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.
Supplemental Digital Content is Available in the Text.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: email@example.com (J. S. Mogil).
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Received June 15, 2015
Received in revised form August 10, 2015
Accepted August 12, 2015