Randomized, Controlled Trial Demonstrates Power of Open-Label Placebos

After spine surgery, patients who were randomized to receive an open-label placebo in addition to pain medications took approximately 30 percent less opioids than those who received medication only

BOSTON — Never underestimate the power of a placebo — even when a patient knows they are receiving one. That’s one of the lessons that emerged from a recent randomized, controlled trial conducted by investigators at Brigham and Women’s Hospital that enrolled patients recovering from spine surgery. The pilot study’s participants were randomized to receive either treatment as usual in the form of opioid pain medication, or pain medication plus a placebo. The trial’s design was transparent — participants were told they were receiving a placebo in addition to pain medication. Yet, patients in the open-label placebo group consumed approximately 30 percent less opioid pain medication than their counterparts who received treatment as usual, while still reporting slightly lower daily pain scores. Findings are reported in the journal Pain.

“We were open and transparent with the participants in this trial, many of whom asked, ‘Is this going to work, even if I know it’s a placebo?’ Surprisingly, the answer is yes — you don’t have to believe in the placebo effect for it to impact you,” said senior author Kristin Schreiber, MD, PhD, a neuroscientist and clinical regional anesthesiologist in the Department of Anesthesiology, Perioperative and Pain Medicine at the Brigham. “The part that I find compelling is that this effect gives the power back to the patient. It’s the opposite of giving them an opioid and relying solely on the medication to relieve pain. Here, you and your brain can participate in the recovery process.”

The authors caution that this is a pilot study that enrolled only 51 participants, several of whom dropped out before the study was completed. The final analysis included 19 participants in the conditioned open-label placebo (COLP) group and 22 in the treatment-as-usual group. Larger trials are needed to fully assess the potential effect.

The study enrolled patients who were scheduled for surgery for degenerative conditions of the spine with a single surgeon at the Brigham between November 2018 and February 2020. Before surgery, participants were assessed in multiple ways. Their baseline pain was measured using the Brief Pain Inventory — a questionnaire about pain — and researchers used several other tools to measure depressive symptoms, pain catastrophizing (when patients become caught in a cascade of negative emotions in anticipation of pain), sleep disturbance, fibromyalgia-type symptoms, and pain sensitivity on a standardized bedside pain test.

Patients in the COLP group were given a bottle of placebo pills — small, white capsules containing plant fiber — and instructed to self-administer one pill with all pain medication. Patients in both groups of the trial were instructed to record their pain scores and any time they took a pill in a study diary. Patients continued to do so after discharge and until their follow-up appointment.

There was a significant difference in opioid consumption between the two groups, with an average 30 percent reduction among participants in the open-label placebo group. The percentage of patients still taking some opioids one week after surgery was 94 percent for treatment-as-usual participants and 68 percent for COLP. After two weeks, it was 75 percent for treatment-as-usual and 52.6 percent for COLP. Average daily pain did not differ significantly between the groups, suggesting that even though participants in the COLP group were taking less pain medication on average, they were not reporting increased pain compared to their counterparts. In fact, the reported “worst daily pain” score was significantly lower in the COLP group.

“While we don’t fully understand why the conditioned open-label placebo has the effect it does, it’s possible that this intervention raises uncertainty, challenging someone’s expectations about pain and allowing them to modulate their pain perception unconsciously,” said lead author Kelsey Mikayla Flowers, MA, of the Department of Anesthesiology, Perioperative and Pain Medicine at the Brigham. “Pairing the placebo and pain medication may also condition the brain to anticipate pain relief.”

The team’s exploratory analysis of the data collected through questionnaires and measurements of pain before surgery raised several interesting leads, including the finding that people with the highest baseline pain sensitivity and those more likely to catastrophize their pain had the greatest response to the intervention. Follow-up studies will be needed to further explore this phenomenon.

“This is definitely a pilot study, but it’s the first to examine the use of a conditioned open-label placebo after spine surgery,” said Schreiber. “And it’s empowering. It suggests that there may be ways to reduce pain without having to rely on opioids, especially for people who struggle most with pain.”

The conduct of this study was supported by funding from the Foundation for the Study of the Therapeutic Encounter and the Department of Anesthesiology, Perioperative, and Pain Medicine at the Brigham.

Paper cited: Flowers, KM et al. “Conditioned Open-Label Placebo for Opioid Reduction Following Spine Surgery: A Randomized, Controlled Trial” PAIN DOI: 10.1097/j.pain.0000000000002185

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