatment of moderate-to-severe cancer pain. The US NDA contained data from 14 clinical trials in >/=1500 patients. In the non-approvable letter, the FDA cited concerns related to the adequacy of a high-dose pharmacokinetic study and animal toxicology study. In June 2002, Endo Pharmaceuticals Holdings Inc. announced results from the first of its three phase III clinical trials for its development product, MorphiDex((R)). In October 2002, the second of these trials was completed. However, in both completed second phase III studies, MorphiDex((R)) did not meet the primary endpoint, which was a significantly more effective analgesia with MorphiDex((R)) than morphine sulfate alone at equivalent doses. The second study also didn't meet its secondary endpoint, which was a reduction in tolerance to the agent. Endo Pharmaceuticals expected to complete enrolment for the third trial in July 2002. The company stated that it would not resubmit the amended NDA for MorphiDex((R)) until the full analysis of the data from these trials. Patents and licences: Endo Pharmaceuticals licensed patents and pending patent applications concerning MorphiDex((R)) and other combinations of dextromethorphan with opioids from Virginia Commonwealth University. Under the terms of licensing agreement, Endo will pay royalties equal to 4% of sales of products resulting from the licensed patents. Additionally, Endo will pay Virginia Commonwealth University 50% of royalty payments received from any sublicensees. The licence is valid until patents expire.
Novelty and pain
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Signalling mechanisms
The extended amygdala
Opioids, mood and cognition
Neuropathic pain and NMDA antagonists
Tolerance, sensitization and dependence

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