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Review

Targeting Nav Channels for Pain Relief: Structural Insights and Therapeutic Opportunities

by
Yuzhen Xie
1,†,
Xiaoshuang Huang
1,†,
Fangzhou Lu
1,2 and
Jian Huang
1,*
1
Institute of Bio-Architecture and Bio-Interactions (IBABI), Shenzhen Medical Academy of Research and Translation (SMART), Shenzhen 518107, China
2
Westlake University, Hangzhou 310030, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2026, 27(3), 1180; https://doi.org/10.3390/ijms27031180
Submission received: 30 November 2025 / Revised: 15 January 2026 / Accepted: 16 January 2026 / Published: 23 January 2026
(This article belongs to the Special Issue Role of Ion Channels in Human Health and Diseases)
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Abstract

Pain is an unpleasant but essential sensory experience that serves as a protective mechanism, yet it can also manifest maladaptively in a wide range of pathological conditions. Current analgesic strategies rely heavily on opioid medications and non-steroidal anti-inflammatory drugs (NSAIDs); however, concerns regarding addiction, tolerance, and dose-limiting adverse effects highlight the urgent need for safer and more effective therapeutics. Voltage-gated sodium (Nav) channels, which govern the initiation and propagation of action potentials, have emerged as promising targets for mechanism-based analgesic development. In particular, the Nav1.7–Nav1.9 subtypes have attracted substantial interest owing to their enrichment in the peripheral nervous system—despite broader expression elsewhere—and their central roles in nociception, offering the potential for non-addictive, subtype-selective pain modulation. This review summarizes the physiological roles of these channels in nociception, examines how disease-associated mutations shape pain phenotypes, and highlights recent advances in drug discovery targeting Nav1.7 and Nav1.8. The recent FDA approval of VX-548 (suzetrigine), a first-in-class and highly selective Nav1.8 inhibitor, marks a major milestone that validates peripheral Nav channels as clinically actionable targets for analgesia. We also discuss the remaining challenges and emerging opportunities in the pursuit of next-generation, mechanism-informed analgesics.

1. Introduction

Pain is a major global health issue arising from diverse pathological processes [1]. It can be categorized by duration (acute or chronic) and by underlying mechanisms, including nociceptive, neuropathic, nociplastic, and mixed pain, as well as secondary pain syndromes associated with specific diseases [2,3,4]. Although multiple classes of analgesics, such as opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and various adjuvant agents, are clinically available, their utility is constrained by safety concerns, dependence liability, and insufficient efficacy in many patients [5,6]. These limitations highlight the urgent need for safer and more effective mechanism-based pain therapeutics.
Voltage-gated sodium (Nav) channels have emerged as promising molecular targets for developing non-addictive analgesics due to their crucial roles in the initiation and propagation of action potentials and in the regulation of nociceptor excitability [7]. Aberrent function or dysregulation of these channels can alter neuronal excitability and drive diverse disease phenotypes, including congenital insensitivity to pain and various forms of chronic pain [8]. In this review, we provide an overview of the functional and structural characteristics of the peripheral Nav1.7–Nav1.9 subtypes and summarize recent advances in the development of therapeutics targeting these channels for pain management.

2. Methodology

Search strategy: A comprehensive literature search was conducted in PubMed and Google Scholar using combinations of keywords including “voltage-gated sodium channel,” “pain,” “analgesic,” “structural basis,” “drug development,” and related synonyms. Searches were conducted up to November 2025.
Inclusion criteria: Studies were included if they (i) reported original experimental research, (ii) were directly relevant to pain mechanisms or analgesia involving Nav1.7–Nav1.9, and (iii) addressed the development, pharmacology, or structural characterization of therapeutics targeting these channels.
Exclusion criteria: Studies were excluded if they (i) were not published in English, (ii) were deemed irrelevant based on title and abstract screening, (iii) lacked assessable full-text data, or (iv) were not original research papers.

3. VGSC Family Overview

Nav channels are crucial for neuronal excitability and the propagation of action potentials [9]. In 1952, Hodgkin and Huxley first demonstrated the role of Nav channels in generating action potentials using the voltage clamp technique [10], laying the conceptual foundation for voltage-dependent sodium permeability well before the channel itself was characterized. Subsequent biochemical purification and molecular cloning efforts provided the first molecular insights into these channels [11]. Early structural insights were obtained using pore-blocking neurotoxins such as saxitoxin (STX) and tetrodotoxin (TTX) [12]. Catterall and colleagues later purified and functionally characterized Nav channels from mammalian brain membranes, defining their pharmacology and gating properties [12,13]. Soon after, Noda and Numa isolated the cDNA encoding the Nav channel from Electrophorus electricus electroplax, revealing its four-domain architecture and demonstrating that a single α-subunit is sufficient for sodium conductance upon expression in Xenopus oocytes [14,15].
Nav channels display a fourfold (pseudo-)symmetry around a central axis perpendicular to the membrane [16]. The α-subunit of eukaryotic Nav channels is a single polypeptide comprising four homologous repeats, each containing six transmembrane segments (S1–S6) (Figure 1A). S1–S4 in each repeat form voltage-sensing domains (VSDs), whereas S5–S6 from all repeats assemble into the central pore domain (PD) [17]. Most Nav channels adopt a domain-swapped architecture, in which each VSD interacts with the pore of the adjacent domain in a clockwise arrangement when viewed from the extracellular side [16]. Ion selectivity of the Nav1 family is conferred by the highly conserved Asp-Glu-Lys-Ala (DEKA) selectivity filter, with one residue contributed by each repeat [18].
Nav channels transition among three major voltage-dependent conformational states: resting, activated, and inactivated states (Figure 1B). Upon depolarization, outward movement of the S4 helices initiates pore opening and drives the rapid influx of Na+ ions. Within milliseconds, channels undergo fast inactivation mediated by the conserved Ile-Phe-Met (IFM) motif in the III–IV linker. The IFM motif binds to a hydrophobic receptor site between repeats III and IV, promoting S6 helix constriction and preventing further ion conduction [17]. Impaired or incomplete inactivation results in a persistent sodium current, which contributes to subthreshold excitability and supports repetitive firing in nociceptors and other excitable cells [19].
In humans, nine α-subunit isoforms (Nav1.1 to Nav1.9) and four auxiliary β-subunits (β1 to β4) constitute the Nav channel family. β subunits modulate channel gating, trafficking, and membrane localization. A classical framework for distinguishing Nav isoforms is their sensitivity to TTX, which is currently under clinical evaluation for cancer-related and chemotherapy-induced neuropathic pain [20]. Nav1.5, Nav1.8, and Nav1.9 are TTX-resistant isoforms, and accumulating evidence implicates them in the development and maintenance of neuropathic pain [16,20].
Nav isoforms exhibit highly distinct tissue-specific expression patterns. Nav1.1–Nav1.3 are predominantly expressed in the central nervous system (CNS), where they regulate neuronal excitability, and mutations in their corresponding genes are associated with epilepsy and other neurodevelopmental disorders [21,22]. Nav1.4 is the principal isoform in skeletal muscle, whereas Nav1.5 is the major isoform in cardiac myocytes. Nav1.6 is broadly distributed across both the CNS and peripheral nervous system (PNS). In contrast, Nav1.7–Nav1.9 are preferentially expressed in peripheral sensory neurons, particularly nociceptors (Figure 1C) [21]. Extensive evidence indicates that these peripheral isoforms are crucial for transmitting nociceptive signals from the periphery to the CNS, positioning them as key molecular targets for analgesic development.

4. Overview of Peripheral VGSC Isoforms and Nociception

Nociceptors are primary sensory neurons that detect noxious mechanical, thermal, or chemical stimuli and convey pain information to the CNS [2]. They are widely distributed throughout the body, including skin, joints, and organ walls. Nociception involves three key stages: transduction, where peripheral terminals of nociceptors convert harmful stimuli into electrical signals; transmission, during which action potentials propagate along the axon from the peripheral terminals toward the central terminals; and synaptic transmission, in which neurotransmitters are released in the dorsal horn of the spinal cord to activate CNS neurons. Nav channels are essential to each of these processes by mediating action potential initiation and propagation, thereby enabling nociceptors to encode and transmit pain information with high fidelity [23].
Nociceptors comprise two major fiber types: large myelinated Aδ fibers, which transmit sharp, well-localized pain, and unmyelinated C fibers, which convey slower, burning, or aching sensations. Single-cell RT-PCR analyses have demonstrated that the three peripheral Nav channel isoforms, Nav1.7–Nav1.9, are predominantly expressed in C fiber sensory neurons [24]. These channels display distinct yet complementary biophysical properties that collectively shape nociceptor excitability [25]. Accordingly, genetic mutations or altered expression of these channels can give rise to a range of pain disorders, underscoring their potential as therapeutic targets [26].
In addition to its prominent expression in C fibers, Nav1.7 is robustly localized to the nodes of Ranvier in a subpopulation of myelinated Aδ fibers [27], positioning it to influence both action potential initiation and propagation. Consistent with this distribution, Nav1.7 exhibits rapid activation and inactivation kinetics together with a slow onset of inactivation, enabling it to act as a threshold channel and facilitate action potential initiation in nociceptors [28,29]. By contrast, Nav1.8 activates at more depolarized membrane potentials and exhibits slower inactivation, contributing substantially to the action potential upstroke and supporting repetitive firing during sustained stimuli [30,31]. Nav1.9 produces a persistent, subthreshold sodium current that modulates resting membrane potential and overall neuronal excitability [32]. Together, these channels orchestrate the initiation and propagation of nociceptive signals in peripheral sensory neurons.
The following section examines the physiological and pathological roles of Nav1.7–Nav1.9, with particular emphasis on the functional consequences of disease-associated mutations, recent progress in isoform-selective drug development, and emerging therapeutic strategies.

5. Nav1.7: Pathophysiological Role and Structural Basis

5.1. Physiological Function and Disease Mutations

Nav1.7, encoded by SCN9A, is broadly expressed across the PNS and CNS, with particularly high enrichment in small-diameter dorsal root ganglia (DRG) neurons and sympathetic ganglia (Figure 2A) [27]. Within nociceptive pathways, Nav1.7 operates as a threshold channel that amplifies subthreshold depolarizations and supports action potential initiation at both peripheral and central terminals [33]. Dysregulation of Nav1.7 can therefore shift neuronal excitability into pathological ranges.
The clinical relevance of Nav1.7 is underscored by the striking genotype-phenotype correlations observed across inherited channelopathies. Gain-of-function (GOF) mutations drive hyperexcitability and give rise to three major syndromes. In inherited erythromelalgia (IEM), patients experience burning pain in the extremities, often associated with hyperpolarizing shifts in channel activation [29]. Paroxysmal extreme pain disorder (PEPD) is characterized by severe rectal, ocular, and submandibular pain and frequently results from impaired fast inactivation, often linked to mutations in the III-IV linker [34]. Small fiber neuropathy (SFN) presents with burning pain and autonomic dysfunction due to selective damage to unmyelinated C fibers and thinly myelinated Aδ fibers [35,36]. Nav1.7 variants associated with SFN typically impair slow inactivation, shift steady-state inactivation toward depolarized potentials, or generate enhanced resurgent currents, providing biophysical features that distinguish SFN from IEM and PEPD [35,37,38].
In contrast, loss-of-function (LOF) mutations in Nav1.7 produce a diametrically opposite phenotype. Biallelic LOF variants cause congenital insensitivity to pain (CIP), a condition characterized by a complete absence of pain perception despite preserved tactile sensation [23,39]. Electrophysiological studies demonstrate that CIP-associated nonsense mutations abolish Nav1.7–mediated currents, thereby eliminating its contribution to spike initiation in nociceptors [40]. However, studies in Nav1.7–null models have shown that the excitability of peripheral sensory neurons is preserved, suggesting that factors beyond impaired action potential generation may contribute to the analgesic phenotype. Potential explanations include alterations in opioid signaling and compensatory upregulation of interacting proteins such as other Nav subtypes and auxiliary subunits [41,42]. These findings imply that analgesia associated with Nav1.7 loss of function cannot be explained solely by reduced peripheral excitability. Instead, downstream pathways linked to Nav1.7 function, including opioid signaling, may represent alternative targets for pain modulation [43].
These GOF and LOF phenotypes establish Nav1.7 as a key molecular determinant of human pain sensitivity. A review published in 2020 mapped known pathogenic variants onto the Nav1.7 structure, providing a valuable framework linking structural elements to biophysical and clinical phenotypes [44].

5.2. Channel Modulators

Two main therapeutic strategies have been explored for targeting Nav1.7: pore blockers and gating-modifier toxins (GMTs). State-dependent pore blockers bind within the central cavity and preferentially interact with a specific functional state [45]. Despite the clinical success of state-dependent Nav channel inhibitors in epilepsy, analogous strategies for pain relief have faced challenges, primarily due to the high conservation of pore residues across Nav isoforms, which limits subtype selectivity [46]. Although clinical candidates such as PF-05089771 (Pfizer) and vixotrigine (Biogen) achieved high Nav1.7 selectivity in vitro, both were ultimately discontinued due to the lack of meaningful analgesic efficacy in clinical trials, with only modest pain reduction observed (Figure 2B and Table 1). More broadly, many Nav1.7–selective inhibitors have failed in clinical development owing to a combination of factors, including off-target effects leading to adverse events such as nausea and vomiting, inadequate potency in human nociceptors, and poor translation from rodent to human pain phenotypes [30]. Recent efforts have shifted toward identifying small molecules that exploit structural divergence in VSDs and cytoplasmic linkers to improve isoform selectivity [45,47].
GMTs, primarily venom-derived peptides, target VSDs and stabilize specific channel states. Depending on their mode of action, GMTs can either suppress hyperexcitability or trigger sustained channel activation [45]. Although many GMTs exhibit exceptional subtype selectivity for Nav1.7, their in vivo efficacy remains variable. For example, protoxin II (ProTx-II), isolated from the tarantula Thrixopelma pruriens, displays at least 100-fold selectivity for Nav1.7 over other isoforms but shows limited analgesic activity in vivo, likely due to restricted blood–brain barrier penetration and rapid systemic clearance (Figure 2C) [45].
Broad-spectrum Nav channel inhibitors, including lidocaine, mexiletine, and carbamazepine, remain clinically relevant but exhibit weak inhibitory potency and poor subtype selectivity [46,47]. While their precise mechanisms of action are not fully resolved, their proven efficacy in both preclinical and clinical settings supports the notion that appropriately tuned modulation of Nav activity can yield effective analgesia without necessitating complete channel blockade [46].
Collectively, these pharmacological and genetic insights illustrate how even subtle alterations in Nav1.7 function can profoundly influence nociceptor excitability and pain perception. The limited clinical success of existing inhibitors underscores the need for next-generation, subtype-selective modulators guided by structural and biophysical understanding. Recent advances in cryo-electron microscopy (cryo-EM) and computational modeling have begun to elucidate the molecular determinants underlying Nav1.7 gating, pharmacology, and disease-associated mutations, offering a powerful framework for structure-guided drug discovery in pain therapeutics.

5.3. Structural Insights into Drug Targeting and Remaining Challenges

The first cryo-EM structure of human Nav1.7, a toxin-bound E406K variant, was reported by Shen et al. (2019), providing the foundational model of the channel’s architecture [100]. Subsequent studies improved the resolution of the wild-type channel to 2.2 Å, allowing detailed visualization of gating helices, voltage sensors, and drug-binding pockets (Figure 2A) [101]. Comparative analysis between toxin-bound and apo structures revealed a gating-linked α→π helical transition in S6IV, which reshapes the pore geometry and influences the conformational states accessible to small-molecule modulators (Figure 2D).
These structural advances have delineated multiple ligand-binding sites on Nav1.7, including: Site E, the extracellular peptide toxin interface; Site S, the selectivity filter recognized by guanidinium toxins such as TTX/STX; Site C, the central cavity for diverse small molecules; Site F, lipid-facing fenestrations accessed by compounds like vixotrigine; Site G, the intracellular gate that modulates state-dependent block; Site BIG, a pocket beneath the intracellular gate; and Site I, an inactivation-motif docking site targeted by cannabidiol (Figure 2E) [46,47]. The integration of these high-resolution structural maps with disease-related mutations enables the 3D annotation of pharmacologically relevant residues and supports structure-guided drug design. Future cryo-EM structures of Nav1.7 variants associated with pain disorders may further reveal how pathogenic substitutions perturb gating properties, destabilize specific functional states, or alter ligand selectivity, thereby refining opportunities for selective modulator design [47,100,102].
Despite strong genetic evidence supporting Nav1.7 as a pain target, efforts to develop clinically effective analgesics have repeatedly fallen short. Small-molecule inhibitors such as XEN402 (Funapide) exhibited state-dependent block and promising in vitro selectivity but showed limited efficacy in clinical trials, likely due to pharmacokinetic limitations, and development was discontinued in 2020 [67]. Moreover, Nav1.7 expression extends beyond nociceptive neurons, and it is also found in olfactory neurons and pancreatic β-cells, where it contributes to olfactory signaling and glucose homeostasis [103]. Consequently, systemic inhibition risks metabolic and sensory side effects that complicate dose optimization. Achieving the right therapeutic window is further constrained by the physiological role of Nav1.7, as human genetic data suggest that at least ~50% inhibition can produce analgesia without compromising protective pain sensation, whereas complete blockade mimics congenital insensitivity to pain [30].
Current efforts are moving beyond conventional pore blockers toward state-dependent gating modifiers and structure-guided allosteric inhibitors that leverage conformational plasticity revealed by recent cryo-EM studies (Figure 3) [46,47]. Alternative strategies such as gene therapy and monoclonal antibodies targeting voltage-sensing domains are emerging as promising directions for achieving isoform-selective modulation [45,104]. A major barrier remains the translation gap between preclinical models and human pain perception, complicated by differences in pain etiology (neuropathic vs. chronic), species-specific gating properties, and limited demographic diversity in clinical trials [105]. Despite this, as observed in CIP, loss of Nav1.7 expression might affect the endogenous opioid system, providing a possible explanation for the limited efficacy of selective Nav1.7 modulators and motivating alternative strategies such as targeting downstream effectors or employing synergistic therapeutic approaches [106]. Additionally, Nav1.7 is also dynamically regulated by inflammatory signaling. Mediators such as protein kinase C (PKC) can elevate Nav1.7 expression and alter its gating properties in nociceptive neurons during chronic inflammation [25,29]. Such regulation highlights Nav1.7 as an important mediator of inflammatory and neuropathic pain pathways.
Looking forward, the integration of structural biology with molecular dynamics simulations and large-scale computational screening is poised to accelerate the discovery of selective and non-addictive Nav1.7 modulators. Yet, despite its compelling genetic validation, converting structural insights into effective clinical therapies remains a major challenge that requires multidisciplinary collaboration across structural biology, pharmacology, and neurophysiology.

6. Nav1.8

6.1. Physiological Function, Disease Mutations, and Channel Modulators

SCN10A encodes Nav1.8, which is expressed predominantly in peripheral sensory neurons, particularly DRG neurons, with relatively low expression in most other tissues and regions [107]. Nav1.8 generates a TTX-resistant current and is considered a major contributor to the rising phase of the action potential in nociceptive neurons under depolarized conditions, as well as to repetitive firing during nociceptive signaling [31]. Additionally, previous studies have shown that human Nav1.8 exhibits a substantial persistent current that contributes to the regulation of repetitive firing [108]. These electrophysiological features establish Nav1.8 as an important regulator in chronic and neuropathic pain [30,31].
Genetic analyses have identified several GOF mutations in Nav1.8 that enhance neuronal excitability, while LOF variants have not been clearly documented. However, some polymorphisms are associated with reduced pain sensitivity [9,23]. GOF mutations generally accelerate recovery from inactivation or shift activation thresholds in the hyperexcitable direction, promoting increased firing of nociceptive neurons. These functional alterations are linked to pain syndromes such as SFN and other neuropathic conditions [109,110,111]. Beyond genetic variants, inflammatory mediators and tissue injury can also modulate Nav1.8 expression and gating properties, providing alternative mechanisms through which the channel contributes to pathological pain [29].
Nav1.8 is also expressed in visceral sensory pathways, with emerging evidence implicating its involvement in visceral pain disorders, including inflammatory bowel disease (IBD). Certain Nav1.8 variants correlate with altered visceral pain sensitivity, though the mechanistic basis remains to be clarified [112,113]. These findings highlight the broad physiological relevance of Nav1.8 across peripheral and visceral nociceptive pathways.
Therapeutic efforts targeting Nav1.8 have faced challenges due to the difficulty of achieving selective modulation with minimal side effects. A major breakthrough came with VX-548 (suzetrigine), optimized from VX-150, a highly selective Nav1.8 inhibitor with remarkable isoform specificity (>30,000-fold) and favorable pharmacokinetic properties. Clinical studies have demonstrated its efficacy in acute postoperative pain, providing opioid-comparable analgesia without addictive potential or significant CNS adverse effects [114].
Using 10 nM VX-548 (IC50 < 1 nM), Stewart et al. demonstrated that VX-548 significantly reduced both the peak amplitude and the shoulder of action potentials in DRG neurons, consistent with previous findings that Nav1.8 contributes to the later rising phase of the action potential [115]. They further observed that repetitive firing during sustained depolarization was attenuated, but not fully eliminated, by VX-548. This incomplete suppression may reflect the high expression of Nav1.8 in DRG neurons or compensatory activity mediated by Nav1.7 [115]. Collectively, these findings offer a mechanistic basis for the limited analgesic efficacy observed in a subset of clinical cases.
This FDA approval of VX-548 marks a significant milestone in Nav channel-targeted analgesia, positioning Nav1.8 as a clinically validated molecular target for pain management. While current evidence supports its role primarily in acute and neuropathic pain, further investigations are needed to explore efficacy across diverse pain conditions and patient populations, including special clinical settings such as pregnancy [6].
In summary, the unique biophysical properties and critical roles of Nav1.8 in nociceptive signaling underscore its importance in pain pathophysiology and therapeutic intervention. The success of selective Nav1.8 inhibitors opens a new avenue for developing safer, non-opioid analgesics tailored to modulate peripheral neuronal excitability in various pain disorders.

6.2. Structural Insights into Drug Targeting

The first high-resolution cryo-EM structures of human Nav1.8 in both apo and A-803467-bound state were resolved in 2022 by Huang et al., with overall resolutions of 2.7–3.2 Å (Figure 4A). This study revealed that variations at the VSDI–PD interface contribute to the high voltage requirement for activation unique to Nav1.8 and identified key residues governing the selectivity of A-803467 (Figure 4B). In addition, the authors proposed a potential functional role for the extracellular loops, suggesting new opportunities for future drug design [116]. Together, these findings provide important structural insights for structure-guided discovery of Nav1.8-targeted analgesics.
Building on these results, Wang et al. (2024) systematically mapped the druggable sites on Nav1.8 using structural and computational analyses [114]. Four major sites were highlighted: Site E, the extracellular loop region above the pore domain targeted by conotoxins; Site C, the central pore cavity accommodating small-molecule inhibitors; Site V2E, an extracellular pocket in VSDII that recognizes both small molecules and peptide toxins; and Site BIG, a broader intracellular interface, serves as a binding site for non-selective analgesics [114,117].
More recently, Neumann et al. (2025) resolved the cryo-EM structure of human Nav1.8 bound to Protoxin-I, a tarantula-derived peptide that shifts channel activation toward more depolarized potentials (Figure 4C) [118]. This study not only elucidated the molecular interaction between Protoxin-I and VSDII but also emphasized the value of venom-derived peptides as templates for selective modulator development.
A similar binding site has been proposed for VX-548. Although the structure of VX-548-bound Nav1.8 has not yet been resolved, its binding site has been inferred through domain-swap experiments between Nav1.8 and Nav1.2. VX-548 is thought to stabilize Nav1.8 in the closed state; however, sufficient depolarization can promote dissociation of the compound [119]. These studies suggest that the KKGS sequence within VSDII confers isoform selectivity, suggesting a mechanism that offers a blueprint for designing future Nav1.8-selective modulators (Figure 4D–F) [48].
In summary, advances in cryo-EM-based structural biology have substantially accelerated progress in Nav1.8 research, enabling visualization of inhibitor binding sites and conformational dynamics at near-atomic resolution. While bridging the gap between preclinical efficacy and clinical translation remains a challenge, the FDA approval of VX-548 (suzetrigine) underscores the therapeutic potential of Nav1.8 as a validated target for pain relief and highlights the power of structure-guided drug discovery in developing safer, non-opioid analgesics.

7. Nav1.9

7.1. Physiological Function, Disease Mutations, and Inflammatory Pain

Compared with Nav1.7 and Nav1.8, both of which have been extensively studied as therapeutic targets, research on Nav1.9 has progressed more slowly, largely due to difficulties in isolating the channel from native neurons and establishing reliable heterologous expression systems. Recent advances, including the robust expression platform reported by Theys et al., have begun to overcome these technical barriers and allow more systematic functional and pharmacological characterization of this channel [32].
Nav1.9, encoded by SCN11A, is predominantly expressed in nociceptive neurons of the PNS, especially DRG neurons, where it contributes to pain signaling [120,121]. Although several studies mention the expression of Nav1.9 in the CNS (such as the spinal cord, hypothalamus), its precise cellular and subcellular distribution remains incompletely defined [122,123]. This channel activates at relatively negative membrane potentials and produces a TTX-resistant sodium current with ultraslow gating kinetics, resulting in a persistent current following activation [8]. These properties generate a substantial window current within the physiological voltage range, allowing Nav1.9 to amplify weak depolarizing inputs and maintain subthreshold depolarization [8,32]. Rather than driving the action potential upstroke, Nav1.9 regulates excitability by lowering the action potential threshold and facilitating repetitive firing in nociceptors [124].
SCN11A mutations are associated with clinical phenotypes ranging from CIP to episodic pain syndromes, SFN, and other painful neuropathies [125]. Unlike Nav1.7, where GOF mutations consistently cause hyperexcitability and LOF mutations cause hypoexcitability, Nav1.9 mutations present a more complex relationship between channel activity and clinical phenotype. Many pathogenic variants induce hyperpolarizing shifts in activation and expand the window current, consistent with GOF mechanisms. Yet patients may paradoxically experience pain insensitivity [126]. This counterintuitive phenotype can potentially be explained by a U-shaped model in which moderate depolarization increases neuronal firing, but excessive depolarization inactivates other peripheral Nav channels, prevents action potential generation, and produces hypoexcitability [125,126].
Beyond genetic variants, Nav1.9 is strongly regulated by inflammatory mediators, positioning the channel as a key contributor to inflammatory pain. Molecules such as Bradykinin, ATP, histamine, prostaglandin-E2, and norepinephrine potentiate Nav1.9 activity [127,128]. These signaling pathways act synergistically through G-protein-dependent mechanisms, increasing open probability and mean open time, and may engage downstream kinases such as PKC to further influence gating [129]. These mechanisms amplify Nav1.9 function during inflammation, promoting persistent nociceptor hyperexcitability.

7.2. Development of Channel Modulators Targeting Nav1.9

Despite strong evidence supporting the role of Nav1.9 in nociception and inflammatory pain, the development of subtype-specific modulators has proven exceptionally challenging. Major obstacles include the channel’s complex and incompletely defined physiological functions, longstanding difficulties in achieving robust recombinant expression. To date, no high-resolution structural information is available for Nav1.9. Consequently, structural and functional insights have largely relied on homology modeling based on other Nav channel isoforms, as well as the use of chimeric constructs to study gating properties and disease-associated dysfunction [32]. As a result, progress in identifying Nav1.9-selective small molecules has been slow. Most reported compounds that modulate Nav1.9 activity lack subtype specificity and often exhibit concurrent inhibition of Nav1.7 and Nav1.8, leading to broad-spectrum effects across multiple pain modalities (Table 1) [68].
In the future, alternative therapeutic strategies may emerge by targeting the regulatory proteins and signaling pathways that modulate Nav1.9 activity under inflammatory conditions. Intervening in these upstream or downstream effectors could provide an alternative route for achieving functional specificity even in the absence of direct, selective Nav1.9 inhibitors.

8. Future Directions and Limitations

8.1. Challenges and Opportunities

Earlier efforts on Nav1.7 ultimately yielded disappointing outcomes in clinical trials, and the physiological and pharmacological properties of Nav1.9 remain only partially understood. Consequently, attention has increasingly shifted toward Nav1.8. The recent approval of VX-548 is particularly encouraging, as its development from gene identification and functional characterization to recognition as a validated drug target illustrates a successful, decades-long trajectory that provides a framework for developing novel, effective, and durable non-opioid analgesics (Figure 5).
Despite this progress, many investigational Nav-targeting drugs have failed during development. One major challenge is the high degree of structural conservation among Nav channel subtypes, particularly within the pore domain, which limits isoform selectivity and increases the risk of off-target effects [100,116]. The broad distribution of Nav1.7–1.9 might hinder selectivity, which can also cause side effects. In addition, mechanistic insights from Nav1.7 loss-of-function models indicate that inhibition of Nav1.7 alone may be insufficient to produce robust analgesia, as other downstream signaling pathways might also be involved in pain insensitivity. Although recent advances in experiments have substantially improved our understanding of pain mechanisms and drug actions, a major gap remains between in vitro observations and clinical performance. A key challenge is the complexity of the in vivo environment, where Nav channel dysfunction is influenced not only by changes in channel gating but also by transcriptional regulation, membrane trafficking, auxiliary protein interactions, and post-translational modifications [130]. A deeper characterization of these regulators may reveal new intervention points within peripheral pain pathways and guide future target discovery. External factors such as diet, concomitant medications, and metabolic variability can also affect drug efficacy and should be systematically addressed in clinical trial design. Ensuring demographic diversity across age, sex, race, and comorbid conditions is essential for accurately evaluating both analgesic responses and safety profiles.
The clinical success of VX-548 provides compelling proof of concept for non-opioid analgesics in the treatment of acute pain, demonstrating that effective analgesia can be achieved through peripheral Nav inhibition while minimizing opioid-associated adverse effects. Peripherally restricted and subtype-selective Nav inhibitors are particularly well suited for acute pain management, where rapid onset and short-term efficacy are desired, although long-term safety and effectiveness warrant careful evaluation [131].
By contrast, chronic pain presents distinct therapeutic challenges that require sustained modulation of nociceptor activity. Rather than targeting a single Nav subtype, further drug development may benefit from broader or combinatorial modulation of Nav1.7–Nav1.9 to more effectively suppress pathological excitability while minimizing CNS involvement. In addition, combination therapies that integrate Nav-targeting agents with opioids or downstream modulators of nociceptor signaling may enhance analgesic efficacy at lower doses, thereby reducing the risk of central adverse effects such as tolerance and dependence [132]. Emerging strategies, including gene therapy strategies to selectively silence Nav1.8-expressing DRG neurons and peptide-based therapeutics derived from venom toxins, represent promising avenues for achieving durable and mechanism-informed analgesia [70,133,134].
Together, these advances highlight both the challenges and substantial opportunities that lie ahead. As our understanding of peripheral Nav channel regulation deepens and the intervention of novel therapeutics, next-generation targeted analgesics may hopefully bridge the longstanding gap between mechanistic insights and effective clinical pain relief.

8.2. Limitations of This Review

This review focuses on Nav1.7–Nav1.9 as specific molecular targets for pain relief, with an emphasis on improving drug efficacy and long-term sustainability. General analgesics that modulate Nav channels in a non-selective manner are acknowledged as alternative therapeutics, whereas their MOA and signaling pathways fall beyond the scope of this review. Given the extensive efforts in this field, the most recent drug candidates or unpublished developments may not be fully captured. In addition, emerging therapeutics, including peptide-based and nucleic acid-based sodium channel modulators, are not discussed in detail and warrant further consideration in future studies.

9. Conclusions

Peripheral voltage-gated sodium channels Nav1.7–Nav1.9 are central regulators of nociception and represent critical molecular targets for the development of non-opioid analgesics, as demonstrated by converging genetic, electrophysiological and pharmacological studies. The recent clinical approval of the Nav1.8-selective inhibitor VX-548 for acute pain provides clinical validation for peripheral Nav targeting and highlights the therapeutic potential of Nav1.7–Nav1.9 in pain management. Advances in cryo-EM have enabled high-resolution structural characterization of Nav1.7 and Nav1.8, supporting structure-guided drug discovery. Future progress in Nav-targeted analgesics will benefit from integrating structural, genetic, and physiological insights with a deeper understanding of the downstream pathways and compensatory mechanisms triggered by Nav channel dysfunction.

Author Contributions

J.H. conceived the project. Y.X., X.H., F.L. and J.H. prepared the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China, grant number 32501082, and the start-up funding from Shenzhen Medical Academy of Research and Translation (SMART), grant number 40108-13010800724.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

ATFB10Familial atrial fibrillation, type 10
ATRST1Atrial standstill, type 1
BFIS3Benign familial infantile seizures, type 3
BRGDA1Brugada syndrome, type 1
CIPCongenital insensitivity to pain
CIPNChemotherapy-induced peripheral neuropathy
CMS16Congenital myasthenic syndrome, type 16
CMD1EDilated cardiomyopathy, type 1E
CNSCentral nervous system
CPECryptogenic partial epilepsy
DEKAAsp–Glu–Lys–Ala
DRGDorsal root ganglia
DSDravet syndrome
EIEE6Epileptic encephalopathy, early infantile, 6
EIEE11Epileptic encephalopathy, early infantile, 11
EIEE13Epileptic encephalopathy, early infantile, 13
FEBFebrile seizures
FEB3AFamilial febrile seizures, type 3A
FEPS3Familial episodic pain syndrome, type 3
FHM3Familial hemiplegic migraine, type 3
FDAFood and Drug Administration
GEFS+2Generalized epilepsy with febrile seizures plus 2
GOFGain-of-function
GMTsGating-modifier toxins
HSAN7Hereditary sensory and autonomic neuropathy, type 7
HOKPP2Periodic paralysis, hypokalemic, type 2
HYPPPeriodic paralysis, hyperkalemic
IBDInflammatory bowel disease
IEMInherited erythromelalgia
ICEGTCIntractable childhood epilepsy with generalized tonic–clonic seizures
IFMIle–Phe–Met
IVIntravenous
LQT3Long QT syndrome, type 3
LOFLoss-of-function
MEPPCMultifocal ectopic Purkinje-related premature contraction
MYOSCN4AMyotonia SCN4A-related
NDANew drug application
NMDA receptorN-methyl-D-aspartate receptor
NSAIDsNon-steroidal anti-inflammatory drugs
NKPPPeriodic paralysis, normokalemic
PDPore domain
PEPDParoxysmal extreme pain disorder
PFHB1AProgressive familial heart block, type 1A
PHNPostherpetic neuralgia
PNAPeptide nucleic acid
PMCParamyotonia congenita of von Eulenburg
PKCProtein kinase C
PNSPeripheral nervous system
ProTx-IIProtoxin II
SFNSmall fiber neuropathy
SIDSSudden infant death syndrome
SSS1Sick sinus syndrome, type 1
STXSaxitoxin
TTXTetrodotoxin
VF1Familial paroxysmal ventricular fibrillation, type 1
VGSCVoltage-gated sodium channel
VSDVoltage-sensing domain

References

  1. Kumar, K.H.; Elavarasi, P. Definition of pain and classification of pain disorders. J. Adv. Clin. Res. Insights 2016, 3, 87–90. [Google Scholar] [CrossRef]
  2. Świeboda, P.; Filip, R.; Prystupa, A.; Drozd, M. Assessment of pain: Types, mechanism and treatment. Ann. Agric. Environ. Med. 2013, 1, 2–7. [Google Scholar]
  3. Cao, B.; Xu, Q.; Shi, Y.; Zhao, R.; Li, H.; Zheng, J.; Liu, F.; Wan, Y.; Wei, B. Pathology of pain and its implications for therapeutic interventions. Signal Transduct. Target. Ther. 2024, 9, 155. [Google Scholar] [CrossRef]
  4. Nijs, J.; De Baets, L.; Hodges, P. Phenotyping nociceptive, neuropathic, and nociplastic pain: Who, how, & why? Braz. J. Phys. Ther. 2023, 27, 100537. [Google Scholar] [CrossRef]
  5. Alorfi, N.M. Pharmacological Methods of Pain Management: Narrative Review of Medication Used. Int. J. Gen. Med. 2023, 16, 3247–3256. [Google Scholar] [CrossRef] [PubMed]
  6. Hang Kong, A.Y.; Tan, H.S.; Habib, A.S. VX-548 in the treatment of acute pain. Pain. Manag. 2024, 14, 477–486. [Google Scholar] [CrossRef]
  7. Wang, J.; Doan, L.V. Clinical pain management: Current practice and recent innovations in research. Cell Rep. Med. 2024, 5, 101786. [Google Scholar] [CrossRef] [PubMed]
  8. Bennett, D.L.; Clark, A.J.; Huang, J.; Waxman, S.G.; Dib-Hajj, S.D. The Role of Voltage-Gated Sodium Channels in Pain Signaling. Physiol. Rev. 2019, 99, 1079–1151. [Google Scholar] [CrossRef] [PubMed]
  9. Chen, R.; Liu, Y.; Qian, L.; Yi, M.; Yin, H.; Wang, S.; Xiang, B. Sodium channels as a new target for pain treatment. Front. Pharmacol. 2025, 16, 1573254. [Google Scholar] [CrossRef]
  10. Hodgkin, A.L.; Huxley, A.F. A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. 1952, 117, 500–544. [Google Scholar] [CrossRef]
  11. Catterall, W.A. Ion Channel Voltage Sensors: Structure, Function, and Pathophysiology. Neuron 2010, 67, 915–928. [Google Scholar] [CrossRef]
  12. Hartshorne, R.P.; Catterall, W.A. Purification of the saxitoxin receptor of the sodium channel from rat brain. Proc. Natl. Acad. Sci. USA 1981, 78, 4620–4624. [Google Scholar] [CrossRef] [PubMed]
  13. Catterall, W.A. Neurotoxins that Act on Voltage-Sensitive Sodium Channels in Excitable Membranes. Annu. Rev. Pharmacol. Toxicol. 1980, 20, 15–43. [Google Scholar] [CrossRef]
  14. Noda, M.; Shimizu, S.; Tanabe, T.; Takai, T.; Kayano, T.; Ikeda, T.; Takahashi, H.; Nakayama, H.; Kanaoka, Y.; Minaminot, N.; et al. Primary structure of Electrophorus electricus sodium channel deduced from eDNA sequence. Nature 1984, 312, 121–127. [Google Scholar] [CrossRef] [PubMed]
  15. Noda, M.; Numa, S. Structure and Function of Sodium Channel. J. Recept. Res. 1987, 7, 467–497. [Google Scholar] [CrossRef] [PubMed]
  16. Huang, J.; Pan, X.; Yan, N. Structural biology and molecular pharmacology of voltage-gated ion channels. Nat. Rev. Mol. Cell Biol. 2024, 25, 904–925, Erratum in Nat. Rev. Mol. Cell Biol. 2024, 25, 947. [Google Scholar] [CrossRef]
  17. Payandeh, J.; Scheuer, T.; Zheng, N.; Catterall, W.A. The crystal structure of a voltage-gated sodium channel. Nature 2011, 475, 353–358. [Google Scholar] [CrossRef]
  18. Favre, I.; Moczydlowski, E.; Schild, L. On the structural basis for ionic selectivity among Na+, K+, and Ca2+ in the voltage-gated sodium channel. Biophys. J. 1996, 71, 3110–3125. [Google Scholar] [CrossRef]
  19. Fouda, M.A.; Ghovanloo, M.; Ruben, P.C. Late sodium current: Incomplete inactivation triggers seizures, myotonias, arrhythmias, and pain syndromes. J. Physiol. 2022, 600, 2835–2851. [Google Scholar] [CrossRef]
  20. González-Cano, R.; Ruiz-Cantero, M.C.; Santos-Caballero, M.; Gómez-Navas, C.; Tejada, M.Á.; Nieto, F.R. Tetrodotoxin, a Potential Drug for Neuropathic and Cancer Pain Relief? Toxins 2021, 13, 483. [Google Scholar] [CrossRef]
  21. Jiang, D.; Zhang, J.; Xia, Z. Structural Advances in Voltage-Gated Sodium Channels. Front. Pharmacol. 2022, 13, 908867. [Google Scholar] [CrossRef] [PubMed]
  22. Wang, J.; Ou, S.-W.; Wang, Y.-J. Distribution and function of voltage-gated sodium channels in the nervous system. Channels 2017, 11, 534–554. [Google Scholar] [CrossRef]
  23. Goodwin, G.; McMahon, S.B. The physiological function of different voltage-gated sodium channels in pain. Nat. Rev. Neurosci. 2021, 22, 263–274. [Google Scholar] [CrossRef]
  24. Ho, C.; O’Leary, M.E. Single-cell analysis of sodium channel expression in dorsal root ganglion neurons. Mol. Cell. Neurosci. 2011, 46, 159–166. [Google Scholar] [CrossRef]
  25. Dib-Hajj, S.D.; Cummins, T.R.; Black, J.A.; Waxman, S.G. Sodium Channels in Normal and Pathological Pain. Annu. Rev. Neurosci. 2010, 33, 325–347. [Google Scholar] [CrossRef]
  26. Strickland, I.T.; Martindale, J.C.; Woodhams, P.L.; Reeve, A.J.; Chessell, I.P.; McQueen, D.S. Changes in the expression of NaV 1.7, NaV 1.8 and NaV 1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur. J. Pain 2008, 12, 564–572. [Google Scholar] [CrossRef]
  27. Black, J.A.; Frézel, N.; Dib-Hajj, S.D.; Waxman, S.G. Expression of Nav1.7 in DRG Neurons Extends from Peripheral Terminals in the Skin to Central Preterminal Branches and Terminals in the Dorsal Horn. Mol. Pain 2012, 8, 82. [Google Scholar] [CrossRef] [PubMed]
  28. Ma, R.S.Y.; Kayani, K.; Oshodi, D.W.; Whyte Oshodi, A.; Nachiappan, N.; Gnanarajah, S.; Mohammed, R. Voltage gated sodium channels as therapeutic targets for chronic pain. J. Pain Res. 2019, 12, 2709–2722. [Google Scholar] [CrossRef]
  29. Cummins, T.R.; Sheets, P.L.; Waxman, S.G. The roles of sodium channels in nociception: Implications for mechanisms of pain. Pain 2007, 131, 243–257. [Google Scholar] [CrossRef] [PubMed]
  30. Alsaloum, M.; Higerd, G.P.; Effraim, P.R.; Waxman, S.G. Status of peripheral sodium channel blockers for non-addictive pain treatment. Nat. Rev. Neurol. 2020, 16, 689–705. [Google Scholar] [CrossRef]
  31. Heinle, J.W.; Dalessio, S.; Janicki, P.; Ouyang, A.; Vrana, K.E.; Ruiz-Velasco, V.; Coates, M.D. Insights into the voltage-gated sodium channel, NaV1.8, and its role in visceral pain perception. Front. Pharmacol. 2024, 15, 1398409. [Google Scholar] [CrossRef]
  32. Theys, M.; De Waele, J.; Garud, S.; Willegems, K.; Van Petegem, F.; Bosmans, F. A robust expression system reveals distinct gating mechanisms and calmodulin regulation of NaV 1.9 channels. Sci. Adv. 2025, 11, eadt9799. [Google Scholar] [CrossRef]
  33. Alexandrou, A.J.; Brown, A.R.; Chapman, M.L.; Estacion, M.; Turner, J.; Mis, M.A.; Wilbrey, A.; Payne, E.C.; Gutteridge, A.; Cox, P.J.; et al. Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release. PLoS ONE 2016, 11, e0152405. [Google Scholar] [CrossRef] [PubMed]
  34. Fertleman, C.R.; Baker, M.D.; Parker, K.A.; Moffatt, S.; Elmslie, F.V.; Abrahamsen, B.; Ostman, J.; Klugbauer, N.; Wood, J.N.; Gardiner, R.M.; et al. SCN9A Mutations in Paroxysmal Extreme Pain Disorder: Allelic Variants Underlie Distinct Channel Defects and Phenotypes. Neuron 2006, 52, 767–774. [Google Scholar] [CrossRef] [PubMed]
  35. Lee, S.; Hoeijmakers, J.G.J.; Faber, C.G.; Merkies, I.S.J.; Lauria, G.; Waxman, S.G. The small fiber neuropathy NaV1.7 I228M mutation: Impaired neurite integrity via bioenergetic and mitotoxic mechanisms, and protection by dexpramipexole. J. Neurophysiol. 2020, 123, 645–657. [Google Scholar] [CrossRef] [PubMed]
  36. Hoeijmakers, J.G.J.; Han, C.; Merkies, I.S.J.; Macala, L.J.; Lauria, G.; Gerrits, M.M.; Dib-Hajj, S.D.; Faber, C.G.; Waxman, S.G. Small nerve fibres, small hands and small feet: A new syndrome of pain, dysautonomia and acromesomelia in a kindred with a novel NaV1.7 mutation. Brain 2012, 135, 345–358. [Google Scholar] [CrossRef]
  37. Faber, C.G.; Hoeijmakers, J.G.J.; Ahn, H.; Cheng, X.; Han, C.; Choi, J.; Estacion, M.; Lauria, G.; Vanhoutte, E.K.; Gerrits, M.M.; et al. Gain of function Nav1.7 mutations in idiopathic small fiber neuropathy. Ann. Neurol. 2012, 71, 26–39. [Google Scholar] [CrossRef]
  38. Labau, J.I.R.; Estacion, M.; Tanaka, B.S.; De Greef, B.T.A.; Hoeijmakers, J.G.J.; Geerts, M.; Gerrits, M.M.; Smeets, H.J.M.; Faber, C.G.; Merkies, I.S.J.; et al. Differential effect of lacosamide on Nav1.7 variants from responsive and non-responsive patients with small fibre neuropathy. Brain 2020, 143, 771–782. [Google Scholar] [CrossRef]
  39. Emery, E.C.; Luiz, A.P.; Wood, J.N. Nav 1.7 and other voltage-gated sodium channels as drug targets for pain relief. Expert Opin. Ther. Targets 2016, 20, 975–983. [Google Scholar] [CrossRef]
  40. Cox, J.J.; Reimann, F.; Nicholas, A.K.; Thornton, G.; Roberts, E.; Springell, K.; Karbani, G.; Jafri, H.; Mannan, J.; Raashid, Y.; et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 2006, 444, 894–898. [Google Scholar] [CrossRef]
  41. MacDonald, D.I.; Sikandar, S.; Weiss, J.; Pyrski, M.; Luiz, A.P.; Millet, Q.; Emery, E.C.; Mancini, F.; Iannetti, G.D.; Alles, S.R.A.; et al. A central mechanism of analgesia in mice and humans lacking the sodium channel NaV1.7. Neuron 2021, 109, 1497–1512.e6. [Google Scholar] [CrossRef]
  42. Pereira, V.; Millet, Q.; Aramburu, J.; Lopez-Rodriguez, C.; Gaveriaux-Ruff, C.; Wood, J.N. Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors. Wellcome Open Res. 2018, 3, 101. [Google Scholar] [CrossRef]
  43. Iseppon, F.; Kanellopoulos, A.H.; Tian, N.; Zhou, J.; Caan, G.; Chiozzi, R.; Thalassinos, K.; Çubuk, C.; Lewis, M.J.; Cox, J.J.; et al. Sodium channels Nav1.7, Nav1.8 and pain; two distinct mechanisms for Nav1.7 null analgesia. Neurobiol. Pain 2024, 16, 100168. [Google Scholar] [CrossRef]
  44. Baker, M.D.; Nassar, M.A. Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels. Pflüg. Arch. Eur. J. Physiol. 2020, 472, 865–880. [Google Scholar] [CrossRef] [PubMed]
  45. Eagles, D.A.; Chow, C.Y.; King, G.F. Fifteen years of NaV 1.7 channels as an analgesic target: Why has excellent in vitro pharmacology not translated into in vivo analgesic efficacy? Br. J. Pharmacol. 2022, 179, 3592–3611. [Google Scholar] [CrossRef] [PubMed]
  46. Kitano, Y.; Shinozuka, T. Inhibition of Nav1.7: The possibility of ideal analgesics. RSC Med. Chem. 2022, 13, 895–920. [Google Scholar] [CrossRef]
  47. Wu, Q.; Huang, J.; Fan, X.; Wang, K.; Jin, X.; Huang, G.; Li, J.; Pan, X.; Yan, N. Structural mapping of Nav1.7 antagonists. Nat. Commun. 2023, 14, 3224. [Google Scholar] [CrossRef] [PubMed]
  48. Osteen, J.D.; Immani, S.; Tapley, T.L.; Indersmitten, T.; Hurst, N.W.; Healey, T.; Aertgeerts, K.; Negulescu, P.A.; Lechner, S.M. Pharmacology and Mechanism of Action of Suzetrigine, a Potent and Selective NaV1.8 Pain Signal Inhibitor for the Treatment of Moderate to Severe Pain. Pain Ther. 2025, 14, 655–674. [Google Scholar] [CrossRef]
  49. Bertoch, T.; D’Aunno, D.; McCoun, J.; Solanki, D.; Taber, L.; Urban, J.; Oswald, J.; Swisher, M.W.; Tian, S.; Miao, X.; et al. Suzetrigine, a Nonopioid Na V 1.8 Inhibitor for Treatment of Moderate-to-severe Acute Pain: Two Phase 3 Randomized Clinical Trials. Anesthesiology 2025, 142, 1085–1099. [Google Scholar] [CrossRef]
  50. Jones, J.; Correll, D.J.; Lechner, S.M.; Jazic, I.; Miao, X.; Shaw, D.; Simard, C.; Osteen, J.D.; Hare, B.; Beaton, A.; et al. Selective Inhibition of NaV1.8 with VX-548 for Acute Pain. N. Engl. J. Med. 2023, 389, 393–405. [Google Scholar] [CrossRef]
  51. Kingwell, K. NaV1.8 inhibitor poised to provide opioid-free pain relief. Nat. Rev. Drug Discov. 2024, 24, 3–5. [Google Scholar] [CrossRef] [PubMed]
  52. Jemincare. A Phase 2, Multicenter, Randomized, Double-Blind, Placebo and Active Drug-Controlled Trial to Evaluate the Ef-ficacy and Safety of JMKX000623 in Participants with Diabetic Peripheral Neuropathic Pain [Internet]. Available online: https://clinicaltrials.gov/study/NCT06221241 (accessed on 31 October 2025).
  53. Latigo Biotherapeutics. Latigo Biotherapeutics Doses First Participant in Phase 1 Clinical Trial of LTG-305 for Non-Opioid Treatment of Pain—Latigo Biotherapeutics [Internet]. 2024. Available online: https://latigobio.com/latigo-biotherapeutics-doses-first-participant-in-phase-1-clinical-trial-of-ltg-305-for-non-opioid-treatment-of-pain/ (accessed on 31 October 2025).
  54. May, M. New approaches to opioid-free pain treatment. Nat. Med. 2025, 31, 1372–1373. [Google Scholar] [CrossRef]
  55. Brazil, R. Peptide Nucleic Acids Promise New Therapeutics and Gene Editing Tools. ACS Cent. Sci. 2023, 9, 3–6. [Google Scholar] [CrossRef]
  56. Su, M.; Ouyang, X.; Zhou, P.; Dong, L.; Shao, L.; Wang, K.; Liu, Y. Inhibition of TTX-S Na+ currents by a novel blocker QLS-278 for antinociception. J. Pharmacol. Exp. Ther. 2025, 392, 100030. [Google Scholar] [CrossRef]
  57. Rothenberg, M.E.; Tagen, M.; Chang, J.H.; Boyce-Rustay, J.; Friesenhahn, M.; Hackos, D.H.; Hains, A.; Sutherlin, D.; Ward, M.; Cho, W. Safety, Tolerability, and Pharmacokinetics of GDC-0276, a Novel NaV1.7 Inhibitor, in a First-in-Human, Single- and Multiple-Dose Study in Healthy Volunteers. Clin. Drug Investig. 2019, 39, 873–887, Erratum in Clin. Drug Investig. 2019, 39, 889–890. https://doi.org/10.1007/s40261-019-00832-2. [Google Scholar] [CrossRef]
  58. SiteOne Therapeutics, Inc. A Phase 1, Randomized, Double-Blind, Placebo-Controlled Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of ST-2427 IV Infusion in Healthy Subjects [Internet]. Available online: https://clinicaltrials.gov/study/NCT04475198 (accessed on 31 October 2025).
  59. Vishnu, P.N. SiteOne Therapeutics Begins Trial of Non-Opioid Analgesic for Acute Pain. Clinical Trials Arena. 21 April 2021. Available online: https://www.clinicaltrialsarena.com/news/siteone-trial-acute-pain/?cf-view&cf-closed (accessed on 11 January 2026).
  60. Dormer, A.; Narayanan, M.; Schentag, J.; Achinko, D.; Norman, E.; Kerrigan, J.; Jay, G.; Heydorn, W. A Review of the Therapeutic Targeting of SCN9A and Nav1.7 for Pain Relief in Current Human Clinical Trials. J. Pain Res. 2023, 16, 1487–1498. [Google Scholar] [CrossRef]
  61. Shin, Y.; Lee, H.-G.; Kwon, M.; Kim, S.-Y.; Han, J.; Park, C. Safety, Tolerability and Pharmacokinetics/Pharmacodynamic Evaluation of Properties of IN1011-N17 after Oral Administration in Healthy Volunteers with Effect Comparison of Solubility Enhanced Formulation. Osteoarthr. Cartil. 2022, 30, S65–S66. [Google Scholar] [CrossRef]
  62. Siebenga, P.; van Amerongen, G.; Hay, J.L.; McDonnell, A.; Gorman, D.; Butt, R.; Groeneveld, G.J. Lack of Detection of the Analgesic Properties of PF-05089771, a Selective Nav1.7 Inhibitor, Using a Battery of Pain Models in Healthy Subjects. Clin. Transl. Sci. 2020, 13, 318–324. [Google Scholar] [CrossRef] [PubMed]
  63. McDonnell, A.; Collins, S.; Ali, Z.; Iavarone, L.; Surujbally, R.; Kirby, S.; Butt, R.P. Efficacy of the Nav1.7 blocker PF-05089771 in a randomised, placebo-controlled, double-blind clinical study in subjects with painful diabetic peripheral neuropathy. Pain 2018, 159, 1465–1476. [Google Scholar] [CrossRef]
  64. Dunbar, J.; Versavel, M.; Zhao, Y.; Tate, S.; Morisset, V.; Giblin, G.M.P.; Palmer, J.; Tidemann-Miller, B.; Naik, H. Evaluation of the Pharmacokinetic Interaction Between the Voltage- and Use-Dependent Nav1.7 Channel Blocker Vixotrigine and Carbamazepine in Healthy Volunteers. Clin. Pharmacol. Drug Dev. 2020, 9, 62–73. [Google Scholar] [CrossRef] [PubMed]
  65. Zakrzewska, J.M.; Palmer, J.; Bendtsen, L.; Di Stefano, G.; Ettlin, D.A.; Maarbjerg, S.; Obermann, M.; Morisset, V.; Steiner, D.; Tate, S.; et al. Challenges recruiting to a proof-of-concept pharmaceutical trial for a rare disease: The trigeminal neuralgia experience. Trials 2018, 19, 704. [Google Scholar] [CrossRef] [PubMed]
  66. Naik, H.; Steiner, D.J.; Versavel, M.; Palmer, J.; Fong, R. Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of Vixotrigine in Healthy Volunteers. Clin. Transl. Sci. 2021, 14, 1272–1279. [Google Scholar] [CrossRef]
  67. Price, N.; Namdari, R.; Neville, J.; Proctor, K.J.W.; Kaber, S.; Vest, J.; Fetell, M.; Malamut, R.; Sherrington, R.P.; Pimstone, S.N.; et al. Safety and Efficacy of a Topical Sodium Channel Inhibitor (TV-45070) in Patients With Postherpetic Neuralgia (PHN): A Randomized, Controlled, Proof-of-Concept, Crossover Study, With a Subgroup Analysis of the Nav1.7 R1150W Genotype. Clin. J. Pain 2017, 33, 310–318. [Google Scholar] [CrossRef] [PubMed]
  68. Goldberg, Y.; Pimstone, S.; Namdari, R.; Price, N.; Cohen, C.; Sherrington, R.; Hayden, M. Human Mendelian pain disorders: A key to discovery and validation of novel analgesics. Clin. Genet. 2012, 82, 367–373. [Google Scholar] [CrossRef]
  69. Bagal, S.K.; Chapman, M.L.; Marron, B.E.; Prime, R.; Storer, R.I.; Swain, N.A. Recent progress in sodium channel modulators for pain. Bioorg. Med. Chem. Lett. 2014, 24, 3690–3699. [Google Scholar] [CrossRef] [PubMed]
  70. Kamei, T.; Ishibashi, F.; Takada, Y.; Ohno, A.; Tani, N.; Ikeda, K.; Oyamada, Y. A novel Nav1.7, Nav1.8, and Nav1.9 blocker, ANP-230, has broad analgesic efficacy in preclinical pain models with favorable safety margins. Biochem. Biophys. Res. Commun. 2025, 777, 152197. [Google Scholar] [CrossRef]
  71. Kamei, T.; Kudo, T.; Yamane, H.; Ishibashi, F.; Takada, Y.; Honda, S.; Maezawa, Y.; Ikeda, K.; Oyamada, Y. Unique electrophysiological property of a novel Nav1.7, Nav1.8, and Nav1.9 sodium channel blocker, ANP-230. Biochem. Biophys. Res. Commun. 2024, 721, 150126. [Google Scholar] [CrossRef]
  72. Okuda, H.; Inoue, S.; Oyamada, Y.; Koizumi, A.; Youssefian, S. Reduced pain sensitivity of episodic pain syndrome model mice carrying a Nav1.9 mutation by ANP-230, a novel sodium channel blocker. Heliyon 2023, 9, e15423. [Google Scholar] [CrossRef]
  73. de Abreu, M.M.; Binda, N.S.; Reis, M.P.F.C.A.; Diniz, D.M.; Cordeiro, M.d.N.; Borges, M.H.; de Lima, M.E.; Ribeiro, F.M.; Gomez, M.V.; da Silva, J.F. Spinal antinociceptive effect of the PnTx4(5-5) peptide is possibly mediated by the NMDA autoreceptors. J. Venom. Anim. Toxins Trop. Dis. 2024, 30, e20230103. [Google Scholar] [CrossRef]
  74. Lopez-Mateos, D.; Harris, B.J.; Hernández-González, A.; Yarov-Yarovoy, V.; Wulff, H. Recent advances in the pharmacology of voltage-gated ion channels. Pharmacol. Rev. 2025, 77, 100090. [Google Scholar] [CrossRef]
  75. Goldlust, S.A.; Kavoosi, M.; Nezzer, J.; Kavoosi, M.; Korz, W.; Deck, K. Tetrodotoxin for Chemotherapy-Induced Neuropathic Pain: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Dose Finding Trial. Toxins 2021, 13, 235. [Google Scholar] [CrossRef]
  76. Kavoosi, M.; O’Reilly, T.E.; Kavoosi, M.; Chai, P.; Engel, C.; Korz, W.; Gallen, C.C.; Lester, R.M. Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults. Toxins 2020, 12, 511. [Google Scholar] [CrossRef] [PubMed]
  77. Lago, J.; Rodríguez, L.P.; Blanco, L.; Vieites, J.M.; Cabado, A.G. Tetrodotoxin, an Extremely Potent Marine Neurotoxin: Distribution, Toxicity, Origin and Therapeutical Uses. Mar. Drugs 2015, 13, 6384–6406. [Google Scholar] [CrossRef]
  78. Tran, P.; Tran, H.N.T.; McMahon, K.L.; Deuis, J.R.; Ragnarsson, L.; Norman, A.; Sharpe, S.J.; Payne, R.J.; Vetter, I.; Schroeder, C.I. Changes in Potency and Subtype Selectivity of Bivalent NaV Toxins are Knot-Specific. Bioconjug. Chem. 2023, 34, 1072–1083. [Google Scholar] [CrossRef]
  79. Fan, X.; Chen, J.; Huang, X.; Hou, Z.; Xie, Y.; Li, Z.; Yan, N.; Huang, J. Phrixotoxin-3 binds to three distinct antagonistic sites on human Nav1.6. Cell Res. 2025, 35, 610–613. [Google Scholar] [CrossRef]
  80. Tran, H.N.T.; Tran, P.; Deuis, J.R.; Agwa, A.J.; Zhang, A.H.; Vetter, I.; Schroeder, C.I. Enzymatic Ligation of a Pore Blocker Toxin and a Gating Modifier Toxin: Creating Double-Knotted Peptides with Improved Sodium Channel NaV1.7 Inhibition. Bioconjug. Chem. 2020, 31, 64–73. [Google Scholar] [CrossRef]
  81. Emerich, B.L.; Ferreira, R.C.M.; Machado-de-Avila, R.A.; Resende, J.M.; Duarte, I.D.G.; de Lima, M.E. PnAn13, an antinociceptive synthetic peptide inspired in the Phoneutria nigriventer toxin PnTx4(6-1) (δ-Ctenitoxin-Pn1a). Toxicon X 2020, 7, 100045. [Google Scholar] [CrossRef]
  82. Mintz, M.; Badner, V.; Feldman, L.K.; Mintz, P.; Saraghi, M.; Diaz, J.; Mezhebovsky, I.; Axelrod, I.; Gleeson, J.; Liu, C.; et al. Lidocaine Ineffectiveness Suggests New Psychopharmacology Drug Target. Psychopharmacol. Bull. 2022, 52, 20–30. [Google Scholar] [CrossRef]
  83. Resch, F.J.; Heber, S.; Shahi, F.; Zauner, M.; Ciotu, C.I.; Gleiss, A.; Sator, S.; Fischer, M.J.M. Human cold pain: A randomized crossover trial. Pain 2025, 166, 1406–1417. [Google Scholar] [CrossRef] [PubMed]
  84. Jirachaipitak, S.; Euasobhon, P.; Cenpakdee, S.; Wangnamthip, S.; Rushatamukayanunt, P. Intravenous Lidocaine Response as a Predictor for Oral Oxcarbazepine Efficacy in Neuropathic Pain Syndrome: A Prospective Cohort Study. Med. Sci. Monit. Int. Med. J. Exp. Clin. Res. 2024, 30, e945612. [Google Scholar] [CrossRef] [PubMed]
  85. Xiao, H.; Ma, K.; Huang, D.; Liu, X.-G.; Liu, T.-H.; Liu, Q.; Liu, G.-Z.; Song, T.; Tao, W.; Wu, D.-S.; et al. Expert consensus of the Chinese Association for the Study of Pain on ion channel drugs for neuropathic pain. World J. Clin. Cases 2021, 9, 2100–2109. [Google Scholar] [CrossRef]
  86. Marin-Gracia, M.; Cantero-Lozano, D.; Garces-Anton, E.; Lopez-Bravo, A.; Garrido-Fernandez, A.; Navarro-Perez, M.P.; Santos-Lasaosa, S.; Garces-Redondo, M. Lacosamide associated with high-degree block in a patient with trigeminal neuralgia. Rev. Neurol. 2018, 66, 189–192. [Google Scholar]
  87. García-Escrivá, A.; López-Hernández, N.; Gil-Cortés, C. Treatment of neuropathic pain with lacosamide. Rev. Neurol. 2012, 54, 167–172. [Google Scholar]
  88. Ghisa, M.; Barbuscio, I.; Bonazzi, E.; Fassan, M.; Barberio, B.; Senzolo, M.; Savarino, E.V. Mexiletine-Induced Esophageal Ulceration: Two Case Reports and a Review of the Literature. Reports 2025, 8, 9. [Google Scholar] [CrossRef]
  89. Fassoulaki, A.; Sarantopoulos, C.; Melemeni, A.; Hogan, Q. Regional block and mexiletine: The effect on pain after cancer breast surgery. Reg. Anesth. Pain Med. 2001, 26, 223–228. [Google Scholar] [CrossRef] [PubMed]
  90. Iseki, M.; Yamamoto, T.; Ogawa, Y.; Majima, Y.; Abe, Y.; Watanabe, D.; Amaya, F.; Hasegawa, T.; Inafuku, K.; Kosugi, T.; et al. Efficacy and safety of intravenous fosphenytoin for patients with acute herpes zoster-associated pain: A placebo-controlled randomized trial. J. Dermatol. 2024, 51, 234–242. [Google Scholar] [CrossRef] [PubMed]
  91. Shkodina, A.D.; Bardhan, M.; Chopra, H.; Anyagwa, O.E.; Pinchuk, V.A.; Hryn, K.V.; Kryvchun, A.M.; Boiko, D.I.; Suresh, V.; Verma, A.; et al. Pharmacological and Non-pharmacological Approaches for the Management of Neuropathic Pain in Multiple Sclerosis. CNS Drugs 2024, 38, 205–224. [Google Scholar] [CrossRef] [PubMed]
  92. Hille, B. Local anesthetics: Hydrophilic and hydrophobic pathways for the drug-receptor reaction. J. Gen. Physiol. 1977, 69, 497–515. [Google Scholar] [CrossRef]
  93. Paganelli, M.A.; Popescu, G.K. Actions of bupivacaine, a widely used local anesthetic, on NMDA receptor responses. J. Neurosci. Off. J. Soc. Neurosci. 2015, 35, 831–842. [Google Scholar] [CrossRef]
  94. Dasta, J.; Ramamoorthy, S.; Patou, G.; Sinatra, R. Bupivacaine liposome injectable suspension compared with bupivacaine HCl for the reduction of opioid burden in the postsurgical setting. Curr. Med. Res. Opin. 2012, 28, 1609–1615. [Google Scholar] [CrossRef]
  95. Hansen, T.G. Ropivacaine: A pharmacological review. Expert Rev. Neurother. 2004, 4, 781–791. [Google Scholar] [CrossRef]
  96. McClure, J.H. Ropivacaine. Br. J. Anaesth. 1996, 76, 300–307. [Google Scholar] [CrossRef] [PubMed]
  97. Dick, I.E.; Brochu, R.M.; Purohit, Y.; Kaczorowski, G.J.; Martin, W.J.; Priest, B.T. Sodium channel blockade may contribute to the analgesic efficacy of antidepressants. J. Pain 2007, 8, 315–324. [Google Scholar] [CrossRef] [PubMed]
  98. Horishita, T.; Yanagihara, N.; Ueno, S.; Okura, D.; Horishita, R.; Minami, T.; Ogata, Y.; Sudo, Y.; Uezono, Y.; Sata, T.; et al. Antidepressants inhibit Nav1.3, Nav1.7, and Nav1.8 neuronal voltage-gated sodium channels more potently than Nav1.2 and Nav1.6 channels expressed in Xenopus oocytes. Naunyn. Schmiedebergs Arch. Pharmacol. 2017, 390, 1255–1270. [Google Scholar] [CrossRef] [PubMed]
  99. Moore, R.A.; Derry, S.; Aldington, D.; Cole, P.; Wiffen, P.J. Amitriptyline for neuropathic pain in adults. Cochrane Database Syst. Rev. 2015, 2015, CD008242. [Google Scholar] [CrossRef]
  100. Shen, H.; Liu, D.; Wu, K.; Lei, J.; Yan, N. Structures of human Nav 1.7 channel in complex with auxiliary subunits and animal toxins. Science 2019, 363, 1303–1308. [Google Scholar] [CrossRef]
  101. Huang, G.; Liu, D.; Wang, W.; Wu, Q.; Chen, J.; Pan, X.; Shen, H.; Yan, N. High-resolution structures of human Nav1.7 reveal gating modulation through α-π helical transition of S6IV. Cell Rep. 2022, 39, 110735. [Google Scholar] [CrossRef]
  102. Wisedchaisri, G.; Gamal El-Din, T.M.; Zheng, N.; Catterall, W.A. Structural basis for severe pain caused by mutations in the S4-S5 linkers of voltage-gated sodium channel NaV 1.7. Proc. Natl. Acad. Sci. USA 2023, 120, e2219624120. [Google Scholar] [CrossRef]
  103. Mulcahy, J.V.; Pajouhesh, H.; Beckley, J.T.; Delwig, A.; Du Bois, J.; Hunter, J.C. Challenges and Opportunities for Therapeutics Targeting the Voltage-Gated Sodium Channel Isoform NaV 1.7. J. Med. Chem. 2019, 62, 8695–8710. [Google Scholar] [CrossRef]
  104. Kang, C.Y.; Been, K.W.; Kang, M.-H.; Choi, M.S.; Kang, R.H.; Hur, J.W.; Hur, J.K. Advances in Therapeutic Applications of CRISPR Genome Editing for Spinal Pain Management. Neurospine 2025, 22, 421–440. [Google Scholar] [CrossRef]
  105. Yang, J.; Xie, Y.-F.; Smith, R.; Ratté, S.; Prescott, S.A. Discordance between preclinical and clinical testing of NaV1.7–selective inhibitors for pain. Pain 2025, 166, 481–501. [Google Scholar] [CrossRef]
  106. Minett, M.S.; Pereira, V.; Sikandar, S.; Matsuyama, A.; Lolignier, S.; Kanellopoulos, A.H.; Mancini, F.; Iannetti, G.D.; Bogdanov, Y.D.; Santana-Varela, S.; et al. Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7. Nat. Commun. 2015, 6, 8967. [Google Scholar] [CrossRef]
  107. Shields, S.D.; Ahn, H.-S.; Yang, Y.; Han, C.; Seal, R.P.; Wood, J.N.; Waxman, S.G.; Dib-Hajj, S.D. Nav1.8 expression is not restricted to nociceptors in mouse peripheral nervous system. Pain 2012, 153, 2017–2030. [Google Scholar] [CrossRef] [PubMed]
  108. Han, C.; Estacion, M.; Huang, J.; Vasylyev, D.; Zhao, P.; Dib-Hajj, S.D.; Waxman, S.G. Human Nav 1.8: Enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons. J. Neurophysiol. 2015, 113, 3172–3185. [Google Scholar] [CrossRef] [PubMed]
  109. Faber, C.G.; Lauria, G.; Merkies, I.S.J.; Cheng, X.; Han, C.; Ahn, H.-S.; Persson, A.-K.; Hoeijmakers, J.G.J.; Gerrits, M.M.; Pierro, T.; et al. Gain-of-function Nav 1.8 mutations in painful neuropathy. Proc. Natl. Acad. Sci. USA 2012, 109, 19444–19449. [Google Scholar] [CrossRef] [PubMed]
  110. Garrison, S.R.; Weyer, A.D.; Barabas, M.E.; Beutler, B.A.; Stucky, C.L. A gain-of-function voltage-gated sodium channel 1.8 mutation drives intense hyperexcitability of A- and C-fiber neurons. Pain 2014, 155, 896–905. [Google Scholar] [CrossRef]
  111. Xie, Y.-F. Nav1.8 and Chronic Pain: From Laboratory Animals to Clinical Patients. Biomolecules 2025, 15, 694. [Google Scholar] [CrossRef]
  112. Coates, M.D.; Walter, V.; Stuart, A.; Small, J.; Dalessio, S.; Carkaci-Salli, N.; Ouyang, A.; Clarke, K.; Tinsley, A.; Williams, E.D.; et al. Impact of SCN10A Polymorphism on Abdominal Pain Perception and Visceral Hypoalgesia in Crohn’s Disease and Ulcerative Colitis. Clin. Transl. Gastroenterol. 2024, 15, e00778. [Google Scholar] [CrossRef]
  113. Kapur, M.M.; Soliman, M.; Blanke, E.N.; Herold, P.B.; Janicki, P.K.; Vrana, K.E.; Coates, M.D.; Ruiz-Velasco, V. Heterologous expression of the human wild-type and variant NaV 1.8 (A1073V) in rat sensory neurons. Neurogastroenterol. Motil. 2024, 36, e14748. [Google Scholar] [CrossRef]
  114. Wang, H.; Huang, J.; Zang, J.; Jin, X.; Yan, N. Drug discovery targeting Nav1.8: Structural insights and therapeutic potential. Curr. Opin. Chem. Biol. 2024, 83, 102538, Erratum in Curr. Opin. Chem. Biol. 2025, 84, 102546. [Google Scholar] [CrossRef]
  115. Stewart, R.G.; Osorno, T.; Fujita, A.; Jo, S.; Ferraiuolo, A.; Carlin, K.; Bean, B.P. Modulation of human dorsal root ganglion neuron firing by the Nav1.8 inhibitor suzetrigine. Proc. Natl. Acad. Sci. USA 2025, 122, e2503570122. [Google Scholar] [CrossRef] [PubMed]
  116. Huang, X.; Jin, X.; Huang, G.; Huang, J.; Wu, T.; Li, Z.; Chen, J.; Kong, F.; Pan, X.; Yan, N. Structural basis for high-voltage activation and subtype-specific inhibition of human Nav 1.8. Proc. Natl. Acad. Sci. USA 2022, 119, e2208211119. [Google Scholar] [CrossRef] [PubMed]
  117. Wood, J.N.; Yan, N.; Huang, J.; Zhao, J.; Akopian, A.; Cox, J.J.; Woods, C.G.; Nassar, M.A. Sensory neuron sodium channels as pain targets; from cocaine to Journavx (VX-548, suzetrigine). J. Gen. Physiol. 2025, 157, e202513778. [Google Scholar] [CrossRef]
  118. Neumann, B.; McCarthy, S.; Gonen, S. Structural basis of inhibition of human NaV1.8 by the tarantula venom peptide Protoxin-I. Nat. Commun. 2025, 16, 1459. [Google Scholar] [CrossRef]
  119. Vaelli, P.; Fujita, A.; Jo, S.; Zhang, H.X.B.; Osorno, T.; Ma, X.; Bean, B.P. State-Dependent Inhibition of Nav1.8 Sodium Channels by VX-150 and VX-548. Mol. Pharmacol. 2024, 106, 298–308. [Google Scholar] [CrossRef]
  120. Fang, X.; Djouhri, L.; Black, J.A.; Dib-Hajj, S.D.; Waxman, S.G.; Lawson, S.N. The Presence and Role of the Tetrodotoxin-Resistant Sodium Channel Nav 1.9 (NaN) in Nociceptive Primary Afferent Neurons. J. Neurosci. 2002, 22, 7425–7433. [Google Scholar] [CrossRef] [PubMed]
  121. Rugiero, F.; Mistry, M.; Sage, D.; Black, J.A.; Waxman, S.G.; Crest, M.; Clerc, N.; Delmas, P.; Gola, M. Selective Expression of a Persistent Tetrodotoxin-Resistant Na+ Current and NaV 1.9 Subunit in Myenteric Sensory Neurons. J. Neurosci. 2003, 23, 2715–2725. [Google Scholar] [CrossRef]
  122. Blum, R.; Kafitz, K.W.; Konnerth, A. Neurotrophin-evoked depolarization requires the sodium channel NaV1.9. Nature 2002, 419, 687–693. [Google Scholar] [CrossRef]
  123. Jeong, S.-Y.; Goto, J.; Hashida, H.; Suzuki, T.; Ogata, K.; Masuda, N.; Hirai, M.; Isahara, K.; Uchiyama, Y.; Kanazawa, I. Identification of a Novel Human Voltage-Gated Sodium Channel α Subunit Gene, SCN12A. Biochem. Biophys. Res. Commun. 2000, 267, 262–270. [Google Scholar] [CrossRef]
  124. Dib-Hajj, S.D.; Black, J.A.; Waxman, S.G. NaV1.9: A sodium channel linked to human pain. Nat. Rev. Neurosci. 2015, 16, 511–519. [Google Scholar] [CrossRef]
  125. Brackx, W.; Collaço, R.D.C.; Theys, M.; Vander Cruyssen, J.; Bosmans, F. Understanding the physiological role of NaV1.9: Challenges and opportunities for pain modulation. Pharmacol. Ther. 2023, 245, 108416. [Google Scholar] [CrossRef]
  126. Huang, J.; Vanoye, C.G.; Cutts, A.; Goldberg, Y.P.; Dib-Hajj, S.D.; Cohen, C.J.; Waxman, S.G.; George, A.L. Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability. J. Clin. Investig. 2017, 127, 2805–2814. [Google Scholar] [CrossRef] [PubMed]
  127. Maingret, F.; Coste, B.; Padilla, F.; Clerc, N.; Crest, M.; Korogod, S.M.; Delmas, P. Inflammatory Mediators Increase Nav1.9 Current and Excitability in Nociceptors Through a Coincident Detection Mechanism. J. Gen. Physiol. 2008, 131, 211–225. [Google Scholar] [CrossRef] [PubMed]
  128. Amaya, F.; Wang, H.; Costigan, M.; Allchorne, A.J.; Hatcher, J.P.; Egerton, J.; Stean, T.; Morisset, V.; Grose, D.; Gunthorpe, M.J.; et al. The Voltage-Gated Sodium Channel Nav 1.9 Is an Effector of Peripheral Inflammatory Pain Hypersensitivity. J. Neurosci. 2006, 26, 12852–12860. [Google Scholar] [CrossRef] [PubMed]
  129. Vanoye, C.G.; Kunic, J.D.; Ehring, G.R.; George, A.L. Mechanism of sodium channel NaV1.9 potentiation by G-protein signaling. J. Gen. Physiol. 2013, 141, 193–202. [Google Scholar] [CrossRef]
  130. Zhang, F.; Wang, Y.; Liu, Y.; Han, H.; Zhang, D.; Fan, X.; Du, X.; Gamper, N.; Zhang, H. Transcriptional Regulation of Voltage-Gated Sodium Channels Contributes to GM-CSF-Induced Pain. J. Neurosci. 2019, 39, 5222–5233. [Google Scholar] [CrossRef]
  131. Sibomana, O.; Okereke, M.; Hakayuwa, C. Suzetrigine Approval Breaks a 25-Year Silence: A New Era in Non-Opioid Acute Pain Management. J. Pain Res. 2025, 18, 2805–2808. [Google Scholar] [CrossRef]
  132. Haroun, R.; Gossage, S.J.; Luiz, A.P.; Arcangeletti, M.; Sikandar, S.; Zhao, J.; Cox, J.J.; Wood, J.N. Chemogenetic Silencing of NaV 1.8-Positive Sensory Neurons Reverses Chronic Neuropathic and Bone Cancer Pain in FLEx PSAM4-GlyR Mice. Eneuro 2023, 10, ENEURO.0151-23.2023. [Google Scholar] [CrossRef]
  133. Li, Y.; Ji, R.-R. Gene therapy for chronic pain management. Cell Rep. Med. 2024, 5, 101756. [Google Scholar] [CrossRef]
  134. Pereira, A.F.M.; Cavalcante, J.S.; Angstmam, D.G.; Almeida, C.; Soares, G.S.; Pucca, M.B.; Ferreira Junior, R.S. Unveiling the Pain Relief Potential: Harnessing Analgesic Peptides from Animal Venoms. Pharmaceutics 2023, 15, 2766. [Google Scholar] [CrossRef]
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Figure 1. Topology, gating, and classification of human Nav channels. (A) Schematic illustration showing the transmembrane topology of human Nav channels. (B) Gating of Nav channels. (C) Classification of the nine human Nav isoforms. Top: Phylogenetic tree of human Nav channels, with the three TTX-resistant subtypes (Nav1.5, Nav1.8, and Nav1.9) highlighted in orange. Bottom: Tissue distribution of human Nav channels and representative channelopathies caused by functional disorders of these channels. Nav1.1 is associated with GEFS+2, EIEE6, ICEGTC, FHM3, and FEB3A; Nav1.2 with BFIS3, EIEE11, and DS; Nav1.3 with CPE; Nav1.4 with multiple neuromuscular disorders including PMC, HOKPP2, HYPP, NKPP, MYOSCN4A, and CMS16; Nav1.5 with PFHB1A, LQT3, BRGDA1, SSS1, VF1, SIDS, ATRST1, CMD1E, ATFB10, and MEPPC; Nav1.6 with EIEE13; Nav1.7 with IEM, PEPD, CIP, DS, SFN, and FEB; Nav1.8 with SFN; and Nav1.9 with FEPS3 and HSAN7. See the Abbreviations section for full disease names.
Figure 1. Topology, gating, and classification of human Nav channels. (A) Schematic illustration showing the transmembrane topology of human Nav channels. (B) Gating of Nav channels. (C) Classification of the nine human Nav isoforms. Top: Phylogenetic tree of human Nav channels, with the three TTX-resistant subtypes (Nav1.5, Nav1.8, and Nav1.9) highlighted in orange. Bottom: Tissue distribution of human Nav channels and representative channelopathies caused by functional disorders of these channels. Nav1.1 is associated with GEFS+2, EIEE6, ICEGTC, FHM3, and FEB3A; Nav1.2 with BFIS3, EIEE11, and DS; Nav1.3 with CPE; Nav1.4 with multiple neuromuscular disorders including PMC, HOKPP2, HYPP, NKPP, MYOSCN4A, and CMS16; Nav1.5 with PFHB1A, LQT3, BRGDA1, SSS1, VF1, SIDS, ATRST1, CMD1E, ATFB10, and MEPPC; Nav1.6 with EIEE13; Nav1.7 with IEM, PEPD, CIP, DS, SFN, and FEB; Nav1.8 with SFN; and Nav1.9 with FEPS3 and HSAN7. See the Abbreviations section for full disease names.
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Figure 2. Structural features of Nav1.7 and binding modes of representative inhibitors. (A) Overall structure of Nav1.7 in complex with β1 and β2 subunits (PDB: 7W9T). (B) Coordination of PF-05089771 in Nav1.7, with key interacting residues shown as blue sticks (PDB: 8I5G). Hydrogen bonds are indicated by gray dashed lines. (C) Cryo-EM density of the toxin ProTx-II positioned above VSDII. The toxin density is shown in cyan, and VSDII is shown in grey cylinders. (D) Structural comparison of the toxin-bound and apo Nav1.7 showing an α to π helical transition in S6IV (α helix PDB: 7W9T; π helix PDB: 7W9P). The right panel highlights residues that undergo notable rotational changes. (E) Representative Nav1.7 inhibitors mapped onto the structural model to illustrate the major pharmacological binding sites.
Figure 2. Structural features of Nav1.7 and binding modes of representative inhibitors. (A) Overall structure of Nav1.7 in complex with β1 and β2 subunits (PDB: 7W9T). (B) Coordination of PF-05089771 in Nav1.7, with key interacting residues shown as blue sticks (PDB: 8I5G). Hydrogen bonds are indicated by gray dashed lines. (C) Cryo-EM density of the toxin ProTx-II positioned above VSDII. The toxin density is shown in cyan, and VSDII is shown in grey cylinders. (D) Structural comparison of the toxin-bound and apo Nav1.7 showing an α to π helical transition in S6IV (α helix PDB: 7W9T; π helix PDB: 7W9P). The right panel highlights residues that undergo notable rotational changes. (E) Representative Nav1.7 inhibitors mapped onto the structural model to illustrate the major pharmacological binding sites.
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Figure 3. Chemical structures of representative broad-spectrum VGSC inhibitors and Nav1.7–selective inhibitors.
Figure 3. Chemical structures of representative broad-spectrum VGSC inhibitors and Nav1.7–selective inhibitors.
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Figure 4. Structural and functional features of Nav1.8 and its inhibitors. (A) Overall structure of Nav1.8 in complex with the selective inhibitor A-803467 (PDB: 7WE4). (B) A-803467 clenches S6IV of Nav1.8 beneath the selectivity filter. Inset: Coordination of A-803467. Direct and water-mediated hydrogen bonds (H-bonds) are indicated by red and black dashed lines, respectively. (C) ProTxI binds above VSDII of Nav1.8, with VSDII colored in cyan and ProTxI shown in light-coral surface representation. Inset: Detailed coordination between Nav1.8 and ProTxI (PDB: 9DBN). (D) Predicted binding pose of the clinical inhibitor VX-548, derived from Glide docking in Maestro using the Nav1.8 structure (PDB: 7WE4). Residues in the S3-4 loop adjacent to VX-548 are highlighted as blue sticks. (E) Sequence alignment of the VSDII S3-4 linker. Residues highlighted by the red dashed box are experimentally verified to influence the inhibitory potency of VX-548 on Nav1.8. (F) Top left: Chemical structures of VX-150 and VX-548. Bottom left: Schematic representation of action potentials in DRG neurons before and after VX-548 inhibition, showing that VX-548 markedly decreases both the peak amplitude and the shoulder of action potentials. Right: IC50 values of VX-548 across human Nav isoforms, measured by patch-clamp recordings. IC50 values were determined based on inhibition of the peak currents (Ref. [50]).
Figure 4. Structural and functional features of Nav1.8 and its inhibitors. (A) Overall structure of Nav1.8 in complex with the selective inhibitor A-803467 (PDB: 7WE4). (B) A-803467 clenches S6IV of Nav1.8 beneath the selectivity filter. Inset: Coordination of A-803467. Direct and water-mediated hydrogen bonds (H-bonds) are indicated by red and black dashed lines, respectively. (C) ProTxI binds above VSDII of Nav1.8, with VSDII colored in cyan and ProTxI shown in light-coral surface representation. Inset: Detailed coordination between Nav1.8 and ProTxI (PDB: 9DBN). (D) Predicted binding pose of the clinical inhibitor VX-548, derived from Glide docking in Maestro using the Nav1.8 structure (PDB: 7WE4). Residues in the S3-4 loop adjacent to VX-548 are highlighted as blue sticks. (E) Sequence alignment of the VSDII S3-4 linker. Residues highlighted by the red dashed box are experimentally verified to influence the inhibitory potency of VX-548 on Nav1.8. (F) Top left: Chemical structures of VX-150 and VX-548. Bottom left: Schematic representation of action potentials in DRG neurons before and after VX-548 inhibition, showing that VX-548 markedly decreases both the peak amplitude and the shoulder of action potentials. Right: IC50 values of VX-548 across human Nav isoforms, measured by patch-clamp recordings. IC50 values were determined based on inhibition of the peak currents (Ref. [50]).
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Figure 5. Molecular and functional roles of Nav1.7–Nav1.9 in pain signaling and their implications for peripheral Nav-targeted analgesic development.
Figure 5. Molecular and functional roles of Nav1.7–Nav1.9 in pain signaling and their implications for peripheral Nav-targeted analgesic development.
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Table 1. Development of next-generation analgesics targeting the Nav1 family in advanced clinical trials.
Table 1. Development of next-generation analgesics targeting the Nav1 family in advanced clinical trials.
DrugsCompaniesTargetsMechanisms of ActionClinical
Development		CommentsRef.
Selective Inhibitors
Suzetrigine/Journavx
(VX-548)		Vertex PharmaceuticalsNav1.8Highly selective Nav1.8 blockers Phase 3 COMPLETED
(NDA submitted)		First-in-class Nav1.8 selective inhibitor. Demonstrated significant pain reduction vs. placebo in post-surgical acute pain. Non-opioid with potential for chronic pain applications[48,49,50]
VX-993Vertex PharmaceuticalsNav1.8Next-gen Nav1.8 selective blockerPhase 2 failedVertex is developing additional Nav1.8 candidates (e.g., VX-993) as follow-ons to VX-548[51]
JMKX-000623Shanghai JemincareNav1.8Selective Nav1.8 blockerPhase 2Evaluated the efficacy and safety of JMKX-000623 in participants with diabetic peripheral neuropathic pain[51,52]
LTG-305Latigo BioNav1.8-Phase 1LTG-305, a potential best-in-class non-opioid therapeutic candidate for the treatment of chronic pain[51,53]
HBW-004285HyperwayNav1.8Nav1.8 blocker Phase 2Indication for pain, less information about clinical efficacy[51]
STC-004SiteOne (Lilly)Nav1.8-Phase 1 COMPLETEDA novel inhibitor in development for the non-opioid treatment of pain[54]
OLP-1002OlipassNav1.7Nav1.7 selective down-regulatory effect PNAPhase 2Currently in an Australian phase 2a clinical trial for treating osteoarthritis[51,55]
QLS-278Research CompoundNav1.7 selective (TTX-sensitive)Inactivation- and concentration-dependent Nav1.7 blockade; hyperpolarization shift of inactivationPreclinical (2024)IC50 1.2 ± 0.2 μM; effective in neuropathic and inflammatory pain models[56]
GDC-0276Genentech/RocheNav1.7Selective Nav1.7 voltage-gated sodium channel blockadeDISCONTINUED
(Phase 1 terminated)		Dose-limiting hypotension and liver toxicity, discontinued in 2019[57]
ST-2427SiteOne (Lilly)Nav1.7-DISCONTINUED
(Phase 1 terminated)		Indication for pain, less information about clinical efficacy[51,58,59]
iN1011-N17iN TherapeuticsNav1.7Nav1.7 channel blockerPhase 1 COMPLETEDIndication for pain, relatively safe in phase 1 trials.[60,61]
PF-05089771PfizerNav1.7Selective Nav1.7 sodium channel blockadeDISCONTINUED
(Phase 2 failed)		Showed some efficacy in trigeminal neuralgia but failed broader neuropathic pain trials. Well-tolerated up to 450 mg bis in die[62,63]
Vixotrigine
(BIIB074/CNV1014802)		Biogen/ConvergenceNav1.7Voltage- and use-dependent Nav1.7 channel blockerDISCONTINUED
(Phase 2/3 failed)		Developed for trigeminal neuralgia and peripheral neuropathic pain. Discontinued due to insufficient efficacy[64,65,66]
Funapide (XEN402/TV-45070)Xenon PharmaceuticalsNav1.7Voltage-dependent Nav1.7 blockade (topical)DISCONTINUED
(Phase 2 failed)		Topical formulation for postherpetic neuralgia. Some responder subgroups identified, particularly Nav1.7 R1150W genetic carriers (63% vs. 35% response)[67,68]
AZD-3161AstraZenecaNav1.7-DISCONTINUEDPart of the Nav1.7 inhibitor failures; discontinued[69]
PF-04531083PfizerNav1.7Selective Nav1.7 sodium channel blockadeDISCONTINUEDPart of Pfizer’s Nav1.7 program alongside PF-05089771[69]
Multi-Target Nav Channel Blockers
ANP-230/DSP-2230Anest/Nippon PharmaNav1.7, Nav1.8, Nav1.9Equipotent blockade of three pain-related Nav channels; peripheral selectivityEarly Clinical DevelopmentInnovative multi-target approach; addresses potential redundancy between Nav subtypes[70,71,72]
PnTx4(5-5)Academic ResearchNav1.2–Nav1.6 + NMDA receptorsDual mechanism-sodium channel blockade + NMDA autoreceptor modulationPreclinicalP. nigriventer spider venom. More potent than MK-801; no motor impairment[73]
ATX01AlgoTherapeutixNav1.7, Nav1.8 and Nav1.9Nav1.7, Nav1.8, Nav1.9 triple blockerPhase 2 COMPLETEDIndicated for CIPN, locally delivered to the nerve endings where pain signals originate and propagate[74]
Tetrodotoxin (TTX)WEX PharmaceuticalsNon-selective VGSC (especially Nav1.7, Nav1.8)Highly specific voltage-gated sodium channel blocker; peripherally actingPhase 2 COMPLETEDPositive trends in chemotherapy-induced neuropathic pain; natural neurotoxin from pufferfish[75,76,77]
Engineered Peptides & Biotechnology
Pro[LPATG6]SxAcademic ResearchNav1.7 dual-siteBivalent design: ProTx-II + SxIIIC fusion (gating modifier + pore blocker)Research ToolEngineering innovation: Sortase A ligation, combined mechanisms[78]
PaurTx3Academic ResearchNav1.2 and Nav1.7Blockade by inducing a depolarizing shift in gating kineticsResearch ToolTarantula Phrixotrichus auratus venom. PaurTx3 exhibits a slower inhibition on Nav1.7 compared to Nav1.4 and Nav1.5[78,79,80]
PnAn13Academic ResearchMulti-targetδ-Ctenitoxin derivative with cannabinoid system involvementPreclinicalSynthetic optimization of spider toxin, multiple pain models[81]
Approved Agents
LidocaineMultiple (Generic)Non-selective VGSC (Nav1.1–Nav1.9)Use-dependent sodium channel blockade; prevents action potential propagationFDA ApprovedGold standard for local and neuropathic pain; topical patches for PHN, IV infusion[82,83,84]
CarbamazepineMultiple (Generic)Nav1.2, Nav1.3, Nav1.6 primarilyUse-dependent sodium channel blockade; stabilizes inactivated stateFDA ApprovedFirst-line for trigeminal neuralgia; well-established efficacy[84,85]
OxcarbazepineMultiple (Generic)Nav1.2, Nav1.3, Nav1.6 primarilySimilar to carbamazepine but better tolerability profileFDA ApprovedBetter tolerability than carbamazepine; second-generation anticonvulsant[84,85]
LacosamideUCB/PfizerNon-selective VGSCSlow inactivation enhancement (vs. fast inactivation blockade)FDA ApprovedUnique mechanism. Approved for epilepsy, off-label neuropathic pain. Cardiac monitoring required[86,87]
MexiletineMultiple (Generic)Nav1.5 (cardiac) + peripheral NavsClass IB antiarrhythmic; use-dependent sodium channel blockadeFDA ApprovedLimited efficacy in pain studies; off-label pain use; significant side effects; originally antiarrhythmic[88,89]
Dilantin/PhenytoinMultiple (Generic)Multiple VGSC subtypesVoltage-dependent sodium channel blockade; multiple mechanismsFDA ApprovedSome evidence for acute zoster pain (IV fosphenytoin); limited chronic pain applications[90,91]
BupivacaineMultiple (Pfizer Inc., Marcaine® and Generic)Non-selective VGSC (Nav1.1–Nav1.9)Direct Nav blocker for regional anesthesiaFDA ApprovedCanonical anesthesia. Blocks nerve impulses by increasing the threshold for nerve excitation, preventing pain signals from reaching the brain. Adverse effects (e.g., cardiotoxicity) linked to cardiac Nav1.5 inhibition[92,93,94]
RopivacaineGlenmark Pharmaceuticals Inc. (Generic), AstraZeneca (Naropin)Broad Nav block (Nav1.1–Nav1.9)Non-selective Nav blocker, similar site as bupivacaine with lower affinity for cardiac Nav1.5FDA ApprovedCanonical anesthetic Nav blocker with reduced cardiotoxicity compared to bupivacaine[95,96]
AmitriptylineMultiple (original: Merck & Co, Elavil®)Non-selective VGSC (Nav1.1–Nav1.9)Use-dependent block of Nav channels in addition to potent SERT/NET inhibitionFDA ApprovedCanonical anesthesia. Indirect cardiac effects via multiple channels[97,98,99]
CIPN, chemotherapy-induced peripheral neuropathy; FDA, Food and Drug Administration; IV, intravenous; NDA, new drug application; NMDA receptor, N-methyl-D-aspartate receptor; PHN, postherpetic neuralgia; PNA, peptide nucleic acid; VGSC, voltage-gated sodium channel; -, not clear or poorly investigated.
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MDPI and ACS Style

Xie, Y.; Huang, X.; Lu, F.; Huang, J. Targeting Nav Channels for Pain Relief: Structural Insights and Therapeutic Opportunities. Int. J. Mol. Sci. 2026, 27, 1180. https://doi.org/10.3390/ijms27031180

AMA Style

Xie Y, Huang X, Lu F, Huang J. Targeting Nav Channels for Pain Relief: Structural Insights and Therapeutic Opportunities. International Journal of Molecular Sciences. 2026; 27(3):1180. https://doi.org/10.3390/ijms27031180

Chicago/Turabian Style

Xie, Yuzhen, Xiaoshuang Huang, Fangzhou Lu, and Jian Huang. 2026. "Targeting Nav Channels for Pain Relief: Structural Insights and Therapeutic Opportunities" International Journal of Molecular Sciences 27, no. 3: 1180. https://doi.org/10.3390/ijms27031180

APA Style

Xie, Y., Huang, X., Lu, F., & Huang, J. (2026). Targeting Nav Channels for Pain Relief: Structural Insights and Therapeutic Opportunities. International Journal of Molecular Sciences, 27(3), 1180. https://doi.org/10.3390/ijms27031180

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