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Towards Safer Narcotic Pain Relief

Combat medics Image: Flickr - U.S. Army

Combat medics

Image: Flickr - U.S. Army

Morphine provides very effective pain relief for acute traumatic injury but the hypoxia and hypotension associated with narcotic use can lead to cardio-respiratory collapse and, potentially, death. One approach to reducing the risk of respiratory failure, whilst maintaining analgesia, would be to use low-level narcotic antagonist feedback. Naloxone is an effective, short-acting opioid antagonist that, at low doses, can reverse morphine-induced respiratory depression with relatively little effect on analgesia. Scientists at the University of Michigan have now described a pro-drug approach that releases naloxone only when tissues become hypoxic. Indolequinone-containing pro-drugs show good naloxone releasing properties under hypoxic conditions and, in the present study, a linker was attached so that the pro-drug can be tethered to other macromolecules to enhance retention time in vivo. Pro-drug (2) was stable for 24 hours at 37oC in PBS buffer but was cleaved to give naloxone on addition of the reductase, DT-Diaphorase. Naloxone was also released from pro-drug (2) in fresh human plasma under conditions of low oxygen pressure, but not under normoxic conditions.
Naloxone prodrug, Compound 2

Naloxone prodrug, Compound 2


The primary aim of the study, which is published in the journal Bioorganic and Medicinal Chemistry Letters, was to provide safer pain relief for soldiers injured in combat who are typically treated with morphine on the battlefield, but such a system could also potentially be used to improve pain management for many patients with chronic illnesses. The team plan to test their pro-drug approach in animal studies and also to develop dendrimer nanoparticles to which the pro-drug can be tethered to enhance in vivo performance.