Rethinking how we study human pain

The human pain system is complex and nuanced, making it difficult to study and reduce to basic principles that can support biomedical research. As a result, the pain drug discovery pipeline has suffered high value losses for decades. Compounds that look compelling in preclinical studies repeatedly fail in the clinic. However, chronic pain is still a huge unmet need, evidenced by the opioid crisis and a long list of high-profile misses. Can better models change that? Increasingly, the evidence says yes.
   

Chronic pain affects an estimated half of the UK population. In the US, nearly one in four adults lived with chronic pain in 2023, up from one in five in 2019, according to CDC's National Health Interview Survey. Despite this scale, meaningful new treatments have been almost nonexistent. Vertex's NaV1.8 blocker suzetrigine became the first new generalized pain treatment approved in over 20 years — a signal that well-validated human targets can make it through, and that the field is ready to move. 

To sustain that momentum, the field needs translational models that better mirror human pain biology from the start. A collaboration between Medicines Discovery Catapult (MDC)*,  a Life Sciences service dedicated to turning drug discovery into commercial breakthroughs, and ApconiX, is doing exactly that; using iPSC-derived sensory neurons monitored by live-cell imaging to build a genuinely human-relevant platform for pain therapeutics.

The Translational Problem

The human pain system differs from other mammals in ways that matter. Ion channel expression profiles, neuropeptide distributions, and the pharmacology of key targets like NaV1.8 all differ between species – differences that can complicate the translation of preclinical findings to the clinic.

Regulators are taking notice. In March 2026, the FDA released new draft guidance explicitly welcoming new approach methodologies (NAMs), and the NIH pledged $150 million through its Complement-ARIE program, with neurological disorders among the priority areas. Human-relevant data is no longer just acceptable; it is actively preferred.

iPSC-derived sensory neurons, differentiated into models of the dorsal root ganglia (DRG), the neurons responsible for transmitting pain signals, sit at the center of this shift. 

Building the Right Model

MDC validated RealDRG™ neurons from Anatomic Incorporated before putting them to work in drug discovery. The neurons expressed key markers of peripheral nociceptors (including NaV1.8, peripherin and CGRP) and responded to the recently approved NaV1.8 blocker suzetrigine exactly as you would expect human pain-sensing neurons to respond, providing pharmacological validation.

_{iPSC sensory neurons express key markers of peripheral DRG neurons: Immunocytochemistry and ELISA demonstrate expression of NaV1.8 (published with permission from MDC).}

Next, MDC used live calcium imaging to test how the neurons responded to a range of pain-relevant targets, including TRPV1, P2X3, and histamine receptors. All produced clear signals. 

In further studies focused on the P2X3 receptor, two clinically developed antagonists, eliapixant and gefapixant, were added ahead of the agonist challenge, and both reduced the calcium response in line with their known pharmacology.

 

Seeing Neuropathy in Real Time

MDC used the Incucyte^® SX5 Live-Cell Analysis System to model chemotherapy-induced peripheral neuropathy (CIPN), a painful side effect of drugs like paclitaxel and oxaliplatin. Because the system captures images continuously without disturbing the culture, it tracked the full progression of neurite degeneration in living cells across the experiment. That is the kind of kinetic picture a fixed endpoint assay would miss entirely.

Neurofilament light chain (NF-L) release, an emerging biomarker of nerve damage, corroborated the imaging findings and revealed meaningful differences in how the two drugs actually cause harm. Together, the imaging and biomarker data recapitulate features seen in patients with CIPN, in a fully human system.

_{Modelling of CIPN in vitro: Kinetic live-cell analysis shows neurite degeneration in response to paclitaxel. NF-L release correlates with neurite degeneration (published with permission from MDC).}

A Platform Worth Building On

MDC's work shows that iPSC-derived sensory neurons, properly validated and paired with continuous, high-throughput, live-cell imaging, can screen analgesic candidates, characterize mechanism, and model disease features like neuropathy, all in a human system. 

For labs ready to adopt NAM strategies more broadly, Mattek, now part of Sartorius, offers a diverse range of assay-ready, lab-engineered human tissue models for preclinical safety and efficacy testing.

The regulatory window is open, the biology is compelling, and the tools now exist. There has never been a better moment to make the switch.
 

*Medicines Discovery Catapult works with entrepreneurial scientists to make every move count. It validates their ideas, de-risks investments, and feeds insights back into the sector to drive productivity and impact. Find out more at https://md.catapult.org.uk/