Improving Preclinical Development of Novel Interventions to Treat Pain: Insanity Is Doing the Same Thing Over and Over and Expecting Different Results

Abstract

Preclinical pain research has applied state-of-the-art methods over the past 40 years to describe, characterize, and image molecules, cells, and circuits in rodents to understand the pathophysiology of chronic pain. Despite generating a plethora of novel analgesic targets, pharmaceuticals for chronic pain treatment remain largely limited to the same 6 drug classes as present 40 years ago. It is possible that 40 years of effort has brought us to the verge of a paradigm shift and an explosion of novel analgesic drug classes with remarkable safety, efficacy, and tolerability. We think it more likely that advances will not occur until we follow the description of exciting discoveries with hypothesis testing using clinically relevant preclinical animal models and ethologically relevant outcome measures, which better reflect the clinical characteristics of chronic pain syndromes. Furthermore, to be valuable, experiments using such models must be conducted to the highest levels of internal validity, rigor, and reproducibility. Efforts by funders, most recently the Helping End Addiction Long-Term by the National Institutes of Health, aim to address some of these challenges and enhance communication and collaboration between preclinical and clinical investigators. However, the greater problem is a culture that emphasizes novelty and number of publications over scientific rigor and robust replication leading to a high likelihood of false-positive results. A path forward is provided by the evolution of clinical research beginning 50 years ago that resulted in methods to reduce bias and enhance transparency and ethics of reporting, moving from case reports to randomized controlled trials to innovative study designs with a focus on rigor, generalizability, and reproducibility. We argue that culture changed in clinical science in part because powerful forces outside the peer review system, especially from federal regulators that approve new drugs and human studies committees that addressed ethical failures of earlier research, mandated change in studies within their purview. Whether an external force will affect change in peclinical pain research is unclear. (Anesth Analg 2022;135:1128-37) GLOSSARY ARRIVE = Animal Research: Reporting of In Vivo Experiments; HEAL = helping to end addiction long term; NSAID = nonsteroidal anti-inflammatory drug; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2

Opportunities for Improving Basic and Translational Pain Research

“…Furthermore, there is a growing expectation in the HEAL initiative pain funding announcements that the perspectives of clinicians and individuals with lived experience will be included in guiding the preclinical development of the pain therapeutic development projects. This additional perspective is also suggested by Eisenach and Rice 2 in their current review. Input from patients and caregivers on the therapeutic goals of the project, even at this early stage, can help researchers develop products that will address the symptoms and needs of these affected individuals.…”

“…The review by Eisenach and Rice 2 in this issue of Anesthesia & Analgesia , titled “Improving Pre-Clinical Development of Novel Interventions to Treat Pain: Insanity Is Doing the Same Thing Over and Over and Expecting Different Results,” identifies shortcomings in preclinical and translational pain research that could have contributed to the failure over the last 40 years of the translation of preclinical pain science to novel therapeutics. In addition, this review suggests changes to the pain research enterprise to increase the likelihood of the translation of that research into novel effective pain therapeutics with minimal or no addictive potential.…”

“…In summary, the apt review by Eisenach and Rice 2 not only identifies and clearly enumerates many potential problems with historical preclinical pain research, but also provides useful suggestions for how to improve the basic and translational preclinical pain research enterprise. Their review comes at a critical time, as the epidemic of chronic pain, opioid addiction, and overdose deaths are taking a terrible toll.…”

“…Clinical investigators provide an important perspective that should be incorporated into experimental designs to determine how representative a particular model is of the human disease population and to assure that end points are translatable to humans. Eisenach and Rice 2 also note that back translating discoveries made in human pain populations into animal models could also increase their ability to be used in translational research.…”

“…The recommendations by Eisenach and Rice 2 fall essentially into 2 categories: (1) those related to enhancing the rigor and reproducibility of research in pain science, and (2) the types of animal models used for pain discovery and translational research. The authors rightly note that their comments related to the rigor and reproducibility of research are not specific to the preclinical pain research field.…”