A Randomized Sham‐Controlled Cross‐Over Study on the Short‐Term Effect of Non‐Invasive Cervical Vagus Nerve Stimulation on Spinal and Supraspinal Nociception in Healthy Subjects

Objective The aim of the present study was to test the effects of vagus nerve stimulation (VNS) on the descending pain inhibition, quantified by the nociceptive flexor (RIII) reflex and the conditioned pain modulation (CPM) paradigm, and on supraspinal nociceptive responses, assessed by pain intensity and unpleasantness ratings and late somatosensory evoked potentials (SEPs), in healthy subjects. Background Non‐invasive vagus nerve stimulation (nVNS) showed promising effects on headache and pain treatment. Underlying mechanisms are only incompletely understood but may include the activation of the descending pain inhibitory system and/or the modification of emotional responses to pain. Methods Twenty‐seven adult, healthy, and pain‐free subjects participated in this double‐blind cross‐over study conducted at a university research center. They received 4 minutes of cervical nVNS or sham stimulation in randomized order. RIII reflexes, pain ratings, and SEPs were assessed before, during, and 5, 15, 30, and 60 minutes after nVNS/sham stimulation, followed by CPM testing. The primary outcome was the nVNS effect on the RIII reflex size. Three subjects were excluded after the preparatory session (before randomization), 1 subject was excluded after outlier analysis, leaving 23 for analysis. Results RIII reflex areas were 917.1 ± 563.8 µV × ms (mean ± SD) before, 952.4 ± 467.4 µV × ms during and 929.2 ± 484.0 µV × ms immediately after nVNS and 858.4 ± 489.2 µV × ms before, 913.9 ± 539.7 µV × ms during and 862.4 ± 476.0 µV × ms after sham stimulation, revealing no differences between the immediate effects of nVNS and sham stimulation (F [3,66] = 0.67, P = .574). There also were no effects of nVNS over sham on RIII reflex areas up to 60 minutes after nVNS (F [1.7,37.4] = 1.29, P = .283). Similarly, there was no statistically significant effect of nVNS on pain intensity ratings and thresholds, RIII reflex thresholds, late SEP amplitudes, and the CPM effect, compared to sham. Pain unpleasantness ratings statistically significantly decreased from 4.4 ± 2.4 (NRS 0‐10) to 4.1 ± 2.5 during nVNS compared to sham stimulation (F [1,22] = 8.74, P = .007), but there were no longer lasting effects (5‐60 minutes after stimulation). Conclusions The present study does not support an acute effect of nVNS on descending pain inhibition, pain intensity perception or supraspinal nociception in healthy adults. However, there was a small effect on pain unpleasantness during nVNS, suggesting that nVNS may preferentially act on affective, not somatosensory pain components

Non-invasive neuromodulation for migraine and cluster headache : a systematic review of clinical trials

Non-invasive neuromodulation therapies for migraine and cluster headache are a practical and safe alternative to pharmacologics. Comparisons of these therapies are difficult because of the heterogeneity in study designs. In this systematic review of clinical trials, the scientific rigour and clinical relevance of the available data were assessed to inform clinical decisions about non-invasive neuromodulation. PubMed, Cochrane Library and ClinicalTrials.gov databases and the WHO's International Clinical Trials Registry Platform were searched for relevant clinical studies of non-invasive neuromodulation devices for migraine and cluster headache (1 January 1990 to 31 January 2018), and 71 were identified. This analysis compared study designs using recommendations of the International Headache Society for pharmacological clinical trials, the only available guidelines for migraine and cluster headache. Non-invasive vagus nerve stimulation (nVNS), single-transcranial magnetic stimulation and external trigeminal nerve stimulation (all with regulatory clearance) were well studied compared with the other devices, for which studies frequently lacked proper blinding, sham controls and sufficient population sizes. nVNS studies demonstrated the most consistent adherence to available guidelines. Studies of all neuromodulation devices should strive to achieve the same high level of scientific rigour to allow for proper comparison across devices. Device-specific guidelines for migraine and cluster headache will be soon available, but adherence to current guidelines for pharmacological trials will remain a key consideration for investigators and clinicians

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

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 repeatedmeasures 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 120minutes 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

Effect of non-invasive vagus nerve stimulation on resting-state electroencephalography and laser-evoked potentials in migraine patients : mechanistic insights

A recent multicenter trial provided Class I evidence that for patients with an episodic migraine, non-invasive vagus nerve stimulation (nVNS) significantly increases the probability of having mild pain or being pain-free 2 h post-stimulation. Here we aimed to investigate the potential effect of nVNS in the modulation of spontaneous and pain related bioelectrical activity in a subgroup of migraine patients enrolled in the PRESTO trial by using resting-state electroencephalography and trigeminal laser-evoked potentials (LEPs). LEPs were recorded for 27 migraine patients who received active or sham nVNS over the cervical vagus nerve. We measured power values for frequencies between 1–100 Hz in a resting-state condition and the latency and amplitude of N1, N2, and P2 components of LEPs in a basal condition during and after active or sham vagus nerve stimulation (T0, T1, T2). The P2 evoked by the right and the left trigeminal branch was smaller during active nVNS. The sham device also attenuated the P2 amplitude evoked by the left trigeminal branch at T1 and T2, but this attenuation did not reach significance. No changes were observed for N1 amplitude, N1, N2, P2 latency, or pain rating. nVNS induced an increase of EEG power in both slow and fast rhythms, but this effect was not significant as compared to the sham device. These findings suggest that nVNS acts on the cortical areas that are responsible for trigeminal pain control and pave the ground for future studies aimed at confirming the possible correlations with clinical outcomes, including the effect on symptoms that are directly correlated with trigeminal pain processing and modulation

Effects of non-invasive vagus nerve stimulation on attack frequency over time and expanded response rates in patients with chronic cluster headache: a post hoc analysis of the randomised, controlled PREVA study

Background: In the PREVention and Acute treatment of chronic cluster headache (PREVA) study, attack frequency reductions from baseline were significantly more pronounced with non-invasive vagus nerve stimulation plus standard of care (nVNS + SoC) than with SoC alone. Given the intensely painful and frequent nature of chronic cluster headache attacks, additional patient-centric outcomes, including the time to and level of therapeutic response, were evaluated in a post hoc analysis of the PREVA study. Findings: After a 2-week baseline phase, 97 patients with chronic cluster headache entered a 4-week randomised phase to receive nVNS + SoC (n = 48) or SoC alone (n = 49). All 92 patients who continued into a 4-week extension phase received nVNS + SoC. Compared with SoC alone, nVNS + SoC led to a significantly lower mean weekly attack frequency by week 2 of the randomised phase;the attack frequency remained significantly lower in the nVNS + SoC group through week 3 of the extension phase (P = 25%, >= 50%, and >= 75% from baseline (>= 25% and >= 50%, P = 75%, P = 0.009). The 100% response rate was 8% with nVNS + SoC and 0% with SoC alone. Conclusions: Prophylactic nVNS led to rapid, significant, and sustained reductions in chronic cluster headache attack frequency within 2 weeks after its addition to SoC and was associated with significantly higher >= 25%, >= 50%, and >= 75% response rates than SoC alone. The rapid decrease in weekly attack frequency justifies a 4-week trial period to identify responders to nVNS, with a high degree of confidence, among patients with chronic cluster headache

Cost-effectiveness analysis of non-invasive vagus nerve stimulation for the treatment of chronic cluster headache

Background: Cluster headache (CH) is a debilitating condition that is generally associated with substantial health care costs. Few therapies are approved for abortive or prophylactic treatment. Results from the prospective, randomised, open-label PREVA study suggested that adjunctive treatment with a novel non-invasive vagus nerve stimulation (nVNS) device led to decreased attack frequency and abortive medication use in patients with chronic CH (cCH). Herein, we evaluate whether nVNS is cost-effective compared with the current standard of care (SoC) for cCH. Methods: A pharmacoeconomic model from the German statutory health insurance perspective was developed to estimate the 1-year cost-effectiveness of nVNS + SoC (versus SoC alone) using data from PREVA. Short-term treatment response data were taken from the clinical trial;longer-term response was modelled under scenarios of response maintenance, constant rate of response loss, and diminishing rate of response loss. Health-related quality of life was estimated by modelling EQ-5D T data from PREVA;benefits were defined as quality-adjusted life-years (QALY). Abortive medication use data from PREVA, along with costs for the nVNS device and abortive therapies (i.e. intranasal zolmitriptan, subcutaneous sumatriptan, and inhaled oxygen), were used to assess health care costs in the German setting. Results: The analysis resulted in mean expected yearly costs of (sic)7096.69 for nVNS + SoC and (sic)7511.35 for SoC alone and mean QALY of 0.607 for nVNS + SoC and 0.522 for SoC alone, suggesting that nVNS generates greater health benefits for lower overall cost. Abortive medication costs were 23 % lower with nVNS + SoC than with SoC alone. In the alternative scenarios (i.e. constant rate of response loss and diminishing rate of response loss), nVNS + SoC was more effective and cost saving than SoC alone. Conclusions: In all scenarios modelled from a German perspective, nVNS was cost-effective compared with current SoC, which suggests that adjunctive nVNS therapy provides economic benefits in the treatment of cCH. Notably, the current analysis included only costs associated with abortive treatments. Treatment with nVNS will likely promote further economic benefit when other potential sources of cost savings (e.g. reduced frequency of clinic visits) are considered

Noninvasive peripheral vagal nerve stimulation prevents migraine aura: A case report

We describe a patient affected by migraine with visual and somatosensory aura, whose symptoms were consistently attenuated by noninvasive peripheral vagal nerve stimulation (nVNS) in multiple prospectively recorded attacks. When compared with the current standard of care, nVNS significantly reduced the duration of visual aura in all the attacks ( n = 5) and prevented the somatosensory aura in three of the five attacks. The overall duration of nVNS-treated auras was 19.0 ± 4.2 min, significantly shorter than the duration of aura in attacks treated with standard of care (103.8 ± 10.3 min). This single-case study requires confirmation in a larger sample size, but we believe that this first report is suggestive of likely efficacy given the relatively high number of treated attacks and the consistent effect of nVNS

Non-invasive vagus nerve stimulation for primary headache: A clinical update.

Background Non-invasive vagus nerve stimulation (nVNS) is a proven treatment for cluster headache and migraine. Several possible mechanisms of action by which nVNS mitigates headache have been identified. Methods We conducted a narrative review of recent scientific and clinical research into nVNS for headache, including findings from mechanistic studies and their possible relationships to the clinical effects of nVNS. Results Findings from animal and human studies have provided possible mechanistic explanations for nVNS efficacy in headache involving four core areas: Autonomic nervous system functions; cortical spreading depression inhibition; neurotransmitter regulation; and nociceptive modulation. We discuss how overlap and interplay among these areas may underlie the utility of nVNS in the context of clinical evidence supporting its safety and efficacy as acute and preventive therapy for both cluster headache and migraine. Possible future nVNS applications are also discussed. Conclusion Significant progress over the past several years has yielded valuable mechanistic and clinical evidence that, combined with the excellent safety and tolerability profile of nVNS, suggests that it should be considered a first-line treatment for both acute and preventive treatment of cluster headache, an effective option for acute treatment of migraine, and a highly relevant, practical option for migraine prevention

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

Background: The PRESTO study of non-invasive vagus nerve stimulation (nVNS; gammaCore\uae) featured key primary and secondary end points recommended by the International Headache Society to provide Class I evidence that for patients with an episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 h post stimulation. Here, 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. Methods: Patients recorded pain intensity for treated migraine attacks on a 4-point scale. 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. Results: A significantly higher percentage of patients who used acute nVNS treatment (n = 120) vs sham (n = 123) reported a 65 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. Similar significant results were seen when assessing the benefit in all attacks. The proportion of patients who did not require rescue medication was significantly 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). Conclusions: This post hoc analysis demonstrated that acute nVNS treatment quickly and consistently reduced pain intensity while decreasing rescue medication use. These clinical benefits provide guidance in the optimal use of nVNS in everyday practice, which can potentially reduce use of acute pharmacologic medications and their associated adverse events. Trial registration: ClinicalTrials.gov identifier: NCT02686034