Trial characteristics
We identified 1133 articles, and we finally included 15 RCTs (n=2545) described by 17 articles[14, 25–41]. The process of study screening and selection and the lists of the excluded studies were showed in Appendix B and C. The mean age of the included study ranged from 38.8 to 48.8 years. Female participants constituted 44-91.5% of the total population, and the median proportion was 76.3%. The duration of migraine ranged from 3 to 28.1 years, and the median duration was 16 years. Table 1 shows the details of the included treatments and comparisons. Risk of bias assessment showed that 11 RCTs were at low risk of bias, 3 RCTs at moderate risk of bias, and 1 RCT at high risk of bias. Appendix D shows risk of bias in individual RCTs.
Monthly headache days
Acupuncture was the most effective at week 12 (10 RCTs and 2061 participants; SMD -1.61, 95%CI -2.35 to -0.87; P-score=0.98; global I2 = 86.2%; Figure 1A). Topiramate was the most effective at week 4 (8 RCTs and 1784 participants; SMD -1.47, 95%CI -2.44 to -0.5; P-score=0.96; global I2 =96%) and at week 8 (7 RCTs and 1725 participants; SMD -2.54, 95%CI -3.42 to -1.67; P-score=1; global I2 =88%; Appendix G). BoNT-A was the most effective at week 16 (4 RCTs and 1731 participants; SMD -0.48, 95%CI -0.73 to -0.24; P-score=0.94; global I2 =72.1%) and week 24 (5 RCTs and 1682 participants; SMD -0.36, 95%CI -0.67 to -0.05; P-score=0.65; global I2 =83.6%; Appendix G). Acupuncture reduced more monthly headache days than BoNT-A at week 12 (Table 2), but no difference between the three treatments was found at other time points. The design-by-treatment consistency tests showed that inconsistency of the network originated mainly from the comparison between BoNT-A and placebo (Appendix F).
Migraine days
Topiramate was the most effective at week 12 (4 RCTs and 582 participants; SMD -0.4, 95%CI -0.75 to -0.04; P-score=0.96; global I2 =39.3%; Figure 2B), but no significant difference between treatments was found. Network meta-analysis was not performed at the other time points because of few available data.
Moderate or severe headache days
Acupuncture was more effective than topiramate at week 12 (3 RCTs and 245 participants; SMD -0.83, 95%CI -1.33 to -0.32).
Headache intensity
Acupuncture ranked the most effective at week 12 (3 RCTs and 528 participants; SMD -0.37, 95%CI -1.04 to 0.31; P-score=0.89; Figure 2A); and acupuncture was found more effective than BoNT-A (SMD -0.44, 95%CI -0.82 to -0.05; Table 2). BoNT-A was the most effective at week 4 (1 RCT and 162 participants; SMD -1.03, 95%CI -1.43 to -0.63; P-score=1), and acupuncture was the most effective at week 8 (1RCT and 162 participants; SMD -0.43, 95%CI -0.81 to -0.05; P-score=0.83).
Responder rate
Acupuncture was the most effective at week 12 (6 RCTs and 726 participants, RR 3.39, 95%CI 0.76 to 15.05; P-score=0.9; global I2 =66%; Figure 2B). Topiramate was the most effective at week 4 (2 RCTs and participants, RR 8, 95%CI 0.47 to 137.62; P-score=0.83). No difference was found between the three treatments (Table 2).
MIDAS
Acupuncture was the most effective at week 12 (8RCTs and 826 participants, SMD -1.72, 95%CI -3.69 to 0.25; P-score=0.91; global I2 =92.9%; Figure 2C). No difference between the three treatments at week 12. Topiramate was more effective than BoNT-A (1 RCT and 60 participants, SMD -0.62, 95%CI -1.14 to -0.1) at week 24.
Frequency of acute medication intake
Acupuncture was the most effective at week 12 (SMD, -1.04, -1.64 to -0.44; P-score=0.94; global I2 =95.2%; Figure 2D). BoNT-A was the most effective at week 4 (2 RCTs and 164 participants; SMD -2.77, 95%CI -3.52 to -2.02; P-score=1) and week 8 (2 RCTs and 164 participants; SMD 0.15, 95%CI -0.38 to 0.67; P-score=0.46). No difference was observed between the three treatments (Table 2).
Adverse event and tolerability
Topiramate caused the most total adverse events at both week 12 (10 RCTs and 1001 participants, RR 1.51, 95%CI 1.03 to 2.22; P-score=0.94; global I2 =52.2%; Figure 3A) and week 24 (4 RCTs and 1516 participants, RR 1.34, 95%CI 1.12 to 1.6; P-score=0.96; global I2 =0%; Figure 3B).
Topiramate also caused the most treatment-related adverse events at both week 12 (4 RCTs and 579 participants; RR 1.51, 95%CI 1.23 to 1.85; P-score=0.98; global I2 =0%; Figure 3A) and week 24 (3 RCTs and 1444 participants; RR 3.24, 95%CI 2.16 to 4.84; P-score=0.99; global I2 =0%; Figure 3B). Topiramate caused more treatment-related adverse events than BoNT-A at week 24 (RR 1.39, 95%CI 1 to 1.94; Table 2).
Topiramate had the least tolerability—caused the most drop-outs due to adverse events (4 RCTs and 1500 participants; RR 8.62, 95%CI 2.03 to 36.62; P-score=0.97; global I2 =0%; Figure 3B). However, no significant difference between topiramate and BoNT-A concerning tolerability (topiramate versus BoNT-A, RR 2.67, 95%CI 0.78 to 9.09; Table 2)
Sensitivity analysis
Eight RCTs (n=2157) were included for sensitivity analysis of the primary outcomes, and topiramate ranked the most effective in monthly headache days(SMD -1.47, 95%CI -2.44 to -0.50; P-score =0.96) and monthly migraine days(SMD -0.28, 95%CI -2.44 to -0.77; P-score =0.20). Six RCTs (n=1874) were included for sensitivity analysis of tolerability, and topiramate had similar tolerability to BoNT-A (RR, 0.29 95%CI 0.29 to 1.77).