Drs Brian Lacy and Anthony Lembo on the Placebo and Nocebo Effects

In this podcast, Anthony Lembo, MD, joins our host, Brian Lacy, MD, to discuss the placebo effect, and the nocebo effect in clinical trials and practice.
 

Anthony Lembo, MD, is director of the GI Motility and Functional Bowel Disorders Program at Beth Israel Deaconess Medical Center and professor of medicine at Harvard Medical School in Boston, MA.

TRANSCRIPT:

Brian Lacy, MD:

Welcome to this Gastroenterology Learning Network podcast. My name is, Brian Lacy. I'm a professor of medicine, at the Mayo clinic in Jacksonville, Florida. I am absolutely delighted to be speaking today to Dr. Anthony Lembo, professor medicine at Harvard Medical School and an internationally recognized clinician at the Beth Israel Hospital in Boston, Massachusetts. Our topic today is one that is important in all fields of medicine. So placebo and nocebo response. Dr. Lembo welcome. This topic is a bit different than many others. We've covered on the Gastroenterology Learning Network, as we are not going to really focus on a specific disease state or disorder, but rather focus on the placebo and nocebo response because this really affects every aspect of medicine every day. To begin, could you help set the stage for our discussion today and define the placebo response for our listeners?

Anthony Lembo, MD:

Sure Brian. Well first let me thank you for the invitation to come speak on this topic. Yeah, let's dive right into the placebo. It means different things, in different contexts. Thinking about medicine in general, we could look back at the history of medicine for really thousands of years. Most of it was related to placebo almost as the history of placebo and medicine, right up until the introduction of a randomized double blind placebo controlled trials, which wasn't until the 1930s and 1940s, where it became standard of care, literally almost, overnight. And it comes from a trial that was conducted in Britain, where it was purported that there was this clay product that would cure the common cold. And researchers in Britain got together and decided to do a multicenter placebo controlled trial to show that it really didn't have effects.

Anthony Lembo, MD:

And this, made the front page of most major journals and most newspapers. And literally, shortly thereafter it became standard without much fan fare. But if you go back in time, there were some, reports of placebo controlled trials. They just didn't call it placebo. One of the more famous ones was Frank Mesner that where the term mesmerized comes from. And at that time he became very famous and the French courts as a clinician that could make an inanimate object a rock or a tree have powers to heal.

Anthony Lembo, MD:

And what they did at that time, they put together a group of esteemed scientists, Benjamin Franklin was among them, and they went, sought out to disprove this or to prove it, whether it was true or not, they didn't think it was true. And what they did is they took an object that wasn't mesmerized, so to speak or activated and showed that the effects were exactly the same. Now at the time, almost everybody believed that they were able to heal patients. They just didn't think it was related to this object. And so then there's some additional examples of where the placebo was used or a sham was used. Again, they didn't really call it that.

Brian Lacy, MD:

So it's nice to put this all in perspective because some people believe the placebo response is saying more recent. But we know this goes back hundreds, and literally, as you point out thousands of years. The basic question, whether it's in GI medicine or any other field of medicine, Tony, how does the placebo response work? Is it the same in everyone?

Anthony Lembo, MD:

It probably is different from person to person. If we go back in history and think about how medicine was conducted, we can learn a little bit how placebo may be effective. And if you think back to some of the Charmin's and other people over the generations, oftentimes it was a very complex solution to a medical problem. And so a lot of times it was different, a potion that had a lot of different ingredients and usually given by somebody that was esteemed in the community, people had a lot of respect for, and we can think about in today's world, some of that is still similar. Certainly physicians or clinicians are generally very well respected. Patients put a lot of trust in their clinicians and they have a fairly high expectation that they will get improvement in symptoms.

Anthony Lembo, MD:

Even back in the day where there wasn't proof of it, people still had that belief. We do know that there are a lot of factors that contribute to the placebo, one of which is expectation. Certainly the environment that someone is in will contribute to it as well. And then there are individual factors. There have been reports of the type of placebo pill. If it's a type of treatment, the more invasive a treatment may be probably the higher, the placebo response rate will be. Devices tend, we see may have slightly higher placebo response rate than simple pills. And again, the more pills that you would give the higher, the placebo response rate. Again, dealing with some of it's thought to be due to the expectation. If we think about in practice, for a clinician or a patient, that's coming to see a clinician getting a treatment.

Anthony Lembo, MD:

And generally this is an active treatment that has been in today's world has been shown compared to a placebo to be more effective. We do know that about, a large percentage of that effect in any trial. Any, any treatment that's been studied is related to the so called placebo effect. And that effect should be broken down into a number of different factors. It's not just one effect. And I think this is what you are getting at. It's different for different people. It's not just one effect. So if you think about, in a study, what would contribute to someone getting better, who receives a placebo pill? We've already mentioned expectation the environment. We also know that self-reflection is important. The desire to heal or for wellness would be an important factor. So those are the people that will tend to come into a study or in practice.

Anthony Lembo, MD:

That's why you are going to see a clinician that is to have that improvement. We also know, in studies, just filling out questionnaires and thinking about your problem and hearing discussing about it can also contribute to it. And when someone is engaged enough to seek care, they'll also do other things in their lives that may also influence the placebo effect. And there, it depends on the type of disease. So for example, if you have a cancer, yes, it's going to be the chemotherapy that's going to improve it. You may make small improvements by changing your diet or your lifestyle, or having a positive outlook or et cetera. But those are going to be relatively small as opposed to a disease state that's more just for symptoms alone. So for example, arthritis or joint pains, or in our field, Brian would be irritable bowel syndrome, or even inflammatory bowel disease.

Anthony Lembo, MD:

There, some of the factors such as lifestyle changes that you may employ may have a significant effect in changing the overall outcome of this study. So there are a number of different factors. And then on top of all of this, there's also what we call the placebo effect. And there, we know that is a true biological effect that can occur. And we know that it's mediated by certain neurotransmitters. For example, the opioid system, the [inaudible 00:07:56] system, the dopaminergic system, these are in laboratories has been shown to, those neurotransmitters have been shown to be important in it. And it's not just one neurotransmitter. So in the body is very good at having multiple potential effects with things that are really important for it. And that we know that placebo or this what we call placebo effect in this circumstance, is an important part. And there's also been studies in the using FMRI showing that there are active changes in the brain for someone who's receiving a placebo treatment. So we know that, and again, it's going to be different for different people and in different scenarios.

Brian Lacy, MD:

Tony, such a comprehensive overview of what many people think is a simple topic, the placebo response, and how many different levels there are to it. And if we were to think about clinicians in the clinic today, Tony, and they are going to possibly talk about a study or a medication, are there predictors somebody could use in clinic, such as a younger patient, are they more likely to respond to a placebo or have a placebo effect on an older patient or women versus men?

Anthony Lembo, MD:

It depends on the situation, but when we've looked at it and when other people have done these large meta analyses in general, it doesn't seem to differ between gender. So males and females seem to have a similar, same thing with age. Although some studies do show older, people may have a higher placebo response rate or vice versa, but in the meta analyses, it generally hasn't been shown. So things like age, sex, psychological data, such as baseline anxiety, or depression that don't seem to correlate with placebo response. One of the things that we did when we looked at a trial with patients with IBS, with constipation, and we found that one of the factors was the variation in pain or symptoms that occurred during the baseline period. So whether it fluctuates more or less maybe correlates, but with a higher placebo response rate. But interesting, most of the other factors don't seem to correlate

Brian Lacy, MD:

Tony. I want to follow up a little bit on something you mentioned earlier, and this last question too, about devices versus medications. And we know that some interventions have a higher placebo rate than others. For example, you performed a great research study in the past, looking at acupuncture for treating IBS symptoms and sham acupuncture had a higher placebo response than pills if I recall correctly. And so do you think that the level of intervention has a significant role in the placebo response?

Anthony Lembo, MD:

Yeah, so surgical interventions tend to have a higher placebo response. We believe that's due to patient expectation of improvement. So the fact that you are going through a major or bigger procedure, maybe the case. We did look at the role of complimentary and alternative therapies, such as acupuncture, herbs, and other factors thinking that the patients that are entering into those type of studies may be more susceptible or more open as is another way to put it open-minded and maybe to the placebo effect, but interestingly, and we didn't really see that to be, to be different.

Brian Lacy, MD:

So Tony, back in about 2008, you published a fascinating study in BMJ involving the placebo effect in patients with IBS. Can you tell us a little bit about that study and why it's so important?

Anthony Lembo, MD:

Sure. So this was a study. Well, let me just put the context, I think would be interesting at that time, several years earlier there had been a publication entitled The Powerless Placebo, and this was published in a New England journal about seven, eight years earlier. And the investigators had done a meta-analysis of all trials that had included a no treatment arm plus a placebo arm plus a treatment arm. And they compared the no treatment arm versus the placebo arm and showed that in a large meta-analysis there wasn't a lot of differences, but they did see a relatively small difference when pain was being measured. Importantly, none of these studies were actually designed to look at placebo. So we sought to really, to determine whether we could design a trial, a placebo trial that could actually show differences in placebo.

Anthony Lembo, MD:

In other words, we would give a little bit of placebo in a lot of placebo, as well as a no treatment arm. And hoping to show that we could show this dose ranging effect, all of which would was considered placebo. Now the term placebo is some people think of it as being, a sham device or sham pill, but it's also the intervention that occurs in a treatment. So it's not what we would consider an active pill or an active device. And so we did two different things. One is we gave a sham acupuncture to patients, except for the patients that were in the no treatment arm. And we broke the other arm into two different groups. So they both got sham acupuncture, which was the one placebo. And in one group, we gave them what we call a limited clinician, patient interaction and the other group in augmented clinician patient interaction.

Anthony Lembo, MD:

That was the only difference. So we had, again, two types of placebo. One is the interaction and one's the sham acupuncture. And one of them, we gave a little bit more than the other. And what we found was that after three, and then again in six weeks that the patients that the patient that got an augmented interaction had a far superior outcome than patients that got limited, and those that got wait lists. So we used several outcomes and one outcome was something where we are in the IBS literature we are familiar with, it's called adequate relief, a very simple global measure of, did you have adequate relief of your symptoms with the past week? Yes or no. And then there, after six weeks, we found that over 60% of patients that got were in the augmented group said they had adequate relief versus about 45% in the limited versus about 30%, 28% in the no treatment arm.

Anthony Lembo, MD:

And so again, showing that there are differences in that adding, so not only does sham acupuncture improve over wait list, but also adding the interaction in an augmented way can have even more effect. So it is both a clinician patient interaction study as well as a placebo study. So we were also interested in the mechanism whereby people would feel that had improvement in symptoms to placebo basically. And one of the things we looked at was the COMP gene, and this is a gene that regulates dopamine metabolism. And we know dopamine, as I mentioned earlier, is I important for the placebo effect. And interestingly, we could find that patients that tended to have higher amounts of dopamine tended to do better in the augmented patient arm. So, which was really, really quite interesting that there could be a genetic basis behind why some people respond better than others.

Brian Lacy, MD:

Tony, you followed up that really interesting study, which still resonates in the literature, looking at the use of placebos without deception. And this study was published in 2010. Why did you do that study and what were the results?

Anthony Lembo, MD:

Sure. We decided that the next important question in placebo was, does it need to be blinded? And we all know that, and this had been preceded by a study done by Ted Kaptchuk and others. And Ted has been my mentor in the placebo, really the guru of placebo that I've been fortunate enough to work with for the past, 10 to 15 years. And Ted had done a study where they asked internist and actually rheumatologist, but representative in the United States, if they had ever prescribed the medication that they knew was ineffective for its placebo effect. And lo behold found that about 50% said yes, that we had prescribed it. And so the idea was why shouldn't we try open label placebo instead of deceiving patients and seeing if we can replicate what happens in a double blind placebo controlled trial.

Anthony Lembo, MD:

So for example, that we are most familiar with the functional GI literature where, in IBS about 38% to 40% of patients receive in double blind placebo would have improvement in symptoms. Again, it depends on the outcome measure. It is lower more rigorous of the outcome measure, but let's say about 35%, 40% of people report improvement in symptoms in a study. So we figured why don't we try an open label placebo. And in that study, what we did was we randomized the 90 plus patients with IBS to either receive open label placebo or their usual treatment. So we didn't stop any medications. All patients got their usual treatment. We added the open label placebo and with it, we told them exactly what was true. That a double blind placebo controlled trials is a very effective treatment.

Anthony Lembo, MD:

It has no side effects. It is a mind body or gut brain type of interaction that's occurring. And it's, you are promoting overall wellness. We don't know exactly how it works, but we think that this probably will be effective for you. So we did increase their expectations, so to speak for this, but with all true statements and gave it to them for a total of three weeks. And, and then that study, we filed out about 60% of patients reported adequate relief versus about 35% that we are receiving usual care. So again, showing for the first time that you could actually perhaps give open label, please. Now we are not saying that it works for all diseases. It'd be very clear that it's not going to, prevent heart attacks. It's not going to cure cancer, but in diseases where symptoms are the major factor and where there is a high placebo response rate, that there is the opportunity where you could potentially give open label placebo rather than doing the deception, which is oftentimes somewhat some practice in these type of diseases where we don't have a very good treatment or cure for their disease.

Brian Lacy, MD:

Fascinating, especially since it was just three weeks of open label placebo, right? Not a long period of time. You mentioned disease states, so that's a great segue. And so just thinking a little bit about many of our listeners today who treat patients with disorders of gut brain interaction, previously called functional bowel disorders, thinking about those disorders, do you think the placebo response is the same in all these disorders? Or do you think that's some disorders of gut brain interaction, maybe IBS versus functional dyspepsia, as an example, have the higher placebo response rates than others?

Anthony Lembo, MD:

Yeah, it is going to be different and partly it's different because the outcome measures are different. We don't use the exact same outcome measure for each disorder and the pathophysiology is going to be different. And so will the type of patients that we may see in each disorder. So yeah, it's going to be different. And we know, again, there are different pathways that are involved in the placebo effect.

Brian Lacy, MD:

So Tony let's shift gears now and think about the nocebo response. And that's a topic that many listeners are not quite as familiar with. Can you explain the nocebo response?

Anthony Lembo, MD:

Sure. So, so nocebo is really whatever adverse reaction that you may be getting to a treatment based on the anticipation that is causing a side effect, was it just a possibility or again, the anticipation or the worry that you may be getting a side effect from that treatment

Brian Lacy, MD:

And how does the nocebo response work?

Anthony Lembo, MD:

We don't know it's exact mechanism, but we do know that patients that anticipate or believe that they are going to have a side effect are at a higher risk for that side effect. And I'll give you an example of, so we were interested in this topic and a few years ago thought that we could intervene on by reducing a placebo effect by explaining to patients who were receiving a new treatment. In this case, it was a tricyclic antidepressant, which we all know is effective for patients with functional GI disorders by reducing pain, but they are associated with a fair amount of side effects. So what we did in this study, we randomized patients into two groups. One that was given, the list of side effects and said, here, the known side effects just we typically would. And then we would emphasize the side effects we were most concerned about, like we would always do in practice and that we considered that to be our standard of practice.

Anthony Lembo, MD:

And in the other group, we spent 30 extra seconds. And we explained to them that a lot of these side effects that are listed occur also occurred in patients that were receiving placebo and that's, but basically all that we said to them and what we found, we followed up in two weeks to see what side effects that patients may have. And what we found was that, again, this was a very small, this is a pilot study, so this is definitely not a definitive study, but we did find that there were trends towards both improvement and overall symptoms, which was interesting enough and compliance with the medication and the report of side effects.

Anthony Lembo, MD:

So again, what we are hoping to do in the future is to do a larger trial where we could employ this into, a real world type study, employing the clinical practice and say, are we able to reduce some of these non-specific side effects? Again, we are not trying to say that we are going to, we are not trying to, stop side effects, but a lot of the reports, and a lot of times when people stop it, could maybe avoided if a proper explanation is given to patients.

Brian Lacy, MD:

That's great. So that additional 30 seconds potentially could have a huge impact. And you've mentioned the word expectations a couple time. And coming back to an earlier question, do you think we can accurately predict who may have a nocebo response as an example, is anxiety a marker? What about somatization or catastrophization?

Anthony Lembo, MD:

Yeah. Is in that study, I alluded to, which was just a pilot study. We did measure those things, because those are what we would expect. It's not clear from that study whether that is the case or not. Again, it wasn't a large enough trial to really see that. But the expectation would be that someone who has had the experience of having side effects and this goes back to one of the factors, that even occur in the placebo, but also occurs in nocebos, what we call just a simple conditioning effect, the Pavlov's dog example, but also occurs in humans too.

Anthony Lembo, MD:

So in the placebo realm, if you take an aspirin pill and it relieves your headaches, you will be conditioned after a few times that taking this type of pill where relieve your headache and studies have shown at least laboratory studies with opioids and other type of medications that you can get a placebo effect from this conditioning type behavior. Same is true from the nocebo effect. If you've taken a drug and got a side effect or another drug and got side effects, you can be conditioned to get side effects and reports you'd be more likely to report those type of side effects. So patients that have had more side effects for medication, one would expect, not well proven, but one would expect that they'd have more adverse events associated with pills.

Brian Lacy, MD:

And just as a clinical scenario, I always very carefully look at the list of allergies and adverse drug reactions. And when you see somebody with 15 or 20, they are probably not really allergic to drugs, but they are having side effects. And so that extra time may help minimize premature discontinuation of a drug. Tony, just to bring this home to our listeners here today. Can you give us maybe one or two concrete examples of a nocebo response and GI practice, especially in disorders of gut brain interaction?

Anthony Lembo, MD:

So yeah, it's going to be a treatment that patients know or suspect, or they are told that we'll have a side effect and so when you give them that medication, the odds of them having a side effect are going be quite high, and that would be the typical nocebo type of effect. So it's again, when we talked about conditioning, it's expectation of having a side effect, knowledge of having a side effect, as opposed to someone who has, who has no... It's not ethical to withhold, potential adverse events, reactions for patients. But if they had no idea that this was going to happen, at least some of these non-specific effects that they may attribute to the medication may be avoided. Again, medications that are active and have side effects will occur that we are not saying that, but some of the non-specific ones may be less likely.

Anthony Lembo, MD:

And I'll give you another example of this. So we did a study recently where we asked patients to report from a list of, symptoms that they've had. We didn't call it, it's not always on the side effect, just regular symptom headaches, in this case was non-GI symptoms, fatigue, things that are commonly reported with medication and medication trials. And we asked them at pre and then in post treatment, along the way too, to report those type of side effects or symptoms. And what we found was that, if anything, those symptoms went down during a trial, but if you were enrolling in a clinical trial and patients and you were asked, does this X, Y, Z drug, did you experience fatigue, headaches? And the answer would be yes.

Anthony Lembo, MD:

And so you'll see on a package insert that 10% of people report headaches and you do compare it to placebo. And oftentimes it matches, but not always, of course, because these are secondary measures. And so you may see a higher rate of headaches for example, and what we are left as clinicians and patients are trying to figure out is that higher level of just, luck of the draw or does it really cause that? And so some people have advocated for testing or measuring symptoms beforehand, so we can get a realistic number of what, of what new symptoms are occurring and not necessarily relying on patients recall of that.

Brian Lacy, MD:

No, that's great. And then just to fine tune things a little bit, Tony, as we start wrapping things up, you've mentioned setting the stage for patient, you educate, you, set expectations, you reassure maybe you even mention side effects with placebos. Do you think there are other ways to minimize the nocebo response in clinical trials?

Anthony Lembo, MD:

In clinical trials? I wouldn't want to, other than measuring what was going on beforehand for symptoms. So patients were aware because that does make patients aware of what they are experiencing by filling out a questionnaire. And again, most of us day in and day out, don't think about these various aches and pains and, we just live with them and then if you enter into a trial, you may be more aware of your symptoms. Because now you are being asked if you'd had any adverse reactions or any new symptoms. So I think, asking them, making them aware of it may be helpful in a trial.

Brian Lacy, MD:

Tony, this has been a wonderful conversation today. You've certainly educated me, like many times in the past. I know you've educated our listeners, any last thoughts for our listeners?

Anthony Lembo, MD:

I think this is an evolving field. So we still have a lot to learn about placebo. Well, we need to learn how to harness the placebo better. We've done open label placebo trial. That was a small trial since been replicated and a number of other disorders and diseases where symptoms are the main endpoint. And there aren't very good treatments. And I'll give you an example of, lower back pain, chronic fatigue, things like that. And they've also shown that patients can have improvement in symptoms. And maybe someday this will be the first line treatment for these type of disorders, rather than giving them, a drug that may have side effects associated with it. And again, it's not going to work in every patient, but in some people will. And then the other point is to identify those patients that are most likely. So we are hopeful that something the COMP gene or another type of marker can be found in the future.

Brian Lacy, MD:

Tony, once again, thank you so much for our listeners. We've just had this amazing discussion with Dr. Anthony Lembo, professor of medicine at Harvard Medical School on the placebo nocebo response. Thank you for tuning in today. And we look forward to having you join us for future lectures and podcasts on the Gastroenterology Learning Network podcast. Thanks so much.

Anthony Lembo, MD:

Thank you, Brian.