Clinical trials in pain research fail at an unexpectedly high rate. Of course, failure of the drug or intervention is an undesirable reason for this, yet responsive subsets can often be identified, suggesting the inclusion criteria is the problem. Outcomes in pain are by nature problematic, being purely subjective, but there are methods of objectification which are a partial remedy to this. The use of “old school” statistics makes trials huge, cumbersome, incredibly expensive, and make recruitment a significant issue in many endeavors. Industry, trying to cut corners, often skips Phase II—an opportunity to refine methodology, such as determining responsive vs unresponsive outcomes—which is a principal issue in trial failure. Research methodology hasn’t changed much since the mid-90s, which results in not learning from, and correcting, mistakes, thus research design is at a standstill. Preclinical research unfortunately does not often translate well to clinical research. Failure to consider and perhaps exclude significant psychosocial issues causes many trials to fail. There are likely myriad reasons analgesic trials fail, and the major reasons will be discussed in detail in this talk.