Advertisement

Review of the Uses of Vagal Nerve Stimulation in Chronic Pain Management

  • Krishnan Chakravarthy
  • Hira Chaudhry
  • Kayode Williams
  • Paul J. Christo
Neuromodulation (M Gofeld, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Neuromodulation

Abstract

Recent human and animal studies provide growing evidence that vagal nerve stimulation (VNS) can deliver strong analgesic effects in addition to providing therapeutic efficacy in the treatment of refractory epilepsy and depression. Analgesia is potentially mediated by vagal afferents that inhibit spinal nociceptive reflexes and transmission and have strong anti-inflammatory properties. The purpose of this review is to provide pain practitioners with an overview of VNS technology and limitations. It specifically focuses on clinical indications of VNS for various chronic pain syndromes, including fibromyalgia, pelvic pain, and headaches. We also present potential mechanisms for VNS modulation of chronic pain by reviewing both animal and human studies.

Keywords

Vagal nerve stimulation Chronic pain Headache Inflammation Pelvic pain Fibromyalgia 

Notes

Compliance with Ethics Guidelines

Conflict of Interest

Krishnan Chakravarthy, Hira Chaudhry, and Paul J. Christo declare that they have no conflict of interest.

Kayode Williams declares a grant from Medtronic Inc. to study Mechanisms of Spinal Cord Stimulation for the treatment of Chronic Pain.

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.

References

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

  1. 1.
    Randich A, Gebhart GF. Vagal afferent modulation of nociception. Brain Res Brain Res Rev. 1992;17:77–99.CrossRefPubMedGoogle Scholar
  2. 2.
    Ren K, Zhuo M, Randich A, Gebhart GF. Vagal afferent stimulation-produced effects on nociception in capsaicin-treated rats. J Neurophysiol. 1993;69:1530–40.PubMedGoogle Scholar
  3. 3.
    Sylvie M, Schoenen J. Pain control by vagus nerve stimulation: from animal to man…and back. Acta Neurol Belg. 2005;105:62–7.Google Scholar
  4. 4.
    Kirchner A, Birklein F, Stefan H, Handwerker HO. Left vagus nerve stimulation suppresses experimentally induced pain. Neurology. 2000;55:1167–71.CrossRefPubMedGoogle Scholar
  5. 5.
    Ness TJ, Fillingim RB, Randich A, Backensto EM, Faught E. Low intensity vagal nerve stimulation lowers human thermal pain thresholds. Pain. 2000;86:81–5.CrossRefPubMedGoogle Scholar
  6. 6.
    Ness TJ, Randich A, Fillingim RB, Faught E, Backensto EM. Left vagus nerve stimulation suppresses experimentally induced pain. Neurology. 2001;56:985–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Sedan O, Sprecher E, Yarnitsky D. Vagal stomach afferents inhibit somatic pain perception. Pain. 2005;113:354–9.CrossRefPubMedGoogle Scholar
  8. 8.••
    Ben-Menachem E, Revesz D, Simon BJ, Silberstein S. Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability. Eur J Neurol. 2015;22:1260–8. Excellent review on vagal nerve stimulators and their clinical utility.CrossRefPubMedGoogle Scholar
  9. 9.
    Hatton KW, McLarney JT, Pittman T, Fahy BG. Vagal nerve stimulation: overview and implications for anesthesiologists. Anesth Analg. 2006;103:1241–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Krahl SE. Vagus nerve stimulation for epilepsy: a review of the peripheral mechanisms. Surg Neurol Int. 2012;3:S47–52.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Foley JO, Dubois F. Quantitative studies of the vagus nerve in the cat, I. The ratio of sensory and motor studies. J Comp Neurol. 1937;67:49–67.CrossRefGoogle Scholar
  12. 12.
    Ricardo JA, Koh ET. Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat. Brain Res. 1978;153:1–26.CrossRefPubMedGoogle Scholar
  13. 13.
    Morest DK. Experimental study of the projections of the nucleus of the tractus solitarius and the area postrema in the cat. J Comp Neurol. 1967;130:277–300.CrossRefPubMedGoogle Scholar
  14. 14.
    Cecheto DF. Central representation of visceral function. Fed Proc. 1987;46:17–23.Google Scholar
  15. 15.
    Krahl SE, Clark KB, Smith DC, Browning RA. Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation. Epilepsia. 1998;39:709–14.CrossRefPubMedGoogle Scholar
  16. 16.
    Matheny RG, Shaar CJ. Vagus nerve stimulation as a method to temporarily slow or arrest the heart. Ann Thorac Surg. 1997;63(6 Suppl):S28–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Ardell JL, Randall WC. Selective vagal innervation of sinoatrial and atrioventricular nodes in canine heart. Am J Physiol. 1986;251(4 Pt 2):H764–73.PubMedGoogle Scholar
  18. 18.
    Ruffoli R, Giorgi FS, Pizzanelli C, Murri L, Paparelli A, Fornai F. The chemical neuroanatomy of vagus nerve stimulation. J Chem Neuroanat. 2011;42:288–96.CrossRefPubMedGoogle Scholar
  19. 19.
    Berthoud HR, Neuhuber WL. Functional and chemical anatomy of the afferent vagal system. Auton Neurosci. 2000;85:1–17.CrossRefPubMedGoogle Scholar
  20. 20.••
    Fahy BG. Intraoperative and perioperative complications with a vagus nerve stimulation device. J Clin Anesth. 2010;22:213–22. Excellent evidence based review on vagus nerve stimulation devices and their intraoperative and perioperative complications.CrossRefPubMedGoogle Scholar
  21. 21.
    Bauman JA, Ridgway EB, Devinsky O, Doyle WK. Subpectoral implantation of the vagus nerve stimulator. Neurosurgery. 2006;58(4 Suppl 2):ONS-322–5.Google Scholar
  22. 22.
    Milby AH, Halpern CH, Baltuch GH. Vagus nerve stimulation for epilepsy and depression. Neurotherapeutics. 2008;5:75–85.CrossRefPubMedGoogle Scholar
  23. 23.
    Ben-Menachem E, Mañon-Espaillat R, Ristanovic R, et al. Vagus nerve stimulation for treatment of partial seizures: a controlled study of effect on seizures. First International Vagus Nerve Stimulation Study Group. Epilepsia. 1994;35:616–26.CrossRefPubMedGoogle Scholar
  24. 24.
    Physician’s Manual VNS Therapy Pulse Model 102 Generator and VNS Therapy Pulse Duo Model 102R Generator, May 2003, U.S. Domestic Version. Houston, TX: Cyberonics, Inc.; 2004. Available at: http://www.vnstherapy.com/manuals.
  25. 25.
    Cyberonics Inc. 2013 Annual Report. http://ir.cyberonics.com/annuals.cfm (accessed 03/05/2014).
  26. 26.
    Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology. 1995;45:224–30.CrossRefGoogle Scholar
  27. 27.
    Uthman BM, Wilder BJ, Penry JK, et al. Treatment of epilepsy by stimulation of the vagus nerve. Neurology. 1993;43:1338–45.CrossRefPubMedGoogle Scholar
  28. 28.
    Rush AJ, Marangell LB, Sackeim HA, et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry. 2005;58:347–54.CrossRefPubMedGoogle Scholar
  29. 29.
    Rush AJ, Sackeim HA, Marangell LB, et al. Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biol Psychiatry. 2005;58:355–63.CrossRefPubMedGoogle Scholar
  30. 30.
    VNS Therapy System Physician’s Manual. Houston, TX: Cyberonics Inc.; 2013. http://dynamic.cyberonics.com/manuals/ (accessed 01/05/2015).
  31. 31.
    Sadler RM, Purdy RA, Rahey S. Vagal nerve stimulation aborts migraine in patient with intractable epilepsy. Cephalalgia. 2002;22:482–4.CrossRefPubMedGoogle Scholar
  32. 32.
    Mauskop A. Vagus nerve stimulation relieves chronic refractory migraine and cluster headaches. Cephalalgia. 2005;25:82–6.CrossRefPubMedGoogle Scholar
  33. 33.
    Schwartz PJ, De Ferrari GM, Sanzo A, et al. Long term vagal stimulation in patients with advanced heart failure: first experience in man. Eur J Heart Fail. 2008;10:884–91.CrossRefPubMedGoogle Scholar
  34. 34.
    Merrill CA, Jonsson MA, Minthon L, et al. Vagus nerve stimulation in patients with Alzheimer’s disease: additional follow-up results of a pilot study through 1 year. J Clin Psychiatry. 2006;67:1171–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Sjogren MJ, Hellstrom PT, Jonsson MA, Runnerstam M, Silander HC, Ben-Menachem E. Cognition-enhancing effect of vagus nerve stimulation in patients with Alzheimer’s disease: a pilot study. J Clin Psychiatry. 2002;63:972–80.CrossRefPubMedGoogle Scholar
  36. 36.
    George MS, Ward Jr HE, Ninan PT, et al. A pilot study of vagus nerve stimulation (VNS) for treatment-resistant anxiety disorders. Brain Stimul. 2008;1:112–21.CrossRefPubMedGoogle Scholar
  37. 37.
    Roslin M, Kurian M. VNS in the treatment of morbid obesity. In: Schacter SC, Schmidt D, editors. VNS. London: Martin-Dunitz; 2012. p. 113–21.Google Scholar
  38. 38.
    Ben-Menachem E. Vagus-nerve stimulation for the treatment of epilepsy. Lancet Neurol. 2002;1:477–82.CrossRefPubMedGoogle Scholar
  39. 39.
    Tatum WO, Moore DB, Stecker MM, et al. Ventricular asystole during vagus nerve stimulation for epilepsy in humans. Neurology. 1999;52:1267–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Ali II, Pirzada NA, Kanjwal Y, et al. Complete heart block with ventricular asystole during left vagus nerve stimulation for epilepsy. Epilepsy Behav. 2004;5:768–71.CrossRefPubMedGoogle Scholar
  41. 41.
    Ardesch JJ, Buschman HP, van der Burgh PH, Wagener-Schimmel LJ, van der Aa HE, Hageman G. Cardiac responses of vagus nerve stimulation: intraoperative bradycardia and subsequent chronic stimulation. Clin Neurol Neurosurg. 2007;109:849–52.CrossRefPubMedGoogle Scholar
  42. 42.
    Schuurman PR, Beukers RJ. Ventricular asystole during vagal nerve stimulation. Epilepsia. 2009;50:967–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Ben-Menachem E, Hellstrom K, Waldton C, Augustinsson LE. Evaluation of refractory epilepsy treated with vagus nerve stimulation for up to 5 years. Neurology. 1999;52:1265–7.CrossRefPubMedGoogle Scholar
  44. 44.
    Husain MM, Stegman D, Trevino K. Pregnancy and delivery while receiving vagus nerve stimulation for the treatment of major depression: a case report. Ann Gen Psychiatry. 2005;4:16.PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    CardioFit Pilot Study. Promising results from the CardioFit pilot study. http://www.biocontrol-medical.com/health_pros.php?ID=23.
  46. 46.
    NEMOS t-VNS for treatment of drug-resistant epilepsy. http://cerbomed.com/upload/Brochure_Epilepsy_Patients_EN.pdf (accessed 01/29/2014).
  47. 47.
    Busch V, Zeman F, Heckel A, Menne F, Ellrich J, Eichhammer P. The effect of transcutaneous vagus nerve stimulation on pain perception—an experimental study. Brain Stimul. 2013;6:202–9.CrossRefPubMedGoogle Scholar
  48. 48.
    Nesbitt AD, Marin JCA, Tomkins E, Ruttledge MH, Goadsby PJ. Non-invasive vagus nerve stimulation for the treatment of cluster headache: a cohort series with extended follow-up. Presented at Biennial World Congress of the International Neuromodulation Society, 8–13 June 2013, Berlin, Germany.Google Scholar
  49. 49.
    Goadsby P, Lipton R, Cady R, Mauskop A, Grosberg B. Non-invasive vagus nerve stimulation (nVNS) for acute treatment of migraine: an open-label pilot study [abstract S40.004]. Presented at Annual Meeting of the American Academy of Neurology, 16–23 March 2013, San Diego, CA.Google Scholar
  50. 50.
    Nesbitt AD, Marin JCA, Tomkins E, Ruttledge MH, Goadsby PJ. Non-invasive vagus nerve stimulation for the treatment of cluster headache: a cohort study [abstract P141]. Cephalalgia. 2013;33:107.Google Scholar
  51. 51.
    Goadsby PJ, Grosberg BM, Mauskop A, Cady R, Simmons KA. Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study. Cephalalgia. 2014;34:986–93.CrossRefPubMedGoogle Scholar
  52. 52.
    Moscato D, Moscato FR. Treatment of chronic migraine by means of vagal stimulator [abstract]. J Headache Pain. 2013;14(Suppl):56–7.Google Scholar
  53. 53.
    Zalvan C, Sulica L, Wolf S, Cohen J, Gonzalez-Yanes O, Blitzer A. Laryngopharyngeal dysfunction from the implant vagal nerve stimulator. Laryngoscope. 2003;113:221–5.CrossRefPubMedGoogle Scholar
  54. 54.
    Amark P, Stödberg T, Wallstedt L. Late onset bradyarrhythmia during vagus nerve stimulation. Epilepsia. 2007;48:1023–4.CrossRefPubMedGoogle Scholar
  55. 55.
    Iriarte J, Urrestarazu E, Alegre M, et al. Late-onset periodic asystolia during vagus nerve stimulation. Epilepsia. 2009;50:928–32.CrossRefPubMedGoogle Scholar
  56. 56.
    Handforth A, DeGiorgio CM, Schachter SC, et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active control trial. Neurology. 1998;51:48–55.CrossRefPubMedGoogle Scholar
  57. 57.
    Lundy DS, Casiano RR, Landy HJ, Gallo J, Gallo B, Ramsey RE. Effects of vagal nerve stimulation on laryngeal function. J Voice. 1993;7:359–64.CrossRefPubMedGoogle Scholar
  58. 58.
    Lundgren J, Ekberg O, Olsson R. Aspiration: a potential complication to vagus nerve stimulation. Epilepsia. 1998;39:998–1000.CrossRefPubMedGoogle Scholar
  59. 59.
    Lundgren J, Amark P, Blennow G, Strömblad LG, Wallstedt L. Vagus nerve stimulation in 16 children with refractory epilepsy. Epilepsia. 1998;39:809–13.CrossRefPubMedGoogle Scholar
  60. 60.
    Marzec M, Edwards J, Sagher O, Fromes G, Malow BA. Effects of vagus nerve stimulation on sleep-related breathing in epilepsy patients. Epilepsia. 2003;44:930–5.CrossRefPubMedGoogle Scholar
  61. 61.
    Khurana DS, Reumann M, Hobdell EF, et al. Vagus nerve stimulation in children with refractory epilepsy: unusual complications and relationship to sleep-disordered breathing. Childs Nerv Syst. 2007;23:1309–12.CrossRefPubMedGoogle Scholar
  62. 62.
    Malow BA, Levy K, Maturen K, Bowes R. Obstructive sleep apnea is common in medically refractory epilepsy patients. Neurology. 2000;55:1002–7.CrossRefPubMedGoogle Scholar
  63. 63.
    Malow BA, Edwards J, Marzec M, Sagher O, Fromes G. Effects of vagus nerve stimulation on respiration during sleep: a pilot study. Neurology. 2000;55:1450–4.CrossRefPubMedGoogle Scholar
  64. 64.
    Ebben MR, Sethi NK, Conte M, Pollak CP, Labar D. Vagus nerve stimulation, sleep apnea, and CPAP titration. J Clin Sleep Med. 2008;4:471–3.PubMedCentralPubMedGoogle Scholar
  65. 65.
    Oshinsky ML, Murphy AL, Hekierski Jr H, Cooper M, Simon BJ. Noninvasive vagus nerve stimulation as treatment for trigeminal allodynia. Pain. 2014;155(5):1037–42.PubMedCentralCrossRefPubMedGoogle Scholar
  66. 66.
    Lange G, Janal MN, Maniker A, Fitzgibbons J, Fobler M, Cook D, et al. Safety and efficacy of vagus nerve stimulation in fibromyalgia: a phase I/II proof of concept trial. Pain Med. 2011;12(9):1406–13.PubMedCentralCrossRefPubMedGoogle Scholar
  67. 67.
    Napadow V, Edwards RR, Cahalan CM, Mensing G, Greenbaum S, Valovska A, et al. Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular vagal afferent nerve stimulation. Pain Med. 2012;13(6):777–89.PubMedCentralCrossRefPubMedGoogle Scholar
  68. 68.
    Barbanti P, Grazzi L, Egeo G, Padovan AM, Liebler E, Bussone G. Non-invasive vagus nerve stimulation for acute treatment of high-frequency and chronic migraine: an open label study. J Headache Pain. 2015;16:61. doi: 10.1186/s10194-015-0542-4.
  69. 69.
    Straube A, Ellrich J, Eren O, Blum B, Ruscheweyh R. Treatment of chronic migraine with transcutaneous stimulation of the auricular branch of the vagal nerve (auricular t-VNS): a randomized, monocentric clinical trial. J Headache Pain. 2015;16(1):543.CrossRefPubMedGoogle Scholar
  70. 70.
    Chandler MJ, Zhang J, Qin C, Foreman RD. Spinal inhibitory effects of cardiopulmonary afferent inputs in monkeys: neuronal processing in high cervical segments. J Neurophysiol. 2002;87:1290–302.PubMedGoogle Scholar
  71. 71.
    Zhang J, Chandler MJ, Foreman RD. Thoracic visceral inputs use upper cervical segments to inhibit lumbar spinal neurons in rats. Brain Res. 1996;709:337–42.CrossRefPubMedGoogle Scholar
  72. 72.
    Zhang J, Chandler MJ, Foreman RD. Cardio-pulmonary sympathetic and vagal afferents excite C1-C2 propriospinal cells in rats. Brain Res. 2003;969:53–8.CrossRefPubMedGoogle Scholar
  73. 73.
    Ammons WS, Blair RWFRD. Vagal afferent inhibition of primate thoracic spinothalamic neurons. J Neurophysiol. 1983;50:926–40.PubMedGoogle Scholar
  74. 74.
    Ren K, Randich A, Gebhart GF. Spinal serotonergic and kappa opioid receptors mediate facilitation of the tail flick reflex produced by afferent stimulation. Pain. 1991;45:321–9.CrossRefPubMedGoogle Scholar
  75. 75.
    Ren K, Randich A, Gebhart GF. Vagal afferent modulation of a nociceptive reflex in rats: involvement of spinal opioid and monoamine receptors. Brain Res. 1988;446:285–94.CrossRefPubMedGoogle Scholar
  76. 76.
    Thies R, Foreman RD. Inhibition and excitation of thoracic spinoreticular neurons by electrical stimulation of vagal afferent nerves. Exp Neurol. 1983;82:1–16.CrossRefPubMedGoogle Scholar
  77. 77.
    Chandler MJ, Hobbs SF, Bolser DC, Foreman RD. Effects of vagal afferent stimulation on cervical spinothalamic tract neurons in monkeys. Pain. 1991;44:81–7.CrossRefPubMedGoogle Scholar
  78. 78.
    Nishikawa Y, Koyama N, Yoshida Y, Yokota T. Activation of ascending antinociceptive system by vagal afferent input as revealed in the nucleus ventralis posteromedialis. Brain Res. 1999;833:108–11.CrossRefPubMedGoogle Scholar
  79. 79.
    Randich A, Aicher A. Medullary substrates mediating antinociception produced by electrical stimulation of the vagus. Brain Res. 1988;445:68–76.CrossRefPubMedGoogle Scholar
  80. 80.
    Randich A, Ren K, Gebhart GF. Electrical stimulation of cervical vagal afferents. II. Central relays for behavioral antinociception and arterial blood pressure decreases. J Neurophysiol. 1990;64:1115–24.PubMedGoogle Scholar
  81. 81.
    Ren K, Randcih A, Gebhart GF. Electrical stimulation of cervical vagal afferents. I. Central relays for modulation of spinal nociceptive transmission. J Neurophysiol. 1990;64:1098–114.PubMedGoogle Scholar
  82. 82.
    Ring HA, White S, Costa DC, Pottinger R, Dick JP, Koeze T, et al. A SPECT study of the effect of vagal nerve stimulation on thalamic activity in patients with epilepsy. Seizure. 2000;9(6):380–4.CrossRefPubMedGoogle Scholar
  83. 83.
    Van Laere K, Vonck K, Boon P, Brans B, Vandekerckhove T, Dierckx R. Vagus nerve stimulation in refractory epilepsy: SPECT activation study. J Nucl Med. 2000;41(7):1145–54.PubMedGoogle Scholar
  84. 84.
    Vonck K, Boon P, Van Laere K, D’Havé M, Vandekerckhove T, O’Connor S, et al. Acute single photon emission computed tomographic study of vagus nerve stimulation in refractory epilepsy. Epilepsia. 2000;41(5):601–9.CrossRefPubMedGoogle Scholar
  85. 85.
    Meller ST, Lewis SJ, Ness TJ, Brody MJ, Genhart GF. Vagal afferent-mediated inhibition of a nociceptive reflex by intravenous serotonin in the rat. I. Characterization. Brain Res. 1990;524:90–100.CrossRefPubMedGoogle Scholar
  86. 86.
    Takeda M, Tanimoto T, Ojima K, Matsumoto S. Suppressive effect of vagal afferents on the activity of the trigeminal spinal neurons related to the jaw-opening reflex in rats: involvement of the endogenous opioid system. Brain Res Bull. 1998;47:49–56.CrossRefPubMedGoogle Scholar
  87. 87.
    Ben-Menachem E, Hamberger A, Hedner T, Hammond EJ, Uthman BM, Slater J, et al. Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures. Epilepsy Res. 1995;20:221–7.CrossRefPubMedGoogle Scholar
  88. 88.
    Hosoi T, Okuma Y, Nomura Y. Electrical stimulation of afferent vagus nerve induces Il-1 beta expression in the brain and activates HPA axis. Am J Physiol Regul Integr Comp Physiol. 2000;279:R141–7.PubMedGoogle Scholar
  89. 89.
    Khasar SG, Green PG, Miao FJ, Levine JD. Vagal modulation of nociception is mediated by adrenomedullary epinephrine in the rat. Eur J Neurosci. 2003;17:909–15.CrossRefPubMedGoogle Scholar
  90. 90.
    Tracey K. Shock Medicine. Sci Am. 2015;312:28–35.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Krishnan Chakravarthy
    • 1
  • Hira Chaudhry
    • 1
  • Kayode Williams
    • 1
  • Paul J. Christo
    • 1
  1. 1.Department of Anesthesiology and Critical Care Medicine, Division of Pain MedicineJohns Hopkins School of MedicineBaltimoreUSA

Personalised recommendations