Reference: JAMA Netw Open. 2025 Oct 1;8(10):e2535739
Practice Point: Addition of open-label placebo to treatment as usual may improve quality of life, even if it doesn’t reduce migraine frequency.
EBM Pearl: A study with inadequate statistical power may fail to detect true differences that exist between groups. Therefore, when numerical differences are observed, they should be viewed as merely “interesting” rather than conclusive. The study must be repeated to confirm any findings.
Placebos are surprisingly powerful, both in research and in real-world treatment. Research has shown that open-label placebos (wherein patients know they are not getting an active drug) can induce significant physiologic changes and can be powerful therapeutic tools, especially when it comes to subjective symptoms like pain or fatigue.
Open-label placebos have been shown to reduce pain in patients with chronic back pain and irritable bowel syndrome and to lessen cancer-related fatigue in cancer survivors. The perks are obvious: Open-label placebos are ethical, cheap, nonaddictive, and safe. They don’t cure underlying conditions, but they may make life more tolerable at least for some people.
In many studies, open-label placebo is dosed twice daily to mimic standard medication regimens, reinforce routine behaviors, and support classical conditioning (think Pavlov’s dogs). The psychological and biological responses to placebo treatment are thought to arise from a combination of factors, including patient expectations, the therapeutic relationship between patient and provider, and learned associations between taking pills and feeling better.
A randomized trial published in JAMA Network Open last month evaluated open-label placebo in 120 adults with episodic or chronic migraine. At baseline, patients experienced a median of 7-8 monthly headache days, with mean pain intensity 4-5 /10. Nearly all patients (92%) were using at least one type of nonpharmacologic treatment, and 34% were on preventive migraine medication. To begin, all patients watched an instructional video about placebo highlighting research for its effectiveness in patients with chronic pain. Then, patients were randomized to take either treatment as usual or treatment as usual plus open-label placebo orally twice daily.
After 3 months, the open-label placebo group had fewer monthly headache days (6 vs. 7 days) and fewer days requiring rescue medication (4 vs. 5 days), but these differences were not statistically significant. On the other hand, significantly more patients in the placebo group reported improved quality of life (46% vs. 24%). Interestingly and perhaps not surprisingly, more patients in the placebo group reported side effects, most likely “nocebo” effects wherein people expect negative symptoms and then experience them. The trial did not reach its planned enrollment target of 150 participants, limiting its ability to draw firm conclusions in any direction. The trial also didn’t report on placebo adherence.
So, what’s the takeaway? Open-label placebos may not dramatically reduce migraine frequency, but they can make people feel better—and that’s not nothing! Interestingly, most studies on open-label placebo treatment have focused on patients with chronic, centrally-agree with dash here! mediated pain conditions. Further research is needed to understand their potential benefits and risks in those with acute or undiagnosed symptoms.
This study is a reminder of the power of mind–body connection and how perception and expectation can shape experience of illness. From a practical standpoint, the logistics of prescribing and accessing placebo products outside of research settings remain largely uncharted, though such products are available online.
For more information, see the topic Migraine Prophylaxis in Adults in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by McKenzie Ferguson, PharmD, BCPS, Senior Clinical Writer at DynaMed. Edited by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Dan Randall, MD, MPH, FACP, Senior Deputy Editor at DynaMed; Claire Symanski, PhD, Medical Editor and Team Lead for ENT at DynaMed; Rich Lamkin, MPH, MPAS, PA-C, Clinical Writer at DynaMed; Matthew Lavoie, BA, Senior Medical Copyeditor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor II at DynaMed; and Jennifer Wallace, BA, Senior Associate Editor at DynaMed.