People may expect more side effects from pricier drugs

The placebo effect, in which people’s expectations lead them to experience the benefits of a treatment despite not receiving an active drug, has an evil twin: the nocebo effect. Scientists don’t know as much about this less pleasant effect, in which people’s negative expectations cause them to experience adverse side effects, mostly because of the ethical challenges of inducing bad outcomes on purpose.

Yet both effects have the power to disrupt a treatment’s outcome or skew the results of clinical drug trials. In these psychological phenomena, many factors can influence a patient’s expectations, including a drug’s price tag. Through tests of people’s behavior and neurological activity, researchers at the University Medical Center Hamburg-Eppendorf now show that more expensive drugs have stronger nocebo effects (Science 2017, DOI: 10.1126/science.aan1221).

In the study, healthy participants were told they were involved in a test of two versions of a topical cream to treat eczema and that the cream may increase sensitivity to pain. One group would test the “cheap” version packaged in an orange box and the other group would test the “expensive” blue box version. None of the creams contained any active ingredient.

The participants applied both what they were told was a control cream and their designated test cream on their arms and put on arm patches attached to a heating machine. During the experiment, the patches were heated to cause a medium amount of pain. Participants in both the “expensive” and “cheap” cream groups experienced the nocebo effect, meaning they felt more pain with the test cream than with the control cream even though the creams had the same ingredients. This effect was more pronounced in the “expensive” group: The pain differential between test and control creams for those participants was 30%, whereas the “cheap” group rated the test cream only 3% more painful.

The researchers propose that participants assume pricier drugs contain ingredients that are more effective and potent and thus cause more side effects.

During the pain exposures, the researchers also monitored participants’ neural activity with functional magnetic resonance imaging (fMRI) using a new method that allows them to look at activation in both the brain and spinal cord. Usually scientists can monitor either the brain or the spinal cord because it’s difficult to find parameters that allow them to see both, says lead author and graduate student Alexandra Tinnermann.

The team was able to correlate the stronger nocebo effect in the “expensive” group with neural interactions in areas of the prefrontal cortex, brain stem, and spinal cord.

The findings suggest that “for the same painful stimulation, we can have different signaling at the level of the spinal cord and brain region because of our expectations based on a drug’s price,” says Luana Colloca, an anesthesiology professor at the University of Maryland School of Nursing.