Quantitative Sensory Testing (QST) is a well-established standardized set of tests describing the sensory profile of patients with chronic pain conditions. Regarding translational pain research, QST offers a bridge from patients to human volunteers in experimental pain models and further back to animal sensory testing. In the recent issue of PAIN, Forsterpointner et al (Pain. 2021 Mar 1;162(3):718-727) published the analysis of a large multicenter cohort of patients with neuropathy extracted from the IMI consortia EUROPAIN and NEUROPAIN.
Clinical QST “failure”
More than 500 participants were analyzed, including patients with (spontaneous) neuropathic pain, patients with painless neuropathic conditions, and healthy volunteers. Surprisingly, there was virtually no difference in the sensory profiles of patients with painful and painless conditions. Furthermore, both groups reported signs of allodynia and hyperalgesia and self-assessed pain sensitivity was increased in painful patients and in painless patients with dynamic mechanical allodynia. As Martin Schmelz (Pain. 2021 Mar 1;162(3):663-664) stated in his Commentary in the same issue of PAIN: “In short, QST failed to provide mechanistic insights into neuropathic pain”. Obviously, this is disappointing for pain research in general and specifically for drug development of new analgesics. What are the consequences for animal testing? Three points should be considered.
How to improve translational value of animal studies?
Should we stop using von Frey filaments? No, demonstration of hypersensitivity is an important proof of the manipulation in animal models of neuropathic pain. It also differentiates neuropathic from nociceptive pain. However, to better characterize anti-hypersensitive efficacy of drug candidates, unilateral hypersensitivity models should be used to compare drug efficacy at both the ipsi-lateral injured and the contra-lateral control side. More complex models of polyneuropathy should be controlled with the same readout in a dedicated sham control group.
Should we rely on von Frey filaments? No, while evoked hypersensitivity is an important measure, it does not easily translate to clinical efficacy. Numerous non-evoked readouts have been applied in animal pain research comprising weight-bearing paradigms, grimace scale, burrowing, among others. Systematic quantification of pharmacological manipulation using different mechanisms has been started but there is a lack of published data which could prove the translational value of these measures of spontaneous pain correlates. Eventually, focusing on more relevant readouts should increase translational value and result in reduced animal numbers following the 3R’s principles.
Do we need novel animal models of pain? This will depend on the outcome of future pain research. Martin Schmelz proposed possible future directions of pain research and there are others to come for sure. A patient-centric research starting with defined patient populations and discovering novel underlying characteristics might well lead to new testing paradigms in the clinical setting. Once these paradigms prove translational relevance for novel treatments, they could give guidance for animal models with higher translational value.
Conlusion
QST profiles are similar in neuropathy patients with and without pain. This is disappointing as QST is a hallmark in clinical assessment of neuropathic pain. The paper by Forsterpointner et al. will stimulate a re-thinking on how we design pre-clinical and clinical studies. Finally, we will gain translational validity by improving our understanding of the clinical situation and transferring this knowledge into the pre-clinical world. Focus on selected animal models with more relevant (non-reflexive) readouts will speed up drug development and reduce animal numbers.
© Thomas Christoph
