Efficacy and Safety of Trigeminal Nerve Stimulation for Migraine: A Meta-Analysis of Randomized Controlled Studies

Abstract

Objective Trigeminal nerve stimulation may have some potential in treating migraine, and this meta-analysis aims to study the efficacy and safety of trigeminal nerve stimulation for migraine patients.

Methods We have searched several databases including PubMed, EMbase, Web of science, EBSCO and Cochrane library databases, and selected the randomized controlled trials (RCTs) comparing the efficacy of trigeminal nerve stimulation for migraine patients. This meta-analysis was conducted using the random-effect or fixed-effect model based on the heterogeneity.

Results Four RCTs were included in this meta-analysis. Compared with sham procedure in migraine patients, trigeminal neurostimulation benefited to improve pain freedom at 2 h (OR=2.69; 95% CI=1.30 to 5.56; P=0.007), pain relief at 2 h (OR=2.05; 95% CI=1.53 to 2.74; P<0.00001), pain freedom at 24 h (OR=2.00; 95% CI=1.42 to 2.81; P<0.0001) as well as pain relief at 24 h (OR=1.71; 95% CI=1.25 to 2.33; P=0.0007), and reduce rescue medication (OR=0.70; 95% CI=0.52 to 0.95; P=0.02), but demonstrated no obvious impact on the incidence of adverse events (OR=2.24; 95% CI=1.21 to 4.13; P=0.01).

Conclusions Trigeminal nerve stimulation is effective and safe for the treatment of migraine patients.

Zusammenfassung

Ziel Die Trigeminus-Nervenstimulation kann ein gewisses Potenzial bei der Behandlung von Migräne haben, und diese Meta-Analyse zielt darauf ab, die Wirksamkeit und Sicherheit der Trigeminus-Nervenstimulation bei Migränepatienten zu untersuchen.

Methoden Wir haben mehrere Datenbanken durchsucht, darunter PubMed, EMbase, Web of Science, EBSCO und Cochrane Bibliotheksdatenbanken und die randomisierten kontrollierten Studien (RCTs) ausgewählt, die die Wirksamkeit der trigeminalen Nervenstimulation bei Migränepatienten vergleichen. Diese Metaanalyse wurde anhand des Zufalls- oder Fixed-Effect-Modells basierend auf der Heterogenität durchgeführt.

Ergebnisse Vier RCTs wurden in diese Metaanalyse einbezogen. Im Vergleich zum Scheinverfahren bei Migränepatienten verbesserte die trigeminale Neurostimulation die Schmerzfreiheit bei 2 h (OR=2.69; 95% CI=1.30 bis 5.56; P=0.007), Schmerzlinderung bei 2 h (OR=2.05; 95% CI=1.53 bis 2.74; P<0.00001), Schmerzfreiheit bei 24 h (OR=2.00; 95% CI=1.42 bis 2.81; P<0.0001) sowie Schmerzlinderung bei 24 h (OR=1.71; CI=1.25% bis 5.56; P=0.007), und Rettungsmedikamente reduzieren (OR=0,70; 95% CI=0,52 bis 0,95; P=0,02), zeigten jedoch keinen offensichtlichen Einfluss auf die Inzidenz unerwünschter Ereignisse (OR=2,24; 95% CI=1,21 bis 4,13; P=0,01).

Schlussfolgerungen Trigeminale Nervenstimulation ist wirksam und sicher für die Behandlung von Migränepatienten.

Key words

headache - pain - physical therapies

Schlüsselwörter

Physikalische Medizin - Rehabilitation - Therapie

Introduction

Migraine has become one of the most common neurological disorders and is ranked as the world’s second leading cause of disability [1] [2] [3] [4] [5]. It is estimated that more than 1 billion people worldwide suffer from migraine, and three-quarters of them are women [6] [7]. The typical symptoms of migraine include recurrent attacks of headache, photophobia, phonophobia, nausea and vomiting [8] [9] [10]. Almost one-third of migraine patients are found to have relatively frequent attacks and need regular preventive treatment [11] [12].

Current first-line treatments for migraine patients include triptans, non-steroidal anti-inflammatory medications (NSAIDS), lasmiditan, and gepants (ubrogepant and rimegepant) [13] [14] [15] [16]. However, they may result in intolerable side effects, and should be contraindicated in patients with cardiovascular and/or cerebrovascular disease. In addition, these drugs can obtain little efficacy [17] [18] [19]. Thus, non-pharmacological approaches should be developed for migraine treatment [20] [21]. External trigeminal nerve stimulation is an increasingly important non-invasive therapeutic alternative for patients with migraine who do not respond to pharmacologic acute migraine therapies, or have intolerances/contraindications to pharmaceutical therapies [22] [23].

Recently, several studies reported the potential of trigeminal nerve stimulation for the treatment of migraine patients, but the results were not well established [23] [24] [25]. This meta-analysis of RCTs aims to explore the efficacy and safety of trigeminal nerve stimulation for the treatment of migraine patients.

Materials and Methods

This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement and Cochrane Handbook for Systematic Reviews of Interventions [26] [27]. No ethical approval and patient consent were required because all analyses were based on previous published studies.

Literature search and selection criteria

Search several databases were systematically searched from inception to December 2022 by using the keywords: “trigeminal nerve stimulation” OR “TNS” AND “migraine”. They included PubMed, EMbase, Web of science, EBSCO and the Cochrane library. The inclusion criteria were presented as follows: (1) study design was RCT, (2) patients were diagnosed with migraine, and (3) intervention treatments were trigeminal nerve stimulation versus sham. Trigeminal stimulation device provided the investigational arm administered symmetrical biphasic waveforms for the bilateral V1 ophthalmic trigeminal branches.

Data extraction and outcome measures

We extracted the baseline information including first author, number of patients, age, female, migraine with aura and detail methods in two groups. Data were extracted independently by two investigators, and discrepancies were resolved by consensus. The primary outcomes were pain freedom at 2 h and pain relief at 2 h. Secondary outcomes included pain freedom at 24 h, pain relief at 24 h, rescue medication and adverse events.

Quality assessment in individual studies

We evaluated the methodological quality of each RCT based on Jadad Scale consisting of three evaluation elements: randomization (0–2 points), blinding (0–2 points), dropouts and withdrawals (0–1 points) [28]. One point would be allocated to each element if they were conducted and mentioned appropriately in the original article. The score of Jadad Scale varied from 0 to 5 points. Jadad score≤2 suggested low quality, while Jadad score≥3 indicated high quality [29].

Statistical analysis

Odd ratio (OR) with 95% confidence intervals (CIs) was used to evaluate dichotomous outcomes. Heterogeneity was evaluated using the I² statistic, and I²>50% indicated significant heterogeneity [30]. This meta-analysis was performed by using the random-effect model for significant heterogeneity, and otherwise fixed-effect model was used. Sensitivity analysis was conducted to detect the influence of a single study on the overall estimate via omitting one study in turn or performing the subgroup analysis. Publication bias was not assessed due to the limited number (<10) of included studies. Results with P<0.05 were considered to have significant difference. All statistical analyses were performed using Review Manager Version 5.3 (The Cochrane Collaboration, Software Update, Oxford, UK).

Results

Literature search, study characteristics and quality assessment

The detail flowchart of the search and selection results was presented in [Fig. 1]. Initially, 258 potentially relevant articles were found and four RCTs were finally eligible for this meta-analysis [23] [24] [25] [31].

Fig. 1 Flow diagram of study searching and selection process.

The baseline characteristics of four included RCTs were shown in [Table 1]. These studies were published between 2019 and 2022, and the total sample size was 808. Four RCTs reported pain freedom at 2 h, pain relief at 2 h and pain freedom at 24 h [23] [24] [25] [31], three RCTs reported pain relief at 24 h [23] [25] [31], three RCTs reported rescue medication [23] [24] [31] and four RCTs reported adverse events [23] [24] [25] [31]. Jadad scores of the four included studies varied from 4 to 5, and all four studies had high quality based on the quality assessment.

Table 1 Characteristics of included studies.

NO.	Author	Trigeminal neurostimulation group					Control group					Jadad scores
		Number	Age (years)	Female (n)	Migraine with aura (n)	Methods	Number	Age (years)	Female (n)	Migraine with aura (n)	Methods
1	Tepper 2022	50	40.3±12.7	58	26	external concurrent occipital and trigeminal device	59	39.9±13.03	51	23	sham	5
2	Kuruvilla 2022	259	40.22±11.62	214	113	external trigeminal nerve stimulation	279	42.0±12.30	229	111	sham	4
3	Daniel 2022	27	29.2±8.6	22	–	external combined occipital and trigeminal neurostimulation	28	30.8±8.2	5	–	sham	4
4	Chou 2019	52	39.71±13.62	43	12	external trigeminal nerve stimulation	54	40.09±12.65	49	5	sham	4

Primary outcomes: pain freedom at 2 h and pain relief at 2 h

The results unraveled that compared to sham procedure in migraine patients, trigeminal neurostimulation resulted in significantly improved pain freedom at 2 h (OR=2.69; 95% CI=1.30 to 5.56; P=0.007) with significant heterogeneity among the studies (I²=60%, heterogeneity P=0.06, [Fig. 2]) and pain relief at 2 h (OR=2.05; 95% CI=1.53 to 2.74; P<0.00001) with low heterogeneity among the studies (I²=24%, heterogeneity P=0.27, [Fig. 3]).

Fig. 2 Forest plot for the meta-analysis of pain freedom at 2 h.

Fig. 3 Forest plot for the meta-analysis of pain relief at 2 h.

Sensitivity analysis

Significant heterogeneity was seen for pain freedom at 2 h. As shown in [Fig. 2], the study conducted by Kuruvilla et al. showed results that were almost out of range of the others and probably contributed to the heterogeneity [23]. After excluding this study, the results suggested that trigeminal neurostimulation still benefited to increase pain freedom at 2 h (OR=4.02; 95% CI=2.09 to 7.73; P<0.0001), and no heterogeneity remained (I²=0, P=0.45).

Secondary outcomes

In comparison with control group in migraine patients, trigeminal neurostimulation was associated with substantially increased pain freedom at 24 h (OR=2.00; 95% CI=1.42 to 2.81; P<0.0001; [Fig. 4]) and pain relief at 24 h (OR=1.71; 95% CI=1.25 to 2.33; P=0.0007; [Fig. 5]), as well as decreased rescue medication (OR=0.70; 95% CI=0.52 to 0.95; P=0.02; [Fig. 6]), but showed no obvious impact on the incidence of adverse events (OR=2.24; 95% CI=1.21 to 4.13; P=0.01; [Fig. 7]).

Fig. 4 Forest plot for the meta-analysis of pain freedom at 24 h.

Fig. 5 Forest plot for the meta-analysis of pain relief at 24 h.

Fig. 6 Forest plot for the meta-analysis of rescue medication.

Fig. 7 Forest plot for the meta-analysis of adverse events.

Discussion

In order to confirm the efficacy and safety of trigeminal neurostimulation for migraine patients, our meta-analysis included four RCTs and 808 migraine patients. The results confirmed that compared to control intervention, trigeminal neurostimulation could significantly improve pain freedom at 2 h, pain relief at 2 h, pain freedom at 24 h as well as pain relief at 24 h, and reduce the need of rescue medication. These results suggested that trigeminal neurostimulation was effective to alleviate pain in these patients with migraine.

Regarding the sensitivity analysis, there was significant heterogeneity for the pain freedom at 2 h. However, several factors may account for the significant heterogeneity. Firstly, the performance of external trigeminal nerve stimulation was not completely same, or in combination with occipital neurostimulation. Secondly, patients with various duration and severity of migraine may cause some bias. Thirdly, different treatment durations of external trigeminal nerve stimulation may affect the pooling results.

The analgesic efficacy of external trigeminal nerve stimulation was confirmed based on the results of this meta-analysis. There were a few proposed mechanisms for the role of trigeminal nerve stimulation for migraine patients. Trigeminovascular system displays an important role in migraine patients. Trigeminal nerve stimulation is able to directly stimulate the supraorbital nerve which is a branch of the first division of the trigeminal nerve [23]. In addition, trigeminal nerve stimulation may have the capability to modulate the function of pain-controlling brain regions [23] [32].

Regarding the safety of trigeminal nerve stimulation, the included RCTs reported nausea, vomiting, dizziness and restlessness etc. Our results also found no increase in adverse events after trigeminal nerve stimulation compared to control intervention. We also should consider several limitations. Firstly, our analysis only included four RCTs, and more RCTs with large sample size should be conducted to explore this issue. Secondly, there was significant heterogeneity during the sensitivity analysis, which may be caused by different treatment duration and combination methods of trigeminal nerve stimulation. Thirdly, various severity of migraine may result in some bias. Fourthly, the drugs of rescue anti-migraine treatments were not described in the original articles, which may affect the pooling results.

Conclusion

The study provides strong evidence that trigeminal nerve stimulation benefits to treat migraine patients.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 09 February 2023

Accepted: 21 June 2023

Article published online:
25 July 2023