Although there have been significant advances in preclinical pain research, the translation of findings from laboratory to clinic has been less satisfactory. In fact, the term “valley of death” has been used to describe the chasm between pain research and its application in clinical practice. This gap “has raised many questions about the validity and clinical relevance of preclinical models and methods of behavioral assessment,” according to the authors of a review published in the Journal of Pain.1
The authors explored the reasons for these failures in translation from bench to bedside, along with the changes needed and potential solutions. “This is an important topic that we and others have written about many times in the past,” said coauthor Robert P. Yezierski, PhD, professor emeritus in the Department of Orthodontics at the University of Florida, Gainesville. “Progress is being made, but we still have many challenges to overcome,” he told Clinical Pain Advisor.
Perhaps the greatest contributor to the translational discrepancy is the lack of emphasis in preclinical research on the distinction between the subjective experience of pain, defined by the International Association for the Study of Pain as an unpleasant sensory and emotional response to actual or potential tissue damage, compared with the physiological process of nociception, defined as the neural process by which noxious stimuli are encoded.2
Although rodents are commonly used in preclinical pain research, evidence suggests they may not be suitable for studies aimed at elucidating mechanisms underlying pain in humans, as rats “and mice do not possess the same anatomical pathways to the forebrain that are crucial to expressing the multiple sensory and emotional dimensions commonly associated with the human pain experience,” underlined the authors. It has been proposed that larger animals such as dogs, cattle, and sheep might be more appropriate subjects.
There are also concerns regarding the age of the animals used in preclinical pain studies. Although chronic pain conditions are most often reported in people aged 45 to 60 years, preclinical studies typically use rats aged 6 months or younger, which corresponds to a human age of approximately 18 years. Because of age-related anatomical and functional changes in the immune, endocrine, and autonomic nervous systems, it is possible that “much of the existing knowledge about mechanisms of nociception in neuropathic and inflammatory states acquired in young rats and mice might be dramatically different to similar conditions in older animals,” noted the review authors.
It is also questionable whether the behavioral effects assessed in preclinical pain models, particularly with reflex-based methods such as von Frey testing for mechanical sensitivity and the Hargreaves test for thermal sensitivity, truly result in data that are clinically relevant to pain in humans. Citing numerous examples in which such approaches failed to translate in clinical trials, the authors stated that these failures highlight the overreliance on animal models as reflective of human disease. Nonetheless, more than 10,000 studies published in the last 60 years have relied on reflex testing.
Reflex-Based vs Operant Measures
The authors note 2 essential factors in assessing pain sensitivity in both humans and animals: measures of pain “must reveal transmission over nociceptive pathways that extend to the cerebral cortex; and…pain reports require comparisons of sensory intensity with previous pain experiences,” they wrote, pointing to results from human imaging studies that demonstrate the involvement of various cortical areas in pain perception and response.3-5 “The fact that withdrawal reflexes require nothing more than spinal or spinal-brainstem-spinal pathways makes the processing distinctly different from the conscious sensation of pain that relies on cortical activation.”
Comparisons between the use of reflex-based and cortically dependent operant measures revealed that opposite results were obtained with each approach.6 Although some studies have characterized the suppression of reflexes in response to stress as “stress-induced analgesia,” for example, research using operant escape testing showed enhanced responses to various stressors. In addition, 2 recent preclinical studies reported clear differences in reflex-based and cortically dependent outcomes in the behavioral assessment of pain after spinal cord injury.7.8
“Accepting the premise that cortical processing is a fundamental prerequisite for pain perception provides a way to define a standard for preclinical testing,” the authors wrote. “It is, therefore, reasonable to propose that any valid measure of pain-related behavior should engage pathways and structures responsible for the sensation being studied.”
Steps Toward Change
The following 7 areas are suggested as targets for change in the field of pain research:
- Produce new, clinically relevant animal models;
- Expand the current conceptual framework to include system-based mechanisms in addition to cellular, molecular, and genetic mechanisms;
- Develop measures of behavioral assessment that are predictive and clinically relevant;
- Develop a strategy for the identification of novel targets for drug development;
- Identify distinct biomarkers of both nociception and pain;
- Improve preclinical design to allow increased statistical power and reproducibility; and
- Reform clinical pain research by reducing the “over-sanitation of subjects and sole dependence on group statistics in clinical trials.”
There is a need for the creation of guidelines pertaining to preclinical pain studies, to include recommendations regarding different behavioral assessment methods and a dependable, reliable, and appropriate set of standards for each type of pain condition. The authors also mentioned the need for improved interaction between clinicians and researchers.
“Clinicians need to appreciate that there are many challenges in doing basic research on a clinical condition as complex as pain,” said Dr Yezierski. “In order to achieve success in the future, it will take clinicians working together with laboratory scientists to develop clinically relevant animal models and methods of assessment that will hopefully provide new insights into solving the challenges of chronic pain.”
- Yezierski RP, Hansson P. Inflammatory and neuropathic pain from bench to bedside: what went wrong? [published online January 4, 2018]. J Pain. 10.1016/j.jpain.2017.12.261
- International Association for the Study of Pain. IASP taxonomy. Available at https://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1698. Accessed February 1, 2018.
- Apkarian AV, Hashmi JA, Baliki MN. Pain and the brain: specificity and plasticity of the brain in clinical chronic pain. Pain. 2011;152(3Suppl):S49-S64.
- Bastuji H, Frot M, Perchet C, Magnin M, Garcia-Larrea L. Pain networks from the inside: spatiotemporal analysis of brain responses leading from nociception to conscious perception. Human Brain Map. 2016;37(12):4301-4315.
- Craggs JG, Price DD, Verne GN, Perlstein WM, Robinson MM. Functional brain interactions that serve cognitive-affective processing during pain and placebo analgesia. Neuroimage. 2007;38(4):720-729.
- Vierck CJ, Yezierski RP. Comparison of operant escape and reflex tests of nociceptive sensitivity. Neurosci Biobehav Rev. 2015;51:223-242.
- Van Gorp S, Deumens R, Leerink M, Nguyen S, Joosten EA, Marsala M. Translation of the rat thoracic contusion model: part 1 – supraspinally versus spinally mediated pain-like responses and spasticity. Spinal Cord. 2014;52(7):524-528.