Dan Martin, MD - Tomatoes, Placebos, Nocebos, & Theories: Educating Medical Professionals on How to Give Your Patients the Right Treatment They Deserve
Patient Awareness Day 2019: HEALTHY MIND & HAPPY PELVIS
Living Your Best Life With Endo
March 10, 2019 (8am - 5pm)
Einhorn Auditorium, Lenox Hill Hospital, New York City
https://www.endofound.org/patientday/2019
[inaudible 00:00:13] I would, really, to appreciate all the work of all the staff of Lennox Hill Hospital and all the staff who work with Tamer for putting this together. This has been a rewarding and enjoyable meeting. I had to change my slides last night because of this meeting because there were things that got ... I read a lot. For any of you who haven't been on my website and looked at my theories paper, it now has 204 theories and concepts and is 33 pages long. Has close to 16,000 words. So I read a lot, but there were things coming up in this meeting that I hadn't seen before. One of the most amazing was Marc Possover's and what he can do in terms of taking not only endometriosis off nerves, but how he manages nerves in patients who are paraplegic, who don't have motion, and some of the changes that are happening there are gonna be amazing.
We'll go back to my talk. We're gonna talk about four different things in quick succession. The first has to do with the concepts and theories ... Okay, for those who wanna see the file, that's where the file lives. It's just danmartinmd/EFA2009.html. That link will be at the bottom of the next two pages for anybody who's trying to write it down.
Have no current conflicts. I did a lot of research on CO2 lasers in the 1980s. There's a company who wants me to come back and see if that research would work with the current versions of the equipment. So, I may start that next month.
First, we're gonna talk about tomatoes. Tomatoes are interesting. In the 16th century, we exported tomatoes from Peru to Portugal or Spain, one of those countries in that part of the area. Where we had exported them from Peru to Spain, not as an edible food, but as a pretty flowering crop. They're pretty, but the Spaniards didn't know this. They thought that these were edible so they ate them. We knew not to eat them in the United States and in South America because these come from the nightshade family. These are the belladonna alkaloids, mandrake ... some of these things are poisonous. We know tomatoes are poisonous. We know not to eat them. Spaniards don't know it. They eat them. Promptly becomes a staple crop all across Europe, and we're still not eating them. It's the late, early 19th century before tomatoes become a food crop in the United States.
Now, this is an interesting story, but it doesn't have much to do with medicine except we've done the same thing time and time again in medicine in terms of deciding something works because we decide it works without good data. We're gonna come back to why data is important to you in here and what it might mean. If you look at colchicine for gout, which works perfectly well, we used it from the 5th to the 18th centuries. When all of a sudden we run into the Renaissance and the Age of Enlightenment. And in the Age of Enlightenment, we decide that it no longer works because it's a placebo. That we just think it works. So, for another five centuries, we won't use it. 18th century, start using it again. We still use it today. Multiple examples of why that's true. That's just one of them. The article that came from is Goodwin and Goodwin. They concluded that there are only three things that matter in medicine. Does it help, how much does it hurt, how much does it cost?
For those of you who are in this audience, you know that's too simple. You know that the real decisions look more like that. Okay. All sorts of things. Those are not in order. If you look at the bottom of each of the lists ... the bottom of the first one, we all of a sudden have to be concerned with do you have an in-network provider, out-of-network provider, what access do we have. On the right-hand side, you get into the politics of narcotics. How do I stay off narcotics, and if I need them, how do I get them? Because in this day and time, if you're that very last one, you understand exactly how hard it is to fight the politics if we've got to fight the epidemic. So, we have two different things fighting each other right there that affect this audience more than anything, more than other audiences. But notice, theories not on that list. Theory is to talk about things, to introduce them so we better understand them. Theory has nothing to do with whether you should or shouldn't use the medication.
Placebos. Simple definition: anything that seems to be a real treatment, but isn't. You think it helped, but it really was just coincidental. Why do placebos happen? We can intentionally create the placebo effect by changing pill colors to make them bright and attractive or acceptable. We can intentionally train interviewers to be positive attitudes that will increase the chance that they get a positive aspect. But then there are random associations which are much harder to measure. Was somebody's disease gonna get worse no matter what you did? Was somebody's disease gonna get better no matter what you did? Okay? You just happened to be there when it happened.
Best example I had of that in my entire career was a patient who came in for surgery. I had four surgeries that day. She was supposed to be the second. They're about to call her up. She's 99 4. 99 4's not that bad, but we decided maybe we should wait and see what's going on. So, we moved her to the third case. When we called back the next time, she's 100.1. Now, we know something's going on. By the end of the day, she's 103 6. Had we operated on her that morning, we'd have blamed her interstitial nephritis on us instead of the fact that we just happened to be there when it happened.
People get better because they get exciting new jobs. They get a new partner they're happy with. The last one, getting fired from a job sometimes makes you happier, sometimes makes you sad. Most people don't like getting fired, but I've known people who were perfectly happy to get fired 'cause they were tired of their jobs anyway.
When we look in specific what that means to us in surgery, lots of graphs like this. Where we can see that in the first three months after surgery, we get a significant placebo response that will disappear by the six months out. There are other curves that will generate this out to 24 months so this is just one set of curves. It's not always this set of months. There's a set of curves from some surgeries that you get worse for the first 12 to 18 months, and then finally get better. Most of those are really severe cases where there's a lot of trauma just from the surgery itself. When you get better after surgery, you can't even be sure it's because you did something right. If we had a way of identifying that before surgery, this might be something more than an interesting observation. But since we only know this after surgery, we just know that it happens. We'll come back to that again.
In general, there's several studies there, and what they found out was that if you look at ... do a scope, don't do anything, 43 percent of patients on those series of studies got better. 29 percent got worse. 29 percent didn't change. Again, if you can tell this going in ... A lot of you are going to study markers to diagnose endometriosis. That's nice. I'd like a marker to diagnose endometriosis, but I wanna ... what I really want is a marker that will tell me who's in which of those groups. Because if I know who's in which of those groups, we might be able to keep them out of surgery.
Nocebos. Exactly the opposite. Nocebo is something that seems to be a real adverse side effect so it seems to be bad, but it's really not. Examples: we can make pill colors make you have an adverse response. Remember, it's not individuals we're talking about but a statistical change in what happens if measure a hundred people. If I could tell you who it was, I'd know what to do with this, but since it's only we know it happens to somebody, we can't predict who it is. Negative attitudes of the researchers, the random things, natural course of the disease. I really think fired from the job outta belong here, but I do know that there are people who are happy to be fired.
The most interesting one I read about was the air filters in the chemotherapy unit. If you don't change the air filters in the chemotherapy unit, it smells like a chemotherapy unit. People throwing up all the time isn't a pretty smell. They have to change the air filters if they're doing research in there, otherwise, they get too many side effects just to the smell, the biologic contents, everything else in the air filters. For those of you who are sensitive and have high sensitivities to molds and everything else, you already understand this. I didn't have to tell you. You already know that if you don't keep your air filters clean, you have a problem.
Things that matter again. We wanna go to things that matter for us. The biggest thing is the delay in diagnosis. Now, we can talk a lot about why the delay in diagnosis is, but I think Staal's paper from two years ago ... probably gives us an idea of what's going on. Although we have a median of 7.4 years, it's only 1.8 years for infertility and 8.3 years for pain. Remember, we talk about a median delay of seven or so years, that's averaging out infertility and pain both. Pain's extended even further out. To make it worse, if you're in the 75th percentile, it's 14 years. So, a quarter of all women with bad endometriosis take more than 14 years to get diagnosed. That looks like it's more than just a theory.
If somebody has a disease or problem that they need to have an answer to, infertility people see as a very important thing compared to pain. Your parents would have told you pain's okay. Your friends would have told you they've got pain. People understand pain's part of life. Not getting pregnant's a major disaster. Getting pregnant is supposed to be as easy as falling off a log, but it's not as easy as falling off a log. So if we had the same emphasis on pain that we have on infertility and the same money put into pain that we have put into infertility, then we might be able to do something more with it. When Staal looked at where the delay was, the major part of the delay was in the primary care physicians getting them to a gynecologist. Once they got to a gynecologist, there wasn't much delay because ... once they got them to a gynecologist like David Redwine or Tamer or me, we're not gonna wait too long. But you've gotta make it to us.
In between that, were patient delays. Same thing we talked about before. Pain is part of life. I don't need to see a doctor. This is okay. Positive attitude, negative attitudes, slow things down. So remember, the biggest problem is not theory, it's evaluation, planning. Severe dysmenorrhea, severe pain is not normal. It's simple things like nonsteroidals, complementary healthcare, massage, heat. I'm gonna say resolve again 'cause I have a hard time not saying [inaudible 00:12:05]. Repose is a new word to me. So how many of you have been in to repose systems? So it's a new word to you. It's a European thing. It has to do with relaxation, meditation, thoughtfulness, all those kinda things that go along, and it's a really interesting concept.
In the European studies, heat was better than anything. Repose was the second best. Meditation, those kinda things were down the line. If you spend a few months, two or three or four months, trying those that's fine. But if it hasn't happened, you need to see someone. If someone wants to try three months of hormonal suppression, six months of hormonal suppression, that's perfectly reasonable, and we'll talk about that as we go along. But you don't wanna spend seven years, eight years, 14 years. There's something wrong with that kind of delay. You don't wanna delay for years.
Theories. Theories are really controversial. I've already talked to you [inaudible 00:13:03] my file, I've got 204 of them. Theories, concepts you have to pay attention to. It's not just one. One of the biggest problems we have with theories is that they're almost all the surgeons you saw today, will see today, that we've had at the practice for here, we've studied this and this. We've studied ... this is deep rectovaginal endometriosis. That thing is the size of a golf ball. It's easy to find, hard to operate on. These are bowel surgeries. Some people end up having colostomies with the bag out on the side, those kind of things. By the time you get there, there's no real theory about anything that we're gonna talk about. Which is a statistical problem, but for most patients it's not a biologic problem.
I would love ... Before anybody hears me say this, I wanted to do it, I understand that what I'm about to say is gonna borderline be unethical. On the other hand, it's unethical not to say it. So we're stuck between the two things. I would love to sit back and sit there and somebody do sham surgery on that. Put one group of patient into one thing, one group of patients into another. One groups gets the real surgery, one group gets three hours of anesthesia and nothing. That'd be science. Unfortunately, David, Tamer, I, all the surgeons are trained under the Jeremy Wright Theorem. Jeremy Wright says that's unethical to even talk about that. As much as it would be a scientifically good thing, it really makes no sense to do sham surgery on this.
The other problem comes in to, if this were on the uterus ... here's the uterosacral ligament down there. See that long line. Ovary is that little white dot up there. If this were here, then there'd be people who want to debate whether you should coagulate it or excise it. Problem is, this isn't down there. This is here. That little round thing there is the ureter. When you're sittin' on top of a ureter, you want something that's precise as you can get it. Again, a theoretical concept, but I don't think anybody's gonna disagree with me that you wanna be really delicate around the ureter. For most of us, delicate means we make an incision up here away from the ureter, we pull this thing over, we push the ureter away, and then we can excise it. Technically, that's an easy description.
Now, these up here are where most of the debate's gonna be. For most of you in this audience, this is the debate on what you tell your daughters. This isn't about the people in the room and what you need 'cause most of you need this, one of those two. You have something that's bad. You have deep disease. Nobody's gonna tell you much of anything different. We anticipate that this up here, really it's hard to see the endometriosis there. The biggest lesion on that thing is 400 microns in size. It's about a 50th to a 100th of an inch. There are things in there that are down at 0.08 millimeters. These are real small things. In theory, a hundred percent of women get something like this at some point in their life. Your daughters are gonna do that. Most of you did it when you were younger.
Most of the debate is gonna come in on what do we do about that because if we had markers for that and knew, is there some sort of anti-inflammatory agent? Something that's on the market like ibuprofen or do we need something that's not developed yet. What kind of marker? Some COX-2 inhibitor, something that we can do to shut this down while it's still an early inflammatory lesion so that it won't develop into this. Then we've got something. The little data I have in my practice is if you operate on someone before 18 years of age and you find this, 80 percent are gonna have surgery again within two years. Surgery doesn't stop this kinda thing. Not in teenagers. Now, if David has data that shows me the difference between a 33-year-old with this whose surgery's gonna work on and a 16=year-old with this who I don't think surgery works on, then maybe we got something to talk about.
If you knew which one of these you had, then you'd know what to do. But when you're talking to your daughters and they're beginning to sound like you ... So those of you who had severe endometriosis and talking to your daughters that are beginning to sound like you, then we don't know where we're going here. On the other hand, the reason we have these pictures is 'cause her mother had severe endometriosis and was a patient of mine. We operated on her at age ... this is age 17, 18. She had another operation about two, three years later and that was it. She did fine, had babies, everything went fine. Was that because of the surgery or in spite of the surgery? We don't know. It's just one case. Nobody knows that. We haven't done the studies to determine that.
Then we come into definitions. Paul Dmowski's on the left, Ray Gary's on the right. Paul's gonna tell you this is a systemic disease. We have to deal with the things that yo see, the epidemiology of it ... excuse me, not the epidemiology of it, the pain associated with it, infertility associated with it, immunologic changes. There's a whole lot more going on than just the lesions themselves. Ray Gary, on the other hand, is like me. He was one of those people who had patients referred to him to have it cut out. Ray, like me, cuts it out. Paul would tell you there's a whole lot more to it than that.
We'll skip that one 'cause Tamer's already lookin' at me like I'm gonna run over time. This has been much better studied with irritable bowel than endometriosis. If you look at irritable bowel ... Then if you're looking in primary care early irritable bowel, medication works, physiology's the same. You don't see much in healthcare utilization. By the time we get to stage three, by the time we get to these referral practice, it's a whole different ballgame. Most of us anticipate that endometriosis is like that. If we could intercept it back in here, we might not get to here. Intercepting it here is more likely you're gonna be medical than surgical because what we worry about in surgical is that some of the endometriosis that happens later is not in spite of us but because of us. We don't know is if surgery doesn't actually increase the chance that endometriosis might recur.
Tamer, how much more time do I have? We'll go- we'll go ... Tamer's up and looking anxious. We'll go real quickly. We'll talk about cells of origin, dissemination, transition theories. If anyone really gets interested in theories, I'm really interested in theories. Come down to this little thing down here at the bottom.
Just for cell of origin, that's my outline. Just for the cell of origin. This is not an easy conversation if you're at a theoretical level. We'll look at the retrograde menstruation theory, Samson's. Remember, retrograde menstruation just means that blood goes out the tubes the same way that sperm and eggs transport. Remember that tube and egg transport is designed to let things go through it. By the time a fertilized egg hits the isthmic part of the tube, it's a hundred microns. Remember that slide I showed you with the teenager, some of those things are smaller than that. This thing's designed to bring eggs through it about a hundred microns in size so it's a good transport system. Once it's in the pelvis, it just disseminates through the whole abdomen. What you hope is, that your body's immunocompetent system knows how to shut it down which it's very effective in. I mean, our bodies take care of infection, nonspecific things all the time. It's perfectly capable of handling this. It's designed to handle it. It just doesn't work all the time.
The interesting thing is, it can also get up into the lungs. If we look at that, it will get into the lungs, one of two different methods, and filtrate straight through the diaphragm toward the lungs or we have these little foramen that fluids goes through all the time. If any of you are in pediatric nurses and have ever dealt with someone who's herniated an organ through one of these things, the ones you're talking about are much larger than this. So really large forms of this can be deadly to babies, but these are fairly normal in people. It's easy for fluid to get everywhere. It's possible that once you get lung endometriosis, it can be this. More probably, most people are gonna think it's gonna be hematogenous dissemination. The body just lets it come through the blood stream which it fairly much routinely does in lots of women all the time and the body clears it.
Implantation. Early implantation like this, 1927 pictures. It gives inflammation. The inflammation that we get at this level is the same that we see with infection and cancer. Nothing fancy about that. We've got fancier picture now. We've gone from 1917 to where we take the color pictures of how it implants in the uterus. On the other hand, there's several Mullerian Theories. At least three of them. If you look at Jacques Donnez in France, he talked about remnant endometriosis in the cul-de-sac coming out. It starts off as a Mullerian remnant. Normal every day Mullerian just the same as endometrium, and it changes as it goes through and it becomes endometriosis. There's got to be a transition from a normal cell to an abnormal cell. No matter which theory you use, that transition has to happen.
Studies that show that we can find this even in fetal tissue. These are down in the cul-de-sac. This is behind the uterus. What we see in fetal tissue is a deep endometriosis which represents 0.3 or three percent of endometriosis, but what we don't find in fetal is up and around the ovaries. We don't find in the appendix. We don't find it in all those other places. This likely means that a lot of cul-de-sac endometriosis ... this kinda thing where you have a normal looking pelvis, can't even see anything really abnormal unless you pay attention to the fact that uterosacral ligaments are missing. There are things that aren't there. The cul-de-sac's flat. This looks like a congenital problem. It looks like someone was born with something hat wasn't right. You just got this little deep nodule right there that you don't find by looking at it. You only find it if you knew it was there before surgery because you either had someone pick it up on an exam, pick it up on a sonogram, pick it up on a MRI, and recognize what it was.
Same thing, different patient. Rectum is here. Cervix is there. Everything's plastered together, and the lesion behind that is the size of a golf ball. Big things and that's all you see is the surface of them. If you look at that, what you see is that surface up here, but the endometriosis is hiding. It's one of those tip of the iceberg problems. I don't know anything except surgery that works for that.
The last thing I'll say, we're not gonna go into this because Tamer's already ready for me. This is my last slide anyway. Where we're going in the future is looking at not only the theories we just talked about but theories that are being developed and being matured right now in terms of what's happening with endometriosis and the chance that's actually coming from things like bone marrow stem cells. Bone marrow stem cells are perfectly capable of regenerating or generating endometrium. So these things can turn endometrium. Non-Mullerian. Remember, David and I talked about Mullerian? These guys are talking about non-Mullerian. These things were not destined to become uterus endometrium. These things were destined to become whatever they wanted to become. I think if you're watching theories and where we're going, I'd be watching bone marrow stem cells because it's more exciting.
On the other hand, if what you're trying to do is take care of yourself, you want that thing I had about what's important. What do I have, what are we gonna do about it, how much is it gonna cost, all that other litany of things that you have to pay attention to. Theory's not really important for those.
