when you stub your toe or get a paper cut on your finger you feel the pain in that part of your body it feels like the pain is coming from that place but of course that's not really what is happening pain doesn't really happen in your toe or your finger it happens in your brain it's a game of telephone really the afferent nerve fiber detects the noxious stimulus passing that signal to the second order neuron and the dorsal root ganglia of the spinal cord which runs it up to the thalamus to be passed to the third order neuron which brings it to the cortex for localization and conscious perception it's not even a very good game of telephone it takes about 100 milliseconds for a pain signal to get from the hand to the brain longer from the feet given the greater distance you see your foot hit the corner of the coffee table and have just enough time to think oh no before the pain hits given the Rube Goldberg nature of the process it would seem like there are any number of places we could stop pain sensation and sure local anesthetics at the site of injury or even spinal anesthetics are powerful if temporary and hard to administer solutions to acute pain but in our everyday armamentarium let's be honest we essentially have three options opioids which activate the MU receptors in the brain to dull pain and cause a host of other nasty side effects NSAIDs which block prostaglandin synthesis and thus limit the ability for pain conducting neurons to get excited and acetaminophen which despite being used for a century is poorly understood but this week we enter the prologue of what might be the next big story in pain control let's talk about VX 548 [Music] if you were to zoom in on the connection between that first afferent pain fiber and the secondary nerve in the spinal cord dorsal root ganglion you would see a receptor called nav 1.8 a voltage-gated sodium Channel this receptor is a key part of the apparatus that passes information from nerve 1 to nerve two but only for fibers that transmit pain signals in fact humans with mutations in this receptor that leave it always in the open State have a severe pain syndrome blocking the receptor therefore might reduce pain in pre-clinical work researchers identified vx548 which doesn't have a brand name yet as a potent Blocker of that channel even in animal or concentrations importantly the compound was highly selective for that particular Channel about 30 000 times more selective than it was for the other sodium channels in that family of course a highly selective and specific drug does not a blockbuster analgesic make to determine how this drug would work on humans and pain they turned to two populations 303 individuals undergoing abdominoplasty and 274 undergoing bunionectomy as reported in a new paper in the New England Journal I know this seems a bit random but abdominoplasty is quite painful and a good model for soft tissue pain bunionectomy is also quite a painful procedure and a useful model of bone pain so after the surgeries patients were randomized to several different doses of vx548 hydrocodone and acetaminophen or Placebo for 48 hours at 19 time points over that 48-hour period participants were asked to rate their pain on a scale from 0 to 10. the primary outcome was the cumulative pain experienced over the 48 hours so higher pain would be worse here but longer duration of pain would also be worse and the story of the study is really told in this chart yes those assigned to the highest dose of vx548 had a statistically significant lower cumulative amount of pain in the 48 hours after surgery but the picture is really worth more than the stats here you can see that the onset of pain relief was fairly quick and that pain relief was sustained over time you can also see that this is not a miracle drug pain scores were a bit better 48 hours out but only by about a point and a half Placebo isn't really the fair comparison here few of us treat our post abdominoplasty patients with Placebo after all the authors do not formally compare the effect of vx548 to that of the opioid hydrocodone for instance but that doesn't stop us this graph which I put together from data in the paper shows pain control across the four randomization categories with higher numbers indicating more cumulative control while all the active agents do a bit better than Placebo vx548 at the higher dose appears to do the best but I should note that five milligrams of hydrocodone may not be an adequate dose for most people yes I would really have killed for an NSAID arm in this trial it's absence given that NSAIDs are a stapled post-operative care is well let's just say notable although not a pain destroying machine vx548 has some other things to recommend it the receptor is really not found in the brain at all which suggests that the drug should not have much risk of dependency though that has not been formally studied the side effects were generally mild headache was the most common and less prevalent than what you see even in the placebo arm perhaps most notable the rate of discontinuation of the study drug was lowest in the vx548 arm patients could stop taking the pill they were assigned for any reason ranging from perceived lack of efficacy to side effects and a low discontinuation rate indicates to me as sort of voting with your feed that suggests this might be a well tolerated and reasonably effective drug vx548 isn't on the market yet phase 3 trials are ongoing but whether it is this particular drug or another in this class I'm happy to see researchers trying to find new ways to Target that most primeval form of suffering pain