When the doctor says, I'm going to give you a placebo...

In fact, the very act of seeing a doctor can have a therapeutic effect.

Compilation | XZ

The so-called placebo, as the name suggests, is usually a sugar tablet or saline solution that has no actual medicinal effect. After taking it, you will feel "comforted." In 1955, Henry K. Beecher of Harvard Medical School proposed the term "placebo effect," which can also be understood as an expectation effect of the subject - comfort brings expectations, and people who expect to get better get better faster. The story about the placebo effect seemed to be a "deception" in the past. In the 1950s, this effect was also called the pseudo-drug effect, the fake drug effect, and the substitute drug effect, that is, when patients receive ineffective treatment without knowing it, their symptoms are eventually relieved because they believe in the treatment drug.

In the past, people believed that this effect could only be exerted when the patient was unaware; but today, relevant research has found that it can still be effective even if the patient is aware of it.

On February 12 this year, Ted Kaptchuk's team at Harvard Medical School published an article titled "Open-label placebo vs double-blind placebo for irritable bowel syndrome" in the journal PAIN [1]. The study compared the effects of open-label placebo and double-blind placebo in the treatment of irritable bowel syndrome (IBS). The results showed that both were effective.

“Over the past decade, experiment after experiment has shown that openly informing patients that they are taking a placebo makes them feel better,” Kaptchuk said. Specifically, Kaptchuk found that placebos not only relieve pain, but also anxiety and fatigue.

With the emergence of this result, the "placebo is a lie" has been debunked, and a series of new questions have arisen. Since placebos are also effective, can they become part of standard medical practice? Will patients be willing to take them? Can they be used strategically to reduce the consumption of addictive opioid painkillers? The answers to these questions may change the way we usually think about medicine, but the most important one is that researchers are not completely sure how placebos work.

Embarrassing placebo: can only be used in secret

“When I first thought of giving patients a sugar pill and telling them it was a placebo, my colleagues thought it was really stupid because placebos usually need to be kept secret from the patient in order to work,” Kaptchuk recalls.

For years, Kaptchuk has been trying to find ways to make the placebo effect stronger, especially in treating irritable bowel syndrome, a very painful chronic disease. But all the placebo research is painful for Kaptchuk because it is based on concealment and deception.

If placebos could only be used in secret, they would never become part of mainstream medical practice. In the context of a clinical trial, patients might be able to accept deception, but in the real world, doctors cannot offer that option.

Deception disturbs Kaptchuk. To analyze patients’ feelings of being deceived, he and his colleagues conducted an anthropological survey of patients participating in clinical trials for irritable bowel syndrome[2] and found that many people were worried about being given placebos. Patients asked, “If I get better on a placebo, what does that mean about my condition? Am I making this whole thing up?”

Irritable bowel syndrome is a common functional digestive tract disease with recurrent abdominal pain and discomfort as the main symptoms, often accompanied by constipation and diarrhea. Although normal function is impaired, no structural abnormalities can be seen in endoscopy, X-ray or blood tests.

Public use of placebos also works

Since hiding the use of placebos from patients would make them worried, why not just tell them that it is a placebo? Kaptchuk thinks that if patients feel better after taking a placebo, it is a sign of recovery, not a fabrication.

In 2010, Kaptchuk et al. published a placebo treatment study on 80 patients with irritable bowel syndrome [3]. He gave half of the patients an open placebo treatment and the other half no treatment. The results showed that the patients who used the open placebo were in better health than those who did not receive any treatment!

Since then, openly giving placebos has also been shown to relieve symptoms of other diseases, such as chronic pain, fatigue, arthritis, anxiety, depression, etc. Researchers have also followed up patients who openly used placebos for up to five years[4], and the results also showed that the health of these patients gradually improved.

Based on these studies, Kaptchuk reinterpreted the placebo effect. He believed that in a clinical context, the patient's confidence in recovery is mainly based on the way the medicine is given. When a person is sick and goes to the doctor, this behavior itself is a potential treatment method, which can be called "the drama of medicine." In this "drama", the pill is just a prop, and the doctor is the key role. A doctor with a warm and friendly personality often produces a stronger placebo effect.

How powerful is "drama"?

To answer this question, Kaptchuk and his collaborators replicated the original 80-person IBS trial [1], the recently published study mentioned at the beginning of this article. This time, they compared three conditions: an open placebo (where both the doctor and the patient knew that a placebo was being given), a double-blind placebo (where neither the doctor nor the patient knew whether a placebo or medication was being given), and a no-treatment control group.

The results showed that in the placebo group (the first two conditions), 70% of patients had their symptoms reduced by at least 50 points (on a 500-point scale, with higher scores indicating more severe symptoms), compared with only 54% of patients in the untreated control group.

In addition, approximately 30% of patients who openly used the placebo reported a 150-point reduction in symptoms, compared with only 12% in the no-treatment group.

The results also showed no significant difference in IBS severity scores between the open placebo group and the double-blind placebo group, meaning that whatever benefit people got from the double-blind placebo, they also got from the open placebo.

Why does it work? Two psychological explanations

Why can the open use of placebos be effective in some cases? Currently, researchers mainly explain it from the perspectives of "expectation" and "conditioned reflex".

“Expectations are your belief that something is going to work,” says Darwin Guevarra, a researcher at Michigan State University. In many studies, expectations seem to be set — the subjects are told what the placebo effect is and that it might work.

But it's not that simple. When you expect to improve, you may start to pay attention to all kinds of signals from your body, both good and bad. So when you change your expectations, you may selectively block out the bad signals sent by your brain and instead look for signals that make you feel good.

But expectations don’t explain all of the public use of placebos. Many people who sign up for clinical trials don’t really expect the placebo to cure their disease, Kaptchuk says, but rather to relieve the pain that comes with it.

This is where conditioning comes into play. The theory of classical conditioning comes from Russian psychologist Pavlov's experiments with dogs: when the dogs learned to associate the sound of a bell with eating, they would start salivating whenever they heard the bell. For humans, we can associate one thing (taking a placebo) with a positive outcome (feeling better). In this way, even if the drug component of the actual treatment is removed, the act of receiving the treatment will make you feel better.

In another study published in PAIN[5], Kaptchuk divided 51 spinal surgery patients into two groups: one group received an open placebo and took opioids, and the other group took opioids alone.

During the experiment, patients took a placebo pill after taking an opioid. Over time, the brain gradually learned to associate the placebo with the real drug. Drugs relieve pain by stimulating the brain to release neurotransmitters, so in theory, even if you only take a placebo, if your brain is conditioned, it will start releasing these neurotransmitters.

The results also showed that compared with the usual care group, those who took a placebo and opioids at the same time had a 30% reduction in opioid dependence and reported a gradual reduction in pain.

Some have questioned this finding: Are patients just saying what researchers want to hear? But other studies have found that overt placebos do seem to reduce neural markers of pain and stress.[6]

Overall, researchers still don't know which factors play a major role in the placebo effect. But it's important to figure this out because it will determine how scientists design placebos for clinical use. The "conditioning theory" seems to require frequent stimulation, while the "expectation theory" can be done in one step and seems more attractive.

Placebos are overlooked as medicines. Maybe that should change.

Kaptchuk said that placebos are not some magic pill, and they may only work for certain people at certain times. Studies have shown that placebos (whether disclosed to patients or not) seem to work mainly on subjective symptoms, such as pain. They have no effect on objective symptoms, such as fractures.

Placebos don’t shrink tumors, they don’t improve diabetes, and they don’t rapidly lower your blood pressure. So does this mean that they are of very limited use?

Kaptchuk believes that all objective diseases have subjective symptoms. For example, cancer is caused by tumors, but it can also make people feel pain or fatigue. There are also some diseases, such as irritable bowel syndrome, which is believed to be caused by the brain misinterpreting normal sensations as pain. The use of placebos may interfere with the brain's interpretation and relieve pain.

Overall, Kaptchuk's new definition of the placebo effect - "medical drama" - is a radical way of thinking about medicine that not every doctor can agree with. Mainstream medicine has long been dismissive of placebos, even thinking that the placebo effect seems to be an obstacle that needs to be cleared before we can determine what is "real medicine." But the placebo itself is acting more and more like a medicine. The placebo effect is an additional healing power that is outside of medicine or used when no good medicine is available.

To this day, we still have many unknown questions about placebos, and more research is needed to determine whether placebos can become a real medicine in the future.

Original link:

https://www.vox.com/unexplainable/22405880/placebo-mystery-open-label-pain-medicine

References

[1] Lembo, A., Kelley, JM, Nee, J., Ballou, S., Iturrino, J., Cheng, V., Rangan, V., Katon, J., Hirsch, W., Kirsch, I., Hall, K., Davis, RB, & Kaptchuk, TJ (2021). Open-label placebo vs double-blind placebo for irritable bowel syndrome: a randomized clinical trial. Pain, 10.1097/j.pain.0000000000002234. Advance online publication.

[2] Kaptchuk, TJ, Shaw, J., Kerr, CE, Conboy, LA, Kelley, JM, Csordas, TJ, Lembo, AJ, & Jacobson, EE (2009). "Maybe I made up the whole thing": placebos and patients' experiences in a randomized controlled trial. Culture, medicine and psychiatry, 33(3), 382–411.

[3] Kaptchuk, TJ, Friedlander, E., Kelley, JM, Sanchez, MN, Kokkotou, E., Singer, JP, Kowalczykowski, M., Miller, FG, Kirsch, I., & Lembo, AJ (2010). Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PloS one, 5(12), e15591.

[4] Kaptchuk, TJ, & Miller, FG (2018). Open label placebo: can honestly prescribed placebos evoke meaningful therapeutic benefits?. Bmj, 363.

[5] Flowers, KM, Patton, ME, Hruschak, VJ, Fields, KG, Schwartz, E., Zeballos, J., Kang, JD, Edwards, RR, Kaptchuk, TJ, & Schreiber, KL (2021). Conditioned open-label placebo for opioid reduction after spine surgery: a randomized controlled trial. Pain, 162(6), 1828–1839.

[6] Guevarra, DA, Moser, JS, Wager, TD et al. Placebos without deception reduce self-report and neural measures of emotional distress. Nat Commun 11, 3785 (2020).