Voltage-gated sodium channels as analgesic targets

This was originally written as an Advanced Studies Extension report for the excellent BIOL2174 course at ANU. It’s a review of a few papers investigating various modalities of sodium channel inhibition in the treatment of various pain syndromes. It was originally entitled The Promises and Pitfalls of Nav1.7-Modulating Analgesics: Central Mechanisms of Pain Insensitivity and the Case for Combination Inhibitors.

Introduction

Pain constitutes a substantial burden on public health.¹ However, standard pharmacotherapies are associated with a range of somatic, central, and peripheral side effects,^{2 3} along with concerns of limited efficacy.⁴ Hence, there is a pressing need for more effective and tolerable analgesics.

A promising analgesic target is voltage-gated sodium channels (VGSCs, also denoted Na_v), a family of transmembrane ion channels found in excitable cells which are responsible for the initiation and propagation of action potentials.⁵ VGSCs consist of a large, pore-forming α-subunit and auxiliary β-subunits,⁵ and exist in nine known isoforms in humans, denoted Na_v1.1–Na_v1.9.⁵ Notably, VGSCs are essential to the functioning of nociceptors, the primary sensory neurons responsible for the generation of pain signals.⁶ Pain-related research has largely focused on the Na_v1.7, Na_v1.8, and Na_v1.9 subtypes, as gain-of-function mutations in these have been associated with a range of pain disorders, including inherited erythromelalgia and small fibre neuropathy.⁷ However, Na_v1.7 has been a particularly desirable target since it was found in 2006 that certain loss-of-function mutations cause a total and congenital insensitivity to pain (CIP),⁸ with no other phenotypic abnormalities beyond anosmia.⁹

The desire to pharmacologically reproduce this pain-free state for therapeutic purposes has prompted the development of numerous potent and selective inhibitors of Na_v1.7.¹⁰ However, the in vivo analgesic efficacy of these agents has been lacklustre, with numerous candidate molecules failing to meet endpoints in clinical trials for conditions such as trigeminal neuralgia and small-fibre neuropathy.¹⁰ Though reasons for these failures have not been conclusively established, in this report, I explore findings regarding the analgesic mechanisms of Na_v1.7. Specifically, I examine the role of central nervous system (CNS) opioidergic pathways in Na_v1.7-related CIP phenotypes, the modulatory effects of Na_v1.9 in Na_v1.7 inhibition-induced analgesia, and the clinical analgesic potential of combination inhibitors of Na_v1.7, Na_v1.8, and Na_v1.9.

Paper summaries

Paper 1

Minett MS, Pereira V, Sikandar S, Matsuyama A, Lolignier S, Kanellopoulos AH, et al. Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7. Nat Commun. 2015 Dec 4;6:8967.

Minett et al conducted a study with the aim of determining why selective Na_v1.7 inhibitors fail to mimic the state of profound analgesia induced by Na_v1.7 loss-of-function mutations. Based on the hypothesis that Na_v1.7 may be involved in processes other than the propagation of action potentials, they compared the changes in gene expression in mouse dorsal root ganglion (DRG) sensory neurons induced by selective deletion of Na_v1.7, Na_v1.8, and Na_v1.9. They found that levels of mRNA for Ceacam10, and Penk, which codes for proenkephalin (PENK), were upregulated in Na_v1.7-null mutant mice, but not in Na_v1.8- or Na_v1.9-null mutants, with Na_v1.7-mediated sodium influx potentially modulating gene expression.

As PENK is the precursor to met-enkephalin and leu-enkephalin, endogenous agonists of µ- and δ-opioid receptors, they administered the opioid antagonist naloxone to Na_v1.7-null mutant mice. At doses which did not affect the pain thresholds of littermate controls, Na_v1.7-null mice experienced a dramatic restoration of their thermal and mechanical pain thresholds to near that of the controls. Electrophysiological studies also found reduced nociceptive input to the CNS in Na_v1.7 knockout mice in response to thermal and mechanical stimuli, which was increased in the presence of naloxone. Finally, naloxone was administered to a human Na_v1.7-null CIP patient, which caused a similarly dramatic reversal of analgesia. They concluded that Na_v1.7 loss-of-function mutations caused upregulation of endogenous opioid signalling, which inhibits nociceptive input to the spinal cord, and speculated that the analgesic mediocrity of Na_v1.7 inhibitors may result from their inability to completely block Na_v1.7-mediated sodium influx.

Paper 2

Zhou X, Ma T, Yang L, Peng S, Li L, Wang Z, et al. Spider venom-derived peptide induces hyperalgesia in Nav1.7 knockout mice by activating Nav1.9 channels. Nat Commun. 2020 May 8;11(1):2293.

Zhou et al studied the pharmacodynamics of the spider-derived toxin HpTx1 and its effects on nociception in Na_v1.7, Na_v1.8, and Na_v1.9-knockout (KO) mice, with the aim of elucidating the role of crosstalk between the Na_v subtypes in pain signalling. HpTx1 was identified as an agent capable of recovering pain responses in Na_v1.7-KO mice through fractionation and screening of crude spider and snake venom. It produced robust pain-inducing effects in mechanical evoked pain models in the Na_v1.7-KO mice, and current-clamp recordings found it increased the membrane excitability of DRG neurons, suggesting a direct effect on nociceptor function. In-vitro assays found HpTx1 inhibited human Na_v1.7 currents, contrary to expectations of Na_v1.7 inhibition producing analgesia, suggesting that other channels may be implicated in its pain-inducing effects. It was also found to activate Na_v1.9, while no effect was observed on Na_v1.8, Additionally, when administered to Na_v1.9-KO mice, HpTx1 produced an analgesic effect, suggesting that its pain-inducing effects were contingent on Na_v1.9 activation. Further in-vivo studies found that HpTx1 did not affect pain responses in Na_v1.8-KO mice, suggesting that despite not directly affecting it, pain induction by HpTx1 was also dependent on Na_v1.8.

Based on this, the authors suggested that HpTx1-induced enhancement of Na_v1.9 activity might antagonise the analgesic activity conferred by Na_v1.7 inhibition, hypothesising that Na_v1.9’s depolarisation of the resting membrane potential (RMP) may compensate for the lack of Na_v1.7 by promoting the activity of other ion channels, such as Na_v1.8, which prior research has implicated in the rising phase of AP generation.

Paper 3

Kamei T, Ishibashi F, Takada Y, Ohno A, Tani N, Ikeda K, et al. A novel Nav1.7, Nav1.8, and Nav1.9 blocker, ANP-230, has broad analgesic efficacy in preclinical pain models with favorable safety margins. Biochemical and Biophysical Research Communications. 2025 Sept 1;777:152197.

Kamei et al performed in-vivo studies of ANP-230, an investigational equipotent inhibitor of Na_v1.7, Na_v1.8, and Na_v1.9, with the aim of characterising its analgesic efficacy, tolerability, and distribution profile. They tested the drug against pregabalin (a modulator of the α₂δ₁ subunit of voltage-gated calcium channels clinically used for neuropathic pain) in rodent models of neuropathic pain and found ANP-230 produced dose-dependent alleviation of neuropathic mechanical allodynia, comparable and in some cases superior to that produced by pregabalin. Furthermore, at therapeutic doses, ANP-230 was found to induce minimal impairment of motor coordination and locomotor activity in healthy rat models compared to pregabalin. Similar studies in models of acute nociceptive (inflammatory) pain found no significant difference in pain response induced by ANP-230 and therapeutic concentrations of the NSAID diclofenac, suggesting that this mechanism holds potential for the treatment of both forms of pain.

To elucidate the reasons for ANP-230’s lack of CNS side effects, autoradiography of rats administered therapeutic doses of ¹⁴C-radiolabelled ANP-230 found substantially lower radioactivity throughout the CNS than in other tissues, suggesting that poor CNS distribution is responsible for its low central side effect burden. Finally, based on prior findings that Na_v inhibition-induced analgesia is potentiated by subtherapeutic doses of opioids, the analgesic efficacy of ANP-230 and morphine administered separately or together was evaluated in the rat spinal nerve ligation (SNL) model of neuropathic pain. At doses insufficient for either to produce significant analgesia alone, the combination produced a pronounced analgesic effect, with greater improvements seen at higher doses.

Experimental methodology of Paper 1

Mice Male and female mice, aged between 8–12 weeks, were given unrestricted access to food and water and maintained on a 12-hour light/dark cycle. Na_v1.7-KO mice were created by crossing mice with a floxed SCN9A gene with Advillin-Cre mice to selectively knockout SCN9A in sensory neurons. Ceacam10 global null mutant mice were supplied.

Gene expression Dorsal root ganglion (DRG) neurons were extracted from all spinal levels of Na_v1.7-KO and littermate control mice and analysed using an Affymetrix microarray system. Existing gene expression data for Na_v1.8 and Na_v1.9-null mutants, was accessed through the GEO database (accession number GSE61373). Differentially expressed (DE) genes were identified via ANOVA and gene ontology-based enrichment analysis was performed to identify overexpressed pathways.

Cell culture DRG neurons from all spinal levels of wild-type mice were harvested and dissociated into individual cells via standard enzymatic protocol. The dissociated neurons were plated and sustained in DMEM, a liquid growth medium, with foetal bovine serum and Glutamax. Plates were incubated in either the sodium ionophore monensin (500 nM), the calcium ionophore ionomycin (200 nM), or the selective Na_v blocker tetrodotoxin (TTX, at 0, 100, 250, and 500 nM).

RNA quantification RNA was extracted from lumbar DRG segments in knockout mice and the cultured DRG neurons, and reverse transcriptase quantitative PCR was performed. cDNA produced was amplified and quantified using a thermocycler. Expression levels of the target genes, Penk and Ceacam10 were normalised relative to the housekeeping gene Gapdh to control for variability due to starting material.

Immunohistochemistry Na_v1.7-null mutants and littermate control mice were perfused with phosphate-buffered saline (PBS) and 4% paraformaldehyde in PBS, and lumbar spinal cord fragments were fixed, cryoprotected in 0.3 M sucrose solution, and stored at −80°C. Free-floating 30µM sections were obtained, goat serum was added to block the tissue, and the slice was permeabilised with Triton X-100. The primary rabbit anti-met-enkephalin antibody was applied overnight, and co-stained with isolectin B4. Slices were imaged using a spectral confocal microscope.

Mouse behavioural testing of analgesia Mechanical nociceptive thresholds were measured using the Randall-Selitto test with a 500-gram cut-off. Thermal nociceptive thresholds were quantified using the Hargreaves apparatus, ramping at 2.25°C per second for a maximum of 20 seconds. Opioid dependence of Na_v1.7-KO analgesia was tested by administration of naloxone hydrochloride dihydrate (2 mg/kg, i.p.).

In-vivo electrophysiology Na_v1.7-null mutant and littermate control mice were anaesthetised, and tungsten electrodes were used to make extracellular recordings of wide dynamic range (WDR) neurons in the deep dorsal horn (200-600 µM deep). Mechanical and thermal stimuli were than applied to the peripheral receptive field on the hindpaw glabrous skin, including 8 g von Frey stimulation (application of a thin plastic filament), noxious prod stimulation (100 g/cm² pressure), and a thermal water jet at 40°C and 45°C. Opioid dependence was tested via naloxone administered subcutaneously (2 mg/kg, s.c.).

Finally, human behavioural testing was conducted on a 39-year-old female patient with Na_v1.7-null CIP and three age-matched healthy controls. An infrared laser was used to stimulate intra-epidermal free nerve endings, targeting thermal nociceptive input, for a phasic pain assessment (testing the probability of detecting 9ms laser pulses), and a tonic pain assessment (rating intensity of sensation of 25 seconds of laser heat at temperatures of 42, 45, and 48°C from 0-100). Participants were administered intravenous naloxone (12 mg) or saline in a randomised order. Assessments were conducted at baseline, during infusion of saline, and during infusion of naloxone.

Discussion

Contributions to and relationships with contemporary thinking in the field

All three papers contributed to current discourse about the role of Na_v1.7 in pain perception. Paper 1¹¹ by Minett et al was the first to characterise upregulation of enkephalin signalling in sensory neurons as a consequence of Na_v1.7 knockout, and implicate it in the pathophysiology of CIP. Previous research attributed such CIP phenotypes solely to the loss of what was assumed to be a channel essential to human nociception.⁸ The importance of CNS opioid signalling in CIP has been subsequently extensively validated.^{12 13 14}

Their paper was also among the first to suggest a mechanism for the observed¹⁵ clinical¹⁶ mediocrity¹⁷ of Na_v1.7 inhibitors as analgesics. They suggested that the upregulation required for CIP may only occur with complete inhibition of Na_v1.7, which is extremely difficult to achieve in-vivo due to the concentrations of inhibitor required. In contrast, in Paper 2¹⁸, Zhou et al propose an alternative explanation—that analgesia from Na_v1.7 inhibition may be largely counteracted by the normal (or even compensatorily upregulated) functioning of Na_v1.9.

Another significant contribution from Paper 1 was the implication that different subtypes of Na_v are capable of compensating for loss-of-function in others, given that normal nociception could be recovered in both mouse and human Na_v1.7-KO solely by opioid antagonism. Further research has since confirmed that Na_v1.7-KO nociceptors show normal excitability and functioning, suggesting other subtypes can functionally emulate the missing isoform.¹⁴ This notion was furthered in Paper 2 by the finding that Na_v1.9 potentiation is capable of not only nullifying Na_v1.7-inhibition-induced analgesia, but also inducing pain, implying peripherally expressed Na_v subtypes (i.e., Na_v1.9) are capable of compensating for the loss-of-function of Na_v1.7, both in CIP knockout and inhibition. If Na_v1.7 function were truly essential and non-redundant for nociception, pain insensitivity would not be so easily reversible.

Furthermore, the finding that activation of Na_v1.9 is capable of restoring pain sensitivity in CIP mice is a significant one, as it suggests that CIP is also reversible by potentiation of nociceptive signalling via other Na_v isoforms. This does not absolutely contradict the opioid-dependent mechanism put forward in Paper 1, but it implies that opioidergic inhibition of central pain perception can be overcome by sufficiently intense peripheral nociceptive signalling.

Paper 3¹⁹ (Kamei et al)’s finding that triple inhibition of Na_v1.7, Na_v1.8, and Na_v1.9 is consistent with Zhou et al’s suggestion that analgesia from inhibition of Na_v1.7 is antagonised by activation of Na_v1.9, a significant contribution to the field. Moreover, it is also significant that the analgesia produced through this simultaneous inhibition is in no way comparable to the complete pain insensitivity arising from Na_v1.7 loss-of-function. It implies that this combined inhibition produces analgesia of a different sort to that in the CIP phenotype, and hints at a possible distinct mechanism involving only ‘simple’ peripheral inhibition of nociception. This is consistent with the earlier finding that the modest analgesia produced by Na_v1.7 knockout in adult mice occurs solely through diminished neuronal excitability.¹³ Perhaps similar mechanisms are at play with ANP-230.

Taken together, these papers track a shift in perspective over the past decade, from the search for a ‘magic bullet’ Na_v1.7 inhibitor to replicate the total pain insensitivity seen in CIP, to the development of combination inhibitors of Na_vs capable of producing robust but not total analgesia.

Comparison and evaluation of methodologies

All three papers involve the use of mutant rodent models and behavioural tests to investigate the effects of various experimental variables on pain sensation and responses. Specifically, Papers 1 and 2 relied primarily on mouse models—likely due to the greater ease with which gene knockouts can be performed—while Paper 3 used various rat models of pain and testing, likely because rats more closely resemble human behavioural responses than mice.²⁰ However, the methodologies otherwise vary in respects reflecting their different aims and approaches.

For instance, in Paper 1, Minett et al includes a human case-study to provide proof-of-concept of the translatability of the enkephalin upregulation-based mechanism from mice to humans. In addition, the behavioural studies in KO mice merely served as supporting evidence, with the study’s main findings coming from gene expression analysis and immunohistochemistry studies. Conversely, Paper 2 also employs a patch-clamp to precisely characterise the effects of HpTx1 on isolated ion channels, and identifies the toxin in-situ by fractionation and protein purification of crude venom. Finally, Paper 3 uniquely uses radiolabelling/autoradiography to study the tissue of its study drug, as well as a variety of preclinical pain models to comprehensively assess its analgesic potential.

The model systems used each have their own benefits and drawbacks. Mutant mice allow study of single genes and can model human genetic diseases, but findings may not always translate to humans due to genetic and physiological differences. Conversely, human subjects, such as the CIP patient studied in Minett et al, provide direct evidence for the role of a gene in human physiology, but the limited number of available patients with rare diseases restricts the generalisability of findings. The pharmacological and behavioural models of pain such as those used in Paper 3 can provide useful information about the safety and efficacy of potential drugs before human trials—but, as with mutant mice, interspecies variations in metabolism, distribution, and drug targets limits translatability to humans. Finally, the cultured neurons, HEK cells and brain slices used in Papers 1 and 2 to characterise drug effects in vitro allow for precise control of the cellular environment and measurement of activity, but suffer from removing the cells from their natural contexts, again limiting their generalisability to real-world conditions and applications.

Limitations and questions for further study

The papers discussed raise several questions and avenues for further study, both directly and implicitly. For instance, in Paper 3, Kamei et al note that the findings were obtained in male subjects only, and that future research on the analgesic effects of ANP-230 in female animals would more effectively characterise its potential clinical efficacy. More fundamentally, they also raise the question of which of Na_v1.7, Na_v1.8, and Na_v1.9 are most important in the drug’s analgesic effects. They propose further studies using knockout and gain-of-function mice for each channel isoform, and investigation of differences in analgesic potency between chemical analogues of ANP-230 with distinct selectivity profiles. Similarly, Minett et al make suggestions for future study in Paper 1, including studying more human CIP patients to further test their findings, and validating combination analgesics involving both an Na_v1.7 inhibitor and an opiodergic agent, based on the mechanisms observed.

The author of this report submits some questions of their own. One, based on the findings of Paper 1, is what conditions are required for the upregulation of enkephalin expression seen in CIP. Though Minett et al propose total inhibition of Na_v1.7 as a requirement, based on the high concentrations of tetrodotoxin required to upregulate Penk, studies involving knockout of Na_v1.7 (effectively total inhibition) in adult mice have not found any change in opioid signalling.¹³ Perhaps Na_v1.7 loss-of-function during some particular developmental critical period may be essential to the development of complete pain insensitivity, or it may simply require prolonged loss-of-function of Na_v1.7, beyond that studied in [13] or elsewhere. If so, Na_v1.7 inhibitors could increase in analgesic effectiveness over time.

Furthermore, the potentiation of the effects of the combination Na_v inhibitor ANP-230 by subtherapeutic doses of opioids prompts the question of whether endogenous opioid signalling pathways are implicated in the drug’s mechanism—i.e., whether its analgesia is achieved purely through inhibition of peripheral neuronal activity, upregulation of enkephalin expression, or some other mechanism.

Epilogue

The dependence of HpTx1-induced pain on the functioning of Na_v1.8 as seen in Paper 2 raises the question of whether inhibition of Na_v1.8 alone might constitute a reasonable analgesic target. This is, it must be said, somewhat rhetorical, as it was answered by the US Food and Drug Administration (FDA) in January 2025 with the approval of suzetrigine (JOURNAVX™, Vertex Pharmaceuticals), an oral, selective Na_v1.8 inhibitor, for the treatment of moderate-to-severe acute pain.²¹ It remains to be seen whether similar successes will be attained by drugs targeting Na_v1.7. However, given the effectiveness of suzetrigine on its own, the preclinical success of the combination inhibitor ANP-230, and the ever-accelerating pace of basic science research into Na_vs and pain, the future seems bright for Na_v1.7 inhibitors.

References

1. Goldberg DS, McGee SJ. Pain as a global public health priority. BMC Public Health. 2011 Oct 6;11:770.

2. Currow DC, Phillips J, Clark K. Using opioids in general practice for chronic non-cancer pain: an overview of current evidence. Med J Aust [Internet]. 2016 May 2 [cited 2025 Oct 16];204(8). Available from: https://www.mja.com.au/journal/2016/204/8/using-opioids-general-practice-chronic-non-cancer-pain-overview-current-evidence

3. Cazacu I, Mogosan C, Loghin F. Safety issues of current analgesics: an update. Clujul Med 1957. 2015;88(2):128–36.

4. Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment. Eur J Pain. 2006;10(4):287–287.

5. Catterall WA, Goldin AL, Waxman SG. International Union of Pharmacology. XLVII. Nomenclature and Structure-Function Relationships of Voltage-Gated Sodium Channels. Pharmacol Rev. 2005 Dec 1;57(4):397–409.

6. Bennett DL, Clark AJ, Huang J, Waxman SG, Dib-Hajj SD. The Role of Voltage-Gated Sodium Channels in Pain Signaling. Physiol Rev. 2019 Apr 1;99(2):1079–151.

7. Yuan JH, Cheng X, Matsuura E, Higuchi Y, Ando M, Hashiguchi A, et al. Genetic, electrophysiological, and pathological studies on patients with SCN9A-related pain disorders. J Peripher Nerv Syst. 2023;28(4):597–607.

8. Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006 Dec 14;444(7121):894–8.

9. Weiss J, Pyrski M, Jacobi E, Bufe B, Willnecker V, Schick B, et al. Loss-of-function mutations in sodium channel Nav1.7 cause anosmia. Nature. 2011 Apr 14;472(7342):186–90.

10. Eagles DA, Chow CY, King GF. Fifteen years of NaV1.7 channels as an analgesic target: Why has excellent in vitro pharmacology not translated into in vivo analgesic efficacy? Br J Pharmacol. 2022;179(14):3592–611.

11. Minett MS, Pereira V, Sikandar S, Matsuyama A, Lolignier S, Kanellopoulos AH, et al. Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7. Nat Commun. 2015 Dec 4;6:8967.

12. Pereira V, Millet Q, Aramburu J, Lopez-Rodriguez C, Gaveriaux-Ruff C, Wood JN. Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors. Wellcome Open Res. 2018;3:101.

13. Iseppon F, Kanellopoulos AH, Tian N, Zhou J, Caan G, Chiozzi R, et al. Sodium channels Nav1.7, Nav1.8 and pain; two distinct mechanisms for Nav1.7 null analgesia. Neurobiol Pain Camb Mass. 2024;16:100168.

14. MacDonald DI, Sikandar S, Weiss J, Pyrski M, Luiz AP, Millet Q, et al. A central mechanism of analgesia in mice and humans lacking the sodium channel NaV1.7. Neuron. 2021 May 5;109(9):1497-1512.e6.

15. Siebenga P, van Amerongen G, Hay JL, McDonnell A, Gorman D, Butt R, et al. 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 Mar;13(2):318–24.

16. McDonnell A, Collins S, Ali Z, Iavarone L, Surujbally R, Kirby S, et al. 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 Aug;159(8):1465–76.

17. Price N, Namdari R, Neville J, Proctor KJW, Kaber S, Vest J, 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 Apr;33(4):310–8.

18. Zhou X, Ma T, Yang L, Peng S, Li L, Wang Z, et al. Spider venom-derived peptide induces hyperalgesia in Nav1.7 knockout mice by activating Nav1.9 channels. Nat Commun. 2020 May 8;11(1):2293.

19. Kamei T, Ishibashi F, Takada Y, Ohno A, Tani N, Ikeda K, et al. 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 Sept 1;777:152197.

20. Bryda EC. The Mighty Mouse: The Impact of Rodents on Advances in Biomedical Research. Mo Med. 2013;110(3):207–11.

21. Vertex. Vertex Announces FDA Approval of JOURNAVX™ (suzetrigine), a First-in-Class Treatment for Adults With Moderate-to-Severe Acute Pain | Vertex Pharmaceuticals Newsroom [Internet]. Vertex Pharmaceuticals. 2025 [cited 2025 Oct 18]. Available from: https://news.vrtx.com/news-releases/news-release-details/vertex-announces-fda-approval-journavxtm-suzetrigine-first-class