Placebo Responses Have Increased Over 30 Years of Migraine Prevention Trials

Migraine prevention trials have evidenced an increase in placebo responses over the last 30 years, according to meta-analysis findings published in The Journal of Headache and Pain.

Recent analgesic failures for the treatment of neuropathic pain symptoms during clinical trials have led to speculation about the placebo effect. Because most trial outcomes for neurological conditions are subjective, these trials are particularly sensitivity to placebo responses.

To evaluate the longitudinal change in placebo response in clinical trials for migraine prevention, investigators from the Geisel School of Medicine at Dartmouth in Hannover, New Hampshire, searched publication databases from 1990 through 2021 for placebo-controlled migraine prevention studies. The meta-analysis included a total of 83 studies lasting a median of 13 weeks and including a median of 89 to 113 patients (median age, 41.0 [range, 38.6-42.3] years; 85.9% female). Placebo was administered orally (48.0%), by injection (45.2%), or intravenously (6.85%).

In studies using continuous outcomes, such as monthly migraine days (MMDs), monthly migraine headache days (MHDs), and episodes per month, the median improvement from baseline in the placebo arm was 1.8 (interquartile range [IQR], 1.0-3.0). For dichotomous outcomes, such as the proportion of patients achieving a 50% or more decrease in MMDs, MHDs, or attack frequency, the reported improvement in the placebo arm was 27.2% (IQR, 16.1%-39.7%).

Placebo responses depended upon administration route (P <.001) for continuous outcomes. The greatest change from baseline was observed for intravenous administration (mean difference [MD], 4.7), followed by injection (MD, 2.2) and oral (MD, 1.5) routes. Similarly, the greatest change from baseline for dichotomous outcomes was observed for intravenous administration (MD, 45.1%), followed by oral administration (MD, 26.7%) and injection (MD, 24.5%)(P =.011).

In the regression analysis, placebo response in continuous studies was associated with intravenous placebo administration (P <.001), some Cochran risk of bias concerns (P =.003), year (P £.033), and patient age (P =.043). In dichotomous studies, placebo response was associated with patient age (P =.003) and intravenous placebo administration (P =.025).

A major limitation of this study was the potential for bias, given that some studies may have gone unpublished if the placebo response made the intervention response appear insignificant.

The study authors concluded, “[W]e found a statistically significant increase in the placebo response in preventive migraine trials from 1990 to 2021. The increase was not constant over the years or detectable when the outcome was reported as a dichotomous variable, which highlights the nuanced relationship between placebo response and year of publication. This study found that different sources of heterogeneity, such as route of administration and patient characteristics, affect placebo response.”

Disclosures: This research was supported by Biohaven Pharmaceuticals. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.