Can a Placebo Improve Migraine? Let’s Be Honest

A new study reports that an open-label placebo improved quality of life and pain-related disability, compared to treatment as usual.

Placebo effects are often viewed unfavorably – and some might like to see them disappear entirely. Pharmaceutical developers, for instance, need to show that a new drug is more effective than a placebo in clinical trials, spurring efforts to minimize the effects of sugar pills. “The drug performed no better than placebo” – it’s often the death knell for many once-promising medications.

But research shows that placebos can actually make patients feel better. In fact, the mind-body connection is so strong that a placebo can sometimes even make people feel worse, known as nocebo effects. Considering these phenomena, what if researchers could harness the beneficial effects of placebo to treat disease? And what if they could do so in an honest way, where patients know they are receiving a placebo – a so-called open-label placebo (OLP)?  It’s an approach that’s been tried before, including in the pain and migraine fields. Now, new results from an OLP migraine trial add to the evidence that placebos too often get a bad rap.

Researchers including first author Julian Kleine-Borgmann, University Hospital Essen, Germany, tested an OLP in a randomized trial including 120 patients with episodic or chronic migraine. While the study did not meet its primary endpoint of change in monthly headache days, participants who received an OLP showed statistically significant improvements in a number of secondary outcomes, including quality of life, pain-related disability, and global improvement, compared to treatment as usual.

“It’s a well-conducted clinical trial contributing valuable data to the field,” said Yoni Ashar, a pain researcher at the University of Colorado Anschutz, Aurora, US, who has studied OLPs in the context of back pain but was not involved in the current study. “It fits very squarely into the literature showing that open-label placebos, relative to usual care, have small benefits for pain and other subjective symptoms,” he added.

The study appeared online in JAMA Network Open on October 8, 2025.

Mixed – but encouraging – results
Previous work showing beneficial effects of placebos on migraine provided the impetus for the new study, Kleine-Borgmann wrote in an email to Migraine Science Collaborative.

“Expectancy and placebo responsiveness can substantially shape migraine treatment outcomes, as demonstrated, for instance, by notable improvements within control groups of recent anti-CGRP antibody trials, or in studies that modulate or directly assess expectations towards active migraine treatments. Given that the use of deceptive placebos is ethically impermissible, we investigated OLPs as a transparent approach to harness these mechanisms.”

The researchers thought that a placebo of the open-label kind would provide a benefit for migraine, especially considering positive results from OLP studies in the context of chronic pain, as well as from a migraine study.

So the group recruited adults with episodic or chronic migraine for their new study, ultimately randomizing 120 participants (85% with episodic migraine, 15% with chronic migraine, median age 34 years) to treatment as usual (TAU) or OLP plus TAU, over three months at two tertiary headache centers in Germany. Study participants were permitted to take migraine preventive medication or be pursuing non-pharmacologic preventive approaches. They received video instructions about OLPs, and took one OLP tablet twice a day for 12 weeks.

The study did not meet its primary end point, with those who received the OLP showing a median of 6 monthly headache days and participants in the TAU group reporting 7 monthly headache days, a non-significant reduction. Nor were there significant differences in some secondary end points, including monthly migraine days, pain intensity, rescue medication days, and the proportion of patients with a 50% or greater reduction in headache days.

However, several other secondary end points were met. Compared to TAU, the OLP group showed statistically significant improvement in quality of life at one and three months (as measured by the physical component of the 12-Item Short-Form Health Survey [SF-12] score); in global impression of change (as assessed by the Patient Global Impression of Change [PGIC]), at one and three months; and in pain-related disability (according to Pain Disability Index [PDI] and Headache Impact Test 6 [HIT-6] scores) at three months.

Despite the mixed findings, the researchers view their results in a quite positive light.

“These findings support previous evidence that OLPs predominantly impact subjective, patient-reported outcomes and evaluative outcomes, rather than the physiological processes driving attack frequency, which is on the unambiguous, more ‘objective’ side in the spectrum of outcome measures. We are encouraged by the results and see them as an important step towards understanding how placebo effects can be ethically integrated into migraine care,” according to Kleine-Borgmann.

Why the mixed findings?
What accounts for the varied results? There are several possibilities, including the study’s relatively small sample size, which could have made it difficult to detect between-group differences.

Another, more interesting possibility, which the study authors acknowledge, relates to the context in which participants received the OLP. That is, previous research shows that the quality of the patient-physician relationship is important for enhancing placebo effects – Ashar pointed to the perceived warmth and competence of physicians as two important factors in this regard. But the design of the study, with, for instance, its minimal direct interaction with participants, and the use of impersonal, standardized video explanations of OLP,  precluded the possibility of a strong, beneficial interpersonal interaction one might see between a patient and a provider in a real-world setting.

Ashar pointed to some other intriguing possibilities, though he cautioned these are purely speculative hypotheses.

“The regimen was one open-label placebo twice a day. But what if they used open-label placebos for primary prevention – so, take the pill when you start to feel like you need a rescue medication – like a rescue open-label placebo? Would that have helped more?”

Another interesting speculation Ashar posed was that perhaps the pills that study participants may have already been taking for their migraine could have circumscribed the impact of the OLP.

“Does it somehow limit the open-label placebo effect if you just add more pills to the pills you’re already taking, versus someone who’s not taking a pill and then starts taking a pill? Because if the open-label placebo benefit comes from the act of taking a pill, and you’re already doing that, then the additional benefit would be limited.”

The study had some other important limitations, according to Luana Colloca, a pain and placebo researcher at the University of Maryland, Baltimore, US, who also was not involved with the new research.

“I suspect that if we were to compare recruitment in a pharmacological study versus an open-label placebo study, probably we would be more likely to select a group that may not be representative of the general population in the open-label placebo study, and that is an issue,” she said. “And that is why we need a larger number of participants, because having a larger number, and also a more geographically diverse population, can be truly helpful to minimize the impact of recruitment bias and highly motivate the people who come to these trials,” she added.

The future
What’s in store for OLPs? Ashar told Migraine Science Collaborative that this approach might be more of  “a research curiosity or research phenomenon to unpack” than anything else. At the same time, he added, “It would be groundbreaking if we could implement this in pain clinics.”

A glance at clinicaltrials.gov suggests a continuing interest in OLPs, with 10 trials currently recruiting subjects for OLP studies in chronic pain research.

Kleine-Borgmann said that future OLP trials should address three questions: “First, which symptoms and diseases are most susceptible to OLPs? Second, how can OLP administration, treatment context, and treatment rationale be personalized to receive the best results? [And] third, what are the underlying psychological and neurobiological mechanisms underlying OLPs’ effect?” Kleine-Borgmann added that knowing more about the mechanisms of OLPs could help researchers answer the first two questions.

There is another reason why it’s important to know about the mechanisms, particularly biological mechanisms: It could help sway people who are skeptical of OLPs.

“One reason this is helpful is because open-label placebos sound so bizarre. But when you show they have measurable effects on pain-regulating neurobiology, then it really starts to ground them as bona fide interventions that engage mechanisms of pain relief,” Ashar said.

Ashar and his colleagues have already shown a neurobiological basis for the effects of OLPs in their own work, having used neuroimaging to document changes in brain activity in pain regulatory regions in a trial of adults with chronic back pain who received an OLP.

Finally, Kleine-Borgmann emphasized that OLPs should work in concert with current migraine treatments.

“OLPs are not intended to replace established, guideline-based therapies. Rather, they may serve as a complementary option in selected situations – such as when patients continue to experience substantial burden despite adequate treatment, wish to avoid side effects, or are open to psychological and behavioral approaches. OLPs might strengthen expectancy, self-efficacy, and active coping, thereby supporting and potentially enhancing the effectiveness of conventional therapies. In this sense, OLPs should be viewed not as an alternative but as a potentially integrative component of comprehensive, patient-centered migraine care,” he said.

Neil Andrews is a science journalist and executive editor of the Migraine Science Collaborative.

Image credit: 123RF Stock Photo.

Reference
Open-label placebos as adjunct for the preventive treatment of migraine: A randomized clinical trial.
Kleine-Borgmann et al.
JAMA Netw Open. 2025 Oct 1;8(10):e2535739.