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Expensive meds might make you feel worse — if you expect them to

Expensive meds might make you feel worse — if you expect them to

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Meet nocebo, placebo’s ‘evil twin’

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Illustration by Alex Castro / The Verge

Pricier drugs might make you feel worse — if you expect to experience negative side effects, according to a new study.

Researchers tested a sham anti-itch cream on 49 people, who were told the cream would make their skin more sensitive to pain. Some received the fake medication in a sleek, blue box that looked like a pricy brand-name product; others got a fake cream in an orange box that resembled a generic. The people who tried the “expensive” sham cream reported feeling more pain, according to a study published this week in Science. And it wasn’t all in their heads, either: those people had increased activity in certain brain areas and the spinal cord, which carries pain signals to the brain.

The two boxes created by study author Alexandra Tinnerman: the top one looks like a cheap generic, the bottom on resembles a pricier brand-name drug.
The two boxes created by study author Alexandra Tinnerman: the top one looks like a cheap generic, the bottom on resembles a pricier brand-name drug.
Photo by Alexandra Tinnerman and Tim Dretzler

What these people experienced is called the nocebo effect. Nocebo is “placebo’s evil twin,” says Irving Kirsch, a faculty member at Harvard Medical School. A placebo is a fake pill or treatment, with no active ingredients, that brings us benefits because we think we’re getting an actual medication and we expect it to work. Placebos are often used in clinical trials as controls, to check whether a new drug actually works. But placebos can also have negative side effects, if we expect the medication to harm us — those negative effects are nocebos.

In a study, lactose intolerant people were given a dose of glucose, but were told they received lactose to study its effects on bowel symptoms. It didn’t matter: 44 percent of them complained of gastrointestinal problems. In another case, a participant in a trial for a new antidepressant drug swallowed 26 placebo tablets in a suicide attempt. His blood pressure dropped dangerously low anyway.

It’s not just our brain going awry

This is not just our brain going awry — in evolutionary terms, it can help us survive. Let’s say you’re walking in a forest where you know there are poisonous snakes, and all of a sudden, you see something squiggly in the path in front of you, Kirsch says. Because you expect there might snakes, your brain quickly identifies the squiggly thing as one — whether or not it actually is — and tells you to run. “After all, better to avoid and run away from a stick than it is to get bitten by a poisonous snake,” Kirsch says. “That’s the evolutionary advantage of being able to experience things based on what you’re expecting and believing.”

But of course, in the context of clinical trials, the nocebo effect can cause troubles. People in control groups, who receive sham treatments, often drop out of studies because of negative side effects. That’s a problem when researchers already have a hard time recruiting participants to begin with. So scientists are trying to understand more about the nocebo effect, to figure out how to avoid it.

In this latest study, researchers wanted to know if a drug’s price and packaging could make people feel worse. So Alexandra Tinnerman, a neuroscientist at University Medical Center Hamburg-Eppendorf in Germany, designed two different boxes for a fake anti-itch cream: one ointment was named Solestan Creme, and looked pricy; the other was called Imotadil-LeniPharma Creme, and looked cheap.

Study participants getting their brains scanned.
Study participants getting their brains scanned.
Photo by Alexandra Tinnerman and Tim Dretzler

Tinnerman then gave the two creams to a group of people, telling them whether they received the expensive or the cheap one. As it’s normal during clinical trials, Tinnerman also told participants what side effects they might expect: increased pain sensitivity in the area of the skin where the cream was applied. In the experiments, the researchers rubbed the fake cream on the participants’ forearms. After a few minutes, they applied a metal plate on the same patch of skin to deliver flashes of heat, up to 113 degrees Fahrenheit. The plate gives a burning sensation, like a hot iron, says Tinnerman.

Those who tried the expensive cream felt more intense pain than the people who tried the cheap cream. And over time, the pain for the expensive cream group got stronger, while it slightly decreased for the other group. Brain scans that record changes in blood flow backed the findings: the researchers found that people who reported feeling more pain had more activity in an area of the brain that processes expectations, called the prefrontal cortex. Their spinal cord, which is key for carrying pain signals from a body part that’s hurt to the brain, also showed more activity. This suggests that the participants trying the expensive cream were actually experiencing more pain, they weren’t just imagining it.

“Pain can be shaped by our expectations.”

It’s not exactly clear why the people using the expensive sham cream had worse side effects, Tinnerman says. A previous study showed that expensive placebos work better than cheap ones. In this latest study, people likely thought that the pricier treatment was stronger, leading to stronger side effects, Tinnerman says. It’s all about what we expect the drug to do. “Pain can be shaped by our expectations,” says Luana Colloca, associate professor at the University of Maryland School of Nursing and School of Medicine, who was not involved in the research.

These findings — and others about the nocebo effect — are key to design better clinical trials, as well as improve treatment outcomes. Doctors still have the ethical obligation of telling patients what side effects they might experience while undergoing treatment, but the way that information is framed is key, Colloca says. Studies show that focusing only on how painful a local anesthesia injection is going to be, rather than also explaining the benefits the anesthesia will bring, increases pain for patients. Kirsch says that, maybe, informing patients about the nocebo effect, so they’re aware of the power of expectations, could also help.

Researchers are still trying to figure all this out, and the nocebo effect is just starting to get research attention. (We know way more about the placebo effect in part because conducting studies to cause people pain straddles a murky ethical line.) But next time you take a medication, try not to focus on its packaging and price too much.