Mindset Matters: Harnessing the Placebo Effect for Patient Benefit
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To a nonmedical professional, the placebo effect is a fairly straightforward concept: give someone a sugar pill, tell them it is medicine, they think they get better. But the reality of what the placebo effect has come to mean in the current health care setting is something entirely different, and more complicated.
“The first thing you have to understand is that we use the term ‘placebo effect’ in a way that confuses people,” Wayne B. Jonas, MD, executive director of Samueli Integrative Health Programs, told Healio Rheumatology. “In short, we use it in two completely different ways.”
One, of course, is the way described above: administer a patient an inert substance and observe the response, usually for investigational purposes. “The other meaning is to optimize the response of anything we are doing as doctors by enhancing the meaning and context in which we deliver treatment, whether the substance has active therapy or not,” Jonas said. As such, he is a proponent of renaming it as “the meaning and context” effect, rather than the placebo effect. “This is what we are talking about today.”
A key researcher in this area, ZeYu Huang, MD, PhD, associate professor in the department of orthopedic surgery at West China Hospital, and visiting scholar in the department of orthopedic surgery at Duke University, defined the terms. “Studies have shown that a number of contextual factors may be used to enhance contextual effects,” he said. “They have been attributed into the following five categories: patient characteristics, physician characteristics, patient-physician interactions, treatment characteristics and environment. Each patient should be analyzed case by case.”
James Galloway, PhD, MSc, senior lecturer at King’s College Hospital in London, expanded on the key contextual factors that everyday physicians can exploit to the benefit of patient outcomes. “The layout of your waiting room matters,” he said. “You should not make patients wait too long for treatment, even the size or color of the pill can make a difference. And, of course, the language you use to describe treatments is critical.”
While proponents believe that a more positive message delivered by a confident doctor can yield improvements in pain, function and patient-reported outcomes, there are concerns to examine. One pertains to the ethics of being too relentlessly positive about treatments that, for many rheumatologic conditions, are not curative. Another is that the data supporting this “meaning and context” effect may be too good to be true. Still another is the matter of aligning patient expectations with the realities of the treatment armamentarium for many rheumatologic and autoimmune diseases. Thus, a rigorous investigation of the data and parameters may prove beneficial.
More Than Just a Conversation
Simply being positive about a treatment is only one part of the equation, according to Luana Colloca, MD, PhD, associate professor of Pain and Translational Symptom Science at the University of Maryland. “You need to be a confident and charismatic physician to promote this positive mindset in your patients,” she said.
That said, Galloway suggested that this may be easier than it seems. “When I talk about a new medication, my opening line should be, ‘This is a drug that works really well for rheumatoid arthritis,’ as opposed to, ‘Here is a list of side effects,’” he said. “Of course, we have to explain the potential side effects, but I tell patients that I have not found them to be too problematic. This creates a much more powerful impression, and one that is conducive to healing.”
Perhaps more importantly, aligning expectations is also necessary. “Of course, we want to shift their expectations from the negative to the positive,” Colloca said. “But we also need to work together to make sure that the outcomes that may occur with the treatment are not too high or too low compared to what the patient expects will happen.”
Leonard H. Calabrese, DO, chief medical editor of Healio Rheumatology and director of the RJ Fasenmyer Center for Clinical Immunology at the Cleveland Clinic, suggested that the power of expectation is best exemplified in the treatment of patients with fibromyalgia and chronic fatigue syndrome. “I see it most clearly not when I am prescribing a drug, but when I am talking about lifestyle interventions such as diet and exercise,” he said. “We do not just tell them, ‘Here is a brochure on sleep; go eat a bowl of raspberries; see you tomorrow.’ It is set up by the ritual of guiding them along a path toward wellness that will lead to slow and steady incremental benefits over time.”
The theory is that the brain and the immune system function as a single organ, and that behavior can influence all kinds of responses in the body. “But you have to empower the patient to walk the walk,” Calabrese said. “Whether we are talking about a drug or a lifestyle change, be honest that it is not going to work tomorrow. Be honest that there may be setbacks or adverse events but continue to encourage.”
This raises the question of how to elicit the type of response that will improve these outcomes. The answer, for many, is surprisingly simple. It comes down to the therapeutic ritual.
“Whether they know it or not, every doctor has a therapeutic ritual surrounding the way they deliver care,” Jonas said. “Before you do a procedure, if you tell the patient it is going to hurt, they are going to experience greater pain. Phrasing things differently can mitigate that pain.”
It is clear, then, that experts who have studied meaning and context in health care delivery hope to convey these messages to clinicians. However, Galloway also believes that patient attitudes are part of the bargain. “You have to have a patient who wants to get better,” he said. “You have to get them to buy in, and you have to keep them invested in the process.”
Part of the message is about expectations. In fact, a critical state-of-the-art review was recently published in The New England Journal of Medicine by Colloca and colleagues, who showed that in many double-blind clinical trials of pharmacotherapies treating pain or psychiatric disorders, placebo and active therapy responses are virtually identical.
In addition, as many as 19% of adults and 26% of elderly individuals on placebo report adverse events, with as many as one quarter of clinical trial patients receiving placebo discontinuing due to side effects. These findings suggest that rheumatologists could be doing a much better job of aligning expectations with the realities of treatment.
Potential Patient Benefit
While the data showing the positive impact of contextual effects continue to accrue, it is important to understand that not all disease outcome and activity measures can be improved simply using positive contextual effects.
For example, Huang and colleagues pooled all the available randomized clinical trials on osteoarthritis treatments to evaluate contextual effects. “The most important finding is that compared with self-reported measures, objective measures have less or lower contextual effects,” Huang said. “This finding suggests that all clinical trials regarding hip and knee OA treatments should include measures of physical function assessments. However, as for the treatment of pain, which is a subjective assessment, the physicians are supposed to use measures such as doctor’s touch to improve effects of the treatments.”
Similarly, in their study in Clinical and Experimental Rheumatology, Zhang and colleagues looked at the potential contextual effects of various types of interventions for mitigating pain. Results showed that more positive context could yield just a 47% improvement when the patient receives an intra-articular corticosteroid injection, compared with a yield of 91% improvement for joint lavage.
“This begs a question on how to improve the overall treatment effect of an OA therapy in clinical practice by enhancing the contextual effect, rather than to separate a specific treatment effect from the contextual effect as we normally do in clinical trials,” the researchers wrote.
It is perhaps because of ambiguous findings like these that Calabrese believes the rheumatology community has “ignored” the placebo effect, or worse. “At times, rheumatologists have viewed it as the enemy in the process of drug development,” he said. “It is time to seize the day, study it and incorporate it into our care packages to reach treatment goals.”
Though a believer in the power of placebo, Calabrese is realistic about the limitations of the effect. “It is not going to stop lupus nephritis or multiple sclerosis,” he said. “But a huge swath of our patients do not feel the way they would like to feel. They are concerned about pain, sleep, fatigue and general well-being; these are the areas where the placebo effect can be beneficial.”
Shifting Patterns
Another reason the rheumatology community may be suspicious of these effects is because the way placebo data have evolved. In their study in Journal of Rheumatology, Bechman and colleagues looked at 32 placebo-controlled clinical trials involving biologic agents or targeted synthetic DMARDs in RA to determine if there have been changes in placebo response in recent decades. Results showed statistically significant increases in both ACR50 (beta = 0.41; P = .01) and ACR70 (beta = 0.18; P = .01) placebo responses over time. The researchers offered shifting RA phenotype, changes in trial design and expectation bias as possible reasons for these changes.
While Galloway is a proponent of providing positive meaning and context for patients, he cautions about interpretation of such data sets. “I am not sure that the evolution of improved placebo effects over time is a true observation,” he said. “There has been a huge shift in the way clinical trials are conducted recently, with many recruiting patients from lower income parts of the world.”
In the 1990s, most trials of rheumatic diseases were conducted in Europe and North America, where participants had some access to health care, according to Galloway. “Patients in recent clinical trials may never have had access to background medications like methotrexate, so they are essentially starting from zero,” he said. “In these trials, the background care package is so much better than anything they have experienced before. So, are the patients in the placebo arm truly experiencing a placebo response, or are they simply responding to an improvement in their baseline level of care?”
While the trend toward positive outcomes associated with the placebo effect has been observed in rheumatology, impacts of positive vs. negative rituals in the clinic are not new. In 1987, Thomas and colleagues conducted a study in which 200 patients with symptoms but no abnormal physical disease, who presented to a general practitioner, were randomly assigned to a positive or a negative consultation. After 2 weeks, 39% of patients who had a negative consultation reported improved symptoms of their condition, compared with 64% for those who had positive consultations.
In light of all of these findings, the message Galloway has for the health care community is to carefully interpret all clinical trial data pertaining to placebo responses. “We need to interrogate both placebo and active treatment arm data to determine the real cause and effect of patient improvement,” Galloway said.
One way to interrogate those data will be to look beyond the results of the trials themselves, and beyond the field of rheumatology and into the field of neuroscience.
Train the Brain
For those who may be skeptical that simply accentuating the positive will suddenly lead to health and happiness in patients who have long suffered from complex chronic diseases, an emerging body of data is demonstrating quantifiable neurological responses to positive messaging. Neural pathways can be targeted to “train the brain,” to feel improvements in pain and other parameters.
“In the last 10 years or so, there has been a concerted effort to understand the neurobiology — what happens in the receptors in our brain — when we manipulate meaning and context to elicit this so-called placebo response,” Jonas said. He described the results of recent research as “fascinating,” and suggested that this research and new technologies such as neuroimaging tools can help rheumatologists treat patients. “We now understand that there are underlying mechanisms to placebo response in the brain.”
In their study published in British Journal of Anaesthesia, Wanigasekera and colleagues conducted a double-blind, randomized, placebo-controlled, three-way crossover trial to determine the utility of neuroimaging in providing objective evidence of neural activity related to drug modulation or a placebo effect.
Results showed that compared with placebo only, pregabalin demonstrated the capacity to suppress “allodynia-evoked neural activity in several nociceptive and pain-processing areas of the brain, despite the absence of behavioral analgesia,” researchers wrote. As a result, they concluded that functional neuroimaging showed evidence of pharmacodynamic efficacy indicating that subjective pain outcome measures can be unreliable. The study provided insight into the neural mechanisms that occur among patients in the placebo arm of placebo-controlled trials.
Jonas addressed three take-home messages regarding neurobiology and placebo effects. “One of those is belief and expectancy, and what lights up in the brain when you think the treatment is going to be effective or not,” he said. “Expectancy changes things in the brain that can have an impact on outcomes.”
The next component pertains to social learning. “This is where the therapeutic relationship and ritual of treatment come into play,” Jonas said, and referenced the data from Thomas and colleagues, as well as Colloca and colleagues. “There is a long history showing that positive messages embedded in the treatment ritual can make patients feel better.”
The final component involves conditioning. “We now know that you can condition neural receptors by linking an active treatment with an inactive treatment and elicit a sort of Pavlovian response,” Jonas said. “We can do the same thing with our therapeutic processes.”
Jonas pointed to research showing that the ritual of simply taking a pill can induce a healing response. “These three mechanisms are throwing light on what underlies the placebo response,” he said. “There is a powerful internal pharmacy in our brains. The more we are able to unlock it, the more we may be able to improve pain and functional outcomes in our patients.”
As rheumatologists begin to wrap their heads around the impact that neuroscience can have on their practice, it may be useful to look closer at what many believe to be the flip side of the placebo effect: the so-called “nocebo” effect.
The ‘Placebo Effect’ Evil Twin
If positive messaging can yield positive outcomes, then negative messaging can yield negative outcomes. This is the nocebo effect.
Kravvariti and colleagues examined the nocebo effect, zeroing in on medication adherence, clinical outcomes and health care policy as target endpoints in their recent study published in Nature Reviews Rheumatology. Their findings showed that in randomized controlled trials in patients with both rheumatic and musculoskeletal diseases, patients in the placebo arm often withdraw due to adverse events.
They suggested that nocebo effects may contribute to this phenomenon. Moreover, they observed poorer retention rates in the biosimilar arm of trials, compared with the bio-originator arms — low expectations about the efficacy of biosimilars may be to blame.
“Many patients already suffer so much, particularly those with OA,” Colloca said. “They are full of pain and fear already. So when we tell them negative information about the efficacy of treatments like biosimilars, it can become a self-fulfilling prophecy for negative outcomes. Some patients can actually get worse rather than better.”
In a recent study, Colloca and colleagues dug deeper to further define the brain’s reaction to both the placebo and nocebo effects when expectancies are violated. “When participants’ expectancies were not aligned with the perceived outcome, there was a blockage of placebo effects and a reduction of nocebo effects. The changes in placebo and nocebo effects were paralleled by an activation of the left inferior parietal cortex, a brain region that redirects attention when discrepancies between sensory and cognitive events occur,” they wrote.
“Our findings highlight the importance of expectancy violation in shaping placebo and nocebo effects and open up new avenues for managing positive and negative expectations in clinical trials and practices,” Colloca said.
Concerns and Considerations
Some experts have voiced concern that spending so much time discussing the positive effects of a drug or treatment while minimizing the time addressing negative outcomes skates the line of honesty. But the experts who spoke with Healio Rheumatology were quick to dismiss these concerns with a straightforward, albeit self-evident, message: Don’t lie.
“Clearly, we should not be giving them a false idea of what the treatments can or cannot do,” Galloway said.
“The caveat is that you as the physician have to believe it works,” Jonas added. “You have to believe that the treatments you are giving your patient will be effective, and you have to believe that optimizing the contextual effects will, in turn, optimize the healing effects of the therapy. It is not only about your patient’s belief, it about yours too.”
For Colloca, ethics and expectations are inextricably tied together. “When we align the patient’s expectations with the outcomes we realistically can achieve, there are no concerns about deception,” she said.
With ethical considerations, then, mostly a nonfactor, Huang stressed one other major hurdle to optimizing outcomes for rheumatology patients. “Rheumatologists should still be seeking more effective treatments,” he said. “Based on our research, functional outcomes are not likely to be much affected by the contextual effects. So, again, to improve functional outcomes, physicians should seek for better effective treatments.”
In the meantime, Calabrese brought the issue to the natural next step, which is to codify a set of meaning and context approaches so rheumatologists can more readily put them into practice. “The research is there, the tools are there,” he said. “Now it is a matter of implementing these principles of empathy science that many experts have spent so much time studying.” – by Rob Volansky
- References:
- Bechman K, et al. J Rheumatol. 2020;doi:10.3899/jrheum.190008.
- Colloca L, et al. N Engl J Med. 2020;doi:10.1056/NEJMra1907805.
- Kravvariti E, et al. Nat Rev Rheumatol. 2018;doi:10.1038/s41584-018-0110-9.
- Thomas KB. Br Med J (Clin Res Ed). 1987;294:1200-1202.
- Wanigasekera V, et al. Br J Anaesth. 2018;doi: 10.1016/j.bja.2017.11.064.
- Zhang W, et al. Clin Exp Rheumatol. 2019;Suppl 120(5):118-123.
- For more information:
- Leonard H. Calabrese, DO, can be reached at 9500 Euclid Ave. #A50, Cleveland, OH 44195; email: calabrl@ccf.org.
- Luana Colloca, MD, PhD, can be reached at 655 W. Lombard St., Baltimore, MD 21201; email: colloca@umaryland.edu.
- James Galloway, PhD, MSc, can be reached at King’s College Hospital, Denmark Hill, London, SE5 9RS; email: james.galloway@kcl.ac.uk.
- ZeYu Huang MD, PhD, can be reached at DUMC 3710, Durham, NC 27710; email: zeyu.huang@duke.edu.
- Wayne B. Jonas, MD, can be reached at 1800 Diagonal Road, Suite 617, Alexandria, VA 22314; email: wayne@drwaynejonas.com.
Disclosures: Calabrese reports serving as an investigator and a consultant to Horizon Pharmaceuticals. Colloca, Galloway, Huang and Jonas report no relevant financial disclosures.
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