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Science Talk

The Science of Pain

Stanford University pain expert Sean Mackey talks about the modern take on pain, how to treat it, why treatment is so important, and the relationship between pain and empathy. Plus, we'll test your knowledge about some recent science in the news. Web sites related to this episode include;

Podcast Transcription

Welcome to Science Talk, the weekly podcast of Scientific American for the seven days starting December 3, 2008, I'm Steve Mirsky. If you hate pain, you'll love this week's program. We will talk with pain expert Sean Mackey. Plus, we will test your knowledge about some recent science in the news.

A few weeks back I was at a conference for journalists called Science Writers 2008 at Stanford University. One of the speakers was Sean Mackey. He is a former engineer who then went to med school and is now associate professor and chief of the pain management division of the Stanford University Medical Center. He is also the director of the Stanford Systems Neuroscience and Pain Lab. He gave a talk about pain after which daily podcast contributor Corinna Wu and I double-teamed an interview with Mackey. First, I want to play a few minutes of his talk having to do with pain and empathy, after which we will go right to the conversation with Corinna, me and Mackey.

Mackey: I am also intrigued by this answer to the empathy. It has been verbally defined. One definition is: the observation of an action or perception or emotional state in an individual that activates a corresponding representation in the observer. Let me give you a down-to-earth example, and this is what primarily motivated me in this. I have an 11-year-old son now. He was five at the time that this all started. I was picking him up at day care and he was running across the linoleum floor to come and give me a big hug and he was running too fast; he is a big physical kid and he fell down on his knees and he slid across the linoleum floor, hit his head right into the wall and down stalled. And you could have heard this gasp through the room, just like what you did. There was a huge gasp from all the parents. So I went over and checked his head and he had this huge goose bump, you know, huge tomato growing on his head; I was just making sure he didn't need to go see a neurosurgeon, he didn't have a step-up and he didn't. So [I] high-fived him and said, "Way to go" and he laughed, and we had a good laugh, and I realized at that moment that hurt me more than it hurt him. That hurt me a lot more than it hurt him, and I was asking myself, "Did I just experience brain activity in the same areas of my brain in seeing it happening as he did in actually experiencing it?." So I came back and decided to study it. So we hypothesize that when you see somebody in pain, that you engage the same brain areas as if you experience[d] it yourself; that, we believe, is the fundamental basis of empathy, so what we did is we applied a noxious stimulus to subjects and then we got onto these underground Web sites and we found a variety of different videos that showed things like that.

Steve: At this point, Mackey showed some really unpleasant videos from football games, the kind where a guy's leg is bending in a direction it's really not supposed to go, things like that.

Mackey: I'm sorry. I was supposed to warn you. (laughs) Let's see that again. How many of you felt that? Okay. There is always a number of people in audience that feels that in their ankle also and the intriguing thing about that is that those of you have feel it in their ankles are people who have had prior ankle injury. I think this is another one here.

Steve: That can't be good. You are not going to show Joe Theismann, are you? (laughs)

Mackey: So the gentleman here just asked that if we were going [show] to Joe Theismann, that's a great question; and you know what, we decided not to use Joe Theismann, why?

Steve: It's too much to bear.

Mackey: Ah! It's too much for you, but the thing is it turns out that Joe Theismann's clip is the most showed sports clip, I think, in the history. Too many people have seen it, they have become desensitized; but I got to tell you, we just published two papers on this. I mean, they just came out and in one of the papers we opened up describing the Joe Theismann clip—you know, so if you go and look at our paper, we'll be happy to send it to you—we opened up describing that Joe Theismann clipping, how people felt about it afterwards.

Voice: I want to see; what's the clipping was about?

Mackey: Oh! It shows Joe Theismann getting a compound fracture of his leg, just being crushed. I can't remember who whacked him.

Steve: Lawrence Taylor.

Mackey: Lawrence Taylor just took him out. It was just an extraordinarily violent hit. He was a former quarterback.

Voice: How long ago was that approximately?

Steve: Twenty years ago.

Mackey: Yeah. It was just in the '80s.

Steve: Yeah.

Mackey: I think it took place in the '80s, but it left an indelible mark on everybody who watched football. I mean, they all felt that and it was played over and over and over again. So we elected not to do this. What we found is that indeed the same areas the brain involved with experiencing pain are involved with seeing other people in pain. It was a tremendous overlap, particularly in these emotional and cognitive areas of the brain.

Mackey: This concept of empathy is constructed, it binds all of us in society that when we see somebody in distress that we similarly feel that persons' distress and we want to reach out and help that person. It is an area of tremendous interest in the research community and we want to better understand, what are the neurophysiologic underpinnings of this. In other words, what's going on our brains when we see somebody who is in distress, somebody who is in pain? And so that was part of the motivation for this. I think I related a story about my son, having an injury and my experiencing his pain probably [to] a greater extent than he experienced it himself and that clearly was also a motivator. So we set out. This was a collaboration working with Kevin Ochsner who is now at Columbia University and Kevin is a wonderful neuroscientist who played a key role in running this study and looking inside the brains of people to understand what happens when we see somebody in pain and compare that against when we experience that pain ourselves.

Corinna: So can you tell me about the study? How did you conduct it, how many people did you look at?

Mackey: We looked at two different aspects of the study, one in which people were experiencing pain themselves; and so what we do is we take healthy volunteers and we apply a noxious—in other words, a painful—thermal stimulus to their arm and we give it at such a temperature that it works out to about a [seven out of 10] pain that they are experiencing on their arm, where 0 is no pain and 10 is the worst pain imaginable. And then what we also do is we give them a series of videos that we show of people in traumatic and painful events, things where they are breaking their arms, breaking their legs, usually sporting-type injuries. And we've now all seen these; when we did the study, we had to go on to these underground Web sites to be able to mine them. And then what we do is we have them experience pain and then in a separate time during the scanning session, we show them these videos and we are scanning their brain during the whole period of time and we look at the areas that are unique to pain, when you are experiencing it yourself and then also when you are seeing somebody else in pain.

Corinna: And what did you find?

Mackey: Well what we found is that there is a tremendous amount of overlap in those brain regions involved with the both the experience of your own pain as well as when you're seeing somebody else experience pain and those brain regions are areas like the anterior insular cortex. This is an area that's involved with interoception, kind of our internal state of bodily awareness. So, when we are self-monitoring, how we're feeling about something, that's an area that's heavily activated and engaged. Also the anterior singular cortex was heavily engaged in both of these conditions, such that this is an area involved with emotional processing, attentional processing and also correcting errors when we are experiencing something that doesn't feel quite right and we need to do something about it. So these areas were both overlapping and engaged with both of these conditions. We also found similar areas and some of the frontal cortical regions involved with our own experience of pain and then seeing somebody else in pain; but there were also some unique areas that ultimately we were able to tease [a]part in our studies. So, pain itself tended to engage more of the sensory systems of the brain, areas like the somatosensory cortex that is engaged whenever you have an acute pain stimulus. Also some of the brainstem regions that have been found to be involved within inhibition of pain, so that when we, for instance, we are distracted away from an event or when we're trying to turn down internal bodily pain, those descending systems tend to get engaged; and we found that was more unique for own experience of pain that we saw somebody else in pain.

Corinna: And how would we as humans benefit from being able to empathize somebody else's pain?

Mackey: Oh! I think without empathy, you know, my senses probably would have died out as a species a long time ago. Think about it. If we didn't come to the rescue of those who were in distress, those that we loved, people would have just died. So it is this construct that binds all of us in society. So I think empathy is extraordinarily important and it's something that has developed through, you know, mammalian evolution and is extraordinarily beneficial to all of us, and I think it's the absence of empathy, when we run into the problems that we see in society. So, you know, the absolute absence of empathy, you know, we run into sociopaths and psychopaths. People who don't engage that empathic response, who don't have those feelings when they see somebody who is in pain and we can all point at people through history that are examples of what has happened when there has been a total lack of empathy and those people are in positions of power.

Corinna: And you mentioned there was one subject in your study or, person in your study, who actually showed no response, is that right?

Mackey: Yes. So as a side note, we had one subject who didn't show much in the way of brain activity at all to these painful videos and we went back and interviewed that subject and found out that he was an ex-convict. Now, you know, I'm careful about drawing any conclusions about that in a more global state and those types of things need to studied more systematically, but I think it is an intriguing finding.

Corinna: I mean, does that suggest, I mean, some kind of diagnostic value to, you know, seeing if someone can empathize with another?

Mackey: And I want to be real careful about extending our findings our any other people's findings to using fMRI or imaging as a diagnostic test in 2008. We're still a long way away from that, and I mention that with such strong emphasis because I'm becoming more and more concerned about the use of neuroimaging tools being used inappropriately as diagnostic tests in the medical field as well as in the legal field, in trying to determine does this person have pain, does this person have a psychiatric condition? I think we're a still long way away from being able to use it in that context.

Corinna: Are there further studies that you are planning in this to investigate this?

Mackey: So we are looking at ranges of empathy in people and being able to characterize empathetic responses within those groups of people; and then also there has been some recent discussions about people with spinal cord injury, for instance, and whether or not you need to have incoming sensory input from the body to be able to actually engage an empathic response. And so there has been some discussions in our group about going down that direction because that might actually help provide additional information as to these neurophysiologic underpinnings of empathy.

Steve: That's really interesting because it gets into, you know, how much a robot could ever be like a human; or well, how much does a human who has lost mobility still fully— I don't mean to denigrate paraplegics—but how much is their experience of, you know, their sensory experience, how much is that now divorced from humanity as well?

Mackey: Yes, where this came up is I've got both some friends as well as patients that I [take] care of that have spinal cord injuries, high spinal cord injuries, and I have simply asked them, you know, can you compare and contrast when before your injury and after your injury when you see somebody in a traumatic situation, in a situation in which you are experiencing pain, does your response to it change? And at least anecdotally they've just suggested that, yes, they are not getting that kicked in the gut feeling that they used to get before the injury. Now I got to tell you, that's a long way away from actually having definitive results, but at least it helps us pose additional questions to understand it.

Steve: I wanted to talk about the brain's reaction to pain. Over the last couple of decades there has been a growing realization that you don't just experience pain, your brain actually rewires your whole nervous system as a reaction to it that can be permanent. And can you tell us something about what's going on in the brain as we experience pain, especially chronic pain?

Mackey: So we've now all heard of this concept of neuroplasticity, this idea of the changing brain, the concept of networks and neurons rewiring and changing their function in the face of chronic pain; and we're beginning to appreciate that this area of neuroplasticity is important not only in perhaps causing pain, but also in maintaining pain and that, you know, patients with chronic pain, these neuroplastic changes that occur are not turning off. Let me take a step back. We know that even in an acute situation, that in an acute pain situation we get neuroplasticity. We get changes within the spinal cord in the brain even after an acute injury and it happens in each and every one of us. We sprain an ankle, we cut our hand, after a period of time, over period of hours of a course of the day, we get neuroplastic changes and it sends a signal to us to protect that injured limb; and it's highly beneficial because if we didn't have that message, that signal, that behavior that was being generated, we would go out and continue to injure that limb over and over again. Now in a normal situation, those factors that cause the plasticity turn off and the limb is perceived as being healthy and normal again. In a chronic pain situations, those neural switches are not turning off and we believe that they are continuing to grow, to continuing to expand; and in many cases, expanding well beyond the area that was originally injured, encompassing other limbs. And we think that that is playing a role in conditions like fibromyalgia and other conditions that involve global, widespread pain. There have been studies in which brain atrophy has been looked at in fibromyalgia patient[s]. Cathy Bushnell did a lovely study, and elegant study looking at changes with the brain in the singular cortex in the parahippocampal gyrus, which is involved with a stress response and showing shrinkage of the brain. Vania Apkarian did a [an] elegant study looking at low-back pain patients and showing changes in prefrontal cortical regions of the brain and insular cortical as well as anterior singular cortex areas of the brain involved with low-back pain. What was most intriguing about his study is that the prefrontal regions of the brain that were shown to shrink were also the same areas that are engaged in things like working memory. (This is what used to be referred to as short-term memory.) And so once again, maybe these cognitive deficits that our patients are experiencing in the face of chronic pain, maybe they are not due to the medications we put people on; maybe it's not just due to depression, maybe it's due to the chronic pain itself that's causing this rewiring within the brain. Now the question comes up: What do these brain changes really represent? What does shrinkage in the brain represent? And the truth is we don't know the answer yet. We have some intriguing guidance from the depression literature in which they've done autopsy studies in people who were scanned before passing away, and they did biopsies of the brain. What they found, at least in depression, was that it wasn't neuronal cell loss that was accounting for the brain shrinkage; it was loss of glial cells, these supporting cells that are now getting a tremendous amount of attention in the area of pain, as well as other disease conditions. Now, we still need to do those types of studies in pain, but at least it gives us some guidance as to what may be going on. The follow up question to that would be: "Can we reverse these changes? Can we actually turn back the clock? Can we turn back the changes in the brain to something in a more normal situation?" And we don't have the date on that yet. Our group is running studies to look at whether those changes are reversible. Other groups are also running this, and we're all hoping that with appropriate therapy not only can we reduce the pain and suffering in our patients and its impact on society, but that we will have objective measures within the brain to correlate with those changes.

Steve: Does this work imply that we should really be more aggressive in pain right at its outset?

Mackey: Absolutely. We realize more and more that it's better to prevent the pain rather than to try to treat it after the fact, rather than trying to get that horses who has already left the barn. And there are a number of studies now that show the preventative measures can have a big impact in reducing the number of people who go on to have chronic pain.

Steve: There is a virtue, I think, there is a cultural kind of virtue in gutting it out rather than taking medications; and should we just, should we get past that and just start popping those Advils as soon as you sprain your ankle?

Mackey: There is this message in society [that] we do have to suck it up, that we do have to tough out the pain; in that, you know, we are a better person as a consequence if we do so and there is some truth to having the internal tenacity to dealing with the pain and continuing to work in the face of pain. However, I want to separate that from the idea of appropriately treating the pain in an acute situation and making sure that we're doing everything we can to prevent that acute pain episode from going on to being one that's more chronic. What we're trying to figure out right now is why, for a given person, the vast number of people who have surgery in our society or who have an injury, why do the vast number of those people go on and heal perfectly well, who have no chronic pain afterwards; but there is a subset of people who do go onto have for a given injury longstanding chronic pain issues? We know that some of those issues are related to genetic differences, you know, and we can't choose unfortunately our parents and the genes they've passed down to us, but we can change some of the environmental influences. And so we're trying to understand both those genetic factors as well as the environmental factors that go on to cause somebody to have chronic pain after an injury or after a surgery and then being able to focus the treatments that can ultimately reduce that incidence of chronic pain; and then hopefully also the amount of medications that people need to use after surgery. Because we're seeing just an epidemic of prescription opioid use in our society. You know, we look at Vicodin, which I believe is prescribed to 135 million times in America alone—I think it's the most prescribed medication in society. You know, we're seeing this medication use more and more and more, and we want to make sure it's being used appropriately; but we know that they are a number of people who go onto misuse these medications and abuse these medications and so this is where pain is very tightly linked with this idea of addiction and addiction to prescription opioids, and that's why we need to do a better job in figuring out who are the people that are going to go on to have chronic pain, who are the people that are going to go on and use these prescription opioids and put the appropriate treatments in place.

Steve: Our opioids, especially in, say, postsurgical situations, are they still sometimes under-utilized though, leading to this next stage where somebody weeks later might then be on them and wind up abusing them?

Mackey: Yes, so there are arguments about using these medications earlier rather than later, to try to stamp out the pain early on rather than try to deal with it afterwards; and opioids play a very useful part of that treatment. There are now other medications that we've learnt that can also be very effective in that acute setting. The typical things that people are used to hearing about things like nonsteroidal anti-inflammatories, the ibuprofen, the Naprosyn, the Tylenols; but there is[are] also new medications that have been used in the acute pain setting that have also been found to reduce pain after surgery; and things like the gabapentinoids—which go under the name gabapentin or pregabalin—have been shown to be very effective in that postsurgical period of time. Now, these medications are used off label, but the studies are showing time and time again that they've been very effective for the treatment of acute pain.

Steve: Big places—like Stanford, like Sloane-Kettering in New York—have established pain centers, so how, though, has this idea that pain as [is] its own condition, how has that translated to society at large to this point?

Mackey: Well, I think first of all, it has helped a lot of patients from [a] validation standpoint; to recognize that pain is a disease in and of it's own right has helped patients that have been suffering in silence, that have been desperate for some degree of validation of their pain problem; and has given them some sense of security and some sense of confidence so they can go out now and seek better treatment. Because the problem with pain ultimately, with chronic pain, is that they still have pain despite the fact that the tissue has healed. And so often times there is no obvious source or site of the pain, but these people are still suffering. And so I think recognizing the pain as a disease in its own right has gone a long way from a patient's standpoint. It's also gone a long way from a government and a societal standpoint in helping to allocate resources. And so we've recently just seen new bills that have been passed by Congress that have allocated moneys towards the VA—and I think very appropriately so—to our veterans who are coming back from Iraq, who are just experiencing horrific injuries, and many of whom unfortunately will have chronic pain problems. And so I am very pleased to see that Congress has been allocating funds and resources from more research in that area. Where we need to be taking the next step is to be recognizing it from an overall societal standpoint. We need to be able to delegate more moneys towards the NIH to deal with this problem of chronic pain and not only just pain, but see the overlap that pain has with all of these other conditions that we face in society. Because in many of these situations, we find it is not the disease state itself that's causing the disability, the loss of work productivity. It's the pain that is doing that, and if we can do a better job with the pain, we would often find that the patients are going back to work earlier. They are using less medical resources and ultimately we end up spending less, not more.

Steve: Well, that's an invested [investment], that's not overhead, because your productivity would [go] way up, nationwide.

Mackey: Oh, indeed. And I think you've seen the large companies start to invest in these early-prevention programs trying to recognize those workers who are more likely to go on and have a chronic pain problem and who are more likely to file a worker's compensation claim, intervene early, get them their help that they need so that they don't end up losing a very productive worker.

Corinna: I am just curious to know how you went from electrical engineering to neuroscience.

Mackey: You know you could not have come across a more linear, in the box, kind of guy than me when I was in electrical engineering, and even when I was early on in medical school. If you had come to me and talk with me about things like the placebo effect or acupuncture or meditation, I would have been asking you, "What were you smoking?" I was a believer in the biomedical model that you find the disease, you find the source of injury or pathology, you give the pill, you reverse the condition and the person is cured. And it took me a long time to realize just how terribly wrong I was. I learned that through spending time with patients. In working in the pain clinic and seeing that it wasn't so much that the injection, the needle, the procedure, the pill that I was giving them that was making them better. It was actually talking with them. It was understanding their painful condition, where were they coming from and what were the factors that were influencing their pain, and it was important then that that we may need to understand that. Because at my core I am still an engineer, but I decided to apply that to the brain, because that's ultimately the seat of who we are. And so all of these factors that go on to change a person's experience has some neural basis within the brain, and so for me, it's an obvious link. It took me a long time to get here, but I think that I am a much better as a consequence for having gone down that path and hopefully will be able to contribute somewhat to answering some of these questions.

Steve: What did motivated you to go to medical school in the first place then?

Mackey: Oh, I think I am an example [of] that old phrase, "You are who hang with", so I always enjoyed both the sciences as well as medicine, and I had a number of friends and mentors who were MD-PhDs in engineering and in medicine and I naturally gravitated towards them, not realizing that you know, we are fairly a small group of people. But while it was uncommon back in the '80s and '90s when I was doing my training, I think we are seeing it becoming more and more common as we see this intersection between technology, engineering, physics and medicine and healthcare, and I think we are going to see more and more people go into this field, and I think we need more people to go into this field. If at the very least, not necessarily to do research in engineering, pure engineering or pure physics, but to act as a bridge between those people who do the engineering and the physics work and health care. So I don't do pure engineering research anymore. I long ago had to give that up. Fortunately, there are a just absolutely amazing engineers here on campus that do that work, and where I fit in is acting as a bridge to be able to communicate the healthcare concepts to them and then take it from them back to my other medical colleagues.

Steve: Especially with more and more bionics coming into play, that's going to be crucial.

Mackey: Oh, that's [it's] an exciting time. The area of bionics and brain-computer interfaces. It is just an exciting time to be alive and it's an exciting time to be doing research in this area.

Steve: One of the other writers who attended Mackey's talk has a nice summary of his entire presentation; you can find it at; and Mackey's Web site is


Steve: Now its time to play TOTALL…… Y BOGUS. Here are four science stories, but only three are true. See if you know which story is TOTALL…… Y BOGUS.

Story number 1: If you feel physically clean, you will probably judge other people more leniently.

Story number 2: It's bad today, but greenhouse gas carbon dioxide may have saved the ancient earth from becoming completely covered with ice.

Story number 3: A species of sea slug, an animal, can carry out photosynthesis.

And story number 4: Researching your medical symptoms on the Web, on average, gets you as good a diagnosis as seeing a general practitioner.

Time is up.

Story 1 is true. Feeling physically clean reduces the severity of moral judgment. That's according to research published in the journal Psychological Science. Study subjects watched a film clip categorized by the researchers as disgusting but some washed their hands just before viewing their film and they were less offended by the film.

Story 2 is true. It looks like carbon dioxide kept the Earth from becoming an ice ball in the Cryogenian period about 842 [million] to 635 million years ago. That research appears in the latest issue of the Nature Geoscience. This view is contrary to the snowball Earth hypothesis, which says that the planet was indeed iced over. The new study says that as the temperature got lower, the ocean water absorbed more oxygen, which broke down organic matter, which released carbon dioxide which started warming things up again.

And story 3 is true. The sea slug is an animal but it can carry on photosynthesis. It basically steals the machinery for doing so from algae and then runs it in its own body for up to nine months, converting light to energy. For more check out the December 1st edition of the daily SciAm podcast, 60-Second Science.

All of which means that story 4, about researching medical conditions on the Web leading to accurate diagnosis, is TOTALL…… Y BOGUS, because what is true is that your far more likely to find zebras rather than horses when you search for your particular health prints. The first study of health-related Web searches found that worst case scenarios come up most often. The sites are more popular and thus get ranked highest by Google algorithms. So on the Web, your chest pain is much more likely to be heart attack than heartburn. For more, check out the December 2nd episode of our neuroscience and psychology podcast, 60-Second Pysch.

Well that's it for this edition of Scientific American's Science Talk. Visit for all the latest science news, and check out our In-Depth Report this week on HIV and AIDS. For Science Talk, I'm Steve Mirsky. Thanks for clicking on us.



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