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Pricier meds mean worse side effects, thanks to ‘nocebo’ effect

Expensive medications tend to make us feel better, even when they’re no different than cheap generics. But they can also make us feel worse, according to a new study. Researchers have found that we’re more likely to experience negative side effects when we take a drug we think is pricier—a flip side of the placebo effect known as the “nocebo” effect. The work could help doctors decide whether to recommend brand-name or generic drugs depending on each patient’s expectations.

In the study, researchers asked 49 people to test out a purported anti-itch cream that, in reality, contained no active ingredient. Some got “Solestan® Creme,” a fake brand name in a sleek blue box designed to look like other expensive brands on the market. Others received “Imotadil-LeniPharma Creme”—another fake, this time housed in a chintzier orange box resembling those typically used for generic drugs. “I put a lot of effort into making the designs convincing,” says study leader Alexandra Tinnermann, a neuroscientist at University Medical Center Hamburg-Eppendorf in Germany.

The researchers rubbed one of the two creams on the volunteers’ forearms and waited a few minutes for it soak in. They told the participants that the cream could cause increased sensitivity to pain—a known side effect of real medications called hyperalgesia. Then the scientists affixed a small device to the volunteers’ arms that delivered a brief flash of heat up to about 45°C (or 113°F).

On average, those who thought they had received the expensive cream initially rated the pain as twice as intense as those who recieved the generic. As the trial wore on, the “expensive” cream group reported the pain becoming more and more intense, whereas the “cheap” cream group experienced a slight decrease in pain.

Brain recordings backed up these findings. Participants who both thought they were applying an expensive cream and reported feeling more pain had more activity in the prefrontal cortex. Other studies have shown increased activity in this brain region when people experience the placebo effect, and when their enjoyment of a product—wine, for example—is influenced by its supposed value, Tinnermann says.

What’s more, spinal cord regions associated with pain response also showed more activation in the “expensive” cream group, suggesting it wasn’t all in the volunteers’ heads: They really were experiencing more pain than the “cheap” cream group, the researchers report today in Science.

“There has been a lot of research on placebo and relatively little on nocebo,” Tinnermann says. “These findings add up to the fact that expectations have a lot of influence on the perception of a drug’s side effects.”

The spinal cord activation finding is particularly interesting, says Fabrizio Benedetti, a neuroscientist at the University of Turin in Italy who wasn’t involved in the study. Most scientists didn’t think that beliefs and perceptions affected nerve sensation in the spinal cord, he notes.

Physicians should be aware of the placebo and nocebo effects when describing medications to patients, says Per Aslaksen, a psychologist at the University of Tromsø in Norway who researches the placebo effect and who wasn’t involved in the work. “Both doctors and patients can often choose between several medications, and the price of the drug is sometimes the only factor that separates different types of drugs,” he says. So if patients expect or fear a drug’s side effect, prescribing them the less expensive option might improve their experience.