Some rare few individuals do not feel pain, and are consequently a danger to themselves, often dying young. Unfortunately little headway has been made in manipulating the mechanisms thought to cause this condition, not just as a matter of treatment, but also as a way to create much safer and more sophisticated methods to temporarily switch off pain in the rest of us. Now, researchers have succeeded in reversing painlessness in an afflicted individual, better characterized the central mechanism of this condition, and this should directly result in a new methodology for efficient pain suppression. While this research is not directly relevant to aging, pain is an important consideration everywhere in medicine, especially in chronic disease, and this has the look of a profound step forward:
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, 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. 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."
Broad-spectrum sodium channel blockers are used as local anaesthetics, but they are not suitable for long-term pain management as they cause complete numbness and can have serious side-effects over time. By contrast, people born without working Nav1.7 still feel non-painful touch normally and the only known side-effect is the inability to smell. Opioid painkillers such as morphine are highly effective at reducing pain, but long-term use can lead to dependence and tolerance. As the body becomes used to the drug it becomes less effective so higher doses are needed for the same effect, side effects become more severe, and eventually it stops working altogether. "Used in combination with Nav1.7 blockers, the dose of opioid needed to prevent pain is very low. 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."