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Flavonoids in the Treatment of Neuropathic Pain

Abstract

Purpose of Review

Chronic pain continues to present a large burden to the US healthcare system. Neuropathic pain, a common class of chronic pain, remains particularly difficult to treat despite extensive research efforts. Current pharmacologic regimens exert limited efficacy and wide, potentially dangerous side effect profiles. This review provides a comprehensive, preclinical evaluation of the literature regarding the role of flavonoids in the treatment of neuropathic pain.

Recent Findings

Flavonoids are naturally occurring compounds, found in plants and various dietary sources, which may have potential benefit in neuropathic pain. Numerous animal-model studies have demonstrated this benefit, including reversal of hyperalgesia and allodynia. Flavonoids have also exhibited an anti-inflammatory effect relevant to neuropathic pain, as evidenced by the reduction in multiple pro-inflammatory mediators, such as TNF-α, NF-κB, IL-1β, and IL-6.

Summary

Flavonoids represent a potentially new treatment modality for neuropathic pain in preclinical models, though human clinical evidence is yet to be explored at this time.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Vos T, Abajobir AA, Abbafati C, Abbas KM, Abate KH, Abd-Allah F, et al. 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. Lancet. 2017;390:1211–59.

    Article  Google Scholar 

  2. Dahlhamer JM, Lucas J, Zelaya C, Nahin R, Mackey S, Debar L, et al. Prevalence of chronic pain and high-impact chronic pain among adults — United States, 2016. Morb Mortal Wkly Rep. 2018;67:1001–6.

    Article  Google Scholar 

  3. Gaskin DJ, Richard P. The economic costs of pain in the United States. J Pain Elsevier Ltd. 2012;13:715–24.

    Article  Google Scholar 

  4. Jensen TS, Baron R, Haanpää M, Kalso E, Loeser JD, Rice ASC, et al. A new definition of neuropathic pain. Pain. International Association for the Study of Pain. 2011;152:2204–5.

    Article  Google Scholar 

  5. Shaygan M, Böger A, Kröner-Herwig B. Predicting factors of outcome in multidisciplinary treatment of chronic neuropathic pain. J Pain Res. Dove Medical Press Ltd. 2018;11:2433–43.

    Article  Google Scholar 

  6. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol Lancet Publishing Group. 2015;14:162–73.

    CAS  Article  Google Scholar 

  7. Bates D, Schultheis BC, Hanes MC, Jolly SM, Chakravarthy KV, Deer TR, et al. A comprehensive algorithm for management of neuropathic pain. Pain Med. 2019;20:S2–12.

    Article  Google Scholar 

  8. Staudt MD, Clark AJ, Gordon AS, Lynch ME, Morley-Forster PK, Nathan H, et al. Long-term outcomes in the management of central neuropathic pain syndromes: a prospective observational cohort study. Can J Neurol Sci. 2018;45:545–52.

    Article  Google Scholar 

  9. Chaparro LE, Wiffen PJ, Moore RA, Gilron I. Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst. Rev. John Wiley and Sons Ltd; 2012. CD008943

  10. Mu A, Weinberg E, Moulin DE, Clarke H. Pharmacologic management of chronic neuropathic pain: review of the Canadian pain society consensus statement. Can. Fam. Physician. College of Family Physicians of Canada; 2017. p. 844–52.

  11. Gaskell H, Derry S, Stannard C, Moore RA. Oxycodone for neuropathic pain in adults. Cochrane Database Syst. Rev. John Wiley and Sons Ltd; 2016.

  12. Cooper TE, Chen J, Wiffen PJ, Derry S, Carr DB, Aldington D, et al. Morphine for chronic neuropathic pain in adults. Cochrane Database Syst. Rev. John Wiley and Sons Ltd; 2017.

  13. Vazhappilly CG, Ansari SA, Al-Jaleeli R, Al-Azawi AM, Ramadan WS, Menon V, et al. Role of flavonoids in thrombotic, cardiovascular, and inflammatory diseases. Inflammopharmacology. Springer International Publishing. 2019;27:863–9 This review provides an excellent background on flavonoid pharmacology.

    Google Scholar 

  14. Inoue K, Tsuda M. Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. Nat Rev Neurosci Nature Publishing Group. 2018;19:138–52.

    CAS  Article  Google Scholar 

  15. Ji RR, Nackley A, Huh Y, Terrando N, Maixner W. Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology. 2018;129:343–66.

    Article  Google Scholar 

  16. Gu N, Peng J, Murugan M, Wang X, Eyo UB, Sun D, et al. Spinal microgliosis due to resident microglial proliferation is required for pain hypersensitivity after peripheral nerve injury. Cell Rep. The Author(s). 2016;16:605–14.

    CAS  Article  Google Scholar 

  17. Spencer JPE, Vafeiadou K, Williams RJ, Vauzour D. Neuroinflammation: modulation by flavonoids and mechanisms of action. Mol Asp Med Elsevier Ltd. 2012;33:83–97.

    CAS  Article  Google Scholar 

  18. Maleki SJ, Crespo JF, Cabanillas B. Anti-inflammatory effects of flavonoids. 2019.

  19. Jaeger BN, Parylak SL, Gage FH. Mechanisms of dietary flavonoid action in neuronal function and neuroinflammation. Mol Asp Med Elsevier Ltd. 2018;61:50–62.

    CAS  Article  Google Scholar 

  20. Sommer C, Leinders M, Üçeyler N. Inflammation in the pathophysiology of neuropathic pain. Pain. 2018;159:595–602.

    CAS  Article  Google Scholar 

  21. Basu P, Basu A. In vitro and in vivo effects of flavonoids on peripheral neuropathic pain. Molecules. 2020;25.

  22. Salehi B, Fokou PVT, Sharifi-Rad M, Zucca P, Pezzani R, Martins N, et al. The therapeutic potential of naringenin: a review of clinical trials. Pharmaceuticals. MDPI AG; 2019.

  23. Zhou Y, Cai S, Moutal A, Yu J, Gómez K, Madura CL, et al. The natural flavonoid naringenin elicits analgesia through inhibition of NaV1.8 voltage-gated sodium channels. ACS Chem Neurosci. Am Chem Soc. 2019;10:4834–46.

    CAS  Google Scholar 

  24. Pinho-Ribeiro FA, Zarpelon AC, Fattori V, Manchope MF, Mizokami SS, Casagrande R, et al. Naringenin reduces inflammatory pain in mice. Neuropharmacology. 2016;105:508–19.

    CAS  Article  Google Scholar 

  25. Al-Rejaie SS, Aleisa AM, Abuohashish HM, Parmar MY, Ola MS, Al-Hosaini AA, et al. Naringenin neutralises oxidative stress and nerve growth factor discrepancy in experimental diabetic neuropathy. Neurol Res. 2015;37:924–33.

    CAS  Article  Google Scholar 

  26. Singh P, Bansal S, Kuhad A, Kumar A, Chopra K. Naringenin ameliorates diabetic neuropathic pain by modulation of oxidative-nitrosative stress, cytokines and MMP-9 levels. Food Funct. Royal Society of Chemistry (RSC); 2020;11.

  27. CY HU, Y-T ZHAO. Analgesic effects of naringenin in rats with spinal nerve ligation-induced neuropathic pain. Biomed Reports. 2014;2:569–73.

    Article  Google Scholar 

  28. Chtourou Y, Gargouri B, Kebieche M, Fetoui H. Naringin abrogates cisplatin-induced cognitive deficits and cholinergic dysfunction through the down-regulation of AChE expression and iNOS signaling pathways in hippocampus of aged rats. J Mol Neurosci. Springer New York LLC. 2015;56:349–62.

    CAS  Article  Google Scholar 

  29. Kandhare AD, Raygude KS, Ghosh P, Ghule AE, Bodhankar SL. Neuroprotective effect of naringin by modulation of endogenous biomarkers in streptozotocin induced painful diabetic neuropathy. Fitoterapia Fitoterapia. 2012;83:650–9.

    CAS  Article  Google Scholar 

  30. Gao W, Zan Y, Wang ZJJ, Hu XY, Huang F. Quercetin ameliorates paclitaxel-induced neuropathic pain by stabilizing mast cells, and subsequently blocking PKCϵ-dependent activation of TRPV1. Acta Pharmacol Sin Nature Publishing Group. 2016;37:1166–77 This study describes the analgesic efficacy of pretreatment with quercetin in the setting of chemotherapy-induced neuropathy.

    CAS  Article  Google Scholar 

  31. Azevedo MI, Pereira AF, Nogueira RB, Rolim FE, Brito GAC, Wong DVT, et al. The antioxidant effects of the flavonoids rutin and quercetin inhibit oxaliplatin-induced chronic painful peripheral neuropathy. Mol Pain. Mol Pain; 2013;9.

  32. Schwingel TE, Klein CP, Nicoletti NF, Dora CL, Hadrich G, Bica CG, et al. Effects of the compounds resveratrol, rutin, quercetin, and quercetin nanoemulsion on oxaliplatin-induced hepatotoxicity and neurotoxicity in mice. Naunyn Schmiedebergs Arch Pharmacol Springer Verlag. 2014;387:837–48.

    CAS  Article  Google Scholar 

  33. Muto N, Matsuoka Y, Arakawa K, Kurita M, Omiya H, Taniguchi A, et al. Quercetin attenuates neuropathic pain in rats with spared nerve injury. Acta Med Okayama. 2018;72:457–65.

    CAS  PubMed  Google Scholar 

  34. Ji C, Xu Y, Han F, Sun D, Zhang H, Li X, et al. Quercetin alleviates thermal and cold hyperalgesia in a rat neuropathic pain model by inhibiting Toll-like receptor signaling. Biomed Pharmacother Elsevier Masson SAS. 2017;94:652–8.

    CAS  Article  Google Scholar 

  35. Çivi S, Emmez G, Dere ÜA, Börcek AÖ, Emmez H. Effects of quercetin on chronic constriction nerve injury in an experimental rat model. Acta Neurochir (Wien). Springer-Verlag Wien. 2016;158:959–65.

    Google Scholar 

  36. Yang R, Li L, Yuan H, Liu H, Gong Y, Zou L, et al. Quercetin relieved diabetic neuropathic pain by inhibiting upregulated P2X4 receptor in dorsal root ganglia. J Cell Physiol. Wiley-Liss Inc. 2019;234:2756–64.

    CAS  Article  Google Scholar 

  37. Ferraz CR, Carvalho TT, Manchope MF, Artero NA, Rasquel-Oliveira FS, Fattori V, et al. Therapeutic potential of flavonoids in pain and inflammation: mechanisms of action, pre-clinical and clinical data, and pharmaceutical development. Molecules. 2020;25.

  38. Carballo-Villalobos AI, González-Trujano ME, Alvarado-Vázquez N, López-Muñoz FJ. Pro-inflammatory cytokines involvement in the hesperidin antihyperalgesic effects at peripheral and central levels in a neuropathic pain model. Inflammopharmacology Birkhauser Verlag AG. 2017;25:265–9.

    CAS  Article  Google Scholar 

  39. Visnagri A, Kandhare AD, Chakravarty S, Ghosh P, Bodhankar SL. Hesperidin, a flavanoglycone attenuates experimental diabetic neuropathy via modulation of cellular and biochemical marker to improve nerve functions. Pharm Biol Informa Healthcare. 2014;52:814–28.

    CAS  Article  Google Scholar 

  40. Carballo-Villalobos AI, González-Trujano ME, Pellicer F, López-Muñoz FJ. Antihyperalgesic effect of hesperidin improves with diosmin in experimental neuropathic pain. Biomed Res Int. 2016;2016:1–12.

    Article  Google Scholar 

  41. Aswar M, Kute P, Mahajan S, Mahajan U, Nerurkar G, Aswar U. Protective effect of hesperetin in rat model of partial sciatic nerve ligation induced painful neuropathic pain: an evidence of anti-inflammatory and anti-oxidative activity. Pharmacol Biochem Behav. Elsevier Inc. 2014;124:101–7.

    CAS  Article  Google Scholar 

  42. Tao J, Liu L, Fan Y, Wang M, Li L, Zou L, et al. Role of hesperidin in P2X3 receptor-mediated neuropathic pain in the dorsal root ganglia. Int J Neurosci. Taylor and Francis Ltd. 2019;129:784–93.

    CAS  Article  Google Scholar 

  43. Bimonte S, Cascella M, Schiavone V, Mehrabi-Kermani F, Cuomo A. The roles of epigallocatechin-3-gallate in the treatment of neuropathic pain: an update on preclinical in vivo studies and future perspectives. Drug Des. Devel. Ther. Dove Medical Press Ltd.; 2017. p. 2737–42.

  44. Xifró X, Vidal-Sancho L, Boadas-Vaello P, Turrado C, Alberch J, Puig T, et al. Novel epigallocatechin-3-gallate (EGCG) derivative as a new therapeutic strategy for reducing neuropathic pain after chronic constriction nerve injury in mice. PLoS One Public Library of Science. 2015;10.

  45. Bosch-Mola M, Homs J, Álvarez-Pérez B, Puig T, Reina F, Verdú E, et al. (-)-Epigallocatechin-3-gallate antihyperalgesic effect associates with reduced CX3CL1 chemokine expression in spinal cord. Phyther Res. John Wiley and Sons Ltd. 2017;31:340–4.

    CAS  Article  Google Scholar 

  46. Renno WM, Al-Khaledi G, Mousa A, Karam SM, Abul H, Asfar S. (-)-Epigallocatechin-3-gallate (EGCG) modulates neurological function when intravenously infused in acute and, chronically injured spinal cord of adult rats. Neuropharmacology. Elsevier Ltd. 2014;77:100–19.

    CAS  Article  Google Scholar 

  47. Renno WM, Benov L, Khan KM. Possible role of antioxidative capacity of (-)-epigallocatechin-3-gallate treatment in morphological and neurobehavioral recovery after sciatic nerve crush injury. J Neurosurg Spine American Association of Neurological Surgeons. 2017;27:593–613.

    Article  Google Scholar 

  48. Álvarez-Pérez B, Homs J, Bosch-Mola M, Puig T, Reina F, Verdú E, et al. Epigallocatechin-3-gallate treatment reduces thermal hyperalgesia after spinal cord injury by down-regulating RhoA expression in mice. Eur J Pain (United Kingdom). Blackwell Publishing Ltd. 2016;20:341–52.

    Article  Google Scholar 

  49. Kuang X, Huang Y, Gu HF, Zu XY, Zou WY. Song Z Bin, et al. Effects of intrathecal epigallocatechin gallate, an inhibitor of Toll-like receptor 4, on chronic neuropathic pain in rats. Eur J Pharmacol. Eur J Pharmacol. 2012;676:51–6.

    CAS  Article  Google Scholar 

  50. Li D, Huang Z, Ling Y, Wei J, Cui Y, Zhang X, et al. Up-regulation of CX3CL1 via nuclear factor-κB–dependent histone acetylation is involved in paclitaxel-induced peripheral neuropathy. Anesthesiology. 2015;122:1–10.

    CAS  Article  Google Scholar 

  51. Zhang ZJ, Jiang BC, Gao YJ. Chemokines in neuron–glial cell interaction and pathogenesis of neuropathic pain. Cell Mol Life Sci. Springer International Publishing. 2017;74:3275–91.

    CAS  Google Scholar 

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Correspondence to Mark Jones.

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Conflict of Interest

Richard D. Urman reports funding or fees from Medtronic, Merck, Acacia, Takeda, Pfizer, and AcelRx. Amitabh Gulati is a consultant for Medtronic, Flowonix, SPR Therapeutics, Nalu Medical, Bausch Health, and advisor for AIS. The other authors declare that no competing interests exist.

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This article is part of the Topical Collection on Alternative Treatments for Pain Medicine

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Rao, P.N., Mainkar, O., Bansal, N. et al. Flavonoids in the Treatment of Neuropathic Pain. Curr Pain Headache Rep 25, 43 (2021). https://doi.org/10.1007/s11916-021-00959-y

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  • DOI: https://doi.org/10.1007/s11916-021-00959-y

Keywords

  • Neuropathic pain
  • Flavonoids
  • Neuroinflammation
  • Chronic pain
  • Treatment