Table 2.

Open-label trials with focus on CM

Device, first author, year	Design	Major findings
Acute treatment
REN Nierenburg 2020 [6]	Dual-center, REN 45 min within 1 h of attack onset. Efficacy outcomes: consistency of pain relief/pain-free at 2 h. n = 42 enrolled, 38 evaluable	Pain relief and pain freedom at 2 h in ≥ 50% treated attacks: 73.7% and 26.3%
REN Unpublished 2020 [7]	Multicenter, REN 45 min within 1 h of attack onset. Primary outcome: the proportion of pain relief at 2 h of test treatment. N = 126 enrolled, 91 with 493 evaluable treatments	Pain relief at 2 h: 59.3%. Pain-free at 2 h: 20.9%
Preventive treatment
eTNS Di Fiore 2017 [10]	Single center, daily 20-min eTNS over 4 months. Co-primary end points: ≥ 50% reduction in MHD and acute medication use. n = 23 enrolled, 19 completed	34.8% achieved both endpoints. 31.0% monthly migraine day reduction, 49.6% acute medication use reduction
eTNS Birlea 2019 [11]	Single center, daily 20-min eTNS for 3 months. Co-primary end points: change in MHD and acute medication use. n = 73 enrolled, 58 treated	MHD change: −3.12 days (p < 0.001). Mean monthly acute medication use change: −8.11 (p < 0.001)
eTNS Ordás 2020 [12]	Two clinics, nightly 20-min eTNS for 3 months. Primary endpoint: change in MMD (moderate/severe or relieved by triptan/ergot). n = 25 enrolled, 24 ITT, 21 PP	Mod/severe headache days reduction: PP −4.00, p = 0.016; ITT −3.37 p = 0.022. Any headache days reduction: PP −2.95, p = 0.022; ITT 2.75 p = 00.016
tDCS Alhassani 2017 [24]	Single center, 5 daily sessions of anodal tDCS (left M1) 1 mA 20 min then anodal trans-spinal DCS (T10) 1 mA 20 min. Feasibility study. n = 9 (CM 3)	In CM, there was an average reduction in headache frequency of 54 ± 24% 30 days following treatment (p = 0.026)
tDCS Mastria 2021 [28]	Single center, tDCS 12 sessions (3 × /week for 4 weeks), 2 mA 20 min anodal stimulation at right-prefrontal, cathodal at occipital. Primary outcome: MHD after 30 and 60 days. N = 16	Significant reduction in MHD from 20.5 ± 6.89 (baseline) to 16.87 ± 7.8 (30 day; p = 0.027) and 14.81 ± 9.13 (60 day; p = 0.01)
deep TMS Rapinesi 2016 [34]	Single center, add-on deep TMS (12 sessions, 3 × /week of 10 Hz 600 pulses in 10 trains/session to left DLPFC, 3 days/week) to standard treatments. Primary outcome: difference in headache frequency. n = 14	At 6 weeks, add-on dTMS with standard of care reduced mean migraine crises (5.432.71 vs. 5.425.57, p = 0.021)
rTMS Shehata 2016 [36]	Single center, Botox vs. 12 sessions of rTMS (20 trains of 10 s 10 Hz stimuli, 10 s apart) over left M1, followed 12 weeks. Primary outcomes: headache frequency, severity. n = 15 Botox, 14 rTMS	Headache frequency and severity Similar reduction until after week 8; Botox more sustained than rTMS
ONS Miller 2016 [48]	Single center, bilateral continuous ONS implant with SOC, median follow-up of 42 months. Primary endpoint: mean monthly migraine days reduction. n = 53	MMD reduction 8.51 days (P < 0.001). MHD reduction 5.66 days (p < 0.001). > 30% responder rate 45.3%
ONS Rodrigo 2017 [49]	Single center, bilateral continuous ONS implant with SOC, outcomes: pain intensity, attack frequency, etc., n = 37 enrolled, 36 implanted, 31 completed 7-year follow up	Pain intensity (VAS) decreased by 4.9 ± 2.0 points. 7 of 35 permanently implanted services were removed, 2 due to inefficacy, and 5 due to cure from pain
ONS Garcia Ortez 2019 [50]	Single center, bilateral burst ONS, followed 2–18 months. Outcome: MHD, pain intensity. N = 12	MHD reduction: −10.2, p = 0.002. 4 had no reduction. Pain intensity reduction: 16.4%
ONS Ashkan 2020 [51]	Multicenter, bilateral continuous ONS, followed for up of 24 months. Endpoints: headache relief, headache days, etc. n = 112, 66 withdrawn or explanted, 45 completed	Headache relief: 25.1% (3 months), 28.5% (24 months). Headache days: −15.2 (3 months), −19.9 (24 months). MIDAS: 126.69 (baseline), 88.43 (3 months), 68.63 (24 months)
SCS Arcioni 2016 [54]	Single center study of a cervical SCS. Subjects had 2–4 week tunneled cervical SCS trial followed by permanent implant if trial effective. Evaluation at baseline and 6 months after implantation. N = 17 enrolled, 14 implanted	MHD decreased by 7.0 days (p = 0.004), with 50% subjects with > 30% decrease in headache days (12.9 ± 5.3 days); MIDAS scores and HIT-6 scores decreased significantly at 24 weeks follow up compared to baseline (p < 0.001 and p < 0.01). Intensity and frequency of headaches decreased significantly at 3 months
Green light Martin 2021 [57]	Single center cross-over study of daily exposure to white light for 10 weeks, followed by a washout period, then exposure to green light for 10 weeks. Primary outcome was number of headache days per month. N = 29 total, EM (n = 7) and CM (n = 22)	Green light exposure resulted in a significant decrease in headache days from 7.9 ± 1.6 to 2.4 ± 1.1 and from 22.3 ± 1.2 to 9.4 ± 1.6 in EM and CM patients, as well as numeric pain scale (for CM, from 8.2 ± 0.3 to 3.1 ± 0.5)

eTNS electrical trigeminal nerve stimulation, PP per protocol, ITT intention-to-treat, MHD mean monthly headache days, MMD mean monthly migraine days, SOC standard of care, ONS occipital nerve stimulation, VAS visual analog scale, MIDAS migraine disability assessment