The Problems – A View from Across the Pond: We’re Going to Need a Bigger Boat

Robert H. Dworkin, PhD
Professor of Anesthesiology, Neurology, and Psychiatry
Professor in the Center for Human Experimental Therapeutics
University of Rochester School of Medicine and Dentistry

A substantial percentage of patients with pain are refractory to existing analgesic treatments, and the patients who do respond to these treatments typically only obtain partial relief of their pain. This presentation will focus on efforts to improve clinical trial research methods as a means of accelerating the identification of analgesic medications with improved efficacy and safety. The impetus for efforts to improve clinical trial methods has come from the observation that numerous recent trials have failed to demonstrate the efficacy of medications that were predicted to have analgesic effects. Unfortunately, it usually cannot be determined whether these studies were “truly negative” trials of medications that lack efficacy or whether they were “falsely negative” trials that were unable to demonstrate the benefits of truly efficacious medications. This uncertainty not only impedes the identification of treatments that could help patients who are refractory to existing therapies but also causes substantial expenditure of scientific and financial resources. Several explanations for these negative results have been proposed, including (1) animal models have identified drugs with limited or no analgesic efficacy in human pain conditions; (2) these recent studies are falsely negative trials in which patients in the placebo groups improved “too much” to allow the analgesic medications to demonstrate their effects; (3) the optimal pain phenotypes were not studied; and (4) analgesic trials have often had inadequate power to detect modest effect sizes. In addition, the roles of patient and investigator misbehavior, misconduct, and outright fraud are receiving increasing attention as potential explanations for both false negative and false positive clinical trial results. It is critically important that the methodologic characteristics of analgesic clinical trials be systematically evaluated so that factors that have adverse impacts on their outcomes can be modified. Such research has the potential to provide the foundation for an evidence-based approach to the design of clinical trials and the development of improved pain treatments.