Discordance between preclinical and clinical testing of NaV1.7-selective inhibitors for pain

Abstract The voltage-gated sodium channel Na V 1.7 plays an important role in pain processing according to genetic data. Those data made Na V 1.7 a popular drug target, especially since its relatively selective expression in nociceptors promised pain relief without the adverse effects associated with broader sodium channel blockade. Despite encouraging preclinical data in rodents, Na V 1.7-selective inhibitors have not yet proven effective in clinical trials. Discrepancies between preclinical and clinical results should raise alarms. We reviewed preclinical and clinical reports on the analgesic efficacy of Na V 1.7-selective inhibitors and found critical differences in several factors. Putting aside species differences, most preclinical studies tested young male rodents with limited genetic variability, inconsistent with the clinical population. Inflammatory pain was the most common preclinical chronic pain model whereas nearly all clinical trials focused on neuropathic pain despite some evidence suggesting Na V 1.7 channels are not essential for neuropathic pain. Preclinical studies almost exclusively measured evoked pain whereas most clinical trials assessed average pain intensity without distinguishing between evoked and spontaneous pain. Nearly all preclinical studies gave a single dose of drug unlike the repeat dosing used clinically, thus precluding preclinical data from demonstrating whether tolerance or other slow processes occur. In summary, preclinical testing of Na V 1.7-selective inhibitors aligned poorly with clinical testing. Beyond issues that have already garnered widespread attention in the pain literature, our results highlight the treatment regimen and choice of pain model as areas for improvement.