By Stephani Sutherland

Millions of Americans live with chronic pain—and the lack of safe, effective pain therapeutics only exacerbates the health crisis.

Aside from antibody agents approved in 2018 for migraine, only one new analgesic drug with a novel mechanism of action has come to market in more than two decades: a drug for moderate-to-severe acute pain, called suzetrigine.

All drugs take many years and millions of dollars to develop, but chronic pain therapeutics face additional hurdles, says William Schmidt, PhD, president of research advisory organization NorthStar Consulting. Schmidt has worked with pharmaceutical companies on efforts to develop pain medications for over 20 years.

Testing takes longer when it involves chronic symptoms (sometimes, drugs first approved for acute conditions are then studied further to assess their viability for chronic conditions). For market acceptance, new pain medications must out-perform the current standard of care and placebo treatments, or they must be substantially safer in a large patient population. And the lack of measurable signatures, or biomarkers, of pain and pain pathology has been a constant limitation for the field.

“When you’re doing drug development, it’s important to choose a particular target condition,” explains Schmidt—and that’s especially true for chronic conditions. A drug for fibromyalgia, for example, would almost certainly not work for someone with osteoarthritis.

From basic research to approved medication

Development of the recently approved suzetrigine is a “beautiful example” of just how arduous the process is, says Ted Price, PhD, a pain researcher and neuroscience professor at the University of Texas at Dallas who has spun several biopharmaceutical companies out of his lab.

The medication stems from decades-long research focused on sodium channels—proteins found throughout the body and brain that allow neurons to “fire” electrical signals.

Attempting to halt pain by broadly blocking all or most sodium channels could cause catastrophic effects in the cardiovascular system or just shut down brain function altogether, says Price. However, in the mid-’90s, researchers discovered voltage-gated sodium channel 1.8, or NaV1.8—found almost exclusively in peripheral sensory neurons. This opened the door to targeting nociceptors, the neurons that trigger pain sensations, while leaving other nerve cells alone.

Researchers spent over a decade isolating compounds that would bind to that target—and then years more testing the therapeutic they developed, until the drug was finally approved in 2025.

“So many things have to fall into the right place,” Price explains. “I don’t think that everything is going to take as long as that one did, but the expectation that when a discovery is made, it can rapidly lead to a drug, is not reasonable.”

Coming around the bend

Price and Schmidt are optimistic about current research efforts by pharmaceutical companies, expanding on mechanisms discovered during the molecular biology explosion around the turn of the 21st century.

Ongoing clinical trials are targeting voltage-gated sodium channels Nav1.7, Nav1.8, and Nav1.9. Others examine molecules that sense harmful chemicals, like acid-sensing ion channels (ASICs), and the entire family of temperature-sensitive TRP channels, including the capsaicin receptor TRPV1.

Another target, KCC2, is the product of a half-century of research stemming from the 1965 Gate Control Theory of Pain, which illustrates how pain and other sensory signals are filtered, or “gated,” in the spinal cord. That process is altered in neuropathic pain conditions—with KCC2, a protein found in spinal cord neurons, playing a key role. At least one agent is in early clinical trials, Price says, “so we’ll have a gate-theory-directed compound.”

Other investigations are targeting molecules that contribute to neuroinflammation itself, raising the prospect of eradicating—rather than blunting—certain types of pain, Price explains.

The potential payoff of these combined efforts in the research pipeline? A new crop of pain therapeutics in the coming years. As Price says: “There’s a lot of reason to be hopeful.”

NOVEL DRUG DEVELOPMENT TIMELINE

Basic research: Optimistically, 4–5 years. Identifies new biological “targets” for medications, mainly using cells, tissues, or animal models to understand disease mechanisms.

Validation: Often 1–5 years. Part of translational research. Bridges the gap between basic research and clinical development, confirming that a target molecule studied in animals or labs plays a role in human disease.

Drug discovery and compound development: Often 3-6 years. Isolates compounds that interact with a validated target. May include early safety tests on animals or cells.

Clinical trials: Each individual step can span several months to several years.
Phase I: Tests the compound for safety in healthy volunteers.
Phase II: Evaluates pain relief for the first time, in a small group of individuals with the condition being studied.
Phase III: Measures efficacy and safety in larger groups of patients with the studied pain or condition, spanning various demographics, risks, comorbidities, and existing medications.
Phase IV: Often indefinite. Takes place after a drug is approved and available on the market, to study long-term effectiveness and safety. Particularly key for chronic condition treatments.

Further slowing the clock

Even when every step goes as planned, the novel drug development process takes many years—and smooth sailing is rare.

“The regulatory bodies would like to see 1,200 to 1,500 patients exposed to at least one dose,” says Schmidt—even more for a chronic indication. “And if the first clinical trial of a new type of drug doesn’t meet safety or other objectives, it could add another three to five years to find a suitable backup compound.”

The financial cost of each step can be staggering. Even after scientists identify and validate a target, only pharmaceutical companies can afford to develop and test compounds that might be used therapeutically. Schmidt notes that research efforts through the National Institutes of Health’s Helping to End Addiction Long-term (HEAL) Initiative are seeking to speed up that process.