Practical and clinical utility of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine: a post hoc analysis of the randomized, sham-controlled, double-blind PRESTO trial

DOI: https://doi.org/10.1186/s10194-018-0928-1

Abstract-Summary We examined additional data from PRESTO to provide further insights into the practical utility of nVNS by evaluating its ability to consistently deliver clinically meaningful improvements in pain intensity while reducing the need for rescue medication.

Data were examined to compare nVNS and sham with regard to the percentage

of patients who benefited by at least 1 point in pain intensity.

We also assessed the percentage of attacks that required rescue medication and

pain-free rates stratified by pain intensity at treatment initiation.

A significantly higher percentage of patients who used acute nVNS treatment (n = 120) vs sham (n = 123) reported a ≥ 1-point decrease in pain intensity at 30 min (nVNS, 32.2%; sham, 18.5%; P = 0.020), 60  min (nVNS, 38.8%; sham, 24.0%; P = 0.017), and 120 min (nVNS, 46.8%; sham, 26.2%; P = 0.002) after the first attack.

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The proportion of patients who did not require rescue medication was signifi- cantly higher with nVNS than with sham for the first attack (nVNS, 59.3%; sham, 41.9%; P = 0.013) and all attacks (nVNS, 52.3%; sham, 37.3%; P = 0.008).

When initial pain intensity was mild, the percentage of patients with no pain after treatment was significantly higher with nVNS than with sham at 60 min (all attacks: nVNS, 37.0%; sham, 21.2%; P = 0.025) and 120 min (first attack: nVNS, 50.0%; sham, 25.0%; P = 0.018; all attacks: nVNS, 46.7%; sham, 30.1%; P = 0.037).

This post hoc analysis demonstrated that acute nVNS treatment quickly and con-

sistently reduced pain intensity while decreasing rescue medication use.

Background nVNS reduces the need for pharmacologic therapies and their related side effects in the treatment of migraine [457, 458].

In the PRospectivE Study of nVNS for the acute Treatment Of migraine (PRESTO), nVNS was superior to sham for the majority of end points including pain freedom, pain relief, and ≥50% responder rates at various time points [459].

In this post hoc analysis, we provide further insight into the practical utility of acute nVNS treatment through the reporting of clinically relevant end points that extend beyond the traditional key end points recommended for pivotal clinical trials by the International Headache Society (IHS) [460].

The objectives of this analysis were to evaluate the likelihood of experiencing at least a 1-point decrease in pain intensity while reducing the need for rescue medica- tion and to assess whether treatment of a migraine attack when the pain is mild affects the efficacy of nVNS.

Methods Patients were instructed to treat up to 5 migraine attacks with nVNS or sham during the double-blind period and up to 5 additional attacks with nVNS during the open- label period.

The percentage of patients with a≥ 1-point reduction in pain intensity on a 4-point scale (0, no pain; 1, mild pain; 2, moderate pain; 3, severe pain) was mea- sured at 30, 60, and 120 min after the first treated attack of the double-blind and open-label periods.

Proportions of patients with pain reductions of ≥1 point and proportions of patients who did not use rescue medication were estimated for the first attack using logistic regression models adjusted for baseline pain score, preventive medication use, and presence of aura.

P-values for comparison of pain-free rates for the first attack between the nVNS and sham groups in the double-blind period were from the chi-square test or Fisher exact test, as appropriate.

Results A total of 285 patients with episodic migraine were enrolled, with 248 randomly assigned to the nVNS (n = 122) and sham (n = 126) groups.

More patients in the nVNS group than in the sham group initiated treatment when attack intensity was severe (first attack: nVNS, 23.5%; sham, 15.1%; all attacks: nVNS, 25.1%; sham, 17.6%).

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Differences in pain-free rates between nVNS and sham were more pronounced in patients who initiated treatment when their attack was mild than for those who waited until the pain was moderate or severe to treat their attack.

When the initial pain intensity was moderate or severe, pain-free rates were not significantly different between the nVNS group and the sham group, though they were generally higher in the nVNS group at all time points.

Discussion The ability of nVNS to offer measurable pain relief for patients without increasing their exposure to pharmacologic adverse events or medication overuse provides a practical rationale for its early use as an acute treatment [461].

Patients who initiated their treatment when their migraine was mild were more likely to abort their attacks than those who treated when their pain was more severe, a finding consistent with clinical studies that demonstrated the efficacy of pharma- cologic therapies during early stages of migraine attacks [462, 463] and when pain was still mild [97, 464–467].

The combination of efficacy and tolerability with nVNS might provide patients with the confidence to initiate treatment earlier in their attacks compared with pharmaco- logic options that, in clinical experience, are often initiated when the pain is more severe because of concerns with drug availability, overuse, and adverse events [464, 468–470]. This analysis supports nVNS as a practical and effective alternative that can be used frequently and as early in an attack as desired to decrease migraine pain while reducing the need for rescue medication and minimizing drug- related adverse events.

Conclusions These data highlight clinically important benefits of nVNS as an acute treatment of migraine.

nVNS decreased pain by at least 1 point while reducing rescue medication use in

most migraine attacks.

These benefits, along with its convenience and ease of use, make nVNS an

appealing practical option for the acute treatment of migraine.

Acknowledgement A machine generated summary based on the work of Grazzi, Licia; Tassorelli, Cristina; de Tommaso, Marina; Pierangeli, Giulia; Martelletti, Paolo; Rainero, Innocenzo; Geppetti, Pierangelo; Ambrosini, Anna; Sarchielli, Paola; Liebler, Eric; Barbanti, Piero; Tassorelli, Cristina; Bitetto, Vito; De Icco, Roberto; Martinelli, Daniele; Sances, Grazia; Bianchi, Monica; Grazzi, Licia; Padovan, Anna Maria; de Tommaso, Marina; Ricci, Katia; Vecchio, Eleonora; Cortelli, Pietro; Cevoli, Sabina; Pierangeli, Giulia; Terlizzi, Rossana; Martelletti, Paolo; Negro, Andrea; Chiariello, Gabriella Addolorata; Rainero, Innocenzo; De Martino, Paola; Gai, Annalisa; Govone, Flora; Masuzzo, Federica; Rubino, Elisa; Torrieri, Maria Claudia; Vacca, Alessandro; Geppetti, Pierangelo; Chiarugi, Alberto; De Cesaris, Francesco; Puma, Simone Li; Lupi, Chiara; Marone, Ilaria; Ambrosini, Anna; Perrotta, Armando; Sarchielli, Paola; Bernetti, Laura; Corbelli, Ilenia; Romoli, Michele; Simoni, Simone; Verzina, Angela; Barbanti, Piero; Aurilia, Cinzia; Egeo,

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Gabriella; Fofi, Luisa; Liebler, Eric; Andersson, Annelie; Spitzer, Lia; Marin, Juana; McClure, Candace; Thackeray, Lisa; Baldi, Maria Giovanna; Di Maro, Daniela. 2018 in The Journal of Headache and Pain.

Remote electrical neuromodulation (REN) in the acute treatment of migraine: a comparison with usual care and acute migraine medications