'Nocebo' effect: Why side-effects may seem worse for expensive drugs

Expensive medicines can seem to create worse side-effects than cheaper alternatives, suggests a new study that looked at the “nocebo” effect of drugs.

The opposite of the placebo effect — perceived improvement when no active medicine is given — nocebo is the perception of negative side-effects from a benign “medication” in a blind trial.

These findings about nocebo effects could help improve the design of clinical trials that test new medications, said Dr. Luana Colloca, who wrote a journal commentary about the study.

“The main information for patients is that they should be aware that sometimes our brain … reacts as a result of our beliefs and expectations,” said Colloca, a pain researcher at University of Maryland School of Nursing.


Researchers used a functional MRI scanner to identify areas along the spinal cord that became activated during the nocebo effect. (Alexandra Tinnermann and Tim Dretzler/University Medical Center Hamburg-Eppendorf)

The study, published recently in the journal Science, focused on the pain perceptions of patients who were treated with creams they believed had anti-itch properties but actually contained no active ingredients.

Researchers in Germany studied 49 people, randomly assigning some to receive a “cheap” cream and others to receive an “expensive” cream.

Those in the expensive group received cream packaged in a colourful box labelled Solestan Creme. The others received cream packaged in a drab box labelled with the more generic sounding name Imotadil-LeniPharma Creme.

Both groups were told the creams may have the side-effect of increasing pain perception. Those who received Solestan were also informed that it was expensive. In reality, the two creams were the same and did not contain any medication.

Dr. Iris Gorfinkel

Dr. Iris Gorfinkel, a family physician in Toronto, sees nocebo effects in her medical practice. (Andy Hincenbergs/CBC)

To gauge participants’ perception of pain, scientists used heat tolerance tests. They spread the cream on subjects’ forearms, then applied heat. Though the scientists ensured the temperatures applied to the two creams were consistent, those who received the expensive cream rated their pain as nearly twice as intense as those who received the cheaper cream.

The study suggested that patient expectations related to price can trigger brain responses resulting in higher perception of pain, said Alexandra Tinnermann, a co-author of the study and neuroscientist at University Medical Center Hamburg-Eppendorf.

Tinnermann’s team used a functional MRI scanner to identify areas along the spinal cord that were activated during participants’ experience of side-effects. They also pinpointed two brain regions that were more stimulated among participants who believed they received the expensive drug.

Nocebo effects influenced by patient’s experience

Placebo effects are significant in medical research, said Dr. Iris Gorfinkel, a family physician in Toronto who designs research trials with pharmaceutical companies. She was not involved in Tinnermann’s study.

In her practice, Gorfinkel said she sees nocebo effects. When a patient is prescribed an antibiotic, for instance, they may quickly experience nausea after swallowing the pill, even though the medication hasn’t yet been absorbed.

Nocebo effect cream boxes

Some patients received a cream that was generically packaged and were told it was relatively cheap. Others received cream in a more colourful box and were told it was relatively expensive. (Alexandra Tinnermann and Tim Dretzler/University Medical Center Hamburg-Eppendorf)

In a doctor’s office or in an experiment, a patient’s suggestibility, past experience, and genetic factors all likely play a role.

“All of a sudden, the patient is seeing a doctor, they’re answering questionnaires, they’re getting answers,” Gorfinkel said. “They’re getting all this additional attention and so placebo effects are massive,” 

Gorfinkel thinks the nocebo study should be taken with a grain of salt. Other factors besides price could have influenced the results. For instance, the name of the expensive cream, Solestan, resembles the word solar, which may create a link to heat and pain for some people.

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