Airing Pain 149 Why pain persists: from childhood trauma to faulty immunity Released: 21st May 2025

Interviews were recorded at the British Pain Society Annual Scientific Meeting in 2024. Paul Evans talks to: • Professor Shafaq Sikandar, a professor of sensory neurophysiology at the William Harvey Research Institute, Queen Mary University, London. • Professor Kathleen Sluka a professor in physical therapy and rehabilitation science at the University of Iowa in the United States. • Professor Gareth Hathway, a professor of neuroscience at the University of Nottingham’s’ School of Life Sciences. They share their research into why pain persists, how we can identify people at risk and whether we could prevent it happening. Transcript begins. Paul Evans: This is Airing Pain. The programme brought to you by Pain Concern, the UK charity providing information and support for those of us living with pain, our family and supporters and the health professionals who care for us. We're grateful to the continued support of the British Pain Society for providing facilities to record at their annual scientific meetings and the content of this edition of Airing Pain was recorded at the 2024 meeting. I'm Paul Evans. Gareth Hathway: We know that children, human children, rodent children, they're much more sensitive to pain. Their pain thresholds are a lot lower, and their responses are longer, larger, and they're a bit inappropriate. They don't respond in the right way. And we learn how to become adults. Shafik Sikander: A lot of patients with fibromyalgia may have had early life stressors, or often – when they come to clinic presenting with fibromyalgia – they have a history of depression. Kathleen Sluka: We know that people with psychological trauma at young ages are more likely to have chronic pain later in life. But what we think is happening, and we've done a little bit of this, psychological trauma or some kind of a stressful event, actually changes your immune system. Evans: One of the great things about coming to these British Pain Society scientific meetings is that you get to hear new insights and developments in the field of pain: things you won't necessarily read in the popular media, which nevertheless could have a huge impact on how we live with pain now and into the future. Conditions like fibromyalgia, for instance. It's one of those conditions that rarely makes headlines beyond how it affects sufferers, particularly, dare I say, celebrities. But not necessarily on understanding the causes and the mechanisms that will drive its management into the future. Shafik Sikander is a professor of sensory neurophysiology at the William Harvey Research Institute, Queen Mary University, London, and her work is trying to understand those mechanisms in animals in preclinical models, and in clinical studies. Shafik Sikander: For decades it's really been considered to be a brain-based disorder. But in the last five to ten years, there's been quite a lot of exciting and emerging evidence suggesting that there is a peripheral pathology driving pain in this disease, which gives us hope that we can target the pain directly in the periphery. The real key question for us is to understand what is going wrong in the peripheral tissues when people say, “my arms hurt”, “my shoulders hurt”, “my legs hurt”. Well, what's driving that pain in the arms and shoulders? We don't think it's only what's going on in the brain. We think that input is coming from the peripheral tissues going into the brain, and then a patient will be perceiving pain as a result of that. Evans: Explain to me how that works and why do you think that? Sikander: One thing that I probably want to start out by saying or, just, sort of introducing the different lines of evidence is to say that I think fibromyalgia is more and more like an umbrella term for a group of disorders that might have the same manifestation, the same symptomatic manifestation. So, some people have found evidence for small fibro neuropathy in a small cohort of patients. Okay, great. We know a little bit about neuropathic pain – that makes sense. We understand why there might be pain in those patients. Other patients don't have small fibro neuropathy. Some patients may have dysfunctional IGG, for example. Evans: What's that? Sikander: This is an immunoglobulin. So, when there's a change in the immune system. We recently discovered that a group of cells called the neutrophils, which are important cells in your innate immune system – important for normal host defence responses to infection and external pathogens and microbes – well, we think neutrophils, even though they tend to be very good for us and very important for your resolution of information, resolution of inflammatory pain, we've seen that in patients with fibromyalgia, actually, neutrophils can behave quite badly and they might be driving pain. Evans: So, does that mean it could be an autoimmune disease? Sikander: No, I wouldn't call it an autoimmune disease per se, at this point. I would say that we're looking at immune dysfunction and that the mechanism of pain lies along the neuroimmune axis, the way the nervous system and the immune system communicate. Evans: Neuroimmune, what does that mean? Explain to me what neuroimmune is. Sikander: Neuroimmune... “apartmento” between neurons and immune system. Evans: Neurons – nerve cells? Sikander: Yeah, nerve cells and the immune system. So, it's just a term to describe that the nervous system (that comprises our nerve cells), and the immune system (that comprises our ability to defend ourselves against infection and disease): these two systems communicate. They're two physiological systems that interact to a much greater depth than we currently understand, I think. And that communication is bidirectional. So, nerve cells, or neurons, can communicate to immune cells and vice versa. Evans: What could be causing this in the first place? Sikander: We can't ignore the history that patients present with. With the immune system, it's extremely plastic and it's highly prone to coating memory to injury and particular salient events. And so, when we talk about the history of patients, a lot of patients with fibromyalgia may have had early life stressors. Or when they come to clinic presenting with fibromyalgia, they usually have a history of depression. So, you know, there might be different triggers that accumulate and then just tip an individual over the edge to then go on and develop a disease. And we've actually modelled this in mice, or this aspect of repeated, salient, noxious events driving chronic widespread pain. So, actually if we injure a mouse once in the leg, well, that mouse develops some pain for a little bit of time. The injury heals after a few days; pain behaviour seems normal. But actually, what we've done is we've primed the nervous system with that injury, so that after a subsequent insult we can trigger latent hypersensitivity and persistent pain. So, animals after another injury will not just have an acute pain episode, they'll actually develop persistent pain. Evans: So, the body is saying, “I remember what happened then. If it happens again, I'm going to continue hurting you”. Sikander: Yeah, like a memory mechanism, akin to a memory mechanism, but yeah. So that's kind of what we refer to when we talk about plasticity within the nervous system and within pain states. So, we know, for example, in some patients neutrophils are pathological, and they are the cells within the circulation that's driving this widespread pain. So, we can try and target how neutrophils communicate with neurons to try and help relieve pain, but then we need to do even more work to try and characterise those neutrophils, to understand how they've come about to becoming these pathological cells. Why aren't they just normal, healthy neutrophils, behaving in a good way, like they do in people that don't have pain? I mean, if we understand what is driving the pain, then we can understand what has caused it. Because I think the root causes could be multiple mechanisms, there could be repeated stress injuries, and every patient history is very different. Right now, we're dealing with this disease that's very heterogeneous in terms of its mechanisms of pain. So, I think what we're going to have to first do is actually be able to stratify different subpopulations of patients with fibromyalgia to understand, in different subpopulations are different mechanisms driving the pain? And then we come back to the root cause. I think trying to find the root cause for a very heterogeneous umbrella term of a disease is maybe not the most... yeah, effective way for us to spend our research time. But right now, what we know is that we have a number of patients coming through pain clinic that have debilitating pain, and we have this potential opportunity to treat their pain. And if that works, then we can go back and see if there's any potential triggers that we can subdue, or we can prevent people from experiencing certain triggers that would transition their pain from an acute to chronic state. Evans: That's Shafiq Sikander of Queen Mary University, London. Well, let's delve a little deeper into the differences between acute and chronic pain, and why preventing the transition from one to the other is so important. Kathleen Sluka is a professor in physical therapy and rehabilitation science at the University of Iowa in the United States. Kathleen Sluka: An acute pain condition would occur after you fall down onto your ankle or have a surgical procedure. Under normal conditions, the great majority of people may recover from that, and their pain goes away. But there's a proportion of somewhere between 20 and 30 per cent of people where that pain remains: three months, six months, a year later. And it's those people that, if we could prevent that transition, if we knew it was happening either before that event – say, if they're going into something that's planned like a surgical procedure – or during that very acute injury stage. If we knew what was different about them, then maybe we could intervene there, and stop them from ever getting into the phase of where they turn into a chronic condition. If we could do that, we can lower the total number of people that have chronic pain and reduce the burden altogether. So, our whole goal with this is to, really, just prevent that transition. We have some animal models of the transition from acute to chronic pain where we've begun to look at mechanisms in the central nervous system and in the immune system. But then we're moving forward into also looking at those factors in people before and after surgery, so we can begin to identify what those factors are. Evans: But not all chronic pain conditions start off as acute pain. Sluka: What I think we've learned over the years is that, in order to induce chronic pain or long-lasting persistent pain, there's a lot of ways to do it. Yes, after a surgical event, a certain number of those will not move on. In animal models, I've probably induced very long-lasting pain with multiple different things. Like I could give, say, two muscle insults, three to four days apart. The first one may not do much of anything and the second one – then I have weeks of pain afterwards. Or I could give a muscle insult that does nothing in a normal weight mouse, and when I do that in an obese mouse, he gets long-lasting pain. Or I could give them a stress event. I could make them stressed and there's different ways we do that in mice. We stress them and then give them that same insult that doesn't do anything under normal conditions. And now I get that. So, it's this combination of stressors that are occurring in some kind of time-window that we think is driving them into this chronic pain. So, when you say, maybe they had these low intensity insults or stressors all occurring simultaneously in life, but they didn't recognise them as the “inciting event”, so, they may not have had an acute, really big pain episode before they transitioned. Evans: Now, I can understand if you give a pain insult, that is, make it hurt to a mouse, and then you give them another one two weeks later – I can understand why the second one could reinforce the first one, or make the brain think, “Ah, we know what's coming, we're going to do something about that in the in the future”. But I don't understand how, say, giving it a psychological trauma could do that. Sluka: Well, we know that in people with psychological trauma, those at young ages are more likely to have chronic pain later in life. But what we think is happening, and we've done a little bit of this psychological trauma, or some kind of a stressful event, it actually changes your immune system, and you might get a little bit more inflammatory cytokines being released. It might activate certain pathways within your central nervous system. That pain is also sending signals through. So, there's not a single pain signal or pain pathway. There are multiple places within the brain that are receiving these signals. And they're processing them all together to get some kind of output that eventually the brain says, “Oh, I got pain!” Well, the same thing happens with stress, it's not a single spot. And sometimes they overlap, and they're in the same areas. And so, if those are hypersensitized by one of those other stressors, like a fatiguing stimulus, or a stressful stimulus, and then the pain comes on top of that, then it might interpret that as a painful event and respond in an exaggerated way. So, I really think it's just a heightened state of the nervous system or the immune system, or some combination of all of those that the body is seeing; and both of those events may be doing some kind of general heightened sensitivity that the other one is then enhancing. Evans: So, the big thing that you're working on and telling the delegates here is stopping that acute pain becoming chronic? Sluka: Yes. We're trying to figure out what factors are different between the individuals who go on to develop that chronic pain at that acute stage. So, maybe there's also some factor in those who don't. That's what we might call a “resilience factor”. That might protect them from moving into that state. That might be equally important for the future in preventing the transition. If we knew that, that could then be a future target as well, to use as a way to increase resilience in the people who were transitioning to that chronic pain condition. Evans: What's your feeling about, if there is an answer, what it might be? Sluka: What I think, what we've come to believe is what we're going to end up with is something that I like to call – not a single biomarker, not a single marker at all – it'll be what we call a “biosignature”, which will be a combination of markers. It'll be a combination of factors. It won't be all biological. There'll be some biology, maybe something happening in the nervous system, something happening in the immune system. But there'll also be some patient characteristics that will add to that; things like pain levels will matter. Other conditions they might have will make a difference; the psychological conditions, if they have depression or anxiety. And what I think we're going to end up with is kind of like a “top ten” list of, if you do these tests, I can do some blood work and I can measure for depression or anxiety or a few simple tests, activity levels. And we know these “top ten” lists, much like we have for cardiovascular disease, and we know that that's your risk and we're going to come up with a “risk profile”. Then we'll be able to target those people based on that, on how they perform on that top ten risk profile, and that's what I'm eventually hoping that we'll come up with. We're in the process of doing a really large study with 2,800 individuals before and after surgery, for six months, where we're looking at brain imaging, hundreds of markers in the blood, sensory testing and a lot of patient outcome measures from psychology to social, just pain levels. And we're hoping that with that data we'll be able to definitively come up with that “top ten” list at the end. We like to try and oversimplify things and assume that everything is going to come down to one answer and I don't think it's going to. And I think there's many ways for us to get to that chronic pain condition and because of that, there's going to be a huge variety of presentations. And treatments are going to have to get to an individualised basis in order for us to make progress. But we don't have the tests yet. We don't have all the measures yet. We don't know the best route yet. And I think that's where the exciting part is, once we start discovering some of this, we'll be able to do that. But we're not quite there. Soon, I hope. Evans: That was Kathleen Sluka of the University of Iowa in the United States. Well, I guess what scientists who study the relationship of pain and the nervous system really need is a definitive measure of a patient's pain. Gareth Hathway is a professor of neuroscience at the University of Nottingham's School of Life Sciences. He was talking to delegates at the British Pain Society Annual Scientific Meeting in 2024 about a new technique to measure how parts of the spinal cord receive, process and respond to innocuous and noxious events, and how that changes over early and later life. Gareth Hathway: Nerve cell neurons are electrically excitable, they're electrically active. Our brains, our spinal cords, our peripheral nervous systems run on electricity. And what we do is use electrodes, which we can put into those tissues, and we can measure that electrical activity. So, every time they fire, like turning a light bulb on and off, we can measure that “on” and “off”. That tells us when neurons are firing, and what they're firing to, and how long they're firing for. So that really gives us a kind of measure, an assay of how excited – in this case – our spinal cord is. And a general rule of thumb which I use with our undergraduate students is the more excited your spinal cord is, the more pain you will feel. So, we can measure the electrical activity and determine how much pain – not susception, but pain, for this purpose – an individual is in at any given time. So, we can also see if drugs can reduce the excitability and therefore reduce the amount of pain. Evans: Okay, so you can see when a person might be experiencing pain in the spinal cord. But what happens when it leaves the spinal cord and goes up? Hathway: Goes up to the brain? Well, that's a very good question. That's one of the things that we want to try and understand. So, this is all in laboratory animals. What is the signal that the spinal cord sends to the brain that says, “That's potentially harmful to me”? That thing that you've just encountered in the environment. And at the moment, many of the techniques that we use can't do that. That's why I'm talking about this new technique, because the way that we've studied the electrical environment of the spinal cord has been the same since the 1950s, pretty much. It kind of relies on us measuring one nerve cell at a time and one particular set of nerve cells, actually, in one particular place in the spinal cord at a time. And the problem is that the spinal cord is very varied. There are thousands of different kinds of neurons. And it's not really how one neuron responds, it's how a population of neurons respond that determines whether or not we get information related to pain. So, our new technique uses lots of electrodes at the same time to measure hundreds, if not thousands of neurons at the same time, from everywhere in the spinal cord. And so, then we can build up what we call a kind of network image. So, how is the whole spinal cord responding, not just how does one cell respond, and then kind of extrapolating that to a much larger population. Evans: So, you can see from “point A” right down in the spinal cord to “point C”, which may be halfway up the spinal cord. You can chart differences. Hathway: Yes. So, at the very top of your spinal cord there are five layers in the dorsal part. There are ten in total, but there are five that we're worried about as pain scientists. So, the top two get information that's related to pain from your bone, your skin, your muscles from the nerve cells in your body. The middle two process. Layer three and four process innocuous information like brush normally. And layer five, which is the deepest one that we measure, that gets information from everything, painful and non-painful, and integrates it all together. And then normally, traditionally we've just recorded from those deep ones in layer five. But actually, what we want to know is what's also happening at the same time in the “painful” layers and in the “non-painful” layers. So, what our technique allows us to do is to measure all the activity at the same time in all five layers, but also, with a bit of mathematical trickery, how the information flows between those layers. So how, let's say, layer one and layer five relate to each other at the same time. So how the network responds. It's a different technique, but it's a similar approach to MRI or something like that, that you'd use in the brain where you're looking at big volumes of brain tissue. It allows us to look at a big volume of tissue in the spinal cord. But we can't use MRI on the spinal cord because it's not good enough. Evans: So, from your research, what is going on between those layers? Hathway: Well, so we've mostly studied at the moment – because I'm particularly interested in early life pains – what happens when we're very young, and how we mature, how we become adults. So, we know that children – human children, rodent children – are much more sensitive to pain. Their pain thresholds are a lot lower, and their responses are longer, larger, and they're a bit inappropriate. They don't respond in the right way, and we learn how to become adults. And so, we've always thought that the dorsal horn, those five layers, are more excited. Actually, what our data is now showing is that they're not more excited, they're a lot less excited. Because if you look at the data, there's a lot less activity across all of those layers than there is in an adult. What that's telling us is that it's not that we've got a runaway system that we need to apply the brakes to, to slow it down as we become adults. Actually, what we've got is a system where there's lots of inactivity in the neurons – and it all needs to be ramped up a little bit. And this is particularly important because we know that injury in early life in a human, if you're born very young and you suffer an injury, or you have an operation, or you've got a disease which is very painful, even after you've been cured of that pain – that pain's gone away, the disease is better, the surgery's over – you're much more susceptible to chronic pain states and altered pain processing as an adult. And so, understanding how it works (which is what we're doing at the moment) normally, and how changes that you might encounter as a very young person – diseases, surgery – how that impacts on that normal development. By understanding how it works, how the machine works, we can then really understand what we can do to try and put it back on a normal path once you're adult. So, one of the projects we're working on at the moment, another one, is looking at cancer survivor pain, children who have developed cancer very early in life and how they survive. But lots of those children, when they grow up, those survivors, have significantly altered pain experience and they suffer from a lot of pain as survivors. And with that comes anxiety and depression and educational problems as well, because they're in pain, so they withdraw a bit more. So, understanding a pain level, how that processing is happening, identifying ways that we might be able to make it better, will then lead to a better life experience for, in that case, cancer survivors. But it's just as applicable to people who've had surgery, as I really love to connect something. Evans: Well, I did have surgery at three months old. Hathway: Mm hmm, okay. Evans: I have chronic pain now, so possibly too late for me. I don't know whether that operation I had is the reason for my chronic pain, but maybe in the future if you recognise, if you know what's going on in the developing child, baby, you'll be able to put things in place. Hathway: Yes, that's the idea – that we can identify new ways of managing the pain experience when you're very young, so that you're less susceptible to chronic pain, when you're very old. Or more so than we normally are, anyway. One of the big problems is that pain in children is under-recognized, because they're not so good at communicating it. So, when you were three months old, you couldn't point to a scale and say, on a scale of one to ten, how much pain you were in. And also, there's a bit of a reluctance to treat it, because people are obviously concerned. And also, the drugs we've got, we know can alter that development as well. So, some of the work that I've been doing for the last fifteen years – but we're doing more of it now – is looking at how opioid analgesics and exposing very young animals to opioid analgesics, how that alters that developmental pathway, that trajectory. And it does. And opioids do that as well. So, it's a catch-22 situation that we're in. The pain is bad, but sometimes the treatment alters things as well and also leaves you more susceptible to things later in life. Evans: I'll go back on that a little bit because it wasn't that long ago that it was thought that babies didn't feel any pain. Hathway: That's exactly right, yeah. Evans: And the person I spoke to who witnessed an operation – in fact, the operation I had – pyloric stenosis. Hathway: Well, my dad had that as well at three months. There you go. Evans: Really? Hathway: Yeah, absolutely. Evans: As a student, she witnessed one of these operations where there was no anaesthetic. I think she called it a “cruciform” or “crucifix” style operation, where the baby's arms are held at the side and of course “babies feel no pain”, so and so... Hathway: “So it's okay, it's just a reflex.” That's what they thought. Evans: “Get stuck in!” Hathway: Yeah, it's horrifying how recently these kinds of things went on. Because I think the dogma (it wasn't accepted clinical practice) was that babies were incapable of feeling pain. Their brains weren't mature enough to be able to consciously perceive it. So therefore, they're not going to remember it. Providing analgesics – and the risk associated with that – it's not needed. But actually, work from Mariah Fitzgerald, again Rebecca Slater who's now at Oxford, has really shown that cortically the conscious part of the human brain, even in the very youngest babies, is able to respond in a consistent and reproducible way to not just stimulation. So, you have to provide anaesthetic and analgesia. But yeah, you know, we're talking 1950s, 1960s, these things were going on. And in some cases, I think... Not surgery like that, but I seem to recall a paper from, it can't have been much more after 2006 and 2007, that looked at circumcision pain in New York, so this a first world country. How many children were actually provided with any analgesia during and following circumcision? And it was a surprising number that weren't. I imagine that's quite painful. Evans: I imagine it is really painful. So, moving on a bit, you said that some of the treatments could cause more issues than non-treatments. Hathway: Before the COVID pandemic, I think the greatest public health concern in bioscience was the opioid epidemic in North America. And it has not gone away, it's still there. Related to that was the number of opiate prescriptions that were taking place in North America, but also in Western Europe, the UK included. Opiates are brilliant for managing acute pain, they're the best drugs we have. And they're great at managing short-term, acute pain. But long term, they're not so great. You become tolerant to them, so you need more and more to have the same effect. Obviously, there are addiction issues, but also, paradoxically, taking opiates can cause something called “opioid induced hyperalgesia”, which is the opiates themselves cause pain. That's a problem for long-term, adults like us taking them. What I showed in my work, when I was with Mariah Fitzgeralds back in the late 2000s, early 2010s, was that during normal development of a rodent, if you rely on the opioid, the natural opioid system in your brain, for your pain system to wire together properly, and if you disturb that by giving an opiate, or by blocking opiates, you've changed the way that those animals process pain for the rest of their lives. Currently I have a grant with my colleague Vicky Chapman and Steve Woodhams from the MRC that's looking at – not in babies now, in young adults – what the effect of an exposure to opiates for a very short period of time, for seven days, has upon their pain experience and their susceptibility to chronic pain later in life. So, we're interested in osteoarthritis and pain of this kind. And we can show a much earlier, brief exposure to opiates makes you much more susceptible to musculoskeletal pain when you're much older. And we did some public engagement before we wrote this grant, and we asked the members of the public that volunteered to help us develop it, “Had they ever taken opiates in their lives?” And most of them said, “No, no, no, no, no, of course not!” And we said, “So, you've never taken codeine, bought codeine over the counter?” “Oh yeah, yeah, I've done that! And uh, when I gave birth, I had something, I had pethidine.” OK, that's another one. And I remember my parents in particular back in the 70s and 80s, distalgesic was an analgesic of choice. My grandmother used to take quite a few – and that was another opiate-acting drug as well. So, people don't realise that they're taking opiates. And what that work is showing is that opiates are great – for short term, acute pain management when you need them. But longer term, they're not great at controlling longer term pain. But they are the best we have. So, lots of people, my own family included, rely on opiate drugs to provide the analgesia. But that's why conferences like this are really needed, to think about better ways of managing longer term pain. Evans: That was Gareth Hathway, Professor of Neuroscience at the University of Nottingham. Now, as in every addition of Airing Pain, I'd like to remind you of the small print that whilst we in Pain Concern believe the information and opinions on Airing Pain are accurate and sound, based on the best judgments available, you should always consult your health professionals on any matter relating to your health and well-being. They're the only people who know you and your circumstances and therefore, the appropriate action to take on your behalf. At Pain Concern’s website which is: painconcern.org.uk, you'll find many resources to learn about and live well with pain. There are links to every edition of Airing Pain and to written transcripts of each one. Now it's important for us at Pain Concern to have your feedback on these podcasts, so that we know that what we're doing is relevant and useful and to know what we're doing well, or maybe not so well. So do please leave your comments or ratings at whichever platform you're listening to this on or the Pain Concern website of course. Once again, it's painconcern.org.uk – and that will help us plan future editions of Airing Pain. But to end this edition of Airing Pain, here's Gareth Hathway again. Hathway: Your pain experience all the way through your life will, in some way, impact on your pain experience at the very end of your life. Yesterday at the conference, it was a great parallel session that started with Suellen Walker talking about pain and late effects in children and then through another lady who was telling us about pain in people with learning differences and people who weren't able to communicate pain, and it ended with a talk from a lady talking about pain in older people. And she had a statistic in her talk that 95% of old people exist with chronic pain and I leant across to my colleague at my side and said that if this was any other disease, the government would be throwing money at it, left, right and centre, if 95% of people were suffering from it. Because the impact that pain has –we've all experienced acute pain, but long-term pain, it makes us depressed and anxious, makes us withdraw from society. So, we're not going to the shops and spending money. The impact it has economically and the burden it places on the health service is massive. But it's not just about thinking about pain in older people, what happens when we're old, it's thinking, well, how can we manage pain appropriately at every point in the life course, so that the person's quality of life is as good as it can be for as long as it can be, so that they're happy, they're active and they're contributing as much or as little as they want to society. Slowly but surely, our understanding of the basic mechanisms is light years ahead of where it was. And, clinically, an appreciation that babies do feel pain. Young people do feel pain. It has a long-term consequence. So, we can't just treat them as small adults. We need a specialist approach to managing pain at every part of the life course. We need to think about how we measure that pain and how we treat that pain.

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