Neuroepigenetic Effects of Non-Pharmacological Pain Treatments: A Narrative Review

Article Sidebar

PDF
Published: Apr 20, 2026
DOI: https://doi.org/10.64444/sjbs.30
Keywords:
Chronic pain, Epigenetics, DNA methylation, Histone modification, microRNAs, non-pharmacological therapy, Neuromodulation

Main Article Content

Dawood Hossaini
Department of Biology and Microbiology, Faculty of Medical Laboratory Technology, Khatam Al- Nabieen University, Kabul, Afghanistan
Ahmad Wali Ataye
Department of Public Health, Faculty of Medicine, Afghan International Islamic University of Kabul, Afghanistan.
Murtaza Haidary
Medical Research and Technology Center, Khatam Al-Nabieen University, Kabul, Afghanistan
Naseer Ahmad Durrani
Department of Public Health, Faculty of Medicine, Afghan International Islamic University of Kabul, Afghanistan.
Mohammad Baryalai Barya
Kabul University of Medical Science, Kabul, Afghanistan.

Abstract

Background: Chronic pain is increasingly recognized as a multidimensional condition shaped by biological, psychological, and environmental factors. Conventional pharmacological treatments, including opioids and non-steroidal anti-inflammatory drugs (NSAIDs), are limited by side effects, tolerance, and poor long-term efficacy, highlighting the need for alternative therapeutic strategies. We aimed to summarize evidence on epigenetic mechanisms underlying chronic pain and to evaluate how non-pharmacological interventions contribute to pain modulation through epigenetic remodeling.


Methods: A narrative review of experimental and clinical studies was conducted, focusing on epigenetic changes associated with chronic pain and the effects of non-pharmacological interventions, including exercise, cognitive behavioral therapy (CBT), mindfulness, neuromodulation techniques, acupuncture, sleep, and dietary modulation.


Results: Chronic pain involves widespread epigenetic remodeling across spinal and supraspinal regions, contributing to central sensitization, neuroinflammation, and maladaptive neuroplasticity. Non-pharmacological interventions converge on shared epigenetic mechanisms: exercise enhances histone acetylation and brain-derived neurotrophic factor (BDNF) expression; CBT and mindfulness normalize stress-related DNA methylation and microRNA profiles; neuromodulation techniques (transcutaneous electrical nerve stimulation, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation) influence histone acetylation and opioid receptor gene methylation; acupuncture regulates DNA methylation and histone acetylation in pain-related neural circuits; and lifestyle factors such as sleep and diet modulate circadian and inflammatory gene expression.


Conclusion: Non-pharmacological pain therapies exert clinically meaningful effects through epigenetic remodeling of nociceptive pathways, positioning them as promising adjunctive or alternative approaches to pharmacological treatment. Future research should prioritize longitudinal multi-omics studies and biomarker-driven precision strategies to optimize therapeutic selection and efficacy.

Article Details

Issue
Vol. 2 No. 1 (2026): Second Volume, First Issue, April 2026
Section
Review Article

References

1. Descalzi G, Ikegami D, Ushijima T, Nestler EJ, Zachariou V, Narita M. Epigenetic mechanisms of chronic pain. Trends Neurosci. 2015;38(4):237-46.

2. Nirvanie-Persaud L, Millis RM, Persaud LN. Epigenetics and pain: new insights to an old problem. Cureus. 2022;14(9).

3. Raja SN, Carr DB, Cohen M, Finnerup NB, Flor H, Gibson S, et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain. 2020;161(9):1976-82.

4. Katz WA, Barkin RL. Dilemmas in Chronic/Persistent Pain Management. Am J Ther. 2008;15(3):256-64.

5. Van den Beuken-van Everdingen MHJ, Van Kuijk SMJ, Janssen DJA, Joosten EAJ. Treatment of Pain in Cancer: Towards Personalised Medicine. Cancers. 2018;10(12):502.

6. Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, et al. Opioid complications and side effects. Pain Physician. 2008;11(2 Suppl):S105-20.

7. Kazemian N, Pakpour S. Understanding the impact of the gut microbiome on opioid use disorder: Pathways, mechanisms, and treatment insights. Microb Biotechnol. 2024; 17(10):e70030.

8. Acute Pain Management for Patients Receiving Maintenance Methadone or Buprenorphine Therapy. Ann Intern Med. 2006;144(2):127-34.

9. Sunzini F, Schrepf A, Clauw DJ, Basu N. The Biology of Pain: Through the Rheumatology Lens. Arthritis Rheumatol. 2023;75(5):650-60.

10. Bird A. Perceptions of epigenetics. Nature. 2007;447(7143):396-8.

11. Denk F, McMahon SB. Chronic pain: emerging evidence for the involvement of epigenetics. Neuron. 2012;73(3):435-44.

12. Bai G, Ren K, Dubner R. Epigenetic regulation of persistent pain. Transl Res. 2015;165(1):177-99.

13. Eichler FS, Li J, Guo Y, Caruso PA, Bjonnes AC, Pan J, et al. CSF1R mosaicism in a family with hereditary diffuse leukoencephalopathy with spheroids. Brain. 2016;139(Pt 6):1666-72.

14. Greenwood BN, Fleshner M. Exercise, stress resistance, and central serotonergic systems. Exerc Sport Sci Rev. 2011;39(3):140-9.

15. Loprinzi PD, Frith E, Edwards MK, Sng E, Ashpole N. The Effects of Exercise on Memory Function Among Young to Middle-Aged Adults: Systematic Review and Recommendations for Future Research. Am J Health Promot. 2018;32(3):691-704.

16. Takahashi JS. Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet. 2017;18(3):164-79.

17. Bower JE, Irwin MR. Mind-body therapies and control of inflammatory biology: A descriptive review. Brain Behav Immun. 2016;51:1-11.

18. Baethge C, Goldbeck-Wood S, Mertens S. SANRA—a scale for the quality assessment of narrative review articles. Res Integ Peer Rev. 2019;4(1):5.

19. Dubin AE, Patapoutian A. Nociceptors: the sensors of the pain pathway. J Clin Invest. 2010;120(11):3760-72.

20. Julius D. TRP Channels and Pain. Annual Review of Cell and Developmental Biology. 2013;29(Volume 29, 2013):355-84.

21. Dib-Hajj SD, Black JA, Waxman SG. Voltage-gated sodium channels: therapeutic targets for pain. Pain Medicine. 2009;10(7):1260-9.

22. Schaible H-G, Ebersberger A, Natura G. Update on peripheral mechanisms of pain: beyond prostaglandins and cytokines. Arthritis Res Ther. 2011;13(2):210.

23. Lüscher C, Malenka RC. NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harb Perspect Biol. 2012;4(6).

24. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Of Pain. 2009;10(9):895-926.

25. Willis WD, Westlund KN. Neuroanatomy of the pain system and of the pathways that modulate pain. J Clin Neurophysiol. 1997;14(1):2-31.

26. Ossipov MH, Morimura K, Porreca F. Descending pain modulation and chronification of pain. Curr Opin Support Palliat Care . 2014;8(2):143-51.

27. Pinho-Ribeiro FA, Verri WA, Jr., Chiu IM. Nociceptor Sensory Neuron-Immune Interactions in Pain and Inflammation. Trends Immunol. 2017;38(1):5-19.

28. Li X-H, Miao H-H, Zhuo M. NMDA receptor dependent long-term potentiation in chronic pain. Neurochem Res. 2019;44(3):531-8.

29. Ren K, Dubner R. Descending modulation in persistent pain: an update. Pain. 2002;100(1):1-6.

30. Luo D, Li X, Tang S, Song F, Li W, Xie G, et al. Epigenetic modifications in neuropathic pain. Molecular Pain. 2021;17:17448069211056767.

31. Pethő G, Kántás B, Horváth Á, Pintér E. The epigenetics of neuropathic pain: a systematic update. Int J Mol Sci. 2023;24(24):17143.

32. Ligon CO, Moloney RD, Greenwood-Van Meerveld B. Targeting epigenetic mechanisms for chronic pain: a valid approach for the development of novel therapeutics. J Pharmacol Exp Ther. 2016;357(1):84-93.

33. Liang L, Lutz BM, Bekker A, Tao YX. Epigenetic regulation of chronic pain. Epigenomics. 2015;7(2):235-45.

34. Ghosh K, Pan H-L. Epigenetic mechanisms of neural plasticity in chronic neuropathic pain. ACS Chem Neurosci. 2022;13(4):432-41.

35. Denk F, Huang W, Sidders B, Bithell A, Crow M, Grist J, et al. HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain. Pain. 2013;154(9):1668-79.

36. Bell JT, Loomis AK, Butcher LM, Gao F, Zhang B, Hyde CL, et al. Differential methylation of the TRPA1 promoter in pain sensitivity. Nature Communications. 2014;5(1):2978.

37. Uchida H, Sasaki K, Ma L, Ueda H. Neuron-restrictive silencer factor causes epigenetic silencing of Kv4.3 gene after peripheral nerve injury. Neurosci. 2010;166(1):1-4.

38. Fila M, Sobczuk A, Pawlowska E, Blasiak J. Epigenetic Connection of the Calcitonin Gene-Related Peptide and Its Potential in Migraine. Int J Mol Sci. 2022;23(11):6151.

39. Mo K, Wu S, Gu X, Xiong M, Cai W, Atianjoh FE, et al. MBD1 Contributes to the Genesis of Acute Pain and Neuropathic Pain by Epigenetic Silencing of Oprm1 and Kcna2 Genes in Primary Sensory Neurons. J Neurosci. 2018;38(46):9883-99.

40. Ding X, Lin Y, Chen C, Yan B, Liu Q, Zheng H, et al. DNMT1 Mediates Chronic Pain-Related Depression by Inhibiting GABAergic Neuronal Activation in the Central Amygdala. Biol Psychiatry. 2023;94(8):672-84.

41. Topham L, Gregoire S, Kang H, Salmon-Divon M, Lax E, Millecamps M, et al. The transition from acute to chronic pain: dynamic epigenetic reprogramming of the mouse prefrontal cortex up to 1 year after nerve injury. Pain. 2020;161(10):2394-409.

42. Géranton SM. Does epigenetic 'memory' of early-life stress predispose to chronic pain in later life? A potential role for the stress regulator FKBP5. Philos Trans R Soc Lond B Biol Sci. 2019;374(1785):20190283.

43. Scarpa JR, Mincer JS. Chronic pain-induced methylation in the prefrontal cortex targets gene networks associated with cognition and Alzheimer’s disease. Neurosci. 2024;561:65-73.

44. Jiang W, Zhang LX, Tan XY, Yu P, Dong M. Inflammation and histone modification in chronic pain. Front Immunol. 2022;13:1087648.

45. Higuchi F, Uchida S, Yamagata H, Abe-Higuchi N, Hobara T, Hara K, et al. Hippocampal MicroRNA-124 Enhances Chronic Stress Resilience in Mice. J Neurosci. 2016;36(27):7253-67.

46. Sun N, Yu L, Gao Y, Ma L, Ren J, Liu Y, et al. MeCP2 Epigenetic Silencing of Oprm1 Gene in Primary Sensory Neurons Under Neuropathic Pain Conditions. Front Neurosci. 2021;15:743207.

47. Zhang H, Zhu Z, Ma WX, Kong LX, Yuan PC, Bu LF, et al. The contribution of periaqueductal gray in the regulation of physiological and pathological behaviors. Front Neurosci. 2024;18:1380171.

48. Zhao Y, Ge Y, Zheng ZL. Brain Imaging-Guided Analysis Reveals DNA Methylation Profiles Correlated with Insular Surface Area and Alcohol Use Disorder. Alcohol Clin Exp Res. 2019;43(4):628-39.

49. Heller EA, Cates HM, Peña CJ, Sun H, Shao N, Feng J, et al. Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors. Nat Neurosci. 2014;17(12):1720-7.

50. Xiong HY, Wyns A, Campenhout JV, Hendrix J, De Bruyne E, Godderis L, et al. Epigenetic Landscapes of Pain: DNA Methylation Dynamics in Chronic Pain. Int J Mol Sci. 2024;25(15).

51. Sah A, Sotnikov S, Kharitonova M, Schmuckermair C, Diepold RP, Landgraf R, et al. Epigenetic Mechanisms Within the Cingulate Cortex Regulate Innate Anxiety-Like Behavior. Int J Neuropsychopharmacol. 2019;22(4):317-28.

52. Yuan M, Yang B, Rothschild G, Mann JJ, Sanford LD, Tang X, et al. Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential. Signal Transduct Target Ther. 2023;8(1):309.

53. Perry S, Sharalla PS, Sarubin DR, Li X, Roesch MR, Brockett AT. Epigenetic manipulation of anterior insular cortex alters neural signals and cognitive control. Neuropsychopharmacol. 2025.

54. Sluka KA, Frey-Law L, Hoeger Bement M. Exercise-induced pain and analgesia? Underlying mechanisms and clinical translation. Pain. 2018;159 Suppl 1(Suppl 1):S91-s7.

55. Núñez-Cortés R, Salazar-Méndez J, Nijs J. Physical Activity as a Central Pillar of Lifestyle Modification in the Management of Chronic Musculoskeletal Pain: A Narrative Review. J Funct Morphol Kinesiol. 2025;10(2):183.

56. Dobson JL, McMillan J, Li L. Benefits of exercise intervention in reducing neuropathic pain. Frontiers Cellular Neurosci. 2014;8:102.

57. Gomez-Pinilla F, Zhuang Y, Feng J, Ying Z, Fan G. Exercise impacts brain-derived neurotrophic factor plasticity by engaging mechanisms of epigenetic regulation. Eur J Neurosci. 2011;33(3):383-90.

58. Jacques M, Hiam D, Craig J, Barrès R, Eynon N, Voisin S. Epigenetic changes in healthy human skeletal muscle following exercise– a systematic review. Epigenetics. 2019;14(7):633-48.

59. Tamargo JA, Strath LJ, Cruz-Almeida Y. High-impact pain is associated with epigenetic aging among middle-aged and older adults: findings from the health and retirement study. J Gerontol Series A: Biol Sci Med Sci. 2024;79(8):glae149.

60. Denham J, O'Brien BJ, Charchar FJ. Telomere Length Maintenance and Cardio-Metabolic Disease Prevention Through Exercise Training. Sports Med. 2016;46(9):1213-37.

61. Plaza-Diaz J, Izquierdo D, Torres-Martos Á, Baig AT, Aguilera CM, Ruiz-Ojeda FJ. Impact of Physical Activity and Exercise on the Epigenome in Skeletal Muscle and Effects on Systemic Metabolism. Biomedicines. 2022;10(1):126.

62. Fernandes J, Arida RM, Gomez-Pinilla F. Physical exercise as an epigenetic modulator of brain plasticity and cognition. Neurosci Biobehav Rev. 2017;80:443-56.

63. Mazzardo-Martins L, Martins DF, Marcon R, dos Santos UD, Speckhann B, Gadotti VM, et al. High-Intensity Extended Swimming Exercise Reduces Pain-Related Behavior in Mice: Involvement of Endogenous Opioids and the Serotonergic System. J Pain. 2010;11(12):1384-93.

64. Kakavandi MA, Shahrbanian S, Kordi MR, Soltani BM. Comparing Effects of Aerobic Versus Resistance Exercise on Expression of MicroRNA-155, Serum- and Glucocorticoid-Regulated Kinase 3, and Pain Threshold in Mice with Experimental Autoimmune Encephalomyelitis. Altern Ther Health Med. 2025;31(1):28-34.

65. Ehde DM, Dillworth TM, Turner JA. Cognitive-behavioral therapy for individuals with chronic pain: efficacy, innovations, and directions for research. Am Psychol. 2014;69(2):153-66.

66. Knoerl R, Lavoie Smith EM, Weisberg J. Chronic pain and cognitive behavioral therapy: an integrative review. Western J Nurs Res. 2016;38(5):596-628.

67. Doehring A, Geisslinger G, Lötsch J. Epigenetics in pain and analgesia: an imminent research field. Eur J Pain. 2011;15(1):11-6.

68. Vukojevic V, Kolassa IT, Fastenrath M, Gschwind L, Spalek K, Milnik A, et al. Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors. J Neurosci. 2014;34(31):10274-84.

69. Seminowicz DA, Wideman TH, Naso L, Hatami-Khoroushahi Z, Fallatah S, Ware MA, et al. Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function. J Neurosci. 2011;31(20):7540-50.

70. Thorn BE. Ronald Melzack Award Lecture: Putting the brain to work in cognitive behavioral therapy for chronic pain. Pain. 2020;161:S27-S35.

71. Seminowicz DA, Shpaner M, Keaser ML, Krauthamer GM, Mantegna J, Dumas JA, et al. Cognitive-Behavioral Therapy Increases Prefrontal Cortex Gray Matter in Patients With Chronic Pain. The J Pain. 2013;14(12):1573-84.

72. Zannas AS, Provençal N, Binder EB. Epigenetics of Posttraumatic Stress Disorder: Current Evidence, Challenges, and Future Directions. Biol Psychiatry. 2015;78(5):327-35.

73. Brivio P, Sbrini G, Tarantini L, Parravicini C, Gruca P, Lason M, et al. Stress Modifies the Expression of Glucocorticoid-Responsive Genes by Acting at Epigenetic Levels in the Rat Prefrontal Cortex: Modulatory Activity of Lurasidone. Int J Mol Sci. 2021;22(12):6197.

74. Gatta E, Grayson DR, Auta J, Saudagar V, Dong E, Chen Y, et al. Genome-wide methylation in alcohol use disorder subjects: implications for an epigenetic regulation of the cortico-limbic glucocorticoid receptors (NR3C1). Mol Psychiatry. 2021;26(3):1029-41.

75. Kleim B, Grey N, Wild J, Nussbeck FW, Stott R, Hackmann A, et al. Cognitive change predicts symptom reduction with cognitive therapy for posttraumatic stress disorder. J Consult Clin Psychol. 2013;81(3):383-93.

76. Musazzi L, Mingardi J, Ieraci A, Barbon A, Popoli M. Stress, microRNAs, and stress-related psychiatric disorders: an overview. Mol Psychiatry. 2023;28(12):4977-94.

77. Maharshak N, Shenhar-Tsarfaty S, Aroyo N, Orpaz N, Guberman I, Canaani J, et al. MicroRNA-132 Modulates Cholinergic Signaling and Inflammation in Human Inflammatory Bowel Disease. Inflammatory Bowel Dis. 2013;19(7):1346-53.

78. Zeidan F, Vago DR. Mindfulness meditation-based pain relief: a mechanistic account. Ann N Y Acad Sci. 2016;1373(1):114-27.

79. Hilton L, Hempel S, Ewing BA, Apaydin E, Xenakis L, Newberry S, et al. Mindfulness Meditation for Chronic Pain: Systematic Review and Meta-analysis. Ann Behav Med. 2017;51(2):199-213.

80. Zeidan F, Emerson NM, Farris SR, Ray JN, Jung Y, McHaffie JG, et al. Mindfulness Meditation-Based Pain Relief Employs Different Neural Mechanisms Than Placebo and Sham Mindfulness Meditation-Induced Analgesia. J Neurosci. 2015;35(46):15307-25.

81. Gard T, Hölzel BK, Lazar SW. The potential effects of meditation on age-related cognitive decline: a systematic review. Ann N Y Acad Sci. 2014;1307:89-103.

82. Kaliman P, Alvarez-López MJ, Cosín-Tomás M, Rosenkranz MA, Lutz A, Davidson RJ. Rapid changes in histone deacetylases and inflammatory gene expression in expert meditators. Psychoneuroendocrinol. 2014;40:96-107.

83. Wasson RS, Barratt C, O'Brien WH. Effects of Mindfulness-Based Interventions on Self-compassion in Health Care Professionals: a Meta-analysis. Mindfulness (N Y). 2020;11(8):1914-34.

84. Zhao J, He Z, Wang J. MicroRNA-124: A Key Player in Microglia-Mediated Inflammation in Neurological Diseases. Front Cell Neurosci. 2021;15:771898.

85. Black DS, Slavich GM. Mindfulness meditation and the immune system: a systematic review of randomized controlled trials. Ann N Y Acad Sci. 2016;1373(1):13-24.

86. Johnson MI. Transcutaneous Electrical Nerve Stimulation (TENS). eLS.

87. Zhang YQ, Ji GC, Wu GC, Zhao ZQ. Excitatory amino acid receptor antagonists and electroacupuncture synergetically inhibit carrageenan-induced behavioral hyperalgesia and spinal fos expression in rats. Pain. 2002; 99(3):525-35.

88. Goudra B, Shah D, Balu G, Gouda G, Balu A, Borle A, et al. Repetitive Transcranial Magnetic Stimulation in Chronic Pain: A Meta-analysis. Anesthesia Essays and Researches. 2017;11(3):751-7.

89. Lefaucheur J-P. Use of repetitive transcranial magnetic stimulation in pain relief. Expert Rev Neurother. 2008;8(5):799-808.

90. Boccard SGJ, Pereira EAC, Moir L, Aziz TZ, Green AL. Long-term Outcomes of Deep Brain Stimulation for Neuropathic Pain. Neurosurgery. 2013;72(2):221-31.

91. Mohseni HR, Smith PP, Parsons CE, Young KS, Hyam JA, Stein A, et al. MEG can map short and long-term changes in brain activity following deep brain stimulation for chronic pain. PloS One. 2012;7(6):e37993.

92. Wang X, Shen X, Xu Y, Xu S, Xia F, Zhu B, et al. The etiological changes of acetylation in peripheral nerve injury–induced neuropathic hypersensitivity. Molecular Pain. 2018;14:1744806918798408.

93. Evertts AG, Zee BM, DiMaggio PA, Gonzales-Cope M, Coller HA, Garcia BA. Quantitative Dynamics of the Link between Cellular Metabolism and Histone Acetylation. J Biol Chem. 2013;288(17):12142-51.

94. Bagot RC, Labonté B, Peña CJ, Nestler EJ. Epigenetic signaling in psychiatric disorders: stress and depression. Dialogues Clin Neurosci. 2014;16(3):281-95.

95. Park I, Kim HJ, Kim Y, Hwang HS, Kasai H, Kim J-H, et al. Nanoscale imaging reveals miRNA-mediated control of functional states of dendritic spines. Proceed National Academy Sci. 2019;116(19):9616-21.

96. Cui P, Ma T, Tamadon A, Han S, Li B, Chen Z, et al. Hypothalamic DNA methylation in rats with dihydrotestosterone-induced polycystic ovary syndrome: effects of low-frequency electro-acupuncture. Exp Physiol. 2018; 103(12):1618-32.

97. Fu S-P, He S-Y, Xu B, Hu C-J, Lu S-F, Shen W-X, et al. Acupuncture promotes angiogenesis after myocardial ischemia through H3K9 acetylation regulation at VEGF gene. PLoS One. 2014;9(4):e94604.

98. Jiang K, Sun Y, Chen X. Mechanism underlying acupuncture therapy in spinal cord injury: a narrative overview of preclinical studies. Front Pharmacol. 2022;13:875103.

99. Liu L, Xu D, Wang T, Zhang Y, Yang X, Wang X, et al. Epigenetic reduction of miR-214-3p upregulates astrocytic colony-stimulating factor-1 and contributes to neuropathic pain induced by nerve injury. Pain. 2020;161(1):96-108.

100. Fan X, Zeng R, Cai L. Microglia inflammatory response contributes to chronic constriction injury-induced neuropathic pain via miR-339/PFKFB3 axis. Trop J Pharmaceut Res. 2021;20(4):695-701.

101. Tang H-y, Wang F-j, Ma J-l, Wang H, Shen G-m, Jiang A-j. Acupuncture attenuates the development of diabetic peripheral neuralgia by regulating P2X4 expression and inflammation in rat spinal microglia. J Physiol Sci. 2020; 70(1):45.

102. Meleady L, Towriss M, Kim J, Bacarac V, Dang V, Rowland ME, et al. Histone deacetylase 3 regulates microglial function through histone deacetylation. Epigenetics. 2023;18(1):2241008.

103. Da Silva JAP, Geenen R, Jacobs JWG. Chronic widespread pain and increased mortality: biopsychosocial interconnections. Ann Rheum Dis. 2018;77(6):790-2.

104. Gutke A, Sundfeldt K, De Baets L. Lifestyle and Chronic Pain in the Pelvis: State of the Art and Future Directions. J Clin Med. 2021; 10(22):5397.

105. Nijs J, D'Hondt E, Clarys P, Deliens T, Polli A, Malfliet A, et al. Lifestyle and Chronic Pain across the Lifespan: An Inconvenient Truth? PM&R. 2020;12(4):410-9.

106. Xiong H-Y, Wyns A, Campenhout JV, Hendrix J, De Bruyne E, Godderis L, et al. Epigenetic landscapes of pain: DNA methylation dynamics in chronic pain. Int J Mol Sci. 2024;25(15):8324.

107. Secondulfo C, Mazzeo F, Pastorino GMG, Vicidomini A, Meccariello R, Operto FF. Opioid and Cannabinoid Systems in Pain: Emerging Molecular Mechanisms and Use in Clinical Practice, Health, and Fitness. Int J Mol Sci. 2024;25(17):9407.

108. Gupta R. Non-pharmaceutical management оf chronic pain. GSC Adv Res Rev. 2023;16:158-65.

109. Odell DW. Epigenetics of pain mediators. Curr Opinion Anesthesiol. 2018;31(4):402-6.

110. Thoma MV, La Marca R, Brönnimann R, Finkel L, Ehlert U, Nater UM. The effect of music on the human stress response. PLoS One. 2013;8(8):e70156.

111. Kaimal G, Ray K, Muniz J. Reduction of Cortisol Levels and Participants' Responses Following Art Making. Art Ther (Alex). 2016;33(2):74-80.

112. Paoloni-Giacobino A, Luthi F, Stenz L, Le Carré J, Vuistiner P, Léger B. Altered BDNF Methylation in Patients with Chronic Musculoskeletal Pain and High Biopsychosocial Complexity. J Pain Res. 2020;13:1289-96.

113. Al-Rawaf HA, Gabr SA, Alghadir AH. Vitamin D Deficiency and Molecular Changes in Circulating MicroRNAs in Older Adults with Lower Back Pain. Pain Res Manag. 2021;2021:6662651.

114. Ayoub SE, Ahmed AM, Abdelwahed MY, Khalefa AA, Awaji AA, Zekry SS, et al. Biochemical analysis of miR-217 and miR-532 in patients with fibromyalgia. Eur J Med Res. 2025;30(1):85.

115. Maiarù M, Acton RJ, Woźniak EL, Mein CA, Bell CG, Géranton SM. A DNA methylation signature in the stress driver gene Fkbp5 indicates a neuropathic component in chronic pain. Clin Epigenetics. 2023;15(1):155.

116. Miller O, Shakespeare-Finch J, Bruenig D, Mehta D. DNA methylation of NR3C1 and FKBP5 is associated with posttraumatic stress disorder, posttraumatic growth, and resilience. Psychol Trauma. 2020;12(7):750-5.

117. Lively S, Milliot M, Potla P, Espin-Garcia O, Layeghifard M, Sundararajan K, et al. Association of presurgical circulating MicroRNAs with 1-year postsurgical pain reduction in spine facet osteoarthritis patients with lumbar spinal stenosis. Osteoarthr Cartil Open. 2022;4(3):100283.

118. Etayo-Urtasun P, Sáez de Asteasu ML, Izquierdo M. Effects of Exercise on DNA Methylation: A Systematic Review of Randomized Controlled Trials. Sports Med. 2024;54(8):2059-69.

119. Xiong HY, Hendrix J, Schabrun S, Wyns A, Campenhout JV, Nijs J, et al. The Role of the Brain-Derived Neurotrophic Factor in Chronic Pain: Links to Central Sensitization and Neuroinflammation. Biomolecules. 2024;14(1).

120. Ramanathan S, Ajit SK. MicroRNA-Based Biomarkers in Pain. Adv Pharmacol. 2016;75:35-62.

121. Provenzi L, Giorda R, Beri S, Montirosso R. SLC6A4 methylation as an epigenetic marker of life adversity exposures in humans: A systematic review of literature. Neurosci Biobehav Rev. 2016;71:7-20.

122. Grossman P, Tiefenthaler-Gilmer U, Raysz A, Kesper U. Mindfulness training as an intervention for fibromyalgia: evidence of postintervention and 3-year follow-up benefits in well-being. Psychother Psychosom. 2007;76(4):226-33.

123. Shin A, Kashyap PC. Multi-omics for biomarker approaches in the diagnostic evaluation and management of abdominal pain and irritable bowel syndrome: what lies ahead. Gut Microbes. 2023;15(1):2195792.

124. Liu Y, Molchanov V, Brass D, Yang T. Recent advances in omics and the integration of multi-omics in osteoarthritis research. Arthritis Res Ther. 2025;27(1):100.

125. Sathappan AV, Luber BM, Lisanby SH. The Dynamic Duo: Combining noninvasive brain stimulation with cognitive interventions. Prog Neuropsychopharmacol Biol Psychiatry. 2019;89:347-60.

126. Saxton JM, Scott EJ, Daley AJ, Woodroofe MN, Mutrie N, Crank H, et al. Effects of an exercise and hypocaloric healthy eating intervention on indices of psychological health status, hypothalamic-pituitary-adrenal axis regulation and immune function after early-stage breast cancer: a randomised controlled trial. Breast Cancer Res. 2014;16(2):R39.

127. Jenke R, Reßing N, Hansen FK, Aigner A, Büch T. Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives. Cancers. 2021;13(4):634.

128. Polli A, Godderis L, Ghosh M, Ickmans K, Nijs J. Epigenetic and miRNA Expression Changes in People with Pain: A Systematic Review. J Pain. 2020;21(7-8):763-80.

129. Ruffilli A, Neri S, Manzetti M, Barile F, Viroli G, Traversari M, et al. Epigenetic Factors Related to Low Back Pain: A Systematic Review of the Current Literature. Int J Mol Sci. 2023;24(3):1854.

130. Mauceri D. Role of Epigenetic Mechanisms in Chronic Pain. Cells. 2022;11(16).