LAUSR

Randomized clinical trials (RCTs) of treatments for pain have a long and distinguished history. The earliest clinical trials not only identified analgesic medications and their efficacious dosages but also contributed to the development of clinical trial research designs andmethods that came to be used throughoutmedicine. The ground-breaking investigators who designed and conducted these early studies recognized that various sources of bias must be addressed, and appreciation of the fundamental roles of study design and statistical principles became widespread as experience conducting RCTs grew. In this article, we first present analyses of a sample of chronic pain trials that show a decline in treatment effect estimates over the past few decades and discuss the implications of these results for determining sample sizes for future chronic pain trials. We then review explanations for the failure of RCTs to demonstrate the efficacy of truly efficacious treatments and address the role of excessive placebo group improvement. Finally, we consider various approaches that have the potential to improve the informativeness of clinical trials and their assay sensitivity, that is, their ability to distinguish an effective treatment from a less effective or ineffective treatment. 2. “The greatest teacher, failure is”: falsely negative and inconclusive clinical trial results