Open-Label Placebos as Adjunct for the Preventive Treatment of Migraine: A Randomized Clinical Trial.

Importance: Placebo effects contribute substantially to the therapeutic success of many treatments, particularly in pain-related conditions. Open-label placebos (OLPs) offer an ethically acceptable approach to harness this potential without deception.

Objective: To evaluate the efficacy of a 3-month OLP regimen in reducing headache and migraine days and improving migraine-related outcomes, including medication use, disability, and quality of life, in patients with migraine.

Design, setting, and patients: This controlled, bicenter, parallel-group randomized clinical trial, with a 3-month treatment phase, enrolled adults with episodic or chronic migraine between November 9, 2020, and November 1, 2022. The trial was conducted at 2 tertiary headache centers in Germany (University Medicine Essen and Headache Center Frankfurt).

Interventions: Participants received OLPs plus treatment as usual (TAU) or TAU alone. OLPs were administered twice daily for 3 months.

Main outcomes and measures: The preregistered primary outcome was the change in monthly headache days from a baseline to a test period after 3 months. Secondary outcomes included patient-reported quality of life assessed using the 12-Item Short-Form Health Survey physical component summary, pain-related disability assessed using the Pain Disability Index and Headache Impact Test, and global improvement.

Results: Of the 120 patients (median age, 34.2 years; 95% CI, 29.8-39.3 years; 103 [86%] female), 102 (85%) had episodic migraine, and 18 (15%) had chronic migraine. All participants completed the study. Headache days did not significantly decrease in the OLP group compared with TAU. Similarly, there was no difference in the number of migraine days, pain intensity, days of rescue medication, and the 50% responder rate. However, OLP-treated patients reported improved quality of life (β = 4.25; 95% CI, 1.33-7.17; d = 0.47; P = .01), reduced pain-related disability (Pain Disability Index: β = -5.96; 95% CI, -9.01 to -2.92; d = 0.53; P < .001; Headache Impact Test 6: β = -1.88; 95% CI, -3.28 to -0.48; d = 0.35; P = .02), and higher global improvement (χ2 = 14.16; P = .01) compared with TAU patients.

Conclusions and relevance: In this randomized clinical trial, OLP treatment did not reduce headache frequency but was associated with improvements in quality of life and pain-related disability. Future research should clarify the mechanisms underlying these effects and determine their potential supportive role in migraine care for selected patients.

Trial registration: drks.de identifier: DRKS00021259.