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Increasing placebo responses over time in U.S. clinical trials of neuropathic pain

Tuttle, Alexander H.a; Tohyama, Sarasaa; Ramsay, Timb; Kimmelman, Jonathanc; Schweinhardt, Petrad; Bennett, Gary J.e; Mogil, Jeffrey S.a,*

doi: 10.1097/j.pain.0000000000000333
Research Paper
Global Year

Abstract: Recent failures of clinical trials of novel analgesics designed to treat neuropathic pain have led to much speculation about the underlying reasons. One often discussed possibility is that the placebo response in these trials has increased in recent years, leading to lower separation between the drug and placebo arms. Whether this has indeed occurred has not yet been adequately addressed. Here, we extracted data from published randomized controlled trials (RCTs) of drugs for the treatment of chronic neuropathic pain over the years 1990 to 2013. We find that placebo responses have increased considerably over this period, but drug responses have remained stable, leading to diminished treatment advantage. This trend has been driven by studies conducted in the United States. Consideration of participant and study characteristics revealed that in the United States but not elsewhere, RCTs have increased in study size and length. These changes are associated with larger placebo response. Analysis of individual RCT time courses showed different kinetics for the treatment vs placebo responses, with the former evolving more quickly than the latter and plateauing, such that maximum treatment advantage was achieved within 4 weeks.

Placebo responses in clinical trials of neuropathic pain have increased considerably over 1990 to 2013. This trend has been driven by studies conducted in the United States.

aDepartment of Psychology, Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada

bClinical Epidemiology Program, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada

cBiomedical Ethics Unit, McGill University, Montreal, QC, Canada

dDepartment of Neurology and Neurosurgery, Faculty of Dentistry, Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada

eDepartment of Anaesthesia, Faculty of Dentistry, Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada

Corresponding author. Address: Department of Psychology, Alan Edwards Centre for Research on Pain, McGill University, 1205 Dr Penfield Ave, Montreal, QC H3A 1B1, Canada. Tel.: +1-514-398-6085. E-mail address: jeffrey.mogil@mcgill.ca (J. S. Mogil).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Received June 15, 2015

Received in revised form August 10, 2015

Accepted August 12, 2015

© 2015 International Association for the Study of Pain
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