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.
