‘Honest’ Placebos Tied to Better Functioning for Migraineurs

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Open-label placebos (OLPs) were associated with reduced pain-related disability and improved overall well-being for patients with migraine, even though headache frequency remained unchanged, results from a new study showed.

 

In a randomized clinical trial, researchers found that participants receiving standard migraine preventive treatment combined with what they knew was a pharmacologically inactive pill, called an open-label or “honest” placebo, reported marked improvements in how migraine attacks affected their daily lives compared with those receiving standard treatment alone.

 

“These findings indicate that open-label placebos may alleviate the burden of migraine without changing attack frequency,” lead investigator Julian Kleine-Borgmann, MD, neurologist and clinician scientist at University Medicine Essen, Essen, Germany, told Medscape Medical News.

 

“Given their excellent tolerability and ethical transparency, OLPs could serve as a safe adjunct to preventive care, particularly to enhance patient-centered outcomes,” he added.

 

The study was published online on October 8 in JAMA Network Open.

A Transparent Placebo Effect?

Migraine is one of the most common and disabling neurologic disorders, affecting about 15% of the global population and ranking among the leading causes of years lived with disability.

 

Despite advances in acute and preventive options, such as CGRP antagonists and monoclonal antibodies, Kleine-Borgmann and colleagues noted that many individuals continue to experience functional impairment or cannot tolerate long-term drug therapy.

 

Previous studies of migraine treatments have shown a significant placebo effect, with response rates as high as 46% in some patients assigned to blinded placebo groups.

 

For decades, clinicians assumed that placebos worked only when their true nature was concealed. More recent research challenges that view, showing that even when administered openly, placebos can yield measurable improvements across conditions such as chronic low back pain, irritable bowel syndrome, and depression.

 

“Taking a pill that is openly described as inert can still elicit beneficial responses and strengthen patients’ engagement with their condition,” Kleine-Borgmann said. “These mechanisms may reduce the perceived interference of migraine in daily life, even if the number of attacks doesn’t change.”

Better Function, Same Frequency

To study that possibility, researchers enrolled 120 adults (median age 34 years; 86% female) between November 2020 and November 2022 at two tertiary headache centers in Germany. Most (85%) had episodic migraine, and the remainder had the chronic form.

 

In addition to their usual preventive regimen, about half of the participants were also told to take an inert tablet twice daily, dispensed in containers clearly labeled “placebo — contains no active medication.” The other patients continued standard care alone.

 

After 3 months of treatment, both groups showed improvement in headache frequency and severity, but there were no significant differences between those who received OPL plus usual treatment and those who followed usual treatment alone.

 

There were also no differences between groups in the use of acute pain medication or the proportion of those who experienced at least a 50% reduction in headache days.

 

However, OLP recipients reported clear benefits on several secondary measures.

 

Physical quality-of-life scores rose by about 4 points (P = .01), pain-related disability scores declined by roughly 6 points (P < .001), and overall headache impact dropped modestly but significantly (P = .02).

 

Nearly half of those taking OLPs rated their condition as improved compared with about 1 in 4 receiving usual care.

Search for Neural Underpinnings

Kleine-Borgmann and colleagues plan follow-up analyses of neuroimaging and psychological data to explore why some individuals have a greater response.

 

“We aim to identify neural networks and personality traits — such as optimism, catastrophizing, or fear of pain — that predict response,” he said. “Ultimately, that could allow a mechanism-based, personalized integration of OLPs into migraine prevention.”

 

The investigators also intend to clarify the mechanisms underlying these effects and determine how OLPs might best complement pharmacologic prevention or serve in a supportive role for selected patients, particularly those seeking non drug options or experiencing medication side effects.

 

The authors noted several limitations, including a smaller-than-planned sample size, largely due to COVID recruitment challenges. They also emphasized that outcomes relied on subjective reports of pain and disability rather than objective physiologic measures.

 

Differences in preventive medication use were a potential source of bias. About one third of participants in the OLP group chose to forgo preventive drugs and use the placebo alone. Kleine-Borgmann said the study was not randomized by medication status, but he noted that similar proportions of participants in each group were using preventive drugs at baseline and kept their regimens unchanged throughout the trial.

 

Participants’ decision to forgo pharmacologic prevention was made before enrollment and may reflect multiple factors, such as prior lack of efficacy, side effects, or a general preference for nonpharmacologic approaches, he added.

 

“To address the interesting question of potential interactions between preventive drug use and OLP efficacy, these factors need to be carefully considered, and we plan to explore them in our forthcoming exploratory analyses,” he said.

 

While these limitations affect generalizability, the findings underscore that perceived improvement can meaningfully enhance quality of life, the researchers wrote. The study also achieved complete retention — an unusually high rate for migraine prevention trials — which they attributed to the simplicity and low-risk appeal of OLP participation.

Potential Adjunct, Not Replacement

Commenting for Medscape Medical News, Ted J. Kaptchuk, professor of medicine at Harvard Medical School and director of the Harvard-wide Program in Placebo Studies and the Therapeutic Encounter at Beth Israel Deaconess Medical Center in Boston, said the findings are consistent with what placebo science would predict.

 

Kaptchuk, whose team conducted the first OLP trial in irritable bowel syndrome, said the findings align with a growing body of evidence showing that OLPs can meaningfully influence how patients experience pain and disability.

 

“Migraine frequency is an objective marker, and open-label placebo is primarily valuable for modulating subjective complaints,” he said. “The modest improvements in pain-related disability and quality of life are statistically significant and clinically meaningful.”

 

He added that the benefit is unlikely to stem from conscious positive expectations alone.

 

“Placebo responses arise from the brain’s automatic modulation of sensations within the context of a healing ritual,” Kaptchuk said. “You don’t think yourself better — the brain turns down unpleasant sensations when the environment signals safety and care.”

 

Kaptchuk said OLPs may be appropriate for people who have exhausted standard pharmacologic options or cannot tolerate medication side effects.

 

“It’s an ethical option for those with persistent symptoms despite treatment,” he said, “but it should never be a first-line therapy.”

 

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