Neuromodulation in the Management of Cluster Headaches: a Systematic Review and Meta-Analysis

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The management of cluster headache usually consists of high flow oxygen, triptans, and verapamil. The exploration of new methods, such as neuromodulation techniques are needed to look for possible alternatives for patients that remain refractory to all types of medications. Methods: Databases including Pubmed, Cochrane, Web of Science, and Google Scholar were systematically reviewed through 2025 for studies involving adult patients (≥18 years) with cluster headache. The terms used for the search included (e.g., occipital nerve stimulation, vagus nerve stimulation, transcranial magnetic stimulation, sphenopalatine ganglion stimulation). The aim was to measure the outcomes of neuromodulation in reducing headache frequency and pain intensity, improving quality of life, and assessing adverse effects. Results: Ten studies met the inclusion criteria. Meta-analysis showed no statistically significant difference in attack frequency (SMD: –0.05; 95% CI: –0.36 to 0.26; p = 0.75) or pain intensity (SMD: –0.26; 95% CI: –0.57 to 0.05; p = 0.10) between neuromodulation and control groups. However, neuromodulation was associated with a significant outcome in improving quality of life (SMD: –0.50; 95% CI: –0.82 to –0.19; p = 0.002). The overall risk of adverse events was comparable between groups (OR: 1.38; 95% CI: 0.37–5.08; p = 0.63), though, the heterogeneity was high in the studies Conclusion: Neuromodulation has been shown to improve the quality of life, specifically to the patients who are refractory to standard management of cluster headache, but it does not reduce the attack frequency or pain intensity. These modalities are generally safe, according to the evaluated high quality randomized trials. Cluster headache vagus nerve stimulation occipital nerve stimulation deep brain stimulation transcranial magnetic stimulation sphenopalatine ganglion stimulation Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Primary headache disorders represent a major source of neurological morbidity, among which cluster headache stands out as one of the most intense and debilitating. It predominantly affects men and is marked by sudden, unilateral periorbital attacks lasting up to three hours. These attacks are often distinctively accompanied by the presence of ipsilateral autonomic symptoms such as lacrimation, conjunctival injection, nasal congestion, rhinorrhea, and, occasionally, partial Horner’s syndrome manifested by ptosis and miosis [ 1 ][ 2 ] . Current initial management measures include high-flow oxygen and tripitans (e.g., sumatripitan), while verapamil remains to serve as the cornerstone of preventive therapy [ 3 ]. Despite these established treatment approaches, a percentage of patients still experience refractory attacks that limit responses to both standard abortive and preventive medications. This clinical gap has shifted attention and prompted exploration toward neuromodulatory-based strategies that modulate pain-processing pathways. Neuromodulation has emerged as a valuable therapeutic option for certain patients with chronic cluster headaches that are medically intractable. A spectrum of techniques have been explored, including deep brain stimulation (DBS), occipital nerve stimulation (ONS), vagus nerve stimulation (VNS), sphenopaplatine ganglion stimulation (SPG), and transcranial magnetic stimulation (TMS). Preliminary studies have reported favorable results in a subset of patients with refractory disease; however, findings demonstrate inconsistency and substantial heterogeneity, and the sustained effectiveness and safety profile of these modalities lack validation [ 4 ]. This systematic review and meta-analysis intends to integrate data from randomized and prospective studies evaluating the efficacy and safety of neuromodulation in managing cluster headaches. It specifically aims to focus on assessing the outcomes related to changes in pain severity, quality of life, and adverse events. Methods & Materials Search Strategy: A systematic literature search was performed to identify studies evaluating neuromodulation in adult patients (≥18 years) with episodic or chronic cluster headache (CH). Multiple electronic databases (PubMed/MEDLINE, Cochrane Library, Web of Science, and Google Scholar) were searched from inception through September 2025. Search terms included MeSH and free-text variants of “cluster headache,” “trigeminal autonomic cephalalgia,” combined with “neuromodulation,” “vagus nerve stimulation,” “deep brain stimulation,” “occipital nerve stimulation,” “transcranial magnetic stimulation,” “sphenopalatine ganglion stimulation,” and related terms. Synonyms and Boolean operators were used to ensure sensitivity (e.g. (“cluster headache” OR “trigeminal autonomic cephalalgia”) AND (“neuromodulation” OR “stimulation”) ). The search was restricted to English-language, peer-reviewed articles. References of key articles were hand-searched to identify additional studies. The review was conducted in accordance with PRISMA guidelines [5]. The protocol was prospectively registered in PROSPERO registration number : ( CRD420251023329) . Inclusion and Exclusion Criteria Eligibility criteria were defined a priori. We included randomized controlled trials (RCTs), prospective cohort studies, and case-control studies that enrolled adults with a confirmed diagnosis of cluster headache (per ICHD criteria) and evaluated any neuromodulation therapy (including non-invasive cervical or auricular vagus nerve stimulation, hypothalamic deep brain stimulation, occipital or peripheral nerve stimulation, transcranial magnetic stimulation, sphenopalatine ganglion stimulation, etc.). Eligible studies compared neuromodulation to sham/placebo or standard medical therapy (e.g. oxygen, verapamil). Studies were required to report at least one clinical outcome of interest (attack frequency, pain intensity, attack duration, responder rate, quality-of-life or disability scores, or adverse events) with a minimum follow-up of four weeks. Only studies in adults (≥18 years) were included. We excluded non-comparative reports (case series without a control group), reviews, editorials, animal studies, and trials in pediatric patients. Studies lacking sufficient outcome data or details of the neuromodulation protocol were also excluded. Data Extraction and Management Two reviewers independently screened titles and abstracts of all retrieved records for eligibility; the title and abstracts were screened between March 2025 and April 2025 . Full texts of potentially relevant studies were obtained and reviewed against inclusion criteria that were also screened between March 2025 and April 2025 . Disagreements were resolved by discussion or by consulting a third reviewer. Data were extracted using a standardized form. Extracted information included study design, year, setting, sample size, and patient characteristics (age, sex, episodic vs chronic CH). Intervention details (type of neuromodulation device, stimulation parameters, duration) and comparators were recorded. Key outcomes extracted were change in headache attack frequency (per week or month), pain intensity (e.g. on visual analog or numeric rating scales), attack duration, responder rates (e.g. ≥50% reduction in frequency), quality-of-life measures (e.g. SF-36 or disease-specific scores), and adverse events (including specific events such as facial flushing). When possible, end-of-study or change values (means and SD) were recorded; if outcomes were reported in medians (with interquartile ranges or range), these were converted to approximate means and standard deviations using established methods. All data were checked for consistency and completeness. Quality Assessment Two reviewers independently assessed the risk of bias for each included study. For RCTs, we used the Cochrane Risk of Bias 2.0 tool [6] (assessing domains such as randomization, deviations from intended interventions, missing outcome data, outcome measurement, and selective reporting). For observational cohort or case-control studies, the Newcastle–Ottawa Scale (NOS) [7] was applied (evaluating selection, comparability, and outcome/exposure ascertainment). Disagreements were resolved by discussion. Studies judged to have a high risk of bias (e.g. serious flaws in design or conduct) were noted; sensitivity analyses excluding high-risk studies were planned. Quality assessments were summarized but not formally used as an exclusion criterion unless a study had insurmountable risk. Statistical Analysis Meta-analyses were conducted for outcomes reported in ≥2 studies using a random-effects model to account for between-study variability. For continuous outcomes (e.g. attack frequency, pain intensity, quality-of-life scores), we calculated the standardized mean difference (SMD) with 95% confidence intervals (CI) comparing neuromodulation vs control. For dichotomous outcomes (e.g. responder rate, adverse events), odds ratios (ORs) with 95% CIs were calculated. Between-study heterogeneity was assessed with the I² statistic and Cochran’s Q-test. An I² >50% was considered moderate-to-high heterogeneity. If medians (with IQR or range) were reported, these were converted to means±SDs using published methods. Forest plots were generated for each pooled outcome. Due to the small number of studies for most outcomes, formal tests for publication bias were not performed. Analyses were performed using standard meta-analysis software using RevMan. Results Study Selection and Screening The initial search of the database yielded 1987 papers. After the removal of duplicates and applying the inclusion criteria, a total of 45 studies for selected for full-text analysis. Based on the methodological quality assessment and inclusion and exclusion criteria, a total of 10 articles finally met the criteria to be included in this systematic review. Figure 1 presents the detailed PRISMA flowchart diagram of the selection process of the included studies. Study Characteristics: The characteristics of all the included studies are given in Table 2. Risk Of Bias: Risk of Bias of RCTs was assessed using the ROB-2 tool. The traffic light plot is given below (Figure 2). Quality Assessment: The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS), which allocates stars based on three domains: Selection (0-4 stars), Comparability (0-2 stars), and Outcome (0-3 stars), making it a total of 9 stars ( Table 3). META-ANALYSIS (i) Attacks/week: Two studies (Fontaine et al., 2010; Silberstein et al., 2016) reported data on the effect of neuromodulation on the weekly duration of cluster headache attacks. The pooled analysis, including 82 patients in the experimental group and 79 in the control group, demonstrated no significant difference between neuromodulation and control interventions (SMD: –0.05; 95% CI: –0.36 to 0.26; p = 0.75). Individual study results were consistent, with Fontaine et al. (2010) favoring neuromodulation (SMD: 0.18; 95% CI: –1.01 to 1.37), whereas Silberstein et al. (2016) showed a slight, non-significant effect in favor of the control group (SMD: –0.07; 95% CI: –0.39 to 0.25). No heterogeneity was detected among the included studies (I² = 0%). Overall, the findings suggest that neuromodulation does not significantly reduce the weekly duration of cluster headache attacks compared to control interventions ( Figure 3). (ii) Adverse Effects: Five studies (Fontaine et al., 2010; Schoenen et al., 2013; Gaul et al., 2015; Silberstein et al., 2016; Guo et al., 2018) reported the occurrence of adverse effects associated with neuromodulation. A total of 346 patients in the experimental group and 337 in the control group were analyzed. The pooled results showed no statistically significant difference in the risk of adverse effects between neuromodulation and control interventions (OR: 1.38; 95% CI: 0.37–5.08; p = 0.63). Considerable heterogeneity was observed across studies (I² = 91%, p < 0.00001), reflecting substantial variability in reported adverse events and their definitions. Individually, Fontaine et al. (2010), Silberstein et al. (2016), and Guo et al. (2018) suggested a higher—but not statistically significant—risk of adverse effects in the neuromodulation group, while Schoenen et al. (2013) favored the control group. Gaul et al. (2015) reported nearly equivalent risks between the two groups. Overall, these findings indicate that while adverse effects are relatively common in neuromodulation trials, the pooled evidence does not demonstrate a significant difference compared to controls, though the high heterogeneity warrants cautious interpretation (Figure 4). (iii) Facial Flushing: The pooled analysis of facial flushing (Figure 5) suggested a higher incidence in the neuromodulation group compared to controls. However, the confidence interval for the odds ratio crossed unity, indicating no statistically significant difference. Heterogeneity among studies was moderate, likely reflecting variation in stimulation protocols (e.g. vagus nerve vs. trigeminal) and in reporting of this autonomic side effect. Clinically, facial flushing is generally a mild and transient parasympathetic phenomenon; thus even a modest increase in its risk is not expected to be of major concern. In practice, patients or clinicians may note flushing, but it typically does not necessitate discontinuation of therapy (Figure 5). (iv) Pain Intensity: Two studies (Fontaine et al., 2010; Silberstein et al., 2016) evaluated the effect of neuromodulation on pain intensity among patients with cluster headache. The pooled analysis of 82 patients in the experimental group and 79 in the control group demonstrated a non-significant trend toward reduction in pain intensity with neuromodulation compared to controls (SMD: –0.26; 95% CI: –0.57 to 0.05; p = 0.10). Individual study results were consistent, with Fontaine et al. (2010) showing a small, non-significant effect in favor of the control group (SMD: 0.05; 95% CI: –1.14 to 1.24), while Silberstein et al. (2016) demonstrated a slight reduction in pain intensity favoring neuromodulation (SMD: –0.28; 95% CI: –0.60 to 0.04). No heterogeneity was detected (I² = 0%). Overall, the results suggest that neuromodulation may contribute to a modest reduction in pain intensity; however, the effect did not reach statistical significance (Figure 6). (v) Quality Of Life: Two studies (Fontaine et al., 2010; Silberstein et al., 2016) were included in the quantitative synthesis, evaluating the efficacy of neuromodulation in cluster headache compared to control. The pooled analysis demonstrated a significant benefit of neuromodulation, with a standardized mean difference (SMD) of –0.50 (95% CI: –0.82 to –0.19; p = 0.002), indicating a moderate effect size favoring the experimental intervention. There was no evidence of statistical heterogeneity between studies (Chi² = 0.00, df = 1, p = 0.96; I² = 0%). The forest plot (Figure 7) illustrates that both included studies consistently favored neuromodulation over control, and the overall effect was statistically significant, reinforcing the robustness of these findings. Discussion This systematic review and meta-analysis examined the clinical effects of neuromodulation therapies in patients with cluster headache across 10 included studies. Overall, pooled estimates did not show a statistically significant reduction in headache attack frequency or intensity with neuromodulation compared to controls. For example, the combined standardized mean difference (SMD) for weekly attack frequency was essentially null (SMD ≈–0.05, 95% CI − 0.36 to 0.26; p = 0.75), indicating no appreciable change (Fig. 3 ). Likewise, pain intensity trended slightly lower in the neuromodulation group (pooled SMD ≈–0.26) but this did not reach statistical significance (95% CI − 0.57 to 0.05). By contrast, neuromodulation was associated with a moderate improvement in patient-reported quality-of-life measures (pooled SMD ≈–0.50, 95% CI − 0.82 to − 0.19; p = 0.002), favoring the intervention (Fig. 7 ). The overall risk of adverse events was similar between neuromodulation and control (pooled OR ≈ 1.38, 95% CI 0.37–5.08; p = 0.63), although heterogeneity was high (I²≈91%), reflecting wide variation in how studies reported and defined adverse outcomes (Fig. 4 ). In summary, our meta-analyses suggest that neuromodulation may improve certain patient-centered outcomes (notably quality of life) despite having limited effect on core headache frequency and intensity. These findings partly align with prior literature. Fernández-Hernando et al. (2023) conducted a systematic review of non-invasive vagus nerve stimulation (nVNS) in cluster headache and found moderate-to-high-quality evidence that nVNS can reduce headache frequency and intensity [ 18 ]. Our analysis, which included a broader array of neuromodulation modalities, did not confirm a significant frequency reduction; this discrepancy may reflect differences in included therapies or endpoints. Similarly, a narrative review recently noted that neuromodulation therapies in chronic cluster headache generally show reduced attack frequency and intensity across studies [ 19 ]. The modest effects observed here (particularly on quality of life) may be consistent with that narrative, but our pooled data highlight that robust, statistically significant effects on headache metrics remain elusive. In contrast, invasive neuromodulation modalities have sometimes shown larger effects. A recent meta-analysis of hypothalamic deep brain stimulation (DBS) for chronic cluster headache (16 studies, 108 patients) demonstrated significant reductions in both attack frequency and intensity (p < 0.0001) [ 20 ]. That analysis reported about 70% of carefully selected patients achieving “excellent” headache control post-DBS, albeit with a 16.7% major complication rate [ 20 ]. Our review included some DBS case series within the observational studies; however, the difference in magnitude of effect likely reflects the highly refractory patient selection and open-label design in those studies. Occipital nerve stimulation (ONS), another invasive approach, has also been reported effective. For example, Kollenburg et al. (2024) found that 70% of patients receiving ONS for refractory chronic cluster headache were classified as responders (≥ 50% improvement) at 1-year follow-up [ 21 ], supporting ONS’s utility. Likewise, multiple reviews have characterized ONS as a viable option for drug-resistant CH. The subgroup of patients who use their implanted ONS device to self-adjust stimulation (“voltage tuners”) may gain additional benefit by aborting attacks, suggesting unexploited potential for acute use [ 21 ]. Sphenopalatine ganglion (SPG) stimulation is yet another modality that has shown promise. Reviews have documented that SPG-targeted stimulation can acutely abort attacks and may have preventative effects with repeated use. In particular, an early SPG trial demonstrated [ 22 ]significant acute pain relief and some reduction in attack frequency, and long-term follow-up suggests maintained efficacy with minimal side effects. Our analysis did not separately meta-analyze SPG outcomes (due to limited RCT data), but our aggregate result that quality of life improved may capture some benefit from such neuromodulation.Against this background, our neutral findings on attack frequency and intensity may stem from heterogeneity across modalities and study designs. Many included trials were small (often n < 30 per group) and some were open-label or single-blind, reducing power. The timing of outcome measurement also varied. In contrast, large cohort studies of DBS or ONS often report more dramatic improvements, but these lack randomization. Notably, we observed a statistically significant quality-of-life benefit with neuromodulation (Fig. 7 ). This suggests that even if attack counts did not fall appreciably, patients felt meaningfully better overall. That improvement might be mediated by even modest symptom relief, improved coping, or placebo effects of an active device. It is supported by prior evidence that cluster headache severely impairs life quality, and any reduction in symptom burden can translate into improved well-being [ 23 ]. This review used a comprehensive search and explicit inclusion criteria to capture all relevant trials of neuromodulation in CH. Inclusion of both RCTs and prospective cohorts allowed us to summarize a broad evidence base. We rigorously assessed study quality using Cochrane RoB2 and NOS tools, and extracted all relevant data. However, several limitations affect our conclusions. First, the total number of high-quality trials is small, and sample sizes were limited, which reduces statistical power. Second, the included studies evaluated heterogeneous devices (ranging from non-invasive stimulators to implanted systems) and protocols, complicating direct comparisons. Third, many studies were not double-blinded (especially surgical series), introducing risk of bias and placebo effects. Fourth, some outcomes were sparsely reported; for example, only two trials contributed to the QoL meta-analysis. Fifth, we converted median-based data into means for pooling, which relies on assumptions and may introduce estimation error. Finally, high heterogeneity (especially in adverse event analysis) means pooled estimates should be interpreted cautiously. Due to the small number of trials, we could not formally assess publication bias, and unpublished negative results (if any) could exist. Additional rigorous research is needed. Large, multicenter RCTs comparing neuromodulation devices to sham or optimal medical therapy would provide more definitive evidence. Trials should use standardized outcome measures (consistent definitions of responder, attack frequency, and validated quality-of-life instruments) to enhance comparability. Long-term follow-up is crucial, given the chronic nature of cluster headache. Subgroup analyses to identify patient characteristics predicting response (e.g. episodic vs chronic CH, biomarkers, imaging findings) would help target therapies. Comparative effectiveness studies (e.g. head-to-head trials of different neuromodulation techniques) are also warranted. Mechanistic studies could clarify how neuromodulation modulates pain pathways in CH. Finally, cost-effectiveness analyses would be valuable given the expense of implantable devices. Conclusion In summary, our systematic review found that neuromodulation therapies for cluster headache were generally well tolerated and improved patient quality of life, but did not significantly reduce attack frequency or intensity in the pooled analysis. This suggests that while neuromodulation may offer symptomatic benefit, the evidence for robust headache suppression is limited. These results are consistent with prior reviews that have noted positive trends but emphasized the need for larger trials. Until more definitive data emerge, neuromodulation should be considered on a case-by-case basis, ideally in refractory patients and within research settings. Further high-quality studies will be essential to clarify the true efficacy and optimal use of these therapies in cluster headache. Declarations Funding: The authors received no specific funding for this work. Conflicts of interest / Competing interests: The authors declare that they have no competing interests. Ethics approval: Not applicable. This study is a systematic review and meta-analysis of previously published studies. Consent to participate: Not applicable. Written consent for publication: Not applicable. Availability of data and material: All data analyzed in this study are derived from published articles and are included within the manuscript and its supplementary materials. Code availability: Not applicable. Authors’ contributions: All authors contributed to the study conception and design. Literature search, data extraction, and analysis were performed by the authors. All authors critically revised the manuscript and approved the final version. References Leroux E, Ducros A. Cluster headache. Orphanet J Rare Dis. 2008;3:20. May A, Schwedt TJ, Magis D, Pozo-Rosich P, Evers S, Wang SJ. Cluster headache. Nat Reviews Disease Primers. 2018;4:18006. Leone M, Bussone G. A review of the pharmacotherapy of cluster headache. Expert Opin Pharmacother. 2009;10(9):1519–26. Schwedt TJ, Vargas B. Neurostimulation for refractory headache disorders. Headache: J Head Face Pain. 2015;55(3):512–25. 1177/0333102415607070. Haddaway NR, Page MJ, Pritchard CC, McGuinness LA. (2022). 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Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Tables.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 05 Mar, 2026 Reviews received at journal 05 Mar, 2026 Reviewers agreed at journal 01 Mar, 2026 Reviews received at journal 03 Feb, 2026 Reviewers agreed at journal 25 Jan, 2026 Reviewers agreed at journal 24 Jan, 2026 Reviewers invited by journal 21 Jan, 2026 Editor assigned by journal 21 Jan, 2026 Submission checks completed at journal 21 Jan, 2026 First submitted to journal 28 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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1","display":"","copyAsset":false,"role":"figure","size":128593,"visible":true,"origin":"","legend":"\u003cp\u003eThe flowchart of the reviewed studies according to PRISMA\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8467974/v1/0a1beafb0f92dcd7be11b74e.png"},{"id":101205847,"identity":"3882e42d-2400-4a8d-ae32-cac83e0494b0","added_by":"auto","created_at":"2026-01-27 09:50:24","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":180190,"visible":true,"origin":"","legend":"\u003cp\u003eTraffic Light Plot of ROB\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8467974/v1/2d3442231dc00ef4bb5f8db0.png"},{"id":101170478,"identity":"ef5d4b94-18ac-45f1-a892-a474bf840d58","added_by":"auto","created_at":"2026-01-27 00:03:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":42174,"visible":true,"origin":"","legend":"\u003cp\u003eForest Plot of Attacks/week\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8467974/v1/fb5718edf8c3c0b7aae49fd4.png"},{"id":101170479,"identity":"3625585a-b18f-448a-b142-460dffd91c89","added_by":"auto","created_at":"2026-01-27 00:03:08","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":87575,"visible":true,"origin":"","legend":"\u003cp\u003eForest Plot of Adverse Effects\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8467974/v1/9a0c3e13f6112d902adaa421.png"},{"id":101205824,"identity":"e5b25dfc-1efa-4278-80f5-f0102e9bcee4","added_by":"auto","created_at":"2026-01-27 09:50:20","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":73904,"visible":true,"origin":"","legend":"\u003cp\u003eForest Plot of Facial Flushing\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-8467974/v1/df8be8ff76855f92a076ada7.png"},{"id":101170474,"identity":"023270d0-d16e-4ee1-9a4c-f4b7eb9579d7","added_by":"auto","created_at":"2026-01-27 00:03:08","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":42480,"visible":true,"origin":"","legend":"\u003cp\u003eForest Plot of Pain Intensity\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-8467974/v1/aea5eddaf999ccc72e897010.png"},{"id":101170482,"identity":"807cb7e9-7a7f-4df7-a4f2-19ffe11c3314","added_by":"auto","created_at":"2026-01-27 00:03:08","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":42334,"visible":true,"origin":"","legend":"\u003cp\u003eForest Plot of Quality of Life\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-8467974/v1/7651ecbf8dcbc286fd7d84a1.png"},{"id":101297080,"identity":"1c55a14d-cc53-486b-b190-42ab8dccce10","added_by":"auto","created_at":"2026-01-28 09:25:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1143839,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8467974/v1/d31983cf-f22e-41b1-ab60-4c71c814a3ff.pdf"},{"id":101206608,"identity":"a21d302c-b134-41f1-ad69-be66f76c1199","added_by":"auto","created_at":"2026-01-27 09:56:32","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":21921,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8467974/v1/68e9c20a83b770560fe3b5d0.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Neuromodulation in the Management of Cluster Headaches: a Systematic Review and Meta-Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePrimary headache disorders represent a major source of neurological morbidity, among which cluster headache stands out as one of the most intense and debilitating. It predominantly affects men and is marked by sudden, unilateral periorbital attacks lasting up to three hours. These attacks are often distinctively accompanied by the presence of ipsilateral autonomic symptoms such as lacrimation, conjunctival injection, nasal congestion, rhinorrhea, and, occasionally, partial Horner\u0026rsquo;s syndrome manifested by ptosis and miosis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e][\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] .\u003c/p\u003e \u003cp\u003eCurrent initial management measures include high-flow oxygen and tripitans (e.g., sumatripitan), while verapamil remains to serve as the cornerstone of preventive therapy [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Despite these established treatment approaches, a percentage of patients still experience refractory attacks that limit responses to both standard abortive and preventive medications. This clinical gap has shifted attention and prompted exploration toward neuromodulatory-based strategies that modulate pain-processing pathways.\u003c/p\u003e \u003cp\u003eNeuromodulation has emerged as a valuable therapeutic option for certain patients with chronic cluster headaches that are medically intractable. A spectrum of techniques have been explored, including deep brain stimulation (DBS), occipital nerve stimulation (ONS), vagus nerve stimulation (VNS), sphenopaplatine ganglion stimulation (SPG), and transcranial magnetic stimulation (TMS). Preliminary studies have reported favorable results in a subset of patients with refractory disease; however, findings demonstrate inconsistency and substantial heterogeneity, and the sustained effectiveness and safety profile of these modalities lack validation [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis systematic review and meta-analysis intends to integrate data from randomized and prospective studies evaluating the efficacy and safety of neuromodulation in managing cluster headaches. It specifically aims to focus on assessing the outcomes related to changes in pain severity, quality of life, and adverse events.\u003c/p\u003e"},{"header":"Methods \u0026 Materials","content":"\u003cp\u003e\u003cstrong\u003eSearch Strategy:\u003c/strong\u003e A systematic literature search was performed to identify studies evaluating neuromodulation in adult patients (\u0026ge;18 years) with episodic or chronic cluster headache (CH). Multiple electronic databases (PubMed/MEDLINE, Cochrane Library, Web of Science, and Google Scholar) were searched from inception through September 2025. Search terms included MeSH and free-text variants of \u0026ldquo;cluster headache,\u0026rdquo; \u0026ldquo;trigeminal autonomic cephalalgia,\u0026rdquo; combined with \u0026ldquo;neuromodulation,\u0026rdquo; \u0026ldquo;vagus nerve stimulation,\u0026rdquo; \u0026ldquo;deep brain stimulation,\u0026rdquo; \u0026ldquo;occipital nerve stimulation,\u0026rdquo; \u0026ldquo;transcranial magnetic stimulation,\u0026rdquo; \u0026ldquo;sphenopalatine ganglion stimulation,\u0026rdquo; and related terms. Synonyms and Boolean operators were used to ensure sensitivity (e.g. \u003cem\u003e(\u0026ldquo;cluster headache\u0026rdquo; OR \u0026ldquo;trigeminal autonomic cephalalgia\u0026rdquo;) AND (\u0026ldquo;neuromodulation\u0026rdquo; OR \u0026ldquo;stimulation\u0026rdquo;)\u003c/em\u003e). The search was restricted to English-language, peer-reviewed articles. References of key articles were hand-searched to identify additional studies. The review was conducted in accordance with PRISMA guidelines [5]. The protocol was prospectively registered in PROSPERO registration number : ( CRD420251023329) .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion and Exclusion Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEligibility criteria were defined a priori. We included randomized controlled trials (RCTs), prospective cohort studies, and case-control studies that enrolled adults with a confirmed diagnosis of cluster headache (per ICHD criteria) and evaluated any neuromodulation therapy (including non-invasive cervical or auricular vagus nerve stimulation, hypothalamic deep brain stimulation, occipital or peripheral nerve stimulation, transcranial magnetic stimulation, sphenopalatine ganglion stimulation, etc.). Eligible studies compared neuromodulation to sham/placebo or standard medical therapy (e.g. oxygen, verapamil). Studies were required to report at least one clinical outcome of interest (attack frequency, pain intensity, attack duration, responder rate, quality-of-life or disability scores, or adverse events) with a minimum follow-up of four weeks. Only studies in adults (\u0026ge;18 years) were included. We excluded non-comparative reports (case series without a control group), reviews, editorials, animal studies, and trials in pediatric patients. Studies lacking sufficient outcome data or details of the neuromodulation protocol were also excluded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Extraction and Management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo reviewers independently screened titles and abstracts of all retrieved records for eligibility; the title and abstracts were screened between \u003cstrong\u003eMarch 2025 and April 2025\u003c/strong\u003e. Full texts of potentially relevant studies were obtained and reviewed against inclusion criteria that were also screened between \u003cstrong\u003eMarch 2025 and April 2025\u003c/strong\u003e . Disagreements were resolved by discussion or by consulting a third reviewer. Data were extracted using a standardized form. Extracted information included study design, year, setting, sample size, and patient characteristics (age, sex, episodic vs chronic CH). Intervention details (type of neuromodulation device, stimulation parameters, duration) and comparators were recorded. Key outcomes extracted were change in headache attack frequency (per week or month), pain intensity (e.g. on visual analog or numeric rating scales), attack duration, responder rates (e.g. \u0026ge;50% reduction in frequency), quality-of-life measures (e.g. SF-36 or disease-specific scores), and adverse events (including specific events such as facial flushing). When possible, end-of-study or change values (means and SD) were recorded; if outcomes were reported in medians (with interquartile ranges or range), these were converted to approximate means and standard deviations using established methods. All data were checked for consistency and completeness.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuality Assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo reviewers independently assessed the risk of bias for each included study. For RCTs, we used the Cochrane Risk of Bias 2.0 tool [6] (assessing domains such as randomization, deviations from intended interventions, missing outcome data, outcome measurement, and selective reporting). For observational cohort or case-control studies, the Newcastle\u0026ndash;Ottawa Scale (NOS) [7] was applied (evaluating selection, comparability, and outcome/exposure ascertainment). Disagreements were resolved by discussion. Studies judged to have a high risk of bias (e.g. serious flaws in design or conduct) were noted; sensitivity analyses excluding high-risk studies were planned. Quality assessments were summarized but not formally used as an exclusion criterion unless a study had insurmountable risk.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMeta-analyses were conducted for outcomes reported in \u0026ge;2 studies using a random-effects model to account for between-study variability. For continuous outcomes (e.g. attack frequency, pain intensity, quality-of-life scores), we calculated the standardized mean difference (SMD) with 95% confidence intervals (CI) comparing neuromodulation vs control. For dichotomous outcomes (e.g. responder rate, adverse events), odds ratios (ORs) with 95% CIs were calculated. Between-study heterogeneity was assessed with the I\u0026sup2; statistic and Cochran\u0026rsquo;s Q-test. An I\u0026sup2; \u0026gt;50% was considered moderate-to-high heterogeneity. If medians (with IQR or range) were reported, these were converted to means\u0026plusmn;SDs using published methods. Forest plots were generated for each pooled outcome. Due to the small number of studies for most outcomes, formal tests for publication bias were not performed. Analyses were performed using standard meta-analysis software using RevMan.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eStudy Selection and Screening\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe initial search of the database yielded 1987 papers. After the removal of duplicates and applying the inclusion criteria, a total of 45 studies for selected for full-text analysis. \u0026nbsp;Based on the methodological quality assessment and inclusion and exclusion criteria, a total of 10 articles finally met the criteria to be included in this systematic review. Figure 1 presents the detailed PRISMA flowchart diagram of the selection process of the included studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Characteristics:\u0026nbsp;\u003c/strong\u003eThe characteristics of all the included studies are given in Table 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk Of Bias:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRisk of Bias of RCTs was assessed using the ROB-2 tool. The traffic light plot is given below (Figure 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuality Assessment:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS), which allocates stars based on three domains: Selection (0-4 stars), Comparability (0-2 stars), and Outcome (0-3 stars), making it a total of 9 stars ( Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMETA-ANALYSIS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e(i) Attacks/week:\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo studies (Fontaine et al., 2010; Silberstein et al., 2016) reported data on the effect of neuromodulation on the weekly duration of cluster headache attacks. The pooled analysis, including 82 patients in the experimental group and 79 in the control group, demonstrated no significant difference between neuromodulation and control interventions (SMD: \u0026ndash;0.05; 95% CI: \u0026ndash;0.36 to 0.26; \u003cem\u003ep\u003c/em\u003e = 0.75). Individual study results were consistent, with Fontaine et al. (2010) favoring neuromodulation (SMD: 0.18; 95% CI: \u0026ndash;1.01 to 1.37), whereas Silberstein et al. (2016) showed a slight, non-significant effect in favor of the control group (SMD: \u0026ndash;0.07; 95% CI: \u0026ndash;0.39 to 0.25). No heterogeneity was detected among the included studies (I\u0026sup2; = 0%). Overall, the findings suggest that neuromodulation does not significantly reduce the weekly duration of cluster headache attacks compared to control interventions ( Figure 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e(ii) Adverse Effects:\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFive studies (Fontaine et al., 2010; Schoenen et al., 2013; Gaul et al., 2015; Silberstein et al., 2016; Guo et al., 2018) reported the occurrence of adverse effects associated with neuromodulation. A total of 346 patients in the experimental group and 337 in the control group were analyzed. The pooled results showed no statistically significant difference in the risk of adverse effects between neuromodulation and control interventions (OR: 1.38; 95% CI: 0.37\u0026ndash;5.08; \u003cem\u003ep\u003c/em\u003e = 0.63). Considerable heterogeneity was observed across studies (I\u0026sup2; = 91%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.00001), reflecting substantial variability in reported adverse events and their definitions. Individually, Fontaine et al. (2010), Silberstein et al. (2016), and Guo et al. (2018) suggested a higher\u0026mdash;but not statistically significant\u0026mdash;risk of adverse effects in the neuromodulation group, while Schoenen et al. (2013) favored the control group. Gaul et al. (2015) reported nearly equivalent risks between the two groups. Overall, these findings indicate that while adverse effects are relatively common in neuromodulation trials, the pooled evidence does not demonstrate a significant difference compared to controls, though the high heterogeneity warrants cautious interpretation (Figure 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;(iii) Facial Flushing:\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe pooled analysis of facial flushing (Figure 5) suggested a higher incidence in the neuromodulation group compared to controls. However, the confidence interval for the odds ratio crossed unity, indicating no statistically significant difference. Heterogeneity among studies was moderate, likely reflecting variation in stimulation protocols (e.g. vagus nerve vs. trigeminal) and in reporting of this autonomic side effect. Clinically, facial flushing is generally a mild and transient parasympathetic phenomenon; thus even a modest increase in its risk is not expected to be of major concern. In practice, patients or clinicians may note flushing, but it typically does not necessitate discontinuation of therapy (Figure 5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e(iv) Pain Intensity:\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo studies (Fontaine et al., 2010; Silberstein et al., 2016) evaluated the effect of neuromodulation on pain intensity among patients with cluster headache. The pooled analysis of 82 patients in the experimental group and 79 in the control group demonstrated a non-significant trend toward reduction in pain intensity with neuromodulation compared to controls (SMD: \u0026ndash;0.26; 95% CI: \u0026ndash;0.57 to 0.05; \u003cem\u003ep\u003c/em\u003e = 0.10). Individual study results were consistent, with Fontaine et al. (2010) showing a small, non-significant effect in favor of the control group (SMD: 0.05; 95% CI: \u0026ndash;1.14 to 1.24), while Silberstein et al. (2016) demonstrated a slight reduction in pain intensity favoring neuromodulation (SMD: \u0026ndash;0.28; 95% CI: \u0026ndash;0.60 to 0.04). No heterogeneity was detected (I\u0026sup2; = 0%). Overall, the results suggest that neuromodulation may contribute to a modest reduction in pain intensity; however, the effect did not reach statistical significance (Figure 6).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e(v) Quality Of Life:\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo studies (Fontaine et al., 2010; Silberstein et al., 2016) were included in the quantitative synthesis, evaluating the efficacy of neuromodulation in cluster headache compared to control. The pooled analysis demonstrated a significant benefit of neuromodulation, with a standardized mean difference (SMD) of \u0026ndash;0.50 (95% CI: \u0026ndash;0.82 to \u0026ndash;0.19; p = 0.002), indicating a moderate effect size favoring the experimental intervention. There was no evidence of statistical heterogeneity between studies (Chi\u0026sup2; = 0.00, df = 1, p = 0.96; I\u0026sup2; = 0%).\u003c/p\u003e\n\u003cp\u003eThe forest plot (Figure 7) illustrates that both included studies consistently favored neuromodulation over control, and the overall effect was statistically significant, reinforcing the robustness of these findings.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis systematic review and meta-analysis examined the clinical effects of neuromodulation therapies in patients with cluster headache across 10 included studies. Overall, pooled estimates did not show a statistically significant reduction in headache attack frequency or intensity with neuromodulation compared to controls. For example, the combined standardized mean difference (SMD) for weekly attack frequency was essentially null (SMD \u0026asymp;\u0026ndash;0.05, 95% CI \u0026minus;\u0026thinsp;0.36 to 0.26; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.75), indicating no appreciable change (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Likewise, pain intensity trended slightly lower in the neuromodulation group (pooled SMD \u0026asymp;\u0026ndash;0.26) but this did not reach statistical significance (95% CI \u0026minus;\u0026thinsp;0.57 to 0.05). By contrast, neuromodulation was associated with a moderate improvement in patient-reported quality-of-life measures (pooled SMD \u0026asymp;\u0026ndash;0.50, 95% CI \u0026minus;\u0026thinsp;0.82 to \u0026minus;\u0026thinsp;0.19; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002), favoring the intervention (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). The overall risk of adverse events was similar between neuromodulation and control (pooled OR\u0026thinsp;\u0026asymp;\u0026thinsp;1.38, 95% CI 0.37\u0026ndash;5.08; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.63), although heterogeneity was high (I\u0026sup2;\u0026asymp;91%), reflecting wide variation in how studies reported and defined adverse outcomes (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). In summary, our meta-analyses suggest that neuromodulation may improve certain patient-centered outcomes (notably quality of life) despite having limited effect on core headache frequency and intensity. These findings partly align with prior literature. Fern\u0026aacute;ndez-Hernando et al. (2023) conducted a systematic review of non-invasive vagus nerve stimulation (nVNS) in cluster headache and found moderate-to-high-quality evidence that nVNS can reduce headache frequency and intensity [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Our analysis, which included a broader array of neuromodulation modalities, did not confirm a significant frequency reduction; this discrepancy may reflect differences in included therapies or endpoints. Similarly, a narrative review recently noted that neuromodulation therapies in chronic cluster headache generally show reduced attack frequency and intensity across studies [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The modest effects observed here (particularly on quality of life) may be consistent with that narrative, but our pooled data highlight that robust, statistically significant effects on headache metrics remain elusive. In contrast, invasive neuromodulation modalities have sometimes shown larger effects. A recent meta-analysis of hypothalamic deep brain stimulation (DBS) for chronic cluster headache (16 studies, 108 patients) demonstrated significant reductions in both attack frequency and intensity (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. That analysis reported about 70% of carefully selected patients achieving \u0026ldquo;excellent\u0026rdquo; headache control post-DBS, albeit with a 16.7% major complication rate [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Our review included some DBS case series within the observational studies; however, the difference in magnitude of effect likely reflects the highly refractory patient selection and open-label design in those studies. Occipital nerve stimulation (ONS), another invasive approach, has also been reported effective. For example, Kollenburg et al. (2024) found that 70% of patients receiving ONS for refractory chronic cluster headache were classified as responders (\u0026ge;\u0026thinsp;50% improvement) at 1-year follow-up [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], supporting ONS\u0026rsquo;s utility. Likewise, multiple reviews have characterized ONS as a viable option for drug-resistant CH. The subgroup of patients who use their implanted ONS device to self-adjust stimulation (\u0026ldquo;voltage tuners\u0026rdquo;) may gain additional benefit by aborting attacks, suggesting unexploited potential for acute use [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Sphenopalatine ganglion (SPG) stimulation is yet another modality that has shown promise. Reviews have documented that SPG-targeted stimulation can acutely abort attacks and may have preventative effects with repeated use. In particular, an early SPG trial demonstrated [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]significant acute pain relief and some reduction in attack frequency, and long-term follow-up suggests maintained efficacy with minimal side effects. Our analysis did not separately meta-analyze SPG outcomes (due to limited RCT data), but our aggregate result that quality of life improved may capture some benefit from such neuromodulation.Against this background, our neutral findings on attack frequency and intensity may stem from heterogeneity across modalities and study designs. Many included trials were small (often n\u0026thinsp;\u0026lt;\u0026thinsp;30 per group) and some were open-label or single-blind, reducing power. The timing of outcome measurement also varied. In contrast, large cohort studies of DBS or ONS often report more dramatic improvements, but these lack randomization. Notably, we observed a statistically significant quality-of-life benefit with neuromodulation (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). This suggests that even if attack counts did not fall appreciably, patients felt meaningfully better overall. That improvement might be mediated by even modest symptom relief, improved coping, or placebo effects of an active device. It is supported by prior evidence that cluster headache severely impairs life quality, and any reduction in symptom burden can translate into improved well-being [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis review used a comprehensive search and explicit inclusion criteria to capture all relevant trials of neuromodulation in CH. Inclusion of both RCTs and prospective cohorts allowed us to summarize a broad evidence base. We rigorously assessed study quality using Cochrane RoB2 and NOS tools, and extracted all relevant data. However, several limitations affect our conclusions. First, the total number of high-quality trials is small, and sample sizes were limited, which reduces statistical power. Second, the included studies evaluated heterogeneous devices (ranging from non-invasive stimulators to implanted systems) and protocols, complicating direct comparisons. Third, many studies were not double-blinded (especially surgical series), introducing risk of bias and placebo effects. Fourth, some outcomes were sparsely reported; for example, only two trials contributed to the QoL meta-analysis. Fifth, we converted median-based data into means for pooling, which relies on assumptions and may introduce estimation error. Finally, high heterogeneity (especially in adverse event analysis) means pooled estimates should be interpreted cautiously. Due to the small number of trials, we could not formally assess publication bias, and unpublished negative results (if any) could exist.\u003c/p\u003e \u003cp\u003eAdditional rigorous research is needed. Large, multicenter RCTs comparing neuromodulation devices to sham or optimal medical therapy would provide more definitive evidence. Trials should use standardized outcome measures (consistent definitions of responder, attack frequency, and validated quality-of-life instruments) to enhance comparability. Long-term follow-up is crucial, given the chronic nature of cluster headache. Subgroup analyses to identify patient characteristics predicting response (e.g. episodic vs chronic CH, biomarkers, imaging findings) would help target therapies. Comparative effectiveness studies (e.g. head-to-head trials of different neuromodulation techniques) are also warranted. Mechanistic studies could clarify how neuromodulation modulates pain pathways in CH. Finally, cost-effectiveness analyses would be valuable given the expense of implantable devices.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, our systematic review found that neuromodulation therapies for cluster headache were generally well tolerated and improved patient quality of life, but did not significantly reduce attack frequency or intensity in the pooled analysis. This suggests that while neuromodulation may offer symptomatic benefit, the evidence for robust headache suppression is limited. These results are consistent with prior reviews that have noted positive trends but emphasized the need for larger trials. Until more definitive data emerge, neuromodulation should be considered on a case-by-case basis, ideally in refractory patients and within research settings. Further high-quality studies will be essential to clarify the true efficacy and optimal use of these therapies in cluster headache.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors received no specific funding for this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest / Competing interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This study is a systematic review and meta-analysis of previously published studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWritten consent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data analyzed in this study are derived from published articles and are included within the manuscript and its supplementary materials.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Literature search, data extraction, and analysis were performed by the authors. All authors critically revised the manuscript and approved the final version.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLeroux E, Ducros A. Cluster headache. Orphanet J Rare Dis. 2008;3:20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMay A, Schwedt TJ, Magis D, Pozo-Rosich P, Evers S, Wang SJ. Cluster headache. Nat Reviews Disease Primers. 2018;4:18006.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeone M, Bussone G. A review of the pharmacotherapy of cluster headache. Expert Opin Pharmacother. 2009;10(9):1519\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchwedt TJ, Vargas B. Neurostimulation for refractory headache disorders. 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Cephalalgia: Int J headache. 2016;36(12):1149\u0026ndash;55. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/0333102416644968\u003c/span\u003e\u003cspan address=\"10.1177/0333102416644968\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFern\u0026aacute;ndez-Hernando D, Justrib\u0026oacute; Manion C, Pareja JA, Garc\u0026iacute;a-Esteo FJ, Mesa-Jim\u0026eacute;nez JA. Effects of Non-Invasive Neuromodulation of the Vagus Nerve for the Management of Cluster Headache: A Systematic Review. J Clin Med. 2023;12(19):6315. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/jcm12196315\u003c/span\u003e\u003cspan address=\"10.3390/jcm12196315\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"sn-comprehensive-clinical-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sncm","sideBox":"Learn more about [SN Comprehensive Clinical Medicine](https://www.springer.com/journal/42399)","snPcode":"42399","submissionUrl":"https://submission.nature.com/new-submission/42399/3","title":"SN Comprehensive Clinical Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Cluster headache, vagus nerve stimulation, occipital nerve stimulation, deep brain stimulation, transcranial magnetic stimulation, sphenopalatine ganglion stimulation","lastPublishedDoi":"10.21203/rs.3.rs-8467974/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8467974/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCluster headache is one of the primary types of headaches that is characterized by unilateral excessive pain that is mostly associated with autonomic symptoms. The management of cluster headache usually consists of high flow oxygen, triptans, and verapamil. The exploration of new methods, such as neuromodulation techniques are needed to look for possible alternatives for patients that remain refractory to all types of medications.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eDatabases including Pubmed, Cochrane, Web of Science, and Google Scholar were systematically reviewed through 2025 for studies involving adult patients (≥18 years) with cluster headache. The terms used for the search included (e.g., occipital nerve stimulation, vagus nerve stimulation, transcranial magnetic stimulation, sphenopalatine ganglion stimulation). The aim was to measure the outcomes of neuromodulation in reducing headache frequency and pain intensity, improving quality of life, and assessing adverse effects.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTen studies met the inclusion criteria. Meta-analysis showed no statistically significant difference in attack frequency (SMD: –0.05; 95% CI: –0.36 to 0.26; p = 0.75) or pain intensity (SMD: –0.26; 95% CI: –0.57 to 0.05; p = 0.10) between neuromodulation and control groups. However, neuromodulation was associated with a significant outcome in improving quality of life (SMD: –0.50; 95% CI: –0.82 to –0.19; p = 0.002). The overall risk of adverse events was comparable between groups (OR: 1.38; 95% CI: 0.37–5.08; p = 0.63), though, the heterogeneity was high in the studies\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNeuromodulation has been shown to improve the quality of life, specifically to the patients who are refractory to standard management of cluster headache, but it does not reduce the attack frequency or pain intensity. These modalities are generally safe, according to the evaluated high quality randomized trials.\u003c/p\u003e","manuscriptTitle":"Neuromodulation in the Management of Cluster Headaches: a Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-27 00:03:03","doi":"10.21203/rs.3.rs-8467974/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-05T21:37:11+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-05T21:33:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"89032812832726144404303078861297123094","date":"2026-03-01T17:40:46+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-03T16:48:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"327231367742967135541790191900300883885","date":"2026-01-25T17:34:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3228427199151649200883068138851081322","date":"2026-01-25T03:36:30+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-21T17:04:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-21T07:38:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-21T07:28:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"SN Comprehensive Clinical Medicine","date":"2025-12-28T22:29:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"sn-comprehensive-clinical-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sncm","sideBox":"Learn more about [SN Comprehensive Clinical Medicine](https://www.springer.com/journal/42399)","snPcode":"42399","submissionUrl":"https://submission.nature.com/new-submission/42399/3","title":"SN Comprehensive Clinical Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b49a4b62-1cbc-4ce5-8bc2-a3a243bd7f8b","owner":[],"postedDate":"January 27th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-13T15:55:42+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-27 00:03:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8467974","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8467974","identity":"rs-8467974","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}