Despite falling rates of opioid overdose deaths in the last several years, the overall number of deaths remains exorbitantly high — reaching over 140 deaths per day for the year ending March 2025. The ongoing crisis underscores the need for non-opioid pain options, and thus the FDA’s January approval of Vertex’s NaV1.8 (voltage-gated sodium channel 1.8) inhibitor, Journavx, was met with great excitement and anticipation.
However, Vertex’s latest Q3 earnings report showed that sales of the drug were down by about $3 million compared to analysts’ expectations, and the company ended their plans to pursue a Phase 3 trial of Journavx to treat a neuropathic pain indication, lumbosacral radiculopathy, after the drug failed to outperform the placebo Phase 2.
Other non-opioid drugs meant to follow in Journavx’s footsteps are also showing signs of trouble. Vertex announced in August that their successor drug, the NaV1.8 inhibitor VX-0993, did not reach the primary endpoint in a Phase 2 trial to treat acute pain after bunionectomy surgery and will not advance further in their pipeline. In addition, Eli Lilly recently discarded their non-opioid drug that inhibits P2X7 (purinergic receptor 7) — making it the second non-opioid pain drug they’ve dropped this year following Lilly’s shelving of a SSTR4 (somatostatin receptor subtype 4) agonist.
An alternative route to ending the opioid crisis is to make novel opioid pain drugs that aren’t addictive in the first place. While this goal remains far off, a new paper published in Nature provides drug developers with a leg up. The work uncovered a new pharmacological understanding of the intracellular signaling that happens after opioid drugs bind to the mu opioid receptor (MOR), a G protein-coupled receptor (GPCR).
The field of opioid pharmacology has increasingly recognized that how effectively an opioid drug induces cellular chain reactions after binding to MORs can drive its hazardous effects. Yet, “the ability to rationally design opioids with customized efficacy has been limited by an incomplete molecular understanding of how different ligands — for example, antagonists, partial agonists, and full agonists — control G-protein activation,” Cornelius Gati, a structural biologist at the University of Southern California who led the new study, told DDN.
Discovering new states
When an opioid drug binds to a MOR, the coupled G protein is activated and then releases a small molecule called guanosine diphosphate (GDP) — which ultimately triggers downstream signaling pathways that regulate pain perception.
Before the new paper, scientists had only observed two states that MORs enter upon binding with an opioid drug. Using cryo-electron microscopy to capture “snapshots” of the earliest steps of G-protein activation with the synthetic opioid loperamide in human cells, Gati’s team observed four additional distinct states and coined the terms latent, engaged, unlatched, and primed.
This suggests that future opioids could be designed to fine-tune GDP release rates — modulating receptor signaling strength without triggering the overstimulation that causes respiratory depression and reward-pathway activation.
– Cornelius Gati, University of Southern California
Gati explained that the engaged state is “likely the most critical one for ligand efficacy,” however the team can only speculate on exactly how loperamide triggers this conformational change currently. “It clearly requires the ‘activation’ of the receptor, including conformational changes in conserved microswitch regions, and opening of transmembrane domain 6 (TM6), but we also believe that there is an intricate crosstalk between MOR and G protein, required for these changes, which will be investigated in follow-up studies,” said Gati.
Overall, the team showed that how quickly the cell releases GDP at the G-protein interface is the rate-limiting step that can change depending on the opioid ligand.
“This suggests that future opioids could be designed to fine-tune GDP release rates — modulating receptor signaling strength without triggering the overstimulation that causes respiratory depression and reward-pathway activation,” said Gati. “We could theoretically envision designing compounds that could stabilize selective intermediate states — for example, the ‘engaged’ but not fully ‘primed’ conformation. We believe that such drugs would activate G proteins to some extent, resulting in analgesic effects, while avoiding the downstream cascades linked to tolerance, dependence, and respiratory suppression.”
A new understanding
The researchers also discovered novel molecular insights about how the lifesaving opioid antagonist, Narcan (naloxone), works to stop the effects of opioids in the brain. Specifically, they showed that it does so by locking the receptor into the latent state to prevent the release of GDP. “Many people in the field have thought that antagonists simply block the interaction between receptor and G protein, so it was surprising to us that naloxone allows an interaction, but blocks the activation of the G protein,” said Gati.
With this new knowledge in hand, drug designers could also work towards developing antagonists that act more quickly and over longer time periods to counteract overdoses.
As a whole, the new results fundamentally change what scientists thought they knew about the cellular interactions that take place at MORs — including the fact that new states could be discovered at all. “The entire field of GPCR structural biology was convinced that the GDP-bound state was too heterogeneous to be imaged at high resolution,” said Gati. That has meant that researchers have only ever studied the two states that were known about prior to the new paper.
“For the past two decades, this led to thousands of published GPCR structures, with all falling into these two categories. So it was a big surprise to us that it was possible for us to capture these GDP-bound states to such level of detail,” said Gati.
Given the potential for these insights to guide the next generation of safer, non-addictive opioid pain medications, the new work emphasizes the importance of continued research in this area from Gati’s team and scientists around the globe.
