All right, let's go ahead and get started. I want to welcome everybody to AAP Virtual Didactics today. We're excited for our guest speaker today. As always, first, we want to recognize and appreciate the people who have been most affected by this COVID-19 pandemic, recognize that not all of us have borne this burden equally, and so we want to recognize and appreciate those of you who are kind of on the front lines of this, so to speak, who are pitching in wherever you are, and we appreciate all of you. So again, the goals of this, as always, are to augment didactic curricula wherever you may be in your program, to offload stretched faculty due to some of the logistical challenges presented by COVID-19 pandemic, and to provide additional learning opportunities for residents and fellows and other trainees that have, we know that, again, logistics of this have caused a lot of off-schedule situations, and so we wanted to assist with additional learning opportunities to develop more digital learning resources and support physiatrists in general during COVID-19 housekeeping stuff. We're going to keep everybody video and audio muted, so if we stop your video or mute you, it's not personal, it's just about bandwidth and trying to limit distractions. You can, if you have any questions that come up over the course of this lecture, please send them to me. You can find them in the participant list. Again, my name is Sterling Herring, so it should be up near the top of the participant list. You can send me a message, and I will pass along Dr. Iaccarino as opportunities present themselves. I want to also remind everybody that we have a second lecture after this. Dr. Chris Visco is going to be joining us and giving a second lecture at noon Central Time, so that's one o'clock Eastern. If you have any general questions, suggestions, or concerns, there's the email address for Candace Treat at physiatry at AAP, or you can find us on Twitter. So without further ado, thank you, Dr. Iaccarino, for joining us. We're excited to hear from you. Thanks, Sterling. Good afternoon, everybody. Thanks for having me back. I'm going to share my screen here. Oh, let me get back to it first. There we go. So good afternoon, everyone. My name's Alexis Icarino. I'm a physiatrist at Spaulding. Thanks for tuning in. Today, we're gonna be talking about a topic that is near and dear to me, and I think it's kind of fun, so it may not be on your boards, but I think it's an important topic, and I hope that you'll just enjoy sitting back and listening and hearing about placebos and their inverse or negative, which are nocebos. So this was already discussed, but I just wanna reiterate that this lecture is being conducted for remote resident education during COVID-19. It is solely for that purpose and should not be reproduced or duplicated, and it's not for CME. Okay, so what do I want to convey to you all today? Why the placebo effect is really, really important and why you need to think about it, know it, and understand it in your practice, how it's evolved over time, how we think about it, some mechanisms by which it works, and then why it might be important for us in post-acute care, in outpatient care, and why we really, really need to know and understand this. And I hope that by the time this lecture's over, you will not really think of placebos as empty bread pills. Placebo is actually a very powerful phenomenon that will impact our patient care and also might be something we can harness and use effectively in practice. Okay, give me one second here. Okay, and then the other reason we should really know about this is that in a study back in 2008, a national survey, 50% of US physicians openly said, yes, I use placebos as treatments on a regular basis. And then they're asked about, well, which ones do you actually use? All kinds of things. Amnesics, which is a mainstay of physiatric practice. Vitamins, even antibiotics, sedatives, right? These are US physicians who are openly using these things, knowing that what they're really getting at is probably a placebo effect. So I'm sure if we all did a little internal soul searching on our clinical practice, we too might find times that we've used something that we didn't know would have a true physiologic benefit, but thought it might ease patient's concerns or ailments. And so I just wanna take us back a little bit to the history. I think it's just so interesting to think about placebos over time, right? And this actually in the 1700s, the second half of that century was when scientific skepticism arised, where the idea may be that not everything we did that patients felt was beneficial actually had a scientific or physiologic merit, right? And a couple of these examples, some which are still in use today. So the first would be mesmerism, right? Mesmer, he thought that he could exert an electrical energy over inanimate objects. And in fact, there were physicians that conducted the first blinded experiments. They blinded a young boy to which tree in a garden had been mesmerized. And the young boy couldn't figure out which one once he hadn't seen the laying of the hands by mesmer. So it was one of the first blinded studies. Perkinism was this idea that you had to have a metal rod with two metal ends and you put this expensive piece of equipment onto the ailing body part and it had healing properties. And there were eventually studies conducted where they used wood rods or a sham rod instead of these expensive metal rods and they got the same effect, right? So perhaps the first sham study to disprove this idea that these metal rods had healing properties. And then homeopathy, which is something that's still in practice today. Folks actually replaced these homeopathic remedies with bread pills, which were the first placebo pills and saw similar benefits. And something that was a constant throughout all of these experiments really was, well, then why do these things work? And it was thought that this was a function of patient bias or the imagination, the patient's imagination that they were getting better. Or it just represented spontaneous remission of disease, right, that a lot of things just get better. And so whether you treat them or not, it doesn't really matter what you treat them with, diseases remit, right? But this idea that it was the patient's imagination or belief system that just induced their response to these things. Okay, fast forward, World War II. So Henry Beecher was an anesthesiologist at the Mass General and he was a World War II medic, right? And he ran out onto the field to do field amputation. And when he got out there, there was no morphine left. And so he thought, how am I gonna reduce the pain to do these field amputations in these injured soldiers? And there was a very astute nurse who hooked up an IV and she injected saline into the patients with the exact same enthusiasm and intensity as she would a shot of morphine. And the patients who got saline reported that they too felt that the pain went away. And he in fact observed this, that about 40% of those injured related that this solution, which they believed was morphine, but which actually saline, eased their pain. And so he was really taken aback by this, right? I mean, this is not just a modest ailment. These are wounded soldiers. And when you give them a shot of saline under the guise of morphine, they actually felt significantly better, right? I mean, this is just a revelation for Beecher. And he went on to study this over his career. And he conducted one of the first sort of quasi meta-analyses on the placebo response. So who's seeing placebo benefit and how much of it do we actually see? And so he looked at 15 studies on placebos that had placebos in them, about 1,000 patients. And again, this is back in the 50s. And he found that patients in placebo groups, about 35% of the time, they had a response. They got better, right? And if I told you that we had a medication or a drug that worked for about a third of people, particularly in PM and R, we treat a lot of refractory disease, you might say that's not such a bad thing, right? 35%. The other thing that Beecher observed is that people in placebo groups had side effects, right? There were these toxic effects that were observed in blinded placebo subjects. And they were all kinds of things, dry mouth, nausea, drowsiness, about half of people got a placebo were drowsy, fatigue, difficulty concentrating, headaches, right? So these placebo groups who believed they were getting treatment but weren't, not only were they seeing a benefit, but they were also seeing side effects to this response, right, and that really piqued a lot of people's interest. And so there are a lot of thoughts that placebo is different than really not giving anybody any treatment, right? Something is happening when we give people placebos. And this is a more recent paper that looked at how the context and the environment might affect who has a placebo response, right? So these external contextual factors that go on in clinical encounters that really influence what people think or expect will happen to them. So how I talk to a patient, what kind of cues are happening, even everything from the exam room to, do I wear my white coat? Am I dressed professionally? How do I look at my patient? What is my body language? Obviously treatment cues matter, needles, syringes, devices, procedures. And not only are those external factors, but also these internal contextual factors. So what does the patient, what is their prior experience with these sort of things? If patients have the prior experience that when they come to the doctor, they feel better and they feel cared for, that will affect how they respond. If they have had prior experiences where going to the doctor has felt harmful or threatening, then that may seriously influence their response. And then there are also some precognitive associations that impact placebo responses. Okay, but is it more than that, right? Is it more than just patient perception or as some of our earlier colleagues thought, the patient imagination, right? Is there a physiologic change that actually happens when you give someone a placebo or its inverse nocebo? And that's what we're gonna dive into right now. And I guess I wouldn't be asking this question if I didn't think the answer was yes, right? So I'm gonna show you some evidence. So the earliest evidence for the physiologic effect of placebos came out of the pain literature. And this was observed by groups who used opioids and placebos. And they found that the placebos had similar properties to opioids in a couple of different ways. One was that people got tolerant. So like opiates, people got tolerant to placebos. They needed more and more placebo to get the same benefit. There needed to be a dose escalation. And then also people would experience some withdrawal symptoms, right? And so there's this hypothesis that well, maybe placebos induce some process that causes a similar effect to the process that's induced when someone gets an opiate. And this is the concept behind endogenous opiates or as we now know them, endorphins, okay? And the original work that looked at this was by Levine's group. And if you're going into pain, you definitely wanna have read this paper, I think. I think any physiatrist should read this paper, but particularly if you're gonna be thinking about pain management. So this is a group of dental patients, okay? And they gave these patients, let me get my cursor here. They gave these patients, they divided them into two groups, okay? And some patients get placebo. So actually everybody in the groups gets placebo here at the first hash mark, right? And we can see what happens to their pain levels. And then they give the group with the open circles here naloxone, right? Which we know would block opioids, but also if there were endogenous opioids like endorphins could block those. And what we actually see is that the group that gets naloxone, their pain shoots up after they get the naloxone once they've had placebo, implying that in fact naloxone can block the effect of placebos, right? So there's something physiologic happening there. And then that group also then took all the people who got placebo and they noticed that, well, some people have a much more robust response to placebo than other people. So not everybody is gonna be a quote placebo responder. And they again took patients, dental patients, measured their pain level, gave everybody placebo, okay? And then gave again naloxone, okay? At a second time point. And what they see is that your placebo responder group again responds a lot better to the placebo as indicated right here, and has a much more robust response to naloxone actually returning their pain up to the non-responder group, okay? So this is early studies that there is a physiologic change that happens in the body when you give somebody a placebo. And so we arrive at this modern day definition, right? The placebos are not actually just make-believe or the patient's imagination, but they're any drug device treatment, right? That does not necessarily have a direct therapeutic effect on the body, but can produce some indirect benefit or potentially indirect harm when placed in the appropriate context, right? And we'll talk about these contextual factors, this what people anticipate will happen and really changes what actually does happen. So one area that I always think that this can have huge effects is in devices. And I'm just gonna use one example of TMS, which is something that is used in physiologic practice a lot, right? So the TMS has this large device for anybody who's used it or seen it. It's often placed over the head. This is a little bit of an older product here, but it delivers flow of current and this causes vibrations. It causes a clicking sound to occur when the device is on a lot of times. And so you can actually, this is just one example of how you could potentially induce somebody to have a response to something based solely on conditioning, right? So if someone hears that clicking sound or that strong vibration, they can believe that the device is on, they can produce a response, right? You can't always blind people to what's happening, particularly when we're talking about devices. So I wanna look a little bit more into these sort of domains of effect, because I think when you see some of the end outcomes that can occur and how placebos can really affect physiology, you might think about how you can apply them or how they are impacting your practice and whether that's clinical practice or research practice. So placebos have been shown to actually cause significant autonomic responses. And again, this is a study from the pain literature. So this is a study of a pain cream, okay? So what they did was they told people that they were gonna get three different types of analgesic creams. The first cream, cream C, is just a wet substance with no analgesic effect. Cream B has some analgesic effect and cream C, or sorry, cream A, is the strongest analgesic, okay? And then they apply a pain stimulus to each of the fingers, okay? And actually, all three creams are the same. It's actually a difference in the perception, right, about what we tell the patients that is different, right? But these are, all these three creams are the same. And what they look at is pupillary diameter, skin conductance responses, and actually EEG, all right? Based, again, on just the expectation of which of these creams is the strongest. And what we see here is that there are changes in pupillary diameter, skin conductance, and even EEG in response to what people expect the pain level to be. So with increasing expectation of analgesia, there are changes in these various autonomic outputs. I often trans-think about that in my TBI population where we see huge changes in autonomics. And so how these placebo responses could affect a group like that, or any other group of patients, particularly those experiencing significant pain. Are there hormonal effects that can happen because of placebos? And I'm gonna show you this example of placebo, but there's also a very good example later of nocebo or the negative effects on hormones. So this was a really phenomenal, interesting study done on ghrelin. So ghrelin is a hormone that's secreted by the brain in response to hunger. And then ghrelin levels go down when people feel full. So this is created by the hypothalamus and very much influence hunger and satiety. So this is a really fun study. They took groups of patients and they exposed them to two kinds of milkshakes. So just hang with me here. One had this label here at the top, the indulgent shake, and the other was the census shake, a low fat shake. And you can zoom in if you want on the nutrition facts, but the indulgent shake has lots of fat and calories and the nutritious shake has zero fat and very few calories and no added sugar. Okay, and the first thing they did to patients was they just had them, for the subjects, was look at the labels, okay? And they wanted to get people's perception of perceived healthiness of the different shakes. And so people look at the label and they think the sensible shake is healthier than the indulgent shake, okay. So then what they did was they actually measured people's serum, so blood ghrelin levels, hormone levels, right, and here's what they see. When people are observing these two shakes, as indicated between bullet number one here and the second bullet up here, when people look at the sensible shake, their ghrelin levels don't go up very much. And when they look at the indulgent shake, their ghrelin levels go up, so they get really hungry, okay. And then when they actually, here at this time point right here, they actually drink the shakes, okay. And the people who drink the indulgent shake, they get really full, their ghrelin levels go down, and the people who drink the sensible shake, they're not so full, right, because it's not as many carbs, not as much sugar, not as indulgent, okay. In fact, these two shakes are exactly the same. They have exactly the same contents, right. The only thing different about them was the label. But they induced, just based on the label, significant more hunger, right. So this sort of deception that one is going to taste so much better than the other. And then we actually have people whose response, both their perception, but also their physiologic response is that they're a lot more full after drinking the indulgent one than the sensible one when it's the exact same contents, right. So we can have huge neurometabolic and hormonal effects just based on perception. There are also other paradigms that have looked at this. And one very good example is neuroimmunologic effects of placebos. So you can pair using conditioning, right, which is a common method. You can pair cyclophosphamide, for example, which has a strong immunologic effect and is immunosuppressive with saccharin, which is a very sweet, sugary substance in animals, right. And you can pair those two things. And you can see suppression of antibodies. You can see reduced thymus and spleen weights when rats are exposed to cyclophosphamide. You can then actually take away the cyclophosphamide and just keep that sweet substance that you paired it with. And again, see similar reductions in thymus and spleen weights and antibody suppression. So you can actually, through conditioning, and again, pairing a strong substance like a taste paradigm, a sweet substance with cyclophosphamide, you can get end organ effects when you take away the cyclophosphamide. Similar conditioning odor paradigms, you can pair an electrical shock, which can suppress different immunologic properties with an odor and then take away the shock, continue the odor and see similar suppression. And you can also do it in an environmental paradigm with morphine that's been done and you can see reduction in interleukins and other immunologic factors. So all this to say that you can induce major changes immunologically through conditioning paradigms and placebo related effects. Okay, we've seen a little bit of placebo. I wanna touch briefly on its opposite lesser known phenomenon, which is the nocebo, right? So this is the negative impact of things like expectation and conditioning. So just to give you an example, and we showed you the example from the Beecher study really early on in the 50s, but this is a more recent study about Maxalt, which is a powerful migraine medication. And this was a study that used Maxalt and placebos, and they looked at reported adverse effects of patients who were receiving either Maxalt or placebo and these patients were blinded to which drug they were on. And in fact, you can see that the placebo group has a lot of side effects in this study, chest tightness, heart palpitations, skin sensitivity, GI problems, drowsiness, other things, unusual things, tingling and dry mouth and moodiness and tiredness, right? And it happens kind of at a similar rate as the treatment group, right? So this is where, again, the expectation that you're getting a drug, that you're in a clinical trial, that there could be side effects can actually play a part in potentially inducing those side effect like symptoms. So again, does this have a physiologic component to it? And I wanna show you a really interesting study. And if you like this, I highly recommend that you read more work by Dr. Benedetti, who is an Italian scientist who does a ton of work in placebo and nocebo. And this is a study that really looked at the physiology of nocebo. And again, this is most well seen in the pain literature. So what they did was they took patients and they gave them a pain stimulus, which was actually to put a tourniquet around the arm, okay? And to leave the tourniquet on for some time. And one group, which over here on this chart is the open circles, and then another group here is the closed black circles. So the black circles recommend the group that just gets a tourniquet. And then the open circles represents a group that gets the tourniquet, but they also get nocebo. And how the nocebo is given is three ways. So one, they tell the patients, this is a power, they give the patients a pill and they tell them that's an, but they tell them they're getting a powerful basal constrictor, okay? They also tell them that because they're getting this, that the pain intensity is gonna be, it's gonna come on faster and it's gonna be much stronger, right? So they induce this anticipation that pain is gonna be a lot worse in this group. And then they say to them, and you can give up at any time. So this stressor environment. So you can, we want you to try to hang in there as long as you can, but you can give up if you need to, because the pain's gonna be so bad, right? So these are their nocebic effects. And in fact, the people who get these nocebic components, suggestion, anticipation, and a stressor, they have more pain here in the open circles, okay? Not only do they have more pain intensity reported, but they have a significant physiologic response to that pain. So if you look centrally at ACTH levels or at stress hormone levels centrally, they're higher. And then also peripherally, cortisol levels in this group are higher, right? So this, giving people the perception that something's really, really gonna hurt, not only makes it hurt more, but it actually causes increase in their stress hormones physiologically, okay? I think about this the next time I put a needle into a patient and tell them this could hurt. But what's really driving all of this? Is it truly the pain that drives this, or is it the anticipation, right? This nocebo, the anxiety about the pain. And so what they did with this group now is they gave these patients two different drugs. One time they gave them diazepam, right? So blocks anxiety. And the other time they gave them this drug proglamide, which blocks a receptor, blocks a neuropeptide called CCK, which is actually responsible for the pain response, right? So on one side they give people, they block the pain and the other group they block, well, you could say the nocebo effect, right? The anxiety and the anticipation. And what they see here, again, looking at stress hormone levels is that the people where you block the nocebo effect, right, the anxiety and the anticipation, we also see reduction in ACTH and cortisol levels. Whereas if you just block the pain, but you don't actually take care of things like the anxiety and the anticipation factors, you still have higher, significantly higher stress hormone responses, both centrally and peripherally, right? So it's not necessarily the pain stimulus itself that's causing increased physiologic responses, but it's actually these nocebic suggestions that cause these physiologic changes. Okay, so we can obviously see how pills and anticipation can impact people, but I want to talk a little bit about devices and procedures, okay? Because when somebody consents to getting a procedure, surgery, or an injection, right, the expectation that it's going to work is even higher than if you just give them a pill. I would argue that. I think most people would. They're accepting significantly higher potentially risk, right, and it's much more dramatic activity to physically go in for a procedure, right? So the expectation is high. It's a higher order of therapy, okay? And I'm going to pause here and actually play a little video from you from the BBC, which is available online. So I didn't take it from them. You can just Google it and get this excerpt. On what happens and what the expectations are around surgical and procedural interventions, and this is related to a trial that we all might know very well, which showed that perhaps for tuberoplasty, which was something that spine physiatrists did all the time, may or may not truly be as helpful as we thought it would be. So I'm going to play this for you right now. After I agree now, I don't think we're able to hear it. You're not able to hear it? No. Oh my goodness, that's terrible. I'm so sorry about that. Oh, I thought it would work. I'm just wondering if there's a way. Maybe if I, I'm sorry, please bear with us. I think this is a really great video. So I want you all to be able to hear it, but let me see. Sterling, let me know what you hear here. Can you hear that, Sterling? I can hear it very quietly, yes. You can? Yes. Is it loud enough? Why don't we try again and see? A few years ago, Dr. Decker. Yes. Okay, so let's listen. Okay, now we can't hear it. All right, let me. You can't hear it? We cannot. If you click the little arrow next to your mute button, your microphone button, you may be able to share your audio that way. Okay, we're gonna give this one more try, everybody. Thanks for hanging in. Thank you. Can you hear it, Sterling? No. All right, guys. Well, I'm terribly sorry. I'm gonna summarize it for you, and maybe I can try to find a way to make the link available, or I would just recommend that you Google the BBC and this particular study. So essentially, okay, Candice says she'll make the link available. Okay, so essentially, Dr. Kelmer's group, and you should go read this New England Journal paper if you have time. They were doing vertebroplasties, and they found that every once in a while, they would inject the wrong level with the right hormone. So they would inject the wrong level with the right hormone, and they would inject the wrong level with the right hormone. And every once in a while, they would inject the wrong level with cement, but that patient still did well and felt better. And so they decided to conduct a blinded study of vertebroplasties in patients with fractures. And so they conduct this extraordinarily elaborate study. Every single patient who gets enrolled, whether they're gonna get a real vertebroplasty or not, they get injected, they get brought in, wheeled into the room, they open up the cement, which has a very strong nail polish-like odor, they prepare all the substances, they would numb every single patient, and this is whether they were gonna get the treatment or not. And then only before they were gonna inject the cement, would they open up a folder to see if the patient was randomized or not getting vertebroplasty. For the patients who did not get the vertebroplasty, they went through this script where they actually would tell the patient, okay, we're mixing the cement, now we're gonna inject it. They would put pressure on the back like they were gonna be injecting cement so that it felt like the patient was getting an injection. And then, okay, ma'am, sir, you're all done. And they go out to recovery. And so really, they went through every single step that you'd otherwise go through except injecting that cement, okay? And what they found was that both the patients who got vertebroplasty and those did not did equally well in their recoveries and with pain, okay? So going through this elaborate process, the odor associated with it, getting the procedure, believing you got the procedure, and this whole elaborate ruse actually in some unusual way and unexpectedly, patients got significant benefit from it. And when you watch the video, there's a really great little old lady who had a fracture and then is now back playing golf and she's very active. And she says, oh, yes, the procedure really worked for me. And in fact, she's in the placebo group. So again, we'll make this available to you guys. And I apologize that it did not work. So that's procedures. What about devices, right? So if I was gonna give someone a placebo and I wanted to get the most bang for my placebo buck, so to speak, would I give them a pill or should I give them a device? Like some sort of product to go home and use. And so this was a study of patients with upper extremity pain where they did only placebos. So sham devices or sham oral placebo. And in fact, sham devices seem to work better for pain than oral placebos. So just interestingly, kind of like procedures, devices have this higher level of expectation that they might work. So next I'm gonna talk a little bit about this concept of social infection and psychobiology. And so if we know that there's something to expectation setting, then what does all the things that our patients are exposed to impact how they might respond to our treatments? And I just pull up here all the potential things that patients are exposed to, right? They Google, they read on blogs, they hear about things on Facebook, they see commercials on TV, right? If I take Lyrica, I'm gonna be really successful female builder. And if I take Cialis, my spouse and I are gonna be in empty bathtubs on the edge of a cliff. I don't know what the appeal is there, but these commercials, things we read, things our patients are exposed to are going to affect how they respond to our treatments. And we have to pay attention to that. And in fact, there was a paper published a couple of years ago now that drew attention to the fact that in U.S. clinical trials, the response to placebo was going up and up and up. The placebo groups were responding more and more. And one of the thoughts actually was that, being allowed to have drug advertisements on television, having people reading more, getting exposed to more to medication and drug ads online, actually might influence their responses in clinical trials and that might be impacting clinical trials on a large scale. So what about all this expectation setting, right? So we see that there are dopaminergic responses to expectation setting. And so this is a neuroimaging, it's a PET neuroimaging study. That's actually looking at Parkinson's patients and dopamine. And what we've got here is, they gave patients, this is a baseline scan right here in the first two. And then we've got Parkinson's patients who are getting levodopa and then Parkinson's patients getting placebo. And they're giving a radio tracer such that the dopamine receptors are lighting up here in orange. And when you induce expectation that somebody's getting, going to get levodopa in the, this is for the placebo folks, even when they don't actually get it, you can see that the dopamine receptors are not available for binding here like they are in the red for the baseline. So these placebo folks have similar outcomes in this PET scan to the levodopa group. And what that actually means is that these people are getting exogenous dopamine, and that's binding their receptors. What's happening is placebo folks is that when you induce the expectation that they're going to get levodopa, they actually release endogenous dopamine such to the extent that they bind similarly, similar efficacy to the levodopa group. So a lot of this expectation has neuronal correlates in our reward pathways and in our dopamine centers. So if expectation matters, how much expectation matters, right? So let's say in practice, I want to use, I want to harness the power of the placebo effect in my practice. Then if I'm going to give somebody a drug and I think, well, maybe they'll have some placebo benefit to it as well as its active benefit, should I say to them, this is definitely going to work for you, right? How much expectation should I give? And so this is a study actually about expectation. And there were four groups here, right? And what they did was they told patients in group A, so this drug is 25% likely to work, or this drug is 50% likely to work or 75%, or they told one group, this drug always works for everybody. So the expectation is that 100% of the time it should work. And what they found with this placebo is that inducing a fair bit of expectation, but not 100% actually got the biggest placebo response. Okay, so telling people or setting the expectation that this really works for a lot of people, but not everyone, okay? If you actually tell people it's a guarantee that it's going to work, that's actually where you get a lot less placebo response. So again, this idea of expectation is very important in giving some expectation, but not complete reassurance that something will work. So I think that's very interesting if we're thinking about the subtle interplay of placebo. The other thing that people have considered is things that are cheap versus things that are expensive. Right, so if you tell, this is a similar study on placebos where now they didn't induce expectation, but they induce cost. So ma'am, I'm gonna give you this new fancy drug that's very, very expensive, new to the market, and it's gonna help you versus the, this is an old drug that's been around for a long, long, long time, right? And what they actually found is that expensive placebo, this is a Parkinson's study, works better than cheap placebo. So when you give people the expectation that something's new and fancy, it works better than if you tell them that it's just something that's been around a long time or it's not very expensive or very exciting. Okay, so again, expectation really matters. Moving from expectation to this concept of what I truly call social infection. So this is again, a study by our Italian placebo, nocebo expert Benedetti. So these are medical students, right? The learned group of people. And what he did was he took medical students and he took them to a bottom of a mountain, okay? And he conducted an experiment in social infection. So let me just tell you this story. He told one medical student, this one circled in the middle here. Sometimes when people climb to the top of the mountain, they get a headache, right? He tells that to one medical student before all the med students climb the mountain. And that medical student, while everybody's still at the base of the mountain, starts to tell the other medical students, right? So he socially infects all these people in yellow, okay? And then before they go to the top of the mountain, they take cheek swabs to look at prostaglandin and cortisol levels in this group. And in fact, those people who've been socially infected, they've got higher prostaglandin and stress hormone levels than the group that doesn't know that maybe you could maybe get a headache when you climb the top of a mountain, okay? So socially infected group already having a physiologic response to being socially infected, okay. Now everybody summits to 3,500 meters and what happens to them? So the socially infected group is here in gray, we call it the nocebo group, right? Of the 36 of them, 31 of them get a headache. Whereas the group that did not know that maybe you could get a headache, the group that was not socially infected, only about 50% of them actually get a headache, right? So social infection really matters. And then very interestingly, they took all these people who got headaches and they randomized them to either get an aspirin for their headache or to get a placebo for their headache. And they blinded them to this or to get no treatment. Interestingly, in the socially infected group of people, they had a much more robust response to getting a placebo for their headache in terms of decreasing their pain and decreasing their stress hormone levels than the control group who was not socially infected, right? So not only can social infection, perhaps in anticipation, perhaps induce people to get symptoms, but it also actually might change their response to getting treatment, right? And so this is, I don't know for all of you, usually I give this talk live and I get to read people's expressions, but this really is quite unbelievable to me that so much could be accomplished through simply biasing somebody prior to an event happening. Okay, so what about your genetics, right? Could your genetics actually play some effect on if you are going to respond to placebo or social infection and these other things? The answer is yes. And I took a lot of the slides out to talk about genetics because I knew we'd be short on time, but I would encourage you to read this paper by Ted Kapschuck and Kathy Hall. So they looked into a variety of genes, many of them that are involved in things like dopamine responses, serotonin, opioid responses. And the answer is yes. There are going to be certain genotypes that are going to be more responsive to placebo based on genetic factors, okay? Particularly around these placebo pathways, dopamine, serotonin, and opioids. So what does that mean for us, right? So clinically, we can all imagine how these things could apply. It means that a group of people are going to be more susceptible to placebo. And not only is that based on their prior experience, but it may be inherent to their genetics, right? So if you think about things like clinical trial design, if the placebo response varies by the genotype, then we would expect this to confound a lot of our research studies and a lot of our clinical patient outcomes, right? This would certainly be worse in smaller studies, which we tend to have smaller studies in PM&R. We don't tend to have huge clinical trials. And so we have to be very aware not only of placebo interactions and drug interactions, but now also these genotype or gene interactions and how they could affect different outcomes, both for research and clinical practice. Okay, last thing I want to touch on. So all these studies we've talked about, patients have been blinded, right? And so is there an ethical conundrum here? I mean, we can't be telling people, oh, yes, take this sugar pill, it's going to make you all better, right? We have transparency in the medicine that we prescribe. We tell people that they're getting something that's an active drug, right? We don't hide from them what we're doing. And we allow patients a lot of their own decision-making responsibilities. So should we be, you know, I don't want to use this term, it's strong, but should we be lying to people that they're getting something that's an active drug when they really aren't? And would these placebo effects actually work if patients knew the truth? So is it right to tell people the truth? And Ted Kaptchuk undertook this. He's an excellent placebo researcher from up here in Boston. And so he conducted one of the first randomized clinical trials in IBS of placebos without deception, okay? So this was an IBS study where they recruited people and they said, and people said, okay, well, what am I going to get? Well, some of you are going to be randomized to no treatment, and others of you are going to get open-label placebo. And that's it. No treatment or open-label placebo. We're going to tell you, I'm giving you something. It makes some people feel better, but it's not an IBS drug. It's a placebo. And in fact, patients still got better. Their global improvement, their symptom severity, quality of life, and relief got better. Now, not all these are statistically stepping that the quality of life measure isn't, but severity change and overall improvement, they're better. They were better. And these people were not deceived. They were not blinded. They knew they were getting placebo, right? So this is extremely interesting and very, very helpful, I think, moving forward in this area of research and how we think about doing this. You don't have to blind people to get these effects. Okay, so bringing it all home, I like to think that we've evolved over the last hour from thinking of placebos as some natural recovery or some function of the patient imagination to maybe thinking about them as inert substances to now thinking, gee, this is a really powerful thing that we have to be aware of in our patients, but that we also could potentially harness to improve outcomes and get a better response. So placebo is not no treatment, right? It's a legitimate series of biological interactions. We have to think about it. We have to think about all of its different effects. And we have to think about how we can use it. So can we employ this to enhance recovery, right? Can we manipulate people's expectations? What are the ethics of that? How do we do it right? Can we avoid placebos or can we avoid nocebos, the negative response? And can we improve our research and other things to think about how placebos might be affecting our clinical research and clinical trials? And then can we use it to impact patient satisfaction to make people feel better? So Dr. Rossifant and Dr. Liam Morales-Quesada are at Spaulding with me, and they do a lot of work in this and really turned me on to this area of study. So I owe them a lot. And I'll take a question or two if we have time. Thank you very much. Looks like we're getting a couple of questions coming in. I think it's a really interesting topic and it's not something that can be avoided. And as you mentioned, it's not just subjective responses. There are a lot of objective responses. And I remember running into this in med school for the first time and kind of dealing with some of these ethical questions of if the patient is better, if the patient came to me to feel better and the patient now feels better, is it okay? Is it not okay? Do the ends justify the means? And I think it's interesting. I've seen a study that showed a placebo effect on seizures in refractory, people that were refractory to other seizure medication. So this is a really interesting subject. Thank you for teaching this. So one question that came in, how do you recommend a physician communicate these things when preparing like for an injection, for example, a pain-related injection procedure? Do you say this isn't gonna hurt or do you say, one, two, three, you're gonna feel a small pinch or, I mean, based on what you're saying, what do you recommend? Good question. So full disclosure, I'm not interventionalist, but I do do some procedures in the office. So in my clinical practice, I tend to go with the little graph you saw about setting expectations, but not certainty. So this may hurt a little, but most people do just fine, right? Most people tell me it's not so bad. So you set some expectation that most people do okay, but if you tell everybody, oh, this won't hurt at all, then you may be falling into that group where 100% certainty actually leads to a lower sort of placebic type response. Whereas if you do the opposite, you say this hurts everyone, then you really set people up. So I think providing some element of reassurance or calming, but leaving the door open for people to feel pain a little bit is probably the best way. And that's what I tend to use in my practice. I don't know 100%, the one, two, I'm just reading the question here, like one, two, three, here it comes. Is that sort of giving people a lot of anticipation, which makes their pain worse? That's possible. So I think that each of us should probably just be very conscious of how we talk to patients about this is gonna hurt or how we do a procedure and start to really think about the language we use and see what the feedback is that we're getting individually. Because the other thing is that your body language and individual physician factors will also affect this, right? Not just what you say. And so it might be different for each of us. That's interesting. That's interesting. I appreciate it. So you're going for the 75% approach. Maybe you combine approaches and say, hey, this helps most people. This doesn't hurt most people. And it was also really expensive. Yeah, yep, yep. You could look at employing a lot of those different techniques. I think it also introduces a question of a waiting room effect, right? Like what are the people's expectations when they walk in? You're talking about social infection and whatnot. I think that's interesting. In a time of social distancing, I think the waiting room effect is interesting. I have to look into that more. Yeah, there's plenty of literature out there for anybody who's interested in clinical trials if you put somebody on a wait list. So if you take a group and you say, well, you're gonna be randomized to the placebo, but after the study's over, you can then get the active drug, those people who wait for the active drug actually sometimes have even greater response to it when they're sort of put on a wait list. So there's plenty of literature out there for that. Interesting. Again, thank you so much for joining us. I think our time has expired, but thank you so much. This was a really outstanding lecture. We appreciate you being with us today. Yeah, thanks everybody. And we'll try to post that link for y'all. All right, thank you very much. Okay, that was a great lecture. Again, if you wanna reach out to her directly, that is her information there on Twitter. You can find me or the AAP, just find us on Twitter, or I think we put up an email address for AAP earlier. Okay, we're gonna go ahead and move directly into our next.

placebos

effects on patients

history of placebos

physiological effects

expectation and conditioning

power of placebo effect

clinical practice

ethical considerations

genetics in placebo responses

communicating placebos