Tapping into the Power of the Placebo Effect
When Wayne Jonas was in medical school 40 years ago, doctors would write out a prescription for placebos, spelling it out backwards in capital letters, O-B-E-C-A-L-P. The pharmacist would fill the prescription with a sugar pill, recalls Jonas, now director of integrative health programs at the Samueli Foundation. It fulfilled the patient's desire for the doctor to do something when perhaps no drug could help, and the sugar pills did no harm.
Today, that deception is seen as unethical. But time and time again, studies have shown that placebos can have real benefits. Now, researchers are trying to untangle the mysteries of placebo effect in an effort to better treat patients.
The use of placebos took off in the post-WWII period, when randomized controlled clinical trials became the gold standard for medical research. One group in a study would be treated with a placebo, a supposedly inert pill or procedure that would not affect normal healing and recovery, while another group in the study would receive an "active" component, most commonly a pill under investigation. Presumably, the group receiving the active treatment would have a better response and the difference from the placebo group would represent the efficacy of the drug being tested. That was the basis for drug approval by the U.S. Food and Drug Administration.
"Placebo responses were marginalized," says Ted Kaptchuk, director of the Program in Placebo Studies & Therapeutic Encounters at Harvard Medical School. "Doctors were taught they have to overcome it when they were thinking about using an effective drug."
But that began to change around the turn of the 21st century. The National Institutes of Health held a series of meetings to set a research agenda and fund studies to answer some basic questions, led by Jonas who was in charge of the office of alternative medicine at the time. "People spontaneously get better all the time," says Kaptchuk. The crucial question was, is the placebo effect real? Is it more than just spontaneous healing?
Brain mechanisms
A turning point came in 2001 in a paper in Science that showed physical evidence of the placebo effect. It used positron emission tomography (PET) scans to measure release patterns of dopamine — a chemical messenger involved in how we feel pleasure — in the brains of patients with Parkinson's disease. Surprisingly, the placebo activated the same patterns that were activated by Parkinson's drugs, such as levodopa. It proved the placebo effect was real; now the search was on to better understand and control it.
A key part of the effect can be the beliefs, expectations, context, and "rituals" of the encounter between doctor and patient. Belief by the doctor and patient that the treatment would work, and the formalized practices of administering the treatment can all contribute to a positive outcome.
Conditioning can be another important component in generating a response, as Pavlov demonstrated more than a century ago in his experiments with dogs. They were trained with a bell prior to feeding such that they would begin to salivate in anticipation at the sound of a bell even with no food present.
Translating that to humans, studies with pain medications and sleeping aids showed that patients who had a positive response with a certain dose of those medications could have the same response if the doses was reduced and a dummy pill substituted, even to the point where there was no longer any active ingredient.
Researchers think placebo treatments can work particularly well in helping people deal with pain and psychological disorders.
Those types of studies troubled Kaptchuk because they often relied on deception; patients weren't told they were receiving a placebo, or at best there was a possibility that they might be randomized to receive a placebo. He believed the placebo effect could work even if patients were told upfront that they were going to receive a placebo. More than a dozen so call "open-label placebo" studies across numerous medical conditions, by Kaptchuk and others, have shown that you don't have to lie to patients for a placebo to work.
Jonas likes to tell the story of a patient who used methotrexate, a potent immunosuppressant, to control her rheumatoid arthritis. She was planning a long trip and didn't want to be bothered with the injections and monitoring required in using the drug, So she began to drink a powerful herbal extract of anise, a licorice flavor that she hated, prior to each injection. She reduced the amount of methotrexate over a period of months and finally stopped, but continued to drink the anise. That process had conditioned her body "to alter her immune function and her autoimmunity" as if she were taking the drug, much like Pavlov's dogs had been trained. She has not taken methotrexate for more than a year.
An intriguing paper published in May 2021 found that mild, non-invasive electric stimulation to the brain could not only boost the placebo effect on pain but also reduce the "nocebo" effect — when patients report a negative effect to a sham treatment. While the work is very preliminary, it may open the door to directly manipulating these responses.
Researchers think placebo treatments can work particularly well in helping people deal with pain and psychological disorders, areas where drugs often are of little help. Still, placebos aren't a cure and only a portion of patients experience a placebo effect.
Nocebo
If medicine were a soap opera, the nocebo would be the evil twin of the placebo. It's what happens when patients have adverse side effects because of the expectation that they will. It's commonly seem when patients claims to experience pain or gastric distress that can occur with a drug even when they've received a placebo. The side effects were either imagined or caused by something else.
"Up to 97% of reported pharmaceutical side effects are not caused by the drug itself but rather by nocebo effects and symptom misattribution," according to one 2019 paper.
One way to reduce a nocebo response is to simply not tell patients that specific side effects might occur. An example is a liver biopsy, in which a large-gauge needle is used to extract a tissue sample for examination. Those told ahead of time that they might experience some pain were more likely to report pain and greater pain than those who weren't offered this information.
Interestingly, a nocebo response plays out in the hippocampus, a part of the brain that is never activated in a placebo response. "I think what we are dealing with with nocebo is anxiety," says Kaptchuk, but he acknowledges that others disagree.
Distraction may be another way to minimize the nocebo effect. Pediatricians are using virtual reality (VR) to engage children and distract them during routine procedures such as blood draws and changing wound dressings, and burn patients of all ages have found relief with specially created VRs.
Treatment response
Jonas argues that what we commonly call the placebo effect is misnamed and leading us astray. "The fact is people heal and that inherent healing capacity is both powerful and influenced by mental, social, and contextual factors that are embedded in every medical encounter since the idea of treatment began," he wrote in a 2019 article in the journal Frontiers in Psychiatry. "Our understanding of healing and ability to enhance it will be accelerated if we stop using the term 'placebo response' and call it what it is—the meaning response, and its special application in medicine called the healing response."
He cites evidence that "only 15% to 20% of the healing of an individual or a population comes from health care. The rest—nearly 80%—comes from other factors rarely addressed in the health care system: behavioral and lifestyle choices that people make in their daily life."
To better align treatments and maximize their effectiveness, Jonas has created HOPE (Healing Oriented Practices & Environments) Note, "a patient-guided process designed to identify the patient's values and goals in their life and for healing." Essentially, it seeks to make clear to both doctor and patient what the patient's goals are in seeking treatment. In an extreme example of terminal cancer, some patients may choose to extend life despite the often brutal treatments, while others might prefer to optimize quality of life in the remaining time that they have. It builds on practices already taught in medical schools. Jonas believes doctors and patients can use tools like these to maximize the treatment response and achieve better outcomes.
Much of the medical profession has been resistant to these approaches. Part of that is simply tradition and limited data on their effectiveness, but another very real factor is the billing process for how they are reimbursed. Jonas says a new medical billing code added this year gives doctors another way to be compensated for the extra time and effort that a more holistic approach to medicine may initially require. Other moves away from fee-for-service payments to bundling and payment for outcomes, and the integrated care provided by the Veterans Affairs, Kaiser Permanente and other groups offer longer term hope for the future of approaches that might enhance the healing response.
This article was first published by Leaps.org on July 7, 2021.
Scientific breakthroughs offer our only solution for a safe return to normal life.
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.
A historical perspective offers insights about how far we have come since the 1918 Spanish flu, and how far we have yet to go.
With a deadly pandemic sweeping the planet, many are questioning the comfort and security we have taken for granted in the modern world.
A century ago, when an influenza pandemic struck, we barely knew what viruses were.
More than a century after the germ theory, we are still at the mercy of a microbe we can neither treat, nor control, nor immunize against. Even more discouraging is that technology has in some ways exacerbated the problem: cars and air travel allow a new disease to quickly encompass the globe.
Some say we have grown complacent, that we falsely assume the triumphs of the past ensure a happy and prosperous future, that we are oblivious to the possibility of unpredictable "black swan" events that could cause our destruction. Some have begun to lose confidence in progress itself, and despair of the future.
But the new coronavirus should not defeat our spirit—if anything, it should spur us to redouble our efforts, both in the science and technology of medicine, and more broadly in the advance of industry. Because the best way to protect ourselves against future disasters is more progress, faster.
Science and technology have overall made us much better able to deal with disease. In the developed world, we have already tamed most categories of infectious disease. Most bacterial infections, such as tuberculosis or bacterial pneumonia, are cured with antibiotics. Waterborne diseases such as cholera are eliminated through sanitation; insect-borne ones such as malaria through pest control. Those that are not contagious until symptoms appear, such as SARS, can be handled through case isolation and contact tracing. For the rest, such as smallpox, polio, and measles, we develop vaccines, given enough time. COVID-19 could start a pandemic only because it fits a narrow category: a new, viral disease that is highly contagious via pre-symptomatic droplet/aerosol transmission, and that has a high mortality rate compared to seasonal influenza.
A century ago, when an influenza pandemic struck, we barely knew what viruses were; no one had ever seen one. Today we know what COVID-19 is down to its exact genome; in fact, we have sequenced thousands of COVID-19 genomes, and can track its history and its spread through their mutations. We can create vaccines faster today, too: where we once developed them in live animals, we now use cell cultures; where we once had to weaken or inactivate the virus itself, we can now produce vaccines based on the virus's proteins. And even though we don't yet have a treatment, the last century-plus of pharmaceutical research has given us a vast catalog of candidate drugs, already proven safe. Even now, over 50 candidate vaccines and almost 100 candidate treatments are in the research pipeline.
It's not just our knowledge that has advanced, but our methods. When smallpox raged in the 1700s, even the idea of calculating a case-fatality rate was an innovation. When the polio vaccine was trialled in the 1950s, the use of placebo-controlled trials was still controversial. The crucial measure of contagiousness, "R0", was not developed in epidemiology until the 1980s. And today, all of these methods are made orders of magnitude faster and more powerful by statistical and data visualization software.
If you're seeking to avoid COVID-19, the hand sanitizer gel you carry in a pocket or purse did not exist until the 1960s. If you start to show symptoms, the pulse oximeter that tests your blood oxygenation was not developed until the 1970s. If your case worsens, the mechanical ventilator that keeps you alive was invented in the 1950s—in fact, no form of artificial respiration was widely available until the "iron lung" used to treat polio patients in the 1930s. Even the modern emergency medical system did not exist until recently: if during the 1918 flu pandemic you became seriously ill, there was no 911 hotline to call, and any ambulance that showed up would likely have been a modified van or hearse, with no equipment or trained staff.
As many of us "shelter in place", we are far more able to communicate and collaborate, to maintain some semblance of normal life, than we ever would have been. To compare again to 1918: long-distance telephone service barely existed at that time, and only about a third of homes in the US even had electricity; now we can videoconference over Zoom and Skype. And the enormous selection and availability provided by online retail and food delivery have kept us stocked and fed, even when we don't want to venture out to the store.
Let the virus push us to redouble our efforts to make scientific, technological, and industrial progress on all fronts.
"Black swan" calamities can strike without warning at any time. Indeed, humanity has always been subject to them—drought and frost, fire and flood, war and plague. But we are better equipped now to deal with them than ever before. And the more progress we make, the better prepared we'll be for the next one. The accumulation of knowledge, technology, industrial infrastructure, and surplus wealth is the best buffer against any shock—whether a viral pandemic, a nuclear war, or an asteroid impact. In fact, the more worried we are about future crises, the more energetically we should accelerate science, technology and industry.
In this sense, we have grown complacent. We take the modern world for granted, so much so that some question whether further progress is even still needed. The new virus proves how much we do need it, and how far we still have to go. Imagine how different things would be if we had broad-spectrum antiviral drugs, or a way to enhance the immune system to react faster to infection, or a way to detect infection even before symptoms appear. These technologies may seem to belong to a Star Trek future—but so, at one time, did cell phones.
The virus reminds us that nature is indifferent to us, leaving us to fend entirely for ourselves. As we go to war against it, let us not take the need for such a war as reason for despair. Instead, let it push us to redouble our efforts to make scientific, technological, and industrial progress on all fronts. No matter the odds, applied intelligence is our best weapon against disaster.