{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:14:48Z","timestamp":1788542088562,"version":"build-2803163510"},"reference-count":182,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>For a long time, pain management has relied on relatively old opioids and broad-spectrum non-opioids, which display efficacy gaps and non-negligible safety risks. This review explores why voltage-gated sodium channels, particularly NaV1.7 and NaV1.8, emerged as prime targets for pain relief, and why early development efforts failed. NaV1.7 was initially considered a promising target due to its role in nociception and genetic evidence linking it to pain disorders. However, clinical trials of selective NaV1.7 inhibitors have repeatedly failed. We explore the reasons for these failures and discuss the clinical shortcomings of non-selective blockers and early NaV1.7 inhibitors. In contrast, NaV1.8 has emerged as a much stronger drug target, because it is mostly limited to peripheral nerves, directly drives continuous pain signaling, and shows less apparent functional redundancy in specific nociceptive axonal compartments. Nevertheless, compensatory mechanisms involving NaV1.7, NaV1.9, and other conductances remain context-, tissue-, and disease-dependent. Suzetrigine, a highly selective inhibitor of this channel, recently gained regulatory approval for acute pain, marking a major breakthrough in non-opioid options, even though its Phase 3 efficacy was comparable to hydrocodone\/acetaminophen rather than superior to it. Its clinical success is built on high selectivity, excellent pharmacokinetics, and a smart trial design that focused specifically on standardized postoperative pain models. While suzetrigine shows that NaV1.8 can be successfully targeted, it represents a regulatory and mechanistic victory rather than a complete replacement for opioids in daily practice. Progress in this field will ultimately require precise targeting, better pharmacology, and trials that better match patient phenotypes.<\/jats:p>","DOI":"10.3390\/medicina62091698","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T16:07:32Z","timestamp":1788538052000},"page":"1698","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chasing the Wrong Door for 30 Years: Is Suzetrigine the Key to Selective Pain Relief?"],"prefix":"10.3390","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9369-3314","authenticated-orcid":false,"given":"Robert","family":"Ancuceanu","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, Department of Pharmaceutical Botany and Cell Biology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athena","family":"Ribigan","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Clinical Neurosciences, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Neurology Department, University Emergency Hospital Bucharest, 050098 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana-Iuliana","family":"Anghel","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Department of Pharmaceutical Botany and Cell Biology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihaela","family":"Dinu","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Department of Pharmaceutical Botany and Cell Biology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1097\/SPC.0000000000000495","article-title":"Opioid analgesia: Recent developments","volume":"14","author":"Stein","year":"2020","journal-title":"Curr. Opin. Support. Palliat. Care"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e67523","DOI":"10.7554\/eLife.67523","article-title":"Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network","volume":"10","author":"Baertsch","year":"2021","journal-title":"eLife"},{"key":"ref_3","first-page":"269","article-title":"Identification and management of opioid-induced neurotoxicity in older adults","volume":"68","author":"Godwin","year":"2022","journal-title":"Can. Fam. Physician Med. Fam. Can."},{"key":"ref_4","unstructured":"Banik, R.K. (2022). Opioid Analgesics, Tolerance, Dependence and Addiction. Anesthesiology In-Training Exam Review, Springer International Publishing."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1002\/jnr.24756","article-title":"Genetic implications in quality palliative care and preventing opioid crisis in cancer-related pain management","volume":"100","author":"Sumitani","year":"2022","journal-title":"J. Neurosci. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1111\/add.16123","article-title":"Understanding the differential effect of local socio-economic conditions on the relation between prescription opioid supply and drug overdose deaths in US counties","volume":"118","author":"Fink","year":"2023","journal-title":"Addiction"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1177\/20494637231216352","article-title":"Does opioid therapy enhance quality of life in patients suffering from chronic non-malignant pain? A systematic review and meta-analysis","volume":"18","author":"Kraft","year":"2024","journal-title":"Br. J. Pain"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Cordero-P\u00e9rez, F.J., P\u00e9rez-Baena, M.J., Pina-Ruviralta, N., Fern\u00e1ndez-Testa, A., and Holgado-Madruga, M. (2026). Optimizing Opioid Use in Pain Management: A Comprehensive Review of Clinical Benefits, Risks, and Dependence. Healthcare, 14.","DOI":"10.3390\/healthcare14040457"},{"key":"ref_9","first-page":"891","article-title":"The Economic Impact of Opioid Use in the Management of Chronic Nonmalignant Pain","volume":"21","author":"Lipman","year":"2015","journal-title":"J. Manag. Care Spec. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1080\/17425255.2020.1721458","article-title":"Pharmacokinetic and pharmacodynamic considerations in developing a response to the opioid epidemic","volume":"16","author":"Balyan","year":"2020","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.2147\/JPR.S457982","article-title":"Review of Opioid Abuse-Deterrent Formulations: Impact and Barriers to Access","volume":"17","author":"Webster","year":"2024","journal-title":"J. Pain Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/jac5.1582","article-title":"Pharmacogenetics: A precision medicine approach to combatting the opioid epidemic","volume":"5","author":"Smith","year":"2022","journal-title":"JACCP J. Am. Coll. Clin. Pharm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1474-4422(14)70251-0","article-title":"Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis","volume":"14","author":"Finnerup","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1002\/jcsm.12352","article-title":"Systematic review and meta-analysis on non-opioid analgesics in palliative medicine","volume":"9","author":"Marinova","year":"2018","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/ar4441","article-title":"Review of pharmacological therapies in fibromyalgia syndrome","volume":"16","author":"Walitt","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1002\/ejp.649","article-title":"Overview review: Comparative efficacy of oral ibuprofen and paracetamol (acetaminophen) across acute and chronic pain conditions","volume":"19","author":"Moore","year":"2015","journal-title":"Eur. J. Pain"},{"key":"ref_17","first-page":"e37080","article-title":"Effects of Non-steroidal Anti-inflammatory Drugs (NSAIDs) and Gastroprotective NSAIDs on the Gastrointestinal Tract: A Narrative Review","volume":"15","author":"Sohail","year":"2023","journal-title":"Cureus"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e00817","DOI":"10.1002\/prp2.817","article-title":"Kidney damage from nonsteroidal anti-inflammatory drugs\u2014Myth or truth? Review of selected literature","volume":"9","author":"Lechowicz","year":"2021","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1093\/fampra\/cms086","article-title":"Non-steroidal anti-inflammatory drugs and chronic kidney disease progression: A systematic review","volume":"30","author":"Nderitu","year":"2013","journal-title":"Fam. Pract."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1038\/s41569-020-0366-z","article-title":"Cardiovascular effects and safety of (non-aspirin) NSAIDs","volume":"17","author":"Schjerning","year":"2020","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.cell.2009.09.028","article-title":"Cellular and molecular mechanisms of pain","volume":"139","author":"Basbaum","year":"2009","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e1309252025","DOI":"10.1523\/JNEUROSCI.1309-25.2025","article-title":"Not Just Neurons: Pain Is Orchestrated in Partnership with Many Non-neuronal Cells","volume":"45","author":"Smith","year":"2025","journal-title":"J. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"\u015al\u0119czkowska, M., Misra, K., Santoro, S., Gerrits, M.M., and Hoeijmakers, J.G.J. (2023). Ion Channel Genes in Painful Neuropathies. Biomedicines, 11.","DOI":"10.3390\/biomedicines11102680"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3644","DOI":"10.1111\/jnc.15742","article-title":"Spinal pain processing in arthritis: Neuron and glia (inter)actions","volume":"168","author":"Schaible","year":"2024","journal-title":"J. Neurochem."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Nijs, J., Lahousse, A., Kapreli, E., Bilika, P., Sara\u00e7o\u011flu, \u0130., Malfliet, A., Coppieters, I., De Baets, L., Leysen, L., and Roose, E. (2021). Nociplastic Pain Criteria or Recognition of Central Sensitization? Pain Phenotyping in the Past, Present and Future. J. Clin. Med., 10.","DOI":"10.3390\/jcm10153203"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/nrd4334","article-title":"Emerging targets in neuroinflammation-driven chronic pain","volume":"13","author":"Ji","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1002\/bab.2086","article-title":"Pain pathways and potential new targets for pain relief","volume":"69","author":"Wang","year":"2022","journal-title":"Biotechnol. Appl. Biochem."},{"key":"ref_28","first-page":"239","article-title":"The Role of Proteases in Pain","volume":"Volume 227","author":"Schaible","year":"2015","journal-title":"Pain Control"},{"key":"ref_29","first-page":"952906","article-title":"Matrix Metalloproteinases in Neuropathic Pain and Migraine: Friends, Enemies, and Therapeutic Targets","volume":"2012","author":"Lakhan","year":"2012","journal-title":"Pain Res. Treat."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Aburamadan, H., Lozon, Y., Cyril, A.C., Parambath, A.N., Ali, N.M., Jan, R.K., Plevin, R., and Radhakrishnan, R. (2026). Modulation of Nociceptive Ion Channels by Protease-Activated Receptor-2 in Inflammatory Pain: Molecular Mechanisms and Therapeutic Potential. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27041769"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Pawlik, K., and Mika, J. (2023). Targeting Members of the Chemokine Family as a Novel Approach to Treating Neuropathic Pain. Molecules, 28.","DOI":"10.3390\/molecules28155766"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1146\/annurev-pharmtox-051921-084047","article-title":"Specialized Pro-Resolving Mediators as Resolution Pharmacology for the Control of Pain and Itch","volume":"63","author":"Ji","year":"2023","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"26331055231220340","DOI":"10.1177\/26331055231220340","article-title":"A Comprehensive Review on the Regulatory Action of TRP Channels: A Potential Therapeutic Target for Nociceptive Pain","volume":"18","author":"Anand","year":"2023","journal-title":"Neurosci. Insights"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"102433","DOI":"10.1016\/j.coph.2024.102433","article-title":"Analgesic potential of voltage gated sodium channel modulators for the management of pain","volume":"75","author":"McDougall","year":"2024","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Felix, R., Corzo-Lopez, A., and Sandoval, A. (2025). Voltage-Gated Ion Channels in Neuropathic Pain Signaling. Life, 15.","DOI":"10.3390\/life15060888"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6289","DOI":"10.1007\/s00210-025-04859-5","article-title":"Targeting NMDA receptors in pain management: Therapeutic innovations through piracetam repurposing","volume":"399","author":"Dhama","year":"2026","journal-title":"Naunyn. Schmiedebergs Arch. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"107984","DOI":"10.1016\/j.pharmthera.2021.107984","article-title":"Wnt signaling: A prospective therapeutic target for chronic pain","volume":"231","author":"Zhou","year":"2022","journal-title":"Pharmacol. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/35093019","article-title":"Molecular mechanisms of nociception","volume":"413","author":"Julius","year":"2001","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Chhabra, S., and Kumar, R. (2025). Pain Pathways: From Periphery to Perception. Handbook of Perioperative Analgesia, Springer.","DOI":"10.1007\/978-981-96-7822-8_2"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/ar3305","article-title":"Update on peripheral mechanisms of pain: Beyond prostaglandins and cytokines","volume":"13","author":"Schaible","year":"2011","journal-title":"Arthritis Res. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s00540-018-2579-4","article-title":"Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain","volume":"33","author":"Matsuda","year":"2019","journal-title":"J. Anesth."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.it.2017.12.003","article-title":"Immune cytokines and their receptors in inflammatory pain","volume":"39","author":"Cook","year":"2018","journal-title":"Trends Immunol."},{"key":"ref_43","first-page":"13","article-title":"TRP Channels in Nociception and Pathological Pain","volume":"Volume 1099","author":"Shyu","year":"2018","journal-title":"Advances in Pain Research: Mechanisms and Modulation of Chronic Pain"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"265","DOI":"10.3233\/NRE-208002","article-title":"Peripheral neuropathic pain","volume":"47","author":"Murphy","year":"2020","journal-title":"NeuroRehabilitation"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1007\/s11916-017-0629-5","article-title":"Neuropathic Pain: Central vs. Peripheral Mechanisms","volume":"21","author":"Meacham","year":"2017","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41572-023-00484-9","article-title":"Central neuropathic pain","volume":"9","author":"Rosner","year":"2023","journal-title":"Nat. Rev. Dis. Primer"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Bu\u0142dy\u015b, K., G\u00f3rnicki, T., Ka\u0142ka, D., Szuster, E., Biernikiewicz, M., Markuszewski, L., and Sobieszcza\u0144ska, M. (2023). What do we know about nociplastic pain?. Healthcare, 11.","DOI":"10.3390\/healthcare11121794"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2098","DOI":"10.1016\/S0140-6736(21)00392-5","article-title":"Nociplastic pain: Towards an understanding of prevalent pain conditions","volume":"397","author":"Fitzcharles","year":"2021","journal-title":"Lancet"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1093\/ptj\/pzy030","article-title":"A Mechanism-Based Approach to Physical Therapist Management of Pain","volume":"98","author":"Chimenti","year":"2018","journal-title":"Phys. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s41582-024-00966-8","article-title":"Deciphering nociplastic pain: Clinical features, risk factors and potential mechanisms","volume":"20","author":"Kaplan","year":"2024","journal-title":"Nat. Rev. Neurol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2398212818810684","DOI":"10.1177\/2398212818810684","article-title":"Sodium channels","volume":"2","author":"Wood","year":"2018","journal-title":"Brain Neurosci. Adv."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2281714","DOI":"10.1080\/19336950.2023.2281714","article-title":"Voltage gated sodium and calcium channels: Discovery, structure, function, and Pharmacology","volume":"17","author":"Catterall","year":"2023","journal-title":"Channels"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"7093","DOI":"10.1021\/jm501981g","article-title":"Voltage-gated sodium channels: Structure, function, pharmacology, and clinical indications","volume":"58","author":"Kraus","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1085\/jgp.201611668","article-title":"Mechanism of sodium channel block by local anesthetics, antiarrhythmics, and anticonvulsants","volume":"149","author":"Tikhonov","year":"2017","journal-title":"J. Gen. Physiol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Savio-Galimberti, E., Gollob, M.H., and Darbar, D. (2012). Voltage-Gated Sodium Channels: Biophysics, Pharmacology, and Related Channelopathies. Front. Pharmacol., 3.","DOI":"10.3389\/fphar.2012.00124"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.1093\/brain\/aws225","article-title":"Neurological perspectives on voltage-gated sodium channels","volume":"135","author":"Eijkelkamp","year":"2012","journal-title":"Brain"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Xie, Y., Huang, X., Lu, F., and Huang, J. (2026). Targeting Nav Channels for Pain Relief: Structural Insights and Therapeutic Opportunities. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27031180"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/s41583-021-00444-w","article-title":"The physiological function of different voltage-gated sodium channels in pain","volume":"22","author":"Goodwin","year":"2021","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1517\/14728222.2016.1162295","article-title":"Nav 1.7 and other voltage-gated sodium channels as drug targets for pain relief","volume":"20","author":"Emery","year":"2016","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1038\/nature05413","article-title":"An SCN9A channelopathy causes congenital inability to experience pain","volume":"444","author":"Cox","year":"2006","journal-title":"Nature"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Park, T.J., Lu, Y., J\u00fcttner, R., Smith, E.S.J., Hu, J., Brand, A., Wetzel, C., Milenkovic, N., Erdmann, B., and Heppenstall, P.A. (2008). Selective Inflammatory Pain Insensitivity in the African Naked Mole-Rat (Heterocephalus glaber). PLoS Biol., 6.","DOI":"10.1371\/journal.pbio.0060013"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Amoroso, V.G., Zhao, A., Vargas, I., and Park, T.J. (2023). Naked Mole-Rats Demonstrate Profound Tolerance to Low Oxygen, High Carbon Dioxide, and Chemical Pain. Anim. Open Access J., 13.","DOI":"10.3390\/ani13050819"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"135","DOI":"10.12688\/f1000research.2642.1","article-title":"Case Report: Neuropathic pain in a patient with congenital insensitivity to pain","volume":"3","author":"Wheeler","year":"2014","journal-title":"F1000Research"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.celrep.2013.12.033","article-title":"Pain without nociceptors? Nav1.7-independent pain mechanisms","volume":"6","author":"Minett","year":"2014","journal-title":"Cell Rep."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Heinle, J.W., Dalessio, S., Janicki, P., Ouyang, A., Vrana, K.E., Ruiz-Velasco, V., and Coates, M.D. (2024). Insights into the voltage-gated sodium channel, NaV1.8, and its role in visceral pain perception. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1398409"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1152\/physrev.00052.2017","article-title":"The Role of Voltage-Gated Sodium Channels in Pain Signaling","volume":"99","author":"Bennett","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/s41573-024-01108-x","article-title":"Voltage-gated sodium channels in excitable cells as drug targets","volume":"24","author":"Alsaloum","year":"2025","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1038\/ng.2767","article-title":"A de novo gain-of-function mutation in SCN11A causes loss of pain perception","volume":"45","author":"Leipold","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/j.ajhg.2013.09.016","article-title":"Gain-of-Function Mutations in SCN11A Cause Familial Episodic Pain","volume":"93","author":"Zhang","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1093\/brain\/awu079","article-title":"Gain-of-function mutations in sodium channel NaV1.9 in painful neuropathy","volume":"137","author":"Huang","year":"2014","journal-title":"Brain"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1007\/s12264-017-0132-3","article-title":"Expression and Role of Voltage-Gated Sodium Channels in Human Dorsal Root Ganglion Neurons with Special Focus on Nav1.7, Species Differences, and Regulation by Paclitaxel","volume":"34","author":"Chang","year":"2018","journal-title":"Neurosci. Bull."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1016\/j.neuron.2023.08.011","article-title":"NaV1.7: A central role in pain","volume":"111","author":"Waxman","year":"2023","journal-title":"Neuron"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Alexandrou, A.J., Brown, A.R., Chapman, M.L., Estacion, M., Turner, J., Mis, M.A., Wilbrey, A., Payne, E.C., Gutteridge, A., and Cox, P.J. (2016). Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0152405"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e2503570122","DOI":"10.1073\/pnas.2503570122","article-title":"Modulation of human dorsal root ganglion neuron firing by the Nav1.8 inhibitor suzetrigine","volume":"122","author":"Stewart","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1744806919858801","DOI":"10.1177\/1744806919858801","article-title":"Nav1.7 and Nav1.8: Role in the pathophysiology of pain","volume":"15","author":"Hameed","year":"2019","journal-title":"Mol. Pain"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e202313526","DOI":"10.1085\/jgp.202313526","article-title":"Nociceptor sodium channels shape subthreshold phase, upstroke, and shoulder of action potentials","volume":"157","author":"Leipold","year":"2025","journal-title":"J. Gen. Physiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.12998\/wjcc.v9.i9.2100","article-title":"Expert consensus of the Chinese Association for the Study of Pain on ion channel drugs for neuropathic pain","volume":"9","author":"Xiao","year":"2021","journal-title":"World J. Clin. Cases"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jpain.2017.08.001","article-title":"Old Friends with New Faces: Are Sodium Channel Blockers the Future of Adjunct Pain Medication Management?","volume":"19","author":"Thomas","year":"2018","journal-title":"J. Pain"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.pain.2006.09.010","article-title":"Are sodium channel blockers useless in peripheral neuropathic pain?","volume":"128","author":"Sindrup","year":"2007","journal-title":"Pain"},{"key":"ref_80","unstructured":"The Cochrane Collaboration (2011). Carbamazepine for acute and chronic pain in adults. Cochrane Database of Systematic Reviews, John Wiley & Sons, Ltd."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Kocot-K\u0119pska, M., Pawlik, K., Ciapa\u0142a, K., Makuch, W., Zaj\u0105czkowska, R., Dobrogowski, J., Przeklasa-Muszy\u0144ska, A., and Mika, J. (2023). Phenytoin Decreases Pain-like Behaviors and Improves Opioid Analgesia in a Rat Model of Neuropathic Pain. Brain Sci., 13.","DOI":"10.3390\/brainsci13060858"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1111\/ene.13950","article-title":"European Academy of Neurology guideline on trigeminal neuralgia","volume":"26","author":"Bendtsen","year":"2019","journal-title":"Eur. J. Neurol."},{"key":"ref_83","first-page":"CD006044","article-title":"Lamotrigine for chronic neuropathic pain and fibromyalgia in adults","volume":"2013","author":"Wiffen","year":"2013","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Lynch, M.E., Craig, K.D., and Peng, P.W. (2022). Anticonvulsants in the management of chronic pain. Clinical Pain Management, Wiley. [1st ed.].","DOI":"10.1002\/9781119701170"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"76","DOI":"10.22514\/jofph.2026.037","article-title":"Slow-inactivated sodium channels as a therapeutic target in trigeminal neuralgia: Evidence from a systematic review and meta-analysis of lacosamide","volume":"40","author":"Meechumnarn","year":"2026","journal-title":"J. Oral Facial Pain Headache"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1080\/14737175.2026.2688513","article-title":"Clinical efficacy of lacosamide in neuropathic pain: A systematic review of randomized controlled trials","volume":"26","author":"Kaur","year":"2026","journal-title":"Expert Rev. Neurother."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1001\/jamaneurol.2023.3711","article-title":"Safety and efficacy of topiramate in individuals with cryptogenic sensory peripheral neuropathy with metabolic syndrome: The TopCSPN randomized clinical trial","volume":"80","author":"Smith","year":"2023","journal-title":"JAMA Neurol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1097\/00000542-199105000-00026","article-title":"Neuropathic Pain Can Be Relieved by Drugs That Are Use-dependent Sodium Channel Blockers: Lidocaine, Carbamazepine, and Mexiletine","volume":"74","author":"Tanelian","year":"1991","journal-title":"Anesthesiology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/S0304-3959(00)00229-3","article-title":"Systemic lidocaine for neuropathic pain relief","volume":"87","author":"Mao","year":"2000","journal-title":"Pain"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1093\/bja\/54.5.501","article-title":"Analgesic responses to i.v. lignocaine","volume":"54","author":"Boas","year":"1982","journal-title":"Br. J. Anaesth."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"73","DOI":"10.64719\/pb.4495","article-title":"Intravenous lidocaine for the management of chronic pain: A narrative review of randomized clinical trials","volume":"54","author":"Onyeaka","year":"2024","journal-title":"Psychopharmacol. Bull."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Djuric, M., and Nenadic, I. (2025). Anesthetics and Cardiovascular Toxicity. Cardiovascular Toxicity: Incidence, Pathogenesis and Treatment Strategies, Springer.","DOI":"10.1007\/978-3-031-90598-8_12"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.pmn.2019.06.008","article-title":"Intravenous Lidocaine for Chronic Neuropathic Pain A Systematic Review Addressing Nursing Care","volume":"21","author":"Lancaster","year":"2020","journal-title":"Pain Manag. Nurs."},{"key":"ref_94","first-page":"1738","article-title":"Systemic administration of local anesthetics to relieve neuropathic pain: A systematic review and meta-analysis","volume":"101","author":"Challapalli","year":"2005","journal-title":"Anesth. Analg."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.jpainsymman.2007.04.022","article-title":"Mexiletine therapy for chronic pain: Survival analysis identifies factors predicting clinical success","volume":"35","author":"Carroll","year":"2008","journal-title":"J. Pain Symptom Manag."},{"key":"ref_96","first-page":"e73683","article-title":"Early Recognition and Management of Flecainide Toxicity: A Case Report and Literature Review","volume":"16","author":"Alraee","year":"2024","journal-title":"Cureus"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1111\/bph.12534","article-title":"Properties of human brain sodium channel \u03b1-subunits expressed in HEK293 cells and their modulation by carbamazepine, phenytoin and lamotrigine","volume":"171","author":"Qiao","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1093\/brain\/awu105","article-title":"Voltage-gated sodium channel mutations and painful neuropathy: Nav1.9 joins the family","volume":"137","author":"Bennett","year":"2014","journal-title":"Brain"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2576","DOI":"10.1523\/JNEUROSCI.4118-04.2005","article-title":"Multiple interacting sites of ectopic spike electrogenesis in primary sensory neurons","volume":"25","author":"Amir","year":"2005","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1080\/13543784.2020.1728254","article-title":"Neuropathic pain: Preclinical and early clinical progress with voltage-gated sodium channel blockers","volume":"29","author":"Kushnarev","year":"2020","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.pharmthera.2016.11.015","article-title":"NaV1.7 as a pain target\u2014From gene to pharmacology","volume":"172","author":"Vetter","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Lanzetti, S., and Di Biase, V. (2022). Small Molecules as Modulators of Voltage-Gated Calcium Channels in Neurological Disorders: State of the Art and Perspectives. Molecules, 27.","DOI":"10.3390\/molecules27041312"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"100616","DOI":"10.1016\/j.bpsgos.2025.100616","article-title":"Clinical Insights Into the Mechanistic Crossroads of Lamotrigine and Therapeutic Ketosis in Bipolar Depression","volume":"6","author":"Ali","year":"2026","journal-title":"Biol. Psychiatry Glob. Open Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.tips.2017.11.010","article-title":"Na V 1.7 as a Pharmacogenomic Target for Pain: Moving Toward Precision Medicine","volume":"39","author":"Yang","year":"2018","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1038\/ncomms1795","article-title":"Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons","volume":"3","author":"Minett","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1744-8069-8-17","DOI":"10.1186\/1744-8069-8-17","article-title":"Reduction of Voltage Gated Sodium Channel Protein in DRG by Vector Mediated miRNA Reduces Pain in Rats with Painful Diabetic Neuropathy","volume":"8","author":"Chattopadhyay","year":"2012","journal-title":"Mol. Pain"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Gingras, J., Smith, S., Matson, D.J., Johnson, D., Nye, K., Couture, L., Feric, E., Yin, R., Moyer, B.D., and Peterson, M.L. (2014). Global Nav1.7 Knockout Mice Recapitulate the Phenotype of Human Congenital Indifference to Pain. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0105895"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1093\/brain\/awh514","article-title":"Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons","volume":"128","author":"Rush","year":"2005","journal-title":"Brain J. Neurol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1136\/jmg.2003.012153","article-title":"Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia","volume":"41","author":"Yang","year":"2004","journal-title":"J. Med. Genet."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/j.neuron.2006.10.006","article-title":"SCN9A mutations in paroxysmal extreme pain disorder: Allelic variants underlie distinct channel defects and phenotypes","volume":"52","author":"Fertleman","year":"2006","journal-title":"Neuron"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrn3404","article-title":"The NaV1.7 sodium channel: From molecule to man","volume":"14","author":"Yang","year":"2013","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1002\/ana.22485","article-title":"Gain of function Na\u03bd1.7 mutations in idiopathic small fiber neuropathy","volume":"71","author":"Faber","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1111\/j.1399-0004.2007.00790.x","article-title":"Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations","volume":"71","author":"Goldberg","year":"2007","journal-title":"Clin. Genet."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.pain.2009.02.016","article-title":"Two novel SCN9A mutations causing insensitivity to pain","volume":"143","author":"Nilsen","year":"2009","journal-title":"Pain"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1124\/molpharm.120.000079","article-title":"Characterization of Vixotrigine, a Broad-Spectrum Voltage-Gated Sodium Channel Blocker","volume":"99","author":"Hinckley","year":"2021","journal-title":"Mol. Pharmacol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s40263-025-01244-x","article-title":"Sodium Channel Inhibitors in Clinical Development for Pain Management: A Focused Review","volume":"40","author":"Banh","year":"2026","journal-title":"CNS Drugs"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"2953","DOI":"10.1021\/acs.jmedchem.1c00049","article-title":"Discovery of Acyl-sulfonamide Nav 1.7 Inhibitors GDC-0276 and GDC-0310","volume":"64","author":"Safina","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"7029","DOI":"10.1021\/acs.jmedchem.7b00598","article-title":"Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771): Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV 1.7","volume":"60","author":"Swain","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"0599","DOI":"10.34133\/research.0599","article-title":"Discovery of Novel Nav 1.7-Selective Inhibitors with the 1H-Indole-3-Propionamide Scaffold for Effective Pain Relief","volume":"8","author":"Wang","year":"2025","journal-title":"Research"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1124\/jpet.116.239590","article-title":"Pharmacologic Characterization of AMG8379, a Potent and Selective Small Molecule Sulfonamide Antagonist of the Voltage-Gated Sodium Channel NaV1.7","volume":"362","author":"Kornecook","year":"2017","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"101","DOI":"10.12688\/wellcomeopenres.14687.1","article-title":"Analgesia linked to Nav1.7 loss of function requires \u00b5- and \u03b4-opioid receptors","volume":"3","author":"Pereira","year":"2018","journal-title":"Wellcome Open Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1016\/j.neuron.2021.03.012","article-title":"A central mechanism of analgesia in mice and humans lacking the sodium channel NaV1.7","volume":"109","author":"MacDonald","year":"2021","journal-title":"Neuron"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"eaah4874","DOI":"10.1126\/scisignal.aah4874","article-title":"Synergistic regulation of serotonin and opioid signaling contributes to pain insensitivity in Nav1.7 knockout mice","volume":"10","author":"Isensee","year":"2017","journal-title":"Sci. Signal."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"8967","DOI":"10.1038\/ncomms9967","article-title":"Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7","volume":"6","author":"Minett","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"40883","DOI":"10.1038\/srep40883","article-title":"Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a","volume":"7","author":"Deuis","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1097\/j.pain.0000000000001567","article-title":"Antiallodynic effects of the selective NaV1.7 inhibitor Pn3a in a mouse model of acute postsurgical pain: Evidence for analgesic synergy with opioids and baclofen","volume":"160","author":"Mueller","year":"2019","journal-title":"Pain"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"100168","DOI":"10.1016\/j.ynpai.2024.100168","article-title":"Sodium channels Nav1.7, Nav1.8 and pain; two distinct mechanisms for Nav1.7 null analgesia","volume":"16","author":"Iseppon","year":"2024","journal-title":"Neurobiol. Pain"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.1016\/j.neuron.2023.05.024","article-title":"Nav1.7 is essential for nociceptor action potentials in the mouse in a manner independent of endogenous opioids","volume":"111","author":"Deng","year":"2023","journal-title":"Neuron"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"10180","DOI":"10.1523\/JNEUROSCI.1049-18.2018","article-title":"Insensitivity to Pain upon Adult-Onset Deletion of Nav1.7 or Its Blockade with Selective Inhibitors","volume":"38","author":"Shields","year":"2018","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1146\/annurev-neuro-060909-153234","article-title":"Sodium Channels in Normal and Pathological Pain","volume":"33","author":"Cummins","year":"2010","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"8695","DOI":"10.1021\/acs.jmedchem.8b01906","article-title":"Challenges and Opportunities for Therapeutics Targeting the Voltage-Gated Sodium Channel Isoform NaV1.7","volume":"62","author":"Mulcahy","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/nature09975","article-title":"Loss-of-function mutations in sodium channel Nav1.7 cause anosmia","volume":"472","author":"Weiss","year":"2011","journal-title":"Nature"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1097\/j.pain.0000000000003425","article-title":"Discordance between preclinical and clinical testing of Na V 1.7-selective inhibitors for pain","volume":"166","author":"Yang","year":"2025","journal-title":"Pain"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"2289256","DOI":"10.1080\/19336950.2023.2289256","article-title":"Sodium currents in na\u00efve mouse dorsal root ganglion neurons: No major differences between sexes","volume":"18","author":"Ghovanloo","year":"2024","journal-title":"Channels"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/s41583-020-0310-6","article-title":"Qualitative sex differences in pain processing: Emerging evidence of a biased literature","volume":"21","author":"Mogil","year":"2020","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_136","doi-asserted-by":"crossref","unstructured":"Salis, F., Sardo, S., Finco, G., Gessa, G.L., Franconi, F., and Agabio, R. (2024). Sex-Gender Differences Are Completely Neglected in Treatments for Neuropathic Pain. Pharmaceuticals, 17.","DOI":"10.3390\/ph17070838"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"2513","DOI":"10.1021\/acs.jmedchem.6b01918","article-title":"Development of New Benzenesulfonamides As Potent and Selective Nav1.7 Inhibitors for the Treatment of Pain","volume":"60","author":"Wu","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"3133","DOI":"10.1016\/j.celrep.2018.08.063","article-title":"Selective NaV1.7 Antagonists with Long Residence Time Show Improved Efficacy against Inflammatory and Neuropathic Pain","volume":"24","author":"Bankar","year":"2018","journal-title":"Cell Rep."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"12706","DOI":"10.1073\/pnas.0404915101","article-title":"Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain","volume":"101","author":"Nassar","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"3592","DOI":"10.1111\/bph.15327","article-title":"Fifteen years of NaV 1.7 channels as an analgesic target: Why has excellent in vitro pharmacology not translated into in vivo analgesic efficacy?","volume":"179","author":"Eagles","year":"2022","journal-title":"Br. J. Pharmacol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1073\/pnas.94.4.1527","article-title":"Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons","volume":"94","author":"Moss","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1002\/j.1460-2075.1995.tb07091.x","article-title":"Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells","volume":"14","author":"Klugbauer","year":"1995","journal-title":"EMBO J."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/1744-8069-7-32","article-title":"Nav1.7 is the predominant sodium channel in rodent olfactory sensory neurons","volume":"7","author":"Ahn","year":"2011","journal-title":"Mol. Pain"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1111\/jns.12123","article-title":"SCN9A-associated congenital insensitivity to pain and anosmia in an Irish patient","volume":"20","author":"Alexander","year":"2015","journal-title":"J. Peripher. Nerv. Syst."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"6293","DOI":"10.1007\/s11033-023-08507-0","article-title":"Novel SCN9A variant associated with congenital insensitivity to pain","volume":"50","author":"Yammine","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1744-8069-2-5","article-title":"NaV 1.8-null mice show stimulus-dependent deficits in spinal neuronal activity","volume":"2","author":"Matthews","year":"2006","journal-title":"Mol. Pain"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1016\/j.pain.2012.04.022","article-title":"Nav1.8 expression is not restricted to nociceptors in mouse peripheral nervous system","volume":"153","author":"Shields","year":"2012","journal-title":"Pain"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.pain.2007.07.026","article-title":"The roles of sodium channels in nociception: Implications for mechanisms of pain","volume":"131","author":"Cummins","year":"2007","journal-title":"Pain"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1113\/jphysiol.2006.121483","article-title":"Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons","volume":"579","author":"Rush","year":"2007","journal-title":"J. Physiol."},{"key":"ref_150","first-page":"RP111490","article-title":"Modulation of human dorsal root ganglion neuron excitability by Nav1.7 inhibition","volume":"15","author":"Fujita","year":"2026","journal-title":"eLife"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"5204","DOI":"10.1523\/JNEUROSCI.3799-16.2017","article-title":"Sodium Channel Nav 1.8 Underlies TTX-Resistant Axonal Action Potential Conduction in Somatosensory C-Fibers of Distal Cutaneous Nerves","volume":"37","author":"Klein","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"e77558","DOI":"10.7554\/eLife.77558","article-title":"A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels","volume":"11","author":"Xiao","year":"2022","journal-title":"eLife"},{"key":"ref_153","doi-asserted-by":"crossref","unstructured":"Rabia, A., Harripaul, R., Mikhailov, A., Mahmood, S., Maqbool, S., Vincent, J.B., and Ayub, M. (2022). Biallelic Loss of Function Mutation in Sodium Channel Gene SCN10A in an Autism Spectrum Disorder Trio from Pakistan. Genes, 13.","DOI":"10.3390\/genes13091633"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1002\/acn3.372","article-title":"Biallelic SCN 10A mutations in neuromuscular disease and epileptic encephalopathy","volume":"4","author":"Kambouris","year":"2017","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1744806916666083","DOI":"10.1177\/1744806916666083","article-title":"A SCN10A SNP biases human pain sensitivity","volume":"12","author":"Duan","year":"2016","journal-title":"Mol. Pain"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/ng.516","article-title":"Genetic variation in SCN10A influences cardiac conduction","volume":"42","author":"Chambers","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1161\/CIRCULATIONAHA.121.054083","article-title":"Variant Intronic Enhancer Controls SCN10A-short Expression and Heart Conduction","volume":"144","author":"Man","year":"2021","journal-title":"Circulation"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/9195","article-title":"The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways","volume":"2","author":"Akopian","year":"1999","journal-title":"Nat. Neurosci."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1097\/j.pain.0000000000003411","article-title":"Na V 1.8\/Na V 1.9 double deletion mildly affects acute pain responses in mice","volume":"166","author":"Teege","year":"2025","journal-title":"Pain"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.tins.2007.08.004","article-title":"From genes to pain: Nav1.7 and human pain disorders","volume":"30","author":"Cummins","year":"2007","journal-title":"Trends Neurosci."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1111\/j.1471-4159.2008.05466.x","article-title":"Identification of the sensory neuron specific regulatory region for the mouse gene encoding the voltage-gated sodium channel NaV1.8","volume":"106","author":"Puhl","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/s41582-020-00415-2","article-title":"Status of peripheral sodium channel blockers for non-addictive pain treatment","volume":"16","author":"Alsaloum","year":"2020","journal-title":"Nat. Rev. Neurol."},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"Weibel, R., Reiss, D., Karchewski, L., Gardon, O., Matifas, A., Filliol, D., Becker, J.A.J., Wood, J.N., Kieffer, B.L., and Gaveriaux-Ruff, C. (2013). Mu Opioid Receptors on Primary Afferent Nav1.8 Neurons Contribute to Opiate-Induced Analgesia: Insight from Conditional Knockout Mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0074706"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"8520","DOI":"10.1073\/pnas.0611364104","article-title":"A-803467, a potent and selective Nav 1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat","volume":"104","author":"Jarvis","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"2654","DOI":"10.1111\/bph.13092","article-title":"A novel selective and orally bioavailable Nav 1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability","volume":"172","author":"Payne","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1093\/pm\/pnab032","article-title":"A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Pharmacodynamic Effects of VX-150, a Highly Selective NaV1.8 Inhibitor, in Healthy Male Adults","volume":"22","author":"Hijma","year":"2021","journal-title":"Pain Med."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1007\/s11916-024-01295-7","article-title":"Frontiers in Acute Pain Management: Emerging Concepts in Pain Pathways and the Role of VX-548 as a Novel NaV1.8 Inhibitor: A Narrative Review","volume":"28","author":"Kaye","year":"2024","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/d41573-024-00203-3","article-title":"NaV1.8 inhibitor poised to provide opioid-free pain relief","volume":"24","author":"Kingwell","year":"2025","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1124\/molpharm.124.000944","article-title":"State-Dependent Inhibition of Nav1.8 Sodium Channels by VX-150 and VX-548","volume":"106","author":"Vaelli","year":"2024","journal-title":"Mol. Pharmacol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1007\/s40122-024-00697-0","article-title":"Pharmacology and Mechanism of Action of Suzetrigine, a Potent and Selective NaV1.8 Pain Signal Inhibitor for the Treatment of Moderate to Severe Pain","volume":"14","author":"Osteen","year":"2025","journal-title":"Pain Ther."},{"key":"ref_171","doi-asserted-by":"crossref","unstructured":"Nguyen, P.T., and Yarov-Yarovoy, V. (2022). Towards Structure-Guided Development of Pain Therapeutics Targeting Voltage-Gated Sodium Channels. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.842032"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"e70414","DOI":"10.1111\/cts.70414","article-title":"Suzetrigine, a Non-Opioid Small-Molecule Analgesic: Mechanism of Action, Clinical, and Translational Science","volume":"18","author":"Rajasingham","year":"2025","journal-title":"Clin. Transl. Sci."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s11916-026-01472-w","article-title":"Selective NaV1.8 Inhibition for Pain Management: Current Evidence and Future Potential of Suzetrigine","volume":"30","author":"Hashimoto","year":"2026","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1097\/j.pain.0000000000000602","article-title":"Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations","volume":"157","author":"Edwards","year":"2016","journal-title":"Pain"},{"key":"ref_175","first-page":"1085","article-title":"Suzetrigine, a Nonopioid Na V 1.8 Inhibitor for Treatment of Moderate-to-severe Acute Pain: Two Phase 3 Randomized Clinical Trials","volume":"142","author":"Bertoch","year":"2025","journal-title":"Anesthesiology"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"115371","DOI":"10.1016\/j.ejmech.2023.115371","article-title":"Discovery of selective NaV1.8 inhibitors based on 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl nicotinamide scaffold for the treatment of pain","volume":"254","author":"Qin","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"2805","DOI":"10.2147\/JPR.S526851","article-title":"Suzetrigine Approval Breaks a 25-Year Silence: A New Era in Non-Opioid Acute Pain Management","volume":"18","author":"Sibomana","year":"2025","journal-title":"J. Pain Res."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1080\/17581869.2024.2421749","article-title":"VX-548 in the treatment of acute pain","volume":"14","author":"Tan","year":"2024","journal-title":"Pain Manag."},{"key":"ref_179","doi-asserted-by":"crossref","unstructured":"Pham, A., Yep, H., Wozniak, S., Javvaji, A., Nada, E., and Bergese, S. (2025). Beyond Opioids: A Review of Suzetrigine for Acute Pain Management. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26209865"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1080\/15360288.2025.2600077","article-title":"Innovation Versus Consolidation: Critical Reflections on Suzetrigine and the Tramadol-Celecoxib Co-Crystal","volume":"40","year":"2026","journal-title":"J. Pain Palliat. Care Pharmacother."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"e001431","DOI":"10.1136\/bmjmed-2025-001431","article-title":"Between promise and peril: Role of suzetrigine as a non-opioid analgesic","volume":"4","author":"Karri","year":"2025","journal-title":"BMJ Med."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1097\/ALN.0000000000005823","article-title":"Suzetrigine for the Treatment of Acute Pain: Comment","volume":"144","author":"Xiang","year":"2026","journal-title":"Anesthesiology"}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/9\/1698\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T16:30:57Z","timestamp":1788539457000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/9\/1698"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,4]]},"references-count":182,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["medicina62091698"],"URL":"https:\/\/doi.org\/10.3390\/medicina62091698","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,4]]}}}