Dr Peter Grace, University of Boulder
Could painkillers actually make the pain worse? Opioid drugs, like morphine and codeine, are extremely powerful but new research shows that they appear to cause chronic pain, as Chris Smith found out from researcher Peter Grace…
Peter - So the opioids do work exceptionally well for acute pain when they’re initially being administered. Their effect actually diminishes over time so it means you need to take more drug to get the same pain relief. What we’re also showing now is that, over a longer period of time, the effect not only wears off but they actually start to paradoxically induce pain in their own right.
Chris - So what did you actually do and how did you stumble on this discover?
Peter - We did an initial study where we looked at rats. We gave them a peripheral nerve injury and waited ten days and then gave them morphine for a five day period. Once that morphine treatment had conclude, we looked at their pain levels and we saw that those rats that had received the injury, but no morphine, recovered after about four to five weeks. But those rats that had received morphine for just that five day period took double the time to recover; their pain only resolved ten or eleven weeks afterwards.
Chris - So what you’re saying is that they continue to show a heightened evidence of being in pain for twice as long if they’d had morphine than animals that didn’t have any morphine?
Peter - That’s exactly right. So we’re looking at the sensitivity of the rats paws to touch. A normal healthy rat will just feel a tickle on the paw that won’t bother them, a rat that is in pain will violently withdraw their paw.
Chris - How did you pursue that then Peter? So you have these animals which, if they’ve been given painkillers, paradoxically seem to then experience more pain for twice as long as if they hadn’t had opioid painkillers - how did you investigate what was actually causing that?
Peter - Our first port of call was looking at these immune cells in the spinal cord called ‘glial cells.’ They are there to surround and support neurons but what we’ve shown is that these cells are really sensitive to any sort of injury or foreign substance. So these cells are activated, that means they start producing these inflammatory mediators that activate pain sensing neurons, and they’re activated after peripheral nerve injury, but they’re also activated by morphine and that then leads to these paradoxical effects on pain.
Chris - So, you injure the nerve and that winds up these glial cells and they start to become more active. At the same time you give morphine to quench the pain that you're experiencing but that also winds up these glial cells and makes them even more active. How do you then end up with this chronic pain, this pain that relentlessly goes on even after the original has subsided - how does that get entrenched?
Peter - Yes, the combined challenge of the peripheral nerve injury and the morphine sends these glial cells into overdrive. So they’re far more reactive, and they’re spewing out far more of these inflammatory signals, with the combined challenge then had either one of them the opioids or the peripheral nerve injury in isolation. So, because this immune response is so great, it leads to perhaps some extra cell damage in the spinal cord as well as enhanced signalling at these pain sensing neurons.
Chris - Could a person, therefore, end up in a sort of feedback loop where they initially have an injury, they get given opioids because they had severe pain and they needed to control it, but the damage to their nervous system, coupled with the exposure to the opioid drug, means they then end up with pain produced by having taken the opioid, so they then take even more opioid to control the pain and it just feeds back on itself and they end up in this loop they can’t get out of?
Peter - Yeah, that’s exactly right, and that’s precisely what our study suggests. Importantly, I think, the silver lining here is that the cycle can be broken if the immune system, specifically within the spinal cord, is blocked and we’ve been able to do that in our rat study here. And we’re currently focused on developing a couple of drugs that will, hopefully, get out to patients to help break that cycle.
Chris - So, what would your advice be then to someone who has an injury, should they not take the morphine if they can avoid it or minimise their exposure? What’s the best way not to end up with one of these chronic pain states?
Peter - Opioids really aren't a long term solution for chronic pain. I think that for an initial acute injury they’re fantastic and they do an excellent job of managing that pain, but if the pain starts to persists, I think it’s best to have a conversation with your doctor to see whether there are any other alternatives that might work for you, and there are some other drugs out there that are really excellent for chronic pain.