Preclinical Neuropathic Pain Assessment; the Importance of Translatability and Bidirectional Research

Abstract

For patients suffering with chronic neuropathic pain the need for suitable novel therapies is imperative. Over recent years a contributing factor for the lack of development of new analgesics for neuropathic pain has been the mismatch of primary neuropathic pain assessment endpoints in preclinical vs. clinical trials. Despite continuous forward translation failures across diverse mechanisms, reflexive quantitative sensory testing remains the primary assessment endpoint for neuropathic pain and analgesia in animals. Restricting preclinical evaluation of pain and analgesia to exclusively reflexive outcomes is over simplified and can be argued not clinically relevant due to the continued lack of forward translation and failures in the clinic. The key to developing new analgesic treatments for neuropathic pain therefore lies in the development of clinically relevant endpoints that can translate preclinical animal results to human clinical trials. In this review we discuss this mismatch of primary neuropathic pain assessment endpoints, together with clinical and preclinical evidence that supports how bidirectional research is helping to validate new clinically relevant neuropathic pain assessment endpoints. Ethological behavioral endpoints such as burrowing and facial grimacing and objective measures such as electroencephalography provide improved translatability potential together with currently used quantitative sensory testing endpoints. By tailoring objective and subjective measures of neuropathic pain the translatability of new medicines for patients suffering with neuropathic pain will hopefully be improved.

Keywords: burrowing; clinical; electroencephalography; endpoints; neuropathic pain; preclinical; quantitative sensory testing; translatability.

FIGURE 1

Integrated bidirectional research approach for neuropathic pain: Linking animal and human biology data. RCT (randomised clinical trial), FTIH (First time in human), TV (target validation), STZ (Streptozocin), PDN (painful diabetic neuropathy), PK (Pharmacokinetic), VAS (Visual analogue scale), TCA (tricyclic antidepressant), SNRI (serotoninnorepinephrine reuptake inhibitor). Bidirectional research illustrates the targets/mechanisms that have successfully translated forward (from preclinical research), back (from clinical research), under development (e.g. α2δ1, blue) and failed (e.g., Neurokinin 1 (NK-1), red) novel targets/mechanisms identified from preclinical research.

FIGURE 2

Mismatch of primary neuropathic pain assessment endpoints in preclinical vs. clinical trials. *Primary endpoint, RCT (randomised clinical trial), EEG (electroencephalography), QoL (quality of life), VFH (von Frey hair), Static (static mechanical allodynia).

FIGURE 3

Multiple preclinical neuropathic pain assessment endpoints in development to improve translatability of preclinical to clinical research. *Primary endpoint, RCT (randomised clinical trial), EEG (electroencephalogram), QoL (quality of life).