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iStock/ Deagreez Non-opioid pain therapies are entering an unprecedented era, marked by the landmark FDA approval of Vertex’s Journavx and a growing number of alternative approaches. Their ultimate uptake, however, remains to be seen. When Vertex Pharmaceuticals won FDA approval for Journavx last month, it opened a new era in a therapeutic space recently fraught with suffering, controversy and thousands of avoidable deaths. Eighty million people in the U.S. suffer from acute pain every year, according to William Blair analyst Myles Minter, who told BioSpace in an email that many of these patients will be treated with opioids. After non-steroidal anti-inflammatory drugs (NSAID) and acetaminophen, standard of care options are varying strengths of opioids, Minter said. “There is a clear treatment gap whereby pain severity for several individuals is not at the threshold of requiring high efficacy opioid therapy [yet] but is beyond that of ‘rescue’ or over the counter NSAID/acetaminophen options.” Minter believes Journavx could fill this gap—and be a “potential game-changer” in addressing the opioid crisis in the U.S. There are also several other non-opioid analgesics in biopharma’s pipeline. Still, there are hurdles to overcome—including price. A single Journavx pill costs $15.50, bringing a patient’s daily spend to $31. Opioids, in comparison, are leagues cheaper at $0.50 for a generic, non-branded pill, Minter said. Of course, this doesn’t take into account larger healthcare and societal costs that opioids accrue because of their addictive risk. The Centers for Disease Control and Prevention (CDC) pegged the cost of opioid use disorder and related fatalities in the U.S. at over $1 trillion in 2017. But Rohan Jotwani, an academic anesthesiologist and pain medicine specialist at Weill Cornell Medicine, isn’t hopeful that insurers will look at this bigger picture. “I would like to believe a story that, because this is an anti-opioid medication, it’s going to get clearance from insurance companies a little faster,” Jotwani said last month on a call hosted by Truist Securities. “But that being said, I’ve also had many fights with insurance companies on all kinds of medications.” Blocking Signals When broken down to a simplistic, molecular level, pain is essentially a series of signals sent from pain receptors located at different parts of the body through a complex network of neurons to, ultimately, the central nervous system. To transmit these signals, nerve cells are studded with voltage-gated sodium channels , which open and close in response to certain stimuli. In turn, the action of these channels results in a series of reactions, which propagate, channel to channel, nerve to nerve, to bring the pain signals to the appropriate region of the brain. Opioids, arguably the most famous—and infamous—form of analgesic, work by binding to certain receptors found on nerves, in turn disrupting the cascade of pain signals through the body. This mechanism is effective at dampening pain but can also be dangerous. Opioid receptors are also found in the reward system area of the brain, and overuse of the drug could lead to feelings of euphoria, which in turn could spin out of control and result in addiction. According to the National Institute on Drug Abuse, nearly 74,000 people died from an overdose of synthetic opioids in 2022. That same year, the CDC estimated that the age-adjusted rate of drug overdose rates from synthetic opioids other than methadone jumped almost 23 times from 2013 levels. Journavx is different. An ion channel blocker, Vertex’s drug selectively targets peripheral nerves, thereby eliminating the potential for addiction. Designed to be taken orally twice a day, it works by selectively targeting and blocking a specific subset of these sodium channels called NaV1.8, preventing pain signals from reaching the spinal cord. “Before Journavx there has not been a non-opioid alternative approved for outpatient use,” Minter said. And Journavx may be only the beginning for this new class of pain medicines as several other biotechs seek to follow in Vertex’s footsteps. One of these is Latigo Bio, which launched in February 2024 with $135 million in starting funds to advance its own oral NaV1.8 blocker LTG-001. At the time of its debut, CEO Desmond Padhi told BioSpace LTG-001 has the potential to be the best in its drug class. Whether Latigo will pose a credible challenge to Vertex remains to be seen, however. The start-up just recently wrapped Phase I testing for LTG-001, launching a Phase II trial last month in patients who have undergone surgical molar extraction. Earlier this month, the company stated in an SEC filing that it is now targeting up to $150 million in new funding. Taking a different approach to non-opioid analgesia is Sangamo Therapeutics. The California–based biotech is working on a very early gene editor that leverages zinc finger technology to target the SCN9A gene, which encodes for NaV1.7, a related type of voltage-gated sodium channel. In May 2023, Sangamo unveiled promising preclinical data at the American Society of Gene & Cell Therapy meeting, demonstrating that the investigational gene editor, ST-503, can strongly repress SCN9A repression in various animal and cell models. The company filed an Investigational New Drug application in November 2024 for ST-503 for the treatment of intractable pain due to idiopathic small fiber neuropathy. Also advancing an editing approach to ion channel blockage is Cambridge-based Korro Bio. According to a company filing , Korro’s pain program targets and edits the mRNA encoding for NaV1.7, in turn dampening the activity of the protein and achieving similar effects as small-molecule channel blockers. The biotech is optimizing and screening potential oligonucleotides that it can use to carry out these RNA edits. Alternative Pathways Aside from preventing the propagation of signals through a network of ion channels, there are many other pathways that can elicit pain relief. A growing number of biotechs are exploring these avenues to develop non-addictive analgesics. One of these, Lexicon Pharmaceuticals, is developing pilavapadin (also known as LX9211), an oral small-molecule compound for neuropathic pain. The neuropathic pain distinction is “essential,” CEO Mike Exton told BioSpace in an email . Acute pain, for which Journavx is indicated, is often “localized and resolves quickly” and typically arises after an injury or surgery. Neuropathic pain, in contrast, “is centrally driven and complex, is often chronic and results from nerve damage” that requires more specialized and long-term care, Exton said. “In the U.S. alone, approximately 9 million people are currently diagnosed with diabetic peripheral neuropathic pain (DPNP),” a number expected to reach 13 million by 2035, according to Exton. These patients face a crucial shortage of non-opioid options, of which there have been no new approvals in more than 20 years, he said. Lexicon hopes to fill this gap with pilavapadin, which works by targeting the adapter-associated kinase 1 (AAK1) protein. AAK1 is highly expressed in the central nervous system and while its exact role in the pain pathology has yet to be elucidated, studies have shown that knocking it out can substantially alleviate neuropathic pain and other neurological disorders. Indeed, Lexicon’s own preclinical studies have found that mice without the AAK1 gene were more resistant to induced neuropathic pain, according to Exton. The biotech is currently running a Phase IIb trial of pilavapadin in DPNP, topline data from which are expected in the first quarter of this year. Thereafter, Lexicon expects to move quickly, leveraging the FDA’s Fast Track designation to accelerate its time to the market. “We are positioned to be the first oral non-opioid approved for neuropathic pain,” Exton said. Earlier in the drug development process is South Rampart Pharma, which is advancing a non-opioid painkiller that not only avoids the addictive potential of opioids but also sidesteps the toxicity typical of other analgesics. The candidate, dubbed SRP-001, is a compound that, inside the body, is broken down into AM404, a known metabolite of acetaminophen that exerts analgesic effects on the brain. Unlike acetaminophen, however, SRP-001 does not produce byproducts that are toxic to the liver, CEO Hernan Bazan told BioSpace in an email. The asset is also classified as a non-NSAID, meaning it is “devoid of the kidney and gastrointestinal damage with overuse,” Hernan said, opening up the possibility of higher or prolonged dosing. Hernan added that unlike Journavx—and other sodium channel blockers in development—SRP-001 “addresses pain centrally” in the central nervous system. “That difference could matter for complex or refractory pain states where peripheral mechanisms alone aren’t sufficient.” An oral formulation of SRP-001 recently cleared Phase I in acute pain, and South Rampart is now working to push it into Phase II development. The biotech is also developing intravenous and topical versions of SRP-001. These are hardly the only players in the crowded non-opioid space. Algiax Pharmaceuticals unveiled promising Phase IIa data for its small-molecule GABA A activator AP-325, and Xgene Pharmaceutical is working on XG005, an investigational pill that in December 2024 cleared Phase IIb . Closer still to the market is Tris Pharma, which last month posted a Phase III win for cebranopadol, an agonist of the nociceptin/orphanin FQ peptide and µ-opioid peptide receptors. Tris is planning an NDA submission for cebranopadol later this year. A Place for Opioids? Even with Journavx’s approval—and with the flood of non-opioid pain relief treatments in development—analysts don’t expect opioids to fade from relevance any time soon. “We don’t think opioids will be eliminated here as they are still effective pain management agents when used correctly,” William Blair’s Minter said. Jotwani, on the Truist call, expressed similar sentiments. Opioids, he said, still have a place in the clinic, especially in cases where other avenues of analgesia fail. “I don’t see this as an either-or,” he said. “I don’t see this as either you get suzetrigine [Journavx] or you get opioids. I see this as a ‘we give probably the suzetrigine first because it has less side effects and has a less addictive pro no addictive pro if that fails, we have opioids as a backup.’” This approach closely mirrors current medical practice, where patients after a surgery are already readied to receive the powerful painkiller oxycodone. But doctors still “make sure they try the Tylenol and the NSAIDs first,” according to Jotwani. Because of their different modes of action, as well as efficacy and safety pro both opioids and non-opioid treatments can comprise a holistic pain management approach, he said. “If the patients do well, I don’t see a reason why a surgeon would say ‘let’s not send them home with suzetrigine instead of the opioid,” Jotwani continued. “If the patient needs an opioid, they will call the office and the surgeon will escalate.” Aside from their analgesic efficacy, cost could also help to maintain the place of opioids in medical care. In a February 2025 report , the Institute for Clinical and Economic Review found that Journavx’s current price tag is “slightly cost-saving relative to opioid therapy, while producing greater health benefits,” but at many times the price of a generic opioid, the new drug has an uphill battle with insurers, Jotwani said. “They will want the patients to try oxycodone before they’ll pay for” these alternatives, he said.