Translation of drug effects from experimental models of neuropathic pain and analgesia to humans

Neuropathic pain research remains a challenging undertaking owing to: (i) the lack of understanding about the underlying disease processes; and (ii) poor predictive validity of the current models of evoked pain used for the screening of novel compounds. Common consensus is that experimental models replicate symptoms (i.e. have face validity but no construct validity). Another issue that requires attention is the sensitivity of endpoints to discriminate drug effects that are relevant to the disease in humans. In this paper we provide an overview of the pre-clinical models that can be used in conjunction with a model-based approach to facilitate the prediction of drug effects in humans. Our review strongly suggests that evidence of the concentration–effect relationship is necessary for translational purposes.

► Neuropathic pain research remains challenging due to the lack of understanding of the underlying disease processes and poor predictive validity of the current models of evoked pain used for the screening of novel compounds.
► Experimental models replicate symptoms, i.e., have face validity but no construct validity. This is compounded by differences in the sensitivity of endpoints to discriminate drug effects which are relevant to the disease in humans.
► Ongoing research strongly suggests that evidence of concentration-effect relationships is necessary for translational purposes. Given the lack of specific biomarkers of disease, assessment of target engagement is fundamental for characterising the pharmacokinetic-pharmacodynamic properties of novel compounds and interpreting response across species.
► A model-based approach is recommended as a tool for drug screening and dose selection in clinical trials.