Table 2.
Characteristics of included studies that report adverse events according to study population.
| Study | Design | Region | N | Age (years) | Gender (F/M) | Number of sessions | Duration (minutes) | Intensity (mA) | Frequency (Hz) | Pulse width (µs) | Device | Stimulation side | Active stimulation site | Sham stimulation site |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Healthy | ||||||||||||||
| Busch 2012 | Cross-over | Germany | 48 | 23.3 ± 2.1 | 24/24 | 1 | 60 | 0.25–10 | 25 | 250 | STV02, Cerbomed | Left | Cymba Conchae | Cymba conchae |
| Capone 2014 | Cross-over | Italy | 10 | 30.2 ± 3.6 | 7/3 | 1 | 60 | n/a | 20 | 300 | Twister, EBM & Ag–AgCl electrodes | Left | External acoustic meatus | Earlobe |
| Jacobs 2015 | Cross-over | The Netherlands | 30 | 60.57 ± 2.54 | 15/15 | n/a | n/a | 5 | 8 | 200 | TENSTem dental, Schwa-medico | Left | External acoustic meatus of the inner side of the tragus | Earlobe |
| Sellaro 2015 | Parallel | The Netherlands | 45 | 20.65 ± 1.7 | 40/5 | 1 | 75 | 0.5 | 25 | 200–300 | CM02, Cerbomed | Left | Outer auditory canal | Earlobe |
| Steenbergen 2015 | RCT, parallel | The Netherlands | 30 | 19.8 | 26/4 | 1 | 25 | 0.5 | 25 | 200–300 | CM02, Cerbomed | Left | Outer ear canal | Earlobe |
| Burger 2016 | Parallel | The Netherlands | 31 | 21.5 | 24/7 | 1 | n/a | 0.5 | 25 | n/a | NEMOS, Cerbomed | Left | Cymba conchae | Earlobe |
| FRØKJÆR 2016 | Cross-over | Denmark | 18 | 51.6 | 8/10 | 1 | 60 | 0.1–10 | 30 | 250 | NEMOS, Cerbomed | Left | Cymba conchae | Earlobe |
| Sellaro 2017 | Cross-over | The Netherlands | 24 | 20.71 ± 2.35 | 15/9 | 2 | 20 | 0.5 | 25 | 200–300 | NEMOS, Cerbomed | Left | Cymba conchae | Earlobe |
| Badran 2018 (Trial 1) | Cross-over | USA | 15 | 26.5 ± 4.99 | 7/8 | 1 | 9 | 200% of the perceived threshold | 1–25 | 100–500 | DS7, Digimeter | Left | Inner side of tragus | Earlobe |
| Badran 2018 (Trial 2) | Cross-over | USA | 20 | 25.65 ± 5.53 | 10/10 | 1 | 10 | 200% of the perceived threshold | 10–25 | 500 | DS7, Digimeter | Left | Inner side of tragus | Earlobe |
| Burger 2018 | RCT, parallel | The Netherlands | 85 | 21.01 ± 1.87 | 71/14 | 1 | 25 | 0.5 | 25 | 250 | NEMOS, Cerbomed | Left | Cymba Conchae | Earlobe |
| Colzato 2018 | Cross-over | The Netherlands | 32 | 21.34 (18–28) | 22/10 | 1 | 50 | 0.5 | 25 | 200–300 | NEMOS, Cerbomed | Left | Outer auditory canal | Earlobe |
| Fischer 2018 | Cross-over | Germany | 21 | 20.3 ± 1.4 | 18/3 | 1 | 36 | 0.4–4.8 | 25 | 200–300 | CMO2, Cerbomed | Left | Cymba conchae | Earlobe |
| Jongkees 2018 | Cross-over | Germany | 40 | 22.4 | 32/8 | 1 | 15 | 0.5 | 25 | 200–300 | CMO2, Cerbomed | Left | Outer auditory canal | Earlobe |
| Ventura-Bort 2018 | Cross-over | Germany | 21 | 20.3 ± 1.4 | 18/3 | 1 | 28 | Adjustable | 25 | 200–300 | NEMOS, Cerbomed | Left | Cymba conchae | Earlobe |
| Sclocco 2019 | One arm | USA | 16 | 27.0 ± 6.6 | 9/7 | 1 | 8 | n/a | 25 | 450 | Grass S88x stimulator, Astro-Med | Left | Cymba Conchae | None |
| Warren 2019 | Cross-over | Germany | 24 | 22.6 | 18/6 | 1 | 20 | 0.5 | 25 | 200–300 | NEMOS, Cerbomed | Left | Cymba conchae | Earlobe |
| Giraudier 2020 | Parallel | Germany | 60 | 23.39 ± 4.67 | 47/13 | 1 | 23 | 0.5–3.5 | 25 | 200–300 | Cerbomed GmbH | Left | Cymba conchae | Earlobe |
| Maraver 2020 | Cross-over | The Netherlands | 43 | 20.00 ± 2.34 | 39/4 | 2 | 60 | 0.5 | 25 | 200–300 | NEMOS, Cerbomed | Left | Cymba conchae | Earlobe |
| Pihlaja 2020 | Cross-over | Finland | 25 | 25.5 ± 4.8 | 16/9 | 1 | n/a | 1.5–3.2 | 30 | 250 | Salustim, Helsinki Ear Institute | Left | Tragus | Earlobe |
| Ricci 2020 | Cross-over | Italy | 8 | 30.5 ± 6.02 | 0/8 | 1 | 60 | 0–8 | 30 | 500 | Twister, EBM & Ag–AgCl electrodes | Left | External acoustic meatus | Earlobe |
| Sclocco 2020 | Cross-over | USA | 30 | 29.0 ± 9.8 | 17/13 | 4 | 8.55 | Adjustable | 2, 10, 25, 100 | 300 | UROstim, Schwa-medico | Left | Cymba conchae | Cymba conchae |
| Sharon 2020 | Cross-over | Israel | 25 | 28.08 ± 5.84 | 0/25 | 1 | 5 | Adjustable | 25 | 200–300 | NEMOS, Cerbomed | Left | Cymba Conchae | Earlobe |
| Thakkar 2020 | Parallel | USA | 37 | 21.05 | 27/10 | n/a | 30 | Adjustable | 5 | 200 | n/a | Left | Cymba conchae | Earlobe and cymba conchae |
| D’Agostini 2021 | Parallel | Belgium | 71 | 23.09 ± 3.62 | 55/16 | 1 | 40 | 0.5 | 25 | 250 | NEMOS, Cerbomed | Left | Cymba conchae | Earlobe |
| D’Agostini 2022 | Cross-over | Belgium | 66 | 21.74 ± 2.60 | n/a | 1 | 50–55 | Adjustable | 25 | 250 | NEMOS, Cerbomed | Left | Cymba conchae | Earlobe |
| Gurtubay 2021 | One arm | Spain | 26 | 22–59 | 13/13 | 1 | 4–8 | 2.4* | 1 | 500 | Custom Ag–AgCl electrodes | Left | Cymba and cavum, cymba and earlobe | n/a |
| Machetanz 2021 | Quasi-randomized, parallel | Germany | 13 | 24.0 ± 3.0 | 8/5 | 1 | 1.5 | 0.05–0.769 | 25 | 100, 260, 500 | STG-4000 series, Harvard Bioscience Inc | Bilateral | Cymba conchae, cavum conchae, outer tragus, inner tragus, crus helicis, fossa triangularis (each separately) | n/a |
| Sun 2021 | Cross-over | China | 46 | 20.39 ± 1.95 | 25/21 | 3 | 15 | Adjustable | 25 | 500 | XD-Kerfun BS-VNS-001, Intelligent Non-invasive Neuromodulation Technology and Transformation Joint Laboratory, Xidian University | Left | Inner side of tragus | Earlobe |
| Széles 2021 | Cross-over | Austria | 9 | 50.7 ± 7.2 | 4/5 | 4 | 44 | n/a | 1 | 500 | PrimeStim, TUWien | Right | Cymba and cavum concha, antihelix crura | n/a |
| Geng 2022 (Study 1) | Cross-over | China | 14 | 23.42 ± 1.29 | 6/8 | 1 | 5 | n/a | 20 | 250 | The Parasym, Parasym | Left | Tragus | Earlobe |
| Geng 2022 (Study 2) | One arm | China | 20 | 21.51 ± 2.12 | 9/11 | 1 | 20 | n/a | 5 or 20 | 50 or 250 | The Parasym, Parasym | Left | Tragus | Earlobe |
| Konjusha 2022 | Cross-over | Germany | 45 | 23.57 ± 0.51 | 37/8 | 1 | 20 | 0.5 | 25 | 200–300 | CM02, Cerbomed | Left | Outer ear | Earlobe |
| Epilepsy | ||||||||||||||
| Stefan 2012 | One arm | Germany | 10 | 37.7 (18–55) | 6/4 | 810 | 60 | n/a | 10 | 300 | n/a | Left | Auricular branch of the vagus nerve | n/a |
| He 2013** | One arm | China | 14 | 7.64 | 3/11 | 216 | 30 | n/a | 20 | n/a | TENS-200, Suzhou | Bilateral | Conchae cavum and cymba conchae | n/a |
| Aihua 2014 | RCT, parallel | China | 60 | 34.5 (26.5–41.3) 29 (24.5–42) | n/a | 1095 | 20 | adjustable | 20 | 200 | TENS-200, Suzhou | Bilateral | Ramsay-hunt zone | Earlobe |
| Peijing 2014 | One arm | China | 50 | 25.2 ± 13.1 | 20/30 | 336 | 30 | 1 | 20–30 | n/a | TENS, Suzhou | n/a | Triangular fossa of the auricle | n/a |
| Rong 2015 | Parallel | China | 144 | n/a | n/a | 336 | 30 | 1 | 20–30 | < 100 | TENS, Suzhou | Bilateral | Triangular fossa of the outer ear canal | n/a |
| Bauer 2016 | RCT, parallel | Germany | 76 | 38.8 | 45/31 | 140 | 240 | Adjustable | 25, 1 | 250 | NEMOS, Cerbomed | Left | Cymba conchae | Cymba conchae |
| Barbella 2018 | Quasi-randomized, crossover-like | Italy | 20 | 38.6 | 10/10 | 180–540 | 60 | 0.6–0.8 | n/a | n/a | n/a | n/a | n/a | n/a |
| Song 2018 | Parallel | China | 52 | 53.7 | 19/33 | 8 | 30 | n/a | 1 | n/a | NEMOSR, Cerbomed | Bilateral | Cymba conchae | n/a |
| Liu 2018 | One arm | China | 17 | 27 ± 9.4 | 7/10 | 540 | 20 | Adjustable | 10 | 200 | TENS-sm, Suzhou | bilateral | Conchae cavum and cymba conchae | n/a |
| Von Wrede 2019 | Case report | Germany | 1 | 24 | 1/0 | 380 | 240 | 1.5 | n/a | n/a | CM02, Cerbomed | n/a | n/a | n/a |
| Sabers 2021 | One arm | Denmark, Norway, The Netherlands, Belgium | 37 | 40& median | 23/14 | 180, 360 | 240 | 0.5–5 | 25 | 250 | NEMOS, Cerbomed | Left | Cymba conchae | n/a |
| Von Wrede 2021 | One arm | Germany | 14 | 41& | 8/6 | 1 | 60 | Adjustable | 25 | n/a | NEMOS, Cerbomed | Left | Cymba conchae | None |
| Tinnitus | ||||||||||||||
| Kreuzer 2012 | One arm | Germany | 24 | 59 ± 10.7 | 14/10 | 5–43 | 300 | n/a | 25 | n/a | CM02, Cerbomed | Left | n/a | n/a |
| LEHTIMÄKI 2013 | Parallel | Finland | 10 | n/a | n/a | 7 | 45–60 | Adjustable | 25 | n/a | Tinnoff pulse generator, Tinnoff Inc | Left | Tragus | n/a |
| Kreuzer 2014 (Phase 2) | One arm | Germany | 50 | n/a | n/a | 96 | 240–360 | 0.1–10 | 25 | n/a | Phase 1 CM02, Cerbomed Phase 2 NEMOS, Cerbomed | n/a | n/a | n/a |
| Shim 2015 | One arm | South Korea | 30 | 58.47 ± 15.85 | 9/21 | 10 | 30 | 1–10 | 25 | 200 | TENS eco2, Schwa-medico | Left | Auricular conchae | n/a |
| Suk 2018 | One arm | South Korea | 24 | 44.58 | 8/16 | 4 | 48 | Adjustable | 30 | 200 | ES-420, Ito Company Ltd | n/a | Cavum, cymba, outer tragus | n/a |
| Ylikoski 2020 | One arm | Finland | 171 | 49 (7–84) | 67/104 | 5 | 60–90 | Adjustable | 25 | 250 | Salustim, Helsinki Ear Institute | Left | tragus | n/a |
| Depression | ||||||||||||||
| Hein 2013 (Study 1) | RCT, Parallel | Germany | 22 | 45.8 | 13/9 | 10 | 15 | Adjustable | 1.5 | n/a | NET-200, Auri-Stim Medical | Bilateral | Outer ear canal | Outer ear canal |
| Hein 2013 (Study 2) | RCT, Parallel | Germany | 15 | 48.1 | 9/6 | 20, 10 | 15 | 0.13 | 1.5 | n/a | NET-1000, Auri-Stim Medical | Bilateral | Outer ear canal | Outer ear canal |
| Rong 2016 | RCT, parallel | China | 160 | 41.99 | 117/43 | 168 | 30 | Adjustable | 20 | 200 | TENS-200, Suzhou | n/a | Cymba conchae | Superior scapha |
| Evensen 2021 | One arm | Denmark | 20 | 49.4 ± 11.2 | 13/7 | 28 | 240 | 0.1–5 | 25 | n/a | NEMOS, Cerbomed | Left | Auricular tract | n/a |
| Kaczmarczyk 2021 | One arm | Poland | 5 | 53.6 | 3/2 | 144 | 120 | 0.5–5 | 25 | n/a | NEMOS, Cerbomed | n/a | n/a | n/a |
| Stroke | ||||||||||||||
| Capone 2017 | Parallel | Italy | 12 | 54.65 | 5/7 | 10 | 60 | Adjustable | 20 | 300 | Twister, EBM & Ag–AgCl electrodes | Left | External acoustic meatus | Earlobe |
| Redgrave 2018 | One arm | United Kingdom | 13 | 64.5 ± 6 | 3/10 | 18 | 60 | 1–3.2 | 25 | 100 | NEMOS Cerbomed | Left | Cymba conchae | n/a |
| Wu 2020 | Parallel | China | 21 | 63.16 | 8/13 | 15 | 30 | Adjustable | 20 | 300 | HD-1A, Bohua | Left | Cymba conchae | Cymba conchae |
| Chang 2021 | Parallel | USA | 36 | 59.02 ± 1.98 | 18/18 | 9 | 60 | 0–5 | 30 | 300 | Custom conductive silicone electrodes with wireless Bluetooth control | Left | Cymba conchae | Cymba conchae |
| Li 2022 | Parallel | China | 60 | 68.75 | 31/29 | 20 | 20 | Adjustable | 20 | 300 | TENS, Suzhou | Left | Cymba conchae | Cymba conchae |
| Migraine | ||||||||||||||
| Straube 2015 | RCT, parallel | Germany | 46 | 41.55 | 39/7 | 90 | 240 | Adjustable | 25, 1 | 250 | NEMOS Cerbomed | Left | Cymba conchae | n/a |
| Cao 2021 | RCT, cross-over | USA | 24 | 31.33 ± 1.55 | 21/3 | 2 | 8 | Adjustable | 20, 1 | 200 | SDZ IIB, Suzhou | Left | Cymba and cavum concha | Cymba and cavum concha |
| Bruxism | ||||||||||||||
| Polini 2022 | One arm | Italy | 10 | 37.2 (19–52) | 7/3 | 4 | 30 | n/a | n/a | n/a | Custom device | Bilateral | Cavum conchae, external auditory meatus, internal tragus | n/a |
| Chronic fatigue syndrome | ||||||||||||||
| Early 2018 | Case report | USA | 1 | 58 | 1/0 | 420 | 240 | n/a | n/a | n/a | n/a | Left | Cymba conchae | n/a |
| Erosive hand osteoarthritis | ||||||||||||||
| Courties 2022 | Pilot study | France | 20 | 69 (66.7–73.2) | 15/3 | 28 | 60 | 0–15 | 25 | 50 | TENS eco2, Schwa-medico | Left | Cymba conchae | n/a |
| Fibromyalgia | ||||||||||||||
| Kutlu 2020 | Parallel | Turkey | 60 | 39.02 | 60/0 | 20 | 30 | n/a | 10 | 500 | TENS device (not specified) | Bilateral | Inner and rear surfaces of tragus and conchae | n/a |
| Functional dyspepsia | ||||||||||||||
| Zhu 2021 | Parallel | China and USA | 36 | 44.2 | 25/11 | 14 | 120 | 0.5–1.5 | 25 | n/a | SNM-FDC01, Ningbo Maida Medical Device | Bilateral | Cymba conchae | n/a |
| Generalized anxiety disorder | ||||||||||||||
| Burger 2019 | Parallel | The Netherlands | 97 | n/a | 78/19 | 1 | 15 | 0.5 | 25 | 250 | NEMOS, Cerbomed | Left | Cymba conchae | Earlobe |
| Heart failure | ||||||||||||||
| Stavrakis 2022 | Parallel | USA | 52 | 69.8 | 32/20 | 90 | 60 | Adjustable | 20 | 200 | The Parasym, Parasym | n/a | Tragus | Earlobe |
| Impaired glucose tolerance | ||||||||||||||
| Huang 2014 | Parallel | China | 72 | 54.4 ± 7.4 | 51/21 | 294 | 20 | 1 | 20 | < 1000 | TENS-200, Suzhou | n/a | Cymba conchae | Superior scapha |
| Insomnia | ||||||||||||||
| Jiao 2020 | RCT, parallel | China | 72 | 48.5 | 60/12 | 40 | 30 | Adjustable | 20 | n/a | SDZ-IIB, Suzhou | Bilateral | Auricular concha | n/a |
| Left-ventricular strain | ||||||||||||||
| Tran 2018 | RCT, cross-over | USA | 24 | 68.3 ± 1.2 | 11/13 | 2 | 60 | Adjustable | 20 | 200 | The Parasym, Parasym | Left | Tragus | Tragus |
| Open laparotomy patients | ||||||||||||||
| Hong 2018 | One arm | Germany | 14 | 57.6 ± 10.5 | 8/6 | 1 | 10 | 10 | 25 | 250 | Transcutaneous, bipolar stimulation probe (Stimulationssonde 522,015, Inomed) | Right | Cymba conchae | n/a |
| Pediatric nephrotic syndrome | ||||||||||||||
| Merchant 2022 | Pilot study | USA | 7 | 9.5 ± 4.2 | 3/4 | 182 | 5 | Adjustable | 30 | 300 | TENS 7000, Roscoe Medical | Left | Cymba conchae | n/a |
| Pediatric oral feeding dysfunction | ||||||||||||||
| Bandran 2020 | One arm | USA | 14 | 45 ± 5 + | 9/5 | 14 | 30 | Adjustable | 25 | 500 | DS7AH, Digitimer | Left | Tragus | n/a |
| Prader-Willi syndrome | ||||||||||||||
| Manning 2019 | One arm | United Kingdom | 5 | 26.4 ± 7.36 | 2/3 | 180, 360 | 240 | 0.1–5 | 25 | 250 | NEMOS, Cerbomed | Left | Cymba conchae | n/a |
| Schizophrenia | ||||||||||||||
| Hasan 2015 | RCT, parallel | Germany | 17 | 36.5 | 9/8 | 182, 96 | 289# | 0.1–10 | 25 | 250 | CM02, Cerbomed | Left | Outer ear canal | Outer ear canal |
| Systemic lupus erythematosus | ||||||||||||||
| Aranow 2020 | Parallel | USA | 18 | 45.7 ± 11.7 | 18/0 | 4 | 5 | Adjustable | 30 | 300 | TENS 7000, Roscoe Medical | Left | Cymba conchae | Earlobe |
| Vegetative state | ||||||||||||||
| Hakon 2020 | One arm | Denmark | 5 | 51.8 ± 24.4 | 1/4 | 56 | 240 | 0.5, 1 | 25 | 250 | NEMOS, Cerbomed | Left | Cymba conchae | n/a |
*mean mA;**pediatric population;&median; + days; #mean duration of 4 groups.
AE: adverse event; SD: standard deviation; Hz: Hertz; µs: micro-seconds; n/a: non-applicable; RCT: randomized clinical trial; F/M: female/male.