John D. Loeser Award Lecture: Size does matter, but it isn't everything: the challenge of modest treatment effects in chronic pain clinical trials

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 and methods that came to be used throughout medicine. The ground-breaking investigators who designed and conducted these early studies recognized that various sources of bias must be addressed, 68, 69, 78,105 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 …