AccScience Publishing / BH / Online First / DOI: 10.36922/BH026030004
REVIEW ARTICLE

Pain at the brain–heart interface: A narrative review

Matteo Luigi Giuseppe Leoni1* Antonella Paladini2 Dariusz Myrcik3 Ameen A. Al Alwany4 Annalisa Caruso5 Giustino Varrassi4,6
Show Less
1 Department of Medical and Surgical Sciences and Translational Medicine, Sapienza University of Rome, Rome, Italy
2 Department of MESVA, University of L’Aquila, L’Aquila, Italy
3 Department of Internal Diseases Propaedeutics and Emergency Medicine, Medical University of Silesia, Bytom, Poland
4 College of Medicine, University of Baghdad, Baghdad, Iraq
5 Department of Surgery, ASST Lodi, Lodi, Italy
6 Fondazione Paolo Procacci, Roma, Italy
Brain & Heart, 026030004 https://doi.org/10.36922/BH026030004
Received: 12 January 2026 | Revised: 7 March 2026 | Accepted: 8 April 2026 | Published online: 22 May 2026
(This article belongs to the Special Issue Pain in Brain and Heart Diseases)
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

Pain is a frequent and clinically meaningful feature of both neurological and cardiovascular diseases, yet it is rarely examined from an integrated brain–heart perspective. Growing evidence indicates that pain perception, autonomic regulation, and cardiovascular vulnerability are closely interconnected through shared central networks, particularly the insula, cingulate cortex, and brainstem, as well as peripheral neuroimmune and neuroendocrine pathways. Despite this progress, current knowledge remains fragmented across neurology, cardiology, and pain medicine, limiting mechanistic insight and translational application. This narrative review synthesizes literature published from January 2020 to December 2025 on pain within brain–heart interactions. The synthesis highlights mechanistic pathways, clinical pain phenotypes, prognostic relevance, and emerging therapeutic strategies bridging neurological and cardiovascular domains. Key thematic areas include stroke–heart syndrome and central autonomic dysfunction, central post-stroke pain and maladaptive nociceptive processing, the role of chronic pain as a modifier of cardiovascular risk, the burden and impact of pain in heart failure and cardiac surgery survivorship, advances in neuroimaging of central autonomic networks, and the translational potential of neuromodulatory interventions such as vagal nerve and spinal cord stimulation. The reviewed evidence supports the concept of pain as a mechanistic “connector” between brain and heart diseases, influencing symptoms, disease progression, and outcomes. However, heterogeneity in pain definitions, study designs, and outcome measures continues to limit causal interpretation. A unified pain–brain–heart framework, incorporating harmonized phenotyping and mechanism-informed research, is warranted to advance precision assessment and management in this complex clinical domain.

Keywords
Pain
Brain
Central post-stroke pain
Neurogenic cardiac injury
Cardiac pain
Neurocardiology
Funding
None.
Conflict of interest
Giustino Varrassi is an Editorial Board Member of this journal and a Guest Editor of this Special Issue, while Matteo Luigi Giuseppe Leoni is also a Guest Editor of this Special Issue, but they were not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
References
  1. Varrassi G, Leoni MLG, Fari G, Al-Alwany AA, Al-Sharie S, Fornasari D. Neuromodulatory Signaling in Chronic Pain Patients: A Narrative Review. Cells. 2025;14(17). doi: 10.3390/cells14171320
  2. Cao B, Xu Q, Shi Y, et al. Pathology of pain and its implications for therapeutic interventions. Signal Transduct Target Ther. 2024;9(1):155. doi: 10.1038/s41392-024-01845-w
  3. Armstrong M, Castellanos J, Christie D. Chronic pain as an emergent property of a complex system and the potential roles of psychedelic therapies. Front Pain Res. 2024;5:1346053. doi: 10.3389/fpain.2024.1346053
  4. Herring N, Ajijola OA, Foreman RD, et al. Neurocardiology: translational advancements and potential. J Physiol. 2025;603(7):1729–1779. doi: 10.1113/JP284740
  5. Hafez OA, Chang RB. Regulation of Cardiac Function by the Autonomic Nervous System. Physiology. 2025;40(3):258– 270. doi: 10.1152/physiol.00018.2024
  6. Ferraro S, Klugah-Brown B, Tench CR, et al. The central autonomic system revisited - Convergent evidence for a regulatory role of the insular and midcingulate cortex from neuroimaging meta-analyses. Neurosci Biobehav Rev. 2022;142:104915. doi: 10.1016/j.neubiorev.2022.104915
  7. Buckley BJR, Harrison SL, Hill A, Underhill P, Lane DA, Lip GYH. Stroke-Heart Syndrome: Incidence and Clinical Outcomes of Cardiac Complications Following Stroke. Stroke. 2022;53(5):1759–1763. doi: 10.1161/STROKEAHA.121.037316
  8. Sposato LA, Hilz MJ, Aspberg S, et al. Post-Stroke Cardiovascular Complications and Neurogenic Cardiac Injury: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;76(23):2768–2785. doi: 10.1016/j.jacc.2020.10.009
  9. Scheitz JF, Sposato LA, Schulz-Menger J, Nolte CH, Backs J, Endres M. Stroke-Heart Syndrome: Recent Advances and Challenges. J Am Heart Assoc. 2022;11(17):e026528. doi: 10.1161/JAHA.122.026528
  10. Duan YW, Chen SX, Li QY, Zang Y. Neuroimmune Mechanisms Underlying Neuropathic Pain: The Potential Role of TNF-alpha-Necroptosis Pathway. Int J Mol Sci. 2022;23(13). doi: 10.3390/ijms23137191
  11. Zhang S, Ning Y, Yang Y, et al. Decoding pain chronification: mechanisms of the acute-to-chronic transition. Front Mol Neurosci. 2025;18:1596367. doi: 10.3389/fnmol.2025.1596367
  12. Hu JR, Abdullah A, Nanna MG, Soufer R. The Brain-Heart Axis: Neuroinflammatory Interactions in Cardiovascular Disease. Curr Cardiol Rep. 2023;25(12):1745–1758. doi: 10.1007/s11886-023-01990-8
  13. van der Wall EE, van Gilst WH. Neurocardiology: close interaction between heart and brain. Neth Heart J. 2013;21(2):51–2. doi: 10.1007/s12471-012-0369-4
  14. Hohenschurz-Schmidt DJ, Calcagnini G, Dipasquale O, et al. Linking Pain Sensation to the Autonomic Nervous System: The Role of the Anterior Cingulate and Periaqueductal Gray Resting-State Networks. Front Neurosci. 2020;14:147. doi: 10.3389/fnins.2020.00147
  15. Matusik PS, Zhong C, Matusik PT, Alomar O, Stein PK. Neuroimaging Studies of the Neural Correlates of Heart Rate Variability: A Systematic Review. J Clin Med. 2023;12(3):1016. doi: 10.3390/jcm12031016
  16. Alemzadeh-Ansari MJ, Ansari-Ramandi MM, Naderi N. Chronic Pain in Chronic Heart Failure: A Review Article. J Tehran Heart Cent. 2017;12(2):49–56.
  17. Walton LL, Duff E, Arora RC, McMillan DE. The Role of the Cardiac Surgery Patient in Pain Management: The Patient Perspective. Clin Nurs Res. 2024;33(7):538–544. doi: 10.1177/10547738241273232
  18. Krakowski JC, Hallman MJ, Smeltz AM. Persistent Pain After Cardiac Surgery: Prevention and Management. Semin Cardiothorac Vasc Anesth. 2021;25(4):289–300. doi: 10.1177/10892532211041320
  19. Vikan KK, Landmark T, Gjeilo KH. Prevalence of chronic pain and chronic widespread pain among subjects with heart failure in the general population: The HUNT study. Eur J Pain. 2024;28(2):273–284. doi: 10.1002/ejp.2176
  20. Raja SN, Carr DB, Cohen M, et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain. 2020;161(9):1976–1982. doi: 10.1097/j.pain.0000000000001939
  21. Karcz M, Abd-Elsayed A, Chakravarthy K, et al. Pathophysiology of Pain and Mechanisms of Neuromodulation: A Narrative Review (A Neuron Project). J Pain Res. 2024;17:3757–3790. doi: 10.2147/JPR.S475351
  22. Treede RD, Jensen TS, Campbell JN, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology. 2008;70(18):1630–1635. doi: 10.1212/01.wnl.0000282763.29778.59
  23. Leoni MLG, Mercieri M, Viswanath O, et al. Neuropathic Pain: A Comprehensive Bibliometric Analysis of Research Trends, Contributions, and Future Directions. Curr Pain Headache Rep. 2025;29(1):73. doi: 10.1007/s11916-025-01384-1
  24. Kosek E. The concept of nociplastic pain-where to from here? Pain. 2024;165(11S):S50–S57. doi: 10.1097/j.pain.0000000000003305
  25. Kaplan CM, Kelleher E, Irani A, Schrepf A, Clauw DJ, Harte SE. Deciphering nociplastic pain: clinical features, risk factors and potential mechanisms. Nat Rev Neurol. 2024;20(6):347–363. doi: 10.1038/s41582-024-00966-8
  26. Fillingim RB, Loeser JD, Baron R, Edwards RR. Assessment of Chronic Pain: Domains, Methods, and Mechanisms. J Pain. 2016;17(9 Suppl):T10–20. doi: 10.1016/j.jpain.2015.08.010
  27. Nijs J, De Baets L, Hodges P. Phenotyping nociceptive, neuropathic, and nociplastic pain: who, how, & why? Braz J Phys Ther. 2023;27(4):100537. doi: 10.1016/j.bjpt.2023.100537
  28. Nijs J, Malfliet A, Nishigami T. Nociplastic pain and central sensitization in patients with chronic pain conditions: a terminology update for clinicians. Braz J Phys Ther. 2023;27(3):100518. doi: 10.1016/j.bjpt.2023.100518
  29. Baethge C, Goldbeck-Wood S, Mertens S. SANRA-a scale for the quality assessment of narrative review articles. Res Integr Peer Rev. 2019;4:5. doi: 10.1186/s41073-019-0064-8
  30. Mitrica M, Lorusso L, Badea AA, et al. The Hidden Heart: Exploring Cardiac Damage Post-Stroke: A Narrative Review. Medicina. 2024;60(10). doi: 10.3390/medicina60101699
  31. Fontes MAP, Dos Santos Machado LR, Viana ACR, et al. The insular cortex, autonomic asymmetry and cardiovascular control: looking at the right side of stroke. Clin Auton Res. 2024;34(6):549–560. doi: 10.1007/s10286-024-01066-9
  32. Barkhudaryan A, Doehner W, Jauert N. Autonomic dysfunction after stroke: an overview of recent clinical evidence and perspectives on therapeutic management. Clin Auton Res. 2025;35(4):553–563. doi: 10.1007/s10286-025-01120-0
  33. Yuan X, Hu S, Fan X, et al. Central post-stroke pain: advances in clinical and preclinical research. Stroke Vasc Neurol. 2025;10(3):391–406. doi: 10.1136/svn-2024-003418
  34. Betancur DFA, Tarrago M, Torres I, Fregni F, Caumo W. Central Post-Stroke Pain: An Integrative Review of Somatotopic Damage, Clinical Symptoms, and Neurophysiological Measures. Front Neurol. 2021;12:678198. doi: 10.3389/fneur.2021.678198
  35. Mohanan AT, Nithya S, Nomier Y, et al. Stroke-Induced Central Pain: Overview of the Mechanisms, Management, and Emerging Targets of Central Post-Stroke Pain. Pharmaceuticals. 2023;16(8). doi: 10.3390/ph16081103
  36. Fan X, Cao J, Li M, et al. Stroke Related Brain-Heart Crosstalk: Pathophysiology, Clinical Implications, and Underlying Mechanisms. Adv Sci. 2024;11(14):e2307698. doi: 10.1002/advs.202307698
  37. Reynolds CA, Minic Z. Chronic Pain-Associated Cardiovascular Disease: The Role of Sympathetic Nerve Activity. Int J Mol Sci. 2023;24(6). doi: 10.3390/ijms24065378
  38. Mhesin D, Nazzal H, Amerah J, et al. Prevalence of pain and its association with quality of life of patients with heart failure in a developing country: findings from a multicenter cross-sectional study. BMC Cardiovasc Disord. 2022;22(1):426. doi: 10.1186/s12872-022-02864-7
  39. Yang Z, Zheng L, Zhao H, et al. Impact of dynamic changes in pain on cardiovascular disease in Chinese middle and elderly people: results from China Health and Retirement Longitudinal Study (CHARLS). BMC Public Health. 2025;25(1):3489. doi: 10.1186/s12889-025-24552-9
  40. Arnlov J. The cardiovascular consequences of chronic pain. Eur J Prev Cardiol. 2025. doi: 10.1093/eurjpc/zwaf404
  41. Qin P, Nicholl BI, Ho FK, Hanlon P, Celis-Morales CA, Pell JP. Association between pain and incident arrhythmias in 422,654 individuals: evidence from the UK Biobank cohort. Eur J Prev Cardiol. 2025. doi: 10.1093/eurjpc/zwaf153
  42. Sikandar S, Ackland GL. Chronic pain: a modifiable target to reduce perioperative cardiovascular morbidity. Br J Anaesth. 2025;134(3):627–631. doi: 10.1016/j.bja.2024.11.019
  43. Zhang Y, Wu X, Gao F, Wang J. Pain in the body, harm to the heart: advances in research on the impact of chronic pain on cardiovascular diseases. Front Cardiovasc Med. 2025;12:1629145. doi: 10.3389/fcvm.2025.1629145
  44. Boccella S, De Filippis L, Giorgio C, et al. Combination Drug Therapy for the Management of Chronic Neuropathic Pain. Biomolecules. 2023;13(12). doi: 10.3390/biom13121802
  45. Xiao MZX, Khan JS, Dana E, et al. Prevalence and Risk Factors for Chronic Postsurgical Pain after Cardiac Surgery: A Single-center Prospective Cohort Study. Anesthesiology. 2023;139(3):309–320. doi: 10.1097/ALN.0000000000004621
  46. Dost B, Karapinar YE, Karakaya D, et al. Chronic postsurgical pain after cardiac surgery: A narrative review. Saudi J Anaesth. 2025;19(2):181–189. doi: 10.4103/sja.sja_829_24
  47. Paradiso B, Pauza DH, Limback C, Ottaviani G, Thiene G. From Psychostasis to the Discovery of Cardiac Nerves: The Origins of the Modern Cardiac Neuromodulation Concept. Biology. 2024;13(4). doi: 10.3390/biology13040266
  48. Gazzeri R, Mosca J, Occhigrossi F, Mercieri M, Galarza M, Leoni MLG. Spinal Cord Stimulation for Refractory Angina Pectoris: Current Status and Future Perspectives, a Narrative Review. J Cardiovasc Dev Dis. 2025;12(1). doi: 10.3390/jcdd12010033
  49. Gasimova NZ, Paltsev AA, Zayachkovskiy NA, et al. Prospective evaluation of spinal cord stimulation in refractory angina: insights from a single-center cohort. Front Cardiovasc Med. 2025;12:1681623. doi: 10.3389/fcvm.2025.1681623
  50. Sun Z, Liu L, Peng H, Zhang R. The efficacy of transcutaneous vagus nerve stimulation in heart failure management - a systematic review and meta-analysis. BMC Cardiovasc Disord. 2025;25(1):481. doi: 10.1186/s12872-025-04919-x
  51. Freynhagen R, Baron R, Gockel U, Tolle TR. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin. 2006;22(10):1911–1920. doi: 10.1185/030079906X132488
  52. Daut RL, Cleeland CS, Flanery RC. Development of the Wisconsin Brief Pain Questionnaire to assess pain in cancer and other diseases. Pain. 1983;17(2):197–210. doi: 10.1016/0304-3959(83)90143-4
  53. Hageman S, Pennells L, Ojeda F, et al. SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe. Eur Heart J. 2021;42(25):2439–2454. doi: 10.1093/eurheartj/ehab309
  54. Valenza G, Matic Z, Catrambone V. The brain-heart axis: integrative cooperation of neural, mechanical and biochemical pathways. Nat Rev Cardiol. 2025;22(8):537– 550. doi: 10.1038/s41569-025-01140-3
  55. Ziegler KA, Engelhardt S, Carnevale D, et al. Neural Mechanisms in Cardiovascular Health and Disease. Circ Res. 2025;136(11):1233–1261. doi: 10.1161/CIRCRESAHA.125.325580
  56. Valenza G, Cio FD, Toschi N, Barbieri R. Sympathetic and parasympathetic central autonomic networks. Imaging Neurosci. 2024;2. doi: 10.1162/imag_a_00094
  57. Kaptan M, Pfyffer D, Konstantopoulos CG, et al. Recent developments and future avenues for human corticospinal neuroimaging. Front Hum Neurosci. 2024;18:1339881. doi: 10.3389/fnhum.2024.1339881
  58. de Melo PS, Gianlorenco AC, Marduy A, et al. A Mechanistic Analysis of the Neural Modulation of the Inflammatory System Through Vagus Nerve Stimulation: A Systematic Review and Meta-analysis. Neuromodulation. 2025;28(1):43–53. doi: 10.1016/j.neurom.2024.03.002
  59. Varrassi G, Fari G, Narvaez Tamayo MA, et al. Mixed pain: clinical practice recommendations. Front Med. 2025;12:1659490. doi: 10.3389/fmed.2025.1659490
  60. Barker TH, Stone JC, Sears K, et al. The revised JBI critical appraisal tool for the assessment of risk of bias for randomized controlled trials. JBI Evid Synth. 2023;21(3):494–506. doi: 10.11124/JBIES-22-00430
  61. Frumkin MR, Carpenter RW, Rodebaugh TL. Heterogeneity in Temporal Dynamics of Pain and Affect Among Individuals With Chronic Back Pain and Associations With Risk for Future Opioid-Related Problems. Clin Psychol Sci. 2024;12(4):706–720. doi: 10.1177/21677026231196121
  62. Yang W, Cai S, Chen X, et al. Patterns of Comorbidity Between Chronic Pain and Chronic Diseases in US Adults: A Cross-Sectional Analysis of NHANES Data. J Pain Res. 2026;19:555970. doi: 10.2147/JPR.S555970
  63. Bahji A, Acion L, Laslett AM, Adinoff B. Exclusion of the non-English-speaking world from the scientific literature: Recommendations for change for addiction journals and publishers. Nord Alkohol Nark. 2023;40(1):6–13. doi: 10.1177/14550725221102227
Share
Back to top
Brain & Heart, Electronic ISSN: 2972-4139 Published by AccScience Publishing