People in clinical trials report more negative side effects even though they received "expensive" inactive substances

People receiving an inert treatment believed they experienced more severe adverse side effects when the dummy drug was labeled as expensive, scientists report in Science. The researchers say brain regions responsible for higher-order cognition can influence primal pain sensing at the spinal level.

To study the neurological causes for the so-called nocebo effect (where people in clinical trials sometimes report negative side effects even though they received inactive substances), Alexandra Tinnermann and colleagues developed a new functional magnetic resonance imaging (fMRI) method for simultaneous activity measurements in the entire central pain system throughout the cortex, brainstem, and spinal cord. For the nocebo treatment, the scientists enrolled 49 people in a trial for a supposed anti-itch cream that, in reality, contained no active ingredients.

All participants were told that increased pain sensitivity was a potential side effect for the inert cream, but some were informed that they were receiving an expensive ointment and others were led to believe that the lotion was cheap (the scientists even created two different packages for the balms, indicating high or low price). People treated with the "expensive" cream reported greater sensitivity on a heat-tolerance test, and the nocebo effects became more pronounced over time.

The researchers identified portions of the spinal cord that became activated during nocebo effect pain, and determined that altered sensations due to perceived price were associated with differences in two brain regions - the periaqueductal gray and the rostral anterior cingulate cortex.

A related Perspective by Luana Colloca gives additional examples where patients' expectations alter placebo (positive) or nocebo effects, advocating for more research into the physiology underlying these phenomena for better clinical trial design.