The evolving landscape of pain drug discovery

For most of us, pain is an unwelcome but vital warning system that tells us when something is wrong. However, for the small number of people living with congenital insensitivity to pain (CIP), a serious and debilitating rare condition, that warning system is entirely absent. Those with CIP may bite through their tongues, fracture bones without realising and face life-threatening injuries from hazards the rest of us instinctively avoid.

CIP is caused by mutations that disable the gene encoding Nav1.7, a key neuronal sodium channel involved in pain signalling. This discovery made sodium channels one of the most pursued targets in pain drug discovery and helped establish the broader case that selectively blocking these channels could offer a new approach to pain relief.

That case has recently been proven. The FDA approval of suzetrigine, a selective sodium channel blocker and the first new class of pain medicine in over two decades, represents a landmark moment for the field. It demonstrates that targeting the specific sodium channels involved in human pain signalling can deliver meaningful benefit and has renewed optimism in pain research.

Pain is a significant and growing public health challenge. Up to half of the UK population lives with chronic pain, a figure projected to rise with ageing populations and increasing rates of musculoskeletal conditions like arthritis. Existing medications, from over-the-counter painkillers to opioids, offer only limited relief or carry substantial side effects. Despite this unmet need, pain has long been a neglected area of drug discovery.

But sustaining this momentum requires an honest look at what has previously held pain research back. Despite compelling targets and genetic rationale, earlier drug candidates failed to demonstrate meaningful efficacy. This was not because the biology was wrong, but because the preclinical models used to test and validate them were unable to capture the full complexity of the human pain response.

The dorsal root ganglia

The dorsal root ganglia (DRG) are bundles of sensory neurons that detect and relay pain signals, making them a primary target for pain treatments. Historically, researchers have relied on rodent DRG neurons to study pain and screen drug candidates, but molecular and functional differences mean these models do not accurately reflect human pain biology.

Sustaining this momentum requires an honest look at what has previously held pain research back

Across species, there are significant differences in the expression levels of the sodium channels involved in pain signalling. Not only are these expressed at different levels within sensory neurons, but the thresholds at which they activate to trigger a response vary too. When models fail to capture these human‑specific differences, they cannot reliably predict how patients will respond to new treatments.

Human-relevant preclinical models

Induced pluripotent stem cells (iPSCs) are human cells that can be reprogrammed into any cell type, offering a platform for human-relevant disease modelling and translational studies. To support human-relevant pain research, human DRG neurons can be generated from iPSCs. These systems enable researchers to test new pain treatments in a more clinically relevant context, ultimately improving the odds of translating them to patients.

For testing, cultures of iPSC-derived DRG neurons can be grown either as monocultures (containing only neurons) or as more complex cultures with other cell types. While neuron monocultures are valuable for isolating and interrogating specific neuronal responses, they do not fully reflect the complexity of how DRG neurons work in the body.

In their native state, DRG neurons exist within complex multicellular environments and communicate continuously with neighbouring cells. These interactions shape how DRG neurons develop, mature and even respond to pain stimuli. After nerve injury, for example, macrophages enter the DRG and, through interactions with DRG neurons, initiate and maintain the pain response. Without supporting cell types included in neuronal cultures, human in vitro pain models will fall short in fully replicating the human pain response.

As the field advances, models that combine iPSC-derived DRG neurons with relevant supporting cells will become increasingly important for pain-relief drug discovery. Complex systems will generate more predictive data to guide the development of the next generation of pain treatments, improving translational success and, ultimately, delivering relief to the many patients who need it.