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verybody’s heard of the placebo effect — the phenomenon in which people report positive health impacts of drugs that are, in fact, nothing more than sugar pills. But there’s also an opposite reaction called the nocebo effect, when patients report negative side effects — dizziness, headaches, nausea — from drugs that aren’t really drugs.

Both the placebo and nocebo effect are known to wreak havoc on drug trials. In fact, it’s become nearly impossible to win approval for new pain meds because the placebo effect is so strong, making the real medication seem weak in comparison. And research shows that when you list a bunch of potential negative side effects to participants in a drug trial, participants will report back those very symptoms whether they get the real drug or a placebo.

Until recently, the placebo and nocebo effects were thought to be entirely psychological, our brain tricking itself into believing that we feel good or bad. But advances in real-time functional MRI technology have revealed a two-way signaling pathway between pain receptors along the spine and higher-order processing areas in the brain. It turns out that the brain feels pain because the body says, “Ouch!”

A team of German researchers developed a new fMRI protocol that allowed them to measure real-time nervous system activity in both the spinal cord and the brain. The idea was to trigger a nocebo response and pinpoint exactly where it was coming from — the body, the brain, or both.

In a paper published in the journal Science, lead investigator Alexandra Tinnermann of the University Medical Center Hamburg-Eppendorf in Hamburg, Germany, described her team’s experiment involving two types of anti-rash creams. Nearly 50 participants were divided into two groups. One was treated with a supposedly cheap rash cream from a generic-labeled box. The other was treated with what they were told was an expensive, brand-name cream. In truth, both creams were identical and neither contained any active ingredients.

Both groups were told that their anti-rash cream — both cheap and expensive — had one potential side effect, that it might increase their sensitivity to pain. To determine the strength of the side effect, participants were told, the researchers were going to treat half their arm with a control cream and the other half with a target drug, either the expensive or cheap version of the cream. Heat pads were then applied to each half of the arm to compare pain levels.

In reality, though, all the creams were identical.

When asked to rate their pain, both groups exhibited a nocebo response, citing increased pain sensitivity in the region treated with the target cream as opposed to the control. But interestingly, the people who received the “expensive” treatment exhibited a much stronger nocebo response, rating their pain as twice as bad compared to the “cheap” group.

In their paper, Tinnermann and her colleagues equate the participants’ nocebo response to earlier findings from placebo studies, theorizing that “participants infer that expensive medication contains a more potent and effective agent and, consequently, produces more side effects.”

But the more interesting question is where the nocebo effect originates. Clearly there’s some higher-order brain activity required to look at a package and determine if a cream is “cheap” or “expensive.” But does that mean that the pain is all in the patient’s head?

Luana Colloca, a professor, researcher, and physician in the department of anesthesiology at the University of Maryland School of Medicine, has been studying the nocebo effect for a decade and wrote an accompanying commentary in the same issue of Science. Colloca has run trials where participants were told that pain medication was stopped, when it fact it was continued, and people immediately reported higher levels of pain. She’s also seen the opposite, where pain meds were covertly turned off and participants reported no increased pain.

Despite the clear psychological component of the placebo and nocebo effect, Colloca says studies like the anti-rash experiment point to something more complicated at play. First off, we know that pain requires more than the brain.

“The reason we can say this stimulus is painful, it’s hurting me, is because there’s a signal from our arm reaching the spinal cord, and then from the spinal cord to the brain,” Colloca told Seeker.

And that’s exactly what the fMRI scans found in the rash-cream experiment. When participants thought they were being treated with an expensive cream, the nerve endings in the peripheral nervous system (as opposed to the central nervous system) sent more pain signals to the spinal cord, which were then transmitted to the brain.

“This is revolutionary,” said Colloca. “For the first time, we switch from a concept and phenomenon that we believed was merely psychological to something more — a neurobiological phenomenon. You believe that you’re going to experience more pain and your spinal cord lets in more information from the periphery signaling an increase of pain.”

Colloca believes that a deeper understanding of this mind-body connection will have an impact far beyond clinical trials. Patients need to know, for example, that their emotional expectations about a treatment can play a huge role in determining whether a drug or therapy works or not. And doctors need to be more careful in how they communicate the benefits and potential side effects of a treatment plan.

“Doctors have a legal requirement to tell the whole truth. We tend to list all the adverse events that are part of a medication, but often we don’t pay the same attention to the positivity, to the reason why a treatment is appropriate,” said Colloca. “It’s probably time to balance information about side effects with positive anticipation of outcomes.”