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Introduction <p>Chronic pain affects almost 20% of the global population, causing significant disability and diminished quality of life. Conventional treatments such as opioids and NSAIDs often fall short due to low effectiveness, side effects, and risk of dependency. Recent advances have identified novel molecular targets involved in pain signaling, including transient receptor potential (TRP) channels—TRPV1 and TRPA1—and voltage-gated sodium channels like Nav1.7. TRPV1 responds to unpleasant heat and inflammatory mediators, while TRPA1 is triggered by irritants and cold. Nav1.7, strongly linked to congenital pain disorders, plays a crucial role in nociceptive transmission though clinical validation of compounds targeting these channels has so far been largely unsuccessful, underscoring a critical need to understand the factors governing their translational failure. These targets represent promising avenues for non-opioid pain therapies.</p> Methods <p>A systematic search (2014–2024) across PubMed, Embase, Cochrane Library, and Web of Science used terms: (“chronic pain” OR “neuropathic pain”) AND (“TRP channels” OR “TRPV1” OR “TRPA1” OR “Nav1.7”) AND (“analgesia” OR “drug development”). From 3,872 records, 2,905 remained after removing duplicates. After screening and full-text evaluation, 146 studies were included (89 preclinical, 42 clinical, 15 reviews) based on relevance, methodology, and outcome quality.</p> Results <p>Among the 146 included studies, preclinical evidence consistently supports TRPV1, TRPA1, and Nav1.7 as mechanistically valid pain targets. However, of the clinical trials reviewed, no TRPV1 antagonist has demonstrated sustained analgesic efficacy without dose-limiting side effects such as hyperthermia, and Nav1.7-selective compounds (e.g., PF-05089771, CNV1014802) have largely failed to replicate preclinical promise, with only vixotrigine (BIIB074) still in active Phase III evaluation. These findings underscore a substantial and persistent translational gap between preclinical validation and clinical success.</p> Conclusion <p>Despite significant clinical setbacks, TRPV1, TRPA1, and Nav1.7 retain mechanistic validity as non-opioid analgesic targets, provided that future development addresses species-specific differences, improves patient stratification, and employs state-dependent or pathway-specific modulation strategies.</p> Clinical Trial Registration <p>Not applicable (review article).</p>

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Emerging Ion Channel Targets in Chronic Pain: A Systematic Review of TRP Channels, Voltage-Gated Sodium Channels, and Other Novel Molecular Modulators

  • 期刊论文

  • 发表日期：

    2026年7月6日

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  • Olayemi Kamoru Wakeel,
  • Aremu Temitope Victor,
  • Ayodeji Folorunsho Ajayi,
  • Oyedayo Phillips Akano

摘要

Introduction

Chronic pain affects almost 20% of the global population, causing significant disability and diminished quality of life. Conventional treatments such as opioids and NSAIDs often fall short due to low effectiveness, side effects, and risk of dependency. Recent advances have identified novel molecular targets involved in pain signaling, including transient receptor potential (TRP) channels—TRPV1 and TRPA1—and voltage-gated sodium channels like Nav1.7. TRPV1 responds to unpleasant heat and inflammatory mediators, while TRPA1 is triggered by irritants and cold. Nav1.7, strongly linked to congenital pain disorders, plays a crucial role in nociceptive transmission though clinical validation of compounds targeting these channels has so far been largely unsuccessful, underscoring a critical need to understand the factors governing their translational failure. These targets represent promising avenues for non-opioid pain therapies.

Methods

A systematic search (2014–2024) across PubMed, Embase, Cochrane Library, and Web of Science used terms: (“chronic pain” OR “neuropathic pain”) AND (“TRP channels” OR “TRPV1” OR “TRPA1” OR “Nav1.7”) AND (“analgesia” OR “drug development”). From 3,872 records, 2,905 remained after removing duplicates. After screening and full-text evaluation, 146 studies were included (89 preclinical, 42 clinical, 15 reviews) based on relevance, methodology, and outcome quality.

Results

Among the 146 included studies, preclinical evidence consistently supports TRPV1, TRPA1, and Nav1.7 as mechanistically valid pain targets. However, of the clinical trials reviewed, no TRPV1 antagonist has demonstrated sustained analgesic efficacy without dose-limiting side effects such as hyperthermia, and Nav1.7-selective compounds (e.g., PF-05089771, CNV1014802) have largely failed to replicate preclinical promise, with only vixotrigine (BIIB074) still in active Phase III evaluation. These findings underscore a substantial and persistent translational gap between preclinical validation and clinical success.

Conclusion

Despite significant clinical setbacks, TRPV1, TRPA1, and Nav1.7 retain mechanistic validity as non-opioid analgesic targets, provided that future development addresses species-specific differences, improves patient stratification, and employs state-dependent or pathway-specific modulation strategies.

Clinical Trial Registration

Not applicable (review article).