The Challenges of Translational Pain Research

Over the past ten years a number of articles have been written detailing the success of researchers in understanding the neurobiology of pain. Over this same period, however, little progress has been made in the development of new long-term interventions for the treatment of chronic pain. Perhaps the most compelling commentary on this topic is the growing world-wide economic burden of pain and the staggering number of people, from young adults to the elderly, affected by chronic pain. If our research strategy is on the right track, then why are the economic and prevalence metrics escalating at a rate faster than at any time in history and why are providers relying on the same drugs to treat pain as they have for over two decades?

In order to address this dilemma, we need to appreciate the fact that when dealing with chronic pain there are no magic bullets. It should also be acknowledged that the basic strategy of research starting with the development and assessment of preclinical models right through to the design and execution of clinical trials, hasn’t changed significantly in over 20 years. Is this a classic example of being influenced by the comfort of tradition without the discomfort of thoughtful reflection and evaluation. Perhaps we should consider the unthinkable possibilities that we are on the wrong track, asking the wrong questions, focusing on the wrong strategies, or at best doing nothing more than tweaking an already thorough understanding of the problem rather than asking critical questions that will take the conceptual understanding of pain to a level that will provide translational benefits.

Is it possible that the discoveries made studying pain in rodents have no meaningful parallels with the human condition? Furthermore, is it possible that preclinical models of putative chronic pain apply primarily to acute pain and are distant relatives to the more clinically relevant condition of chronic pain. Based on the gap between basic research and the development of novel interventions perhaps what is needed is a major overhaul of the strategy used in pain research. Unfortunately, any changes that might occur are likely to be incremental and for this reason the future of pain research is likely to provide nothing more than the occasional “breakthrough” discovery, but unfortunately if history is a benchmark of progress there will be limited translational benefits.

Few would argue that our basic knowledge and understanding of pain mechanisms far exceeds what we imagined 30 years ago.  Over the past three decades we have been rewarded with a rich collection of significant discoveries but to our disappointment have yet to produce an equal assortment of therapeutic milestones. Although it is easy to criticize the research community for possible missteps in strategy it is worth pointing out that the reasons for the lack of progress are not that different today from what they were nearly a decade ago including: (a) lack of relevant pain models and assessment strategies; (b) species differences between rodents and humans; (c) repeated failures of clinical trials; (d) regulatory barriers; and the fact that (e) translational research is difficult for nearly all neurological disorders.  If we are to reverse the historical trend of failed translation, one strategy is to identify what happens in patients and then try to design pain models and experiments accordingly. Continuing the present path of incremental advances in understanding has not proven to provide the foundation for the therapeutic leaps that are so desperately needed? At what point is it necessary to hold the research community accountable not only to those providing the funding but also to those waiting patiently for therapeutic advances.

If our goal is to change the landscape of pain treatment a better strategy is needed that will create a new level of understanding and more opportunities for developing effective interventions. Ideally, the end result should be advances in the clinical arena that reflect the significant investment of time and resources that have been made to achieve a better understanding of the basic mechanisms of chronic pain. Unfortunately, the most fundamental questions that basic scientists answer are not always relevant to any form of treatment or clinical advancement. Is it time to stop and ask ourselves whether more molecules, channels, receptors, or signaling pathways are needed to further enhance our understanding? If history can be our guide perhaps we should take a long hard look at our track record before deciding how to proceed.

At present the current system of research is designed for discovery and rewards novel research strategies but ironically ignores clinical relevance. If we look at the last 30 years we have learned a lot about how rodents process and respond to pain. Unfortunately, each breakthrough raises our hopes but more often than not has failed to deliver clinical advances needed to treat patients. One of the principal contributing factors to this ever-expanding problem is that knowledge gained from basic science is assumed to be a means to achieve better patient care.  The fallacy of this argument must be part of the conversation when discussing reasons for failed translation.  One of the ways to ensure the future success of translational research is for professional organizations to take the lead and encourage young investigators to consider the need for innovative approaches with an emphasis on applied research with endpoints pointing towards clinical objectives.

There is also a need to understand that the scale and complexity of today’s research problems demands that scientists move beyond their own discipline and explore new models of team science. The formula for achieving translational success is going to require basic and clinical scientists working collaboratively in relationships based on a mutual understanding established during their early years of professional development. Creating an interface between science and the clinic will produce clinician-scientists as well as a new breed of scientists anxious to partner with clinicians who recognize the necessity of keeping clinical application a priority. A more detailed description of recommendations for the future are described in the article by Yezierski and Hansson (2018).

The discussion of how to resolve the challenges of translational research needs to continue. As it does we need to recognize the importance of reflecting on where we have been and most importantly whether the strategy we are using to accomplish our goals has achieved expectations. In the future the challenge will be agreeing on the most appropriate guidelines, recommendations, and strategies, and most importantly finding ways to implement changes and make it mandatory rather than recommended that they are followed. Leaders from the scientific, academic, industrial, and government communities need to work together and develop an action plan, monitor its progress, and collectively ensure that we are pursuing the most productive and relevant strategy.

About Robert Yezierski

Dr Robert Yezierski received his Ph.D. in Physiology and has been involved with the development of pain research programs at the University of Miami and the University of Florida. As Director of the Comprehensive Center for Pain Research at the University of Florida he was the Principal Investigator of a training program in translational pain research. Dr. Yezierski’s research has involved the study of pain mechanisms using anatomical, physiological, molecular and behavioral methods associated with neuropathic pain following spinal cord injury and changes in pain processing as a function of age. Dr Yezierski is a Professor Emeritus at the University of Florida.

Reference

Yezierski, RP and Hansson P Inflammatory and neuropathic pain from bench to bedside: what went wrong. Journal of Pain 19: 571-588, 2018.