Table 2.
Summary of neuromodulation trials involving CM patients.
| Authors | Study | Device | Participants | Stimulation protocol | Duration of the treatment (sessions) | Stimulated area | Results | Notes |
|---|---|---|---|---|---|---|---|---|
| Clarke et al., 2006 | Open-label | sTMS | MA (n = 10). MoA (n = 25). pMO (n = 6). Up to headache frequency of 1/day (but no data on % of CM patients). | 2 pulses (5 s apart) | 1–3 | MA: visual or somatosensory cortex. MoA: pain perceiving area. | Pain reduction Lower relapse rate the next day. Trend for a higher improvement in patients with more sessions. | No restriction on medications. (e.g., analgesics, narcotics, antiemetics, sedatives). |
| Bhola et al., 2015 | Open-label | sTMS | MA+MoA (n = 59). CM (n = 131, 87 with also MOH). | 1/2 pulses acutely | No limit within 12 weeks | V1 | Pain reduction. Less headache days. Lower HIT-6 score. | No limitation to change medication during the TMS treatment. MOH was discouraged. Patients on preventives therapy (n = 64). |
| Starling et al., 2018 ESPOUSE trial | Open-label | sTMS | MA (n = 44). MoA (n = 88). CM (n = 13). | Prevention: 2 pulses repeated after 15 min interval twice/day. Acute: 3 pulses repeated after 15 min interval (up to 2 times). | Four pulses twice daily, 3 months of treatment | Less headache days. Higher complete responder rate. Reduce medication intake. | 2.3% on prophylaxis. MOH excluded. Also excluded: mental impairment. Severe active major depression or major psychiatric illness Other neuromodulation therapy in the past month Onabotulinum toxin A in the past 4 months | |
| Conforto et al., 2014 | RCT, double blind, sham-controlled. | CM (n = 9). | High-frequency (10 Hz), 32 trains of 5 s, every 30 s of pause (at 110% of MT). | 23 sessions over 8 weeks. | Left DLPFC. | Inferior to sham. | Excluded patients with concomitant depression. | |
| Misra et al., 2013 | RCT, sham-controlled | rTMS | CM (n = 100). Included MOH. | 600 pulses in 10 trains at 10 Hz with 45.5 s of intertrain interval. | 3/week for 1 month. | Primary motor cortex | Primary outcomes: >50% responders (headache frequency); >50% responders (pain). Secondary outcome: any improvement pain, functional disability, rescue medication, adverse events | |
| Shehata et al., 2016 | RCT | rTMS | CM (n = 29). | 20 trains of 100 stimuli at 10 Hz in tri-weekly sessions. | 1 month. | Primary Motor cortex. | Comparison to botulinum toxin-A injections. Excluded: MOH, patients on prophylaxis (within 4 weeks), comorbid psychiatric disorders. | |
| Rapinesi et al., 2016 | RCT | Deep rTMS | Treatment-resistant CM, no MOH. | 10 Hz trains of 600 pulses. | 4 weeks | Lateral and medial part of the prefrontal cortex bilaterally. | Decrement in pain intensity, number of headache days and also depressive symptoms compared to the standard treatment. | Included patients with depression (n = 3) in both arms. |
| Teepker et al., 2010 | RCT | rTMS | EM (n = 27). | Two trains of 500 pulses at 1 Hz, with inter-train interval 60 s. | 12 in 5 weeks. | Vertex. | Reduced headache days. No different with sham. | – |
| Chen et al., 2016 | Open-label clinical trial | cTBS | EM (n = 6) and CM (n = 3). | Bursts of 3 pulses at 50-Hz every 200-ms intervals for 40 s. | 20 cTBS daily for 4 weeks. | Reduced headache days. | CM patients were on prophylaxis. | |
| Antal et al., 2011 | RCT, sham- controlled trial with crossover design. | Cathodal tDCS | CM (n = 13). | Cathodal 1 mA for 15 min once a day, every 2nd day. | 3 days/week for 6 weeks | Occipital cortex. | Reduced intensity of pain (only superior to sham). | 3 weeks on sham for both groups. |
| Dasilva et al., 2012 | RCT, sham-controlled | Anodal tDCS | CM (n = 8). | 10 sessions of 2 mA anodal for 20 min two or three times a week. | 4 weeks | Contralateral-to-pain M1. | Reduced pain intensity. | Significant clinical improvement after 4 months. |
| Andrade et al., 2017 | RCT, double blind, sham-controlled. | Anodal tDCS | CM (n = 13): 6 with M1 tDCS, 3 with DLPFC tDCS 4 in the sham | 12 sessions of 2 mA lasting 20 min, three times a week. | 4 weeks | M1, Left DLPFC. | Reduced Hit-6 score. Reduced pain. | Higher side effects in M1 group. |
| Silberstein et al., 2016 | RCT, double blind, sham-controlled + open label phase months. | Neck VNS. | CM (n = 59). | Two unilateral 90 s doses three times a day. | 2 months. | Vagus nerve at the neck. | Reduction in headache days in open label. | Phase 1 study. |
| Straube et al., 2015 | RCT, double blind, sham-controlled. | Auricular VNS. | CM (n = 46), included MOH. | Active (25 Hz) or sham (1 Hz) stimulation. | 4-h daily for 3 months. | Auricular branch of the vagus nerve. | Reduction in headache days in the sham arm. | |
| Di Fiore et al., 2017 | Open-label study. | tSNS. | CM (n = 23), included MOH. | Build-up stimulation. | 20 min/day for 4 months. | >50% reduction of headache days. |
The results table present benefit obtained by single studies as reported by the original source. Due to differences in methodology and outcome measure considered, a direct comparison among studies is not possible. sTMS, single pulse TMS; rTMS, repeated pulse TMS; cTBS, continuous theta burst; tDCS, transcranial direct current stimulation; MA, migraine with aura; MoA, migraine without aura; CM, chronic migraine; MOH, Medication Overuse Headache; MT, motor threshold; tSNS, Transcutaneous supraorbital neurostimulation; vNS, vagus nerve stimulation; DLPFC, dorsolateral prefrontal cortex; M1, primary motor cortex; RCT, randomized controlled trial.