Acetaminophen

iStock, tadamichi Alternatives to opioids are desperately needed to better treat moderate to severe acute pain, but to date, we’ve seen few novel analgesics hit the market. In the landscape of modern medicine, pain management stands as a stark outlier. Outside of Vertex Pharmaceuticals’ recently approved Journavx, remedies for pain remain mired in antiquity as fields like oncology and cardiology have embraced groundbreaking immunotherapies, precision medicines and gene therapies. Even opioids, now infamous for an epidemic of misuse, have been marketed for decades, and their core mechanism is unchanged from the opium used in Egypt and India more than three thousand years ago. This needs to change—both to help curb the opioid crisis and to meet the needs of the millions of patients suffering in pain. Often opioids are the only effective treatment for moderate to severe pain, yet they fuel a public health disaster. Even short-term use of opioids for acute pain during post-surgical recovery carries addiction potential. In 2023, nearly 80,000 Americans died of drug overdoses involving opioids, and most were patients first exposed to the drugs via legitimate prescriptions for pain. This well-publicized crisis of addiction and overdoses overshadows another, less visible one, compounding the urgency for new solutions. Namely, due to the risks of opioids, more and more healthcare professionals and patients are declining to use them, leaving acute pain significantly undertreated in many situations. In the U.S., opioids are prescribed in just 15%–20% of acute pain cases. As executives in this notoriously challenging therapeutic area, we are no strangers to the rigor and resilience it takes to develop and bring to market effective and safe pain therapies. Beyond our professional work at Tris Pharma is the personal side of our purpose. We’ve directly witnessed the human impact of untreated pain and opioid addiction, and we feel compelled to help find new solutions. A Field Frozen in Time Pain management lags far behind other therapeutic areas in terms of innovation. In cardiology, statins transformed cholesterol management in the 1980s, followed by PCSK9 inhibitors in the 2010s. Oncology has surged this century with checkpoint inhibitors, CAR T therapies and bispecific antibodies. As a result, deaths from cancer and heart disease have plummeted, and we have changed once-deadly diagnoses into chronic conditions. Cancer Reframing Multiple Myeloma: From Fatal to Chronic and Even Curable Traditionally carrying a dire prognosis, the treatment paradigm for multiple myeloma is changing, with CAR T therapies, bispecifics and more contributing to multifaceted regimens unique to each patient’s needs. January 21, 2025 · 8 min read · Kate Goodwin Read more By contrast, pain’s toolkit is ancient. Aspirin has been used for millennia and was first marketed as a standardized product in 1899. Lidocaine was first produced in the 1940s, acetaminophen became available in 1950 and nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen have been around since the 1960s. For severe pain, opioids reign supreme. Morphine was isolated in 1803, then more than 100 years later, oxycodone hit the market. Today, dozens of prescription opioids have been approved by the FDA for pain management. But these, of course, come with enormous risk. In 2023, 80% of the 80,000 Americans who died of drug overdoses involving opioids had taken illicit drugs like heroin or fentanyl, but research shows that the majority of these people were first exposed to opioids for pain and ~80% used prescription drugs before trying illicit options. Physicians, wary of lawsuits, regulatory scrutiny and addiction and overdose statistics, increasingly avoid prescribing opioids. Patients, influenced not only by media coverage but also by firsthand experience watching loved ones fall victim to the crisis, often refuse even a single dose after major surgeries like knee replacements or cesareans, opting instead for inadequate treatments and suffering in silence. Without effective alternatives for moderate to severe pain, a void is created in which patients’ pain is not effectively managed. That has long-term consequences for patients that go far beyond their immediate comfort. Research shows that undertreated acute pain can become chronic after the injury has healed due to neuronal rewiring. Some studies, including by myself and my colleagues , suggest ineffective pain control in the days following surgery more than doubles chronic pain risk. As of 2021, chronic pain affected 51.6 million U.S. adults—one-fifth of the population—with 17.1 million experiencing impairment of daily life as a result. The economic cost of chronic pain exceeds $600 billion annually in healthcare and lost productivity—a burden that can be prevented with better treatment of acute pain. We thus urgently need acute pain treatments that patients and physicians trust—ones that are effective, non-addictive and free from overdose risk. Why, then, has the industry not delivered? The scarcity of new pain drugs isn’t due to a lack of effort but rather the problem’s inherent complexity. Pain involves diverse pathways—nociceptive, neuropathic, inflammatory—and lacks clear biomarkers for drug development. This complexity has led to repeated failures: from 2000 to 2020, countless candidates faltered in late-stage trials. A 2023 Biotechnology Industry Organization (BIO) study reported a 0.7% success rate for pain drugs reaching FDA approval, among the lowest in medicine. These failures eroded confidence, prompting a funding retreat. By the 2010s, major pharmaceutical companies like Pfizer and AstraZeneca closed pain research divisions, citing high risks and low returns. Venture capital followed suit, diverting funds to more predictable fields like oncology. Federal support has also been meager; the National Institutes of Health allocates a fraction of the amount to pain research that it devotes to cancer or heart disease, despite pain’s prevalence. This created a vicious cycle: reduced funding stifled innovation, further justifying the pullback. Add to that an opioid crisis that intensified scrutiny on pain drugs and made regulatory hurdles steeper, and investment became even less appealing. A New Dawn Despite these challenges, recent breakthroughs signal hope. A few determined companies have targeted novel mechanisms like voltage-gated sodium channels (NaV1.8), which transmit pain signals without affecting reward pathways, avoiding addiction risks. Vertex led with suzetrigine (Journavx), an oral NaV1.8 inhibitor approved by the FDA in January 2025 for moderate to severe acute pain—the first novel pain drug in decades. Editorial FDA Approval of Vertex’s Non-Opioid Journavx Signals New Era in Pain Treatment If the attention generated by BioSpace ’s coverage of this landmark approval is any indication, Americans are hungry for non-opioid pain treatments that could help quell the still raging opioid epidemic. February 7, 2025 · 3 min read · Heather McKenzie Others are advancing. Latigo Biotherapeutics, launched in February 2024 with $135 million, reported positive Phase I data for its NaV1.8 blocker LTG-001 in August 2024. SiteOne Therapeutics, whose lead candidate is the NaV1.8 inhibitor STC-004, was acquired by Eli Lilly in May 2025 in a deal that could be worth up to $1 billion, reflecting improved industry confidence. Our company, Tris Pharma, has progressed through Phase III development with a first-in-class dual NMR agonist (NOP/MOP receptor agonist), which applies an alternative to the traditional mu mechanism utilized by drugs such as morphine, oxycodone and fentanyl. In this new mechanism, both the NOP and MOP receptors add to the pain relief, but also interact with cellular signaling to ameliorate the negative effects of the mu receptor. These developments are reshaping perspectives. Big Pharma is re-entering the space and venture capital is moderately flowing, with pain startups raising hundreds of millions in the last two years. The FDA’s fast-tracking of non-opioid pain candidates further signals regulatory support, addressing the urgent need for alternatives. To dismantle the opioid paradigm, this momentum must endure. New drugs must be clinically successful and be accepted by healthcare providers, insurers and patients, or else the current crises will continue unchanged. Real-world evidence showing fewer addiction cases, overdose fatalities and emergency room visits could spur further investment. Regulatory incentives, like expedited reviews or guaranteed periods of market exclusivity, are vital, as is increased federal funding for pain research. The stakes are immense. Acute pain that can only be effectively treated with opioids affects an estimated 40 million American adults every year and is expected to grow in prevalence with an aging population. Novel mechanisms offer a potential solution: robust pain relief without addiction’s shadow. By fostering research, investment and adoption, we can transform pain management from a relic of ancient medicine into a triumph of modern science, addressing both the visible and hidden opioid epidemics.