The Nocebo Effect—the Flip Side of Placebo—Carries a High Price


An “expensive” treatment with no active ingredients causes more pain than the “cheap” version. Image credit: ayo88/123RF Stock Photo.

The placebo response in clinical trials of new drugs has long puzzled doctors and scientists. When someone receives a placebo—a sugar pill or some other chemically inactive substance, for instance—rather than the drug, that person may experience beneficial effects nonetheless. But they may also experience side effects from the placebo—this is called the nocebo response. Now, new research shows that the perceived cost of a treatment can influence that response.

A team led by Christian Büchel at University Medical Center Hamburg-Eppendorf in Germany show that healthy volunteers who thought they were receiving an expensive treatment showed more pain in experimental laboratory tests than when under the impression that the treatment was cheap. Both treatments, however, had no active ingredients.

Using brain imaging, the researchers also show that interactions between brain regions involved in pain signalling and the spinal cord underlie this effect.

The findings were published online October 6th in the journal Science.

Setting up expectations
The placebo response involves positive expectations of a treatment—people think they will feel better—while the nocebo response involves negative expectations—people believe they will get worse. Both are heavily influenced by patients’ perceptions, prior experiences and the encounter with the doctor or investigator.

Placebo and nocebo are complex phenomena influenced by a host of environmental, cognitive and psychological factors. Previous research has shown that the price of drugs, their packaging and their labelling can also affect the placebo response.

“There have been several studies showing that price information influences the placebo response, so we were interested to find out if the same was true for the nocebo effect,” says Alexandra Tinnermann, first author of the study.

49 participants were recruited for the research. They were told that the aim of the study was to investigate the reported side effects of increased pain sensitivity from two commonly prescribed creams used to treat itchy inflammation of the skin. However, both creams were placebos and contained no active ingredients.

Further, one cream was labelled as cheap and the other as expensive but no actual price was provided for either. In addition, the cheap cream was packaged in a custom-designed, orange-and-white box to imply that it was a cheap, generic medication, while the expensive cream was packaged in a different, blue box to imply it was a more expensive, brand medication.

A separate group of 66 individuals were asked to estimate the actual price of the two creams based on the packaging. They estimated that the price of the more elaborately designed blue box, containing the supposedly expensive cream, was significantly higher than that of the plainer orange-and-white box containing the cheap cream.

More expensive means more pain
Next, the researchers applied the cheap nocebo cream to the forearm of those in one group (the “cheap” group) and the expensive cream to the forearm of people in another group (the “expensive” group) and left it there for 30 minutes. Both groups also received a control cream, in order to compare pain in response to nocebo vs. pain the patients had at the start of the study. This control cream was just like the other creams.

After the researchers removed the creams they applied heat to the patch of skin where the creams had been. They told the participants that they would receive the same amount of heat on both skin patches but, in reality, the investigators secretly lowered the temperature on the control patch of skin and raised it on the nocebo cream patch—this to reinforce the idea of increased pain sensitivity due to side effects of the creams.

To test if there was any difference in pain sensitivity between those receiving the cheap vs. expensive cream, the investigators again administered the nocebo creams and after removing them applied heat  to the participants while they were lying in a magnetic resonance imaging (MRI) scanner.

It turned out that pain sensitivity of the skin on the forearm, in response to the heat, was rated significantly higher by those in the expensive group compared to the cheap group. This suggested that manipulating expectations about the price of a treatment can enhance the nocebo effect.

Meanwhile, MRI showed greater activation of a region in the brain known as the periaqueductal grey (PAG) in the expensive group, compared to the cheap group. The PAG is a key region in the brain for processing of pain signals.

The MRI results also showed synchronized activity of the PAG with another region of the brain called the rostral anterior cingulate cortex, and with the spinal cord. This could account for the differences seen in the amount of pain in the cheap vs. expensive group.

Small differences, big effects
Patients generally prefer more expensive, brand treatments and consider them more effective than cheap, generic ones. The results of the study, then, may appear slightly counterintuitive.

But, “if one assumes that a more expensive treatment causes greater placebo effects because it contains a more potent agent, and if we consider this in the context of nocebo, then the more potent agent may also produce more side effects,” says Tinnermann.

Interestingly, the difference in price between the cheap and expensive creams was estimated to be small—only three or four euros—but still enough to produce differences in pain sensitivity and activation of brain regions.

“The fact that you can see changes in the brain as well as behavior in response to such a small monetary difference was fascinating,” says Marta Pecina, an expert on the placebo response at the University of Pittsburgh but who was not involved in the study.

Tinnermann sees price manipulation as an exciting avenue for future research.

“Does it make a difference if we tell participants the price beforehand? Or if we tell them that the difference in price is 20 or even 200 euros, does this scale to higher nocebo responses?”

To read about the research in more detail, see the IASP Pain Research Forum news story here.

Dara Bree is a postdoctoral fellow at Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, US.