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When Vertex Pharmaceuticals announced last month that its pain pill had received approval from the U.S. Food and Drug Administration (FDA), it marked a major breakthrough in the hunt for new non-opioid pain medication.
Despite the market still being dominated by cheap opioid-based painkillers that are widely available, highly addictive, and firmly established, Vertex’s success has provided a reason to be hopeful. And it’s not just Vertex; other biotech companies are also attempting to develop new, non-addictive ways to fight pain.
Table of contents
The opioid crisis
Opioids work by binding to opioid receptors in the brain, spinal cord, and other areas of the body, triggering the brain’s reward centers and reducing pain signals. They also mute other nerve cell functions, such as breathing, heart rate, and level of alertness. Over time, the body adapts to these medications, and the pain relief lessens. This is known as ‘tolerance,’ and means that more of the same medication is necessary to achieve the degree of pain relief that the person was feeling before their tolerance kicked in.
This tolerance, and ultimately addiction, is what led to the opioid crisis. According to the Centers for Disease Control and Prevention (CDC), the first wave of the crisis began with increased prescribing of opioids in the 1990s, with overdose deaths involving prescription opioids increasing since at least 1999. Then, the second wave began in 2010, with rapid increases in overdose deaths involving heroin. And, most recently, the third wave started in 2013, with significant increases in overdose deaths involving synthetic opioids, particularly illicitly manufactured fentanyl.
The crisis has not yet ended. In fact, as per the CDC, the figures now are even scarier: the number of people who died from a drug overdose in 2021 was over six times the number in 1999, and the number of drug overdose deaths increased more than 16% from 2020 to 2021, with more than 75% of the nearly 107,000 drug overdose deaths in 2021 involving an opioid. According to a report from the Stanford-Lancet Commission on the North American Opioid Crisis, without urgent intervention, 1.2 million people in the U.S. and Canada will die from opioid overdoses by the end of the decade.
Joseph Stauffer, chief medical officer (CMO) of Antibe Therapeutics, told Labiotech that the opioid crisis has “profoundly” impacted how biotech and pharmaceutical companies now approach the development of pain medication. “With widespread concerns about opioid misuse and addiction, there’s a notable shift towards prioritizing the creation of safer, non-addictive alternatives.”
And Vertex has recently succeeded in doing just that after receiving approval for its NaV1.8 inhibitor.
FDA approves Vertex Pharmaceuticals’ non-opioid pain medication Journavx
On January 30 2025, in what was a major milestone in the company’s decades-long efforts to bring a non-opioid pain medicine to market, Vertex announced that the FDA had approved its non-opioid pain medication Journavx (suzetrigine). The drug is a selective NaV1.8 pain signal inhibitor and has been cleared to treat adults with moderate to acute pain that is usually short-term, often resulting from surgery or injury.
The approval came after positive results from two phase 3 studies were announced in January 2024. In the trials, those who received Journavx after surgery experienced a greater reduction in pain over two days compared to those who received placebo. Participants in one study had an abdominoplasty and participants in the second study had bunion surgery. Furthermore, reductions in pain scores were clinically meaningful (>3 points and close to 50% from baseline in each trial) and were rapid and sustained throughout the treatment period. Plus, the drug was safe and well-tolerated.
The studies were also designed to test whether Journavx could beat hydrocodone plus acetaminophen, which is a common pain treatment combo that is best known by the brand name Vicodin. Unfortunately, the non-opioid drug ultimately failed to meet this secondary endpoint; however, it did show comparable efficacy over two days in the abdominoplasty study.
In a comment to Labiotech, Vertex said that selectively inhibiting the NaV1.8 and NaV1.7 sodium channels found in peripheral sensory neurons has long been a heavily pursued area of drug discovery for pain relief, and Vertex is the first company to show phase 3 efficacy data on the NaV1.8 target – a voltage-gated sodium channel that plays a critical role in pain signaling in the peripheral nervous system.
Unlike opioids, Journavx works by blocking pain signals at the source. Vertex’s approach is to selectively inhibit NaV1.8 using small molecules to create a new class of medicines that have the potential to provide effective relief of pain without the limitations of opioids, including their addictive potential.
Moving forward, Vertex said in a business report earlier this month that it expects to begin shipping its painkiller to pharmacies nationwide by the end of February, with retail availability beginning shortly afterward.
Meanwhile, the company is also investigating suzetrigine to treat painful lumbosacral radiculopathy (LSR), a common condition in which nerves in the lower back become compressed, leading to sharp bursts of pain in the same area, as well as in the legs. Although the latest study for this was technically successful, analysts were unhappy with the results and Vertex lost more than $15 billion in value back in December. The company said at the time that its next studies need to be more innovative to control for oversized placebo responses, which is a problem that affected the latest trial results, and that it would consult with regulators and push forward into late-stage testing for painful LSR.
Tris Pharma records positive phase 3 results for non-opioid pain medication cebranopadol
In January 2025, Tris Pharma announced positive topline data from a phase 3 trial of its drug cebranopadol, meaning it might not be long before we see another approval for a non-opioid pain medication.
For the trial, the drug was tested in patients with moderate-to-severe acute pain following abdominoplasty surgery, also known as a “tummy tuck”. It achieved the primary endpoint, demonstrating a statistically significant drop in pain intensity 44 hours post-operation. Additionally, its safety profile was comparable to placebo, with no adverse events related to the drug.
Harold Minkowitz, primary investigator in the study, said in the press release that cebranopadol’s novel mechanism of action (MoA) has the potential to be as effective as opioids in the post-surgical setting. The MoA here involves dual-nociceptin/orphanin FQ peptide (NOP) receptor and µ-opioid peptide (MOP) receptor (dual-NMR) agonism. These receptors are partially homologous (similar) to each other and they play both complementary and distinct roles to modulate pain biology pathways.
Tris said it plans to share results evaluating cebranopadol in two additional studies, an intranasal human abuse potential study and ALLEVIATE-2, a phase 3 clinical study in patients following bunionectomy, with a New Drug Application (NDA) submission expected later in 2025. The company also plans to conduct cebranopadol studies in multiple chronic pain indications beginning in the second half of 2025.
If approved, cebranopadol will be the world’s first dual-NMR agonist.
Algiax Pharmaceuticals’ non-opioid pain medication is shown to reduce neuropathic pain in phase 2a study
Another company announcing positive results in 2025 was Algiax Pharmaceuticals. Continuing the surge of momentum for non-opioid pain medication just days after Journavx’s approval, the company shared positive topline data at the beginning of February from a phase 2a trial of its lead candidate, AP-325, for the treatment of post-surgical neuropathic pain, a potentially chronic condition stemming from damage to nerves that does not usually get better with common painkillers.
The study demonstrated that the painkiller has the potential to rapidly reduce neuropathic pain as well as achieve long-lasting benefits for patients post-treatment. Patients who were treated with the drug saw persistent drops in pain within two weeks of treatment, with between 50% and 70% of people responding. At the end of the trial, the company reported that more than 25% of treated patients had a 50% reduction in pain, compared to just 11% of those receiving placebo. Furthermore, participants showed improvements in sleep quality and a reduction in anxiety and depression scores.
AP-325 is a non-opioid small molecule aimed at reducing neuropathic pain by modulating the GABAA receptor, a major inhibitory neurotransmitter in the central nervous system (CNS).
Algiax said that it will now explore opportunities to support the rapid advancement of AP-325’s clinical development.
Levicept reports positive phase 2 data for LEVI-04
Meanwhile, in August 2024, fellow non-opioid painkiller company Levicept also announced positive phase 2 data regarding its own drug LEVI-04, a neurotrophin-3 inhibitor for the treatment of moderate to severe osteoarthritis that Levicept’s founder and chief scientific officer (CSO), Simon Westbrook, brought with him from Pfizer.
The painkiller is a fully human chimeric fusion protein designed to restore neurotrophin homeostasis, in turn providing profound pain relief without side effects. Neurotrophins are a family of proteins that regulate the growth, survival, and function of neurons in the nervous system.
The phase 2 study of LEVI-04, which enrolled more than 500 participants with pain and disability due to osteoarthritis of the knee, hit its primary endpoint by showing a reduction at week 17 in the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) pain assessment from baseline of greater than 50% for all three doses of LEVI-04 compared to placebo. The trial also hit all secondary endpoints, including assessing function and joint stiffness, as well as daily pain scores, and showed that the drug was well tolerated, with no increase in rapidly progressive osteoarthritis.
In the press release, Eliot Forster, chief executive officer (CEO) of Levicept, said that the company is focused on strategic options to advance LEVI-04’s development.
Latigo Biotherapeutics announces positive phase 1 data for LTG-001 shortly after emerging from stealth
Vertex is not alone in its quest to develop a NaV1.8 inhibitor. Last year, Latigo Biotherapeutics emerged from stealth with $135 million in series A financing and a lead program targeting the same channel.
New technologies related to pain medication
- Analgesic and anti-addictive compositions for the treatment of chronic pain – University of Minnesota
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Latigo’s NaV1.8 pain inhibitor is known as LTG-001 and has the potential to have a rapid onset, meaningful efficacy, and superior safety to standard of care with no CNS effects. In August 2024, the company announced positive phase 1 data for the non-opioid pain medication demonstrating that it was well tolerated with rapid absorption.
Sean Harper, co-founding managing director of Westlake Village BioPartners, which founded and incubated Latigo, told Fierce Biotech last year that he believes Latigo’s molecule will differentiate from Vertex’s by mitigating off-target effects in the brain and by tackling chronic pain. “We have every reason to believe that our NaV1.8 inhibitor will be effective in both acute and chronic pain. But obviously, that remains to be proven.”
Latigo also has another non-opioid Nav1.8 inhibitor candidate in clinical trials for treating pain, called LTG-305. The company announced that the first person was dosed in a phase 1 trial for the drug in October 2024, with topline results expected in mid-2025.
Are there any challenges in bringing new non-opioid pain medications to the market?
“Drawing on my experience as a former FDA medical review officer for anti-inflammatory and analgesic drugs (painkillers), the difficulties of developing novel analgesics are the typical hurdles for any drug developer – time, money, risk,” said Stauffer when asked about the challenges of bringing non-opioid pain medications to the market.
In terms of the general efficacy of non-opioid medications compared to opioids, a study in the Journal of the American Medical Association suggests that opioid drugs are no more effective than a combination of non-opioid painkillers in treating acute pain. This is good news for any biotechs trying to develop non-opioid painkillers that are equally as effective as opioids.
The primary challenge for non-opioid painkillers like Journavx will be competing with the cost and coverage of opioid drugs. As mentioned previously, the pain management market is still dominated by cheap, highly effective opioid medications that are easy to access. According to an article in Biopharma Dive, doctors across the U.S. believe that the biggest barrier to prescribing Journavx will be insurers, as they tend to resist covering new, higher-cost pain drugs. Vertex set the medicine’s price at $31 a day for patients – far more expensive than generic opioids, which can cost as little as $0.50.
However, Vertex is hopeful that Journavx will be broadly available through private and public payer coverage, as well as easy for doctors to deploy in the clinic. According to BioSpace, in an investor call earlier this month, the chief operating officer (COO) of Vertex, Stuart Arbuckle, said that the company was in talks with insurance providers, working hard to secure favorable coverage arrangements for the pain drug.
One particular piece of legislation that could benefit Vertex’s attempts to provide broad access to its drug is The Non-Opioids Prevent Addiction In the Nation (NOPAIN) Act, which came into effect at the start of this year and will provide separate payments for non-opioid pain medications given to patients under Medicare. Vertex expects Journavx to be covered under this act.
As the company expects to launch the drug at the end of this month, we should find out more about its insurance coverage very soon, which will likely also provide an indication of how accessible any non-opioid painkillers approved in the coming years will be.
Non-opioid pain treatment market expected to grow
According to Grand View Research, the global non-opioid pain treatment market size was valued at $38.64 billion in 2021, and is expected to expand at a compound annual growth rate (CAGR) of 8.3% from 2022 to 2030. This expected growth can be attributed to the increasing research and development (R&D) investments by the key players for developing novel non-opioid drugs, and government and private organizations for introducing favorable initiatives and creating awareness about available treatments.
While this is good news, Stauffer pointed out that many of the research efforts being put into novel mechanisms and non-opioid pathways are still in the preclinical stage, meaning it could take some time before we see a real vast array of new non-opioid pain medications with differing MoAs reach the market.
Having said that, there are several ongoing clinical trials – such as the ones being conducted by Tris, Algiax, and Levicept – that are in the later stages of development, meaning that we could see a trickle of approvals for non-opioid pain medications in the next two to three years that do have differing MoAs and are intended for different types of pain. Although the overall variety here might not be as wide as opioid medications, it is certainly a start.
Ultimately, the pain drug market as a whole is in need of an overhaul – one that phases out addictive opioid pain pills and brings in effective new non-opioid medications. Hopefully, Vertex’s recent approval success could be the first step toward this vital transition.
