Thanks, Dr. Dreicer. Today, we're privileged have Dr. Douglas Drossman come in from the University of North Carolina Chapel Hill. He's a professor emeritus of both gastroenterology and psychiatry. Did his residency at UNC Chapel Hill, a fellowship in psychosomatic medicine at the University of Rochester, and then his GI fellowship at Chapel Hill. He has over 200 peer reviewed publications, and has been invited to give over 1,000 talks over his career in all kinds of topics within the field of gastroenterology. He's internationally renowned for his expertise in psychosocial and behavioral aspects of patient care. And today, he'll be speaking to us about understanding and managing a patient with chronic and severe abdominal pain. Additionally, after this grand rounds, he'll be leading an interactive workshop about some aspects of patient-physician communication. All students, residents, fellows, and faculty that are interested are invited to attend, but please join me in welcoming Dr. Drossman. [APPLAUSE] Well, thank you. I want to thank Dr. Frye and Dr. Scheiman for inviting me here. You might want to know I was actually here as the first James [INAUDIBLE] visiting professor 23 years ago, I guess. Can you turn it up? Oh, sure. Yeah. So my career has evolved in a way that moved into gastroenterology and the evolving field of brain-gut interactions, and now we call it neurogastroenterology-- what some people call functional GI disorders. And I try to, in my work, have tried to bring some legitimacy to it. And what we'll do today is talk a little bit about the patient that could really trouble you sometimes with chronic severe abdominal pain, perhaps on opioids. And this, of course, is homologous if you saw a patient with migraine or back pain or fibromyalgia and the like. Just to give you a perspective on this, the latest article shows that abdominal pain is truly the top thing seen in GI office or emergency departments compared to other conditions, and that's just acute. We have adhered to what's called the biopsychosocial model, which is the evolution of how we look at brain-gut interactions-- that there could be early genetic factors. This is-- pointer doesn't work on the mouse. There it is, OK. So early genetic and cultural factors that may play a role in the clinical manifestations and the physiologic manifestations occurring at the gut. Also, there are psychosocial factors that play a role, and we're going to get into this even from a structural standpoint. The brain-gut axis, which derives a lot of the symptoms we see in GI, which leads to the clinical presentation and the health outcome. I want to start with the case history, because I think it's a good way to bring everybody together, and dissect it out into what's going on with this patient. And I'm going to show you a video which we showed at the GI meetings last year-- this past year-- that represents this patient. It is a actual patient, but we dramatized it some. So this is a 33-year-old woman who came in with chronic and severe abdominal pain, nausea, and constipation. That's refractory to prior treatments. She started getting pain at age six. She had school absences. Pain increased after beginning her period, and she had dysmenorrhea as well. At age 19, she went traveling through Mexico, developed an acute gastroenteritis with pain, fever, diarrhea and vomiting, and she was diagnosed at the time with IBS-D, which we know we'd call post infection IBS. Over the last 10 years, the pain became more frequent and changed from diarrhea to constipation. Over the last five years, the pain became constant. So we're moving from an intermittent pain to a more constant pain. Is that-- OK. Well, I'll keep going. And it was associated with bloating and constipation along with straining. That's distracting. [LAUGHTER] She also has fibromyalgia and migraines. She's been on a variety of medications, none of which have really helped. You know the ones-- antispasmodics. Is it gone? OK. So many years ago, [INAUDIBLE] introduced an experimental model. [LAUGHTER] I know. I know it's distracting. It's hard to focus. It's a remarkable tool for research. Anyway, medications didn't work. She had a variety of procedures-- colonoscopies, EGDs, and so on. Five years ago, she even had an exploratory laparotomy. They thought they saw endometriosis. They put her on leuprolide, a GnRH agonist with no benefit. Is there anything I could do here? It's fine? All right, keep going. So you're getting the picture. I wonder if there's another way to-- oh, it stopped. OK, we're OK. Thank you for doing that. All right, the picture is mounting. She had a cholecystectomy three years ago due to a low ejection fraction on HIDA, and that did not help. She's had over 30 ER visits. She receives morphine and ondansetron. She goes out with a week's supply of hydrocodone or oxycodone. Is this starting to sound familiar to anybody? She-- family physician refills narcotics to prevent repeated ER visits. She had five hospitalizations for pain when the ER treatment was unsuccessful. She was even hospitalized a month before she came to see me. She had a second exploratory laparotomy that was negative. Had increased morphine requirement, unable to discharge her because of continued abdominal pain. So what do? They do they call the psychiatrist. She was found to have major depression and PTSD from childhood sexual abuse and deprivation. Her parents were divorced when she was 12. She left home at age 16, became pregnant at age 17. She left her spouse after four years, because he was abusive to her. She's living with her mother the last two years. She's unable to work and on disability. The psychiatrists recommended paroxetine and a follow up at a local mental health center. She was discharged on paroxetine and oxycodone. As you can imagine, she didn't go to the mental health center. Now comes to the office, curled on her side on the table with hips flexed, has severe cramping pain in mid and lower abdomen with nausea. The constipation has gotten worse. An abdominal exam is generalized tenderness and fullness on the right and left, overlying the colon. She requests hospitalization to get IV pain medication. This is your clinic, 4:30, Friday afternoon. What are you going to do next? Let me try to demonstrate that for you. This is the video that represents this patient. It's only a few minutes. Ms. Byers, I'm Megan, Dr. Drossman's PA. Nice to meet you. I'm going to take you back to see him now, OK? OK. Grab your luggage and just follow me. Ms. Byers? Yeah? I'm Dr. Drossman. Hi. I'm here to see you today. Yeah. So I'd like to talk to you a little bit. I wonder if you could come sit down in the chair. Would that be all right? Why don't we try that? Yeah, let me see if I can help you up. OK. This is not a real patient, by the way. Don't forget my suitcase. OK. Ms. Byers, I looked at your records. You've had a lot of symptoms, you've been to a lot of doctors. Can you tell me something about it? Well, it's really bad, doctor. I mean, I need you to give me something. Like, I need a shot of pain medication or something. It's-- I need you to call the ER and just tell them that I'm coming down, because that's the only thing that will help manage my pain is when I'm in the hospital. OK, well you're here now. No, I need it now. You don't understand. I wonder if I could just understand a little bit more about what the pain is like. Can you describe what it's like and other symptoms you have? It's like stabbing knives, like, into your gut. And it just hurts, and it goes through your whole body. And I have constipation, and I have a headache, and I feel like I'm going to throw up. And I'm sure that none of this even matters, because you probably don't care, but I just need you to help me, please. It sounds like this is really bad, and you've not gotten a lot of good care. I want to try to help. Tell me more about, maybe, when this first began. It started about 10 years ago after I got back from a girls trip to Mexico, and I got an infection, and it turned into IBS with diarrhea. And the doctors treated me for the diarrhea, but the pain never went away, and it's just gotten worse and worse and worse ever since. Then they gave me pain medicine, but then that's caused all this constipation. And, like, right now, I haven't even been able to go to the bathroom in like 10 days-- 10 days. I don't-- I don't know what else to do. OK. Well, we're going to try to understand a little bit more and see if we can help. How about earlier? Had you had any symptoms earlier in your childhood? I had some stomach pain off and on when I was a kid, but not like this. It was just, like, when my parents would have a fight or something would be going on and-- you know, it just, like, you get a stomach ache. But then my parents got divorced, and I-- my mom and I fought a lot, and so I left when I was 16, and then my stomach was OK. I didn't really have any problems. And then I got pregnant, and my daughter was born, and everything was fine. But now it's so bad that I had to quit my job. I couldn't even work. I mean, I can't barely get out of bed most mornings. And so I'm trying to raise my daughter by myself. And I lost my job-- you know, I had to quit my job, so I had to move back in with my mom, which, it just exacerbates the whole thing. This has been pretty hard. Yes. I see that. How do they try to treat you for this? Well, so my primary care doctor doesn't know what else to do, so he gives me, like, Percocets. But then that stopped working, and so he gave me a fentanyl patch, which worked for a while, but it's not effective anymore. That's why I need to go to the ER. I go to the ER, they give me IV pain medication that's much stronger or they give me, like, morphine, and just whatever else they got that's strong, and it helps a lot. And that's why I need to go back. Have they ever put you on what we now call neuromodulators or antidepressants for the pain? Yes. I have this doctor that was, like, oh, I think we need to try an antidepressant. And I-- it just pissed me off. I'm not depressed. I mean, I don't know why he thought that would help. They didn't do anything, and it's not in my head. I'm-- keep telling him, the pain is not in my head. It's in my stomach. Like, treat my stomach. But it's-- OK I guess what I'm seeing is that you have needed more and more opioids as well. Yeah. Narcotics. Well, yeah. It's the only thing that helps. And my concern is that it could also make the constipation worse and could even make the pain worse, and so maybe we have to look at other options. So how would you feel if we were to look at a way to treat this, and maybe get you off the narcotics, because that could make things better? No. That's not going to make things better. I don't want to come off. They're the only-- you're not listening to me, Dr. Drossman. They're the only thing that works. So why would you suggest that I come off of them? I don't-- OK. This is the same thing I get with every doctor. All right, so let's do this. We're going to work with you. We're going to do a physical exam now, and when we come back, we'll talk about some options. Is that OK? Yeah, OK. Fine. OK, so we'll come back to this at the end of the visit. What I want to do now is take you through how did she get to this point. Why is this happening? And so if we had time, just as a workshop, we'd be asking you about thoughts. I think there is some pretty predictable thoughts of frustration, helplessness, wanting to help, not knowing how, frustration, and so on. When the fellow saw her, this is the note he left me when he came back to see me. [LAUGHTER] So the first thing that we're struck with is a pattern within psychiatry called illness anxiety and somatic symptom disorder, where there are behavioral features that occur here. And the reasons for this may have a lot to do with early derivatives-- the frustration with the health care system, perceiving doctors are not helping, and so on. So the role that happens is health care seeking frequently. One of the things in terms of outcome is that patients who don't take personal responsibility don't do as well as those who we get to engage and take responsibility. And so here, everything is put on the doctor-- focusing attention on complete relief of symptoms, requests for narcotics, requests for diagnostic studies. Minimizing a role for psychosocial factors, how do you get to the point of showing the brain-gut axis? Urgent reporting of intense symptoms that goes on for years and years, and expressing pain through verbal and nonverbal-- you saw how she was hunched over. Well, let's talk about the brain-gut axis. It turns out that the brain and the gut are hardwired more than any other organ system. It starts with the neural crest in the embryo, and this develops into the brain and the spinal cord, and here's the endoderm and developing GI tract. And during the embryonic development, gangliar come off the somites and populate the endoderm. [INAUDIBLE] called the enteric nervous system. There is many nerves in the enteric nervous system as in the spinal cord. And that's a hardwired system, because the enteric nervous system and the brain share the same neurotransmitters and receptors, but they have different functions. Cholecystokinin in the gut acts on motility, but in the brain is a satiety hormone. So these kind of multiple receptors we can use to our advantage by using certain medications that we borrow from psychiatry. It's hardwired in the sense that if you see someone is walking down the street, someone gets hit by a car and is badly injured, you might throw up. Or if you sprain your ankle during a race, you may not feel the pain until afterwards, because the brain can regulate it. It's a hardwired system. So let's go back to the case. How did she evolve this way? She started out with what we call RAP-- recurrent abdominal pain. In children, it's a pediatric disease. Intermittent episodes of pain. Very common, about 30% of children get RAP. And then she developed, when she went to Mexico, IBS with diarrhea, and that became post-infection IBS. This then changed over time to IBS with constipation. And then she developed what we now call CAPS, or centrally mediated abdominal pain, where the bowel component becomes minimal in the brain. The brain's failure to regulate signals from the gut takes dominance. And then she developed, complicated to that, going on opioids and developing opioid induced constipation. And then something we first reported about 12 years ago, narcotic bowel syndrome, which essentially mediated hyperalgesia-- abdominal hyperalgesia. These are the criteria for post-infection IBS. It's similar to IBS. It's abdominal pain related to defecation that is could be relieved or made worse, associated with the change in the frequency and the appearance of the stool. In addition to that, the patient has to have an infectious etiology defined by a positive stool culture, or two or three of these factors which suggest there was an infection, and it doesn't meet criteria for IBS beforehand. So that's post-infection IBS. We're talking about dysregulation that occurs with post-infection-- that the gastroenteritis leads to the virulence-- bad bacteria-- which leads to impaired bacterial recognition, increased intestinal permeability, loss of tight junctions, and then you get inefficient downregulation of the inflammatory response. This is mediated by stress. The combination of infectious load with stress leads to the clinical expression as to why about 20% of people who get-- 15% who have acute gastroenteritis will develop ongoing symptoms of IBS. Some of my work was with the Institute of Medicine, where we looked at the vets coming back from the Gulf War and Afghanistan and the like, and they developed IBS. And what we found there was the combination of infection occurring at about 50% of soldiers plus the stress of deployment that allowed the VA-- we gave them the evidence so the VA now makes it probable cause. So people who develop IBS after coming back will get VA benefits. So that's an example of how stress can play a role, at least to alter gut function and the infection. So we're talking about the interaction between, in the gut, mucosal immune dysfunction with immune reactivity, release of cytokines, mast cell degranulation-- very similar to IBD. Altered gut flora, which can enable that, and then increase intestinal permeability. Some work has shown that the mast cells, which are very close to the nerves in people with IBS, is shown here. That seems to be, perhaps, the mediator. The degranulation leads to sensitization of the enteric nerves. This is a model to show you what we're talking about-- how stress could play a role. So stress can lead to release of inflammatory mediator CRH, which is a pro-inflammatory agent in the gut acetylcholine. And this can lead to mast cell degranulation, as shown here. And then after the degranulation occurs, you get more-- you see your tight junctions. Might start-- the greens start to disappear as the peptides are released. And then as this disappears, you get, now, some activation of the nerves with sensitization of the nerves, and this becomes a lower pain threshold in the IBS model. And then you get transmigration of bacterial cell products, and the cycle continues. So that's how you can get this combination of stress playing a role. And what we develop is a shift of the stimulus response curve to the left so that after an infection, or it could be trauma of the bowel, you get this shift to the left where, now, stretching of the bowel in the normal person shown here, pain increases. But with the insult, you shift the curve to the left so you have a greater pain response to stretch of the bowel. In GI, you can cut the bowel, and nobody feels anything. If you stretch the bowel, that's where you get the pain. And so that's the model used, and that's why people with functional GI problems get pain. Or it could be colic with fallopian tubes or ureter or any other organ that stretches. And so you can get hyperalgesia or even allodynia, which is a painful response to an innocuous stimulus. So someone with IBS can eat a normal meal and get pain. And the other thing we're learning is that there is a change that, as with this patient, the functional GI disorders or the disorders of gut-brain interaction exists on a spectrum where one day you can have IBS-T, and six months later, have IBS-C. So the pain-- and if you have pain, you have IBS. But if you don't have pain and you have just constipation or diarrhea, you have functional diarrhea or functional constipation. So this is on a continuum. So your patient can, over years, go through various components of this. And then she took opioids. Now, we're in an epidemic. US and Canada is shown here in terms of consumption per capita compared to other countries. This is only going up to 2014. It may be diminishing in the last year with some of the political components of it. This is a study that's about to come out in gastroenterology by Lin Changs group looking at gastroenterologists. And the good news is that if you look at their database-- the database, national database-- the prescribing of opiates is decreasing in gastroenterologists. And actually, gastroenterologists really give very few opiates compared to primary care or surgeons, as you would imagine. Antispasmodics seem to be increasing. And unfortunately, neuromodulies have stayed about the same, but we're going to try to change that after this talk. So the opioids have an effect on slowing everything down, so that's what happened to her. It decreases neurotransmitter release. It suppresses propagated contractions-- PPCs. It alters the firing properties. It reduces secretion, increases sympathetic outflow. And it can lead to peripheral and central sensitization of the nerves, which we'll get into. So when you look at patients on opioids, about 50% or so on high dose opioids will get opioid bowel disorder, which would mean ileus, gastroparesis, constipation. Most of those will get constipation, which has been a targeted market for pharmaceuticals-- to treat opioid induced constipation. But in addition to that, you have this entity called narcotic bowel syndrome, which is different. It's not a bowel problem. So opioid bowel dysfunction is the effect on the GI system in general. OIC is the development of constipation. And narcotic bowel is where pain is the dominant symptom, and it's characterized by a progressive and paradoxical increase in pain, despite escalating doses. So it's centrally mediated hyperalgesia, and it improves with detoxification. We'll show you that. I won't go into this, but I just want to point out that in the last five or seven years, medications have come out to block the peripheral opioid receptor. They're called PAMORAs. Methylnaltrexone, naloxegol, and naldemedine is the other one that block the opioid receptors. So if someone has to be on opioids, you can block the constipation effect through this peripheral effect. OK, so that's peripherally. What happens when it gets-- we started with, kind of, simple IBS. What happens when it gets worse? So now we have to talk about the brain. And the first thing we talked about before the brain is the concept of central sensitisation. You know about visceral hypersensitivity. Central hypersensitivity is when you get upregulation of the dorsal horn or in the brain. So if you repeatedly stimulate the bowel with infection with IBD going into remission, this is what we call IBD IBS. The disease is treated with the biologic, but the pain still continues, because you're getting upregulation here so that the signal going to the brain increases, and the brain's ability to downregulate pain is altered as well. And so you have central sensitization. When you look at GI patients, you see this progression that the CNS contribution, the brain's contribution, to pain goes up as you get more central. So if someone comes into the ER with a bowel obstructure or cholecystitis, they're drawn from a normal population. You take out the obstructed bowel or you take out the gallbladder and they're fine, because they have no a priori difficulties, psychologically or centrally. But as disorders become more central, more chronic, it leads to increasing CNS contribution. Will I continue to have the pain? Will I be able to work? This has impact on pain regulation to the point where you get, essentially, mediated pain where the peripheral signal is minimal. This is just showing the spectrum of that from her having mild to severe IBS to CAPS. This is the population prevalence. The severity goes up. It goes from occasional to constant, the pain. Comorbid psychosocial diagnoses go up. Anxiety, depression, somatization, and the like. Health care utilization goes up. Comorbidities, fibromyalgia, migraine, headache, back pain, TMJ go up. And what you're seeing is a shift from gut dominant influence to pure CNS influence. So treatment has to follow that. The diagnosis for centrally mediated abdominal pain is shown here. It's really continuous pain not related to change in physiologic events. So IBS is pain relieved by defecation, or worse, with eating. Centrally mediated pain, it doesn't matter whether you eat or have a bowel movement. You still have the pain. And this is not a lingering factitious illness. So here's a physiologic example of central sensitisation. This is looking at stretch of the bowel producing various levels of pain looking at perceptual threshold in the gut. And you can see that with IBS, you have a lower sensation threshold, because they have visceral hypersensitivity. The mucosal immune system has been altered by microbiota, by other factors, and they have a lower pain threshold. The control group is shown here in blue, but look at the purple, which is centrally mediated or functional abdominal pain. It's no different than normal. So it's not a peripheral phenomenon. But they're still having the pain, but it's not occurring from stretching of the bowel. So we have this continuum from mild to severe from what we call aferrent excitation in IBS. That is dietary factors, motility, visceral sensitivity. All those things are what you treat with gut-directed agents or dietary factors or antibiotics. But as you get to be more severe and more constant, you're not dealing with these kind of problems. You're dealing with psychosocial variables that are affecting this. So I mentioned we first published this in 2007-- narcotic bowel syndrome. The criteria are chronic or frequently recurring pain that is treated with acute high dose or chronic narcotics. The pain is not explained by a current or previous GI diagnosis, and you have to have two or more of these. The pain worsens or incompletely resolves with continued or escalating dosage as you-- the patient will say, this is the worst pain I've ever had, and they're now on 100 milligrams of morphine equivalent. And it's still going up, but the pain is worse than it was before they started it. And it intensifies, and there is a progression in the frequency and duration. This is a central phenomenon. While opioid induced constipation is related to peripheral mu opioid receptor activity, this is due to dorsal horn glial cell sense activation. Which, other things can affect it as well, but the dorsal horn glial cell, which we thought used to be a nurturing cell, is actually an inflammatory cell. And when you activate this cell, you get release a pro-inflammatory cytokines. You get increased neuron excitability. You upregulate your second order NMDA release, and you get increased pain. So patients who are on chronic opioids with chronic pain need to come off opioids, and they get better. So the psychosocial features are shown here. We talked about illness, anxiety, somatic symptom disorder. Maybe some axis to features in this patient. She had major depression, PTSD, and a reluctant to come off opioids. So here we are. This is some data. We did we had an NIH study looking at the effect of abuse, early sexual or physical abuse, on health status. Followed them, and what we found is this is looking at the graded effect of abuse from none to actual penetration, vaginal or anal rape. And what you can see is that pain scores were significantly higher in those cohort when followed, the number of non-GI symptoms, disability. These patients are at increased risk for surgery because of the interaction with the doctor. Doctor, you've got to do something. Psychologic distress is increased, and their functional disability. We even found that the clinical visits increase. And so in a referral center like this, you're going to get a higher proportion of people with early trauma, because they're self selected into this because of the severity of their condition. We first we pointed the role of abuse in 1990 in the Annals of Internal Medicine. And at that time, we found that 50% of the patients going to the GI clinic had some early trauma history. All right, so all of that is playing a role. And then we have to look at why is this happening, and that's because the brain and the gut are connected and plastic. So there are factors that can play a role of a psychosocial context-- cultural factors, what we call placebo or expectation or conditioning effects or nocebo, the expectation that a drug or treatment won't work, and that can actually alter your pain threshold. And then there are cognitive factors that you see with patients catastrophizing, which is a morbid pessimism. This, I will never get better, an expectation for the doctor to call the shots, and a feeling of helplessness and vulnerability. Lack of distractibility and hypervigilance-- not wanting to go out of the house for fear that they're going to get pain or need to be near a bathroom. And then this has, as I'll show you, actual structural changes due to the maladaptive plasticity of the CNS. And all of this can be enabled by comorbid depression and anxiety. So the descending system, which interacts with the affective and the cognitive circuit, plays a role in the descending pathway. But in patients with functional GI and severe chronic pain have an impaired descending modulatory system, and so the signal going up is not being downregulated. We find that, when we do connectivity analysis and brain imaging, that the non-GI-- the healthy person has different areas of the brain that get acted-- the insula, anterior midcingulate, thalamus. But when you deal with the chronic pain condition, you have more of the emotional centers, like the supergenual ACC, the amygdala, and other areas. So it's a different kind of interpretation of the pain, probably based on early conditioning and early experience. This is a study we did of women who had IBS, and some of them also had abuse history. And what we did is we looked at the combination of IBS plus abuse against those who did not have this combination, and they had-- this group, IBS and abuse, had higher pain ratings to rectal distension compared to the control group of IBS alone or neither. And then this was activation of this midcingulate area. So this is kind of giving you a window that this marker-- it's a biomarker, so to speak-- can upregulate and make the pain worse, and we think it's because the brain is not able to downregulate the incoming signal. The next piece of information is that when this goes on and on, you can get destruction of neural pathways. And if the work has been done with abuse, trauma, functional disorders, and chronic pain conditions, they're associated with reduced neuronal density in brain-pain control areas. Now, when I went to med school, I thought that the brain cells don't grow, and they don't die unless you have a stroke or Alzheimer's, but that's not true. Brain cells are growing and dying all the time, and you're looking at differential rates. And what you find, and this was a study done of Gulf War vets who had PTSD, and we looked at-- not us, this is Bremner's group-- looked at the hippocampus head volume, which is an area of the brain that's associated with memory regulation and mood. The flashbacks of PTSD, the memories, all of that relates to a poor functioning of this area, and you can see about a 15% drop in neuronal density compared to the healthy civilians. It's almost a dose effect, and this correlates with impairment in verbal memory as well. Since that time-- that was, let's say, 10-- 2005, so it's 15 years ago-- there's been other studies looking at major depression, bipolar, the abuse, chronic somatic pain, even IBS. Even chronic pancreatitis is associated with dysregulation of the pain control centers with loss of density. Here's a study showing that in IBS, you have reduced density compared to healthy controls in chronic IBS. So that's what we're dealing with. What's going to be the management approach? How do we deal with this? Well, this patient, of course, is at the pinnacle of this triangle where you have to start looking-- this is not someone who's going to respond to a FODMAP diet or an antispasmodic. She's not going to respond to Linzess for a constipation, at least in terms of the pain. This is where you have to look at a multidisciplinary approach looking at behavioral and central neuromodulators to try to turn this around. And this shows this spectrum that in terms of treatment, that you're dealing with aferrent excitation citation with the vast majority of people with IBS or functional GI seen in primary care or secondary care. But at the medical centers you're moving into, not just the aferrent excitation, but what we call disinhibition, failure of the brain to downregulate, and these are enabled by many of these factors shown here. And that means your treatment has to move up to antidepressants, behavioral treatments, and augmentation treatment. That is combination treatments. So we took these patients with narcotic bowel, we brought them in the hospital, and we detoxified them. And guess what? The pain got better. We looked at 39 patients, and we looked at their visual analog scale, and this was 54 before detox. Usually, it took about a week to detoxify them, and they dropped about 30%, as shown here. We then followed them because of the North Carolina registry and looked at those who stayed off, and about half came back. And you can see that if they stayed off, their pain scores continued to improve to about 70% to 25% of what it was before detox. But those who went back on, the pain scores came back. Kind of a proof of concept of how the opioids might be playing a role here. This is a patient who had 400 milligrams of morphine equivalent, and she reported her pain as 10 out of 10. She was on TPN for six months because she couldn't take anything by mouth. She had inpatient detoxification over six days. She began eating, and two weeks later, she sent this picture of her eating a burrito. So of course that's a dramatic story, but we did get meaningful improvement. The problem is that you get a recidivism rate that's pretty notable, because this is a societal problem. You detoxify them, they go out to the emergency room, they get opioids again. Or they go to the family doctor, because they don't know what else to do. So what we found if we followed them for, like, three months, as you see, 50%, as we saw in the graph, went back. And by one year, only about 25% or 30% were still off opioids. So we're trying to look at other models, like intervening with behavioral intervention, in addition to hypnosis or other factors that might prevent them from going back on the opioids, because the patient have to participate with this. If they go to the doctor with the same pain behaviors, they're more likely to go on the opioids. So next would be the neuromodulators. This is a paper we published about a year and a half ago, which was a working team report from The Rome Foundation, and what I'm going to show you is some of the evidence around that. The first thing is that we're changing the terminology to avoid stigma. The term antidepressants, antipsychotics, anti-anxiety-- those drugs were developed for those conditions in the '50s and '60s. But with neurogastroenterology, we're borrowing those drugs and using them in the enteric nervous system in the gut-brain axis. But when the patient goes to the pharmacist and wants to go on Seroquel and the pharmacist says that's an antipsychotic, that might be not too good. So we're changing the terminology to call them central neuromodulators consistent with neurogastroenterology that we're dealing with, antidepressants and these other agents, centrally. Or in the enteric nervous system, linaclotide, alosetron, delta ligands, pregabalin, gabapentin-- these are peripheral neuromodulators working on the enteric nervous system. And we're hoping-- and you'll see this more and more in the GI field. Doctors are now using this term more, because it's much more accepting by patients. I don't think we have time to go through all of this, but I did want to show you that the classes are the central agents here. You're familiar with it. Most people are familiar with the tricyclics. We are gravitating toward the SNRIs because of lower side effects. The tetracyclics SSRIs are helpful for anxiety and depression, but not for pain, and the atypicals can be used to augment the azapirones. All of these are used in GI. And then we have the-- you've seen the NMDA agents. We use memantine as a third generation. It's a cognitive-- improves cognitive function, but it also activates NMDA receptors, and we use it as third line for treatment of pain, particularly in our older patients. And of course, you're familiar nowadays, it's become very trendy to have these ketamine clinics for treating not only depression, but chronic pain. The peripheral agents we've talked about, and we've talked about the opioids. So the rationale for these treatments is that it does treat psychiatric and brain-gut comorbid conditions. If they have anxiety and depression as well, they're going to have a lower pain threshold. But even if they don't, these medication works because they have peripheral effects, and it improves the brain's pain regulation, and, as I'll show you, may enhance cell growth. So you have the signal going up to the brain. This is the somatosensory cortex for somatic conditions. But visceral conditions go here to the limbic system, which includes the medial thalamus. The insula is the somatosensory cortex of the gut. And this is the cingulate cortex, which is associated with downregulation of pain, as shown here. So this is the system we're working on, and I want to show you an interesting experiment where they induced pain in healthy subjects using heat stimulus to the arm. And what they did is they measured pain threshold. But what they did is they tried to see if inducing a depressed mood would affect that, and so they had a neutral condition and a depressed condition in healthy patients. Now, for the depressed condition, they induced the depression by doing two things, and this gets back to Dr. Scheiman's point. They did the dichotomous effect. They had them also do Velten statements where they had to repeat repeatedly, I am worthless, life is not worth living, while they played in earphones a morbid song of Procopius of Russia under the Mongolian yoke at half speed, which is a very slow, morbid condition. And then for the neutral, they did Velten statements that were like, life is good, the sky is blue, and they played a more upbeat song for them not at half speed. And they were able to show that they had a more depressed mood by estate measure, this group. And then when they did the heat stimulus, this group reported far greater pain, significantly greater pain, than the neutral. And when you look at the brain area, you're looking here at the cingulate cortex and the somatosensory cortex, how much greater activation there is than the neutral. And the areas of downregulation of pain were not occurring here. So that's a good example of how an acute having a bad day at work can do something in terms of pain signal. And the antidepressants can affect motility. The tricyclics with neurotonergic effect can slow things down. And the SSRIs, is the side effect is diarrhea, because it speeds things up in the battle. And it can even reduce pain if-- these are three tricyclics. If you increase the dose, this is a RAP model, you see reduced signaling going to the brain from the gut. The pelvic nerves reduce their signaling. So in addition to that, they reset the dysfunctional pain regulation. The neurogenesis theory is that when chronic illness, social stress, drug abuse, trauma, all of that plays a role based on your genetic susceptibility, you can lead to a vulnerability where the neurogenesis occurring, for instance, in the hippocampus diminishes, and that's the condition that you were seeing earlier with the brain imaging studies. But if you treat them, you can get restored neurogenesis. That's the model. Tarique Perera at Colombia has been able to show this in rhesus monkeys. And here's a good example in humans. When you have chronic pain like a hip, chronic osteoarthritis. This was a study where they looked at the density of the neurons in the cingulate cortex compared to healthy controls, and you could-- yellow is showing reduced density. But four months after hip replacement when the pain goes away, the orange is showing increased density compared to their pre-treatment levels. So this is against controls, and this is compared to them pre-treatment showing increased density to occur. And here's a mouse experiment where they produce brain damage. And they went and had them go through a maze as a novel object recognition, and the brain damaged mice showed decreased performance compared to the controls shown in blue and yellow. But the other group that had brain damage, they put him on imipramine, which is a tricyclic. And you can see that after two weeks, their performance actually increased after the antidepressants. And when you sacrifice them and you look at Ki67 positivity, an RNA precursor of neuronal cell growth, you're seeing greater density in the imipramine group at two and four weeks. So that's presumptive evidence. It's not there in humans yet. We're just beginning to understand it, but there's presumptive data showing that this may be playing a role. So I want to-- this is just showing you the neuromodulators briefly to point out that tricyclics can be good for pain, because they have noradrenergic and serotonergic effect, but they're dirty drugs. They have histaminic effect, other muscarinic effects giving you dry mouth, blurry vision. The SSRIs are pure serotonin, but they don't help pain. The SNRIs are better, because they work. They have noradrenergic and serotonergic. And this is the Remeron. So this is the point to be made, that when you're treating, if you use these tricyclics, you have to expect there'll be side effects. But if you use an SNRI, you won't get those side effects. So you can push-- here, if you push the dose, they get symptomatic side effects, and the SSRIs don't really help for chronic pain. So I think, just to give you a sense about it, the tricyclics you can use in 25 to 75 milligram doses, and you can adjust dosage up to 150. We did that in our-- we had an NIH study looking at that. I would prefer you use the secondary means, because the secondary means shown here have less of these side effects. SNRIs we prefer because of the less constipated effects. In this patient, I would use that over a tricyclic. The main side effect is nausea, which you can reduce by giving it to them with food. And the SSRIs are not helpful, but they do help if anxiety is a dominant feature. Behavioral treatments also work, and this is data to show how the number needed to treat could be as good or better than many medications that we use for these disorders. When do you want to select someone for psychological treatment? Well, some of the guidelines you could look at is they've been told by the provider. You, as a provider, you tell them that they have a disorder of gut-brain interaction, and they're accepting that rather than a psychiatric problem. They're open to the possibility of behavioral change. They can make connections between stress, anxiety, and symptoms. They agree that they're coping could be improved, and they have time to participate in therapy. We had an NIH study looking at CBT, and we found the predictors of a good response were three conditions-- they felt they could achieve a control over the symptoms, they felt that the symptoms were changeable, and they had a good relationship with the therapists. So that's when they had better effect. They're unlikely to benefit if they have severe psychopathology, so they can't do the work of the therapy. They have a personality disorder. If they have an eating disorder, sometimes beliefs are so fixed that they are not willing to engage. No insight and unable to commit treatment and substance abuse. The last concept is that of augmentation, which is what we do in our program, because they come to us already been on these medications, and it's not working or they have lots of side effects. Have you ever had a patient say, every medication I have, within three hours, I have severe side effects, and I have to stop it? Well, we've shown from a study with desipramine that those side effects are not related to the drug. They're related to anxiety. We found that at two weeks out, their SEL scores correlated highly with the severity of their side effects, whereas blood levels or pill counts of desipramine showed no correlation. So that's where the work of the psychologists could be, or you in working with them, or if you come to the workshop we'll talk a bit about that. So you do combinations, and the first set would be to increase the dose and then augment, or you could do a combination with psychologic-- have a partner working with it. And this is, I think, the last slide or next to last slide that, as I mentioned, the SSRIs are for anxiety, but the TCAs and the SNRIs are more for pain. And when that's not working, you then do augmentation. And we've looked at-- we've used the atypical agents like Seroquel or quetiapine. And again, we can give you that information. You can email me, or Jeanette has the article. And then the other augmentation is the psychologic treatment or sometimes the azapirones. The last slide, I think, is that we put them on the medication for 6 to 12 months, because you can get symptomatic benefit in a month or two. But if you really want to effect neuroplasticity, you have to keep them on it longer. And this has been shown in psychiatry in a bed analysis of 4,000 patients. Continue treatment after they got better reduced the odds of relapse by 70%. So we usually keep them on it for about a year or so. Oh, this is the last slide on pharmacogenomic testing. People are becoming more aware of getting DNA profiles looking at genetic factors that affect metabolism of the drug. So if they're a slow metabolizer of a drug, they might be more likely to build up side effects. If they're a rapid metabolizer, they may not respond. So in about a third of my patients who are like this patient, we tend to do pharmacogenomic testing to help guide us and to reassure the patient that there could be other options. So I'll show you the last video where-- and if you stay for the workshop, we'll go into more detail. But here's the effort to try to deal with this to at least engage her. We don't get full benefit, but we get enough to forward. Well, Ms. Byers, from the exam, I can see you are having a lot of pain there. Even on my exam, you have a fair amount of stool over on the right side. So you have a lot of constipation. Yeah. I agree with you that maybe that the constipation is not causing the pain, but we have to try to figure out what our best treatment option is for you. I don't know how much you know about what's going on, and I wonder if we should take some time for me to explain to you why you're having all these symptoms. Would that be OK? Sure. Well, you know, it may have began when you went to Mexico. You had some occasional pain in childhood, but when you went to Mexico, you got something that we call post-infection IBS. And when you got an infection, what we find, as you see here, that the lining of the bowel can get disrupted with an infection because of bad bacteria, and that leads to bacteria coming in, and it actually alters the nerves, and this is what we call visceral hypersensitivity. So with you, if you eat a meal or if you just have pain in general, you're having much more pain than someone else who didn't have this occur. So this is what happened at the level of the bowel, and that's how it may have started for you. But it got to be more challenging. Now, I want to show you this diagram that what you have is really a combination of increased sensitivity of the bowel, we call that visceral hypersensitivity, from that infection, and a failure of the brain to control that pain that's coming from the bowel. Now, if you're running a race and you sprain your ankle, you know, during the race, you may not feel that pain, right? Yeah. And then after the race, you might not be able to walk. Right. Why do you think that is? Because of adrenaline? Well, that's pretty much something like that. What's happening is that the brain has the ability to control what's going on in the bowel in terms of pain and motility. And in these conditions, you have not only increased what we call signaling, or activity going to the brain, but a failure of the brain to control it. So we'd have a dysregulation of what we call the brain-gut axis. This is going to continue and maybe even get worse, because the pain is making you anxious and depressed. You are upset. You're getting no relief from anybody. You're getting frustrated. You feel nobody understands you. Yeah. And in that regard, that's affecting your brain and making it even more difficult. You know-- The pain's not in my head, it's real. The brain is not doing its job of controlling the bowel. So we have to be able to resolve not only the pain, but the emotional distress around it, because that's making the pain worse, too. And you know, what we've learned is that over time, the brain starts not only to lose its function, but we have evidence that the brain cells can actually die out. Recall that neurodegenration. Now, that sounds really bad, doesn't it? But there are treatments that we can use that can help regrow those nerves. We call that neurogenesis. Yeah, that's helpful. Thank you. No one's ever shown me that before. OK. So some of the things we can do is that at this point in time, the IBS component has become maybe less important than this chronic abdominal pain, which we call centrally mediated abdominal pain. And the effect of opioids, which are making the constipation worse, and it might even be making the pain worse, we call that narcotic bowel. Well, what I'd like to do is to work with you to put you on a medication that might help improve the brain's ability to control the pain, and we call that an SNRI. It's a type of antidepressant, but it's one that's used for pain in particular. In fact, some of the SNRIs aren't even used for depression. They're just used for pain. Oh. And let me ask you this-- if you could feel 25% better in a couple of months, would that be helpful to you? 25? Yeah, that would be great, because then I could maybe get my job back. Well, and let me go further that we want to keep you on it for longer, for maybe about a year, because then we might be able to take you off the medication, and you may not have to go back on it again. These medications and these treatments might help to regrow those nerves, rewire things so that eventually you may not able to be on it. Wow, that would be great. My concern is that the narcotics are contributing to the constipation. Now, we can put you on medication for the constipation due to narcotics, but I'm also wondering if eventually we can get you off of narcotics completely. But not right-- like, not today? Well, we can discuss that. We're not looking to abandon you in pain. So eventually, we may want to take you off it, and we can decide together about that. OK. We'll make that decision together? Right. OK. So if you're OK, we're going to talk more about the medication, and then we'll set up an appointment to see you in about two or three weeks. OK. OK? All right, that sounds good. Thank you. OK. So the key points from the interview is what did I do different? I validated the symptoms. I stated the diagnosis using diagrams and gave clearer physiologic explanations. What we're learning is that when a functional diagnosis is made, whether it's GI or otherwise, the doctor does it with hesitation and uncertainty, and the patients go away not hearing that they had that diagnosis. Whereas if it's a structural diagnosis like Crohn's or pancreatic disease, you have Crohn's disease, and they know what they have. So that has been associated with more procedures when the doctor's uncertain and the patients hear less. So making a positive diagnosis is critical. Giving a physiologic explanation that this is not psychiatric, it's a dysregulation of a system-- the brain-gut axis. And then you check with the patient's understanding, and then you kind of say, we're not going to do further studies. You want to get away from the idea of finding something that's being overlooked, that you want to try to focus on management and use the idea that if you're starting to get better, you probably won't want to continue with studies. You give the rationale for the neuromodulators. Realistic expectations for a satisfactory outcome, I use 25%. And you work together. And we accepted her choice. She didn't want to come off opioids now. But what I've done is I've established a relationship that might later lead her to be more willing to come off, especially if she's getting some improvement and agreeing to work with the patient and not abandon them. I often use this diagram. And then the last thing, very important which we'll cover later, is have I answered all your questions. And patients don't want to be abandoned. Regardless of how things go, we'll work on this together. Thank you. [APPLAUSE] Given our time crunch, we're going to hold questions. But if you'd like to stay for the interactive workshop, that'll start here in just a couple of minutes. Dr. Drossman, thank you so much for being here.