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    Research Letter
    Public Health
    April 16, 2020

    Effect of Treatment Expectation on Placebo Response and Analgesic Efficacy: A Secondary Aim in a Randomized Clinical Trial

    Author Affiliations
    • 1Division of Pediatric and Public Health, Adams School of Dentistry, University of North Carolina at Chapel Hill
    • 2Department of Community Dentistry and Behavioral Science, University of Florida, Gainesville
    • 3Department of Oral and Maxillofacial Surgery, University at Buffalo, State University of New York, Buffalo
    • 4Rho Inc, Durham, North Carolina
    • 5Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill
    JAMA Netw Open. 2020;3(4):e202907. doi:10.1001/jamanetworkopen.2020.2907

    Amid the United States’ chronic pain crisis, novel analgesics are failing to show efficacy in clinical trials.1 High failure rates are attributed to an upward trend in placebo response,2 driven by patients’ heightened expectation of treatment benefit.3 We hypothesized that heightened expectations differentially amplify placebo analgesia, leading to underestimation of the treatment effect in randomized clinical trials.

    SOPPRANO (Study of Orofacial Pain and Propranolol) is a double-blind, placebo-controlled, parallel-group, phase 2b randomized clinical trial that enrolled 200 adults aged 18 to 65 years with examiner-verified temporomandibular disorder–associated myalgia from August 1, 2015, to January 31, 2018, at 3 US study sites. Participants were randomized 1:1 to propranolol hydrochloride (60 mg twice a day) or placebo administered for 9 weeks. Using daily pain diaries, treatment response was defined as the proportion with at least 30% reduction in mean pain index (facial pain intensity multiplied by duration) at 9 weeks. Efficacy was further quantified as the number needed to treat (NNT) with 95% CIs. Treatment expectation was determined from participants’ baseline expectation that the study treatment would reduce their facial pain. Ratings of moderate or strong were classified as high treatment expectation, and ratings of none or slight were classified as low expectation. In this planned, intention-to-treat analysis, we tested whether treatment expectation modified the analgesic efficacy of propranolol using a log binomial generalized estimating equation regression model incorporating data from 4 study visits with adjustment for covariates. The generalized score statistic for generalized estimating equation models was used to test for modification of analgesic efficacy. A 2-tailed P < .05 was deemed statistically significant, and values of .05 to .10 were deemed credible. Other results were deemed statistically significant when 2-tailed 95% CIs excluded the null value. A separate logistic regression model assessed the odds of high treatment expectation using continuous measures of clinical and experimental pain, psychological factors, and health-related quality of life at baseline, all standardized to z scores.