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. 2023 Mar 30:14:1100426.
doi: 10.3389/fneur.2023.1100426. eCollection 2023.

An open-label observational study and meta-analysis of non-invasive vagus nerve stimulation in medically refractory chronic cluster headache

Lucy Simmonds  1 , Susie Lagrata  1 , Anker Stubberud  1   2 , Sanjay Cheema  1 , Erling Tronvik  2   3 , Manjit Matharu  1   2 , Salwa Kamourieh  1
Affiliations

An open-label observational study and meta-analysis of non-invasive vagus nerve stimulation in medically refractory chronic cluster headache

Lucy Simmonds et al. Front Neurol. .

Abstract

Background: Many patients with cluster headache (CH) are inadequately controlled by current treatment options. Non-invasive vagus nerve stimulation (nVNS) is reported to be effective in the management of CH though some studies suggest that it is ineffective.

Objective: To assess the safety and efficacy of nVNS in chronic cluster headache (CCH) patients.

Method: We prospectively analysed data from 40 patients with refractory CCH in this open-label, observational study. Patients were seen in tertiary headache clinics at the National Hospital for Neurology and Neurosurgery and trained to use nVNS as preventative therapy. Patients were reivewed at one month and then three-monthly from onset. The primary endpoint was number of patients achieving ≥50% reduction in attack frequency at 3 months. A meta-analysis of all published studies evaluating the efficacy of nVNS in CCH was also conducted. We searched MEDLINE and EMBASE for all studies investigating the use of nVNS as a preventive or adjunctive treatment for CCH with five or more participants. Combined mean difference and responder proportions with 95% confidence intervals (CI) were calculated from the included studies.

Results: 17/40 patients (43%) achieved ≥50% reduction in attack frequency at 3 months. There was a significant reduction in monthly attack frequency from a baseline of 124 (±67) attacks to 79 (±63) attacks in month 3 (mean difference 44.7; 95% CI 25.1 to 64.3; p < 0.001). In month 3, there was also a 1.2-point reduction in average severity from a baseline Verbal Rating Scale of 8/10 (95% CI 0.5 to 1.9; p = 0.001). Four studies, along with the present study, were deemed eligible for meta-analysis, which showed a responder proportion of 0.35 (95% CI 0.07 to 0.69, n = 137) and a mean reduction in headache frequency of 35.3 attacks per month (95% CI 11.0 to 59.6, n = 108), from a baseline of 105 (±22.7) attacks per month.

Conclusion: This study highlights the potential benefit of nVNS in CCH, with significant reductions in headache frequency and severity. To better characterise the effect, randomised sham-controlled trials are needed to confirm the beneficial response of VNS reported in some, but not all, open-label studies.

Keywords: chronic cluster headache; medically refractory; meta-analysis; non invasive vagus nerve stimulation; vagus nerve (VN) stimulation.

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Conflict of interest statement

SL has received payment for attending advisory meetings and development of presentation from Allergan Novartis, Eli Lilly and TEVA. AS is co-founder of Nordic Brain Tech, a company developing a non-pharmacological biofeedback treatment for migraine and holds a pending patent application relating to the company’s product. ET is co-founder and shareholder of Nordic Brain Tech AS and Palion Medical AS. He serves on advisory board for Eli Lilly and Novartis and TEVA. He has received speaker honoraria from Eli Lilly, Novartis, Allergan and TEVA. MM serves on the advisory board for Abbott, Allergan, Eli Lilly, Medtronic, Novartis, TEVA; has received payment for the development of educational presentations from Allergan, electroCore, Eli Lilly, Medtronic, Novartis, and TEVA; and, has received research grants from Abbott, electroCore and Medtronic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Flow of patients through the study.
Figure 2
Figure 2
PRISMA flow diagram.
Figure 3
Figure 3
Meta-analysis of mean difference in monthly headache attack frequency between baseline and final follow-up.
Figure 4
Figure 4
Meta-analysis of responder proportion.
See this image and copyright information in PMC

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