Researchers have created a novel non-opioid chemical called SBI-810 that exhibits potent analgesic effects in animal studies without the negative side effects or addiction linked to opioids. What sets SBI-810 apart is the chemical’s dual impact on both the central and peripheral nervous systems, effectively reducing pain while minimizing the risk of opioid-induced complications such as addiction, constipation, and withdrawal symptoms. This innovation, detailed in an article published in Cell, provides a new therapeutic path to develop medications for acute and chronic pain, including conditions like postoperative pain, inflammation, and neuropathy. As the opioid crisis continues to take a toll globally, this research adds to the growing effort to develop safer, more effective approaches to pain relief.
How SBI-810 works
Recent efforts to develop safer alternatives to opioids, which remain the primary treatment for severe and postoperative pain, have focused on ion channels in peripheral sensory neurons, like Nav1.7 and Nav1.8. Still, chronic pain often requires targeting both the peripheral (PNS) and central (CNS) nervous systems. G-protein-coupled receptors (GPCRs) offer promising targets, including neurotensin receptors (NTSRs), which regulate pain and inflammation. While neurotensin analogs show strong analgesic effects, severe side effects have limited their clinical use.
SBI-810 belongs to a new class of biased allosteric modulators (BAMs). These compounds selectively activate specific signaling pathways, enhancing therapeutic effects while minimizing side effects. SBI-810 binds to NTSR1 and selectively recruits β-arrestin-2 (βarr2), bypassing G-protein pathways associated with adverse effects. Co-lead authors Ran Guo, PhD, and graduate student Ouyang Chen demonstrated that in mouse models, the SBI-810 raises pain thresholds in healthy animals and effectively reduces various types of pain, including postoperative pain from incisions and bone fractures, inflammatory pain from tissue injury, and neuropathic pain following nerve damage. Administered systemically or directly to the spinal cord, the compound significantly increased pain thresholds, underscoring its potential to treat conditions ranging from postoperative discomfort to neuropathic pain.
The NTSR1 BAM works centrally by suppressing excitatory signaling in spinal cord neurons through βarr2, targeting key pathways like NMDAR and ERK. Peripherally, SBI-810 lowers the surface levels of Nav1.7 sodium channels and reduces ERK phosphorylation, dampening the excitability of both mouse and human pain-sensing neurons. It also decreases C-fiber nerve responses that transmit pain signals in live animals. Beyond pain relief, SBI-810 counters acute opioid-induced reward behaviors and lessens opioid-related side effects such as constipation and withdrawal symptoms, highlighting its potential as a safer, multi-functional pain treatment.
Advantages over current treatments
The main difference between SBI-810 and VX-548 (suzetrigine), which was approved earlier this year by the FDA for treating moderate to severe acute pain in adults, lies in the part of the nervous system being targeted. Unlike selective peripheral inhibitors like VX-548, which only target Nav1.8, SBI-810 works on both the central nervous system (CNS) and peripheral nervous system (PNS), and the authors believe this dual action makes the NTSR1 BAM effective in different types of pain. A clinical study focusing on painful diabetic neuropathy is currently evaluating VX-548 for chronic pain. However, in the phase II trial results comparing VX-548 to a placebo for lumbosacral radiculopathy, VX-548 worked similarly to the placebo, indicating that just focusing on peripheral mechanisms might not be enough to treat chronic pain. Vertex, the developer of VX-548, is in talks with the FDA about next steps.
Additionally, SBI-810 does not exhibit the central side effects of cognitive impairment associated with gabapentin and also addresses opioid-related challenges. This positions SBI-810 as a crucial tool in the ongoing effort to manage pain while combating the opioid epidemic. Another compelling advantage is its synergy with neurotensin. SBI-810 amplifies neurotensin’s natural pain-relieving effects, offering a novel strategy for enhancing endogenous pain relief mechanisms.
Duke University has filed two U.S. patent applications for novel non-opioid pain treatments: a provisional patent (63/689,904) covering methods using biased allosteric modulators (BAMs) of neurotensin receptor 1 to treat acute and chronic pain, and a second patent (18/560,394) for non-opioid analgesics and their therapeutic uses. The study doesn’t list any affiliated commercial entities.
Despite its promise, questions remain about SBI-810’s precise interaction with NTSR1 and its broader implications. Further studies are needed to explore its potential in other disease contexts, such as diabetes and cancer, and to clarify its effects on brain regions involved in pain perception and reward.
