Background
Standard pharmacologic agents for the acute treatment of migraine can be limited by side effects, inconsistent efficacy, contraindications, risk of drug interactions, and their potential contribution to migraine chronification and medication overuse headache [
1‐
5]. Opioids should be discouraged for the acute treatment of migraine due to significant safety concerns and lack of documented efficacy but remain frequently used in the emergency department setting, which significantly increases healthcare costs [
6‐
9]. Practical alternatives are needed to address this healthcare challenge. Non-invasive neuromodulation therapies could represent a novel option for these patients [
10,
11].
Non-invasive vagus nerve stimulation (nVNS; gammaCore®; electroCore, Inc., Basking Ridge, NJ, USA) demonstrated efficacy in studies of acute migraine treatment and has a strong safety and tolerability profile [
12‐
15]. The multicenter, randomized, double-blind, sham-controlled PRESTO trial provided Class I evidence that for patients with an episodic migraine, acute treatment of migraine attacks with nVNS significantly increases the probability of having mild pain or being pain-free 2 h post stimulation [
11]. The study also clearly demonstrated the practicality, safety, and tolerability of nVNS. Here, we report additional pre-defined secondary and other end points from the PRESTO study to illustrate the consistency and durability of nVNS effects across a broad range of outcomes.
Discussion
These additional results from the PRESTO study further demonstrate that nVNS is superior to sham across a broad range of relevant end points. In the nVNS group, significantly greater percentages of all attacks were pain-free or had pain relief at 60 and 120 min than in the sham group. The nVNS group also had significantly greater decreases from baseline in mean pain score for the first attack (60 and 120 min) and for all attacks (60 min). Among nVNS-treated attacks that were pain-free at 120 min, > 75% had a sustained response at 24 h. Ninety-eight percent of patients in the ITT population completed the open-label period, suggesting that the benefit from nVNS was maintained and that nVNS is a durable acute therapy. The results for the total population during the open-label period were generally similar to those seen for the nVNS group during the double-blind period. Throughout the study, the incidence of AEs and ADEs was low, and no serious AEs were reported.
The findings from PRESTO are consistent with those from other clinical studies of acute nVNS use in migraine [
12,
13]. They are supported by several potential mechanisms of action for the acute benefits of vagus nerve stimulation, including inhibition of central excitability through suppression of glutamate release, suppression of acute nociceptive activation of trigeminocervical neurons, and curbing expression of proteins associated with central sensitization of trigeminal neurons [
17‐
19].
The high rates of sustained 24-h pain-free response to nVNS seen in PRESTO (> 75%) stand in contrast to the lower rates reported for oral triptans (10%–30%) and single-pulse transcranial magnetic stimulation (29%) [
10,
20]. The protocol of the single-pulse transcranial magnetic stimulation study called for a study population restricted to patients with aura and a treatment time that was independent from the onset of pain (ie, within 1 h after aura onset), making comparison with the nVNS findings challenging [
10]. The majority of patients enrolled in the PRESTO study had migraine without aura, and nVNS was delivered promptly after the onset of migraine pain (ie, within 20 min) [
11]. In the majority of the triptan clinical trials, treatment was not initiated until migraine pain reached a moderate/severe level, partially due to the desire to avoid unnecessary adverse effects [
20,
21]. Consistent with findings from PRESTO [
22], rates of sustained response appear to be higher with the use of triptans during the early stages of migraine (34%–53%) than during the later stages (19%–31%) [
21,
23]. These observations suggest that there are benefits to treating early in the course of migraine attacks—in a sense, intervening before the migraine process is fully activated. High rates of sustained pain-free response in both the nVNS and sham groups in PRESTO suggest that intervention early in the course of migraine might confer benefits, irrespective of the treatment.
Together with findings from multiple previous studies [
12‐
15,
24‐
26], these results from PRESTO further highlight the clinical utility, practicality, and flexibility of nVNS. Across the double-blind and open-label periods, nVNS was used to treat > 900 migraine attacks, with data collected at multiple time points for each attack, demonstrating its consistent efficacy, safety, and tolerability as acute treatment for these attacks. nVNS can be used as monotherapy or in conjunction with other treatments without risk of pharmacologic interactions, offering a clinical versatility that other acute migraine treatments lack. These advantages, along with its convenience and ease of use, make nVNS an appealing and pragmatic option for early, adjunctive, and/or frequent use in the acute treatment of migraine. nVNS could also help minimize the risk of medication overuse associated with traditional acute treatments and reduce the frequency of opioid use for the acute treatment of migraine in the emergency department setting.
This study has a number of limitations. The selection of an appropriate sham device in neuromodulation studies is challenging. In accordance with previous recommendations to ensure maintenance of the study blind [
27], the sham device used in PRESTO produced an active signal that could be perceived by the user but was not designed to stimulate the vagus nerve; recent data suggest that the strength of the sham device’s signal may have inadvertently activated the vagus nerve and could have inflated the responses to sham treatment across all end points [
28]. This phenomenon, which merits further investigation, may have been related to a psychobiological placebo effect but more likely resulted from the unanticipated physiologically active signal that may have decreased the difference in therapeutic gain seen between the nVNS and sham groups [
11].
During both the double-blind and open-label periods, the mean number of acute medications used per migraine attack was substantially lower than that seen during the observational period. Such a decrease in medication use could be interpreted as evidence of treatment efficacy; however, these results must be interpreted with caution, as patients were encouraged to refrain from using acute medications for 120 min after stimulation with the study device. This study limitation most likely contributed to decreases in acute medication use in both the nVNS and sham groups during the double-blind period and may partially explain the lack of significance between treatment groups for this end point.
Acknowledgments
Medical writing support was provided by Elizabeth Barton, MS, of MedLogix Communications, LLC, in cooperation with the authors. Statistical analyses were conducted by Candace McClure, PhD, of North American Science Associates Inc.
Co-investigators:
The PRESTO Study Group
Coinvestigators are listed by study site: 1. Headache Science Centre, National Neurological Institute C. Mondino Fo undation and University of Pavia: Cristina Tassorelli, MD, PhD (Principal Investigator); Vito Bitetto (Subinvestigator); Roberto De Icco, MD (Subinvestigator); Daniele Martinelli, MD (Subinvestigator); Grazia Sances, MD (Subinvestigator); Monica Bianchi, MD (Research Nurse); 2. Carlo Besta Neurological Institute and Foundation: Licia Grazzi, MD (Principal Investigator); Anna Maria Padovan (Subinvestigator); 3. University of Bari Aldo Moro: Marina de Tommaso, MD, PhD (Principal Investigator); Katia Ricci (Subinvestigator); Eleonora Vecchio, MD, PhD (Subinvestigator); 4. IRCCS Istituto delle Scienze Neurologiche di Bologna: Pietro Cortelli, MD, PhD (Principal Investigator); Sabina Cevoli, MD, PhD (Subinvestigator); Giulia Pierangeli, MD, PhD (Subinvestigator); Rossana Terlizzi, MD (Subinvestigator); 5. Sapienza University of Rome: Paolo Martelletti, MD, PhD (Principal Investigator); Andrea Negro, MD (Subinvestigator); Gabriella Addolorata Chiariello (Research Nurse); 6. University of Turin: Innocenzo Rainero, MD, PhD (Principal Investigator); Paola De Martino, MD, PhD (Subinvestigator); Annalisa Gai, MD (Subinvestigator); Flora Govone, MD (Subinvestigator); Federica Masuzzo, MD (Subinvestigator); Elisa Rubino, MD, PhD (Subinvestigator); Maria Claudia Torrieri, MD (Subinvestigator); Alessandro Vacca, MD (Subinvestigator); 7. University Hospital of Careggi: Pierangelo Geppetti, MD, PhD (Principal Investigator); Alberto Chiarugi, MD, PhD (Subinvestigator); Francesco De Cesaris (Subinvestigator); Simone Li Puma (Subinvestigator); Chiara Lupi (Subinvestigator); Ilaria Marone (Subinvestigator); 8. IRCCS Neuromed: Anna Ambrosini, MD, PhD (Principal Investigator); Armando Perrotta, MD, PhD (Subinvestigator); 9. Santa Maria della Misericordia Hospital: Paola Sarchielli, MD, PhD (Principal Investigator); Laura Bernetti, MD (Subinvestigator); Ilenia Corbelli, MD, PhD (Subinvestigator); Michele Romoli, MD (Subinvestigator); Simone Simoni, MD (Subinvestigator); Angela Verzina, MD (Subinvestigator); 10. IRCCS San Raffaele Pisana: Piero Barbanti, MD, PhD (Principal Investigator); Cinzia Aurilia, MD (Subinvestigator); Gabriella Egeo, MD, PhD (Subinvestigator); Luisa Fofi, MD (Subinvestigator).
electroCore Study Team: Eric Liebler (Senior Vice President, Neurology); Annelie Andersson (Senior Director, Clinical Director); Lia Spitzer (Senior Director, Clinical/Study Manager); Juana Marin, MD (Clinical Advisor, Safety Monitor); Candace McClure, PhD (North American Science Associates Inc., Statistician); Lisa Thackeray, MS (North American Science Associates Inc., Statistician), Maria Giovanna Baldi (Monitor); Daniela Di Maro (Monitor).
Competing interests
P. Martelletti has received research grants, advisory board fees, or travel fees from ACRAF; Allergan S.p.A.; Amgen Inc.; electroCore, Inc.; Novartis AG; and Teva Pharmaceutical Industries Ltd.
L. Grazzi has received consultancy and advisory fees from Allergan S.p.A. and electroCore, Inc.
G. Pierangeli has nothing to disclose.
I. Rainero has received consultancy fees from electroCore, Inc., and Mylan N.V. and research grants from the European Commission – Horizon 2020. He is also a principal investigator for RCTs sponsored by Axovant Sciences Ltd. and TauRx Pharmaceuticals Ltd.
P. Geppetti has received consultancy fees from Allergan S.p.A.; electroCore, Inc.; Evidera; Novartis AG; Pfizer Inc.; and Sanofi S.p.A. and research grants from Chiesi Farmaceutici S.p.A. He is also a principal investigator for RCTs sponsored by Eli Lilly and Company; Novartis AG; and Teva Pharmaceutical Industries Ltd.
A. Ambrosini has received consultancy fees from Almirall, S.A., and travel grants from Allergan S.p.A., Almirall, S.A., and Novartis.
P. Sarchielli has received clinical study fees from Allergan S.p.A.
P. Barbanti has received consultancy fees from Allergan S.p.A.; electroCore, Inc.; Janssen Pharmaceuticals, Inc.; Lusofarmaco; and Visufarma and advisory fees from Abbott Laboratories; Merck & Co., Inc.; Novartis AG; and Teva Pharmaceutical Industries Ltd. He is also a principal investigator for RCTs sponsored by Alder BioPharmaceuticals Inc.; Eli Lilly and Company; GlaxoSmithKline Pharmaceuticals Ltd.; and Teva Pharmaceutical Industries Ltd.
C. Tassorelli has consulted for Allergan S.p.A.; electroCore, Inc.; Eli Lilly and Company; and Novartis AG and has received research grants from the European Commission and the Italian Ministry of Health. She is also a principal investigator or collaborator for RCTs sponsored by Alder BioPharmaceuticals Inc.; Eli Lilly and Company; Novartis; and Teva Pharmaceutical Industries Ltd.
E. Liebler is an employee of electroCore, Inc., and receives stock ownership.
M. de Tommaso has received advisory fees from Allergan S.p.A.; Neopharmed; and Pfizer Inc.