Treatment of chronic migraine with transcutaneous stimulation of the auricular branch of the vagal nerve (auricular t-VNS): a randomized, monocentric clinical trial

Andreas Straube, J Ellrich, O Eren, B Blum, R Ruscheweyh, Andreas Straube, J Ellrich, O Eren, B Blum, R Ruscheweyh

Abstract

Background: Aim of the study was assessment of efficacy and safety of transcutaneous stimulation of the auricular branch of the vagal nerve (t-VNS) in the treatment of chronic migraine.

Methods: A monocentric, randomized, controlled, double-blind study was conducted. After one month of baseline, chronic migraine patients were randomized to receive 25 Hz or 1 Hz stimulation of the sensory vagal area at the left ear by a handhold battery driven stimulator for 4 h/day during 3 months. Headache days per 28 days were compared between baseline and the last month of treatment and the number of days with acute medication was recorded The Headache Impact Test (HIT-6) and the Migraine Disability Assessment (MIDAS) questionnaires were used to assess headache-related disability.

Results: Of 46 randomized patients, 40 finished the study (per protocol). In the per protocol analysis, patients in the 1 Hz group had a significantly larger reduction in headache days per 28 days than patients in the 25 Hz group (-7.0 ± 4.6 vs. -3.3 ± 5.4 days, p = 0.035). 29.4 % of the patients in the 1 Hz group had a ≥50 % reduction in headache days vs. 13.3 % in the 25 Hz group. HIT-6 and MIDAS scores were significantly improved in both groups, without group differences. There were no serious treatment-related adverse events.

Conclusion: Treatment of chronic migraine by t-VNS at 1 Hz was safe and effective. The mean reduction of headache days after 12 weeks of treatment exceeded that reported for other nerve stimulating procedures.

Figures

Fig. 1
Fig. 1
Study design
Fig. 2
Fig. 2
NEMOS® device and positioning of the electrode for stimulation of the vagus afferents at the concha
Fig. 3
Fig. 3
Patient disposition
Fig. 4
Fig. 4
Mean course of number of headache days per 28 days during t-VNS treatment. Results of the per protocol set are shown (1 Hz: n = 17, 25 Hz: n = 22). Values are mean ± SEM. Mean values are also given in the figure

References

    1. Headache Classification Subcommittee of the International Headache Society The International Classification of Headache Disorders, 3rd edition (beta version) Cephalalgia. 2013;33:629–808. doi: 10.1177/0333102413485658.
    1. Bigal ME, Serrano D, Reed M, Lipton RB. Chronic migraine in the population: burden, diagnosis, and satisfaction with treatment. Neurology. 2008;71:559–566. doi: 10.1212/01.wnl.0000323925.29520.e7.
    1. Dodick DW. Clinical practice. Chronic daily headache. N Engl J Med. 2006;354:158–165. doi: 10.1056/NEJMcp042897.
    1. Lipton RB, Bigal ME. Chronic daily headache: is analgesic overuse a cause or a consequence? Neurology. 2003;61:154–155. doi: 10.1212/WNL.61.2.154.
    1. Diener HC, Dodick DW, Aurora SK, Turkel CC, DeGryse RE, Lipton RB, Silberstein SD, Brin MF. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. 2010;30:804–814. doi: 10.1177/0333102410364677.
    1. Silberstein SD, Lipton RB, Dodick DW, Freitag FG, Ramadan N, Mathew N, Brandes JL, Bigal M, Saper J, Ascher S, Jordan DM, Greenberg SJ, Hulihan J. Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial. Headache. 2007;47:170–180. doi: 10.1111/j.1526-4610.2006.00684.x.
    1. Martelletti P, Jensen RH, Antal A, Arcioni R, Brighina F, de Tommaso M, Franzini A, Fontaine D, Heiland M, Jurgens TP, Leone M, Magis D, Paemeleire K, Palmisani S, Paulus W, May A. Neuromodulation of chronic headaches: position statement from the European Headache Federation. J Headache Pain. 2013;14:86. doi: 10.1186/1129-2377-14-86.
    1. Saper JR, Dodick DW, Silberstein SD, McCarville S, Sun M, Goadsby PJ. Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM feasibility study. Cephalalgia. 2011;31:271–285. doi: 10.1177/0333102410381142.
    1. Lipton RB, Goadsby PJ, Cady RK, Aurora SK, Grosberg BM, Freitag FG, Silberstein SD, Whiten DM, Jaax KN. PRISM study: occipital nerve stimulation for treatment-refractory migraine. Cephalalgia. 2009;29:30.
    1. Silberstein SD, Dodick DW, Saper J, Huh B, Slavin KV, Sharan A, Reed K, Narouze S, Mogilner A, Goldstein J, Trentman T, Vaisman J, Ordia J, Weber P, Deer T, Levy R, Diaz RL, Washburn SN, Mekhail N. Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: results from a randomized, multicenter, double-blinded, controlled study. Cephalalgia. 2012;32:1165–1179. doi: 10.1177/0333102412462642.
    1. Schoenen J, Vandersmissen B, Jeangette S, Herroelen L, Vandenheede M, Gerard P, Magis D. Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. Neurology. 2013;80:697–704. doi: 10.1212/WNL.0b013e3182825055.
    1. Beekwilder JP, Beems T. Overview of the clinical applications of vagus nerve stimulation. J Clin Neurophysiol. 2010;27:130–138. doi: 10.1097/WNP.0b013e3181d64d8a.
    1. Hord ED, Evans MS, Mueed S, Adamolekun B, Naritoku DK. The effect of vagus nerve stimulation on migraines. J Pain. 2003;4:530–534. doi: 10.1016/j.jpain.2003.08.001.
    1. Sadler RM, Purdy RA, Rahey S. Vagal nerve stimulation aborts migraine in patient with intractable epilepsy. Cephalalgia. 2002;22:482–484. doi: 10.1046/j.1468-2982.2002.00387.x.
    1. Mauskop A. Vagus nerve stimulation relieves chronic refractory migraine and cluster headaches. Cephalalgia. 2005;25:82–86. doi: 10.1111/j.1468-2982.2005.00611.x.
    1. Lenaerts ME, Oommen KJ, Couch JR, Skaggs V. Can vagus nerve stimulation help migraine? Cephalalgia. 2008;28:392–395. doi: 10.1111/j.1468-2982.2008.01538.x.
    1. Ellrich J. Transcutaneous vagus nerve stimulation. Eur Neurol Rev. 2011;6:254–256.
    1. He W, Jing XH, Zhu B, Zhu XL, Li L, Bai WZ, Ben H. The auriculo-vagal afferent pathway and its role in seizure suppression in rats. BMC Neurosci. 2013;14:85. doi: 10.1186/1471-2202-14-85.
    1. Clancy JA, Mary DA, Witte KK, Greenwood JP, Deuchars SA, Deuchars J. Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity. Brain Stimul. 2014;7:871–877. doi: 10.1016/j.brs.2014.07.031.
    1. Kraus T, Kiess O, Hosl K, Terekhin P, Kornhuber J, Forster C. CNS BOLD fMRI effects of sham-controlled transcutaneous electrical nerve stimulation in the left outer auditory canal - a pilot study. Brain Stimul. 2013;6:798–804. doi: 10.1016/j.brs.2013.01.011.
    1. Frangos E, Ellrich J, Komisaruk BR. Non-invasive access to the vagus nerve central projections via electrical stimulation of the external Ear: fMRI evidence in humans. Brain Stimul. 2015;8:624–636. doi: 10.1016/j.brs.2014.11.018.
    1. Kirchner A, Birklein F, Stefan H, Handwerker HO. Left vagus nerve stimulation suppresses experimentally induced pain. Neurology. 2000;55:1167–1171. doi: 10.1212/WNL.55.8.1167.
    1. 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;6:202–209. doi: 10.1016/j.brs.2012.04.006.
    1. 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;34:986–993. doi: 10.1177/0333102414524494.
    1. Beck AT, Erbaugh J, Ward CH, Mock J, Mendelsohn M. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561–571. doi: 10.1001/archpsyc.1961.01710120031004.
    1. Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the Migraine Disability Assessment (MIDAS) questionnaire to assess headache-related disability. Neurology. 2001;56:S20–S28. doi: 10.1212/WNL.56.suppl_1.S20.
    1. Kosinski M, Bayliss MS, Bjorner JB, Ware JE, Jr, Garber WH, Batenhorst A, Cady R, Dahlof CG, Dowson A, Tepper S. A six-item short-form survey for measuring headache impact: the HIT-6. Qual Life Res. 2003;12:963–974. doi: 10.1023/A:1026119331193.
    1. Freitag FG, Diamond S, Diamond M, Urban G. Botulinum toxin type A in the treatment of chronic migraine without medication overuse. Headache. 2008;48:201–209.
    1. Silvestrini M, Bartolini M, Coccia M, Baruffaldi R, Taffi R, Provinciali L. Topiramate in the treatment of chronic migraine. Cephalalgia. 2003;23:820–824. doi: 10.1046/j.1468-2982.2003.00592.x.
    1. Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ. Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia. 2007;27:814–823. doi: 10.1111/j.1468-2982.2007.01326.x.
    1. Aurora SK, Dodick DW, Turkel CC, DeGryse RE, Silberstein SD, Lipton RB, Diener HC, Brin MF. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia. 2010;30:793–803. doi: 10.1177/0333102410364676.
    1. The Vagus Nerve Stimulation Study Group A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology. 1995;45:224–230. doi: 10.1212/WNL.45.2.224.
    1. Milby AH, Halpern CH, Baltuch GH. Vagus nerve stimulation for epilepsy and depression. Neurotherapeutics. 2008;5:75–85. doi: 10.1016/j.nurt.2007.10.071.
    1. Ellrich J. Long-term depression of orofacial somatosensory processing. Suppl Clin Neurophysiol. 2006;58:195–208. doi: 10.1016/S1567-424X(09)70069-8.
    1. Ellrich J. Electric low-frequency stimulation of the tongue induces long-term depression of the jaw-opening reflex in anesthetized mice. J Neurophysiol. 2004;92:3332–3337. doi: 10.1152/jn.00156.2004.
    1. Jung K, Rottmann S, Ellrich J. Long-term depression of spinal nociception and pain in man: influence of varying stimulation parameters. Eur J Pain. 2009;13:161–170. doi: 10.1016/j.ejpain.2008.04.001.
    1. Rottmann S, Jung K, Vohn R, Ellrich J. Long-term depression of pain-related cerebral activation in healthy man: an fMRI study. Eur J Pain. 2010;14:615–624. doi: 10.1016/j.ejpain.2009.10.006.
    1. Rottmann S, Jung K, Ellrich J. Electrical low-frequency stimulation induces long-term depression of sensory and affective components of pain in healthy man. Eur J Pain. 2010;14:359–365. doi: 10.1016/j.ejpain.2009.06.001.
    1. Jung K, Larsen LE, Rottmann S, Ellrich J. Heterotopic low-frequency stimulation induces nociceptive LTD within the same central receptive field in man. Exp Brain Res. 2011;212:189–198. doi: 10.1007/s00221-011-2718-8.
    1. Jung K, Lelic D, Rottmann S, Drewes AM, Petrini L, Ellrich J. Electrical low-frequency stimulation induces central neuroplastic changes of pain processing in man. Eur J Pain. 2012;16:509–521. doi: 10.1016/j.ejpain.2011.08.006.
    1. Rottmann S, Jung K, Ellrich J. Electrical low-frequency stimulation induces homotopic long-term depression of nociception and pain from hand in man. Clin Neurophysiol. 2008;119:1895–1904. doi: 10.1016/j.clinph.2008.02.022.
    1. Aymanns M, Yekta SS, Ellrich J. Homotopic long-term depression of trigeminal pain and blink reflex within one side of the human face. Clin Neurophysiol. 2009;120:2093–2099. doi: 10.1016/j.clinph.2009.08.027.
    1. Yekta SS, Lamp S, Ellrich J. Heterosynaptic long-term depression of craniofacial nociception: divergent effects on pain perception and blink reflex in man. Exp Brain Res. 2006;170:414–422. doi: 10.1007/s00221-005-0226-4.
    1. Ellrich J, Schorr A. Low-frequency stimulation of trigeminal afferents induces long-term depression of human sensory processing. Brain Res. 2004;996:255–258. doi: 10.1016/j.brainres.2003.08.068.
    1. Noseda R, Burstein R (2013) Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, CSD, sensitization and modulation of pain. Pain. 154 Suppl 1.
    1. Peuker ET, Filler TJ. The nerve supply of the human auricle. Clin Anat. 2002;15:35–37. doi: 10.1002/ca.1089.
    1. Lyubashina OA, Sokolov AY, Panteleev SS. Vagal afferent modulation of spinal trigeminal neuronal responses to dural electrical stimulation in rats. Neuroscience. 2012;222:29–37. doi: 10.1016/j.neuroscience.2012.07.011.
    1. Multon S, Schoenen J. Pain control by vagus nerve stimulation: from animal to man…and back. Acta Neurol Belg. 2005;105:62–67.
    1. Bossut DF, Maixner W. Effects of cardiac vagal afferent electrostimulation on the responses of trigeminal and trigeminothalamic neurons to noxious orofacial stimulation. Pain. 1996;65:101–109. doi: 10.1016/0304-3959(95)00166-2.
    1. Zerari-Mailly F, Buisseret P, Buisseret-Delmas C, Nosjean A. Trigemino-solitarii-facial pathway in rats. J Comp Neurol. 2005;487:176–189. doi: 10.1002/cne.20554.
    1. Randich A, Gebhart GF. Vagal afferent modulation of nociception. Brain Res Brain Res Rev. 1992;17:77–99. doi: 10.1016/0165-0173(92)90009-B.
    1. Coppola G, Pierelli F, Schoenen J. Habituation and migraine. Neurobiol Learn Mem. 2009;92:249–259. doi: 10.1016/j.nlm.2008.07.006.
    1. De Marinis M, Pujia A, Colaizzo E, Accornero N. The blink reflex in “chronic migraine”. Clin Neurophysiol. 2007;118:457–463. doi: 10.1016/j.clinph.2006.10.011.
    1. Aurora SK, Barrodale PM, Tipton RL, Khodavirdi A. Brainstem dysfunction in chronic migraine as evidenced by neurophysiological and positron emission tomography studies. Headache. 2007;47:996–1003. doi: 10.1111/j.1526-4610.2007.00853.x.
    1. Coppola G, Iacovelli E, Bracaglia M, Serrao M, Di LC, Pierelli F. Electrophysiological correlates of episodic migraine chronification: evidence for thalamic involvement. J Headache Pain. 2013;14:76. doi: 10.1186/1129-2377-14-76.
    1. Henry TR. Therapeutic mechanisms of vagus nerve stimulation. Neurology. 2002;59:S3–S14. doi: 10.1212/WNL.59.6_suppl_4.S3.
    1. Ben-Menachem E, Hamberger A, Hedner T, Hammond EJ, Uthman BM, Slater J, Treig T, Stefan H, Ramsay RE, Wernicke JF. Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures. Epilepsy Res. 1995;20:221–227. doi: 10.1016/0920-1211(94)00083-9.
    1. Richter F, Mikulik O, Ebersberger A, Schaible HG. Noradrenergic agonists and antagonists influence migration of cortical spreading depression in rat-a possible mechanism of migraine prophylaxis and prevention of postischemic neuronal damage. J Cereb Blood Flow Metab. 2005;25:1225–1235. doi: 10.1038/sj.jcbfm.9600120.
    1. Pietrobon D, Striessnig J. Neurobiology of migraine. Nat Rev Neurosci. 2003;4:386–398. doi: 10.1038/nrn1102.
    1. Cernuda-Morollon E, Martinez-Camblor P, Alvarez R, Larrosa D, Ramon C, Pascual J. Increased VIP levels in peripheral blood outside migraine attacks as a potential biomarker of cranial parasympathetic activation in chronic migraine. Cephalalgia. 2015;35:310–316. doi: 10.1177/0333102414535111.
    1. Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain. 2009;132:16–25. doi: 10.1093/brain/awn307.
    1. Bussone G, Diener HC, Pfeil J, Schwalen S. Topiramate 100 mg/day in migraine prevention: a pooled analysis of double-blind randomised controlled trials. Int J Clin Pract. 2005;59:961–968. doi: 10.1111/j.1368-5031.2005.00612.x.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe