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Placebo Effect's Sweet Spot

November 2, 2016
For the first time, scientists say they have found a region in the brain responsible for the ''placebo effect'' in pain relief; they say the discovery has the potential to improve clinical trial accuracy and to personalize pain treatments.

Interview with Marwan Baliki, PhD

For the first time, researchers say they have identified the ''sweet spot'' in the brain responsible for the ''placebo effect'' in pain relief.1 If the discovery bears out in further research, it could help improve the accuracy of clinical trials, scientists say. It could also personalize pain relief treatment by predicting the responses of individual patients based on brain imaging.

Where Is the Sweet Spot?

"The area is in the frontal part of the brain, the midfrontal gyrus, the region known to be involved in emotional regulation and decision making," says study coauthor Marwan Baliki, PhD, a research scientist at the Rehabilitation Institute of Chicago and an assistant professor of physical medicine and rehabilitation at Northwestern University Feinberg School of Medicine. "Historically, the placebo effect was just considered a random effect," Dr. Baliki tells Practical Pain Management. His research, which was published Oct. 27 in PLOS Biology, suggests otherwise.1

Dr. Baliki and his colleagues had 2 aims: to identify the sweet spot of placebo effect on pain in the brain, and to determine if the sweet spot is also involved when an active drug is given—or if the responses are distinctly different.

After a series of 3 studies, the researchers found that the sweet spot is specific for placebo, but that other regions are activated when a specific drug is given. They studied duloxetine (Cymbalta), an antidepressant approved for pain, which was given to help knee pain in osteoarthritis (OA) patients.

In the first study, Dr. Baliki's team took brain images of 17 knee OA patients, using resting state functional magnetic resonance imaging (rs-fMRI).  Next, they gave the patients 2 weeks of placebo pills and evaluated the decrease in knee pain. The participants did not know if they were taking placebo or active drug. "In this study we used imaging to identify a biomarker for placebo," Dr. Baliki said.

"We had them report their pain level before, during, and after treatment," Dr. Baliki said. "We saw that [about] half of the patients responded to the placebo, their pain went down 50%," he noted.

The researchers then went back and compared brain activity on the initial scans between responders andnon responders. One area of difference stood out—the midfrontal gyrus.

Studies 2 and 3 included 42 patients, who were randomly assigned to receive either placebo (study 2) or active drug (study 3). In study 2, half of the 42 patients received placebo treatment for 3 months and validated the finding from the first study, confirming that the placebo ''hot spot'' was consistent in this second group of subjects. "We found that the hot spot identified in study 1 predicted placebo response with 85% accuracy," Dr. Baliki reported.

In study 3, the other 21 patients received duloxetine for 3 months. The researchers looked to see if the same hot spot was activated in those who got pain relief from the drug. It wasn't. "We found that the placebo hot spot cannot predict the drug response at all,'' Dr. Baliki said, ''thus indicating the hot spot is unique to placebo effect."

The researchers found that another area in the brain corresponded to the drug effect. The region was the hippocampus formation, a brain region involved in memory, he said.

The finding suggests that different drugs may have unique hotspots, Dr. Baliki says.

Research & Practical Applications

The findings need replication, Dr. Baliki told PPM, but if they bear out, it ''will allow you to hand pick your research subjects to eliminate the effect of the placebo response." It also could help doctors assess which pain drugs would work for which patients.

In the future, he said, it also may be possible to use neuroimaging to predict which patients will respond to placebo and may not need drug treatments. Maps of certain biomarkers of the brain can help doctors decide which patients will respond to which treatments, whether pharmacological or not, Dr. Baliki added.

Dr. Baliki is hopeful that using these discoveries and future ones will ''give us the shortest path to pain relief'' for individual patients.

Eli Lilly Pharmaceuticals funded the second study. The research was also supported by grants from the National institute of Neurological Disorders and Stroke and the National Center for Complementary and Integrative Health and postdoctoral fellowships from the Canadian Institutes of Health Research.


Last updated on: November 2, 2016

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