Low-dose opioids plus Nav1.7 pain channel blocker

People born with a rare genetic mutation are unable to feel pain, but previous attempts to recreate this effect with drugs have had surprisingly little success. Using mice modified to carry the same mutation, University College London (UCL) researchers have now discovered the recipe for painlessness.

'Channels' that allow messages to pass along nerve cell membranes are vital for electrical signalling in the nervous system. In 2006, it was shown that sodium channel Nav1.7 is particularly important for signalling in pain pathways and people born with non-functioning Nav1.7 do not feel pain. Drugs that block Nav1.7 have since been developed but they had disappointingly weak effects. The new study reveals that mice and people who lack Nav1.7 also produce higher than normal levels of natural opioid peptides.

To examine if opioids were important for painlessness, the researchers gave naloxone, an opioid blocker, to mice lacking Nav1.7 and found that they became able to feel pain. They then gave naloxone to a 39-year-old woman with the rare mutation and she felt pain for the first time in her life.

"After a decade of rather disappointing drug trials, we now have confirmation that Nav1.7 really is a key element in human pain," says senior author Professor John Wood (UCL Medicine). "The secret ingredient turned out to be good old-fashioned opioid peptides, and we have now filed a patent for combining low dose opioids with Nav1.7 blockers. This should replicate the painlessness experienced by people with rare mutations, and we have already successfully tested this approach in unmodified mice."

"Used in combination with Nav1.7 blockers, the dose of opioid needed to prevent pain is very low," explains Professor Wood. "People with non-functioning Nav1.7 produce low levels of opioids throughout their lives without developing tolerance or experiencing unpleasant side-effects. We hope to see our approach tested in human trials by 2017 and we can then start looking into drug combinations to help the millions of chronic pain patients around the world."

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