Effectiveness and acceptability of noninvasive brain and nerve stimulation techniques for migraine prophylaxis: a network meta-analysis of randomized controlled trials

Background Current pharmacologic prophylactic strategies for migraine have exhibited limited efficacy, with response rates as low as 40%–50%. In addition to the limited efficacy, the acceptability of those pharmacologic prophylactic strategies were unacceptable. Although noninvasive brain/nerve stimulation strategies may be effective, the evidence has been inconsistent. The aim of this network meta-analysis (NMA) was to compare strategies of noninvasive brain/nerve stimulation for migraine prophylaxis with respect to their effectiveness and acceptability. Methods The PubMed, Embase, ScienceDirect, ProQuest, ClinicalTrials.gov, ClinicalKey, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov databases were systematically searched to date of June 4th, 2021 for randomized controlled trials (RCTs). Patients with diagnosis of migraine, either episodic migraine or chronic migraine, were included. All NMA procedures were conducted under the frequentist model. Results Nineteen RCTs were included (N = 1493; mean age = 38.2 years; 82.0% women). We determined that the high frequency repetitive transcranial magnetic stimulation (rTMS) over C3 yielded the most decreased monthly migraine days among all the interventions [mean difference = − 8.70 days, 95% confidence intervals (95%CIs): − 14.45 to − 2.95 compared to sham/control groups]. Only alternating frequency (2/100 Hz) transcutaneous occipital nerve stimulation (tONS) over the Oz (RR = 0.36, 95%CIs: 0.16 to 0.82) yielded a significantly lower drop-out rate than the sham/control groups did. Conclusions The current study provided a new direction for the design of more methodologically robust and larger RCTs based on the findings of the potentially beneficial effect on migraine prophylaxis in participants with migraine by different noninvasive brain/nerve stimulation, especially the application of rTMS and tONS. Trial registration CRD42021252638. The current study had been approval by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center (TSGHIRB No. B-109-29). Supplementary Information The online version contains supplementary material available at 10.1186/s10194-022-01401-3.


10-11
10b List and define all other variables for which data were sought (e.g. participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.

11-12
Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

11-12
Effect measures 12 Specify for each outcome the effect measure(s) (e.g. risk ratio, mean difference) used in the synthesis or presentation of results. 11-12 Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

11-12
13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions. 11-12 13c Describe any methods used to tabulate or visually display results of individual studies and syntheses.
12-13 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

12-13
13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression). 12-13 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results.
12-13 Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases). [12][13] Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. 12-13

RESULTS
Study selection 16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.
14-15, Fig 1, eTab 2 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.

Item # Checklist item
Page where item is reported characteristics Risk of bias in studies 18 Present assessments of risk of bias for each included study. [14][15]eFig 4 Results of individual studies 19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g. confidence/credible interval), ideally using structured tables or plots.
14-15, eTab 4 Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies. 14-15, eFig 4 20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect. 19-20 23c Discuss any limitations of the review processes used.
19-20 23d Discuss implications of the results for practice, policy, and future research. 20

OTHER INFORMATION
Registration and protocol 24a Provide registration information for the review, including register name and registration number, or state that the review was not registered. 7 24b Indicate where the review protocol can be accessed, or state that a protocol was not prepared. 7 24c Describe and explain any amendments to information provided at registration or in the protocol. 7 Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review. 24 Competing interests 26 Declare any competing interests of review authors. 24 Availability of data, code and other materials 27 Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.

24
The current checklist followed the latest PRISMA 2020 guideline [1].  Cross-over study and not provided the detailed outcome data at the end of 1st block 1 [4] Duplicate samples with other trials included in the current network meta-analysis 3 [5][6][7] Lack of adequate control 2 [8,9] Meta-analysis 10 [10][11][12][13][14][15][16][17][18][19] Not        Interventions are reported in order of mean ranking of monthly migraine days improvement, and outcomes are expressed as mean difference (MD) (95% confidence intervals). For the pairwise meta-analyses, MD of less than 0 indicate that the treatment specified in the row got more improvement than that specified in the column. For the network meta-analysis (NMA), MD of less than 0 indicate that the treatment specified in the column got more improvement than that specified in the row. Bold results marked with * indicate statistical significance. Interventions are reported in order of mean ranking of monthly migraine days improvement, and outcomes are expressed as mean difference (MD) (95% confidence intervals). For the pairwise meta-analyses, MD of less than 0 indicate that the treatment specified in the row got more improvement than that specified in the column. For the network meta-analysis (NMA), MD of less than 0

Reference
indicate that the treatment specified in the column got more improvement than that specified in the row. Bold results marked with * indicate statistical significance. Pairwise (upper-right portion) and network (lower-left portion) meta-analysis results are presented as estimate effect sizes for the outcome of response rate. Interventions are reported in order of mean ranking of treatment response, and outcomes are expressed as response rate ratio (RR) (95% confidence intervals). For the pairwise meta-analyses, RR of more than 1 indicate that the treatment specified in the row got better response than that specified in the column. For the network meta-analysis (NMA), RR of more than 1 indicate that the treatment specified in the column got better response than that specified in the row. Bold results marked with * indicate statistical significance. Pairwise (upper-right portion) and network (lower-left portion) meta-analysis results are presented as estimate effect sizes for the outcome of response rate. Interventions are reported in order of mean ranking of treatment response, and outcomes are expressed as response rate ratio (RR) (95% confidence intervals). For the pairwise meta-analyses, RR of more than 1 indicate that the treatment specified in the row got better response than that specified in the column. For the network meta-analysis (NMA), RR of more than 1 indicate that the treatment specified in the column got better response than that specified in the row. Bold results marked with * indicate statistical significance.  Pairwise (upper-right portion) and network (lower-left portion) meta-analysis results are presented as estimate effect sizes for the outcome of tolerability in aspect of drop-out rate. Interventions are reported in order of mean ranking of tolerability, and outcomes are expressed as odds ratio (OR) (95% confidence intervals). For the pairwise meta-analyses, OR of less than 1 indicate that the treatment specified in the row got more tolerability than that specified in the column. For the network meta-analysis (NMA), OR of less than 1 indicate that the treatment specified in the column got more tolerability than that specified in the row. Bold results marked with * indicate statistical significance.