‘Exploring the power of their mind’: Data may offer clues to harnessing the placebo effect
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Despite the placebo effect’s long history in medicine — not to mention the critical role placebo plays in randomized trials — the mechanism driving it remains poorly understood.
However, recent research has shown that it may be possible to harness placebo responses to improve pain, fatigue and other symptoms that impact rheumatology patients.
Source: Luana Colloca, MD, PhD, MS
“The placebo effect is one of the oldest effects identified in medicine,” Bharat Kumar, MD, clinical associate professor of allergy, immunology and rheumatology at the University of Iowa, told Healio Rheumatology. “But it is still unclear, exactly, what is going on.”
Although some experts argue that the effect is simply “statistical noise” from placebo-controlled clinical trial results, Kumar said the explanation of the data may not be so simple.
“Even well-designed studies show that there is an effect,” he said.
According to Kumar, one potential explanation may lie at the intersection between the mental and the physical.
“Classically, in medicine, we have detached the mind and the body,” Kumar said. “But an increasing body of research is showing that there is an intimate relationship between them that can’t be disentangled.”
That evidence is mounting, largely, in open-label placebo (OLP) trials, where placebo is given to patients with their full knowledge. Despite knowing they are not on active therapy, many patients experience improvement in their conditions.
However, medications are just one part of the equation, according to Luana Colloca, MD, PhD, MS, a professor of pain and translational symptom science, and director of the Placebo Beyond Opinions Center, at the University of Maryland School of Nursing.
“All humans are able to create a placebo effect in the form of healing,” she said. “One way we can harness it is to create a powerful interaction between doctor and patient to become therapeutic.”
Leonard Calabrese, DO, RJ Fasenmyer chair of clinical immunology at the Cleveland Clinic, has for years, in presentations, editorials and articles, been championing the power of this interaction, or “physician-patient dyad.”
According to Calabrese, there is an “underlying biology” when a patient feels good leaving a doctor visit in which the physician has communicated with empathy.
“It can impact the nervous system and inflammatory pathways,” he said.
The thinking is that a strong rheumatologist-patient relationship can amplify the benefit of disease-modifying antirheumatic drugs or biologic medications.
“There is reasonable evidence that a supportive relationship will increase placebo effects,” Ted J. Kaptchuk, MD, professor of medicine at Harvard Medical School and director of the Harvard-wide Program in Placebo Studies and the Therapeutic Encounter (PiPS) at Beth Israel Deaconess Medical Center, told Healio Rheumatology.
That said, these benefits have largely been observed in subjective, patient-reported outcomes like pain and fatigue, rather than objective, physician-measured parameters such as joint damage. Whether trusting communication in the clinic can impact a broader array of disease metrics remains to be seen.
However, given that most rheumatology treatments are not curative, and that patients regularly deal with symptoms like pain, fatigue and sleep quality that are notoriously difficult to quantify, many clinicians would welcome any way to leverage therapeutic benefit. The placebo effect may provide that leverage.
Great Expectancy
A growing number of rheumatology researchers, including Colloca and Tuhina Neogi, MD, of Boston University, have dug deep into the mechanism of placebo response. In a review article published in Nature Reviews Rheumatology, the two experts assessed the necessity, utility and possibilities of the placebo effect in osteoarthritis.
The first step on this path, as per their conclusions, would be to accurately identify potential placebo responders. According to Neogi and Colloca, achieving this goal could lead to several positive outcomes. One, of course, would be better managing the disease in individual patients. Another potential outcome would be designing clinical trials that will lead to more effective therapies.
“Leveraging placebo effects in the clinical management of OA can also offer adjunctive treatment options to improve symptoms and quality of life in people with OA,” they wrote in the paper.
However, before it is possible to leverage the placebo effect to reach these outcomes, it is necessary to understand the nature of placebo response itself.
“Expectancy, prior therapeutic experiences, observation of benefits in others, contextual and treatment cues, and the overall patient-clinical interactions trigger placebo responses,” Neogi and Colloca wrote.
The notion of expecting a positive outcome is familiar to most experts who work in the placebo space, including Kumar.
“One thing that may be underpinning placebo results is expectancy,” he said. “We know that when a patient expects a therapeutic benefit, it is more likely to happen.”
It is one thing for an individual patient to be more likely to experience an additional therapeutic benefit from a placebo response. However, predicting which patients may experience that benefit has proven exceedingly more difficult.
“Patient self-report of expectancy is still not correlated with likelihood of success of placebo response in trials,” Kumar said. “Meaning, even if a patient has a positive expectation of response, it does not always translate to positive response to placebo. The questions always get deeper.”
Neogi and Colloca aimed to answer some of those questions in their review paper, with a closer analysis of the mechanism of placebo.
“The mere act of taking a treatment can engage various neurobiological and physiological mechanisms, including activation of the opioid, serotonin, noradrenaline, endocannabinoid, oxytocin, arginine vasopressin and dopamine systems, as well as modulation of cytokines,” they wrote.
Colloca referred to these processes as a “top-down modulation” of pain and other symptoms via a positive interaction.
“The act of taking a pill in the morning and a pill in the evening can help the brain feel better,” she told Healio Rheumatology. “It allows the brain to access positive memories and create positive memories of what to expect from the medication.”
‘It Starts with Trust’
It is at this point that the physician-patient relationship enters the equation, according to Kumar.
“It starts with trust,” he said. “When the patient feels comfortable with their provider, there is a greater likelihood that some benefit will occur. They will be psychologically more receptive to effects.”
Most rheumatologists are familiar with the concepts of empathic communication and shared decision-making that can help develop trust in their relationships. However, the “big challenge” is in quantifying a meaningful therapeutic interaction that contributes to a change in symptoms, Colloca said.
“We have to determine whether it is conditioning, or whether co-intervention leads to a regression to the mean,” she added.
In addition, Kumar warned that not all conditioning and expectations in clinical settings will be positive.
“There are large variations in the nature of expectancy based on factors like culture,” he said.
Essentially, some patients may be more likely to trust their doctor than others.
However, a solution to this issue may be that the doctor-patient relationship is not the only way to activate the conditioning of the mind that leads to positive responses, according to Colloca.
“Significant others, siblings, friends and parents, anyone with a nurturing relationship with the patient, can facilitate this positive reaction,” she said. “We can activate meaningful systems in the brain to minimize the experience of suffering.”
With this broad backdrop of neurological response as the playing field, researchers have begun to investigate the real-world clinical possibilities for improving patient outcomes through the placebo effect.
‘Honesty and Full Transparency’
In a paper published in Pain, Cláudia Carvalho, PhD, of the ISPA University Institute, in Lisbon, Portugal, aimed to assess whether the addition of OLP to usual treatment for 3 weeks could induce a placebo effect in 97 adults with chronic low back pain.
Results showed that the addition of OLP to the regimen yielded greater pain reduction vs. usual treatment alone, with moderate-to-large effect sizes. In addition, disability scores improved at a greater rate in the placebo group compared with the usual treatment group. Moreover, when patients who were treated as usual were switched to OLP, improvements were seen in both pain and disability.
“There is an emerging body of research that placebo pills given with honesty and full transparency — known as open-label placebo — work as well as double-blind placebos in conditions characterized by aberrant symptom application, or central sensitization,” Kaptchuk said.
Evidence supporting this claim is increasing. In another paper published in Pain, Lembo and colleagues examined OLP in 262 adults with irritable bowel syndrome. Patients were either assigned OLP or to a control group, in which they received no pill.
Results showed that OLP significantly improved on no-pill control as assessed by the IBS Severity Scoring System (P = .038). The researchers also compared outcomes between OLP and double-blind placebo. Results demonstrated similar outcomes in IBS severity for the OLP and double-blind arms.
“Open-label placebo and [double-blind placebo] had similar effects that did not differ significantly, suggesting that blinding may not be necessary for placebos to be effective and that OLP could play a role in the management of patients with refractory IBS,” Lembo and colleagues wrote.
Other findings have contributed to this possibility. In a paper published in JAMA Pediatrics, Nurko and colleagues conducted an OLP study in a cohort of 30 adolescent patients with functional abdominal pain or IBS.
Compared with controls, patients in the OLP group experienced significantly lower pain scores (P = .03) along with a significant reduction in the number of hyoscyamine pills taken.
“The research to date has largely centered on patients with mostly nociplastic pain, such as IBS, low back pain and migraines,” Kaptchuk said. “There is also research in patients with OA, where symptoms also can be amplified through the central nervous system.”
Researchers have also tested the OLP hypothesis in other complications with unclear etiology, such as cancer-related fatigue, as well as conditions where the correlation between symptom and physiology is “not 1-to-1, like menopausal hot flashes,” Kaptchuk added.
“It would worth trying open-label placebo in a population of rheumatology patients to see it if helps amplification of pain coming from the central nervous system or other symptoms like fatigue,” he said.
Another area of OLP research pertains to the durability of its effect. In another paper published in Pain, Carvalho and colleagues conducted a 5-year follow-up assessment of patients who participated in a 3-week OLP trial for chronic low back pain. Findings at 3 weeks showed significant reductions in the primary endpoints of both pain and disability in the placebo arm.
At 5 years, improvements in those domains persisted, with patients reporting significantly less use of pain medications, analgesics, antidepressants and benzodiazepines. Meanwhile, patients nearly doubled their use of alternative approaches to pain management.
“Although the reduction in pain and medication is comparable with the improvements that occurred in the original study, a major limitation of this long-term follow-up is the absence of controls for spontaneous improvement and new cointerventions,” the researchers wrote. “Nonetheless, our data suggest that reductions in pain and disability after OLP may be long lasting.”
Based on all the above data, Colloca said it may be possible to extend the efficacy of active drugs using a sub-therapeutic dose and placebo. Meanwhile, although Kumar said he is hopeful that more such data sets will validate the findings in the long-term study conducted by Carvalho and colleagues, he suggested that it will be important to explore and potentially rule out other explanations for prolonged placebo-like responses.
“In some subsets of patients, their immune milieu changes over time,” he said. “They may enter remission because of a placebo response or for some other unexplained reason. This is another really important unanswered question.”
Even without a complete understanding of the mechanism, it is clear to many physicians that placebo responses commonly benefit patient-reported symptomatology. However, it will take well designed clinical trials to understand the depths of those benefits and whether more objective markers of disease activity can also be improved.
‘Control for Placebo Responses’
In a paper published in JAMA Network Open, Vollert and colleagues assessed the placebo arms of five double-blind, randomized, placebo-controlled clinical trials that included a total of 788 patients with RA. The results demonstrated significant decreases not only in patient-reported pain intensity, but also in C-reactive protein and erythrocyte sedimentation rate (ESR). The researchers reached the important conclusion that placebo response could extend beyond subjective measures like pain.
“Even if these findings could largely demonstrate a regression to the mean, they should be considered for future trial design, as unexpected favorable placebo responses may result in a well-designed trial becoming underpowered to detect the treatment difference needed in clinical drug development,” Vollert and colleagues wrote.
In further commentary from her paper with Neogi, Colloca suggested that better metrics to assess OA symptoms and structural damage could improve clinical trial design and further harness the placebo effect in OA. Another suggestion would be to standardize tools for measuring the expectations for treatment outcomes for both patients and practitioners.
“Implementing study designs in OA clinical trials that better dissociate placebo from treatment effects” may also be effective, the pair wrote.
There is a role for technology, as well. According to Colloca, machine learning and AI could be used to develop predictive models to stratify patients based on their likelihood of placebo response.
“We should utilize this machine learning and AI boom to help distinguish people who are going to respond to placebo,” she said. “We can look at so many variables and risk factors.”
Clinical factors, of course, may enter the algorithm. However, these are not the only variables that could be useful, Colloca added.
“More educated patients are more likely to experience placebo effects,” she said. “Zip code, education level and family background may be as useful as severity of pain for determining who will benefit from placebo response.”
Another way to improve clinical trial design is to avoid exclusion of placebo responders from clinical trials to optimize drug validation and generalization, according to Neogi and Colloca.
“The best strategy is to control for placebo responses,” Colloca said. “We must control for confounding factors to this response.”
Kumar added that he has no illusions that it will be easy to sort out the variables in the equation.
“This is an art,” he said. “But there is not a lot of good guidance in how to develop a clinical trial to assess placebo response. It is not simple.”
The main issue is that placebos have been used as a control for determining the therapeutic benefit of medications, according to Calabrese.
“To get a new drug approved, you have to show that it is better than placebo, in most cases,” he said. “As an unintended consequence, placebo response has been largely viewed as an obstacle in our field and, until recently, little focus has been placed on the important positive aspects of placebo responses. That mindset needs to change.”
Ongoing data may convince naysayers and regulators alike that the placebo response should be considered as an independent entity across the rheumatology spectrum. As the focus on placebo response intensifies, ethical considerations should be top of mind in both the research and clinical arenas.
‘Lies and Deception Are Out of the Game’
“Giving placebo deceptively is ethically wrong,” Kaptchuk said.
Some variation of this point was echoed by the other experts who spoke to Healio Rheumatology.
“Lies and deception are out of the game — we do not endorse that at all,” Colloca said. “They have no place in clinical practice.”
However, in the same way a doctor will tell a patient that ibuprofen might make their headache better, rheumatologists can inform patients of the mechanism of action of a given DMARD or biologic medication, and how it may improve their symptoms.
“We can use therapeutic strategies to leverage therapeutic effect,” Colloca said.
A companion point to the ethical consideration is understanding the limits of placebo response.
“It is not going to cure pancreatic cancer or lower HIV viral load,” Calabrese said.
Colloca agreed, stating the placebo effect would be unlikely, for example, to impact joint erosion.
“There is no evidence that we can change the bone,” she said.
However, what can change is the way clinical practitioners approach the subject of placebo response, according to Neogi and Colloca. They called for the development of programs to educate providers about the nature of placebo, along with the evaluation and implementation of dose-extending placebo designs to mimic the action of drugs used in OA management. In addition, open-label placebo could be evaluated and implemented as adjuvant therapy to approved OA treatments, they said.
These steps may require multidisciplinary interventions, according to Kumar.
“In addition to rheumatologists, neuroscience and psychiatry will be essential to advance the field,” he said.
In the meantime, though, Colloca said rheumatologists can harness placebo response in daily clinical practice.
“I would encourage them to learn more about this phenomenon,” she said. “Then I would encourage them to make their patients aware of this phenomenon.”
Colloca added that she spent enough time studying these effects that she has developed relationships with patients who have seen how it can benefit their lives.
“So many patients tell me they wish they knew sooner that this function could help them,” she said. “When you go to a rheumatologist, no one tells you how much impact your brain can have on your symptoms.”
Although the ratios are still being debated, Colloca, with an eye toward the current rheumatology treatment landscape, offered that placebo response could improve patients’ symptoms.
“We can improve your symptoms with pharmaceutical approaches,” she said. “But we can improve those symptoms even more by engaging your mind. We need to let patients know they are empowered, that by exploring the power of their mind, they have it within themselves to take control of their disease.”
- References:
- Carvalho C, et al. Pain. 2016;doi:10.1097/j.pain.0000000000000700.
- Carvalho C. Pain. 2021;doi:10.1097/j.pain.0000000000002162.
- Lembo A, et al. Pain. 2021;doi:10.1097/j.pain.0000000000002234.
- Neogi T, Colloca L. Nat Rev Rheum. 2023;doi:10.1038/s41584-023-01021-4.
- Nurko S. JAMA Pediatr. 2021;doi:10.1001/jamapediatrics.2021.5750.
- Vollert J, et al. JAMA Netw Open. 2020;doi:10.1001/jamanetworkopen.2020.13196.
- For more information:
- Leonard Calabrese, DO, can be reached at 9500 Euclid Ave., Cleveland, OH 44195; email: calabrl@ccf.org.
- Luana Colloca, MD, PhD, MS, can be reached at 655 W. Lombard St., Floor 7 Suite 729A, Baltimore, MD; email: colloca@umaryland.edu.
- Ted J. Kaptchuk, MD, can be reached at 641 Huntington Ave., Boston, Massachusetts 02115; email: ted_kaptchuk@hms.harvard.edu.
- Bharat Kumar, MD, can be reached at 200 Hawkins Drive, Iowa City, IA 52245; email: bharat-kumar@uiowa.edu.
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