[+]Enlarge Credit: Courtesy of Alexandra Tinnermann

The placebo effect, in which a patient’s expectations lead them to experience the benefits of a treatment despite not actually receiving an active drug, has an evil twin: the nocebo effect. Scientists don’t know as much about this less pleasant effect, in which patients’ negative expectations cause them to experience adverse side effects, mostly because of the ethical challenges of designing experiments that induce 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 neuorological 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 cause hyperalgesia, or sensitivity to pain. One group would test the “cheap” version packaged in an orange box and the other group tested the “expensive” blue box version. In reality, none of the creams contained any active ingredient. (In another experiment involving a separate group of participants, the researchers confirmed that people considered the blue box more expensive.)

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 machine that would heat the patches. During the experiment, the patches were heated to about 115 °F on average, which caused a medium amount of pain. The team found that participants in the “expensive” cream group experienced stronger nocebo effects than the cheap group, reporting 30% higher intensity of pain with the test cream than the control, which suggested they were experiencing more of the hyperalgesia side effect.

Credit: Adapted from image provided by Alexandra Tinnermann

The researchers propose that participants assume that pricier drugs contain ingredients that are more effective and potent, thus causing more side effects. A similar connection between price and potency has been seen in studies of placebo effects.

During the pain exposures, the researchers also monitored the participants’ neural activity with functional magnetic resonance imaging (fMRI) using a new method that allowed them to look at activation in the brain and spinal cord. Usually scientists can only monitor the brain or the spinal cord at a given time because it’s difficult to find parameters that allow you to see both, says lead author and graduate student Alexandra Tinnermann, adding the new feature was “the most exciting part of the study” to her.

The team was able to correlate the stronger nocebo effect seen in the expensive group with neural interactions in the so-called descending pain system which includes areas of the prefrontal cortex, brainstem, and spinal cord.

“For the first time they were able to correlate price and nocebo pain with spinal cord modulation,” says Luana Colloca, a professor of pain and anesthesiology at University of Maryland School of Nursing, adding that the spinal cord plays a critical role in pain modulation. The findings suggest that “for the same painful stimulation, we can have different signalling at the level of the spinal cord and brain region because of our expectations based on a drug’s price,” she says.