Measuring and realizing the translational significance of preclinical in vivo studies of painful osteoarthritis

Abstract

In this communication, we discuss some key issues surrounding the translation of preclinical efficacy studies in models of painful osteoarthritis (OA) to the clinical arena. We highlight potential pitfalls which could negatively impact successful translation. These include lack of alignment between a model + endpoint and the intended clinical population, employing testing strategies in animals that are not appropriate for the targeted human population such as pre-emptive treatment and lastly, underestimating the magnitude of the efficacy signal in animals that may be needed to see an effect in the clinical population. Through careful analysis, we highlight the importance of each pitfall by providing relevant examples that will hopefully improve future chances of optimizing translation in the area of OA pain research. We advocate advancing publications directed at comparing methods, outcomes and conclusions between preclinical and clinical studies, regardless of whether the findings are positive or negative, are important for improving the potential for a desired successful translation from the bench to bedside.

A Review of the Effects of Pain and Analgesia on Immune System Function and Inflammation: Relevance for Preclinical Studies

“…In this context, the possibility should be considered that in some instances the translatability of animal models may be improved if analgesics are administered, not withheld, and used in a manner that more closely matches human treatment. 39,90 What is clear from this review is that many questions remain regarding the impact of analgesics on immune function and that there is no one drug that represents the "Magic Bullet" analgesic for all models. In many cases, the literature is incomplete, or does not exist, necessitating empirical choices or pilot studies to evaluate or optimize the use of analgesics for in vivo studies of immunology and inflammation.…”

The beneficial role of companion animals in translational pain research

“…While existing therapies for chronic, persistent pain have significant limitations, the current practice of translational biomedical research is not producing novel therapeutics to address this unmet need ( 6 , 7 ). Consequently, the induced rodent models and the outcome measures used in pain research have come under scrutiny with proposals for refinement of current models ( 8 ) as well as development of new models and outcome measures that are more directly applicable to prevalent painful conditions ( 9 , 10 ). The majority of preclinical models are “induced” (i.e., created) to “model” or “mimic” the target clinical conditions ( Figure 1 ).…”

Animal models of osteoarthritis

“…In part, optimal translation of statistically significant experimental findings to clinically meaningful patient outcomes arises from aligning the preclinical model pheno-/ endo-type with that of the target human subpopulation. 1,[3][4][5][6][26][27][28][29][30] This model-patient alignment should include known disease risk variables, such as age, sex, metabolic status, and induced disease/illness characteristics such as degree of joint inflammation, cartilage, and/or bone pathology, and severity and type of pain. 6 Highly uniform progressive preclinical models arguably best represent/align with individuals with substantial progressive cartilage loss and pain, who make up less than 15% of all knee OA patients.…”