Skip to main content

Advertisement

SpringerLink
Log in

Mechanism of Action of Peripheral Nerve Stimulation

  • Neuromodulation (AA Abd-Elsayed, Section Editor)
  • Published:
Current Pain and Headache Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The number of applications for peripheral nerve stimulation (PNS) in the pain management field is ever-growing. With the increasing number of clinical applications for peripheral nerve stimulation, the purpose of this article is to review the mechanism of action surrounding PNS, the recent literature from January 2018 to January 2021, and pertinent clinical outcomes.

Recent Findings

The authors searched articles identified from PubMed (January 2018–January 2021), Cochrane Central Register of Controlled Trials databases (January 2018–January 2021), and Scopus (January 2018–January 2021) databases, and manually searched references of identified publications. Broad MeSH terms and Boolean operators were queried in each search, including the following terms and their respective synonyms: peripheral nerve stimulation, mechanism of action, biochemical pathway, and pain pathway. 15 consensus articles were selected for in-depth review and inclusion for qualitative analysis.

Summary

PNS may activate and modulate higher central nervous system (CNS) centers, including the dorsal lateral prefrontal cortex, somatosensory cortex, anterior cingulate cortex, and parahippocampal areas. Neuromodulatory effects from PNS may also extend into the spinal columns. Also, PNS may lead to changes in endogenous neurotransmitters and affect the plasticity of NMDA pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

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

  1. Ottestad E, Orlovich DS. History of peripheral nerve stimulation-update for the 21st century. Pain Med. 2020;21(Suppl 1):S3–5. https://doi.org/10.1093/pm/pnaa165.

    Article  PubMed  Google Scholar 

  2. Cambiaghi M, Sconocchia S. Scribonius Largus (probably before 1CE-after 48CE). J Neurol. 2018;265(10):2466–8. https://doi.org/10.1007/s00415-018-8739-5.

    Article  PubMed  Google Scholar 

  3. Althaus J. A treatise on medical electricity, theoretical and practical: and its uses in the treatment of paralysis, neuralgiz, and other diseases. 3rd ed. London: Longmans, Green and Co.; 1873.

    Google Scholar 

  4. Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965;150(3699):971–9. https://doi.org/10.1126/science.150.3699.971.

    Article  CAS  PubMed  Google Scholar 

  5. Sweet WH, Wepsic JG. Treatment of chronic pain by stimulation of fibers of primary afferent neuron. Trans Am Neurol Assoc. 1968;93:103–7.

    CAS  PubMed  Google Scholar 

  6. Campbell JN, Long DM. Peripheral nerve stimulation in the treatment of intractable pain. J Neurosurg. 1976;45(6):692–9. https://doi.org/10.3171/jns.1976.45.6.0692.

    Article  CAS  PubMed  Google Scholar 

  7. Slavin KV. History of peripheral nerve stimulation. Prog Neurol Surg. 2011;24:1–15. https://doi.org/10.1159/000323002.

    Article  PubMed  Google Scholar 

  8. Sivanesan E, Gulati A. Resurgence of peripheral nerve stimulation with innovation in device technologies. Reg Anesth Pain Med. 2019;44(6):615–6. https://doi.org/10.1136/rapm-2019-100488.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Food and Drug Administration. Sprint peripheral nerve stimulation system section 510(k) pma approval letter, July 31, 2018. 2018. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf18/K181422.pdf. Accessed 15 Jan 2021.

  10. Lee P, Huh BK. Peripheral nerve stimulation for the treatment of primary headache. Curr Pain Headache Rep. 2013;17(3):319. https://doi.org/10.1007/s11916-012-0319-2.

    Article  PubMed  Google Scholar 

  11. Roy H, Offiah I, Dua A. Neuromodulation for pelvic and urogenital pain. Brain Sci. 2018;8(10). https://doi.org/10.3390/brainsci8100180.

  12. • Chakravarthy K, Nava A, Christo PJ, Williams K. Review of recent advances in peripheral nerve stimulation (PNS). Curr Pain Headache Rep. 2016;20(11):60. https://doi.org/10.1007/s11916-016-0590-8This study highlights recent advances in peripheral nerve stimulation and presents an overview of the indications.

    Article  PubMed  Google Scholar 

  13. Ahmed S, Plazier M, Ost J, Stassijns G, Deleye S, Ceyssens S, et al. The effect of occipital nerve field stimulation on the descending pain pathway in patients with fibromyalgia: a water PET and EEG imaging study. BMC Neurol. 2018;18(1):191. https://doi.org/10.1186/s12883-018-1190-5.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bhadra N, Foldes E, Vrabec T, Kilgore K. Temporary persistence of conduction block after prolonged kilohertz frequency alternating current on rat sciatic nerve. J Neural Eng. 2018;15(1):016012. https://doi.org/10.1088/1741-2552/aa89a4.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ceccanti M, Onesti E, Rubino A, Cambieri C, Tartaglia G, Miscioscia A, et al. Modulation of human corticospinal excitability by paired associative stimulation in patients with amyotrophic lateral sclerosis and effects of riluzole. Brain Stimul. 2018;11(4):775–81. https://doi.org/10.1016/j.brs.2018.02.007.

    Article  CAS  PubMed  Google Scholar 

  16. Meyer-Frießem CH, Wiegand T, Eitner L, Maier C, Mainka T, Vollert J, et al. Effects of spinal cord and peripheral nerve stimulation reflected in sensory profiles and endogenous pain modulation. Clin J Pain. 2019;35(2):111–20. https://doi.org/10.1097/AJP.0000000000000661.

    Article  PubMed  Google Scholar 

  17. Sun KF, Feng WW, Liu YP, Dong YB, Gao L, Yang HL. Electrical peripheral nerve stimulation relieves bone cancer pain by inducing arc protein expression in the spinal cord dorsal horn. J Pain Res. 2018;11:599–609. https://doi.org/10.2147/JPR.S149470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yecies T, Li S, Zhang Y, Cai H, Shen B, Wang J, et al. Spinal interneuronal mechanisms underlying pudendal and tibial neuromodulation of bladder function in cats. Exp Neurol. 2018;308:100–10. https://doi.org/10.1016/j.expneurol.2018.06.015.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Bandeira JS, Antunes LDC, Soldatelli MD, Sato JR, Fregni F, Caumo W. Functional spectroscopy mapping of pain processing cortical areas during non-painful peripheral electrical stimulation of the accessory spinal nerve. Front Hum Neurosci. 2019;13:200. https://doi.org/10.3389/fnhum.2019.00200.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Beauchene C, Sacre P, Yang F, Guan Y, Sarma SV. Modeling responses to peripheral nerve stimulation in the dorsal horn. Annu Int Conf IEEE Eng Med Biol Soc. 2019;2019:2324–7. https://doi.org/10.1109/EMBC.2019.8856566.

    Article  PubMed  Google Scholar 

  21. Finch P, Drummond P. High-frequency peripheral nerve stimulation for craniofacial pain. Prog Neurol Surg. 2020;35:85–95. https://doi.org/10.1159/000509665.

    Article  PubMed  Google Scholar 

  22. Franz KS, Yoo PB. Transecting the hypogastric nerve to uncover the bladder-inhibitory pathways involved with saphenous nerve stimulation in anesthetized rats. Auton Neurosci. 2020;226:102672. https://doi.org/10.1016/j.autneu.2020.102672.

    Article  CAS  PubMed  Google Scholar 

  23. García-Magro N, Negredo P, Martin YB, Nuñez Á, Avendaño C. Modulation of mechanosensory vibrissal responses in the trigeminocervical complex by stimulation of the greater occipital nerve in a rat model of trigeminal neuropathic pain. J Headache Pain. 2020;21(1):96. https://doi.org/10.1186/s10194-020-01161-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liao CF, Hsu ST, Chen CC, Yao CH, Lin JH, Chen YH, et al. Effects of electrical stimulation on peripheral nerve regeneration in a silicone rubber conduit in taxol-treated rats. Materials (Basel). 2020;13(5). https://doi.org/10.3390/ma13051063.

  25. Luckey AM, McLeod SL, Robertson IH, To WT, Vanneste S. Greater occipital nerve stimulation boosts associative memory in older individuals: a randomized trial. Neurorehabil Neural Repair. 2020;34(11):1020–9. https://doi.org/10.1177/1545968320943573.

    Article  PubMed  Google Scholar 

  26. Mohapatra A, Chen J, Zhao J, Zhong Y, Armann K, Shen B, et al. Bladder underactivity induced by prolonged pudendal afferent activity in cats. Am J Physiol Regul Integr Comp Physiol. 2021;320(1):R80–R7. https://doi.org/10.1152/ajpregu.00239.2020.

    Article  CAS  PubMed  Google Scholar 

  27. Tu L, Gharibani P, Zhang N, Yin J, Chen JD. Anti-inflammatory effects of sacral nerve stimulation: a novel spinal afferent and vagal efferent pathway. Am J Physiol Gastrointest Liver Physiol. 2020;318(4):G624–G34. https://doi.org/10.1152/ajpgi.00330.2019.

    Article  CAS  PubMed  Google Scholar 

  28. Schaible HG, Hope PJ, Lang CW, Duggan AW. Calcitonin gene-related peptide causes intraspinal spreading of substance P released by peripheral stimulation. Eur J Neurosci. 1992;4(8):750–7. https://doi.org/10.1111/j.1460-9568.1992.tb00184.x.

    Article  CAS  PubMed  Google Scholar 

  29. Men DS, Matsui Y. Peripheral nerve stimulation increases serotonin and dopamine metabolites in rat spinal cord. Brain Res Bull. 1994;33(6):625–32. https://doi.org/10.1016/0361-9230(94)90225-9.

    Article  CAS  PubMed  Google Scholar 

  30. Kupers R, Laere KV, Calenbergh FV, Gybels J, Dupont P, Baeck A, et al. Multimodal therapeutic assessment of peripheral nerve stimulation in neuropathic pain: five case reports with a 20-year follow-up. Eur J Pain. 2011;15(2):161.e1–9. https://doi.org/10.1016/j.ejpain.2010.06.015.

    Article  Google Scholar 

  31. Torebjörk HE, Hallin RG. Responses in human A and C fibres to repeated electrical intradermal stimulation. J Neurol Neurosurg Psychiatry. 1974;37(6):653–64. https://doi.org/10.1136/jnnp.37.6.653.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Deer TR, Jain S, Hunter C, Chakravarthy K. Neurostimulation for intractable chronic pain. Brain Sci. 2019;9(2). https://doi.org/10.3390/brainsci9020023.

  33. Papuć E, Rejdak K. The role of neurostimulation in the treatment of neuropathic pain. Ann Agric Environ Med. 2013;Spec no. 1:14–7.

    PubMed  Google Scholar 

  34. •• Deer TR, Naidu R, Strand N, Sparks D, Abd-Elsayed A, Kalia H, et al. A review of the bioelectronic implications of stimulation of the peripheral nervous system for chronic pain conditions. Bioelectron Med. 2020;6:9. https://doi.org/10.1186/s42234-020-00045-5This review provides a thorough description of indications and locations for peripheral nerve stimulation.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kapural L, Yu C, Doust MW, Gliner BE, Vallejo R, Sitzman BT, et al. Novel 10-kHz high-frequency therapy (HF10 therapy) is superior to traditional low-frequency spinal cord stimulation for the treatment of chronic back and leg pain: the SENZA-RCT randomized controlled trial. Anesthesiology. 2015;123(4):851–60. https://doi.org/10.1097/ALN.0000000000000774.

    Article  PubMed  Google Scholar 

  36. D’Souza RS, Strand N. Neuromodulation with burst and tonic stimulation decreases opioid consumption: a post hoc analysis of the success using neuromodulation with BURST (SUNBURST) randomized controlled trial. Neuromodulation. 2021;24(1):135–41. https://doi.org/10.1111/ner.13273.

    Article  PubMed  Google Scholar 

  37. Finch P, Price L, Drummond P. High-frequency (10 kHz) electrical stimulation of peripheral nerves for treating chronic pain: a double-blind trial of presence vs absence of stimulation. Neuromodulation. 2019;22(5):529–36. https://doi.org/10.1111/ner.12877.

    Article  PubMed  Google Scholar 

  38. Manning A, Ortega RG, Moir L, Edwards T, Aziz TZ, Bojanic S, et al. Burst or conventional peripheral nerve field stimulation for treatment of neuropathic facial pain. Neuromodulation. 2019;22(5):645–52. https://doi.org/10.1111/ner.12922.

    Article  PubMed  Google Scholar 

  39. Garcia-Ortega R, Edwards T, Moir L, Aziz TZ, Green AL, FitzGerald JJ. Burst occipital nerve stimulation for chronic migraine and chronic cluster headache. Neuromodulation. 2019;22(5):638–44. https://doi.org/10.1111/ner.12977.

    Article  PubMed  Google Scholar 

  40. van Balken MR, Vandoninck V, Messelink BJ, Vergunst H, Heesakkers JP, Debruyne FM, et al. Percutaneous tibial nerve stimulation as neuromodulative treatment of chronic pelvic pain. Eur Urol. 2003;43(2):158–63; discussion 63. https://doi.org/10.1016/s0302-2838(02)00552-3.

    Article  PubMed  Google Scholar 

  41. Hodges PW, Danneels L. Changes in structure and function of the back muscles in low back pain: different time points, observations, and mechanisms. J Orthop Sports Phys Ther. 2019;49(6):464–76. https://doi.org/10.2519/jospt.2019.8827.

    Article  PubMed  Google Scholar 

  42. Deckers K, De Smedt K, Mitchell B, Vivian D, Russo M, Georgius P, et al. New therapy for refractory chronic mechanical low back pain-restorative neurostimulation to activate the lumbar multifidus: one year results of a prospective multicenter clinical trial. Neuromodulation. 2018;21(1):48–55. https://doi.org/10.1111/ner.12741.

    Article  PubMed  Google Scholar 

  43. Frahm KS, Hennings K, Vera-Portocarrero L, Wacnik PW, Mørch CD. Nerve fiber activation during peripheral nerve field stimulation: importance of electrode orientation and estimation of area of paresthesia. Neuromodulation. 2016;19(3):311–8. https://doi.org/10.1111/ner.12371.

    Article  PubMed  Google Scholar 

  44. Mørch CD, Nguyen GP, Wacnik PW, Andersen OK. Mathematical model of nerve fiber activation during low back peripheral nerve field stimulation: analysis of electrode implant depth. Neuromodulation. 2014;17(3):218–25; discussion 25. https://doi.org/10.1111/ner.12163.

    Article  PubMed  Google Scholar 

  45. Mauck WD, Hunt CL, Olatoye OO, Warner NS, Lamer TJ. Spinal cord and peripheral nerve stimulation for painful disorders. Adv Anesth. 2019;37:163–86. https://doi.org/10.1016/j.aan.2019.08.010.

    Article  PubMed  Google Scholar 

  46. Gilmore CA, Ilfeld BM, Rosenow JM, Li S, Desai MJ, Hunter CW, et al. Percutaneous 60-day peripheral nerve stimulation implant provides sustained relief of chronic pain following amputation: 12-month follow-up of a randomized, double-blind, placebo-controlled trial. Reg Anesth Pain Med. 2019;45:44–51. https://doi.org/10.1136/rapm-2019-100937.

    Article  Google Scholar 

  47. Ilfeld BM, Grant SA. Ultrasound-guided percutaneous peripheral nerve stimulation for postoperative analgesia: could neurostimulation replace continuous peripheral nerve blocks? Reg Anesth Pain Med. 2016;41(6):720–2. https://doi.org/10.1097/AAP.0000000000000481.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Ilfeld BM, Gabriel RA, Saulino MF, Chae J, Peckham PH, Grant SA, et al. Infection rates of electrical leads used for percutaneous neurostimulation of the peripheral nervous system. Pain Pract. 2017;17(6):753–62. https://doi.org/10.1111/papr.12523.

    Article  PubMed  Google Scholar 

  49. Rauck RL, Cohen SP, Gilmore CA, North JM, Kapural L, Zang RH, et al. Treatment of post-amputation pain with peripheral nerve stimulation. Neuromodulation. 2014;17(2):188–97. https://doi.org/10.1111/ner.12102.

    Article  PubMed  Google Scholar 

  50. Deer T, Pope J, Benyamin R, Vallejo R, Friedman A, Caraway D, et al. Prospective, multicenter, randomized, double-blinded, partial crossover study to assess the safety and efficacy of the novel neuromodulation system in the treatment of patients with chronic pain of peripheral nerve origin. Neuromodulation. 2016;19(1):91–100. https://doi.org/10.1111/ner.12381.

    Article  PubMed  Google Scholar 

  51. Pereira EA, Aziz TZ. Neuropathic pain and deep brain stimulation. Neurotherapeutics. 2014;11(3):496–507. https://doi.org/10.1007/s13311-014-0278-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Regnier SM, Chen J, Gabriel RA, Chakravarthy KV. A review of the StimRouter(®) peripheral neuromodulation system for chronic pain management. Pain Manag. 2020;11:227–36. https://doi.org/10.2217/pmt-2020-0042.

    Article  PubMed  Google Scholar 

  53. Gabriel RA, Swisher MW, Ilfeld BM. Percutaneous peripheral nerve stimulation for acute postoperative pain. Pain Manag. 2019;9(4):347–54. https://doi.org/10.2217/pmt-2018-0094.

    Article  PubMed  Google Scholar 

  54. Russo M, Deckers K, Eldabe S, Kiesel K, Gilligan C, Vieceli J, et al. Muscle control and non-specific chronic low back pain. Neuromodulation. 2018;21(1):1–9. https://doi.org/10.1111/ner.12738.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Mayo Clinic Arizona, 5777 East Mayo Boulevard, Phoenix, AZ, 85054, USA

    Natalie H. Strand, Christopher Wie, John Freeman & Jillian Maloney

  2. Department of Anesthesiology, Mayo Clinic Minnesota, Rochester, MN, USA

    Ryan D’Souza

  3. Department of Physician Medicine and Rehabilitation, Mayo Clinic Minnesota, Rochester, MN, USA

    Stephen Covington

  4. Department of Anesthesiology, University of Texas Health Sciences Center San Antonio, San Antonio, TX, USA

    Moustafa Maita

Authors
  1. Natalie H. Strand
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ryan D’Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher Wie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephen Covington
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Moustafa Maita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John Freeman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jillian Maloney
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Natalie H. Strand.

Ethics declarations

Conflict of Interest

Christopher Wie, Jillian Maloney, Stephen Covington, John Freeman, and Ryan D’Souza declare no conflict of interest. Natalie Strand has consulted for Abbott Neuromodulation which is not listed as a vendor in this paper.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Neuromodulation

Supplementary information

ESM 1

(DOCX 12 kb).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Strand, N.H., D’Souza, R., Wie, C. et al. Mechanism of Action of Peripheral Nerve Stimulation. Curr Pain Headache Rep 25, 47 (2021). https://doi.org/10.1007/s11916-021-00962-3

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11916-021-00962-3

Keywords

Search

Navigation