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Placebo responses in migraine prevention trials appear to have risen over time, a systematic review and meta-analysis showed.

A significant increase in placebo response was seen by publication year in migraine prevention studies that involved oral placebo (rho 0.39, P=0.047) but not in studies with injectable placebo (rho -0.07, P=0.724), reported Stewart Tepper, MD, of Dartmouth-Hitchcock Medical Center and Geisel School of Medicine at Dartmouth in Hanover, New Hampshire, in a presentation at the American Headache Society annual meeting.

"Treatment efficacy in randomized controlled trials is evaluated by the differential response of treatment and placebo groups, which is the specific treatment effect," Tepper noted.

Several studies have supported and decreasing treatment effect size over time in pain and other conditions. "There's limited research examining temporal trends of placebo in migraine prophylaxis trials," he said.

To study placebo response over time in migraine prevention trials, Tepper and colleagues combed Cochrane library, EMBASE, and PubMed databases for studies published from January 1990 to August 2021. Randomized, double-blind, placebo-controlled trials evaluating preventive migraine treatments in adults with episodic and chronic migraines were included.

Of 1,455 records identified in the databases, 54 studies with a total of 7,840 patients were eligible. Placebo was administered orally in 27 studies and by injection in the other 27.

The researchers extracted continuous migraine efficacy outcomes at baseline and endpoint. In order of relevance, outcomes were monthly migraine days, migraine headache days per month, migraine attacks per month, and migraine episodes per month.

"We had in our back pocket a subsequent analysis to cover four additional outcomes -- migraine days, attack frequencies, headache days per month, and headache days," Tepper noted.

The researchers calculated mean change from baseline for the placebo arm, plotted against study publication year and assessed by Spearman rank correlation coefficients. They also examined whether the route of drug administration affected placebo response.

"What we found immediately was that for oral studies, there was a statistically significant increase in placebo response by publication across the years," Tepper said. "There was no statistically significant difference in placebo response over time for the injectable placebo, but you could see a trend."

When oral and injection studies were combined, a positive but nonsignificant relationship emerged between publication year and ranking of mean change in migraine outcome from baseline in the placebo arm (rho 0.25, P=0.065).

When the researchers added the four additional outcomes, the analysis expanded to include 73 studies with continuous outcome data evaluating oral, injectable, and IV treatments. It showed a significant positive correlation between change in the placebo arm from baseline by year (rho 0.32, P=0.006).

Why would placebo responses change over time?

"We've all talked about this," Tepper noted. "There is increased expectation of patients and heightened expectation tends to reduce the delta between the treatment and placebo."

In addition, "study participants in the placebo groups of trials receive a lot more clinical attention and intensive contact with the clinical staff, which can produce positive results in terms of symptom improvement," he said.

Varying expectations among trial participants have been observed in other headache studies, observed Jessica Ailani, MD, of MedStar Georgetown University Hospital in Washington, who was not involved with the study. "You wonder, by the time a patient takes an injectable, their hope may be down," she said.

The findings raise important issues for future research, Tepper pointed out.

"If an increased placebo response is going on and the difference between active and placebo is shrinking, that's going to mandate larger sample sizes for powering appropriate clinical trials," he said. "And for those who do meta-analyses, an increased placebo response over time makes it difficult to compare the effectiveness of preventive migraine medications if the time span is large."

Future studies need to evaluate the reasons and context behind this trend, Tepper added. "Investigating the underlying mechanisms behind placebo response in migraine treatment is going to be very important for therapy development and for clinical practice," he said.

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