Challenges and Opportunities for Therapeutics Targeting the Voltage-Gated Sodium Channel Isoform Na_V1.7

Voltage-gated sodium ion channel subtype 1.7 (Na_V1.7) is a high interest target for the discovery of non-opioid analgesics. Compelling evidence from human genetic data, particularly the finding that persons lacking functional Na_V1.7 are insensitive to pain, has spurred considerable effort to develop selective inhibitors of this Na⁺ ion channel target as analgesic medicines. Recent clinical setbacks and disappointing performance of preclinical compounds in animal pain models, however, have led to skepticism around the potential of selective Na_V1.7 inhibitors as human therapeutics. In this Perspective, we discuss the attributes and limitations of recently disclosed investigational drugs targeting Na_V1.7 and review evidence that, by better understanding the requirements for selectivity and target engagement, the opportunity to deliver effective analgesic medicines targeting Na_V1.7 endures.