Unraveling Chronic Pain: From Mechanisms and Risks to Diagnosis and Treatment

Abstract

Chronic pain is a globally prevalent and complex condition, encompassing three primary subtypes, that is, nociceptive, neuropathic, and nociplastic, each with distinct biopsychosocial mechanisms. Chronic pain was historically viewed as a monolithic symptom and managed with opioid-centric models, causing widespread therapeutic failure. While recognition of its heterogeneity has driven a paradigm shift toward precision medicine, tailoring multimodal strategies to the dominant pain mechanism, critical challenges persist. These include difficulty in identifying treatable root causes, limited long-term efficacy of therapies, and significant side-effect burdens. To address these gaps, this review systematically synthesized contemporary knowledge, predominantly from the last decade, on the molecular mechanisms, risk factors, diagnostic frameworks, and therapeutic modalities for chronic pain, framed by its pathophysiological subtypes. Furthermore, it explored two novel frontiers aimed at advancing personalized pain medicine. First, it proposed cold atmospheric plasma as an innovative therapeutic intervention capable of modulating key molecular pathways underlying diverse pain manifestations. Second, it introduced an original neurobiological model positing the hippocampus as a putative sensor for nociplastic pain, interfacing with higher-dimensional information fields. These insights may offer transformative potential for refining diagnostic and therapeutic strategies, potentially revolutionizing the management of chronic pain.

Keywords

chronic pain / cold atmospheric plasma / hippocampus / nociceptive pain / neuropathic pain / nociplastic pain

References

[1] R.-D. Treede, W. Rief, A. Barke, et al., “A Classification of Chronic Pain for ICD-11,” Pain 156, no. 6 (2015): 1003–1007.

[2] Collaborators, G.b.o.d.s., Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. The Lancet 2017. 390(10100): p. 1211–1259.

[3] O. Gureje, M. Von Korff, G. E. Simon, and R. Gater, “Persistent Pain and Well-being,” Jama 280, no. 2 (1998): 147.

[4] H. Kehlet, T. S. Jensen, and C. J. Woolf, “Persistent Postsurgical Pain: Risk Factors and Prevention,” The Lancet 367, no. 9522 (2006): 1618–1625.

[5] O. Van Hecke, S. K. Austin, R. A. Khan, B. H. Smith, and N. Torrance, “Neuropathic Pain in the General Population: A Systematic Review of Epidemiological Studies,” Pain 155, no. 4 (2014): 654–662.

[6] J. Scholz, N. B. Finnerup, N. Attal, et al., “The IASP Classification of Chronic Pain for ICD-11: Chronic Neuropathic Pain,” Pain 160, no. 1 (2019): 53–59.

[7] E. Kosek, M. Cohen, R. Baron, et al., “Do We Need a Third Mechanistic Descriptor for Chronic Pain States?,” Pain 157, no. 7 (2016): 1382–1386.

[8] K. Q. Nuseir, A. Y. Altarifi, A. Tasslaq, A. Y. Alhusban, and K. H. Alzoubi, “Early and Late Anti Nociceptive Effects of Sucrose on Neonatal Inflammatory Pain in Rats: Comparison to a Non-steroidal Anti-inflammatory Drug,” Physiology & Behavior 206 (2019): 37–42.

[9] M. Kołacz, D. Kosson, R. Rzepliński, et al., “Effectiveness of Antidepressants in Neuropathic Pain Management: A Retrospective, Multicenter Cross-sectional Analysis,” Anaesthesiology Intensive Therapy 57, no. 1 (2025): 226–230.

[10] C. Zhang, P. Zhang, Y. Zhao, et al., “The Effect of a Remote Network Technology Supervised Exercise Program Combined with Drug Treatment for Fibromyalgia: Randomized, Single-Blind, Controlled Trial,” Journal of Medical Internet Research 27 (2025): e71624.

[11] M. R. Janevic, S. J. Mclaughlin, A. A. Heapy, C. Thacker, and J. D. Piette, “Racial and Socioeconomic Disparities in Disabling Chronic Pain: Findings from the Health and Retirement Study,” The Journal of Pain 18, no. 12 (2017): 1459–1467.

[12] C. M. Kaplan, E. Kelleher, A. Irani, A. Schrepf, D. J. Clauw, and S. E. Harte, “Deciphering Nociplastic Pain: Clinical Features, Risk Factors and Potential Mechanisms,” Nature Reviews Neurology 20, no. 6 (2024): 347–363.

[13] C. G. Guo and W. K. Leung, “Potential Strategies in the Prevention of Nonsteroidal Anti-inflammatory Drugs-Associated Adverse Effects in the Lower Gastrointestinal Tract,” Gut and Liver 14, no. 2 (2020): 179–189.

[14] H. E. Vonkeman and M. A. van de Laar, “Nonsteroidal Anti-inflammatory Drugs: Adverse Effects and Their Prevention,” Seminars in Arthritis and Rheumatism 39, no. 4 (2010): 294–312.

[15] M.-È. Mcgennis, M.-A. Gagnon, J. Paquet, et al., “Pain Management Strategies and Adverse Effects of Opioids in Patients With Neurotrauma With Acute and Chronic Pain,” Neurotrauma Reports 6, no. 1 (2025): 686–699.

[16] S. Straube, “On the Adverse Effects of Gabapentinoids,” Pain 165, no. 10 (2024): 2141–2142.

[17] E. E. Benarroch, “What Is the Mechanism of Therapeutic and Adverse Effects of Gabapentinoids?,” Neurology 96, no. 7 (2021): 318–321.

[18] X. Dai, S. Feng, and Y. Zheng, “Cold Atmospheric Plasma: Possible Cure of Autoimmune Disorders and Cancer via Attenuating Inflammation,” International Journal of Biological Sciences 20, no. 14 (2024): 5436–5449.

[19] X. Dai, K. Bazaka, D. J. Richard, E. R. W. Thompson, and K. K. Ostrikov, “The Emerging Role of Gas Plasma in Oncotherapy,” Trends in Biotechnology 36, no. 11 (2018): 1183–1198.

[20] X. Dai, L. Shen, and J. Zhang, “Cold Atmospheric Plasma: Redox Homeostasis to Treat Cancers?,” Trends in Biotechnology 41, no. 1 (2023): 15–18.

[21] X. Dai, Z. Xu, X. Lv, et al., “Cold Atmospheric Plasma Potentiates Ferroptosis via EGFR(Y1068)-mediated Dual Axes on GPX4 Among Triple Negative Breast Cancer Cells,” International Journal of Biological Sciences 21, no. 2 (2025): 874–892.

[22] X. Dai, D. Cai, P. Wang, et al., “Cold Atmospheric Plasmas Target Breast Cancer Stemness via Modulating AQP3-19Y Mediated AQP3-5K and FOXO1 K48-ubiquitination,” International Journal of Biological Sciences 18, no. 8 (2022): 3544–3561.

[23] T. Jackson, S. Thomas, V. Stabile, M. Shotwell, X. Han, and K. Mcqueen, “A Systematic Review and Meta-Analysis of the Global Burden of Chronic Pain without Clear Etiology in Low- and Middle-Income Countries: Trends in Heterogeneous Data and a Proposal for New Assessment Methods,” Anesthesia & Analgesia 123, no. 3 (2016): 739–748.

[24] F. M. Blyth, L. M. March, A. J. M. Brnabic, L. R. Jorm, M. Williamson, and M. J. Cousins, “Chronic Pain in Australia: A Prevalence Study,” Pain 89, no. 2-3 (2001): 127–134.

[25] K. J. Reid, J. Harker, M. M. Bala, et al., “Epidemiology of Chronic Non-cancer Pain in Europe: Narrative Review of Prevalence, Pain Treatments and Pain Impact,” Current Medical Research and Opinion 27, no. 2 (2011): 449–462.

[26] C. Bonezzi, D. Fornasari, C. Cricelli, A. Magni, and G. Ventriglia, “Not all Pain Is Created Equal: Basic Definitions and Diagnostic Work-Up,” Pain and Therapy 9, no. Suppl 1 (2020): 1–15.

[27] J. Dahlhamer, J. Lucas, C. Zelaya, et al., “Prevalence of Chronic Pain and High-Impact Chronic Pain among Adults—United States, 2016,” MMWR Morbidity and Mortality Weekly Report 67, no. 36 (2018): 1001–1006.

[28] M. H. Pitcher, M. Von Korff, M. C. Bushnell, and L. Porter, “Prevalence and Profile of High-Impact Chronic Pain in the United States,” The Journal of Pain 20, no. 2 (2019): 146–160.

[29] R. Del Giorno, P. Frumento, G. Varrassi, A. Paladini, and S. Coaccioli, “Assessment of Chronic Pain and Access to Pain Therapy: A Cross-sectional Population-based Study,” Journal of Pain Research 10 (2017): 2577–2584.

[30] D. Bouhassira, M. Lantéri-Minet, N. Attal, B. Laurent, and C. Touboul, “Prevalence of Chronic Pain With Neuropathic Characteristics in the General Population,” Pain 136, no. 3 (2008): 380–387.

[31] A. Fayaz, P. Croft, R. M. Langford, L. J. Donaldson, and G. T. Jones, “Prevalence of Chronic Pain in the UK: A Systematic Review and Meta-analysis of Population Studies,” BMJ Open 6, no. 6 (2016): e010364.

[32] H. Breivik, B. Collett, V. Ventafridda, R. Cohen, and D. Gallacher, “Survey of Chronic Pain in Europe: Prevalence, Impact on Daily Life, and Treatment,” European Journal of Pain 10, no. 4 (2006): 287–333.

[33] G. Harifi, M. Amine, M. Ait Ouazar, et al., “Prevalence of Chronic Pain With Neuropathic Characteristics in the Moroccan General Population: A National Survey,” Pain Medicine 14, no. 2 (2013): 287–292.

[34] S. Inoue, F. Kobayashi, M. Nishihara, et al., “Chronic Pain in the Japanese Community—Prevalence, Characteristics and Impact on Quality of Life,” PLoS ONE 10, no. 6 (2015): e0129262.

[35] A. Alcantara Montero and A. C. Arias, “[Should osteoarthritis be considered a model of nociceptive pain?],” Atencion Primaria 57, no. 8 (2025): 103218.

[36] Y. Abdullah, O. O. Olubowale, and K. V. Hackshaw, “Racial Disparities in Osteoarthritis: Prevalence, Presentation, and Management in the United States,” Journal of the National Medical Association 117, no. 1 (2025): 55–60.

[37] F. Cervero and J. M. Laird, “Understanding the Signaling and Transmission of Visceral Nociceptive Events,” Journal of Neurobiology 61, no. 1 (2004): 45–54.

[38] R. Freynhagen and R. Baron, “The Evaluation of Neuropathic Components in Low Back Pain,” Current Pain and Headache Reports 13, no. 3 (2009): 185–190.

[39] S. Y. Park, H. S. An, S. H. Moon, et al., “Neuropathic Pain Components in Patients With Lumbar Spinal Stenosis,” Yonsei Medical Journal 56, no. 4 (2015): 1044.

[40] A. Johansen, L. Romundstad, C. S. Nielsen, H. Schirmer, and A. Stubhaug, “Persistent postsurgical pain in a general population: Prevalence and predictors in the Tromsø study,” Pain 153, no. 7 (2012): 1390–1396.

[41] R. Ahmadi, R. Kuner, N. Weidner, et al., “The Diagnosis and Treatment of Neuropathic Pain,” Deutsches Arzteblatt International 121, no. 25 (2024): 825–832.

[42] A. Bernetti, F. Agostini, A. De Sire, et al., “Neuropathic Pain and Rehabilitation: A Systematic Review of International Guidelines,” Diagnostics 11, no. 1 (2021): 74.

[43] K. Bannister, J. Sachau, R. Baron, and A. H. Dickenson, “Neuropathic Pain: Mechanism-Based Therapeutics,” Annual Review of Pharmacology and Toxicology 60 (2020): 257–274.

[44] L. Colloca, T. Ludman, D. Bouhassira, et al., “Neuropathic Pain,” Nature Reviews Disease Primers 3 (2017): 17002.

[45] N. Attal, D. Bouhassira, and L. Colvin, “Advances and Challenges in Neuropathic Pain: A Narrative Review and Future Directions,” British Journal of Anaesthesia 131, no. 1 (2023): 79–92.

[46] M.-A. Fitzcharles, S. P. Cohen, D. J. Clauw, G. Littlejohn, C. Usui, and W. Häuser, “Nociplastic Pain: Towards an Understanding of Prevalent Pain Conditions,” The Lancet 397, no. 10289 (2021): 2098–2110.

[47] R. Freynhagen, R. Rolke, R. Baron, et al., “Pseudoradicular and Radicular Low-back Pain–a Disease Continuum Rather Than Different Entities? Answers from Quatitative Sensory Testing,” Pain 135, no. 1-2 (2008): 65–74.

[48] M.-A. Fitzcharles, S. Perrot, and W. Häuser, “Comorbid Fibromyalgia: A Qualitative Review of Prevalence and Importance,” European Journal of Pain 22, no. 9 (2018): 1565–1576.

[49] A. M. Dydyk and A. Givler, Central Pain Syndrome (StatPearls Publishing, 2020).

[50] M. Hoegh, “Pain Science in Practice (Part 3): Peripheral Sensitization,” Journal of Orthopaedic & Sports Physical Therapy 52, no. 6 (2022): 303–306.

[51] N. Gao, M. Li, W. Wang, Z. Liu, and Y. Guo, “The Dual Role of TRPV1 in Peripheral Neuropathic Pain: Pain Switches Caused by Its Sensitization or Desensitization,” Frontiers in Molecular Neuroscience 17 (2024): 1400118.

[52] K. Honda, M. Shinoda, M. Kondo, et al., “Sensitization of TRPV1 and TRPA1 via Peripheral mGluR5 Signaling Contributes to Thermal and Mechanical Hypersensitivity,” Pain 158, no. 9 (2017): 1754–1764.

[53] G. Varrassi and A. Paladini, “The Development of Pain Medicine in Italy and the Rest of Europe 40 Years After the First International Association for the Study of Pain Congress,” Pain Management 7, no. 1 (2017): 15–18.

[54] P. Qi, Q. Li, M. Han, et al., “The Analgesic Mechanism of Electroacupuncture at the central Level for Neuropathic Pain: A Review of Studies Based on Animal Experiments,” Frontiers in Neurology 16 (2025): 1587471.

[55] S. Kendroud, “Physiology, Nociceptive Pathways,” in StatPearls, Disclosure: Lauren Fitzgerald declares no relevant financial relationships with ineligible companies. Disclosure: Ian Murray declares no relevant financial relationships with ineligible companies. Disclosure: Andrew Hanna declares no relevant financial relationships with ineligible companies (Treasure Island (FL) ineligible companies, 2025).

[56] S. E. Harte, R. E. Harris, and D. J. Clauw, “The Neurobiology of central Sensitization,” Journal of Applied Biobehavioral Research 23 (2018): e12137.

[57] M. Zhuo, “Neuronal Mechanism for Neuropathic Pain,” Molecular Pain 3 (2007): 14.

[58] N. B. Finnerup and T. S. Jensen, “Mechanisms of Disease: Mechanism-based classification of neuropathic pain—a critical analysis,” Nature Clinical Practice Neurology 2, no. 2 (2006): 107–115.

[59] C. J. Woolf, “Evidence for a central Component of Post-injury Pain Hypersensitivity,” Nature 306, no. 5944 (1983): 686–688.

[60] C. J. Woolf, “Central Sensitization: Implications for the Diagnosis and Treatment of Pain,” Pain 152, no. 3 Suppl (2011): S2–S15.

[61] J. Nijs, S. Z. George, D. J. Clauw, et al., “Central Sensitisation in Chronic Pain Conditions: Latest Discoveries and Their Potential for Precision Medicine,” The Lancet Rheumatology 3, no. 5 (2021): e383–e392.

[62] M. Curatolo, “Central Sensitization and Pain: Pathophysiologic and Clinical Insights,” Current Neuropharmacology 22, no. 1 (2024): 15–22.

[63] J. J. McDougall, “Arthritis and Pain. Neurogenic Origin of Joint Pain,” Arthritis Research & Therapy 8, no. 6 (2006): 220.

[64] M. S. Gold and G. F. Gebhart, “Nociceptor Sensitization in Pain Pathogenesis,” Nature Medicine 16, no. 11 (2010): 1248–1257.

[65] V. Pereira and C. Goudet, “Emerging Trends in Pain Modulation by Metabotropic Glutamate Receptors,” Frontiers in Molecular Neuroscience 11 (2018): 464.

[66] Z. Bahari and G. H. Meftahi, “Spinal α 2 -adrenoceptors and neuropathic pain modulation; therapeutic target,” British Journal of Pharmacology 176, no. 14 (2019): 2366–2381.

[67] E. Szabadi, “Functional Organization of the Sympathetic Pathways Controlling the Pupil: Light-Inhibited and Light-Stimulated Pathways,” Frontiers in Neurology 9 (2018): 1069.

[68] W. Zieglgänsberger, “Substance P and Pain Chronicity,” Cell and Tissue Research 375, no. 1 (2019): 227–241.

[69] A. Koivisto, N. Jalava, R. Bratty, and A. Pertovaara, “TRPA1 Antagonists for Pain Relief,” Pharmaceuticals 11, no. 4 (2018): 117.

[70] M. J. Pérez De Vega, A. Ferrer-Montiel, and R. González-Muñiz, “Recent Progress in Non-opioid Analgesic Peptides,” Archives of Biochemistry and Biophysics 660 (2018): 36–52.

[71] L. S. Ro and K. H. Chang, “Neuropathic Pain: Mechanisms and Treatments,” Chang Gung Medical Journal 28, no. 9 (2005): 597–605.

[72] K. Inoue and M. Tsuda, “Microglia in Neuropathic Pain: Cellular and Molecular Mechanisms and Therapeutic Potential,” Nature Reviews Neuroscience 19, no. 3 (2018): 138–152.

[73] A. Schrepf, S. Moser, S. E. Harte, et al., “Top Down or Bottom up? An Observational Investigation of Improvement in Fibromyalgia Symptoms Following Hip and Knee Replacement,” Rheumatology 59, no. 3 (2020): 594–602.

[74] D. Dutta, C. M. Brummett, S. E. Moser, et al., “Heritability of the Fibromyalgia Phenotype Varies by Age,” Arthritis & Rheumatology 72, no. 5 (2020): 815–823.

[75] R. Berwick, C. Barker, A. Goebel, and The Guideline Development Group, “The Diagnosis of Fibromyalgia Syndrome,” Clinical Medicine 22, no. 6 (2022): 570–574.

[76] V. Vasic and M. H. H. Schmidt, “Resilience and Vulnerability to Pain and Inflammation in the Hippocampus,” International Journal of Molecular Sciences 18, no. 4 (2017): 739.

[77] V. Fasick, R. N. Spengler, S. Samankan, N. D. Nader, and T. A. Ignatowski, “The Hippocampus and TNF: Common Links Between Chronic Pain and Depression,” Neuroscience & Biobehavioral Reviews 53 (2015): 139–159.

[78] M. Kędziora, S. Boccella, I. Marabese, et al., “Inhibition of anandamide breakdown reduces pain and restores LTP and monoamine levels in the rat hippocampus via the CB1 receptor following osteoarthritis,” Neuropharmacology 222 (2023): 109304.

[79] Z. Li, Z. He, Z. Li, T. Sun, W. Zhang, and H. Xiang, “Differential Synaptic Mechanism Underlying the Neuronal Modulation of Prefrontal Cortex, Amygdala, and Hippocampus in Response to Chronic Postsurgical Pain With or Without Cognitive Deficits in Rats,” Frontiers in Molecular Neuroscience 15 (2022): 961995.

[80] H. Cardoso-Cruz, D. Lima, and V. Galhardo, “Impaired Spatial Memory Performance in a Rat Model of Neuropathic Pain Is Associated with Reduced Hippocampus–Prefrontal Cortex Connectivity,” The Journal of Neuroscience 33, no. 6 (2013): 2465–2480.

[81] Z.-W. Peng, C.-H. Zhou, S.-S. Xue, et al., “High-frequency Repetitive Transcranial Magnetic Stimulation Regulates Neural Oscillations of the Hippocampus and Prefrontal Cortex in Mice by Modulating Endocannabinoid Signalling,” Journal of Affective Disorders 331 (2023): 217–228.

[82] V. Neugebauer, P. Presto, V. Yakhnitsa, N. Antenucci, B. Mendoza, and G. Ji, “Pain-related Cortico-limbic Plasticity and Opioid Signaling,” Neuropharmacology 231 (2023): 109510.

[83] D. M. Mccall, R. Homayouni, Q. Yu, S. Raz, and N. Ofen, “Meta-Analysis of Hippocampal Volume and Episodic Memory in Preterm and Term Born Individuals,” Neuropsychology Review 34, no. 2 (2024): 478–495.

[84] C. Van Petten, “Relationship Between Hippocampal Volume and Memory Ability in Healthy Individuals Across the Lifespan: Review and Meta-analysis,” Neuropsychologia 42, no. 10 (2004): 1394–1413.

[85] M. C. Anderson, J. G. Bunce, and H. Barbas, “Prefrontal–hippocampal pathways underlying inhibitory control over memory,” Neurobiology of Learning and Memory 134 Pt A, no. Pt A (2016): 145–161.

[86] B. E. Depue, “A Neuroanatomical Model of Prefrontal Inhibitory Modulation of Memory Retrieval,” Neuroscience & Biobehavioral Reviews 36, no. 5 (2012): 1382–1399.

[87] J. A. Avery, M. Carrington, J. E. Ingeholm, et al., “Automatic Engagement of Limbic and Prefrontal Networks in Response to Food Images Reflects Distinct Information About Food Hedonics and Inhibitory Control,” Communications Biology 8, no. 1 (2025): 270.

[88] H. Zhou, Z. Wang, H. Jin, X. Chen, and L. Lei, “A Systematic Review and Meta-analysis of Independent Risk Factors for Postherpetic Neuralgia,” Annals of Palliative Medicine 10, no. 12 (2021): 12181–12189.

[89] H. L. Hébert, A. Veluchamy, N. Torrance, and B. H. Smith, “Risk Factors for Neuropathic Pain in Diabetes Mellitus,” Pain 158, no. 4 (2017): 560–568.

[90] G. Duan, S. Guo, Y. Zhang, et al., “The Effect of SCN9A Variation on Basal Pain Sensitivity in the General Population: An Experimental Study in Young Women,” The Journal of Pain 16, no. 10 (2015): 971–980.

[91] Y. Indo, M. Tsuruta, Y. Hayashida, et al., “Mutations in the TRKA/NGF Receptor Gene in Patients With Congenital Insensitivity to Pain With Anhidrosis,” Nature Genetics 13, no. 4 (1996): 485–488.

[92] A. Veluchamy, H. L. Hébert, W. Meng, C. N. A. Palmer, and B. H. Smith, “Systematic Review and Meta-analysis of Genetic Risk Factors for Neuropathic Pain,” Pain 159, no. 5 (2018): 825–848.

[93] S. C. Warner, J. B. Van Meurs, D. Schiphof, et al., “Genome-wide Association Scan of Neuropathic Pain Symptoms post Total Joint Replacement Highlights a Variant in the Protein-kinase C Gene,” European Journal of Human Genetics 25, no. 4 (2017): 446–451.

[94] K.-I. Cheng, S.-R. Lin, L.-L. Chang, J.-Y. Wang, and C.-S. Lai, “Association of the Functional A118G Polymorphism of OPRM1 in Diabetic Patients With Foot Ulcer Pain,” Journal of Diabetes and Its Complications 24, no. 2 (2010): 102–108.

[95] C. Fernández-De-Las-Peñas, S. Ambite-Quesada, M. Palacios-Ceña, et al., “Catechol-O-Methyltransferase (COMT) rs4680 Val158Met Polymorphism Is Associated with Widespread Pressure Pain Sensitivity and Depression in Women with Chronic, but Not Episodic, Tension-Type Headache,” The Clinical Journal of Pain 35, no. 4 (2019): 345–352.

[96] Q. S. Li, P. Cheng, R. Favis, A. Wickenden, G. Romano, and H. Wang, “SCN9A Variants May be Implicated in Neuropathic Pain Associated with Diabetic Peripheral Neuropathy and Pain Severity,” The Clinical Journal of Pain 31, no. 11 (2015): 976–982.

[97] W. Cui, X. Yu, and H. Zhang, “The Serotonin Transporter Gene Polymorphism Is Associated With the Susceptibility and the Pain Severity in Idiopathic Trigeminal Neuralgia Patients,” The Journal of Headache and Pain 15, no. 1 (2014): 42.

[98] J. Nissenbaum, M. Devor, Z. E. Seltzer, et al., “Susceptibility to Chronic Pain Following Nerve Injury Is Genetically Affected by CACNG2,” Genome Research 20, no. 9 (2010): 1180–1190.

[99] S. D. Dib-Hajj, A. M. Rush, T. R. Cummins, et al., “Gain-of-function Mutation in Nav1.7 in Familial Erythromelalgia Induces Bursting of Sensory Neurons,” Brain 128, no. Pt 8 (2005): 1847–1854.

[100] H. Y. Chung, E. Y. Song, J. A. H. Yoon, et al., “Association of human Leukocyte Antigen With Postherpetic Neuralgia in Koreans,” Apmis 124, no. 10 (2016): 865–871.

[101] C. A. Dominguez, M. Kalliomäki, U. Gunnarsson, et al., “The DQB1 *03:02 HLA Haplotype Is Associated With Increased Risk of Chronic Pain After Inguinal Hernia Surgery and Lumbar Disc Herniation,” Pain 154, no. 3 (2013): 427–433.

[102] M. Sato-Takeda, H. Ihn, J. Ohashi, et al., “The human Histocompatibility Leukocyte Antigen (HLA) Haplotype Is Associated With the Onset of Postherpetic Neuralgia After herpes Zoster,” Pain 110, no. 1-2 (2004): 329–336.

[103] D. Sumiyama, E. F. Kikkawa, Y. F. Kita, et al., “HLA Alleles Are Associated With Postherpetic Neuralgia but Not With herpes Zoster,” The Tokai Journal of Experimental and Clinical Medicine 33, no. 4 (2008): 150–153.

[104] A. Ozawa, Y. Sasao, K. Iwashita, et al., “HLA-A33 and -B44 and susceptibility to postherpetic neuralgia (PHN),” Tissue Antigens 53, no. 3 (1999): 263–268.

[105] N. Noponen-Hietala, I. Virtanen, R. Karttunen, et al., “Genetic Variations in IL6 Associate With Intervertebral Disc Disease Characterized by Sciatica,” Pain 114, no. 1-2 (2005): 186–194.

[106] K. Stephens, B. A. Cooper, C. West, et al., “Associations Between Cytokine Gene Variations and Severe Persistent Breast Pain in Women Following Breast Cancer Surgery,” The Journal of Pain 15, no. 2 (2014): 169–180.

[107] M.-L. Kalliomäki, G. Sandblom, M. Hallberg, et al., “Genetic susceptibility to postherniotomy pain. The influence of polymorphisms in the Mu opioid receptor, TNF-α, GRIK3, GCH1, BDNF and CACNA2D2 genes,” Scandinavian Journal of Pain 12 (2016): 1–6.

[108] A. L. Wadley, Z. Lombard, C. L. Cherry, P. Price, and P. R. Kamerman, “Analysis of a Previously Identified “Pain-Protective” Haplotype and Individual Polymorphisms in the GCH1 Gene in Africans With HIV-Associated Sensory Neuropathy,” JAIDS Journal of Acquired Immune Deficiency Syndromes 60, no. 1 (2012): 20–23.

[109] D. A. Hegarty, “Multivariate Prognostic Modeling of Persistent Pain Following Lumbar Discectomy,” Pain Physician 15, no. 5 (2012): 421–434.

[110] A. R. Kallianpur, P. Jia, R. J. Ellis, et al., “Genetic Variation in Iron Metabolism Is Associated With Neuropathic Pain and Pain Severity in HIV-infected Patients on Antiretroviral Therapy,” PLoS ONE 9, no. 8 (2014): e103123.

[111] L. Diatchenko, A. D. Anderson, G. D. Slade, et al., “Three major haplotypes of the β 2 adrenergic receptor define psychological profile, blood pressure, and the risk for development of a common musculoskeletal pain disorder,” American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 141B, no. 5 (2006): 449–462.

[112] M. Offenbaecher, B. Bondy, S. D. E. Jonge, et al., “Possible Association of Fibromyalgia With a Polymorphism in the Serotonin Transporter Gene Regulatory Region,” Arthritis & Rheumatism 42, no. 11 (1999): 2482–2488.

[113] S. Paredes, S. Cantillo, K. D. Candido, and N. N. Knezevic, “An Association of Serotonin With Pain Disorders and Its Modulation by Estrogens,” International Journal of Molecular Sciences 20, no. 22 (2019): 5729.

[114] K. J. A. Johnston, M. J. Adams, B. I. Nicholl, et al., “Genome-wide Association Study of Multisite Chronic Pain in UK Biobank,” PLOS Genetics 15, no. 6 (2019): e1008164.

[115] M. Crow, F. Denk, and S. B. McMahon, “Genes and Epigenetic Processes as Prospective Pain Targets,” Genome Medicine 5, no. 2 (2013): 12.

[116] F. Salis, S. Sardo, G. Finco, G. L. Gessa, F. Franconi, and R. Agabio, “Sex-Gender Differences Are Completely Neglected in Treatments for Neuropathic Pain,” Pharmaceuticals 17, no. 7 (2024): 838.

[117] G. Marcianò, A. Siniscalchi, G. Di Gennaro, et al., “Assessing Gender Differences in Neuropathic Pain Management: Findings From a Real-Life Clinical Cross-Sectional Observational Study,” Journal of Clinical Medicine 13, no. 19 (2024): 5682.

[118] V. Coraggio, F. Guida, S. Boccella, et al., “Neuroimmune-Driven Neuropathic Pain Establishment: A Focus on Gender Differences,” International Journal of Molecular Sciences 19, no. 1 (2018): 281.

[119] M. Alkhatatbeh and K. K. Abdul-Razzak, “Neuropathic Pain Is Not Associated With Serum Vitamin D but Is Associated With Female Gender in Patients With Type 2 Diabetes Mellitus,” BMJ Open Diabetes Research & Care 7, no. 1 (2019): e000690.

[120] S. E. E. Mills, K. P. Nicolson, and B. H. Smith, “Chronic Pain: A Review of Its Epidemiology and Associated Factors in Population-based Studies,” British Journal of Anaesthesia 123, no. 2 (2019): e273–e283.

[121] J. S. Mogil, M. Parisien, S. J. Esfahani, and L. Diatchenko, “Sex Differences in Mechanisms of Pain Hypersensitivity,” Neuroscience & Biobehavioral Reviews 163 (2024): 105749.

[122] M. Racine, Y. Tousignant-Laflamme, L. A. Kloda, D. Dion, G. Dupuis, and M. Choinière, “A systematic literature review of 10 years of research on sex/gender and experimental pain perception – Part 1: Are there really differences between women and men?,” Pain 153, no. 3 (2012): 602–618.

[123] K. Hankerd, K. E. Mcdonough, J. Wang, S.-J. Tang, J. M. Chung, and J.-H. La, “Postinjury Stimulation Triggers a Transition to Nociplastic Pain in Mice,” Pain 163, no. 3 (2022): 461–473.

[124] M. Gulati, E. Dursun, K. Vincent, and F. E. Watt, “The Influence of Sex Hormones on Musculoskeletal Pain and Osteoarthritis,” The Lancet Rheumatology 5, no. 4 (2023): e225–e238.

[125] K. Okuda, H. Iwasaka, S. Hagiwara, et al., “The Antinociceptive Effects of Estradiol on Adjuvant-induced Hyperalgesia in Rats Involve Activation of Adrenergic and Serotonergic Systems,” Journal of Anesthesia 25, no. 3 (2011): 392–397.

[126] Y. R. Smith, C. S. Stohler, T. E. Nichols, J. A. Bueller, R. A. Koeppe, and J.-K. Zubieta, “Pronociceptive and Antinociceptive Effects of Estradiol Through Endogenous Opioid Neurotransmission in Women,” The Journal of Neuroscience 26, no. 21 (2006): 5777–5785.

[127] K. Vincent, C. Warnaby, C. J. Stagg, J. Moore, S. Kennedy, and I. Tracey, “Brain Imaging Reveals That Engagement of Descending Inhibitory Pain Pathways in Healthy Women in a Low Endogenous Estradiol state Varies With Testosterone,” Pain 154, no. 4 (2013): 515–524.

[128] J. B. Lesnak, S. Inoue, L. Lima, L. Rasmussen, and K. A. Sluka, “Testosterone Protects Against the Development of Widespread Muscle Pain in Mice,” Pain 161, no. 12 (2020): 2898–2908.

[129] A. K. Schmitz, M. Vierhaus, and A. Lohaus, “Pain Tolerance in Children and Adolescents: Sex Differences and Psychosocial Influences on Pain Threshold and Endurance,” European Journal of Pain 17, no. 1 (2013): 124–131.

[130] S. Iacovides, I. Avidon, and F. C. Baker, “Does Pain Vary Across the Menstrual Cycle? A Review,” European Journal of Pain 19, no. 10 (2015): 1389–1405.

[131] J. M. Vigil, J. Didomenico, C. Strenth, et al., “Experimenter Effects on Pain Reporting in Women Vary Across the Menstrual Cycle,” International Journal of Endocrinology 2015 (2015): 1–8.

[132] K. Bradford, W. Shih, E. J. Videlock, et al., “Association Between Early Adverse Life Events and Irritable Bowel Syndrome,” Clinical Gastroenterology and Hepatology 10, no. 4 (2012): 385–390.e3.

[133] T. B. Arif, S. H. Ali, K. D. Bhojwani, et al., “Global Prevalence and Risk Factors of Irritable Bowel Syndrome From 2006 to 2024 Using the Rome III and IV Criteria: A Meta-analysis,” European Journal of Gastroenterology & Hepatology 37 (2025): 1314–1325.

[134] R. Li, D. A. Kreher, T. A. Jusko, B. P. Chapman, A. D. Bonham, and C. L. Seplaki, “Prospective Association Between Dysmenorrhea and Chronic Pain Development in Community-Dwelling Women,” The Journal of Pain 22, no. 9 (2021): 1084–1096.

[135] A. Gordois, P. Scuffham, A. Shearer, and A. Oglesby, “The Health Care Costs of Diabetic Nephropathy in the United States and the United Kingdom,” Journal of Diabetes and Its Complications 18, no. 1 (2004): 18–26.

[136] D. M. Nathan, S. Genuth, J. Lachin, Diabetes Control and Complications Trial Research Group, et al., “The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-term Complications in Insulin-dependent Diabetes Mellitus,” New England Journal of Medicine 329, no. 14 (1993): 977–986.

[137] A. J. Boulton, “Treatment of Symptomatic Diabetic Neuropathy,” Diabetes/Metabolism Research and Reviews 19, no. Suppl 1 (2003): S16–S21.

[138] A. Caraceni, R. K. Portenoy, and I.T.F.o.C.P. a Working Group of the, “An international survey of cancer pain characteristics and syndromes,” Pain 82, no. 3 (1999): 263–274.

[139] J. Hozumi, M. Sumitani, Y. Matsubayashi, et al., “Relationship Between Neuropathic Pain and Obesity,” Pain Research and Management 2016 (2016): 1–6.

[140] V. Spallonel, R. Morganti, C. D'Amato, et al., “Clinical Correlates of Painful Diabetic Neuropathy and Relationship of Neuropathic Pain With Sensorimotor and Autonomic Nerve Function,” European Journal of Pain 15, no. 2 (2011): 153–160.

[141] K. Van Acker, D. Bouhassira, D. De Bacquer, et al., “Prevalence and Impact on Quality of Life of Peripheral Neuropathy With or Without Neuropathic Pain in Type 1 and Type 2 Diabetic Patients Attending Hospital Outpatients Clinics,” Diabetes & Metabolism 35, no. 3 (2009): 206–213.

[142] C. Naranjo, P. Ortega-Jiménez, L. Del Reguero, G. Moratalla, and I. Failde, “Relationship Between Diabetic Neuropathic Pain and Comorbidity. Their Impact on Pain Intensity, Diabetes Complications and Quality of Life in Patients With Type-2 Diabetes Mellitus,” Diabetes Research and Clinical Practice 165 (2020): 108236.

[143] D. Ziegler, W. Rathmann, T. Dickhaus, C. Meisinger, and A. Mielck, “Neuropathic Pain in Diabetes, Prediabetes and Normal Glucose Tolerance: The MONICA/KORA Augsburg Surveys S2 and S3,” Pain Medicine 10, no. 2 (2009): 393–400.

[144] D. Ziegler, W. Rathmann, C. Meisinger, T. Dickhaus, and A. Mielck, “Prevalence and risk factors of neuropathic pain in survivors of myocardial infarction with pre-diabetes and diabetes. The KORA Myocardial Infarction Registry,” European Journal of Pain 13, no. 6 (2009): 582–587.

[145] M. D'Onghia, J. Ciaffi, L. Lisi, et al., “Fibromyalgia and Obesity: A Comprehensive Systematic Review and Meta-analysis,” Seminars in Arthritis and Rheumatism 51, no. 2 (2021): 409–424.

[146] D. Singh, W. Park, D. Hwang, and M. S. Levy, “Severe Obesity Effect on Low Back Biomechanical Stress of Manual Load Lifting,” Work (Reading, Mass) 51, no. 2 (2015): 337–348.

[147] H. S. Park, J. Y. Park, and R. Yu, “Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-α and IL-6,” Diabetes Research and Clinical Practice 69, no. 1 (2005): 29–35.

[148] Y. Kawasaki, L. Zhang, J.-K. Cheng, and R. U.-R. Ji, “Cytokine Mechanisms of Central Sensitization: Distinct and Overlapping Role of Interleukin-1β, Interleukin-6, and Tumor Necrosis Factor-α in Regulating Synaptic and Neuronal Activity in the Superficial Spinal Cord,” The Journal of Neuroscience 28, no. 20 (2008): 5189–5194.

[149] C.-N. Fu, H. Wei, W.-S. Gao, S.-S. Song, S.-W. Yue, and Y. U.-J. Qu, “Obesity Increases Neuropathic Pain via the AMPK-ERK-NOX4 Pathway in Rats,” Aging 13, no. 14 (2021): 18606–18619.

[150] X. Li and Y. X. Tao, “Intrathecal Administration of the Fat-mass and Obesity-associated Protein Inhibitor Mitigates Neuropathic Pain in Female Rats,” Translational Perioperative and Pain Medicine 9, no. 4 (2022): 478–487.

[151] A. Stubbs, S. Harte, D. J. Clauw, et al., “Early Relationships of a Low-Energy Diet With Symptoms of Fibromyalgia,” ACR Open Rheumatology 4, no. 5 (2022): 464–469.

[152] A. Okifuji and B. D. Hare, “The Association Between Chronic Pain and Obesity,” Journal of Pain Research 8 (2015): 399.

[153] H. Chen, T. J. Lamer, R. H. Rho, et al., “Contemporary Management of Neuropathic Pain for the Primary Care Physician,” Mayo Clinic Proceedings 79, no. 12 (2004): 1533–1545.

[154] J. D. Gazewood, S. Meadows, and L. Halverson, “Clinical Inquiries. What Is the Prognosis of Postherpetic Neuralgia?,” Journal of Family Practice 52, no. 6 (2003): 496–497.

[155] K. E. Schmader, “Epidemiology and Impact on Quality of Life of Postherpetic Neuralgia and Painful Diabetic Neuropathy,” The Clinical Journal of Pain 18, no. 6 (2002): 350–354.

[156] R. W. Johnson and T. L. Whitton, “Management of herpes Zoster (shingles) and Postherpetic Neuralgia,” Expert Opinion on Pharmacotherapy 5, no. 3 (2004): 551–559.

[157] K. Kelly, E. Keohane, and G. Davy, “The Effect of Chronic Pain on Memory: A Systematic Review and Meta-analysis Exploring the Impact of Nociceptive, Neuropathic and Nociplastic Pain,” Brain and Cognition 187 (2025): 106305.

[158] S. Kataria, U. Patel, K. Yabut, et al., “Recent Advances in Management of Neuropathic, Nociceptive, and Chronic Pain: A Narrative Review With Focus on Nanomedicine, Gene Therapy, Stem Cell Therapy, and Newer Therapeutic Options,” Current Pain and Headache Reports 28, no. 5 (2024): 321–333.

[159] A. Clairoux, M. Soucy-Proulx, M. Idrissi, and P. Richebé, “Regional Anesthesia Did Not Prevent Chronic Neuropathic Pain After Oncologic Breast Surgery,” Canadian Journal of Anesthesia/Journal canadien d'anesthésie 70, no. 2 (2023): 284–285.

[160] C. Politis, I. Lambrichts, and J. O. Agbaje, “Neuropathic pain after orthognathic surgery,” Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology 117, no. 2 (2014): e102–e107.

[161] T. Miyazaki, K. Matsumoto, T. Sato, et al., “Efficacy and Safety of Add-on Mirogabalin to Conventional Therapy for the Treatment of Peripheral Neuropathic Pain After Thoracic Surgery: The Multicenter, Randomized, Open-label ADMIT-NeP Study,” BMC Cancer 24, no. 1 (2024): 80.

[162] G. Waldolato, G. S. Pereira, I. S. Carvalho, J. C. Polese, and A. A. O. Leopoldino, “Comparison of DN4 and DN4 Interview Tests in the Identification of Neuropathic Pain After Fracture Surgery,” Revista Brasileira De Ortopedia 59, no. 1 (2024): e125–e129.

[163] K. Kwon, J. Ahn, S. O.-N. Kim, et al., “Biomarkers in Cerebrospinal Fluid of Persistent Neuropathic Pain After Lumbar Stenosis Surgery,” European Spine Journal 34, no. 7 (2025): 2995–3002.

[164] L. Kroon, K. Ticehurst, J. Ahonen, J. Norrby, and F. Ruiz-Jasbon, “Causes of Chronic Pain Unrelated to Surgical Trauma After Groin Hernia Repair: A Prospective Cohort Study,” Hernia 29, no. 1 (2024): 13.

[165] K. A. Sluka, J. M. O'Donnell, J. Danielson, and L. A. Rasmussen, “Regular Physical Activity Prevents Development of Chronic Pain and Activation of central Neurons,” Journal of Applied Physiology 114, no. 6 (2013): 725–733.

[166] K. M. Naugle, T. Ohlman, K. E. Naugle, Z. A. Riley, and N. R. Keith, “Physical Activity Behavior Predicts Endogenous Pain Modulation in Older Adults,” Pain 158, no. 3 (2017): 383–390.

[167] J. Glass, A. Lyden, F. Petzke, et al., “The Effect of Brief Exercise Cessation on Pain, Fatigue, and Mood Symptom Development in Healthy, Fit Individuals,” Journal of Psychosomatic Research 57, no. 4 (2004): 391–398.

[168] F. Pan, K. S. Byrne, R. Ramakrishnan, M. Ferreira, T. Dwyer, and G. Jones, “Association Between Musculoskeletal Pain at Multiple Sites and Objectively Measured Physical Activity and Work Capacity: Results From UK Biobank Study,” Journal of Science and Medicine in Sport 22, no. 4 (2019): 444–449.

[169] E. H. Choy, “The Role of Sleep in Pain and Fibromyalgia,” Nature Reviews Rheumatology 11, no. 9 (2015): 513–520.

[170] H. Moldofsky, “Nonrestorative Sleep and Symptoms After a Febrile Illness in Patients With Fibrositis and Chronic Fatigue Syndromes,” Journal of Rheumatology Supplement 19 (1989): 150–153.

[171] H. Moldofsky and P. Scarisbrick, “Induction of Neurasthenic Musculoskeletal Pain Syndrome by Selective Sleep Stage Deprivation,” Psychosomatic Medicine 38, no. 1 (1976): 35–44.

[172] J. N. Ablin, D. J. Clauw, A. K. Lyden, et al., “Effects of Sleep Restriction and Exercise Deprivation on Somatic Symptoms and Mood in Healthy Adults,” Clinical and Experimental Rheumatology 31, no. 6 Suppl 79 (2013): S53–S59.

[173] I. Baryshnikov, T. H. Rosenstrom, and E. T. Isometsa, “Psychological Pain as a Risk Factor for Suicidal Ideation: An Ecological Momentary Assessment Study on Inpatients with Depression with and without Comorbid Borderline Personality Disorder,” Journal of Clinical Psychiatry 85, no. 2 (2024): 23m14926.

[174] R. Pak, M. Mahmoud Alilou, A. Bakhshipour Roudsari, and F. Yousefpour, “Experiential Avoidance as a Factor in Generalized Psychological Vulnerability: In the Relationship between Chronic Pain and Pain Anxiety with Pain Disability,” Pain Management Nursing 25, no. 3 (2024): e256–e264.

[175] R. H. Dworkin, G. Hartstein, H. L. Rosner, R. R. Walther, E. W. Sweeney, and L. Brand, “A High-risk Method for Studying Psychosocial Antecedents of Chronic Pain: The Prospective Investigation of herpes Zoster,” Journal of Abnormal Psychology 101, no. 1 (1992): 200–205.

[176] H. L. Li, G. Gong, J. L. Wang, and F. B. Li, et al., “Analysis of Risk Factors for Postherpetic Neuralgia in Patients with Postmalignancy Herpes Zoster,” Pain Physician Journal 26, no. 4 (2023): E397–E403.

[177] H. J. Forbes, K. Bhaskaran, S. L. Thomas, et al., “Quantification of risk factors for postherpetic neuralgia in herpes zoster patients,” Neurology 87, no. 1 (2016): 94–102.

[178] T. S. Jensen, B. Krebs, J. Nielsen, and P. Rasmussen, “Immediate and Long-term Phantom Limb Pain in Amputees: Incidence, Clinical Characteristics and Relationship to Pre-amputation Limb Pain,” Pain 21, no. 3 (1985): 267–278.

[179] L. Nikolajsen, S. Ilkjær, K. Krøner, J. H. Christensen, and T. S. Jensen, “The Influence of Preamputation Pain on Postamputation Stump and Phantom Pain,” Pain 72, no. 3 (1997): 393–405.

[180] J. M. Iversen, M. S. Indredavik, K. A. I. Evensen, P. R. Romundstad, and M. Rygg, “Self-reported Chronic Pain in Young Adults with a Low Birth Weight,” The Clinical Journal of Pain 33, no. 4 (2017): 348–355.

[181] J. Hohmeister, S. Demirakça, K. Zohsel, H. Flor, and C. Hermann, “Responses to pain in school-aged children with experience in a neonatal intensive care unit: Cognitive aspects and maternal influences,” European Journal of Pain 13, no. 1 (2009): 94–101.

[182] R. Waller, A. J. Smith, P. B. O'Sullivan, H. Slater, M. Sterling, and L. M. Straker, “The Association of Early Life Stressors With Pain Sensitivity and Pain Experience at 22 Years,” Pain 161, no. 1 (2020): 220–229.

[183] E. Generaal, N. Vogelzangs, G. J. Macfarlane, et al., “Biological Stress Systems, Adverse Life Events and the Onset of Chronic Multisite Musculoskeletal Pain: A 6-year Cohort Study,” Annals of the Rheumatic Diseases 75, no. 5 (2016): 847–854.

[184] A. Schrepf, B. Naliboff, D. A. Williams, et al., “Adverse Childhood Experiences and Symptoms of Urologic Chronic Pelvic Pain Syndrome: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Study,” Annals of Behavioral Medicine 52, no. 10 (2018): 865–877.

[185] J. Korterink, N. M. Devanarayana, S. Rajindrajith, A. Vlieger, and M. A. Benninga, “Childhood Functional Abdominal Pain: Mechanisms and Management,” Nature Reviews Gastroenterology & Hepatology 12, no. 3 (2015): 159–171.

[186] V. J. Felitti, R. F. Anda, D. Nordenberg, et al., “REPRINT OF: Relationship of Childhood Abuse and Household Dysfunction to Many of the Leading Causes of Death in Adults: The Adverse Childhood Experiences (ACE) Study,” American Journal of Preventive Medicine 56, no. 6 (2019): 774–786.

[187] D. J. Clauw, E. H. S. Choy, V. Napadow, et al., “Hypothetical Model Ignores Many Important Pathophysiologic Mechanisms in Fibromyalgia,” Nature Reviews Rheumatology 19, no. 5 (2023): 321.

[188] A. Nalbandian, K. Sehgal, A. Gupta, et al., “Post-acute COVID-19 Syndrome,” Nature Medicine 27, no. 4 (2021): 601–615.

[189] D. J. Clauw, W. Häuser, S. P. Cohen, and M.-A. Fitzcharles, “Considering the Potential for an Increase in Chronic Pain After the COVID-19 Pandemic,” Pain 161, no. 8 (2020): 1694–1697.

[190] S. M. Meints and R. R. Edwards, “Evaluating Psychosocial Contributions to Chronic Pain Outcomes,” Progress in Neuro-Psychopharmacology and Biological Psychiatry 87, no. Pt B (2018): 168–182.

[191] C. Berna, S. Leknes, E. A. Holmes, R. R. Edwards, G. M. Goodwin, and I. Tracey, “Induction of Depressed Mood Disrupts Emotion Regulation Neurocircuitry and Enhances Pain Unpleasantness,” Biological Psychiatry 67, no. 11 (2010): 1083–1090.

[192] C. Tanguay-Sabourin, M. Fillingim, G. V. Guglietti, et al., “A Prognostic Risk Score for Development and Spread of Chronic Pain,” Nature Medicine 29, no. 7 (2023): 1821–1831.

[193] M. A. Hanley, M. P. Jensen, D. M. Ehde, A. J. Hoffman, D. R. Patterson, and L. R. Robinson, “Psychosocial Predictors of Long-term Adjustment to Lower-limb Amputation and Phantom Limb Pain,” Disability and Rehabilitation 26, no. 14-15 (2004): 882–893.

[194] C. Gentili, J. Rickardsson, V. Zetterqvist, L. E. Simons, M. Lekander, and R. K. Wicksell, “Psychological Flexibility as a Resilience Factor in Individuals with Chronic Pain,” Frontiers in Psychology 10 (2019): 2016.

[195] Z. Chng, J. J. Yeo, and A. Joshi, “Resilience as a Protective Factor in Face of Pain Symptomatology, Disability and Psychological Outcomes in Adult Chronic Pain Populations: A Scoping Review,” Scandinavian Journal of Pain 23, no. 2 (2023): 228–250.

[196] B. W. Dyal, M. O. Ezenwa, S. L. Yoon, et al., “Relationship of Pain Quality Descriptors and Quantitative Sensory Testing,” Nursing Research 68, no. 5 (2019): 365–373.

[197] R. Melzack, “The McGill Pain Questionnaire: Major Properties and Scoring Methods,” Pain 1, no. 3 (1975): 277–299.

[198] R. Green, J. Kalina, R. Ford, K. Pandey, and I. Kister, “SymptoMScreen: A Tool for Rapid Assessment of Symptom Severity in MS Across Multiple Domains,” Applied Neuropsychology: Adult 24, no. 2 (2017): 183–189.

[199] A. M. Toyota, R. Garcia, A. A. M. Torricelli, et al., “Preoperative Predictors for Acute Pain after Photorefractive Keratectomy,” Cornea 41, no. 8 (2022): 940–949.

[200] O. K.-K. Ham, Y. Kang, H. Teng, Y. Lee, and E.-O. Im, “Consistency and Accuracy of Multiple Pain Scales Measured in Cancer Patients from Multiple Ethnic Groups,” Cancer Nursing 38, no. 4 (2015): 305–311.

[201] R. Melzack, “The Short-form McGill Pain Questionnaire,” Pain 30, no. 2 (1987): 191–197.

[202] D. Boljanovic-Susic, C. Ziebart, J. Macdermid, J. De Beer, D. Petruccelli, and L. J. Woodhouse, “The Sensitivity and Specificity of Using the McGill Pain Subscale for Diagnosing Neuropathic and Non-neuropathic Chronic Pain in the Total Joint Arthroplasty Population,” Archives of Physiotherapy 13, no. 1 (2023): 9.

[203] S. U. Jumbo, J. C. Macdermid, M. E. Kalu, T. L. Packham, G. S. Athwal, and K. J. Faber, “Measurement Properties of the Brief Pain Inventory-Short Form (BPI-SF) and Revised Short McGill Pain Questionnaire Version-2 (SF-MPQ-2) in Pain-related Musculoskeletal Conditions,” The Clinical Journal of Pain 37, no. 6 (2021): 454–474.

[204] A. K. Erdemoglu and R. Koc, “Brief Pain Inventory Score Identifying and Discriminating Neuropathic and Nociceptive Pain,” Acta Neurologica Scandinavica 128, no. 5 (2013): 351–358.

[205] M. I. Bennett, N. Attal, M. M. Backonja, et al., “Using Screening Tools to Identify Neuropathic Pain,” Pain 127, no. 3 (2007): 199–203.

[206] A. Truini, K. Aleksovska, C. C. Anderson, et al., “Joint European Academy of Neurology–European Pain Federation–Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment,” European Journal of Neurology 30, no. 8 (2023): 2177–2196.

[207] S. R. Sarkar, M. D. S. Tauhid, S. A. Khanam, R. Rouf, and J. Biswas, “Validation of the Bengali Version of the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) Pain Scale: A Tool for Differentiating Neuropathic and Nociceptive Pain,” Medicine 104, no. 46 (2025): e45982.

[208] R. Neblett, H. Cohen, Y. Choi, et al., “The Central Sensitization Inventory (CSI): Establishing Clinically Significant Values for Identifying central Sensitivity Syndromes in an Outpatient Chronic Pain Sample,” The Journal of Pain 14, no. 5 (2013): 438–445.

[209] M. A. Shraim, H. Massé-Alarie, and P. W. Hodges, “Methods to Discriminate Between Mechanism-based Categories of Pain Experienced in the Musculoskeletal System: A Systematic Review,” Pain 162, no. 4 (2021): 1007–1037.

[210] K. D. Bruun, H. I. Jensen, M. R. Blichfeldt-Eckhardt, et al., “Performance of the 2016 Diagnostic Criteria for Fibromyalgia in a Tertiary Care Pain Rehabilitation Setting: A Diagnostic Accuracy Study,” Scandinavian Journal of Pain 22, no. 1 (2022): 67–76.

[211] F. Bailly, A. Cantagrel, P. Bertin, et al., “Part of pain labelled neuropathic in rheumatic disease might be rather nociplastic,” RMD Open 6, no. 2 (2020): e001326.

[212] Z. F. Negeri, B. Levis, Y. Sun, et al., “Accuracy of the Patient Health Questionnaire-9 for Screening to Detect Major Depression: Updated Systematic Review and Individual Participant Data Meta-analysis,” Bmj 375 (2021): n2183.

[213] K. Kroenke, R. L. Spitzer, and J. B. Williams, “The PHQ-9,” Journal of General Internal Medicine 16, no. 9 (2001): 606–613.

[214] R. L. Spitzer, K. Kroenke, J. B. W. Williams, and B. Löwe, “A Brief Measure for Assessing Generalized Anxiety Disorder,” Archives of Internal Medicine 166, no. 10 (2006): 1092.

[215] Z. Aktürk, A. Hapfelmeier, A. Fomenko, et al., “Generalized Anxiety Disorder 7-item (GAD-7) and 2-item (GAD-2) Scales for Detecting Anxiety Disorders in Adults,” Cochrane Database of Systematic Reviews (Online) 3, no. 3 (2025): Cd015455.

[216] C. M. Morin, G. Belleville, L. Bélanger, and H. Ivers, “The Insomnia Severity Index: Psychometric Indicators to Detect Insomnia Cases and Evaluate Treatment Response,” Sleep 34, no. 5 (2011): 601–608.

[217] K. Kroenke, T. E. Stump, J. Kean, et al., “Diagnostic Operating Characteristics of PROMIS Scales in Screening for Depression,” Journal of Psychosomatic Research 147 (2021): 110532.

[218] E. Kosek, D. Clauw, J. Nijs, et al., “Chronic Nociplastic Pain Affecting the Musculoskeletal System: Clinical Criteria and Grading System,” Pain 162, no. 11 (2021): 2629–2634.

[219] J. Murphy, S. Clarke, P. Strutton, C. Morgan, K. Bannister, and S. W. Hughes, “Recommendations for the Neurophysiological Assessment of Conditioned Pain Modulation: A Systematic Review of Nociceptive Blink Reflex and Nociceptive Withdrawal Reflex Protocols,” European Journal of Pain 29, no. 10 (2025): e70149.

[220] R. H. Dworkin, D. C. Turk, D. A. Revicki, et al., “Development and Initial Validation of an Expanded and Revised Version of the Short-form McGill Pain Questionnaire (SF-MPQ-2),” Pain 144, no. 1-2 (2009): 35–42.

[221] J. Katz and R. Melzack, The McGill Pain Questionnaire: Development, Psychometric Properties, and Usefulness of the Long-form, Short-form and Short-form-2, in Handbook of Pain Assessment, ed. D. C. Turk and R. Melzack (The Guilford Press, 2011), 45–66.

[222] C. J. Main, “Pain Assessment in Context: A state of the Science Review of the McGill Pain Questionnaire 40 Years On,” Pain 157, no. 7 (2016): 1387–1399.

[223] T. M. Atkinson, B. D. Rosenfeld, L. Sit, et al., “Using Confirmatory Factor Analysis to Evaluate Construct Validity of the Brief Pain Inventory (BPI),” Journal of Pain and Symptom Management 41, no. 3 (2011): 558–565.

[224] T. M. Atkinson, S. Halabi, A. V. Bennett, et al., “Measurement of Affective and Activity Pain Interference Using the Brief Pain Inventory (BPI): Cancer and Leukemia Group B 70903,” Pain Medicine 13, no. 11 (2012): 1417–1424.

[225] C. S. Cleeland and K. M. Ryan, “Pain Assessment: Global Use of the Brief Pain Inventory,” Annals of the Academy of Medicine of Singapore 23, no. 2 (1994): 129–138.

[226] C. S. Cleeland, The Brief Pain Inventory User Guide (The University of Texas MD Anderson Cancer Center, 2009).

[227] F. S. S. Bonafé, L. A. De Campos, J. Marôco, and J. A. D. B. Campos, “Brief Pain Inventory: A Proposal to Extend Its Clinical Application,” European Journal of Pain 23, no. 3 (2019): 565–576.

[228] C. Sommer and M. Kress, “Recent Findings on How Proinflammatory Cytokines Cause Pain: Peripheral Mechanisms in Inflammatory and Neuropathic Hyperalgesia,” Neuroscience Letters 361, no. 1-3 (2004): 184–187.

[229] M. S. Angst, J. D. Clark, B. Carvalho, M. Tingle, M. Schmelz, and D. C. Yeomans, “Cytokine Profile in human Skin in Response to Experimental Inflammation, Noxious Stimulation, and Administration of a COX-inhibitor: A Microdialysis Study,” Pain 139, no. 1 (2008): 15–27.

[230] M. A. Omole, N. Noah, L. Zhou, et al., “Spectroelectrochemical Characterization of Pain Biomarkers,” Analytical Biochemistry 395, no. 1 (2009): 54–60.

[231] K. Krikava, K. Kalla, A. Yamamotová, and R. Rokyta, et al., “Blood Serum Changes in Patients With Pain During Bone Fractures and Acute Pancreatitis,” Neuro Endocrinology Letters 25, no. 1-2 (2004): 62–69.

[232] M. Matsumoto, S. Kondo, T. B. Usdin, and H. Ueda, “Parathyroid Hormone 2 Receptor Is a Functional Marker of Nociceptive Myelinated Fibers Responsible for Neuropathic Pain,” Journal of Neurochemistry 112, no. 2 (2010): 521–530.

[233] C. A. Courtney, “A New Look at Arthritis Management: Nociceptive Reflex Excitability as a Pain Biomarker,” Arthritis Research & Therapy 17 (2015): 303.

[234] J. A. Biurrun Manresa, G. P. Nguyen, M. Curatolo, T. B. Moeslund, and O. K. Andersen, “Probabilistic Model for Individual Assessment of central Hyperexcitability Using the Nociceptive Withdrawal Reflex: A Biomarker for Chronic Low Back and Neck Pain,” BMC Neuroscience [Electronic Resource] 14 (2013): 110.

[235] M. M. Rockholt, G. Kenefati, L. V. Doan, Z. S. Chen, and J. Wang, “In Search of a Composite Biomarker for Chronic Pain by Way of EEG and Machine Learning: Where Do We Currently Stand?,” Frontiers in Neuroscience 17 (2023): 1186418.

[236] K. A. Sluka, T. D. Wager, S. P. Sutherland, et al., “Predicting Chronic Postsurgical Pain: Current Evidence and a Novel Program to Develop Predictive Biomarker Signatures,” Pain 164, no. 9 (2023): 1912–1926.

[237] B. A. Perkins, L. E. Lovblom, V. Bril, et al., “Corneal Confocal Microscopy for Identification of Diabetic Sensorimotor Polyneuropathy: A Pooled Multinational Consortium Study,” Diabetologia 61, no. 8 (2018): 1856–1861.

[238] L. Oudejans, M. Niesters, M. Brines, A. Dahan, and M. Van Velzen, “Quantification of Small fiber Pathology in Patients With Sarcoidosis and Chronic Pain Using Cornea Confocal Microscopy and Skin Biopsies,” Journal of Pain Research 10 (2017): 2057–2065.

[239] M. Brines, D. A. Culver, M. Ferdousi, et al., “Corneal Nerve fiber Size Adds Utility to the Diagnosis and Assessment of Therapeutic Response in Patients With Small fiber Neuropathy,” Scientific Reports 8, no. 1 (2018): 4734.

[240] J. Vollert, N. Attal, R. Baron, et al., “Quantitative sensory testing using DFNS protocol in Europe,” Pain 157, no. 3 (2016): 750–758.

[241] W. Magerl, E. K. Krumova, R. Baron, T. Tölle, R.-D. Treede, and C. Maier, “Reference Data for Quantitative Sensory Testing (QST): Refined Stratification for Age and a Novel Method for Statistical Comparison of Group Data,” Pain 151, no. 3 (2010): 598–605.

[242] M. M. Backonja, N. Attal, R. Baron, et al., “Value of Quantitative Sensory Testing in Neurological and Pain Disorders: NeuPSIG Consensus,” Pain 154, no. 9 (2013): 1807–1819.

[243] G. Zanette, C. Cacciatori, and S. Tamburin, “Central Sensitization in Carpal Tunnel Syndrome With Extraterritorial Spread of Sensory Symptoms,” Pain 148, no. 2 (2010): 227–236.

[244] N. B. Finnerup, S. Haroutounian, P. Kamerman, et al., “Neuropathic Pain: An Updated Grading System for Research and Clinical Practice,” Pain 157, no. 8 (2016): 1599–1606.

[245] N. Attal and D. Bouhassira, “Diagnosis of Neuropathic Pain in Polyneuropathy: Should Screening Questionnaires be Thrown out?,” Pain 164, no. 5 (2023): e260–e261.

[246] Z. Rutter-Locher, N. Arumalla, S. Norton, L. S. Taams, B. W. Kirkham, and K. Bannister, “A Systematic Review and Meta-analysis of Questionnaires to Screen for Pain Sensitisation and Neuropathic Like Pain in Inflammatory Arthritis,” Seminars in Arthritis and Rheumatism 61 (2023): 152207.

[247] N. Attal, D. Bouhassira, and R. Baron, “Diagnosis and Assessment of Neuropathic Pain Through Questionnaires,” The Lancet Neurology 17, no. 5 (2018): 456–466.

[248] L. Garcia-Larrea and K. Hagiwara, “Electrophysiology in Diagnosis and Management of Neuropathic Pain,” Revista De Neurologia 175, no. 1-2 (2019): 26–37.

[249] J. Serra, W. R. Duan, C. Locke, R. Solà, W. Liu, and W. Nothaft, “Effects of a T-type calcium channel blocker, ABT-639, on spontaneous activity in C-nociceptors in patients with painful diabetic neuropathy,” Pain 156, no. 11 (2015): 2175–2183.

[250] V. Novak, M. L. Freimer, J. T. Kissel, et al., “Autonomic Impairment in Painful Neuropathy,” Neurology 56, no. 7 (2001): 861–868.

[251] M. Haanpää, N. Attal, M. Backonja, et al., “NeuPSIG Guidelines on Neuropathic Pain Assessment,” Pain 152, no. 1 (2011): 14–27.

[252] C. Perchet, M. Frot, A. Charmarty, et al., “Do We Activate Specifically Somatosensory Thin Fibres With the Concentric Planar Electrode? A Scalp and Intracranial EEG Study,” Pain 153, no. 6 (2012): 1244–1252.

[253] N. Uceyler, A. K. Kahn, D. Kramer, et al., “Impaired Small fiber Conduction in Patients With Fabry Disease: A Neurophysiological Case-control Study,” BMC Neurology [Electronic Resource] 13 (2013): 47.

[254] K. Hagiwara, C. Perchet, M. Frot, H. Bastuji, and L. Garcia-Larrea, “Insular-limbic dissociation to intra-epidermal electrical Aδ activation: A comparative study with thermo-nociceptive laser stimulation,” European Journal of Neuroscience 48, no. 10 (2018): 3186–3198.

[255] L. Garcia-Larrea and R. Peyron, “Pain Matrices and Neuropathic Pain Matrices: A Review,” Pain 154, no. Suppl 1 (2013): S29–S43.

[256] S. M. Gustin, P. J. Wrigley, A. M. Youssef, et al., “Thalamic Activity and Biochemical Changes in Individuals With Neuropathic Pain After Spinal Cord Injury,” Pain 155, no. 5 (2014): 1027–1036.

[257] K. D. Wilkinson, K. Lee, S. Deshpande, P. Duerksen-Hughes, J. M. Boss, and J. Pohl, “The Neuron-specific Protein PGP 9.5 Is a Ubiquitin Carboxyl-terminal Hydrolase,” Science 246, no. 4930 (1989): 670–673.

[258] M. Nolano, A. Biasiotta, R. Lombardi, et al., “Epidermal innervation morphometry by immunofluorescence and bright-field microscopy,” Journal of the Peripheral Nervous System 20, no. 4 (2015): 387–391.

[259] P. Karlsson, A. M. Hincker, T. S. Jensen, R. Freeman, and S. Haroutounian, “Structural, Functional, and Symptom Relations in Painful Distal Symmetric Polyneuropathies: A Systematic Review,” Pain 160, no. 2 (2019): 286–297.

[260] A. Truini, L. Garcia-Larrea, and G. Cruccu, “Reappraising neuropathic pain in humans—how symptoms help disclose mechanisms,” Nature reviews Neurology 9, no. 10 (2013): 572–582.

[261] E. Galosi, S. La Cesa, G. Di Stefano, et al., “A Pain in the Skin. Regenerating Nerve Sprouts Are Distinctly Associated With Ongoing Burning Pain in Patients With Diabetes,” European Journal of Pain 22, no. 10 (2018): 1727–1734.

[262] P. Karlsson, S. S. Gylfadottir, A. G. Kristensen, et al., “Axonal Swellings Are Related to Type 2 Diabetes, but Not to Distal Diabetic Sensorimotor Polyneuropathy,” Diabetologia 64, no. 4 (2021): 923–931.

[263] D. L. Bennett, A. J. Clark, J. Huang, S. G. Waxman, and S. D. Dib-Hajj, “The Role of Voltage-Gated Sodium Channels in Pain Signaling,” Physiological Reviews 99, no. 2 (2019): 1079–1151.

[264] A. E. Murphy, D. Minhas, D. J. Clauw, and Y. C. Lee, “Identifying and Managing Nociplastic Pain in Individuals with Rheumatic Diseases: A Narrative Review,” Arthritis Care & Research 75, no. 10 (2023): 2215–2222.

[265] M. A. Shraim, K. A. Sluka, M. Sterling, et al., “Features and Methods to Discriminate Between Mechanism-based Categories of Pain Experienced in the Musculoskeletal System: A Delphi Expert Consensus Study,” Pain 163, no. 9 (2022): 1812–1828.

[266] R. Freynhagen, R. Baron, U. Gockel, and T. R. Tölle, “painDETECT: A New Screening Questionnaire to Identify Neuropathic Components in Patients With Back Pain,” Current Medical Research and Opinion 22, no. 10 (2006): 1911–1920.

[267] A. Soni, V. Wanigasekera, M. Mezue, et al., “Central Sensitization in Knee Osteoarthritis: Relating Presurgical Brainstem Neuroimaging and Pain DETECT -Based Patient Stratification to Arthroplasty Outcome,” Arthritis & Rheumatology 71, no. 4 (2019): 550–560.

[268] F. Wolfe, D. J. Clauw, M.-A. Fitzcharles, et al., “2016 Revisions to the 2010/2011 Fibromyalgia Diagnostic Criteria,” Seminars in Arthritis and Rheumatism 46, no. 3 (2016): 319–329.

[269] C. M. Brummett, A. M. Janda, C. M. Schueller, et al., “Survey Criteria for Fibromyalgia Independently Predict Increased Postoperative Opioid Consumption after Lower-extremity Joint Arthroplasty,” Anesthesiology 119, no. 6 (2013): 1434–1443.

[270] A. M. Janda, S. As-Sanie, B. Rajala, et al., “Fibromyalgia Survey Criteria Are Associated With Increased Postoperative Opioid Consumption in Women Undergoing Hysterectomy,” Anesthesiology 122, no. 5 (2015): 1103–1111.

[271] M. A. Shraim, H. Massé-Alarie, L. M. Hall, and P. W. Hodges, “Systematic Review and Synthesis of Mechanism-based Classification Systems for Pain Experienced in the Musculoskeletal System,” The Clinical Journal of Pain 36, no. 10 (2020): 793–812.

[272] G. Lyngstad, P. Skjelbred, D. M. Swanson, and L. A. Skoglund, “Analgesic Effect of Oral Ibuprofen 400, 600, and 800 mg; Paracetamol 500 and 1000 mg; and Paracetamol 1000 mg plus 60 mg Codeine in Acute Postoperative Pain: A Single-dose, Randomized, Placebo-controlled, and Double-blind Study,” European Journal of Clinical Pharmacology 77, no. 12 (2021): 1843–1852.

[273] R. D. Altman, R.-L. Dreiser, C. L. Fisher, W. F. Chase, D. S. Dreher, and J. Zacher, “Diclofenac Sodium Gel in Patients With Primary Hand Osteoarthritis: A Randomized, Double-blind, Placebo-controlled Trial,” The Journal of Rheumatology 36, no. 9 (2009): 1991–1999.

[274] S. Motov, A. Masoudi, J. Drapkin, et al., “Comparison of Oral Ibuprofen at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial,” Annals of Emergency Medicine 74, no. 4 (2019): 530–537.

[275] L. L. Ngo, K. P. Braaten, E. Eichen, J. Fortin, R. Maurer, and A. B. Goldberg, “Naproxen Sodium for Pain Control With Intrauterine Device Insertion,” Obstetrics & Gynecology 128, no. 6 (2016): 1306–1313.

[276] V. B. P. Pereira, R. Garcia, A. A. M. Torricelli, A. Mukai, and S. J. Bechara, “Codeine plus Acetaminophen for Pain after Photorefractive Keratectomy: A Randomized, Double-Blind, Placebo-Controlled Add-On Trial,” Cornea 36, no. 10 (2017): 1206–1212.

[277] E. R. Viscusi, O. De Leon-Casasola, J. Cebrecos, et al., “Celecoxib-tramadol co-crystal in patients with moderate-to-severe pain following bunionectomy with osteotomy: A phase 3, randomized, double-blind, factorial, active- and placebo-controlled trial,” Pain Practice 23, no. 1 (2023): 8–22.

[278] T. Rian, E. Skogvoll, J. Hofstad, et al., “Tapentadol vs Oxycodone for Postoperative Pain Treatment the First 7 Days After Total Knee Arthroplasty: A Randomized Clinical Trial,” Pain 162, no. 2 (2021): 396–404.

[279] M. P. Cristalli, G. La Monaca, C. De Angelis, N. Pranno, and S. Annibali, “Efficacy of Preoperative Administration of Paracetamol-Codeine on Pain Following Impacted Mandibular Third Molar Surgery: A Randomized, Split-Mouth, Placebo-Controlled, Double-Blind Clinical Trial,” Pain Research and Management 2017 (2017): 1–6.

[280] G. A. Macheras, D. Tzefronis, C. Argyrou, E. Nikolakopoulou, A. Gálvez Miravete, and T. S. Karachalios, “Pain Management After Total Hip Arthroplasty: Comparative Study of Analgesic Efficacy and Tolerability Between Oral Tramadol/Dexketoprofen and Injectable Paracetamol + Tramadol,” HIP International 34, no. 3 (2024): 304–310.

[281] T. Giordano, A. Durkin, A. Simi, et al., “High-Dose Celecoxib for Pain After Pediatric Tonsillectomy: A Randomized Controlled Trial,” Otolaryngology–Head and Neck Surgery 168, no. 2 (2023): 218–226.

[282] A. M. Munteanu, S. Cionac Florescu, D. M. Anastase, and C. I. Stoica, “Is there any analgesic benefit from preoperative vs. postoperative administration of etoricoxib in total knee arthroplasty under spinal anaesthesia?,” European Journal of Anaesthesiology 33, no. 11 (2016): 840–845.

[283] D. Reckziegel, H. Bailey, W. J. Cottam, et al., “Imaging Pain Relief in Osteoarthritis (IPRO): Protocol of a Double-blind Randomised Controlled Mechanistic Study Assessing Pain Relief and Prediction of Duloxetine Treatment Outcome,” BMJ Open 7, no. 6 (2017): e014013.

[284] B. A. Gray, J. M. Hagey, D. Crabtree, et al., “Gabapentin for Perioperative Pain Management for Uterine Aspiration,” Obstetrics & Gynecology 134, no. 3 (2019): 611–619.

[285] J. R. Johnson, D. Lossignol, M. Burnell-Nugent, and M. T. Fallon, “An Open-label Extension Study to Investigate the Long-term Safety and Tolerability of THC/CBD Oromucosal Spray and Oromucosal THC Spray in Patients With Terminal Cancer-related Pain Refractory to Strong Opioid Analgesics,” Journal of Pain and Symptom Management 46, no. 2 (2013): 207–218.

[286] F. Johannsen, J. L. Olesen, T. F. Øhlenschläger, et al., “Effect of Ultrasonography-Guided Corticosteroid Injection vs Placebo Added to Exercise Therapy for Achilles Tendinopathy,” JAMA Network Open 5, no. 7 (2022): e2219661.

[287] M. Rambhia, A. Chen, A. H. Kumar, W. M. Bullock, M. Bolognesi, and J. Gadsden, “Ultrasound-guided Genicular Nerve Blocks Following Total Knee Arthroplasty: A Randomized, Double-blind, Placebo-controlled Trial,” Regional Anesthesia & Pain Medicine 46, no. 10 (2021): 862–866.

[288] K. Truong, K. Meier, L. C. Ahrens, et al., “Cryoneurolysis versus Radiofrequency Ablation Outcome on Pain Experience in Chronic Low Back Pain (COPE): A Single-blinded Randomised Controlled Trial,” RMD Open 10, no. 2 (2024): e004196.

[289] L. Kapural, D. G. Patterson, S. Li, et al., “Multiphase Spinal Cord Stimulation in Participants with Chronic Back or Leg Pain: Results of the BENEFIT-02 Randomized Clinical Trial,” Neuromodulation: Technology at the Neural Interface 26, no. 7 (2023): 1400–1411.

[290] D. C. Cherkin, K. J. Sherman, B. H. Balderson, et al., “Effect of Mindfulness-Based Stress Reduction vs Cognitive Behavioral Therapy or Usual Care on Back Pain and Functional Limitations in Adults With Chronic Low Back Pain,” Jama 315, no. 12 (2016): 1240.

[291] C. Gentili, V. Zetterqvist, J. Rickardsson, L. Holmström, B. Ljótsson, and R. Wicksell, “Examining Predictors of Treatment Effect in Digital Acceptance and Commitment Therapy for Chronic Pain,” Cognitive Behaviour Therapy 52, no. 4 (2023): 380–396.

[292] J. W. Burns, M. P. Jensen, B. Thorn, et al., “Cognitive Therapy, Mindfulness-based Stress Reduction, and Behavior Therapy for the Treatment of Chronic Pain: Randomized Controlled Trial,” Pain 163, no. 2 (2022): 376–389.

[293] C. J. Hwang, J. H. Lee, J.-H. Kim, et al., “Gabapentin versus Transdermal Fentanyl Matrix for the Alleviation of Chronic Neuropathic Pain of Radicular Origin: A Randomized Blind Multicentered Parallel-Group Noninferiority Trial,” Pain Research and Management 2019 (2019): 4905013.

[294] K. H. Joung, T. N. Kim, E. J. Ku, et al., “A Phase 4 Randomized Active-controlled Clinical Study to Compare the Efficacy and Safety of Sustained-release Pregabalin With Immediate-release Pregabalin in Type 2 Diabetic Patients With Peripheral Neuropathic Pain,” Journal of Diabetes and Its Complications 38, no. 8 (2024): 108809.

[295] J. Boyle, M. E. V. Eriksson, L. Gribble, et al., “Randomized, Placebo-Controlled Comparison of Amitriptyline, Duloxetine, and Pregabalin in Patients With Chronic Diabetic Peripheral Neuropathic Pain,” Diabetes Care 35, no. 12 (2012): 2451–2458.

[296] I. Gilron, D. Tu, R. R. Holden, A. C. Jackson, and D. Dumerton-Shore, “Combination of Morphine With Nortriptyline for Neuropathic Pain,” Pain 156, no. 8 (2015): 1440–1448.

[297] E. M. L. Smith, H. Pang, C. Cirrincione, et al., “Effect of Duloxetine on Pain, Function, and Quality of Life Among Patients With Chemotherapy-Induced Painful Peripheral Neuropathy,” Jama 309, no. 13 (2013): 1359.

[298] N. Farshchian, A. Alavi, S. Heydarheydari, and N. Moradian, “Comparative Study of the Effects of Venlafaxine and Duloxetine on Chemotherapy-induced Peripheral Neuropathy,” Cancer Chemotherapy and Pharmacology 82, no. 5 (2018): 787–793.

[299] G. Pickering, M. Voute, N. Macian, H. Ganry, and B. Pereira, “Effectiveness and Safety of 5% Lidocaine-medicated Plaster on Localized Neuropathic Pain After Knee Surgery: A Randomized, Double-blind Controlled Trial,” Pain 160, no. 5 (2019): 1186–1195.

[300] J. Y. Moon, P. B. Lee, Y. C. Kim, S. C. Lee, F. S. Nahm, and E. Choi, “Efficacy and Safety of 0.625% and 1.25% Capsaicin Patch in Peripheral Neuropathic Pain: Multi-Center, Randomized, and Semi-Double Blind Controlled Study,” Pain Physician 20, no. 2 (2017): 27–35.

[301] F. Kaguelidou, E. Le Roux, L. Mangiarini, et al., “Non-inferiority double-blind randomised controlled trial comparing gabapentin versus tramadol for the treatment of chronic neuropathic or mixed pain in children and adolescents: The GABA-1 trial—a study protocol,” BMJ Open 9, no. 2 (2019): e023296.

[302] R. Baron, E. Martin-Mola, M. Müller, C. Dubois, D. Falke, and I. Steigerwald, “Effectiveness and Safety of Tapentadol Prolonged Release ( PR ) Versus a Combination of Tapentadol PR and Pregabalin for the Management of Severe, Chronic Low Back Pain With a Neuropathic Component: A Randomized, Double-blind, Phase 3b Study,” Pain Practice 15, no. 5 (2015): 455–470.

[303] W.-T. Chen, R.-Y. Yuan, S.-C. Chiang, et al., “OnabotulinumtoxinA Improves Tactile and Mechanical Pain Perception in Painful Diabetic Polyneuropathy,” The Clinical Journal of Pain 29, no. 4 (2013): 305–310.

[304] G. Pickering, B. Pereira, V. Morel, et al., “Ketamine and Magnesium for Refractory Neuropathic Pain,” Anesthesiology 133, no. 1 (2020): 154–164.

[305] E. Martin, V. Morel, D. Joly, et al., “Rationale and Design of a Randomized Double-blind Clinical Trial in Breast Cancer: Dextromethorphan in Chemotherapy-induced Peripheral Neuropathy,” Contemporary Clinical Trials 41 (2015): 146–151.

[306] M. Serpell, S. Ratcliffe, J. Hovorka, et al., “A double-blind, randomized, placebo-controlled, parallel group study of THC / CBD spray in peripheral neuropathic pain treatment,” European Journal of Pain 18, no. 7 (2014): 999–1012.

[307] E. M. Choi, M. H. Chung, J. H. Jun, et al., “Efficacy of Intermittent Epidural Dexamethasone Bolus for Zoster-associated Pain Beyond the Acute Phase,” International Journal of Medical Sciences 17, no. 12 (2020): 1811–1818.

[308] J.-H. Ryu, C. S. Lee, Y.-C. Kim, S. C. Lee, H. Shankar, and J. Y. Moon, “Ultrasound-Assisted versus Fluoroscopic-Guided Lumbar Sympathetic Ganglion Block: A Prospective and Randomized Study,” Anesthesia & Analgesia 126, no. 4 (2018): 1362–1368.

[309] K. Kumar, R. S. Taylor, L. Jacques, et al., “Spinal Cord Stimulation versus Conventional Medical Management for Neuropathic Pain: A Multicentre Randomised Controlled Trial in Patients With Failed Back Surgery Syndrome,” Pain 132, no. 1-2 (2007): 179–188.

[310] C. Gilmore, B. Ilfeld, J. Rosenow, et al., “Percutaneous Peripheral Nerve Stimulation for the Treatment of Chronic Neuropathic Postamputation Pain: A Multicenter, Randomized, Placebo-controlled Trial,” Regional Anesthesia & Pain Medicine 44, no. 6 (2019): 637–645.

[311] M. M. Eid, M. F. Rawash, M. A. Sharaf, and H. M. Eladl, “Effectiveness of Transcutaneous Electrical Nerve Stimulation as an Adjunct to Selected Physical Therapy Exercise Program on Male Patients With Pudendal Neuralgia: A Randomized Controlled Trial,” Clinical Rehabilitation 35, no. 8 (2021): 1142–1150.

[312] P. S. Gadjradj, S. M. Rubinstein, W. C. Peul, et al., “Full Endoscopic versus Open Discectomy for Sciatica: Randomised Controlled Non-inferiority Trial,” Bmj 376 (2022): e065846.

[313] D. M. Higgins, A. A. Heapy, E. Buta, et al., “A Randomized Controlled Trial of Cognitive Behavioral Therapy Compared With Diabetes Education for Diabetic Peripheral Neuropathic Pain,” Journal of Health Psychology 27, no. 3 (2022): 649–662.

[314] K. A. Rozworska, P. A. Poulin, A. Carson, G. A. Tasca, and H. J. Nathan, “Mediators and Moderators of Change in Mindfulness-based Stress Reduction for Painful Diabetic Peripheral Neuropathy,” Journal of Behavioral Medicine 43, no. 2 (2020): 297–307.

[315] W. Scott, B. J. Guildford, J. Badenoch, et al., “Feasibility randomized-controlled trial of online acceptance and commitment therapy for painful peripheral neuropathy in people living with HIV: The OPEN study,” European Journal of Pain 25, no. 7 (2021): 1493–1507.

[316] C. Toth, S. Brady, F. Gagnon, and K. Wigglesworth, “A Randomized, Single-blind, Controlled, Parallel Assignment Study of Exercise versus Education as Adjuvant in the Treatment of Peripheral Neuropathic Pain,” The Clinical Journal of Pain 30, no. 2 (2014): 111–118.

[317] D. Antcliff, A.-M. Keenan, P. Keeley, S. Woby, and L. Mcgowan, “Testing a Newly Developed Activity Pacing Framework for Chronic Pain/Fatigue: A Feasibility Study,” BMJ Open 11, no. 12 (2021): e045398.

[318] A. Malfliet, D. Lenoir, C. Murillo, et al., “Pain Science Education, Stress Management, and Cognition-Targeted Exercise Therapy in Chronic Whiplash Disorders,” JAMA Network Open 8, no. 8 (2025): e2526674.

[319] A. Hrkać, D. Bilić, E. Černy-Obrdalj, I. Baketarić, and L. Puljak., “Comparison of Supervised Exercise Therapy With or Without Biopsychosocial Approach for Chronic Nonspecific Low Back Pain: A Randomized Controlled Trial,” BMC Musculoskeletal Disorders [Electronic Resource] 23, no. 1 (2022): 966.

[320] S. W. Hopkins, J. Greenberg, J. Isaacs, and A.-M. Vranceanu, ““Practice Makes Perfect”? Associations Between Home Practice and Physical and Emotional Function Outcomes Among Patients with Chronic Pain Enrolled in a Mind–Body Program,” Journal of Integrative and Complementary Medicine 28, no. 4 (2022): 320–327.

[321] K. Vibe Fersum, A. Smith, A. Kvåle, J. S. Skouen, and P. O'Sullivan, “Cognitive functional therapy in patients with non-specific chronic low back pain—a randomized controlled trial 3-year follow-up,” European Journal of Pain 23, no. 8 (2019): 1416–1424.

[322] J. P. Sanabria-Mazo, A. Colomer-Carbonell, X. Borràs, et al., “Efficacy of Videoconference Group Acceptance and Commitment Therapy (ACT) and Behavioral Activation Therapy for Depression (BATD) for Chronic Low Back Pain (CLBP) plus Comorbid Depressive Symptoms: A Randomized Controlled Trial (IMPACT Study),” The Journal of Pain 24, no. 8 (2023): 1522–1540.

[323] R. Taub, N. Agmon-Levin, L. Frumer, I. Samuel-Magal, I. Glick, and D. Horesh, “Mindfulness-based Stress Reduction (MBSR) for Fibromyalgia Patients: The Role of Pain Cognitions as Mechanisms of Change,” Complementary Therapies in Clinical Practice 56 (2024): 101860.

[324] I. J. Koh, M. S. Kim, S. Sohn, K. Y. Song, N. Y. Choi, and Y. In, “Duloxetine Reduces Pain and Improves Quality of Recovery Following Total Knee Arthroplasty in Centrally Sensitized Patients: A Prospective, Randomized Controlled Study,” Journal of Bone and Joint Surgery American Volume 101, no. 1 (2019): 64–73.

[325] D. M. Urquhart, A. E. Wluka, M. Van Tulder, et al., “Efficacy of Low-Dose Amitriptyline for Chronic Low Back Pain,” JAMA Internal Medicine 178, no. 11 (2018): 1474.

[326] A. Clair and B. Emir, “The Safety and Efficacy of pregabalin for Treating Subjects With Fibromyalgia and Moderate or Severe Baseline Widespread Pain,” Current Medical Research and Opinion 32, no. 3 (2016): 601–610.

[327] M. A. Abdelhafeez, A. Reda, A. Elnaggar, H. El-Zeneiny, and J. M. Mokhles, “Gabapentin for the Management of Chronic Pelvic Pain in Women,” Archives of Gynecology and Obstetrics 300, no. 5 (2019): 1271–1277.

[328] J.-W. Yang, L.-Y. Qi, S.-Y. Yan, et al., “Efficacy of ACupuncTure in Irritable bOwel syNdrome (ACTION): A Multicenter Randomized Controlled Trial,” Gastroenterology 169, no. 5 (2025): 958–969.e5.

[329] S. L. Murphy, R. E. Harris, N. R. Keshavarzi, and S. M. Zick, “Self-Administered Acupressure for Chronic Low Back Pain: A Randomized Controlled Pilot Trial,” Pain Medicine 20, no. 12 (2019): 2588–2597.

[330] J. C. Kendall, S. D. French, J. Hartvigsen, and M. F. Azari, “Chiropractic Treatment Including Instrument-assisted Manipulation for Non-specific Dizziness and Neck Pain in Community-dwelling Older People: A Feasibility Randomised Sham-controlled Trial,” Chiropractic & Manual Therapies 26 (2018): 14.

[331] S. Mechsner, J. Grünert, J. J. Wiese, et al., “Transcranial Direct Current Stimulation to Reduce Chronic Pelvic Pain in Endometriosis: Phase II Randomized Controlled Clinical Trial,” Pain Medicine 24, no. 7 (2023): 809–817.

[332] C. Li, J. Hu, and C. He, “Analgesic Efficacy of Transcranial Combined Peripheral Magnetic Stimulation in Chronic Nonspecific Low Back Pain: A fNIRS Study,” European Journal of Physical and Rehabilitation Medicine 61, no. 1 (2025): 93–101.

[333] G. Lange, M. N. Janal, A. Maniker, et al., “Safety and Efficacy of Vagus Nerve Stimulation in Fibromyalgia: A Phase I/II Proof of Concept Trial,” Pain Medicine 12, no. 9 (2011): 1406–1413.

[334] L. M. Facci, J. P. Nowotny, F. Tormem, and V. F. M. Trevisani, “Effects of Transcutaneous Electrical Nerve Stimulation (TENS) and Interferential Currents (IFC) in Patients With Nonspecific Chronic Low Back Pain: Randomized Clinical Trial,” Sao Paulo Medical Journal 129, no. 4 (2011): 206–216.

[335] B. Han, W. M. Compton, C. Blanco, E. Crane, J. Lee, and C. M. Jones, “Prescription Opioid Use, Misuse, and Use Disorders in U.S. Adults: 2015 National Survey on Drug Use and Health,” Annals of Internal Medicine 167, no. 5 (2017): 293–301.

[336] D. Fornasari, “Pharmacotherapy for Neuropathic Pain: A Review,” Pain and Therapy 6, no. Suppl 1 (2017): 25–33.

[337] M. Boom, M. Niesters, E. Sarton, L. Aarts, T. W. Smith, and A. Dahan, “Non-analgesic Effects of Opioids: Opioid-induced respiratory Depression,” Current Pharmaceutical Design 18, no. 37 (2012): 5994–6004.

[338] P. N. Fuchs, C. Roza, I. Sora, G. Uhl, and S. N. Raja, “Characterization of mechanical withdrawal responses and effects of μ-, δ- and κ-opioid agonists in normal and μ-opioid receptor knockout mice,” Brain Research 821, no. 2 (1999): 480–486.

[339] X. Nadal, C. La Porta, S. Andreea Bura, and R. Maldonado, “Involvement of the Opioid and Cannabinoid Systems in Pain Control: New Insights From Knockout Studies,” European Journal of Pharmacology 716, no. 1-3 (2013): 142–157.

[340] A. I. Fraguas-Sánchez and A. I. Torres-Suárez, “Medical Use of Cannabinoids,” Drugs 78, no. 16 (2018): 1665–1703.

[341] J. G. Ramaekers, “Driving Under the Influence of Cannabis,” Jama 319, no. 14 (2018): 1433.

[342] R. J. Tait, D. Caldicott, D. Mountain, S. L. Hill, and S. Lenton, “A Systematic Review of Adverse Events Arising From the Use of Synthetic Cannabinoids and Their Associated Treatment,” Clinical Toxicology 54, no. 1 (2016): 1–13.

[343] J. Bartkowiak-Wieczorek, A. Bienert, K. Czora-Poczwardowska, et al., “Cannabis Sativa L. Extract Alleviates Neuropathic Pain and Modulates CB1 and CB2 Receptor Expression in Rat,” Biomolecules 14, no. 9 (2024): 1065.

[344] K. Cohen, A. Weizman, and A. Weinstein, “Modulatory Effects of Cannabinoids on Brain Neurotransmission,” European Journal of Neuroscience 50, no. 3 (2019): 2322–2345.

[345] J. Choi, G. Li, K. L. Stephens, M. P. Timko, and B. R. Degeorge, “The Use of Cannabinoids in the Treatment of Peripheral Neuropathy and Neuropathic Pain: A Systematic Review,” The Journal of Hand Surgery 50, no. 8 (2025): 954–965.

[346] A. Bhaskar, A. Bell, M. Boivin, et al., “Consensus Recommendations on Dosing and Administration of Medical Cannabis to Treat Chronic Pain: Results of a Modified Delphi Process,” Journal of Cannabis Research 3, no. 1 (2021): 22.

[347] D. Turcotte, M. Doupe, M. Torabi, et al., “Nabilone as an Adjunctive to Gabapentin for multiple sclerosis-induced Neuropathic Pain: A Randomized Controlled Trial,” Pain Medicine 16, no. 1 (2015): 149–159.

[348] H. Meng, B. Johnston, M. Englesakis, D. E. Moulin, and A. Bhatia, “Selective Cannabinoids for Chronic Neuropathic Pain: A Systematic Review and Meta-analysis,” Anesthesia & Analgesia 125, no. 5 (2017): 1638–1652.

[349] L. E. Leggett, L. J. Soril, D. L. Lorenzetti, et al., “Radiofrequency Ablation for Chronic Low Back Pain: A Systematic Review of Randomized Controlled Trials,” Pain Research and Management 19, no. 5 (2014): e146–e153.

[350] Z. L. McCormick, B. Marshall, J. Walker, R. McCarthy, and D. R. Walega, “Long-Term Function, Pain and Medication Use Outcomes of Radiofrequency Ablation for Lumbar Facet Syndrome,” International Journal of Anesthetics and Anesthesiology 2, no. 2 (2015): 028.

[351] H.-J. Kwon, C.-S. Kim, D.-H. Kim, J.-W. Shin, D. Choi, and S.-S. Choi, “Effectiveness of the Cooled Radiofrequency Ablation of Genicular Nerves in Patients With Chronic Knee Pain due to Osteoarthritis: A Double-Blind, Randomized, Controlled Study,” Medicina 60, no. 6 (2024): 857.

[352] D. C. Turk, “Clinical Effectiveness and Cost-effectiveness of Treatments for Patients With Chronic Pain,” The Clinical Journal of Pain 18, no. 6 (2002): 355–365.

[353] J. Caylor, R. Reddy, S. Yin, et al., “Spinal Cord Stimulation in Chronic Pain: Evidence and Theory for Mechanisms of Action,” Bioelectronic Medicine 5 (2019): 12.

[354] M. Saber, D. Schwabe, H.-J. Park, et al., “Tonic, Burst, and Burst-Cycle Spinal Cord Stimulation Lead to Differential Brain Activation Patterns as Detected by Functional Magnetic Resonance Imaging,” Neuromodulation: Technology at the Neural Interface 25, no. 1 (2022): 53–63.

[355] D. De Ridder and S. Vanneste, “Burst and Tonic Spinal Cord Stimulation: Different and Common Brain Mechanisms,” Neuromodulation: Technology at the Neural Interface 19, no. 1 (2016): 47–59.

[356] L. Atkinson, S. R. Sundaraj, C. Brooker, et al., “Recommendations for Patient Selection in Spinal Cord Stimulation,” Journal of Clinical Neuroscience 18, no. 10 (2011): 1295–1302.

[357] J. J. Song, A. Popescu, and R. L. Bell, “Present and Potential Use of Spinal Cord Stimulation to Control Chronic Pain,” Pain Physician 17, no. 3 (2014): 235–246.

[358] F. R. Gondal, J. Bilal, and C. Kent Kwoh, “Tanezumab for the Treatment of Osteoarthritis Pain,” Drugs of Today 58, no. 4 (2022): 187–200.

[359] M. Schmelz, P. Mantyh, A.-M. Malfait, et al., “Nerve Growth Factor Antibody for the Treatment of Osteoarthritis Pain and Chronic Low-back Pain: Mechanism of Action in the Context of Efficacy and Safety,” Pain 160, no. 10 (2019): 2210–2220.

[360] A. M. Rush and T. R. Cummins, “Painful Research: Identification of a Small-molecule Inhibitor That Selectively Targets Nav1.8 Sodium Channels,” Molecular Interventions 7, no. 4 (2007): 192–195.

[361] Y.-F. Xie, J. Yang, S. Ratté, and S. A. Prescott, “Similar Excitability Through Different Sodium Channels and Implications for the Analgesic Efficacy of Selective Drugs,” Elife 12 (2024): RP90960.

[362] Y. Goldberg, J. Macfarlane, M. Macdonald, et al., “Loss-of-function mutations in the Na v 1.7 gene underlie congenital indifference to pain in multiple human populations,” Clinical Genetics 71, no. 4 (2007): 311–319.

[363] D. Bhansali, S. L. Teng, C. S. Lee, B. L. Schmidt, N. W. Bunnett, and K. W. Leong, “Nanotechnology for Pain Management: Current and Future Therapeutic Interventions,” Nano Today 39 (2021): 101223.

[364] J. D. Sydney-Smith, A. B. Spejo, P. M. Warren, and L. D. F. Moon, “Peripherally Delivered Adeno-associated Viral Vectors for Spinal Cord Injury Repair,” Experimental Neurology 348 (2022): 113945.

[365] Y. Zhang, D. Yi, Q. Hong, et al., “Platelet-rich Plasma-derived Exosomes Enhance Mesenchymal Stem Cell Paracrine Function and Nerve Regeneration Potential,” Biochemical and Biophysical Research Communications 699 (2024): 149496.

[366] Y. Zhang, D. Yi, Q. Hong, et al., “Platelet-rich Plasma-derived Exosomes Boost Mesenchymal Stem Cells to Promote Peripheral Nerve Regeneration,” Journal of Controlled Release 367 (2024): 265–282.

[367] R. J. Duarte-Moreira, L. Shirahige, I. E. Rodriguez-Prieto, et al., “Evidence-Based Umbrella Review of Non-Invasive Neuromodulation in Chronic Neuropathic Pain,” European Journal of Pain 29, no. 2 (2025): e4786.

[368] A. D. Kaye, G. Armistead, L. S. Amedio, et al., “Evolving Treatment Strategies for Neuropathic Pain: A Narrative Review,” Medicina 61, no. 6 (2025): 1063.

[369] I. Gilron, R. Baron, and T. Jensen, “Neuropathic Pain: Principles of Diagnosis and Treatment,” Mayo Clinic Proceedings 90, no. 4 (2015): 532–545.

[370] E. R. Zeldin, A. R. Goddard, M. S. Boyle, et al., “An overview of the non-procedural treatment options for peripheral neuropathic pain,” Muscle & Nerve 71, no. 5 (2025): 791–801.

[371] Y. Deng, L. Luo, Y. Hu, K. Fang, and J. Liu, “Clinical Practice Guidelines for the Management of Neuropathic Pain: A Systematic Review,” BMC Anesthesiology 16 (2016): 12.

[372] R. Patel and A. H. Dickenson, “Mechanisms of the gabapentinoids and α2δ -1 calcium channel subunit in neuropathic pain,” Pharmacology Research & Perspectives 4, no. 2 (2016): e00205.

[373] G. Cruccu and A. Truini, “A Review of Neuropathic Pain: From Guidelines to Clinical Practice,” Pain and Therapy 6, no. Suppl 1 (2017): 35–42.

[374] F. Porreca, Q. Tang, D. Bian, M. Riedl, R. Elde, and J. Lai, “Spinal Opioid Mu Receptor Expression in Lumbar Spinal Cord of Rats Following Nerve Injury,” Brain Research 795, no. 1-2 (1998): 197–203.

[375] C. A. Odonkor, T. Alfarra, P. Adekoya, et al., “Dorsal Column Stimulation and Cannabinoids in the Treatment of Chronic Nociceptive and Neuropathic Pain: A Review of the Clinical and Pre-clinical Data,” Current Pain and Headache Reports 26, no. 2 (2022): 103–118.

[376] A. B. Kesdoğan, A. Neureiter, A. J. Gaebler, A. K. Kalia, J. Körner, and A. Lampert, “Analgesic Effect of Botulinum Toxin in Neuropathic Pain Is Sodium Channel Independent,” Neuropharmacology 253 (2024): 109967.

[377] B. Jabbari and A. Tohidian, “An Update on Botulinum Toxin Treatment of Painful Diabetic Neuropathy, Post-traumatic Painful Neuropathy/Neuralgia, Post-herpetic Neuralgia and Occipital Neuralgia,” Toxicon 255 (2025): 108237.

[378] R. F. Bell and E. A. Kalso, “Ketamine for Pain Management,” PAIN Reports 3, no. 5 (2018): e674.

[379] C. Pușcașu, C. Chiriță, S. Negreș, and N. M. Blebea, “Exploring the Therapeutic Potential of N-Methyl-D-Aspartate Receptor Antagonists in Neuropathic Pain Management,” International Journal of Molecular Sciences 25, no. 20 (2024): 11111.

[380] M. J. C. Scanio, L. Shi, I. Drizin, et al., “Discovery and biological evaluation of potent, selective, orally bioavailable, pyrazine-based blockers of the Nav1.8 sodium channel with efficacy in a model of neuropathic pain,” Bioorganic & Medicinal Chemistry 18, no. 22 (2010): 7816–7825.

[381] E. Mcgowan, S. B. Hoyt, X. Li, K. A. Lyons, and C. Abbadie, “A Peripherally Acting Nav1.7 Sodium Channel Blocker Reverses Hyperalgesia and Allodynia on Rat Models of Inflammatory and Neuropathic Pain,” Anesthesia & Analgesia 109, no. 3 (2009): 951–958.

[382] M. F. Jarvis, P. Honore, C.-C. Shieh, et al., “A-803467, a Potent and Selective Nav1.8 Sodium Channel Blocker, Attenuates Neuropathic and Inflammatory Pain in the Rat,” Proceedings of the National Academy of Science of the United States of America s 104, no. 20 (2007): 8520–8525.

[383] L. Wei, P. Yu, H. Wang, and J. Liu, “Adeno-associated Viral Vectors Deliver Gene Vaccines,” European Journal of Medicinal Chemistry 281 (2025): 117010.

[384] M. J. Eaton, B. Blits, M. J. Ruitenberg, J. Verhaagen, and M. Oudega, “Amelioration of Chronic Neuropathic Pain After Partial Nerve Injury by Adeno-associated Viral (AAV) Vector-mediated Over-expression of BDNF in the Rat Spinal Cord,” Gene Therapy 9, no. 20 (2002): 1387–1395.

[385] C. Y. Kang, K. W. Been, M.-H. Kang, et al., “Advances in Therapeutic Applications of CRISPR Genome Editing for Spinal Pain Management,” Neurospine 22, no. 2 (2025): 421–440.

[386] C. Herrera León, N. A. Kalacas, A. Mier, et al., “Synthetic Peptide Antibodies as TNF-α Inhibitors: Molecularly Imprinted Polymer Nanogels Neutralize the Inflammatory Activity of TNF-α in THP-1 Derived Macrophages,” Angewandte Chemie International Edition 62, no. 34 (2023): e202306274.

[387] H. Mitoma, T. Horiuchi, H. Tsukamoto, and N. Ueda, “Molecular mechanisms of action of anti-TNF-α agents – Comparison among therapeutic TNF-α antagonists,” Cytokine 101 (2018): 56–63.

[388] G. Dell'Antonio, A. Quattrini, E. D. Cin, A. Fulgenzi, and M. E. Ferrero, “Relief of inflammatory pain in rats by local use of the selective P2X7 ATP receptor inhibitor, oxidized ATP,” Arthritis & Rheumatism 46, no. 12 (2002): 3378–3385.

[389] J. Wu, Y. Xu, S. Pu, W. Jiang, and D. Du, “p38/MAPK Inhibitor Modulates the Expression of Dorsal Horn GABA(B) Receptors in the Spinal Nerve Ligation Model of Neuropathic Pain,” Neuroimmunomodulation 18, no. 3 (2011): 150–155.

[390] N. Mangano, A. Torpey, C. Devitt, G. A. Wen, C. Doh, and A. Gupta, “Closed-Loop Spinal Cord Stimulation in Chronic Pain Management: Mechanisms, Clinical Evidence, and Emerging Perspectives,” Biomedicines 13, no. 5 (2025): 1091.

[391] R. Treister, M. Lang, M. M. Klein, and A. L. Oaklander, “Non-invasive Transcranial Magnetic Stimulation (TMS) of the Motor Cortex for Neuropathic Pain—At the Tipping Point?,” Rambam Maimonides Medical Journal 4, no. 4 (2013): e0023.

[392] Y. Liang, S. Niu, and Y. Wang, “Repetitive Transcranial Magnetic Stimulation for Musculoskeletal Pain: A Systematic Review and Meta-analysis,” British Journal of Pain 19, no. 6 (2025): 20494637251356812.

[393] T. Li, G. Lin, T. Zhang, et al., “Repetitive Transcranial Magnetic Stimulation Ameliorates Chronic Pain Behavior and Modulates the Brain Transcriptome in a Mouse Model of Chronic Constriction Injury,” Brain Research Bulletin 227 (2025): 111383.

[394] A. Michel, D. Kang, R. B. Fillingim, N. L. Balderston, D. S. Bond, and V. R. Steele, “Repetitive Transcranial Magnetic Stimulation for Substance Use Disorders and Chronic Pain: A Review of the Evidence and Call for Increased Mechanistic Understanding,” Current Addiction Reports 12 (2025), https://doi.org/10.1007/s40429-025-00620-3.

[395] J. Qu, H. Zhou, Q. Wang, et al., “Efficacy of Repetitive Transcranial Magnetic Stimulation for Post-stroke Shoulder Pain: A Systematic Review and Meta-analysis,” Topics in Stroke Rehabilitation 32, no. 3 (2025): 1–15.

[396] G. E. Ferreira, C. Abdel-Shaheed, M. Underwood, et al., “Efficacy, Safety, and Tolerability of Antidepressants for Pain in Adults: Overview of Systematic Reviews,” Bmj 380 (2023): e072415.

[397] F. Migliorini, N. Maffulli, M. Knobe, G. Tenze, A. Aljalloud, and G. Colarossi, “Pregabalin Administration in Patients With Fibromyalgia: A Bayesian Network Meta-analysis,” Scientific Reports 12, no. 1 (2022): 12148.

[398] NICE, Chronic Pain (Primary and Secondary) in Over 16s: Assessment of All Chronic Pain and Management of Chronic Primary Pain National Institute for Health and Care Excellence: Guidelines 2021.

[399] G. J. Macfarlane, C. Kronisch, L. E. Dean, et al., “EULAR Revised Recommendations for the Management of Fibromyalgia,” Annals of the Rheumatic Diseases 76, no. 2 (2017): 318–328.

[400] D. C. Turk and L. M. Adams, “Using a Biopsychosocial Perspective in the Treatment of Fibromyalgia Patients,” Pain Management 6, no. 4 (2016): 357–369.

[401] Y. Tanaka, M. Kanazawa, S. Fukudo, and D. A. Drossman, “Biopsychosocial Model of Irritable Bowel Syndrome,” Journal of Neurogastroenterology and Motility 17, no. 2 (2011): 131–139.

[402] A. T. Wilson, J. L. Riley, M. D. Bishop, J. M. Beneciuk, Y. Cruz-Almeida, and J. E. Bialosky, “Characteristics and Outcomes of Patients Receiving Physical Therapy for Low Back Pain With a Nociplastic Pain Presentation: A Secondary Analysis,” Pain Research and Management 2023 (2023): 1–10.

[403] D. J. Kohns, R. Scott, J. Castellanos, D. Scribner, R. Hodges, and D. J. Clauw, “The Impact of Nociplastic Pain Features on the Response to Physical Therapy in Patients With Primary Myofascial Pain,” Journal of Back and Musculoskeletal Rehabilitation 35, no. 5 (2022): 1143–1151.

[404] A. C. Skelly, E. D. Brodt, S. Kantner, et al., Systematic Review on Noninvasive Nonpharmacological Treatment for Chronic Pain: Surveillance Report 3: Literature Update Period: January 2021 through March 2022, in Noninvasive Nonpharmacological Treatment for Chronic Pain: Surveillance Reports. Rockville (MD) (2019).

[405] A. Demeco, M. Gusai, M. F. Masi, A. Frizziero, and C. Costantino, “Acupuncture for Chronic Pain Management in Haemophilic Arthropathy: A Systematic Review,” Haemophilia 5 (2025): 865–873.

[406] K. Jia and Y. Yang, “Effect of Acupuncture and Massage on Adolescent Idiopathic Scoliosis and Pain Severity,” Frontiers in Medicine 12 (2025): 1613800.

[407] L. Ang, E. Song, T.-Y. Choi, et al., “Effects of Acupuncture on Musculoskeletal Pain: An Evidence Map,” Frontiers in Medicine 12 (2025): 1575226.

[408] E. Aydın Özaslan, F. Gülçin Ural Nazlıkul, G. Avcıoğlu, and Ö. Z. Erel, “Effects of acupuncture on oxidative stress mechanisms, pain, and quality of life in fibromyalgia: A prospective study from Türkiye,” Turkish Journal of Physical Medicine and Rehabilitation 71, no. 2 (2025): 174–186.

[409] H. A. Suilik, J. F. Alsamhori, M. Abuelazm, et al., “The Effect of Acupressure on Pain and Anxiety in Patients Undergoing Coronary Angiography: A Meta-Analysis of Randomized Controlled Trials,” International Journal of Nursing Practice 31, no. 2 (2025): e70006.

[410] T. K. W. Lee, J. R. Chang, D. Hao, S.-N. Fu, and A. Y. L. Wong, “The Effectiveness of Auricular Acupressure on Chronic Musculoskeletal Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials,” Journal of Integrative and Complementary Medicine 31, no. 1 (2025): 25–35.

[411] K. Sanchez, J. Haas, P. Oakley, and D. Harrison, “Improvement in Chronic Low Back and Intermittent Chronic Neck Pain, Disability, and Improved Spine Parameters Using Chiropractic BioPhysics® Rehabilitation After 5 Years of Failed Chiropractic Manipulation: A Case Report and 1-Year Follow-Up,” Healthcare 13, no. 7 (2025): 814.

[412] I. D. Coulter, P. M. Herman, M. Kommareddi, E. L. Hurwitz, and P. G. Shekelle, “Measuring the Appropriateness of Spinal Manipulation for Chronic Low Back and Chronic Neck Pain in Chiropractic Patients,” Spine 46, no. 19 (2021): 1344–1353.

[413] J. F. Tsai, “A Case of Chiropractic Manipulation Immediately Relieving Depression With Chronic Pain,” Journal of Alternative and Complementary Medicine 15, no. 6 (2009): 611–612.

[414] R. J. Trager, W. M. Burton, J. V. Loewenthal, et al., “Chiropractic Spinal Manipulation and Fall Risk in Older Adults with Spinal Pain: Observational Findings from a Matched Retrospective Cohort Study,” Cureus 16, no. 10 (2024): e72330.

[415] B. Noehren, D. L. Dailey, B. A. Rakel, et al., “Effect of Transcutaneous Electrical Nerve Stimulation on Pain, Function, and Quality of Life in Fibromyalgia: A Double-blind Randomized Clinical Trial,” Physical Therapy 95, no. 1 (2015): 129–140.

[416] D. L. Dailey, B. A. Rakel, C. G. T. Vance, et al., “Transcutaneous Electrical Nerve Stimulation Reduces Pain, Fatigue and Hyperalgesia While Restoring central Inhibition in Primary Fibromyalgia,” Pain 154, no. 11 (2013): 2554–2562.

[417] N. M. Marlow, H. S. Bonilha, and E. B. Short, “Efficacy of Transcranial Direct Current Stimulation and Repetitive Transcranial Magnetic Stimulation for Treating Fibromyalgia Syndrome: A Systematic Review,” Pain Practice 13, no. 2 (2013): 131–145.

[418] K. Chakravarthy, H. Chaudhry, K. Williams, and P. J. Christo, “Review of the Uses of Vagal Nerve Stimulation in Chronic Pain Management,” Current Pain and Headache Reports 19, no. 12 (2015): 54.

[419] P.-A. Zhu, J.-Y. Xie, H. Liu, Y. Wen, Y.-J. Shao, and X. Bao, “Efficacy of High-Frequency Repetitive Transcranial Magnetic Stimulation at 10 Hz in Fibromyalgia: A Systematic Review and Meta-analysis,” Archives of Physical Medicine and Rehabilitation 104, no. 1 (2023): 151–159.

[420] M. E. Gunduz, M. Kocahasan, and Z. Keser, “Transcranial Direct Current Stimulation to Provide Neuroprotection and Enhance Cerebral Blood Flow in Stroke: A Comprehensive Review,” Medicina 60, no. 12 (2024): 2061.

[421] S. Chen, Q. Ma, P. R. Krafft, et al., “P2X7 Receptor Antagonism Inhibits p38 Mitogen-Activated Protein Kinase Activation and Ameliorates Neuronal Apoptosis After Subarachnoid Hemorrhage in Rats,” Critical Care Medicine 41, no. 12 (2013): e466–e474.

[422] R. Meanti, E. Bresciani, L. Rizzi, et al., “Cannabinoid Receptor 2 (CB2R) as Potential Target for the Pharmacological Treatment of Neurodegenerative Diseases,” Biomedicine & Pharmacotherapy 186 (2025): 118044.

[423] G. Godlewski, S. O. Alapafuja, S. Bátkai, et al., “Inhibitor of Fatty Acid Amide Hydrolase Normalizes Cardiovascular Function in Hypertension Without Adverse Metabolic Effects,” Chemistry & Biology 17, no. 11 (2010): 1256–1266.

[424] A. X. Xiao, B. Chen, C. Chiong, N. H. Lee, I. Immerman, and S. Kinjo, “Digital Doses: Virtual Reality Use for Perioperative Pain and Anxiety in Patients Undergoing Hand Surgery,” Journal of Hand Surgery Global Online 7, no. 6 (2025): 100830.

[425] L. Zhong, H. Wang, B. Ni, et al., “Effects of Virtual Reality-Based Digital Therapy on Negative Emotion, Pain Level and Quality of Life in Patients with Postherpetic Neuralgia,” British Journal of Hospital Medicine 86, no. 9 (2025): 1–15.

[426] R. Schaake, I. Leopold, A. Sandberg, et al., “Virtual Reality for the Management of Pain and Anxiety for IR Procedures: A Prospective, Randomized, Pilot Study on Digital Sedation,” Journal of Vascular and Interventional Radiology 35, no. 6 (2024): 825–833.

[427] H. Y. Giravi, Z. Biskupiak, L. S. Tyler, and G. Bulaj, “Adjunct Digital Interventions Improve Opioid-Based Pain Management: Impact of Virtual Reality and Mobile Applications on Patient-Centered Pharmacy Care,” Frontiers in Digital Health 4 (2022): 884047.

[428] T. H. Tran and V. M. Pham, “Effects of Cognitive Behavioral Therapy Combined With Physical Therapy on Improving Outcomes in Chronic Low Back Pain,” Journal of Physical Therapy Science 37, no. 6 (2025): 291–297.

[429] L. L. Debar, M. Mayhew, R. D. Wellman, et al., “Telehealth and Online Cognitive Behavioral Therapy–Based Treatments for High-Impact Chronic Pain,” Jama 334, no. 7 (2025): 592.

[430] A. E. Sanders, E. D. Weatherspoon, B. M. Ehrmann, et al., “Ratio of Omega-6/Omega-3 Polyunsaturated Fatty Acids Associated with Somatic and Depressive Symptoms in People with Painful Temporomandibular Disorder and Irritable Bowel Syndrome,” The Journal of Pain 23, no. 10 (2022): 1737–1748.

[431] M. A. A. Fattah, S. Morsi, S. A. Fattah, N. H. A. Moneim, and M. G. Tawfik, “High-dose Omega-3 Alters Serum Magnesium and Calcium Levels and Affects Fibromyalgia Symptoms: A Randomized, Double-blind, Placebo-Control Study,” Current Rheumatology Reviews 21, no. 4 (2025): 446–454.

[432] A. Eto-Kimura, S. Yasuo, and Y. Kataoka, “Evaluating Methodological Validity in the Analysis of Tai Chi and Cognitive Behavioral Therapy for Inflammation Reduction in Insomnia: A Letter to the Editor,” Brain, Behavior, and Immunity 123 (2025): 863–864.

[433] M. R. Irwin, D. Hoang, R. Olmstead, et al., “Tai Chi Compared With Cognitive Behavioral Therapy and the Reversal of Systemic, Cellular and Genomic Markers of Inflammation in Breast Cancer Survivors With Insomnia: A Randomized Clinical Trial,” Brain, Behavior, and Immunity 120 (2024): 159–166.

[434] X. Dai, Z. Zhang, J. Zhang, and K. K. Ostrikov, “Dosing: The Key to Precision Plasma Oncology,” Plasma Processes and Polymers 17 (2020): e1900178.

[435] S. Karrer, P. Unger, M. Gruber, et al., “In Vitro Safety Study on the Use of Cold Atmospheric Plasma in the Upper Respiratory Tract,” Cells 13, no. 17 (2024): 1411.

[436] X. Dai, X. Lv, and M. Xi, “Cold Atmospheric Plasma Targets Triple Negative Breast Cancer Cells via SCAF11-mediated Competitive Protein Degradation and Synergizes With miRNA-146b-5p,” International Journal of Biological Macromolecules 312 (2025): 144142.

[437] C. Almeida-Ferreira, C. M. Marto, C. Carmo, et al., “Efficacy of Cold Atmospheric Plasma vs. Chemotherapy in Triple-Negative Breast Cancer: A Systematic Review,” International Journal of Molecular Sciences 25, no. 6 (2024): 3254.

[438] P. Wang, R. Zhou, R. Zhou, et al., “Epidermal Growth Factor Potentiates EGFR(Y992/1173)-mediated Therapeutic Response of Triple Negative Breast Cancer Cells to Cold Atmospheric Plasma-activated Medium,” Redox Biology 69 (2024): 102976.

[439] L. Xiang, X. Xu, S. Zhang, D. Cai, and X. Dai, “Cold Atmospheric Plasma Conveys Selectivity on Triple Negative Breast Cancer Cells both in Vitro and in Vivo,” Free Radical Biology and Medicine 124 (2018): 205–213.

[440] D. Yan, W. Xu, X. Yao, L. I. Lin, J. H. Sherman, and M. Keidar, “The Cell Activation Phenomena in the Cold Atmospheric Plasma Cancer Treatment,” Scientific Reports 8, no. 1 (2018): 15418.

[441] M. A. Abdelkhalek, M. M. Abdelaal, and S. A. Abdel Gaber, “Cold Atmospheric Plasma Followed by in-situ Electrospinning of Arginine-loaded Nanofibers Promote Infected Diabetic Wound Healing,” International Journal of Pharmaceutics 683 (2025): 126023.

[442] R. Gao, H. He, X. Yang, W. Wang, J. Gao, and C. Yang, “Cold Atmospheric Plasma and Skin Wound Healing: Influence on Microbial Diversity and Composition,” BMC Microbiology 25, no. 1 (2025): 260.

[443] P.-S. Wu, T.-H. Wong, C.-W. Hou, et al., “Cold Atmospheric Plasma Jet Promotes Wound Healing through CK2-Coordinated PI3K/AKT and MAPK Signaling Pathways,” Molecular & Cellular Proteomics 24, no. 5 (2025): 100962.

[444] S. Roux, A. Marchès, S. Galiacy, N. Merbahi, and M. Simon, “Biological Solutions Activated by Cold Plasma at Atmospheric Pressure: A New Therapeutic Approach for Skin Wound Healing,” Biomedicine & Pharmacotherapy 186 (2025): 118001.

[445] N. Raissi-Dehkordi, N. Raissi-Dehkordi, H. Ebrahimibagha, et al., “Advancing Chronic and Acute Wound Healing With Cold Atmospheric Plasma: Cellular and Molecular Mechanisms, Benefits, Risks, and Future Directions,” Frontiers in Medicine 12 (2025): 1527736.

[446] O. Bakker, P. Smits, C. Van Weersch, et al., “Improved Wound Healing by Direct Cold Atmospheric Plasma Once or Twice a Week: A Randomized Controlled Trial on Chronic Venous Leg Ulcers,” Advances in Wound Care 14, no. 1 (2025): 1–13.

[447] H. Xu, Y. Zhu, M. Du, et al., “Subcellular Mechanism of Microbial Inactivation During Water Disinfection by Cold Atmospheric-pressure Plasma,” Water Research 188 (2021): 116513.

[448] A. Sainz-García, P. Toledano, I. Muro-Fraguas, et al., “Mask Disinfection Using Atmospheric Pressure Cold Plasma,” International Journal of Infectious Diseases 123 (2022): 145–156.

[449] L. Sanesi, V. Puca, V. C. A. Caponio, et al., “Disinfection of dental root canals by cold atmospheric plasma: A systematic review and meta-analysis of dental biofilm,” Frontiers in Oral Health 5 (2024): 1483078.

[450] T. Sun, C. Liu, L. Kong, J. Zha, and G. Ni, “Cold Plasma Irradiation Inhibits Skin Cancer via Ferroptosis,” Biomedical Physics & Engineering Express 10, no. 6 (2024): 065036.

[451] D. Yan, Q. Wang, M. Adhikari, et al., “A Physically Triggered Cell Death via Transbarrier Cold Atmospheric Plasma Cancer Treatment,” ACS Applied Materials & Interfaces 12, no. 31 (2020): 34548–34563.

[452] R. Limanowski, D. Yan, L. Li, and M. Keidar, “Preclinical Cold Atmospheric Plasma Cancer Treatment,” Cancers 14, no. 14 (2022): 3461.

[453] L. Zheng, J. Gao, Y. Cao, et al., “Two Case Reports of Inverse Psoriasis Treated With Cold Atmospheric Plasma,” Dermatologic Therapy 33, no. 6 (2020): e14257.

[454] N. Menéndez-Coto, C. Garcia-Gonzalez, F. J. Baena-Huerta, et al., “Combining Cold Atmospheric Plasma and Environmental Nanoparticle Removal Device Reduces Neurodegenerative Markers,” International Journal of Molecular Sciences 25, no. 23 (2024): 12986.

[455] M. Moelleken, F. Jockenhöfer, C. Wiegand, J. Buer, S. Benson, and J. Dissemond, “Pilot Study on the Influence of Cold Atmospheric Plasma on Bacterial Contamination and Healing Tendency of Chronic Wounds,” JDDG: Journal der Deutschen Dermatologischen Gesellschaft 18, no. 10 (2020): 1094–1101.

[456] G. Hämmerle, S. Ascher, and L. Gebhardt, “Positive Effects of Cold Atmospheric Plasma on pH in Wounds: A Pilot Study,” Journal of Wound Care 32, no. 9 (2023): 530–536.

[457] F. Brehmer, H. A. Haenssle, G. Daeschlein, et al., “Alleviation of chronic venous leg ulcers with a hand-held dielectric barrier discharge plasma generator (PlasmaDerm ®VU -2010): Results of a monocentric, two-armed, open, prospective, randomized and controlled trial ( NCT 01415622),” Journal of the European Academy of Dermatology and Venereology 29, no. 1 (2015): 148–155.

[458] A. Van Welzen, M. Hoch, P. Wahl, et al., “The Response and Tolerability of a Novel Cold Atmospheric Plasma Wound Dressing for the Healing of Split Skin Graft Donor Sites: A Controlled Pilot Study,” Skin Pharmacology and Physiology 34, no. 6 (2021): 328–336.

[459] G. Isbary, T. Shimizu, J. L. Zimmermann, H. M. Thomas, G. E. Morfill, and W. Stolz, “Cold Atmospheric Plasma for Local Infection Control and Subsequent Pain Reduction in a Patient With Chronic Post-operative Ear Infection,” New Microbes and New Infections 1, no. 3 (2013): 41–43.

[460] Y. Xin, X. Wen, and X. Jiang, “Analgesic effect of topical lidocaine is enhanced by cold atmospheric plasma pretreatment in facial CO 2 laser treatments,” Journal of Cosmetic Dermatology 20, no. 9 (2021): 2794–2799.

[461] R. N. Werner, A. F. Nikkels, B. Marinović, et al., “European consensus-based (S2k) Guideline on the Management of Herpes Zoster – guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV), Part 2: Treatment,” Journal of the European Academy of Dermatology and Venereology 31, no. 1 (2017): 20–29.

[462] H. A. Ünal, N. Demirel Öğüt, E. Güler, and A. Alptekin, “Pain Type and Neuropathic Pain Components in Acute herpes Zoster,” Journal of Turkish Society Algology 36, no. 2 (2024): 100–105.

[463] G. Isbary, T. Shimizu, J. L. Zimmermann, et al., “Randomized Placebo-controlled Clinical Trial Showed Cold Atmospheric Argon Plasma Relieved Acute Pain and Accelerated Healing in herpes Zoster,” Clinical Plasma Medicine 2, no. 2 (2014): 50–55.

[464] J. Wang, K. Xue, J. Gao, et al., “Efficacy and Safety of Cold Atmospheric Plasma-Assisted Therapy for Herpes Zoster: A Randomized, Parallel, Positive-Controlled, Non-inferiority Multicenter Clinical Trial,” Dermatology and Therapy 15, no. 9 (2025): 2391–2408.

[465] C. E. B. De Moura, L. E. C. Francelino, G. R. V. Da Silva, et al., “A Combined Treatment for Self-traumatic Chronic Skin Lesions Associated With Post-surgical Neuropathic Pain in a Domestic Cat: A Pharmacological and Cold Atmospheric Plasma Approach,” Veterinary Research Communications 48, no. 5 (2024): 3263–3270.

[466] J.-Y. Jang, Y. J. Hong, J. Lim, et al., “Cold Atmospheric Plasma (CAP), a Novel Physicochemical Source, Induces Neural Differentiation Through Cross-talk Between the Specific RONS Cascade and Trk/Ras/ERK Signaling Pathway,” Biomaterials 156 (2018): 258–273.

[467] Z. Xiong, S. Zhao, X. Mao, et al., “Selective Neuronal Differentiation of Neural Stem Cells Induced by Nanosecond Microplasma Agitation,” Stem Cell Research 12, no. 2 (2014): 387–399.

[468] H.-R. Metelmann, C. Seebauer, V. Miller, et al., “Clinical Experience With Cold Plasma in the Treatment of Locally Advanced Head and Neck Cancer,” Clinical Plasma Medicine 9 (2018): 6–13.

[469] H.-R. Metelmann, D. S. Nedrelow, C. Seebauer, et al., “Head and Neck Cancer Treatment and Physical Plasma,” Clinical Plasma Medicine 3, no. 1 (2015): 17–23.

[470] X. Dai, S. Feng, and T. Li, “Cold Atmospheric Plasma Control Metabolic Syndromes via Targeting Fat Mass and Obesity-associated Protein,” Pharmacological Research 215 (2025): 107720.

[471] L. Shen, X. Lv, Y. Li, and X. Dai, “Spermidine antagonizes the anti-cancer effect of cold atmospheric plasma and induces transit G0/G1 cell cycle arrest of triple negative breast cancers,” Free Radical Biology and Medicine 229 (2025): 30–38.

[472] A. Rezaeinezhad, P. Eslami, H. Mirmiranpour, and H. Ghomi, “The Effect of Cold Atmospheric Plasma on Diabetes-induced Enzyme Glycation, Oxidative Stress, and Inflammation; in Vitro and in Vivo,” Scientific Reports 9, no. 1 (2019): 19958.

[473] O. M. Ighodaro and O. A. Akinloye, “First Line Defence Antioxidants-superoxide Dismutase (SOD), Catalase (CAT) and Glutathione Peroxidase (GPX): Their Fundamental Role in the Entire Antioxidant Defence Grid,” Alexandria Journal of Medicine 54, no. 4 (2018): 287–293.

[474] P. Wang, R. Zhou, R. Zhou, et al., “Cold Atmospheric Plasma for Preventing Infection of Viruses That Use ACE2 for Entry,” Theranostics 12, no. 6 (2022): 2811–2832.

[475] K. Zhu, Q. Lv, X. Lu, Y. Wang, and X. Dai, “Cold Atmospheric Plasma Restores Skewed Macrophage Polarization in Triple Negative Breast Cancers via Enhancing KAT6A Acetylation,” Free Radical Biology and Medicine 226 (2025): 364–373.

[476] Z. Xiong, “Cold Atmospheric Plasmas: A Novel and Promising Way to Treat Neurological Diseases,” Trends in Biotechnology 36, no. 6 (2018): 582–583.

[477] P. Wang, R. Zhou, P. Thomas, et al., “Epithelial-to-Mesenchymal Transition Enhances Cancer Cell Sensitivity to Cytotoxic Effects of Cold Atmospheric Plasmas in Breast and Bladder Cancer Systems,” Cancers 13, no. 12 (2021): 2889.

[478] L. Miebach, H. Mohamed, K. Wende, V. Miller, and S. Bekeschus, “Pancreatic Cancer Cells Undergo Immunogenic Cell Death Upon Exposure to Gas Plasma-Oxidized Ringers Lactate,” Cancers 15, no. 1 (2023): 319.

[479] X. Dai and K. Zhu, “Cold Atmospheric Plasma: Novel Opportunities for Tumor Microenvironment Targeting,” Cancer Medicine 12, no. 6 (2023): 7189–7206.

[480] L. Miebach, E. Freund, R. Clemen, S. Kersting, L.-I. Partecke, and S. Bekeschus, “Gas plasma–oxidized sodium chloride acts via hydrogen peroxide in a model of peritoneal carcinomatosis,” Proceedings of the National Academy of Sciences of the United States of America 119, no. 31 (2022): e2200708119.

[481] L. Miebach, E. Freund, S. Horn, et al., “Tumor Cytotoxicity and Immunogenicity of a Novel V-jet Neon Plasma Source Compared to the kINPen,” Scientific Reports 11, no. 1 (2021): 136.

[482] P. R. Sreedevi, K. Suresh, and S. Yugeswaran, “Cold Atmospheric Plasma-induced Oxidative Stress and Ensuing Immunological Response—a Neo-Vista in Immunotherapy,” Free Radical Research 56, no. 7-8 (2022): 498–510.

[483] S. M. Grundy, “Inflammation, Metabolic Syndrome, and Diet Responsiveness,” Circulation 108, no. 2 (2003): 126–128.

[484] S. Dzięgielewska-Gęsiak and M. Muc-Wierzgoń, “Inflammation and Oxidative Stress in Frailty and Metabolic Syndromes—Two Sides of the Same Coin,” Metabolites 13, no. 4 (2023): 475.

[485] Q. Chen, W. Zhang, N. Sadana, and X. Chen, “Estrogen Receptors in Pain Modulation: Cellular Signaling,” Biology of Sex Differences 12, no. 1 (2021): 22.

[486] B. L. Chen, Y. Q. Li, D. H. Xie, Q. L. He, and X. X. Yang, “Blocking TNF-α with infliximab alleviates ovariectomy induced mechanical and thermal hyperalgesia in rats,” Neurological Sciences 33, no. 3 (2012): 527–533.

[487] W. Zhang, H. Wu, Q. Xu, et al., “Estrogen modulation of pain perception with a novel 17β-estradiol pretreatment regime in ovariectomized rats,” Biology of Sex Differences 11, no. 1 (2020): 2.

[488] Z.-Z. Xu, Q.-Y. Chen, S.-Y. Deng, et al., “17β-Estradiol Attenuates Neuropathic Pain Caused by Spared Nerve Injury by Upregulating CIC-3 in the Dorsal Root Ganglion of Ovariectomized Rats,” Frontiers in Neuroscience 13 (2019): 1205.

[489] P. J. Shughrue, M. V. Lane, and I. Merchenthaler, “Comparative distribution of estrogen receptor-? and -? mRNA in the rat central nervous system,” The Journal of Comparative Neurology 388, no. 4 (1997): 507–525.

[490] J. M. Hall, J. F. Couse, and K. S. Korach, “The Multifaceted Mechanisms of Estradiol and Estrogen Receptor Signaling,” Journal of Biological Chemistry 276, no. 40 (2001): 36869–36872.

[491] L. Li, X. Fan, M. Warner, X.-J. Xu, J.-Å. Gustafsson, and Z. Wiesenfeld-Hallin, “Ablation of estrogen receptor α or β eliminates sex differences in mechanical pain threshold in normal and inflamed mice,” Pain 143, no. 1-2 (2009): 37–40.

[492] M. Marino, P. Galluzzo, and P. Ascenzi, “Estrogen Signaling Multiple Pathways to Impact Gene Transcription,” Current Genomics 7, no. 8 (2006): 497–508.

[493] N. Heldring, A. Pike, S. Andersson, et al., “Estrogen Receptors: How Do They Signal and What Are Their Targets,” Physiological Reviews 87, no. 3 (2007): 905–931.

[494] A. J. Cooper, S. R. Gupta, A. F. Moustafa, and A. M. Chao, “Sex/Gender Differences in Obesity Prevalence, Comorbidities, and Treatment,” Current Obesity Reports 10, no. 4 (2021): 458–466.

[495] Y. Zhu, J. Shen, L. Gao, and Y. Feng, “Estrogen Promotes Fat Mass and Obesity-associated Protein Nuclear Localization and Enhances Endometrial Cancer Cell Proliferation via the mTOR Signaling Pathway,” Oncology Reports 35, no. 4 (2016): 2391–2397.

[496] G. Bauer, D. Sersenová, D. B. Graves, and Z. Machala, “Cold Atmospheric Plasma and Plasma-Activated Medium Trigger RONS-Based Tumor Cell Apoptosis,” Scientific Reports 9, no. 1 (2019): 14210.

[497] D. Yan, A. Talbot, N. Nourmohammadi, et al., “Principles of Using Cold Atmospheric Plasma Stimulated media for Cancer Treatment,” Scientific Reports 5 (2015): 18339.

[498] H. Tanaka, K. Nakamura, M. Mizuno, et al., “Non-thermal Atmospheric Pressure Plasma Activates Lactate in Ringer's Solution for Anti-tumor Effects,” Scientific Reports 6 (2016): 36282.

[499] Q. Li, J. Choi, N. Shin, et al., “Cold Atmospheric Plasma for Gas Therapy and Gas-activated Drug Delivery,” Advanced Drug Delivery Reviews 227 (2025): 115719.

[500] J. Chen, J. Zhao, J. Liu, and X. Miao, “Cold Atmospheric Plasma in Drug Delivery and Skin Treatment,” Drug Discovery Today 30, no. 8 (2025): 104428.

[501] N. Gaur, B. L. Patenall, B. Ghimire, et al., “Cold Atmospheric Plasma-Activated Composite Hydrogel for an Enhanced and on-Demand Delivery of Antimicrobials,” ACS Applied Materials & Interfaces 15, no. 16 (2023): 19989–19996.

[502] X. Wen, Y. Xin, M. R. Hamblin, and X. Jiang, “Applications of Cold Atmospheric Plasma for Transdermal Drug Delivery: A Review,” Drug Delivery and Translational Research 11, no. 3 (2021): 741–747.

[503] S. Yang and M. C. Chang, “Chronic Pain: Structural and Functional Changes in Brain Structures and Associated Negative Affective States,” International Journal of Molecular Sciences 20, no. 13 (2019): 3130.

[504] Y. Zheng, S. Shao, Y. Zhang, et al., “HCN2 Channels in the Ventral Hippocampal CA1 Regulate Nociceptive Hypersensitivity in Mice,” International Journal of Molecular Sciences 24, no. 18 (2023): 13823.

[505] X. Zhang, Y. Zhang, T. Zhang, et al., “HCN2 deficiency Correlates With Memory Deficits and Hyperexcitability of dCA1 Pyramidal Neurons in Alzheimer's Disease,” Alzheimer's Research & Therapy 17, no. 1 (2025): 55.

[506] L. G. Da Silva, R. C. A. De Menezes, R. A. Souza Dos Santos, M. J. Campagnole-Santos, and M. A. Peliky Fontes, “Role of Periaqueductal Gray on the Cardiovascular Response Evoked by Disinhibition of the Dorsomedial Hypothalamus,” Brain Research 984, no. 1-2 (2003): 206–214.

[507] K. C. G. De Git, D. C. Van Tuijl, M. C. M. Luijendijk, et al., “Anatomical Projections of the Dorsomedial Hypothalamus to the Periaqueductal Grey and Their Role in Thermoregulation: A Cautionary Note,” Physiological Reports 6, no. 14 (2018): e13807.

[508] F. Ullah, T. Dos Anjos-Garcia, J. Mendes-Gomes, et al., “Connexions Between the Dorsomedial Division of the Ventromedial Hypothalamus and the Dorsal Periaqueductal Grey Matter Are Critical in the Elaboration of Hypothalamically Mediated Panic-Like Behaviour,” Behavioural Brain Research 319 (2017): 135–147.

[509] A. Babalian, S. Eichenberger, A. Bilella, et al., “The Orbitofrontal Cortex Projects to the Parvafox Nucleus of the Ventrolateral Hypothalamus and to Its Targets in the Ventromedial Periaqueductal Grey Matter,” Brain Structure and Function 224, no. 1 (2019): 293–314.

[510] G. Rao, H. Gao, X. Wang, J. Zhang, M. Ye, and L. Rao, “MRI Measurements of Brain Hippocampus Volume in Relation to Mild Cognitive Impairment and Alzheimer Disease: A Systematic Review and Meta-analysis,” Medicine 102, no. 36 (2023): e34997.

[511] K. Zhao, Y. Ding, Y. Han, et al., “Independent and Reproducible Hippocampal Radiomic Biomarkers for Multisite Alzheimer's Disease: Diagnosis, Longitudinal Progress and Biological Basis,” Science Bulletin 65, no. 13 (2020): 1103–1113.

[512] T. V. To, D. X. Wang, C. B. Wolfe, and B. C. Lega, “Neurophysiological Evidence of human Hippocampal Longitudinal Differentiation in Associative Memory,” Nature Communications 16, no. 1 (2025): 6845.

[513] J. J. Lobo, L. J. Ayoub, M. Moayedi, and S. D. Linnstaedt, “Hippocampal Volume, FKBP5 Genetic Risk Alleles, and Childhood Trauma Interact to Increase Vulnerability to Chronic Multisite Musculoskeletal Pain,” Scientific Reports 12, no. 1 (2022): 6511.

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