Jeffrey S. Mogil is currently the E.P. Taylor Professor of Pain Studies and the Canada Research Chair in the Genetics of Pain at McGill University, and the Director of the Alan Edwards Centre for the Study of Pain. Dr. Mogil has made seminal contributions to the field of pain genetics and is the author of many major reviews of the subject, including an edited book, The Genetics of Pain (IASP Press, 2004).
This episode is so fascinating and so much fun because we dive deep into some fascinating topics as well as clear up some of the myths and discussion and debate around others. I have Professor Jeffrey Mogil. He is a neuroscientist who studies pain. He works at McGill University where he is the Research Chair in the Genetics of Pain Department as well as the Director of the Alan Edwards Centre for the Study of Pain. He is recognized as a leading authority regarding the sex differences in pain, and he is one of the pre-eminent researchers in the field of Genetics. If genetics and pain interest you, this is the guy to go to. He has won multiple awards for his research, he is an international speaker, and he currently serves as the counselor at the International Association for the Study of Pain.
This is one of my favorite podcasts to date because Dr. Mogil takes us on a deep dive and exploration about the current state and evidence of genetics and how it’s informing both the research as well as the care that we provide to patients with painful conditions. He also takes the time to clear up the old debate around who tolerates pain or who is more sensitive to pain, men or women, and the findings about that may surprise you.
Sex Differences In Pain And Pain Inhibition with Dr. Jeffrey Mogil
Jeff, how are you doing? Thanks for joining me.
My pleasure, Joe.
You are a neuroscience researcher. The field of neuroscience is expanding rapidly. Everyone’s interested in the brain and how the brain works, especially when it comes to pain. Taking you back a little bit, how did you choose to study pain when there are so many different things you could have studied about the brain and the nervous system?
It’s completely by accident. When I started in science, I was doing a reward system, pleasure centers in the brain. I thought I was going to research that. I applied to work with a bunch of people who did that, and somehow a pain researcher got on the list. To be honest, I don’t even know how. I made a whole bunch of trips to visit people and he gave me the best feeling, not so much that I was interested in research more than anything else. I got the safest feeling from him that he was going to take care of me. I was looking for some sort of father figure. The next thing I know I was a pain researcher. It happened entirely by accident.
The reward center has a lot to do with pain. What you were initially interested in still has a segue to that.
At the time, I told myself it’s not that much of a switch, pleasure and pain. They are two sides of the same coin. Amazingly, those fields were entirely separate until about five years ago. The impact and influence and reward systems on pain is a big topic. This is only in the last five years that people have made that connection.
What does a typical day look like for you as a pain researcher?
I always would like to dispel the notion that scientists wear white coats and are in their labs all day. There are a few of those, but generally speaking, that’s what the twenty-year-olds do. The 50‑year‑olds sit in their office and send or respond to email. I remember when my son was about eight, I overheard him talking with a friend of his about what their fathers did. My son’s description of my job was, “I don’t know. I think he answers emails.” It’s pretty close to true. Every so often, I will make a graph or edit a paper or even write a bit of a paper, write a grant. Generally, I’m in my office at my computer. I go into the lab six or seven times a day, but that’s only to get coffee.
The experiments that you’re working on and ones you oversee because you have people working under you at the lab, are they focused on human studies or are they mostly animal studies?
Until very recently, we only did mouse studies. In fact, we only did mouse genetic studies. In the last five or ten years, my lab has gotten a lot more diverse than that. Now, we do a fair number of studies on humans as well, not patients. We don’t do patient studies, but we do a lot of studies on undergraduates. In fact, many of the studies that are going on in my lab are designed specifically to show that you get the same finding in mice and undergraduates.
That’s cool because so often, for those of us who understand research on some level, people say, “You can’t apply mouse studies to real life,” and that’s not always the case necessarily.
It’s very clearly not the case. They’re not exactly the same, but no one ever pretended that they were going to be. People need to remember that if you want to understand something mechanistically, if you want to learn something more than correlations, you simply have no choice. You have to move to an animal model or else you’ll never know what causes anything. In humans, you can’t do the research that would lead you to understand the cause of something, so you have to go to animals.
The only question is which one? People have settled in on rats and mice, and some may question why rats and mice are the best choice. At this point, we’re more or less stuck with them, and mice especially are the smallest and the cheapest mammals, and so this is what’s done. It’s very important for people as much as possible to look into in what domains does the relationship between mice and humans break down, and in what domains is it surprisingly strong and critical. There are good examples of both.
It’s also important to mention that there’s definitely not enough money that goes towards research and funding for pain even though we have a bit of a hoopla around pain recently with opioids and things like that. Can you explain to us a little bit on why mice studies are important? We can’t necessarily do things to humans in a way we do to mice in the lab.
There’re a number of reasons. First of all, you can’t give humans any drugs that haven’t been approved. You can’t take anything out. You can’t add anything. You have no control over how the human subject has lived their life. You have complete control over everything in mice. Within limits, you can do whatever you want as long as you minimize pain and suffering of the subjects. Any experimental manipulation you can think of, you can do. You can change their genetics at will. You can make sure they grow up in a certain way and not in another way. Everything is open and that’s incredibly valuable.
The only way of understanding what causes what is to do it in animals where everything is the same and you’ve only made one change, and then you can see what the effect of that change is. Those experiments simply aren’t possible in humans. You can put them in scanners, you can collect data. I’m not saying you can’t do experiments on humans, you can. It’s just that all that you will come up with at the end of those experiments are correlations. This is associated with that, and of course that might mean that this causes that, or it might mean that that causes this, or it might mean that some other thing you hadn’t thought of causes this and that. There’s simply no way of ever knowing what it is, so it’s important. We need to do it. We need to get these associations. Once these associations are there, then you simply have to go to animal models to figure out what they mean.
The fact of social and the environment that you can control in a mouse or mice is so interesting. We don’t have that ability necessarily to control that in humans. I want to dive into some of your more pivotal research around sensitivity and the different sexes, men and women. Can you tell us who is more sensitive to pain or who feels pain more intensely, men or women? Can you talk about that debate a little bit?
I’d like to point out that it’s an odd question because most scientific questions, you go to people on the street and you say, “What is your opinion on this scientific question?” They look at you like you’re an idiot and say, “How would I know? I’m not a scientist,” but if you ask them that question, everyone will guess. They will all guess, 100%, mostly they guess wrong. The idea that people seem to have in their mind is because women undergo labor, they must be more tolerant of pain and less sensitive to pain. We know that women are greatly overrepresented as pain patients.
If you go and you talk to pain doctors that have specialty practices in pain and ask them what percentage of patients are women, you’ll get answers that are around 70%. That could mean that women are more sensitive to pain, but there are other possible explanations there. It’s possible that women are more likely to go to the doctor. You can’t become a patient unless you go to the doctor. Maybe women go to the doctor more than men, and of course they do. This is well known. It’s not so much that women go to the doctor more than men; it is that men refuse to go to the doctor.
A better way of answering the question is not by looking at how many patients are, but by doing broad surveys, by questionnaire, or by phone survey, and asking large numbers of people, “Have you had pain in the last three months?” or however you define it. Those big epidemiological surveys had been done for pain. There are about 50 new studies that have been published. Every one of those shows that women are more likely to say that they have pain symptoms than men, and that’s fairly good evidence. That might not have anything to do with sensitivity either.
That might simply mean that women are more susceptible to developing diseases and conditions that happen to be painful. The only way of knowing who’s more sensitive to pain, men or women, is to take them into the laboratory and test them using controlled stimuli for their pain sensitivity. Of course, that’s been done hundreds and hundreds of times. It’s a little bit amazing to me that there’s still a debate going on in the scientific world, but there is because in some of those studies, they see a sex difference.
In others of those studies, they don’t see any statistical sex difference. If you look at which direction those studies go and you forget about the issue of statistics for a second, you find that overwhelmingly those studies show that women are more sensitive to pain, less tolerant to pain, and give higher pain ratings than men. The evidence is overwhelming. It’s just that some of those studies are too small to show statistical significance, whereas others are big enough to show. This debate is over.
Women are more sensitive to pain. It’s not what everyone would have guessed, but it’s clearly true and it doesn’t matter how you measure it and it doesn’t matter what kind of pain you’re talking about, women are more sensitive to pain. The thing is, that’s not the interesting thing. It’s the thing that everyone wants to know the answer to, but there are much bigger fish to fry, in this world. Although it’s true that women are more sensitive to pain, what’s remarkably more important and more interesting is that males and females appear to have different circuitry subserving pain in their nervous systems
The circuitry is somewhat a big topic, but is that circuitry linked to the genetic differences? Is it linked to hormonal differences? Is it nature versus nurture?
It links to all of those things. There’s evidence for what are called organizational hormonal differences. These are hormonal differences that set up your brain in the first place in utero. There’re differences that have been attributed to so-called activational hormones. These are the hormones that come online after you hit puberty. There’s some evidence that some of it is genetic and has to do with the X chromosome and nothing to do with hormones at all. Of course there are lots of evidence that won’t surprise anyone that there are socio-cultural influences as well, in terms of pain reporting, pain behavior, and who is expected or allowed to be macho or stoic, and things of that nature.
Once the human genome project started, everyone was super excited that we’re going to be able to find one gene for every kind of condition or disease out there. Maybe you can explain to us how that has worked out, and the science, and what we’re looking at it in the future as far as genetics go?
The frustrating thing about genetics is that on the one hand we know that it is not the answer, but much of the answer. It’s about half the answer. Who does or doesn’t develop chronic pain and whether that chronic pain hurts a lot or just a little? Who does or doesn’t respond well to opioids or aspirin? We know that genetic factors account for somewhere between 40% and 60% of that theory, so that’s the good news. The bad news is that, we all naïvely expected that there would be a gene for everything or five or twenty, and all we needed to do was find them and this would all be figured out. It turns out not to work that way. The current best estimate of the people I talk to in the world that study the genetics of pain, of which there are 50, most of us are now thinking that there’s probably 4,000 genes that contribute to the variability in pain-related phenomenon.
I’ve heard about 400 or maybe a thousand. You mentioned 4,000, and part of me is shocked because that’s a lot of genes. The other part of me is not shocked because when you think of the importance of pain to the human species and survival, and you would say, “It makes perfect sense that there’re a lot of genes because I want to continue living.”
It astounded me how naïve we were twenty years ago when we thought we were looking for five, but there’s more to say. 4,000 genes but remember that there are only 22,000 genes. If you’re looking for 4,000 things, of which we found 80 so far, we can find them easily. You can easily find genes related to pain or anything else by brute force. It just needs big cohorts. You spend a lot of money, you will find gene. The problem is that what’s the point of knowing 300 of the 4,000? How does that help you? It doesn’t. It doesn’t help you predict it. You’ll never get all 4,000, or maybe we will 80 years from now. People have said, “No, you don’t have to collect all the genes. All you have to find out is which pathways they’re involved with.” The problem is if it’s 4,000 out of 22,000, it’s all of the pathways.
I’m starting to believe and it’s painful for me to admit this because I’m a guy who made his career. I had tenure because I’d been studying pain genetics from the beginning, and now I have to conclude that this is blind alley in a sense. It’s not going to be useful. It’s not because genes don’t contribute; they do. It’s just because it looks like the problem is intractable. It’s not a problem that we’re going to be able to solve. It’s too multidimensional for us to ever get our head around. It didn’t have to be that way but that’s the way biology made it. I’m starting to believe personally that this is not a profitable angle, that we should be devoting great resources to that we should look in other places. That’s painful for me to admit because this is a sub-field that I have been given some credit for starting.
To your credit, it’s super important that research is meant to take us in a direction that’s more fruitful. If studying every single gene is not the way to go, then you know that you can take your research and morph into things that are beneficial in other ways.
A lot of people don’t take into account that on the one hand, scientists are looking for truth. On the other hand, we’re spending taxpayer money. At some point you need to have a discussion about what that money is buying you. Maybe it’s better to spend the money somewhere else even though you believe that this is where truth eventually lies. It’s a subtle issue.
Just piggybacking off of the genes, because people want to know what’s the gene for low back pain? What’s the gene for rheumatoid arthritis? Why is that not a good thing when it comes to pain necessarily when we’re looking at a gene for different conditions?
I can never give you the answer. What’s the gene for low back pain? Of those 4,000 genes, 3,000 of them are going to be relevant to low back pain, each one contributing a little tiny bit of the variance. Which of those genes are involved in back pain? All of them and none of them, none enough to deserve you memorizing its name. I’m sorry, that’s just the way it turned out. Biology is complicated and evolution has had millions and millions of years of taking a string and tying it into this vicious knot.
We try to put the ball of yarn that’s knotted open and expecting it to all come out into straight line is expecting too much. We’re just not going to get there. We chip away at the edges and we hope we help people by doing that, but anyone that’s expecting that scientists are around the corner of understanding something like low back pain just doesn’t understand the complexity of what low back pain is. We kind of understand why it hurts if the coffee in this cup is too hot. Low back pain is a whole other level of complexity beyond that.
We give people these diagnostic labels like chronic low back pain, like fibromyalgia. Most of us who work with pain are just moving toward the idea of saying someone has a problem processing pain or someone has a pain problem and there’s not necessarily these different conditions. There are insurance companies in our medical system that like to chop it up that way.
This is the famous lumping and splitting problem. In pain, it’s a big one. Human beings have this great need to classify and subdivide and that’s fine assuming that it’s useful, assuming that the classifications lead to different treatments, but actually, with very few exceptions, we treat pain the same way almost regardless of what type of pain it is or where it is or whether it involves inflammation or not or nerve damage or not. The treatment modalities that end up being effective as effective as any of them are turn out to be the same in any case, so a lot of people think that “Go ahead and try to classify,” but let’s not take those classifications too seriously.
You’ve begun to do research around environment and the psychosocial, specifically the social realm of pain. Can you talk about why that’s important and what it means for people who have pain?
People talk a lot about the biopsychosocial model that the only way you’re going to understand health or pain is by understanding the biological determinants, the psychological determinants, and social determinants. We started doing social experiments simply because there is a lot of work going on in the biological determinants and I’d been involved in that for a long time; there’s a lot of work going on, on the psychological determinants; and there’s almost no work that’s ever been published on the social determinants. Why is that? It’s harder. For one thing, if you’re going to do a social study instead of having one subject, you generally have to have two, and they both have to be scheduled to come in at the same time and everything is more complicated. People like to make their lives simple and they’ve avoided this.
It’s too bad because it’s well known that social support, for example, is a key determinant of prognosis in chronic pain patients. People with better social support end up doing a lot better. Social isolation is the worst thing that you could have for pain. If we understood how this worked, it might be a fruitful avenue to try to do, and so we started doing social experiments in both mice and humans trying to show that the principles appear to be the same. If we can convince people that that’s true, then I might be able to draw on a lot more basic scientists into trying to do these social studies so that we can figure out mechanisms that underlie the social modulation of pain and dealings as well, and so far it’s going well. It’s been exciting. It’s fun to design studies in both species and try to make them as similar as possible.
Do you have any inkling as to the ingredients that are needed for a positive social environment for people or a negative social environment? I think the positive is what people want to start to tease out.
In our studies, we’re starting simpler than that just because no one’s ever done this in a systematic way. We’re at the level of our experiments where we’re simply trying to figure out “What happens to pain if people are tested in twos instead of by themselves? What is the relationship between one person and the other person that’s being tested right beside them have on pain?” We’re doing experiments that are simple as “Do people or mice approach people in pain, or avoid people in pain?” Any prescription of what to do with patients is a long way off from what I’m trying to do. I’m getting yet the mechanisms, but the mechanisms are showing that there are sex differences here. The sex differences are exactly the same in mice and people. It looks like the underlying principles are the same in mice and people.
I see the problem. It’s one thing to say social isolation is bad and social support is good. It’s quite another thing to be able to do something. There’s only so much we can do to help people with social isolation, although there is something we can do. I have a feeling that a lot of people live alone in their apartment for whatever reasons. If their doctor prescribes them, “What you need to do is go join a bowling league or at the very least go to this support group that we’ve set up,” people would get out of their house. Just getting out of your house has been shown to be pretty effective as a treatment for chronic pain.
Along those lines, I know you’ve done some research around empathy and you mentioned briefly how people interact with someone else who may have pain in the room. It’s important for the person who has pain as well as practitioners working with patients. Can you talk about the empathy part a little bit?
Although the results of the empathy studies are a little bit counter-intuitive because we all think of empathy as being a good fit. In our experiments, of course, empathy makes pain worse. We’ve shown this in mice and people that if you’re tested for pain alongside or, in the case of humans, across from someone else who is also in pain that you know, that’s a friend of yours. Their pain makes your pain a little bit worse. You have your pain but you’re also empathizing with their pain, and that’s adding to your pain.
People end up giving higher pain rate. This is only true if you know them. This is true in mice and humans. You’re having empathy with this other person, which is good, but of course it’s making the pain worse. What the relevance of this in real life is I’m not quite sure. People are rarely in pain together at the same time. If the other person isn’t in pain, then you don’t see any exacerbation of the first person’s pain, so I would hardly say that people should avoid their friends when they’re in pain. That’s not what the research suggests at all. It’s just that two people in pain at the same time, in the same place, there is a little bit of contagium.
It’s an important distinction because at times people can confuse empathy with compassion.
Empathy is not sympathy. Empathy is not prosocial behavior. Scientists make very clear distinctions between these concepts, although clearly they’re all related to each other. In fact, Paul Bloom from Yale just wrote a book. It’s called Against Empathy. He made a pretty compelling case in my mind that we say we want people to be more empathetic, but that’s not what we want. What we want is for them to be more compassionate. You will only have empathy or you will only have strong levels of empathy for people who are like you, people you are familiar with same race, same gender, same age.
You change any of those things and empathy falls way off. This is just a biological thing. It’s not because people are being mean. In fact, if we just left it to empathy, this wouldn’t solve the problems we have in the world. To solve the problems we have in the world, you have to do nice things for people you don’t know, to the people that aren’t like you. That’s not going to happen through empathy. It’s going to have to happen through something else: compassion, sympathy, prosociality, whatever you want to call it.
I’ve been speaking with Professor Jeffrey Mogil. He is a pain biology researcher. He got some incredible research in the realm of genetics and sex differences and all the things we’ve been talking about. Jeff, I want to give you an opportunity so everyone know how they can find out more information about you. Let us know some of the exciting things that you’re up to in the next year or so.
If I can ever get my website working again, you can go to www.PainGeneticsLab.ca, which is increasingly misnamed as I increasingly have not been doing genetics anymore, or they can look me up on Medline or wherever you find scientific data.
The exciting things you have going on over the next year?
We’ve got some interesting things going on. We have more of these mouse-human social experiments in the offer. We have an interesting finding in both mice and humans related to the impact of pain on mortality. This also turns out to be sex-dependent for reasons that are strange. , Chronic pain does in fact increase your risk of death. It turns out that it does that in men but not women. We believe we have an explanation for that that we figured out in the mice, so I’m very excited about that story. We’ve got some fun stuff.
If you’re interested in learning more about Dr. Mogil’s work, you can find him at PainGeneticsLab.ca. You can hop over to DrJoeTatta.com/Podcast and find out all the information and read about many of the fascinating things that we spoke about. I encourage you to share this out with your friends and family on social media, whether it’s Facebook, Twitter or whatever social handle you use, and make sure you go onto iTunes and give us a five-star review. I want to thank Jeff for being with us.
About Jeffrey Mogil
Jeffrey S. Mogil is currently the E.P. Taylor Professor of Pain Studies and the Canada Research Chair in the Genetics of Pain at McGill University, and the Director of the Alan Edwards Centre for the Study of Pain. Dr. Mogil has made seminal contributions to the field of pain genetics and is the author of many major reviews of the subject, including an edited book, The Genetics of Pain (IASP Press, 2004). He is also a recognized authority in the fields of sex differences in pain and analgesia, and pain testing methods in the laboratory mouse. Dr. Mogil is the author of over 200 journal articles and book chapters since 1992, and has given over 280 invited lectures in that same period. He is the recipient of numerous awards, including the Neal E. Miller New Investigator Award from the Academy of Behavioral Medicine Research, the John C. Liebeskind Early Career Scholar Award from the American Pain Society, the Patrick D. Wall Young Investigator Award from the International Association for the Study of Pain, the Early Career Award from the Canadian Pain Society, the SGV Award from the Swiss Laboratory Animal Science Association, and the Frederick W.L. Kerr Basic Science Research Award from the American Pain Society. He currently serves as a Councilor at IASP, and was the chair of the Scientific Program Committee of the 13th World Congress on Pain.
The Healing Pain Podcast features expert interviews and serves as:
A community for both practitioners and seekers of health.
A free resource describing the least invasive, non-pharmacologic methods to heal pain.
A resource for safe alternatives to long-term opioid use and addiction.
A catalyst to broaden the conversation around pain emphasizing biopsychosocial treatments.
A platform to discuss pain treatment, research and advocacy.
If you would like to appear in an episode of The Healing Pain Podcast or know someone with an incredible story of overcoming pain contact Dr. Joe Tatta at firstname.lastname@example.org. Experts from the fields of medicine, physical therapy, chiropractic, nutrition, psychology, spirituality, personal development and more are welcome.