Noninvasive Vagus Nerve Stimulation for Cluster Headache and Migraine: A Health Technology Assessment.

Background: Cluster headache and migraine are 2 distinct types of primary headache that can cause substantial pain, disability, and decreased quality of life. Noninvasive vagus nerve stimulation (nVNS) is a treatment option that delivers a mild electrical stimulation to a nerve in the neck. nVNS is intended to reduce the pain and duration of a headache attack, and to prevent headaches from occurring. We conducted a health technology assessment of nVNS for the acute treatment and prevention of cluster headache or migraine, which included an evaluation of effectiveness, safety, cost-effectiveness, the budget impact of publicly funding nVNS, and patient preferences and values. Methods: We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Cochrane Risk of Bias tool and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature search and conducted 2 cost-utility and cost-effectiveness analyses with a 1-year time horizon from a public payer perspective. We also analyzed the budget impact of publicly funding nVNS for people with cluster headache and migraine in Ontario. To contextualize the potential value of nVNS, we spoke with people with cluster headache and migraine. Results: We included 8 randomized trials in the clinical evidence review (3 on cluster headache, 5 on migraine). For the acute treatment of cluster headache with nVNS, we found no statistically significant improvements in terms of overall response (pain relief), pain freedom, and duration of attacks (GRADEs: Low to Very low), or acute medication use (GRADE: Moderate). We observed little to no difference in mean pain intensity or adverse events (GRADE: Low). For the preventive treatment of cluster headache (based on 1 trial), nVNS reduced the frequency of attacks per week (GRADE: Low), improved response (GRADE: Low), reduced acute medication use (GRADE: Low), and improved quality of life (GRADE: Low to Very low). More overall adverse events were observed with nVNS, but results were uncertain (GRADE: Low). For the acute treatment of migraine (based on 1 study), nVNS improved response to treatment (i.e., pain relief; GRADE: Moderate to Low) but had little to no effect on sustained response (GRADE: Low). nVNS improved pain freedom, but the results were not statistically significant (GRADE: Moderate) and there was no difference in sustained pain freedom (GRADE: Low). There was little to no difference in mean pain intensity (GRADE: Very low) or acute medication use (GRADE: Low), and the risk of adverse events was very uncertain (GRADE: Very low). For the preventive treatment of migraine (based on 4 studies), nVNS may slightly reduce the number of headache and migraine days, but we could not exclude the possibility of no effect (GRADE: Low). nVNS made little to no difference in acute medication use (GRADE: Low), and the evidence was very uncertain for the impact on functional status (GRADE: Very low). nVNS may make little to no difference in adverse events, but the evidence was very uncertain (GRADE: Low to Very low).For the prevention of cluster headache, nVNS in addition to standard care was more effective and more costly than standard care alone. The incremental cost-effectiveness ratio (ICER) for nVNS in addition to standard care compared with standard care alone was $27,338 per QALY gained. The probability of nVNS in addition to standard care being cost-effective was 88.5% at a willingness-to-pay (WTP) value of $50,000 per QALY gained and 97% at a WTP value of $100,000 per QALY gained. However, these results need to be interpreted with caution because the clinical inputs used to inform the model were of Low to Very low quality based on the GRADE framework. For the prevention of migraine, nVNS in addition to standard care was similarly effective but more costly than standard care alone. The ICER for nVNS in addition to standard care compared with standard care alone was $952,116 per QALY gained. nVNS was unlikely to be cost-effective at commonly used WTP values of $50,000 and $100,000 per QALY gained. The 5-year budget impact of publicly funding nVNS in Ontario for cluster headache was estimated to be $11.88 million for acute treatment and $9.92 million for preventive treatment. The 5-year budget impact of publicly funding nVNS for migraine was estimated to be $1.12 billion for acute treatment and $278.77 million for preventive treatment.People with cluster headache and migraine described the negative impact of these conditions on their day-to-day activities, work, social life and family relationships, and mental health. They reflected on their experiences of seeking proper treatment. One participant who had tried nVNS did not see positive effects on their symptoms, but all participants were interested in trying nVNS. Participants emphasized the importance of noninvasive treatment options for cluster headache and migraine. Conclusions: nVNS may be an effective and generally safe treatment option for people with cluster headache or migraine, but the evidence was of Very low to Moderate certainty, and the degree of effect was dependent on the type of headache and the indication for treatment. nVNS in addition to standard care is likely to be cost-effective for the prevention of cluster headache, but not for the prevention of migraine. We estimate that publicly funding nVNS for the acute treatment of cluster headache in Ontario would result in an additional cost of $11.88 million over 5 years. Publicly funding nVNS for the preventive treatment of cluster headache in Ontario would result in an additional cost of $9.92 million over 5 years. Publicly funding nVNS for migraine would result in very high additional costs: $1.12 billion for acute treatment and $287.77 million for preventive treatment over 5 years. People with cluster headache and migraine were interested in nVNS as a noninvasive option for treatment and prevention.