A study was conducted regarding the pain-related genes and non-pain-related genes that capsaicin and resiniferatoxin upregulate and downregulate in rats. The scientists found that resiniferatoxin not only downregulates more target pain genes than capsaicin but also pain genes that weren't targeted, which might be a reason for the overwhelming difference in potency of pain relief between resiniferatoxin and capsaicin . Resiniferatoxin downregulated more than capsaicin off-target pain genes associated with nociception or those related to hypersensitivity. These off-target pain genes Kcnk2, Kcnj5, Gal, Nt5e, Gfra2, Comt, and Ptgdr, which are pain genes associated with nociception, and Kcnk2, Acpp, Nt5e, Kcnt1, which are pain genes associated with hypersensitivity . Resiniferatoxin's ability to downregulate effectively both target pain genes and off-target pain genes reveals a reason behind its potency. However, resiniferatoxin further inhibits desired genes, which alleviates nociception and hypersensitivity. These desirable genes include . Phase 2a Clinical Trial Results for resiniferatoxin in treating knee osteoarthritis pain were recently released by Sorrento Therapeutics in September 2023. In the study, all doses of resiniferatoxin from 7.5 to 20 µg were well tolerated, with few severe adverse events and side effects. The 20 µg dose provided the best results, having the best efficacy and a durability of over 26 weeks after treatment. Future studies like Phase 2 pivotal trials and Phase 3 clinical trials may potentially allow resiniferatoxin to become a key treatment for knee osteoarthritis pain.