Safety and Feasibility Study of Non-Invasive Vagus Nerve Stimulation in Spontaneous Subarachnoid Hemorrhage

Application of Non-Invasive Vagus Nerve Stimulation in Spontaneous Subarachnoid Hemorrhage: A Randomized Safety and Feasibility Study Report

Spontaneous subarachnoid hemorrhage (SAH) is often accompanied by severe thunderclap headaches, which patients typically describe as the “worst headache of their lives.” The vast majority of patients (90%) continue to experience severe headaches during their intensive care unit (ICU) stay, and more than one-third of patients suffer from persistent headaches for years after brain injury, significantly affecting their quality of life. Currently, there is a lack of effective treatments or guidelines for these patients, and data evaluating the efficacy of analgesics are scarce. Due to the lack of effective pain management methods, clinicians often rely on opioids for pain relief. However, the side effects and addiction risks of opioids have become one of the main causes of opioid abuse in the United States. Additionally, opioids may adversely affect the neurological status of patients by altering levels of consciousness, which is particularly dangerous for SAH patients. Therefore, clinicians strive to avoid or minimize opioid use, and there is a critical need to find multimodal treatment methods to reduce opioid use while providing adequate pain control.

Non-invasive vagus nerve stimulation (NVNS) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of migraines and cluster headaches and has been proven to be safe and well-tolerated. However, its safety in SAH patients is still unclear. Recent studies have shown that NVNS is safe in ischemic stroke patients, but only included 8 patients with intracranial hemorrhage, without clearly indicating whether SAH patients were included. SAH induces systemic inflammatory response syndrome, which may lead to cortical spreading ischemia and blood-brain barrier disruption, mechanisms believed to be involved in the headaches and secondary brain injuries of SAH patients. NVNS has the potential to mitigate the damage caused by these pathways.

Study Background

This paper, titled “Application of Non-Invasive Vagus Nerve Stimulation in Spontaneous Subarachnoid Hemorrhage: A Randomized Safety and Feasibility Study,” was authored by Tania Rebeiz et al., from the departments of neurosurgery at North Shore University Hospital, South Shore University Hospital, and Lenox Hill Hospital in New York. The paper was published in the journal “Brain Stimulation” and was made available online on April 18, 2024.

Study Methods and Procedures

Study Design

This study employed a multicenter, randomized, double-blind trial design aimed at evaluating the safety, feasibility, and efficacy of NVNS in treating headaches in spontaneous SAH patients. Patients were recruited from three hospitals between October 30, 2019, and June 20, 2022. The trial adhered to good clinical practices and the standards of the Declaration of Helsinki, and the research protocol was approved by the Northwell Health Institutional Review Board.

Participants

Inclusion criteria included patients aged 18 to 75 years who were hospitalized due to severe headaches or had a visual analog scale (VAS) score of 7 or higher and were diagnosed with aneurysmal or perimesencephalic SAH. Patients needed to be able to express their pain scores during the enrollment and throughout the study. Exclusion criteria included contraindications for vagus nerve stimulation, current alcohol or substance abuse history, chronic opioid use history, or a history of cardiac conduction block or ventricular arrhythmias.

Randomization and Masking

Patients were randomly assigned to either the treatment group or the sham stimulation group in a 1:1 ratio using a variable block design. Devices were assigned through a serial number marking system. The active and sham devices were identical in design, color, and functionality, but the sham device did not produce any electrical stimulation signals. A non-blind study assistant was responsible for randomizing patients and recording participant and device serial numbers. The medical team and patients were blinded to the specific device to ensure blinding.

Procedure

GammaCore® (NVNS; ElectroCore, Inc.), an FDA-approved handheld nerve stimulation device for cluster headaches and migraines, was used. It delivers non-invasive transcutaneous current through two electrodes placed on the surface of the skin on the neck. Study assistants provided the device and instructed patients on its use, with stimulation intensity adjustable from 0 to 40 a.u. Each “stimulation” session lasted 2 minutes and automatically shut off afterward.

Patients were informed that they might feel discomfort during stimulation. The stimulation device was provided by nurses or clinicians at specified times, and patients’ vital signs and headache intensity were monitored. All patients were continuously monitored, and any abnormal blood pressure or heart rate would result in the termination of stimulation. Pain intensity was measured using a 0 to 10 visual analog scale (VAS), recording changes before and after stimulation.

Results

Safety and Feasibility

A total of 120 participants were screened, 40 were enrolled, and randomized to either the treatment group (19) or the sham stimulation group (21). Results indicated that the NVNS group showed a significant decrease in systolic blood pressure post-stimulation (p=0.02), but no significant difference when compared to the sham stimulation group (p=0.68). There were no significant changes in heart rate and diastolic blood pressure within or between groups (p>0.05). No patients experienced neurological deterioration or severe adverse events related to the device during stimulation.

Medication and Pain Outcomes

At baseline, the active group’s average morphine equivalent dose (MED) was 14.69 mg, and the sham stimulation group’s MED was 14.50 mg. The NVNS group’s average MED decreased by 10% at 7 days and 15% at 14 days. Headache intensity significantly decreased in the active group (p<0.001), with no significant change in the sham stimulation group (p=0.21).

Exploratory Endpoints

Regarding hospital stay duration, the median hospital days were 16 for the NVNS group and 18 for the sham group. The incidence of new cerebral infarctions was 5.6% in the NVNS group and 23.8% in the sham group.

Discussion and Conclusion

This study demonstrates that NVNS is safe and feasible in SAH patients, significantly reducing headache intensity and showing a tendency to reduce opioid use. Larger randomized controlled trials are needed to further validate its efficacy and neuroprotective effects. The application of NVNS in SAH warrants further research, as it has potential clinical value in reducing pain and possibly improving patients’ quality of life. The high safety profile of this device (already used for migraine and cluster headache treatment) makes it a viable pain management option.

Although the study results preliminarily show the safety and efficacy of NVNS, further, larger-scale studies are needed to comprehensively assess its application effects in SAH patients.