Published: Aug. 6, 2019

LISA: Welcome to Brainwaves, a new podcast about big ideas produced by the University of Colorado Boulder. I'm Lisa Marshall.

This week, we're talking about pain. According to government estimates, about fifty million Americans, or one-in-five adults suffers from chronic pain. Many turn to opioids for relief. 

Tragically, many become addicted. Every day, about 130 people die from an opioid overdose. But what alternatives are there?

Today, we'll discuss a promising new therapy already in use in pets and people. We’ll also talk about the role the mind can play in perpetuating or easing pain.

So we'll start this week's show with an interview with Linda Watkins, a distinguished professor of psychology and behavioral neuroscience at the University of Colorado Boulder. Welcome, Linda. 

LINDA: Thank you.

LISA: So you've been studying pain, the drivers of pain and some of the potential ways to treat pain for a long time, decades. So my first question for you is, can you talk a little bit about what the prevailing assumptions were when you first got into this field?

LINDA: When I first got into this field, they had just discovered opiate receptors. It was that long ago. And the prevailing views back there was that it must all be because neurons change their activity, and neurons are responsible, solely responsible for chronic pain and that opiates were going to be good for treating such pain. And that view has really changed over the last number of years.

LISA: What are some of the problems with the opioids both, I think a lot of people have heard about about the addiction problems, but there are other problems that you've discovered even in your own lab.

LINDA: Oh, absolutely. I mean very broadly speaking, not only the addiction issues, but also the very bad side effects. Severe constipation, hormones get shifted, all kinds of changes, because there's opiate receptors throughout your body and throughout your brain and spinal cord. So if you're taking an opiate, it acts everywhere. 

But in addition to that one of the things that my lab is discovered recently is that they have a very nasty side to them that people had not expected. And that is that if you give opiates early after trauma, early after surgery, for example, then you will actually make chronic pain worse and much longer lasting. That it interacts with the pain itself and causes the whole chronic pain problem to become much worse.

LISA: Wow. Your lab has also stumbled upon or helped to discover another driver, potential driver of chronic pain that was unexpected. Can you talk a little bit about that?

LINDA: Yes, well originally people always thought it was only neurons that were responsible for driving pain but we and others started to think that that we had to have been missing a fundamental part of what chronic pain is about. Because if you think about the drugs that are used to treat pain, if you have surgery, you break a bone, and the doctor gives you opiates for your acute pain, they work great.

But if you become a chronic pain patient, now opiates fail. In fact, all the drugs fail. The definition of a good drug for chronic pain is that it fails 80 percent of the time. It works on very few people, and even on those people, only partially are they effective in terms of suppressing pain, and they all come with very bad side effects.

So, we started thinking that it's got to be another player in pain. And what we and other people discovered was that there are non-neuronal sources of pain. Your immune system contributes your immune-like glial cells and central nervous system contribute. And they are very important both in the creation and maintenance of chronic pain states. 

LISA: And what does the glial cell do? I know that when you're sick, your glial cells really rise up and act up. 

LINDA: Right, the glial cells are the immune system of your brain and spinal cord. And if you think back to the last time you had a really ugly flu, and what you're going through, you were running a fever. You wanted to sleep all the time. Even the bedsheets hurt.

Your brains creating all of that. Your brain’s creating that in order to help you fight the infection, and the glial cells are actually driving all of those changes, which you associate as being with the flu. And that's their normal job. That's what helps you survive, but when they get activated under conditions of chronic pain, that's pathological activation, rather than the normal activation. And now things go very, very bad.

LISA: So it sounds like it's almost a natural ancient survival system gone bad.

LINDA: Yes, that's exactly how we think of it.

LISA: How are you using this information right now?

LINDA: We've been focused on trying to find new ways to target those cells, because none of the chronic pain drugs that are out there do that. And we've come up with a non-viral gene therapy that drives a natural protein, an anti-inflammatory protein, called interleukin 10, very potent, and we are now in human clinical trials has progressed that far. 

In order to—in this, in this clinical trial to be targeting human knee osteoarthritis, and to use this localized gene therapy in the affected join itself to keep a localized anti-inflammatory natural protein to suppress pain and disability.

LISA: If this works, what kind of an impact could it have on the opioid epidemic?

LINDA: Tremendous ones, I hope. Because, what it would do is by relieving the pain and disability, you don't need the opiates, number one, and number two, anything we can do to find way around using opiates for chronic pain is a good thing. They work no better than the other drugs, but none of them work well.

LISA: Well, thank you so much for your time and we're happy to have you here.

LINDA: Thank you.


Now let's turn to Brainwaves’ Dirk Martin for a look at how professor Watkins research is already having a real-world impact for dogs and their guardians.

DIRK: Shane is a 10-year-old McNab Border Collie that acts more like a puppy.

TARYN: People keep thinking he's a puppy, and you know he's almost 11 years old.

DIRK: That's Taryn Sergeant, Shane's guardian and best friend. 

If Taren sounds amazed, she is. Two years ago, Shane could barely walk after being hit by a car. The impact tore through the cartilage of Shane's left shoulder. Arthritis and scar tissue set in.

TARYN: Before he was hit by the car, I mean he was almost an out-of-control dog. He would jump over fences at dog parks and disappear for 20 minutes back. And after he was hit by the car, I needed to carry him up three flights of stairs every time he had to go to the bathroom for about eight weeks. 

Right before the treatment I couldn't take him on walks for longer than about ten minutes, sometimes having to carry him back to the house.

DIRK: The treatment that Taryn is talking about is the result of a gene therapy invented by CU Boulder’s neuroscientist Linda Watkins. About two years ago, Shane received a single shot of a long-lasting immune modulator known as XT 150, and now he is nearly pain-free.

When did you first see signs that this was actually working?

I would say within about three weeks. You know I noticed a difference, but just the fact that over a couple of years I've noticed even more of a difference, I mean he's where he was taking a pain medication every day and still being sore and not able to go for long walks to, I think now it's been over two years, and he's only taking one twice a week, and honestly could probably go even longer than that. I'm really passionate about this study, and everything it's done for us.

DIRK: The gene therapy is based on a hunch Watkins had decades ago. Instead of focusing on neurons as messengers for pain, Watkins looked at glial cells, which are immune cells in the brain and spinal cord that make people ache when they're sick or injured.

Activated glial cells produce inflammatory compounds, which drive pain, but they also come with a built-in shutoff valve, a compound called interleukin 10, to dampen the pain process they started. 

But for some reason, sometimes glial cells stay switched on, creating chronic pain. Watkins devised a shot either into the fluid filled space around the spinal cord, or the site of an inflamed joint, that delivers DNA to cells instructing them to ramp up production of the body's natural painkillers.

ROB LANDRY: I see a lot of patients that have degenerative joint disease. Based on her science with the immune response to pain, it was a no-brainer for me.

DIRK: That's veterinary chronic pain specialist Rob Landry. He teamed up with Watkins to launch the research study in dogs at his animal pain management clinic. When did you realize that this was going to work?

LANDRY: Immediately. With the first few dogs we put it actually directly in the spinal cord and saw a pretty impressive response. No adverse events. Zero adverse events, but complete reversal of a lot of their struggles. And then we expand this to joint disease, and the changes have been pretty amazing. 

Shane is probably the longest one out I've… and he's actually getting better. I think it's something that is revolutionary therapy for degenerate joint disease in aging animals, and animals age quicker than we do.

DIRK: Revolutionary it may be, but all Shane knows is he can now run and play like there's no tomorrow.


LISA: Now we're going to turn our attention to another exciting field of research: looking at the role that thoughts and emotions can play in fueling pain. We're here with Yoni Asher, a graduate student in neuroscience and clinical psychology. He's currently conducting the largest brain imaging study to date to look at mind-body approaches at addressing pain. Welcome, Yoni.

YONI: Hi, Lisa thanks for having me.

LISA: So I'll start by asking you the same question we asked our previous guest, which is how has our understanding of what drives pain really changed in recent years?

YONI: Our understanding of what drives chronic pain is undergoing a paradigm shift, in my view. In the past years, we used to think that chronic pain was driven primarily by problems in the body. If there's a feel of chronic shoulder pain, there's a problem in the shoulder. If you have chronic knee pain, there's a problem in your knee. 

What we've been learning, and recently from research, is that the brain can play a central role in chronic pain. And in some cases, the knee or the shoulder can be completely fine and the chronic pain is perpetuated by changes in the brain.

LISA: So, can you give me a couple concrete examples of where we see that?

YONI: Yeah, one story we like to share comes from, you know, to illustrate the point, a couple years ago, there was a construction worker in England who jumped off scaffolding at the construction site. When he landed, he saw a nail poking up through his boot, and when the he saw that he had a tremendous surge of pain, and had to be taken immediately to the hospital. He was sedated twice along the way because of the pain. And when he got there, they pried off the boot and found that the nail had perfectly gone between two of his toes, and once he saw that that there wasn't a scratch, not a drop of blood, the pain disappeared, and he walked home. 

And the way we explain that his brain believed that his body was in danger. He had a nail coming through his boot, and it created the pain, because pain serves as a danger signal. But once he saw that there was no danger, the signal the danger signal turned off.

LISA: Wow. Well, so, pain is a danger signal. I know you do brain imaging studies, so how does chronic pain look different in the brain than acute pain? That I stubbed my toe pain?

YONI: There are some really compelling studies coming from the laboratory of Vania Apkarian at Northwestern that have looked at the difference between acute and chronic pain in the brain. And what they found is that while acute pain is associated with activity and say somatosensory pathways that produce that kind of like, the ‘I stubbed my toe pain,’ like you said. 

Chronic pain seems to be more associated with brain activity in medial prefrontal and stradle pathways that we know from other research are very involved in learning and emotion, and in one amazing study that they did, they actually followed people as immediately after a back injury, and followed people for two years. And in many of them, that pain chronified, and what they saw is that in these patients the pain actually shifted.

Immediately after the injury, the pain was related to activity in the somatosensory brain regions and two years later, once the pain had become chronic, that pain had shifted to these medial prefrontal regions related to emotion and reward. So, they really saw the brain learning the pain.

LISA: Does that mean that the pain is just all in your head? If it's in the region that is involved with emotions and thoughts, and not necessarily tissue damage?

YONI: That's a great question. The pain is always real. What we want to know is what's driving the pain? Are there problems in the body that's driving it? Are there problems in the way the brain is wired that are driving the pain?

One metaphor I like to use to explain this is, imagine you're driving your car and the engine light goes off. So you take the car in to the mechanic, and the mechanic checks out the engine, and comes back to you, and says, “Hey, Lisa the engine’s totally fine. Not a problem at all in the engine. What I’ve found though, was that there's a problem in the wiring connecting the engine to the back of the dashboard. So the engine light was stuck in the ‘On’ state, even though the engine’s totally fine.”

So, all we have to do to fix this is to change the wiring, so the dashboard accurately reflects the state of engine. So the danger light isn't going off when there is no danger.

LISA: And how do you do that? How do you turn off that false alarm if you're someone who suffers from chronic pain?

YONI: We've been working with our collaborators, Alan Gordon and Howard Schubiner, in developing a treatment that targets that. And we just finished a clinical trial and the results are very, very promising.

And two steps: first, diagnosis. Figure out what's driving your pain. Are there problems in the body, or are all the tests coming back negative? Does the body seem fine, as far as we can tell? And once you've established that the pain is likely to be what we call centralized pain due to central nervous system activity, say the brain, then the heart of the treatment is teaching yourself that the sensations are safe.

And just for starters, you can just imagine that, “Oh this pain is a false alarm,” you know the fire alarm is going off, but there's no fire, and reassuring yourself.

LISA: How can you get rid of that association that says, “This hurts?” 

YONI: It's often a longer process. In our study, we had eight sessions of psychotherapy, but for some people it can be quick. And if you can shift the way you're thinking about it—I'm safe, this sensation is safe, and you can start with self-talk, just talking to yourself. You know it could be that for some people standing up, it hurts their back, so just saying to yourself, ‘Standing is safe, my back is totally fine to stand.’

LISA: Well, it sounds like there's a lot of promise there. Thank you so much for sharing your research with us, and we were really happy to have you.

YONI: Thanks, Lisa, it’s been a pleasure.


LISA: To learn more about Yoni's research go to and search for “unlearning pain.”

That's it for this week's edition of Brainwaves. Thanks for joining us, I'm Lisa Marshall. Listen in next time when we talk about the science of humor. What makes things funny, anyway?

Thanks to Andres Belton for creating our introduction. Dirk Martin and Paul Beique produced today's show. Andrew Sorensen is our executive producer. See you next week on Brainwaves.