Erin Spain: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, executive editor of the Breakthroughs newsletter. Chronic pain affects 100 million Americans, some for a short period of time, others for a lifetime, many rely on opioids for longterm management of pain, but this doesn't help them get better and it could contribute to the current opioid crisis.
Vania Apkarian:, professor of physiology, anesthesiology and physical medicine and rehabilitation here at Feinberg leads a team of scientists focused on understanding pain. They've found that brain anatomy pays an important role in chronic pain, and they've discovered that placebos, in the form of sugar pills, can be effective treatments in some. Thanks for joining me today.
Vania Apkarian:: Thank you for inviting me.
Erin Spain: How would you define chronic pain? Does it usually develop after an injury?
Vania Apkarian:: So chronic pain is a complicated issue and it's been controversial for a long time its definition in fact, waxes and wanes in different ways. The simplest definition is that pain exists and you cannot control it, and in a sense pain that's persisting more than three months. Overall, in general. We think of it as chronic pain in more detail, essentially, the way we think about it is that once you, when you have an injury, for example, and the signs of the injury, the local inflammation and the tissue and tissue damage heal away, and yet the pain stays then that really is a chronic pain condition. Now there is a whole variety of chronic pain conditions that can happen on any part of the body. Um, and in many ways it's mechanistic properties have been highly controversial and hard to pinpoint.
Erin Spain: You mentioned chronic pain can be anywhere in the body, but it often as in lower back you see it?
Vania Apkarian:: Ah ha! So that's a good point. Low back pain. I was just reading it again yesterday, is the number one disability condition in the U.S., considering all other health conditions, it is the number six disability condition worldwide. So the scale of the disability is, is massive. Fortunately it doesn't kill people, but it definitely disables people. It impacts quality life. Of course, many people lose their jobs on account of it, and so it has a big financial impact on people's a living and it has a huge impact on healthcare costs. It one of the leading healthcare costs in the U.S. Chronic pain itself is probably the leading healthcare costs. It's more than half a trillion dollars a year of healthcare costs.
Erin Spain: Right now. When someone has the chronic lower back pain, how is it treated? What do physicians do for them?
Vania Apkarian:: Since we don't really understand underlying mechanisms, we don't have scientifically validated treatment options, so at least the World Health Organization says that there is no treatment better than any other treatment for chronic back pain and neither drug therapies, no surgical procedures, no alternative medical procedures, for example, acupuncture, exercise, all of those things or about equally efficacious and we don't know who to treat with what.
Erin Spain: So a lot of people are turning to prescription medication.
Vania Apkarian:: Yes, and and prescription medication is very popular means what large parts of society, although alternative procedures are also becoming popular, especially for chronic pain conditions. Yeah.
Erin Spain: Well, how would you describe the current state we're in here in America with both chronic pain and now with drug abuse as well?
Vania Apkarian:: Given that there is a huge number of chronic pain patients in the U.S. worldwide and given the large number of chronic pain patients who are treated with opiates in the U.S., the chronic pain population itself is a major source of opiate addiction in this country. It is probably the primary medical source of opiate addiction in the country and yet the science behind opiate treatment for chronic pain remains uncertain. It may help some people, it may not help a large majority of others. On the other hand, both physicians and patients tend to to use it mostly because it has immediate effects and those immediate effects in many cases has longterm non non beneficial outcomes that may people may end up being having addictive type responses to the treatment.
Erin Spain: And this is a big motivation for you and the work you do to try to find a different way to manage this pain or maybe even cure some day.
Vania Apkarian:: We definitely already involved in trying to understand what mechanisms underlying chronic pain and in fact my group of scientists in my lab have spent at least the last 20 years of studying what are the mechanisms for chronic pain and specifically what are the mechanisms for chronic back pain. We've constantly have done chronic back pain because it is the most common condition and in fact, when we started studying chronic back pain, essentially nothing was known on the topic. So today, I can state that chronic back pain compared to any other chronic pain condition is probably the best understood chronic pain conditions.
Erin Spain: Thanks to your people in your.
Vania Apkarian:: A lot of students who have spent lots and lots of years doing these studies and tanks were a lot of patients who have volunteered in a lot of studies over many, many years, so we've had hundreds and hundreds of patients volunteering in our studies. A lot of these studies have been studying the brains of these patients. We do brain scans in these patients and look at the properties of their brains and and see what is different in their brains from other people and then how these, how they change in people when they move from an acute pain condition to chronic pain.
Erin Spain: Let's dive into that a little bit. You were among one of the first to use imaging techniques on people's brains to start understanding pain. When was that? That was about 15?
Vania Apkarian::That was before I came to Chicago and so when I came to Chicago we had just started. We had just made the conscious decision that if we're going to understand chronic pain, we actually have to study chronic pain patients. It is something that still I go around, you know, advocating, you know, scientific communities and that in fact has been amazingly successful and fun and we have discovered lots and lots of signatures and about chronic pain in the brain and if we can now say that the brain of people who have chronic pain is a different brain, it's anatomy and it's functional properties have changed and have become the brain in chronic pain. Again, maybe not very surprising because pain is always in the brain. It's a perception, it's a subjective state and it's a negative subject, emotional, subjective state. None of us like having pain, not having not liking. Having pain is a stress on the wane and so that stress itself reorganize the brain. On the other hand, we have also been able to identify risk factors for chronic pain and use factor is a big issue. It is something we are all very keen on, on discovering because the risk factors are exactly the things we can probably control down the line and identify specific therapy options for them. Risk factors from psychological viewpoint, from the injury review point, have been studied for probably at least 50 years now. They are some risk factors along those lines, but they are small risk factors. Their prediction of outcome is relatively tiny. So yes, they influenced the outcome, but they're not things that they are, we are going to be able to target specifically. On the other hand, the excitement and the how in our lab over the last 15 years has been that every time we have looked for risk factors in the brain, we have seen some very large effect sizes and some of these things that have now been replicated by other groups. We have replicated so many studies back in animal models and so we have quite a lot of confidence about what we are finding and in fact I'll make another plug about NIH, just announced a huge about $50,000,000 proposal to make a very large study across the nation and probably worldwide to study the transition from acute to chronic pain. Basically inspired by the research done we have done over the last 20 years.
Erin Spain: So that's very exciting.
Vania Apkarian:: That's very exciting. But makes us even more busy because we have to write the scope grant proposals in the next few weeks as well.
Erin Spain: Wow. Okay. You're a busy lot going on in the, in the world of pain. I want to backtrack a little to some of those risk factors and then also what you are seeing inpatients in the brain anatomy that's different when they are more subject to chronic pain.
Vania Apkarian:: So not just anatomy but it is anatomy and function in the brain go together right there. That's the brain function is defined by its anatomical properties. That's how we think. And we create culture, et Cetera, right? So it's all based on the anatomical properties and how those anatomy interacts functionally with each other. So if we look at the brain of chronic back pain patients, for example, there are specific brain regions where the anatomy has changed and, and we think it's reflecting the information processing deficits that these people that develop over time, living with the stress of chronic pain. And in fact we also show that many cognitive tasks that you and I can do, chronic pain patients have deficits on them. So those things go hand in hand, both the anatomy, the function and cognitive abilities are all interacting and it's the stress of the pain. And as well as the coping. So any patient who has chronic pain has to create new strategies to cope with this thing that is there all the time that's creating an interference to anything that they have to do. I mean, you can, it's very simple to imagine chronic pain state, for example, think of you walking on the street with a pebble in your shoe all the time. Yes, exactly. And so you personality is going to change and you have to react to it and you have to cope with it and you have to live with it. And of course different people have very different reactions to all of those things. Uh, and in many cases, yes, they suffer with this for the rest of their lives. So it's a, it's a huge cost to society.
Erin Spain: Your latest study published in nature communications builds on a lot of your previous work and you showed that you can actually predict which chronic pain patients will respond to a sugar placebo pill based on their brain anatomy and psychological characteristics. Tell me about that.
Vania Apkarian:: Placebo is a really interesting topic and people in general can respond to placebo, and this has been studied for more than 50 years and in general, many other groups have actually shown the brain responses to placebo. So there's no question that it is a physiological response and in a sense one could simply think as an expectation and a consequence of that expectation process. On the other hand, the placebo properties in both the brain and psychologically has been studied for the most part in healthy subjects. The reason has been, at least spoused, was that that's, that's how we can identify the underlying mechanisms. And there's a fair amount of research on the topic. On the other hand, why do we even care about placebo? The placebo is a strange thing. I'm giving you a sugar pill and saying, okay, your pain is going to go away. That's, that's a strange concept. But there is a very long history in clinical trials of placebo response. So if you look at any clinical trial for any drug development, you have to have a randomized clinical trial where you contrast a placebo with the actual drug and you want to make sure that your response to the drug is better than just the placebo. And of course in every clinical trial there a placebo response. Not only that, in fact, if we actually look at the size of the placebo response, it is usually bigger than that of the drug, but of course the drug has to become superior. So it has to just beat the placebo for the FDA to approve to the drug for the specific condition that we're looking at. By and large, the scientific community had decided that this clinical trial based placebo response is not informative and it is simply a statistical artifact of clinical designs. And so it has no physiological interest. So we kind of try to challenge that concept and in fact said no, no, no, at least in chronic pain patients, where the brain is actually reorganizing specifically with the pain itself, these people have been subject to the health environment for many, many years. Either liking the healthcare that they're getting or disliking their experience. All of these things bring in their massive expectation of how they would respond or not respond to a placebo pill in that sense, at least in this population, these responses should be physiologically well-defined, predictable apreorie, and in a sense they should underlie personality, psychology, behavior and brain signatures that we should be able to identify. So that's the concept that we sort of started with and this paper is in fact a confirmation that that concept has some bearing and in a sense that we could identify a whole variety of brain properties before we exposed the subject to anything that predict down the line, who will respond and how much they will respond to sugar pill.
Erin Spain: Who are these people? How are their brains different? And what about their personalities or their psychological profile makes them more likely to respond to the sugar pill?
Vania Apkarian:: So we specifically against studying chronic back pain patients because that's our expertise. We know the properties of your subjects best and in fact we relied on some earlier studies. We have done, smaller studies that actually can guide us as to what properties to to hone into. And so we recruited, I don't remember the exact number, 60 patients into the study. The study is relativity complicated. It's complicated to make it a rigorous in a sense there's an arm of no treatment at all where we bring people in and don't do anything with them. That's an observational, no treatment arm that in a sense controls for the nonspecific effects of the placebo you're getting from a classical viewpoint one would assume that all placebo effects in clinical trials would be the same as the no treatment arm, so that's a control for that condition. And then the subjects are a simply randomized into either receiving placebo or receiving an active drug. Before we do any of these things, we studied their personality. We collect a whole variety of data about their personality and their brains, and then we simply treat them for, for a period of time. We take the treatment away to see if, if that would change their outcome and repeat this multiple times. The treatments that went on for about six weeks altogether. There are many other complicated details that I will not bore you with, but by and large are in this study we are looking at the properties of the brain, anatomical and functional properties of the brain and personality properties that all of which would be predicting before the subject is exposed to the pill, their outcome with the pill. I should emphasize that the instructions we give to the patients is important. And in a sense we tried to replicate a standard randomized clinical trial design, just like every clinical trial where one is trying to develop and you do organic test its efficacy. I don't know if they in the placebo group or not. They have no idea. Everybody is double blinded, neither the subjects. No. The experimenter, no. The PI knows what subject is in, is in what group. Moreover, the subjects are given completely neutral The participants are given completely neutral instructions. So we tell them you are going to be given a drug, it may or may not be efficacious for you and you may be given either a non effective drug or placebo and always standard treatment and that's it. And then we simply follow them in timed and look at their responses. At the end of the study we also asked the patients, the participants, what was your expectation? And then we compared their expectation with outcome as well. That's also interesting because their expectation and the outcome have no correlation with each other in this case. Yes. So in a sense on like healthy subjects where we think placebos primarily and expectation to even condition here, we think it's being driven by their brain anatomy, by their personality, independent of the expectations. So in a sense, a, it's a really, it's a concept that placebo is a useful in these patients.
Erin Spain: In this particular study you did find that brains were different and the participants and you're able to sort of pull out which folks you thought would respond to the sugar pill, right?
Vania Apkarian:: That's exactly, that's the main points. So that in a sense, both personality and brain anatomy and weigh in functional properties, the amount information these people exchange across brain areas, all of them are uniquely different between those who are responding to the placebo pill and those who are not responding. And let me spend a minute discussing the difference between the two. The ones who are not responding don't show any response at all. The ones who are responding, they have a pain relief of about 30 percent. That number is important because 30 percent is clinically significant and it is comparable or even superior to any drugs out on the market that we sell to these patients. So the size of placebo in the placebo responders is as good as any other treatment available on the market.
Erin Spain: Opioids and morphine?
Vania Apkarian:: Everything, all, all drugs out there, all drugs, all treatments, exercise, yoga, meditation, surgical procedures, surgical procedures, they're not any better than what we are showing. So in a sense, just that fact says that in the future when people are trying to develop treatments, they have to demonstrate that they can outcompete the placebo responders placebo response. Okay, that's a little more complicated. It's not just the placebo response, because when you simply look at placebo response, this data shows 50 percent of the people that respond to placebo. Fifty percent don't. Okay, so the placebo response in the population in general is 50 percent under appreciated. If you actually look at patients who who are responding to placebo, it gives us a 30 percent pain relief.
Erin Spain: Does this finding help put to rest some of the conversations out there about the placebo effect in some of the controversy about it now that you have some actual data to show?
Vania Apkarian:: Well, we'll see. I mean society is complicated. I'm not going to say we have answered it and everybody's going to believe it. Right? It takes time. Besides just the size effect. Yeah. The fact that we can ask who your are, identify responders versus nonresponders gives us a very exciting pathway forward. Right, and in fact we're hoping in the next few papers we will actually show that perhaps we don't even need to do this brain imaging because the brain imaging based parameters can be mapped back to the subjects, personality, psychology, behavioral assessment tools and maybe they will be sufficient for us to identify placebo responders versus nonresponders and once we are there, then there is no reason why a physician can not prescribe this object a placebo pill and say this field, although it is an inert pill, will affect your psychology. You will respond to this pill. And in fact I know how much pain you're really, if you're going to get with this pill, given your response to these set of questions, for example. So that's the future we would like to go to. And that is a really exciting future because in many ways, you know, it at least gives these patients their holiday from all these other treatments that they are exposed to more side effects with all these side effects. Exactly. And, and in a sense, or even if, if we don't know, for example, how long such a treatment would be would work, I suspect in time you will wane away. We are not going to cure the chronic pain by placebo. It's not, it's not a cure. It is a psychological response to the, to that, to that, to that pill. And so in time it should wane away and then you have to replace it with something else. But even that by itself would give us a nice window with in which I think it will be completely ethical to actually tell the patients what you are giving them and they should still respond to it because they have all the anatomy and physiology behind it to response to the procedure. And so that's the benefit to the, to the patient. The other half of this is also the benefit to the whole industry of drug development. In a sense we pushing them to be more precise and to take into consideration that placebo response a events and that they have to to actually assess patients who are entering into the study as to whether they are placebo responders or not before they do any clinical trials.
Erin Spain: And drug companies and physicians for that matter are more under the microscope than ever before with this opioid crisis that's happening in America. Can you just talk a little bit from your point of view about what's happened in recent years and what can the scientific community do to help reign this in.
Vania Apkarian:: Our position has been, and this is maybe segues into our new grant I just got funded, has been that in fact if you look at the brain properties that put people at risk for chronic pain and are predictors of chronic pain, they are the same brain circuity that put people at risk for addiction to opiates, so. That's a concept that we are actually pursuing both in animal and in human studies and we just got funded for it to start a center to specifically study the interaction between chronic pain and drug abuse, specifically opiate addicted effects on the brain anatomy, physiology, both in humans and in animal models.
Erin Spain: This new center is funded by the NIH, first of its kind.
Vania Apkarian:: It's the first of its kind and we're very excited. We just got the funding a few weeks ago. They will be more things happening. We're hoping to create the center and actually have an impact both from a science viewpoint, from a clinical viewpoint, from teaching education and engagement of patient population, patient involvement in our center and hopefully come up with ... I mean, the actual concept of the center is to develop methods and tools both to identify who are at risk, for example, for addiction, who are not at risk? And maybe is there a subpopulation that in fact can be treated adequately with opioids and they're happy and satisfied and don't develop signs of addiction and other group who are vulnerable and should be spared and not be given opiates. Part of the center is also to in fact very aggressively develop, given the pathways and the mechanisms we know or we have discovered, for the condition, alternative medicine. It's all in the pipeline.
Erin Spain: Read more about Dr. Apkarian's recent discoveries at news.feinberg.northwestern.edu