Knowing that you are eating a candy pill can also reduce the pain

The story of the placebo effect used to be simple: A sugar pill might work when a patient didn’t know they were taking it or thought they were receiving a real treatment.

Until Ted Kaptchuk came on the scene.

Kapchuk, a professor at Harvard Medical School, and his colleagues have repeatedly shown in study after study over the past decade that giving patients placebos openly—telling them they are taking a placebo—can make them feel better. They have found that placebos can reduce not only pain but also anxiety and fatigue.

Just in February 2021, Kapchak and his colleagues published the results of a clinical trial comparing the effects of open-label placebo and double-blind placebo (the gold standard for medical research) in the treatment of irritable bowel syndrome. The conclusion was that both were equally effective.

The myth that placebos require deception has been busted, Kapchak said.

This makes people start to think about a series of new questions. For example:

Could placebos become part of standard medical practice?

Will patients be willing to take them?

Can placebos be used to reduce the use of addictive opioid painkillers?

Medical care could change as a result. But one thing researchers still don't know is how these sugar pills, which contain no active ingredients, work.

Tell patients they are taking a placebo.

The patient will get better

Kapchuk recalls that when he first thought of giving patients sugar pills and telling them explicitly that they were placebos, his colleagues said, "That's the dumbest idea you've ever had." Everyone took it for granted that placebos had to be kept secret to be effective.

But his idea of ​​confessing to his patients was no joke. It came from his empathy for his patients and his frustration with his research.

For years, Kapchak has been trying to make the placebo effect more significant and powerful. He is particularly concerned about patients with irritable bowel syndrome, a painful chronic disease that is difficult to treat. Patients with irritable bowel syndrome often suffer from bloating, diarrhea, or constipation that can last from a few days to a few months at a time. Patients find it difficult to live a normal life.

Irritable bowel syndrome | mayo clinic health system

“Deep down I was always troubled that everything I was studying depended on concealment or deception,” Kapnick said.

Kapchuk knew that as long as placebos were used in a furtive way, they would never become part of mainstream medical practice. If patients in clinical trials were willing to accept the possibility of being deceived, doctors in the real world would not be able to offer that option. Therefore, no matter how good the placebo effect was, it would never benefit everyday medicine.

Kapchuk was not reassured by this. In 2009, he and his colleagues conducted an anthropological survey of patients who had participated in a clinical trial for irritable bowel syndrome that used a deceptive placebo. What they wanted to know was: How did the patients feel about being deceived?

They found that many patients were anxious about the possibility that they might be assigned to the placebo group. Patients would say, "If I'm assigned to the placebo group and I get better, what does that mean? ... Does that mean that I'm imagining my illness?"

For Kapchak, the 2009 study was a turning point. When he read the conclusions, he wondered: Why don't we just tell patients they're taking a placebo? That way they don't have to worry about whether they're getting the drug or not?

He realized that he could be honest with his patients: “If you get better on a placebo, that’s a sign of recovery. Don’t be alarmed by it. It’s not something wrong with your brain.”

Kapchak designed another small study. In 2010, he recruited 80 patients with irritable bowel syndrome, gave half of them a placebo such as a sugar pill and told them that they were using a placebo, and did not give the other half any treatment. At the end of the trial, the patients in the placebo group felt better than those in the non-treatment group.

In 2010, Kaptchak designed another small study, the results of which showed:

Patients in the placebo group felt better than those in the no-treatment group | Reference [4]

Since then, studies have shown that open-label placebos can also reduce symptoms of other conditions, including chronic pain, hot flashes, fatigue, allergies, arthritis, anxiety, and depression. Long-term studies have also been conducted, observing patients who took open-label placebos and showed sustained improvement over a five-year period.

The placebo effect comes from the "drama" performed by doctors

These studies led Kaptchak to write a new definition of the placebo effect. He said,

“The placebo effect is the positive health benefits that patients gain from the rituals, symbols, and behaviors associated with placebo pills during clinical interactions.

When a patient goes to a healer, the drama of the healing itself is a powerful form of healing.”

The “drama” he mentioned is not a metaphor. Medicine is a kind of theatrical performance. The pills are props in this medical story. The doctors in white coats who care about you are the characters in the play—a 2008 study by Kapnick also found that the gentler and friendlier the doctors are, the stronger the placebo effect is. A good attitude means that the doctor is warm and friendly, actively listens to the patient (will repeat what the patient says and confirm what the patient means), shows confidence in the treatment plan ("I have treated this disease very well in the past, and I think this time will be a good result"); and is focused and serious during the diagnosis and treatment process (pondering for 20 seconds and focusing on the treatment plan).

In a paper published in the journal Pain in February this year, Kapchak and his colleagues replicated the original trial on patients with irritable bowel syndrome on a larger scale. Unlike the last time, they compared three conditions: an open-label placebo group, a double-blind placebo group, and a no-treatment control group. From a methodological point of view, this study is very interesting: none of these three conditions is a "real treatment."

The results showed that, first, the open-label placebo was effective. Among the patients taking the open-label placebo, 70% of them had their symptom severity reduced by at least 50 points (out of a total score of 500), while in the untreated control group, only 54% of the patients had a 50-point reduction. In addition, about 30% of the patients in the open-label placebo group reported a 150-point reduction in their symptoms, while this proportion was 12% in the untreated group.

“There’s no doubt this is a worthwhile direction to pursue,” said Beth Darnall, director of Stanford University’s Pain Relief Innovation Lab. “It’s a free treatment and it’s virtually risk-free. That’s very important.”

Of course, not every patient in the open-label placebo group experienced improvement. But if you were in the group that experienced a 50- to 150-point reduction in symptoms, “that’s a big improvement, isn’t it?” Darnell said.

The study also showed that open-label placebos produced similar responses to double-blind placebos, meaning that patients got all the benefits from the double-blind placebo that they also got from the open-label placebo.

Again, “you don’t have to deceive the patient,” says Daniel Keszthelyi, MD, PhD, a professor of philosophy and medicine at Maastricht University Medical Center in the Netherlands, who specializes in studying and treating irritable bowel syndrome. “This is an effect that can be really exploited in clinical practice,” he says.

It is the expectation that you will be fine.

Or is it because of the established conditioned reflex?

Why do open-label placebos work for certain diseases? Researchers have proposed two theories: the expectancy theory and the conditioning theory.

“Expectancy is your belief that something is going to have an effect,” says Darwin Guevarra of Michigan State University, who studies the effects of placebos on emotion regulation. His research, like many of Kaptchak’s, sets expectations for placebos through education. He educates study participants about the placebo effect and tells them that an open-label placebo can also help.

However, this is not a simple "belief will work". When you have an expectation that your condition will improve, you may start to pay attention to the various signals from your body. Our nervous system is transmitting a large number of signals at all times. Some of the signals sent by the body to the brain will be interpreted by the brain as pain, while others will be interpreted as non-pain signals. When your expectations change, you may ignore those signals that mean "I am in pain" or "I am anxious" and pay more attention to those clues that you feel better.

Neuroscientists have long understood that our perception of our bodies (or anything else) is our brain’s best guess at using the imperfect information coming from our senses. So the principle here is simple: When you start paying attention to different sensory signals, your sense of reality changes as well.

“Expectations are what you think something will do.” | simple learning pro

However, expectations cannot fully explain the open-label placebo effect. Kapchuk points out from experience that many people who come to clinical trials do not actually expect their condition to get better. They sign up for it as a last resort aimed at relieving pain. "They are all experiencing despair and pain," he said.

This brings us to the theory of conditioning. A conditioning is a response that is learned automatically and does not require you to believe in anything. Its classic example is Pavlov's dogs: these dogs learned to associate the sound of a bell with being fed. Later, the ringing of the bell would make them salivate. And research has found that humans can also associate one thing (taking a placebo) with a positive outcome (feeling better).

“The mere act of receiving treatment can make you feel better, even if you take away the active ingredients of real therapy,” Guevara explains.

Another recent study published in the journal Pain revealed the effectiveness of using non-blind placebos to establish conditioned reflexes in reality.

In the study, 51 patients undergoing spinal surgery were divided into two groups. One group received an open-label placebo (while taking opioid pain medication) to induce conditioning, while the other group received conventional pain management.

In the conditioning group, each time patients took their regular opioid pain medication after surgery, the researchers asked them to also take an open-label placebo. One to two days later, the patients were told to take their placebos as scheduled.

The logic of this experiment is that the brain will establish a connection between taking a placebo and real painkillers, and finally the placebo will release neurotransmitters in the brain. "In theory, even if you only take a placebo, as long as your brain has a conditioned reflex, it will still release these neurotransmitters." Kelsey Flowers, one of the leaders of the study, said.

The researchers followed all patients through postoperative day 17. At the end, they found that those who had been conditioned with a placebo took 30% less opioids than those in the conventional pain control group. They also reported less pain every day.

Interestingly, Flowers said, many of those who developed the conditioning told the researchers they weren't sure it worked. "That's the beauty of our findings," he said. "Even if you don't expect the outcome, you can still benefit from it."

It was only a small pilot study, but it proves that this type of research is possible and suggests that if more doctors were willing to use placebos to establish conditioning, future medical care could change dramatically.

Of course, there is still a question: Could it be that those patients just said what the researchers wanted to hear out of kindness? It is possible. But other studies have found that in terms of some neural signals, open-label placebos do seem to reduce pain and stress.

Even when people don't expect results, they still benefit from placebos | sitn.hms.harvard.edu

In a recent study led by Guevara, he used electrodes attached to the scalp to measure that an open-label placebo can reduce stress. “We found that the amplitude of these brain waves decreased after the subjects took the placebo, and the decrease occurred gradually,” he said. “This shows that what they took did reduce their distress.”

Overall, researchers are still studying which factors play a greater role in the placebo effect, which factors have a better effect, and how different factors stack up. These questions are quite important because they are related to how placebos are used. After all, establishing conditioned reflexes is a tedious process, and it seems more attractive to expect that they can be established with just one educational intervention.

It is not a panacea, but works best on subjective symptoms.

There is one thing that must be said: Placebo is by no means a panacea. It only works for some people sometimes, and not every time.

Placebos, whether open-label or concealed, work primarily on subjective symptoms, such as pain. They have no effect on objective symptoms, those that doctors can see or diagnose, such as broken bones. "A placebo won't shrink a tumor, it won't improve your diabetes, it won't lower your blood pressure for more than 15 minutes," Kaptchak says.

Ultimately, the only things that placebos seem to work on are those that travel through the brain’s sensory systems, where they stimulate the release of opioids and endorphins (both pain-relieving chemicals).

Does this mean that the effectiveness of placebos is quite limited?

At this point, Kaptchak defended the placebo, saying that all objective diseases contain subjective symptoms. For example, cancer is caused by tumors, but it also makes people feel tired. There are also some diseases where doctors can't objectively find out what's wrong with the patient, such as irritable bowel syndrome, which afflicts about 10% of the population and many people suffer from chronic pain due to it, but there is no effective treatment.

IBS is thought to be caused by the brain misinterpreting signals from the gut, interpreting normal sensations as pain. Perhaps placebos can fix this faulty circuit.

Conditions like irritable bowel syndrome, for which there is currently no drug, actually make up a large part of medicine. This is the not-so-glamorous side of medicine. These are places where placebos may be able to help.

Are doctors ready to prescribe placebos to their patients?

Every doctor and scientist who studies placebos says that open-label placebos are not ready for prime time. There are still too many unanswered questions.

Keszthely, a gastroenterologist who specializes in irritable bowel syndrome, says they can be used in some patients who have difficulty tolerating medications: “If there is evidence that drug therapy causes serious adverse effects, then I would definitely give patients an open-label placebo.”

In fact, to some extent, doctors already prescribe placebos to patients. They just use real drugs - sometimes doctors prescribe unrelated drugs or vitamins, and they also know that if those drugs help patients recover, it is due to the placebo effect. In this case, doctors will no longer have to hide it and can directly prescribe open-label placebos.

Others are not so optimistic about the future of open-label placebos. Luana Colloca, a physician, neuroscientist, and placebo researcher at the University of Maryland, is concerned that prescribing open-label placebos to patients will become a way for doctors to get rid of patients.

Koloka says that you don’t necessarily need a placebo pill to elicit a placebo effect. (Kapchuk’s definition of the placebo effect doesn’t require a pill. A pill is just a convenient tool used to change a patient’s expectations or induce a conditioned response.)

Koloka’s own research shows that a placebo doesn’t even have to be a physical object. The right words, said at the right time, can help patients get greater medical value from already powerful drugs like morphine. What’s more, there are many creative ways to help patients manage pain that don’t rely on placebos. For example, Darnell’s research uses elements of cognitive behavioral therapy, which can also reduce patients’ use of opioids.

Stop Disdaining Placebos

Kapchuk believes that the placebo effect is a medical "drama." This is a radical view of medicine. Some doctors may disagree.

But Kapchak argues that mainstream medicine has downplayed this "drama" for too long, always dismissing it as "just a placebo effect."

"It's a real slur," Kapchak said.

People have always viewed the placebo effect as a threshold, as if a drug only becomes a "real" drug after crossing it. But now it seems that the placebo itself is becoming more and more like a drug. The so-called placebo effect can also be an additional therapeutic force, allowing doctors to make an already effective drug work extra, or use placebos when there are no other good drugs available. This is a wealth we have not yet used.

Ultimately, though, Kapchuk still doesn’t know how placebos work. “But I know you have to be honest with your patients and not hide anything,” he said. “We sell honesty here.”

References

[1]Resnick, B. (2021). Placebo pills can help treat people in pain. But how? Vox. Retrieved from https://www.vox.com/unexplainable/22405880/placebo-mystery-open-label-pain-medicine

[2]Lembo, A., Kelley, JM, Nee, J., Ballou, S., Iturrino, J., Cheng, V., ...Kaptchuk, TJ (2021). Open-label placebo vs double-blind placebo for irritable bowel syndrome: a randomized clinical trial. Pain, Articles in Press. doi: 10.1097/j.pain.0000000000002234

[3]Kaptchuk, TJ, Shaw, J., Kerr, CE, Conboy, LA, Kelley, JM, Csordas, TJ, ...Jacobson, EE (2009). "Maybe I made up the whole thing": placebos and patients' experiences in a randomized controlled trial. Cult. Med. Psychiatry, 19597976. Retrieved from https://pubmed.ncbi.nlm.nih.gov/19597976

[4]Kaptchuk, TJ, Friedlander, E., Kelley, JM, Sanchez, MN, Kokkotou, E., Singer, JP, ...Lembo, AJ (2010). Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS One, 21203519. Retrieved from https://pubmed.ncbi.nlm.nih.gov/21203519

[5]Kaptchuk, TJ, Kelley, JM, Conboy, LA, Davis, RB, Kerr, CE, Jacobson, EE, ...Lembo, AJ (2008). Components of placebo effect: randomized controlled trial in patients with irritable bowel syndrome. BMJ, 336(7651), 999. doi: 10.1136/bmj.39524.439618.25

By Brian Resnick

Translation: Porco Rosso

Editor: You Shiyou, Cloud

Compiled by: Vox