Captioning sponsored by Rose Communications from our studios in new york city, this is charlie rose. Tonight we continue to exploring our brain with the conversation about pain. Pain serves a very important function for us to survive, it teaches us what to avoid and lets us know when to seek medical help. At the same time, though it can create tremendous suffering. St. Augustine once said the greatest evil is physical pain, 100 million americans live with it every day would yo would wouo doubt agree, pain knows no boundaries, regardless of age and race, beyond the physical symptoms the experience of chronic pain often leads to feelings of isolation and hopelessness. Laura klein had been living with pain since a knee injury in 2008 and joins me this evening to speak about her experiences and Incredible Group of scientists are also here to discuss how we perceive and process pain, david bar stiewk of Childrens Hospital and david julius of the university of california, san francisco, allan basbaum, also of the university of california san francisco, Robert Dworkin of the university of rochester and once again my cohost dr. Eric kandel a nobel laureate, and a Howard Hughes medical investigator. Our subject is pain. Hrchl is really one of the great unmet medical needs and enormous problem in society. And the most, in the most general terms, bain is a unpleasant sensation in response to a real or potential threat of body injury, and it has an extremely important defensive damnive role, it is designed to remove the injured part of the body from the source of damage. And usually this is transient in nature, but with some diseases, such as cancer or arthritis, it becomes persistent and becomes not an damnive process but, adaptive process and part of the disease itself and adds to the pain. As we will hear from laurie klein, chronic pain is a disease in its own right. As these arguments make clear, this is an enormous Public Health problem. 100 million americans as you pointed out suffer from pain every year, and it is the most common reason people seek medical attention. There are two kinds of chronic pain, inflammatory and neuropathic pain, inflammatory, receptive pain is damage to soft tissue and it shows the adaptive role of pain perfectly, it is designed to move the injured part of the body away from the damaging stimulus, so as to prevent further damage from occurring, and to allow the reparative processes to take place. But sometimes sort of a hypersensitivity develops with as a result of the inflammatory process so that relatively noxious stimulus like just touching the hand feels painful to the person. Inflammatory pain is due to damage of soft tissue, but neuropathic pain involves in addition to soft tissue damage actually damage to the nerve fibers themselves. And this, not only involves hypersensitivity but spontaneous pain and burning pain. More over, it shows an interesting phenomenon that we see with laurie klein, and that is a phenomena of sensitization where the pain spreads from its initial site of injury to other parts of the body, for example, if i damage my fingertip, with sensitization it can spread up the finger to the hand, the forearm, all the way reaching to the shoulder. So this is really a very serious process, that can cause a great deal of pain for the person. These processes need not be independent, so inflammatory and neuropathic pain can occur together as is lauries case, the inflammatory and can lead to neuropathic pain. One of the remarkable things about pain is that we have made enormous progress in understanding it, in the last two decades. Our understanding of pain until recently was amazingly limited, it is the most mysterious of all sent tall at this and only. Recently made significant progress and the people around the table are major contributors for this. One of the first people to think about this was a stot until the fourth century before christ, and he thought pain was do two the fact an evil spirit entered the body at the sight of injury. Rose punishment from god. Punishment from god and it persisted through the middle ages into the renaissance, these are bad people and thats why they were suffering pain. This changed in the 17th century with this great philosopher, mathematician, rene december katrina, descartes, who developed a different view of pain. He thought of pain as a biological process and drew this wonderful drawing of a young boy being burnt. His toes being injured, and finers were carrying the information about injury directly from the toe into the brain, although the details of this model are not what we view as the pain process the general idea that it is a biological process is the current view. But the question is, what is the nature of the biological process. It is remarkable to realize that until 20 years ago, we did not have a good understanding until of the nature of the biological process involved. People thought that pain was very different from all of the instrumentalities, for each modality you have different receptors like rods and cones in the rhett na, you have old factory receptors old factory receptors in the nose. Each one has a private line, receptors specific to it and nerve fibers that lead to it. Rose hear, feel, touch. Exactly, with pain people thought that it may not have a system of its own, that it hijacks other systems and doesnt have receptors of its own. For example, many people thought that pain was the touch system, tactile system that were firing inappropriately. We know this is wrong. Many of these are small caliber fibers, many are these are finers that are specific to mechanical pain, cerebral pain and chemically induced pain. Rose and this is a breakthrough is. This is a major breakthrough and another occurred when we began to identify specific receptors that mediate this, and david julius who is here was one of the people who characterized one of these receptors. These are iron channels called trip channels, they respond to both thermal and chemical stimuli, this is a wonderful advance, and a major scientist in england jeffrey wood discovered tactile pain receptors. He discovered a group of kids that actually began with a pakastani family, then extended it to others, congenitally insensitive to pain this was written up in last sundays new yorks time. These kids are feelers, they can put their hand into boiling water without even being aware they are doing it. They dont feel pain so the whole defensive function of pain is lost for them. They do unbriefably, unbelievably still litigate things and Dangerous Things because they dont have a fear of pain because they never perceived it. So this turned out to be due to a sodium channel and that is also interesting because we have sodium channels all over the body, thats how we generate action potentials but this is a special kind of sodium channel that carries this particular kind of mutation that gives rise to insensitivity to pain and another mutation in that channel gives to hypersensitivity of pain, so for the first time we were getting a profound understanding into the nature of pain, often a, not only in a biological but in a psychological sense. We will see as we discuss lauries injured which occurred in a gymnastic competition that unlike many of the things in medicine, you cannot measure pain objectively. It is a completely personal experience. So your response to pain will vary depending on the context in which you experience it, whether you are attending it or not, your sex, physicians have to learn how to listen to patients very carefully in order to really appreciate how in particular person is responding to pain and we are going to see as we go around the table with these four people, each of whom have pioneered a different aspect of pain, how not only clinical sensitivity but also important advances in biology have brought us to a new level. Rose this is the New York Times article base says blockers, ashlands life would be a lot ease yen we she stuck her hand in a pot of boiling water she could feel it, go ahead. As eric noted there is no measure, there is no blood test for this disease and for the patients it is a silent disease and so we are dependent on speaking to our patients and trying to extract some concept of what they are going through, and the two issues that come through in terms of trying to understand an individuals pain relate to pain intensity and the emotional background related to pain. And without understanding those two factors, it is very difficult to actually appreciate what patients are going through. And i think in reality, many patients end up not feeling that their clinicians really understand their problem, and for those of white house are in the clinical domain of pain treatment, it is very tough when we dont have a specific diagnosis. Rose so let me talk to laurie. First of all, i want to stay how much we appreciate you coming here and sharing your own experiences. Tell me about the pain you experienced and how it evolved. Sure. Well, i was a gymnast on the club team at the university of texas at austin, and i was competing in gymnastic meets during the spring of 2008, and in march of 2008 is when i had a really bad knee injury when i was vaulting, this is a picture of a tina and i before one of our gymnastic meets. This is the event that i got hurt on. This was the actual picture right before i got hurt, and i was vaulting when i landed, basically blew my knee out and just had extensive damage to my knee. I tore a lot of ligaments. This is just 24 hours after that injury, and i had severe bruising and swelling and severe localized pain in my knee. Basically, i did not have Reconstructive Surgery until august of 2008, so that was about five months later. And after that surgery, there was a difference in the pain that i felt. It started to spread through my entire left leg, from my knee all the way through my toes, as opposed to just my knee. Rose what did it feel like . It was like a burning, a very severe burning pain, and then also kind of like an electrical jolt, where you kind of felt like you could feel things firing off in your leg. And then i also had sensitivity to touch. Rose right. To where i couldnt handle feeling the bed sheets touch my leg at night. Rose and when they did, what would you feel . Extreme burning pain and just it felt like my leg was kind of on fire, it was just really uncomfortable. I think this shows in a very interesting fashion two characteristics features, one is that innocuous stimuli now becomes painful and, two, the sensation, from the initial site of injury to involve the whole leg. Rose right. And then some of the other things that happened was there was a color change in my left leg and foot and it was kind of red and sometimes it would be purple and then i also had extreme teach change just in my left limb to where it felt colder, and other things were i had abnormal hair growth where the hair on my leg would grow a lot faster than on my other leg, and then my leg would feel pretty sweaty and kind of clammy, and then my the skin on my shin and my leg was very shiny, so these were all Different Things i had not had at the original injury. Rose and what psychological changes were going on . Well, i definitely developed extreme anxiety. I had a very hard time sleeping and not only because of the pain but then constantly worrying about, oh i am not getting any sleep and i cant stand things touching my leg. And i also had you know, i was very afraid of people kind of running into me or hitting my leg, bumping into me or even just reinjuring my leg itself. Rose and what were your doctors telling you at this time . Well, immediately after my surgery in august, they were just telling me that this was normal postoperative pain and symptoms, but it wasnt until about two months after, in october, of 2008, that we finally well my doctor fenylly accepted that Something Else was going on, so thats when he recommended me to a Pain Management doctor, who then gave me the diagnosis of complex regional pain syndrome. Rose and how long was this after the injury when you got that analysis . Six to seven months after. Rose . Before you realized this was an example of stream pain of which they needed special response . Right. Right. So where i actually was referred to another doctor to see what was going on. And it was very nice to get a diagnosis, just because i knew something was going on but then again, it was also not great because i never had heard of complex regional pain syndrome and i had never met anyone who had it before so it was all very new to me. Rose david julius, tell us, you know, where do we take this now . Well, our records, as we alluded to earlier, the study of pain was in its infancy and blossomed quite a bit in understanding the mechanisms and pathways that are involved in acute sort of pain that laurie experienced and then subsequent to that how changes in the system lead to these chronic pain syndromes. I think the big breakthrough intellectually as eric said was the realization that pain is really not that different than other sensory modalities that it shares some overall characteristics and namely that neurons, neurons are specialized, there are specialized lanes or groups of cells in the first slide, we can see that if you take a crosssection, for example, we would look through a crosssection through a nerve bundles such as a sig sciatic ne that runs through your leg you can see right away there are different kind of nerve fibers and some that are large diameter and wrapped with a thick insulating myelin sheet and others that are thin diameter and lack any insulation, and the form of these, the large cells are really the ones that the a betas are devoted to the detection of things that eric discussed, light touch, vibration, innocuous stimuli, we regard as not important, what we call c fibers receptors are the ones that really carry out the majority of signaling in with regard to how we detect painful stimuli and are the ones that sense knock noxious heat, noxios cold, noxious pressure and send this information to the spinal cord so we can see this general outlay is the, is of the system, so these are carried out by the c fibers on injury, and go to the dorsal horn and these messages are transduced through a number of synapses to the brain, where we cognitively understand this as a pain response, and so for example, these c fibers would be the sorts of neurons that were initially activated when laurie did this vault and hurt her knee and felt this acute pain. And the other big breakthrough in this field, as eric alluded to was really to understand the Molecular Devices that make the c fiber receptor know what it is, in other words the proteins that endow these cells with the pass to detect noxious stimuli and transmit this information to the spinal cord. And i just wanted to, i think there are basically two interesting discoveries in this area that are worth highlighting, and one is the discovery of a family of molecules of ion channels we call trip channels, these are found on a variety of different c fiber receptors shown here and the way these were discovered actually was as targets for a number of irritants that we experience, natural product irritants in our environment, the most familiar is cap say sin the pungent ingredient in chili peppers that give them the hot burning zinc and it turns out it rely sits that response. By binding to the receptor, called trip d 1 and when it does so it activates a nerve fiber, initiates an electrical potential, change and we sense this as a burning sensation. This is why we sort of conflate the experience of a hot chilly pepper with a burning experience. These ar are all in the last ten, 15 years . Ten, 15 years and trip eight which is a receptor for a natural product from menthol which we all experienced the cooling phenomenon and it turns out this channel is also activated by cold which is again why psycho physically we experience a mentally cold sensation and other such molecules and all of these play defined roles in allowing sub sets of these c5 receptors to detect noxious heat, cold, et cetera. And then the other another big discovery that eric alluded to were these this family of sodium channels, he said sodium channels are present in every neuron in the body, but c fibers actually are a subset of c fibers reflect a certain subset of channels and this has really come to the fore because of people who, such as the one described in the New York Times, individuals who have mutation ms. These channels, and these. Mutations have very, have very profound effect os ten pain transduction experience and these are responsible for taking the initial activation of the nerve fiber by capsasin or heat and conducting this to the spinal cord. They allow the electrocurrent to continue flowing and mutation ms. This particular channel have very profound and fascinating effects on pain sensation, in individuals in whom this channel mutations render it nonfunctional, they cannot experience pain, interestingly they can experience innocuous stimuli such as light touch but incapable of experiencing pain and as eric alluded to you can easily identify such children because they have they lack the protective function that the pain system normally affords us and do not know when they have burnt themselves or may be running around on an ankle that has broken bones, et cetera and this has grie grievous conseque0 for these kids because they have to be watched very carefully. To illustrate how dramatically the field is moving this is only six years old we discovered this. And then there is a flip side of such mutations in which people have mutations in the same channel that render the channel hypersensitive so it is sending signals ordinarily in the absence of any peripheral stimulus like heat, cold, et cetera and in these individuals they have ongoing chronic pain that is unlinked to any peripheral stimulus and these patients will come into their see their physicians sometimes with their hands or feet in buckets of ice water because they feel such extreme burning pain at their extremities and so these studies really show that these nerve fibers are functionally and molecular specified to carry out this process of pain 7ation, and we are beginning to identify some of the. Molecules that endow them with these properties. Tell us how the pain goes from the receptors to the brain. The key thing is that the information travels from the spinal cord up to the brain and really accesses at least two major areas, because on the one hand you have the experience where is the stimulus, how intense is the stimulus . You have a century component to it you can detect, sensory component and there is an emotional stimulus it, and there are emotional areas of the brain that are activated and there are sensory disjimive areas so there is. No one pain area of the brain. There is a matrix of activity turned on in the brain and that causes the pain experience. But what is special i