Noninvasive vagus nerve stimulation as acute therapy for migraine: The randomized PRESTO study

Cristina Tassorelli, Licia Grazzi, Marina de Tommaso, Giulia Pierangeli, Paolo Martelletti, Innocenzo Rainero, Stefanie Dorlas, Pierangelo Geppetti, Anna Ambrosini, Paola Sarchielli, Eric Liebler, Piero Barbanti, PRESTO Study Group, Cristina Tassorelli, Vito Bitetto, Roberto De Icco, Daniele Martinelli, Grazia Sances, Monica Bianchi, Licia Grazzi, Anna Maria Padovan, Marina de Tommaso, Katia Ricci, Eleonora Vecchio, Pietro Cortelli, Sabina Cevoli, Giulia Pierangeli, Rossana Terlizzi, Paolo Martelletti, Andrea Negro, Gabriella Addolorata Chiariello, Innocenzo Rainero, Paola De Martino, Annalisa Gai, Flora Govone, Federica Masuzzo, Elisa Rubino, Maria Claudia Torrieri, Alessandro Vacca, Pierangelo Geppetti, Alberto Chiarugi, Francesco De Cesaris, Simone Li Puma, Chiara Lupi, Ilaria Marone, Anna Ambrosini, Armando Perrotta, Paola Sarchielli, Laura Bernetti, Ilenia Corbelli, Michele Romoli, Simone Simoni, Angela Verzina, Piero Barbanti, Cinzia Aurilia, Gabriella Egeo, Luisa Fofi, Eric Liebler, Annelie Andersson, Lia Spitzer, Juana Marin, Candace McClure, Lisa Thackerey, Maria Giovanna Baldi, Daniela Di Maro, Cristina Tassorelli, Licia Grazzi, Marina de Tommaso, Giulia Pierangeli, Paolo Martelletti, Innocenzo Rainero, Stefanie Dorlas, Pierangelo Geppetti, Anna Ambrosini, Paola Sarchielli, Eric Liebler, Piero Barbanti, PRESTO Study Group, Cristina Tassorelli, Vito Bitetto, Roberto De Icco, Daniele Martinelli, Grazia Sances, Monica Bianchi, Licia Grazzi, Anna Maria Padovan, Marina de Tommaso, Katia Ricci, Eleonora Vecchio, Pietro Cortelli, Sabina Cevoli, Giulia Pierangeli, Rossana Terlizzi, Paolo Martelletti, Andrea Negro, Gabriella Addolorata Chiariello, Innocenzo Rainero, Paola De Martino, Annalisa Gai, Flora Govone, Federica Masuzzo, Elisa Rubino, Maria Claudia Torrieri, Alessandro Vacca, Pierangelo Geppetti, Alberto Chiarugi, Francesco De Cesaris, Simone Li Puma, Chiara Lupi, Ilaria Marone, Anna Ambrosini, Armando Perrotta, Paola Sarchielli, Laura Bernetti, Ilenia Corbelli, Michele Romoli, Simone Simoni, Angela Verzina, Piero Barbanti, Cinzia Aurilia, Gabriella Egeo, Luisa Fofi, Eric Liebler, Annelie Andersson, Lia Spitzer, Juana Marin, Candace McClure, Lisa Thackerey, Maria Giovanna Baldi, Daniela Di Maro

Abstract

Objective: To evaluate the efficacy, safety, and tolerability of noninvasive vagus nerve stimulation (nVNS; gammaCore; electroCore, LLC, Basking Ridge, NJ) for the acute treatment of migraine in a multicenter, double-blind, randomized, sham-controlled trial.

Methods: A total of 248 participants with episodic migraine with/without aura were randomized to receive nVNS or sham within 20 minutes from pain onset. Participants were to repeat treatment if pain had not improved in 15 minutes.

Results: nVNS (n = 120) was superior to sham (n = 123) for pain freedom at 30 minutes (12.7% vs 4.2%; p = 0.012) and 60 minutes (21.0% vs 10.0%; p = 0.023) but not at 120 minutes (30.4% vs 19.7%; p = 0.067; primary endpoint; logistic regression) after the first treated attack. A post hoc repeated-measures test provided further insight into the therapeutic benefit of nVNS through 30, 60, and 120 minutes (odds ratio 2.3; 95% confidence interval 1.2, 4.4; p = 0.012). nVNS demonstrated benefits across other endpoints including pain relief at 120 minutes and was safe and well-tolerated.

Conclusion: This randomized sham-controlled trial supports the abortive efficacy of nVNS as early as 30 minutes and up to 60 minutes after an attack. Findings also suggest effective pain relief, tolerability, and practicality of nVNS for the acute treatment of episodic migraine.

Clinicaltrialsgov identifier: NCT02686034.

Classification of evidence: This study provides Class I evidence that for patients with an episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 hours poststimulation (absolute difference 13.2%).

© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Participant disposition
Figure 1. Participant disposition
AE = adverse event; ITT = intent-to-treat; nVNS = noninvasive vagus nerve stimulation. *Other reasons for discontinuation included inability to fulfill visits because of injury, inability to continue the study because of family commitments, dissatisfaction with or discontinued/lack of use of the device, and noncompliance with study procedures.
Figure 2. Responder rates after the first…
Figure 2. Responder rates after the first treated attack during the double-blind period
(A) Pain freedom and (B) pain relief. CI = confidence interval; nVNS = noninvasive vagus nerve stimulation. Data for no. of participants in (A) are unadjusted numbers. *Statistically significant. **Primary endpoint.
Figure 3. Mean percentage pain score reductions
Figure 3. Mean percentage pain score reductions
Changes are from baseline for the first treated attack in the double-blind period; post hoc analysis. CI = confidence interval; nVNS = noninvasive vagus nerve stimulation. *Statistically significant.
Figure 4. ≥50% responder rates at 120…
Figure 4. ≥50% responder rates at 120 minutes during the double-blind period
CI = confidence interval; nVNS = noninvasive vagus nerve stimulation. *Statistically significant. **Post hoc analysis.
Figure 5. Blinding
Figure 5. Blinding
nVNS = noninvasive vagus nerve stimulation. *Inclusion of zero in the 95% confidence interval (CI) indicates successful blinding.

References

    1. Buse DC, Serrano D, Reed ML, et al. . Adding additional acute medications to a triptan regimen for migraine and observed changes in headache-related disability: results from the American Migraine Prevalence and Prevention (AMPP) study. Headache 2015;55:825–839.
    1. Puledda F, Goadsby PJ. An update on non-pharmacological neuromodulation for the acute and preventive treatment of migraine. Headache 2017;57:685–691.
    1. Serrano D, Buse DC, Kori SH, et al. . Effects of switching acute treatment on disability in migraine patients using triptans. Headache 2013;53:1415–1429.
    1. Ferrari MD, Goadsby PJ, Roon KI, Lipton RB. Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials. Cephalalgia 2002;22:633–658.
    1. Lipton RB, Buse DC, Serrano D, Holland S, Reed ML. Examination of unmet treatment needs among persons with episodic migraine: results of the American Migraine Prevalence and Prevention (AMPP) study. Headache 2013;53:1300–1311.
    1. Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache 2008;48:1157–1168.
    1. Yuan H, Silberstein SD. Vagus nerve stimulation and headache. Headache 2017;57:29–33.
    1. 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.
    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.
    1. Kinfe TM, Pintea B, Muhammad S, et al. . Cervical non-invasive vagus nerve stimulation (nVNS) for preventive and acute treatment of episodic and chronic migraine and migraine-associated sleep disturbance: a prospective observational cohort study. J Headache Pain 2015;16:101.
    1. Silberstein SD, Calhoun AH, Lipton RB, et al. . Chronic migraine headache prevention with noninvasive vagus nerve stimulation: the EVENT study. Neurology 2016;87:529–538.
    1. Hougaard A, Tfelt-Hansen P. Are the current IHS guidelines for migraine drug trials being followed? J Headache Pain 2010;11:457–468.
    1. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013;33:629–808.
    1. Tfelt-Hansen P, Pascual J, Ramadan N, et al. . Guidelines for controlled trials of drugs in migraine: third edition: a guide for investigators. Cephalalgia 2012;32:6–38.
    1. Voss T, Lipton RB, Dodick DW, et al. . A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia 2016;36:887–898.
    1. Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 2001;358:1668–1675.
    1. Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the American Headache Society evidence assessment of migraine pharmacotherapies. Headache 2015;55:3–20.
    1. Silberstein SD, Newman LC, Marmura MJ, Nahas SJ, Farr SJ. Efficacy endpoints in migraine clinical trials: the importance of assessing freedom from pain. Curr Med Res Opin 2013;29:861–867.
    1. Brandes JL, Kudrow D, Stark SR, et al. . Sumatriptan-naproxen for acute treatment of migraine: a randomized trial. JAMA 2007;297:1443–1454.
    1. Diener HC, Montagna P, Gacs G, et al. . Efficacy and tolerability of diclofenac potassium sachets in migraine: a randomized, double-blind, cross-over study in comparison with diclofenac potassium tablets and placebo. Cephalalgia 2006;26:537–547.
    1. Lipton RB, Grosberg B, Singer RP, et al. . Efficacy and tolerability of a new powdered formulation of diclofenac potassium for oral solution for the acute treatment of migraine: results from the International Migraine Pain Assessment Clinical Trial (IMPACT). Cephalalgia 2010;30:1336–1345.
    1. Hougaard A, Tfelt-Hansen P. Review of dose-response curves for acute antimigraine drugs: triptans, 5-HT1F agonists and CGRP antagonists. Expert Opin Drug Metab Toxicol 2015;11:1409–1418.
    1. Lipton RB, Dodick DW, Silberstein SD, et al. . Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomised, double-blind, parallel-group, sham-controlled trial. Lancet Neurol 2010;9:373–380.
    1. Schoenen J, Vandersmissen B, Jeangette S, et al. . Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. Neurology 2013;80:697–704.
    1. Akerman S, Simon B, Romero-Reyes M. Vagus nerve stimulation suppresses acute noxious activation of trigeminocervical neurons in animal models of primary headache. Neurobiol Dis 2017;102:96–104.
    1. Gaul C, Diener HC, Silver N, et al. . Non-invasive vagus nerve stimulation for prevention and acute treatment of chronic cluster headache (PREVA): a randomised controlled study. Cephalalgia 2016;36:534–546.
    1. Goadsby PJ, de Coo IF, Silver N, et al. . Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: a randomized, double-blind, sham-controlled ACT2 study. Cephalalgia 2018;38:959–969.
    1. Grazzi L, Egeo G, Calhoun AH, McClure CK, Liebler E, Barbanti P. Non-invasive vagus nerve stimulation (nVNS) as mini-prophylaxis for menstrual/menstrually related migraine: an open-label study. J Headache Pain 2016;17:91.
    1. Silberstein SD, Mechtler LL, Kudrow DB, et al. . Non-invasive vagus nerve stimulation for the acute treatment of cluster headache: findings from the randomized, double-blind, sham-controlled ACT1 study. Headache 2016;56:1317–1332.
    1. Asano E, Goadsby PJ. How do we fashion better trials for neurostimulator studies in migraine? Neurology 2013;80:694.
    1. Benedetti F, Carlino E, Pollo A. How placebos change the patient's brain. Neuropsychopharmacology 2011;36:339–354.
    1. Oshinsky ML, Murphy AL, Hekierski H Jr, Cooper M, Simon BJ. Noninvasive vagus nerve stimulation as treatment for trigeminal allodynia. Pain 2014;155:1037–1042.
    1. Frangos E, Komisaruk BR. Access to vagal projections via cutaneous electrical stimulation of the neck: fMRI evidence in healthy humans. Brain Stimul 2017;10:19–27.
    1. Nonis R, D'Ostilio K, Schoenen J, Magis D. Evidence of activation of vagal afferents by non-invasive vagus nerve stimulation: an electrophysiological study in healthy volunteers. Cephalalgia 2017;37:1285–1293.
    1. Westergaard ML, Steiner TJ, MacGregor EA, et al. . The Headache Under-Response to Treatment (HURT) Questionnaire: assessment of utility in headache specialist care. Cephalalgia 2013;33:245–255.
    1. Puledda F, Messina R, Goadsby PJ. An update on migraine: current understanding and future directions. J Neurol 2017;264:2031–2039.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel