Blair Smith: Searching for the genes behind chronic pain
Blair Smith: Image courtesy of Blair Smith
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Let’s move from Chronic Fatigue Syndrome to another chronic, life-limiting health issue - chronic pain. Medically speaking, this is pain that has lasted for three months or more, and it can be very difficult to manage and treat effectively.
Professor Blair Smith is a consultant in pain medicine at Ninewells Hospital in Dundee and a clinical researcher at the University of Dundee working on Generation Scotland - a large research study looking at the health, wellbeing and genetics of more than 24,000 people living in Scotland, from around 7,000 families.
As you might expect, Blair has a particular interest in trying to find out whether there’s any genetic connection with chronic pain. But before we talked about that, I wanted to know a bit more about what chronic pain actually is.
Blair: So pain is different for every person and I, as a doctor, can't tell you what your pain is like, but pain can arise from some definite physical insults, such as an injury or surgery, or very often we can't find an underlying cause or sometimes there's tissue damage that is ongoing causing the pain. Very often, it's associated with psychological factors or social factors such as your circumstances in which you're living or recent or ongoing distress, which can either cause, or certainly compound the pain and the combination of physical, psychological, social, spiritual factors are all important in creating the impact of the pain on the individual.
Kat: And when we're diagnosing people with chronic pain, what are the kinds of things that people are coming with? Can you give me some examples?
Blair: Yes. I think the commonest presentation of chronic pain is back pain, chronic low back pain. And actually the global burden of disease study shows that chronic back pain is the single greatest cause of disability everywhere in the world, Scotland, UK, globally,, every single country. But other important causes of chronic pain or arthritis, surgery, nerve related pain arising from diabetes. We have conditions such as fibromyalgia, which is one of the ones for which we are yet to find an underlying physiological reason, chronic headaches. But as I say, very often, it's a combination of causes or conditions or things which are difficult to describe and even harder to diagnose firmly.
Kat: And I guess then it becomes even harder to think about how best to treat these kinds of things. What are the kinds of treatment approaches at the moment?
Blair: Well receiving most attention at the moment is treatment with medications, drugs, and particularly in the news treatment with opioids, strong potentially harmful drugs, which can relieve pain in the short term, but for which there is limited research for effectiveness in the long term. Other drugs such as Gabapentinoids are also becoming more important. But there's the standards such as paracetamol and non-steroidal inflammatory medicines like ibuprofen. But we're moving away from a focus entirely on analgesic treatment and moving away from the word painkiller, for example, because we can't kill pain, it's always there. And we're trying to increase the emphasis on non Pharmacal approaches, such as physical activity, self-management approaches, psychological approaches and looking at the social environment in which people are living, seeing how we can adapt that.
Kat: And then we get to the focus of this podcast, which is the genetics of it. So when we're starting to think about how do you bring together the world of genetics and the world of pain? What are the kinds of questions that you can ask through this kind of lens of genetics about pain itself and about the kind of people and the conditions that are linked to it?
Blair: I mean, the first question I suppose to ask is does pain run in families? Does chronic pain run in families? In other words, is it heritable? And we can look at that, for example, in the Scottish family health study, which is one of the generation Scotland studies. And there, we did find that there is a degree of heritability in chronic pain. So if you look at any chronic pain, the heritability was around about 29%. In other words, almost a third of the experience of pain runs in families. However, if you then adjust for factors like shared household environment, the way you were brought up, your age and your gender, that heritability was down from 29 to 16%.
Kat: So not very heritable then?
Blair: Well, exactly. It's higher, so it's 44%, If you just look at severe chronic pain unadjusted, but then adjusting for these factors, it was down to 30%. So about a third of the chronic pain was heritable. And then if you look at specific causes like neuropathic pain in a twin study, it was found to be 37% heritable. So I mean, it's a reasonable amount of heritability, but as you're implying, what I find most interesting and important as a doctor treating these people with chronic pain is that, that means the vast majority of it is not heritable, therefore not genetic. And we have to focus on these other causes. However, it is important to look at, now that you've established that there is a heritable component important to look at for the genes are, if we can, that are involved in that heritability because they give a clue as to the physiological mechanisms that might be generating that pain.
Kat: It definitely feels like these approaches are kind of trying to get a chink, something that you can get a tool into when you've got something that is as big and challenging as trying to understand pain. So how do you go about that? For example, in the studies in like generation Scotland, how are you trying to investigate the genetics of pain?
Blair: Well, Generation Scotland is a reasonable sized study. It was a big study when we set it up. Of course there are many, much larger studies and there are smaller studies as well. The strength of Generation Scotland is that it's recruited in family groups. So that increases the power to look at heritability and then genetics.
Blair: I think there are two main approaches to looking at genes involved, potentially involved in pain. And one is to look at what we call candidate genes, genes that have been found in other studies, perhaps in animal studies or in other smaller human studies as being potentially important in the development of pain. And we can test for those. We can assess the connection association between those specific genes and chronic pain as we defined it in Generation Scotland or in other studies that's a following up on a hypothesis that's been generated by other studies.
Blair: The other approach is to have a hypothesis free approach, which is a fancy word for a fishing trip. So we can take a genome wide approach where we just look at all the genes, all the genetic variants that we've been able to genotype in the sample and we can put in pain phenotype and we can look at this associations between those hundreds of thousands or even millions of genetic variance and the occurrence of chronic pain in a so called genome wide association study.
Kat: And so what do we know so far? Has anything come out of this approach coming from either direction you're sort of fishing or looking for your usual suspect?
Blair: First of all, of course, we have to look at fairly well-known, but rare conditions, which are Mendelian in other words, purely genetics. So For example, a condition called congenital insensitivity to pain. It's not a cause of pain obviously, it's an insensitivity to pain where you can't feel pain and there's one gene, a sodium channel gene SNC9A, has been identified as the underlying cause for that. So we can look at that as a candidate gene associated with other pain related phenotypes. And we do find that it does come up with some degree of association in some studies.
Blair: One thing which we do find is that few, if any of these candidate genes have been replicated consistently, in other words, they might come up in one study, but they're not definitively reproduced when you try and do the same, test the same gene in a different study. And I think that's because often, because first of all, the associations are relatively weak. There is not one pain gene. So the associations are relatively weak in terms of the overall effect. And therefore you need larger actually very large sample sizes in order to confirm them.
Blair: And secondly, we haven't really gone into it, but how to identify pain in large population studies is a whole branch of discussion and science in itself. And it's difficult to do it, or it's impossible to do it objectively, It's difficult to do it subjectively with any validity. And it's almost never done the same way in two related studies. So it might be associated in one study and not in the next, and we don't know if that's because it's a different way of defining pain or if it's a different population or if the gene just was a false finding in the first study.
Kat: I guess it must be so frustrating when it's not something you can just do a blood test for, or a scan and say, yep, you've got X amount of this in you and so we can tell that your pain is Y, and therefore we find this association.
Blair: Yeah, I mean, it's a frustration, but it's part of the natural phenomenon of pain and goes back to what I said at the beginning, that your individual pain experience is determined not just by any underlying physical problem, even if there is a physical issue there, but the other factors that are so important. There is work being done, of course, in trying to develop a biometric signature for pain, which will include blood tests, stress hormones with implied already, but MRI scanning a lot of work going on there. So we're working towards trying to get a fingerprint for pain, but it's a long way off. And once we've developed that, then tying that up with genetic signals is going to be another separate challenge.
Kat: And I guess coming back to the patients and their experience, how does having the sort of genetic clues, how will that actually help patients and help to improve their experience and ideally reduce their pain?
Blair: I mean, it's interesting you focused on the positive, I'll come back to the negative, potential negative, in due course, which I came across in our clinic last week. I mean, the positive potential positive is, as I've said, if we can identify underlying mechanisms of pain, whether that's a specific cause of the pain or the association between other things and the pain, then we've then potentially got a target for developing prevention or treatment for that pain, but also just a general understanding of how pain developed. So for example, if you take neuropathic pain, that's nerve related pain in our research group, we've done a lot of work on the genetic factors associated with neuropathic pain. And a lot of, as I say on replicated genes, but genes that are potentially associated with neuropathic pain tend to be involved in neurotransmission, the passage of nerve signals between one nerve and another, or metabolic processes or immune response is very important. So how her body responds to infections or foreign bodies.
Blair: And so by identifying those and the stress response system is another one, by identifying those as important underlying biological pathways, then we can maybe begin to address the bigger picture of these pathways in addressing pain. Stress response being an obvious one, if as has been the general clinical impression, stress is closely related to pain. If we can identify and implement therapeutic approaches that deal with stress, then perhaps we can improve the pain or the impact of it in individual patients, which confirms clinical impression.
Kat: And you mentioned there was potentially a downside to this approach. What have you experienced?
Blair: Yeah, so this is, and it's obvious when you think about it, but this is a patient I saw in clinic. I've been seeing for quite some time and she's actually doing quite well in response to treatment. But at the end of our last meeting, she asked me without knowing anything about my research interests, she asked me what the genetic factors underlying pain were and whether it ran in families because her daughter and her granddaughter also had chronic pain conditions.
Blair: And I started off in a very well-informed discussion about the genetic factors associated with pain and the heritability, and then occurred to me that her daughter is 17 and has just been diagnosed with a chronic pain condition fibromyalgia, I think it was, and I became aware of that if I was giving this information, that pain does run in families and that there is a genetic basis, then potentially I could be subconsciously consigning that 17 year old girl to the belief that her pain and the lifetime of pain is inevitable, which it's not, but it's closely associated with your expectations and your beliefs and your attitudes and if she's entering adulthood with the belief that the pain that she's experienced is genetic and therefore beyond her control, then that will be a self fulfilling prophecy.
Blair: So I then went back on myself and said what I started off this conversation by saying that the heritable and genetic component of pain is a very small component and by far, the majority is what we do about it and the other circumstances. So to focus on the things that she can change, rather than the things that she can't.
