Table 1.
Summary of clinical studies of VNS for the treatment of chronic pain
| Author (year) | Pain syndrome | Model, sample size | Device type | Study design | Stimulation schedule | Follow-up | Efficacy | Tolerability |
|---|---|---|---|---|---|---|---|---|
| Goadsby et al. [43] (2014) | Migraine | Human, n = 30 | tcVNS | Open-label observational cohort study | Two 90 s doses at a 15 min interval applied at the right neck | 6 weeks | Pain-free rate was 22% at 2 h after tcVNS | Well-tolerated |
| Barbanti et al. [44] (2015) | Migraine | Human, n = 50 | tcVNS | Open-label observational cohort study | Two 120 s doses at a 3 min interval applied at the right neck | 2 weeks | Pain-free rate was 22.9% at 2 h after treatment | Well-tolerated |
| Silberstein et al. [45] (2016) | Chronic migraine | Human, n = 59 | tcVNS | RCT | Two 120 s doses at a 5–10 min interval applied unilaterally three times/day | Randomized phase: 2 months Open-label phase: 6 months | Randomized phase: no difference in reduction of headache days Open-label phase: significant difference in headache days compared to baseline in tcVNS group | Well-tolerated |
| Najib et al. [46] (2022) | Chronic migraine | Human, n = 113 | tcVNS | RCT | Randomized phase: 12 weeks | The percentage of participants with a ≥50% reduction in migraine days was greater in the tcVNS group than the sham group (p = 0.0481) | Well-tolerated | |
| Nesbitt et al. [47] (2015) | Cluster headache | Human, n = 19 | tcVNS | Open-label observational cohort study | Acute treatment: three consecutive 120 s doses applied unilaterally | 13 months | Acute treatment: 47% of all attacks could be aborted within an average of 11±1 min of initial device application Prevention: 24 h attack frequency reduction from a mean of 4.5–2.6 (p < 0.0005) | Well-tolerated |
| Prevention: two or three consecutive 120 s doses applied unilaterally twice/day | ||||||||
| Gaul et al. [48] (2016) | Cluster headache | Human, n = 97 | tcVNS | RCT | Three 120 s doses at a 5-min interval applied at the right side of the neck twice/day | Randomized phase: 4 weeks | Significant reduction in weekly cluster attacks and improvement of at least 50% response rate in tcVNS group | Well-tolerated |
| Open-label phase: 4 weeks | ||||||||
| Straube et al. [49] (2015) | Chronic migraine | Human, n = 46 | taVNS | RCT | A total of 4 h per day without specific distribution applied to the left ear | 3 months | Significant reduction in headache days in both 1 HZ and 25 HZ group while 1 HZ group has more profound effect | Well-tolerated |
| Zhang et al. [50] (2021) | Chronic migraine | Human, n = 70 | taVNS | RCT | 30 min for each session applied at left ear and complete 12 sessions during 4 weeks | 4 weeks | Significant reduction in number of migraine days, pain intensity, and migraine attack time in taVNS group | Well-tolerated |
| Silberstein et al. [51] (2016) | Cluster headache | Human, n = 150 | tcVNS | RCT | Three consecutive 120 s doses applied to the right side of the neck | Randomized phase: 1 month Open-label phase: 3 months | Randomized phase: significant difference of response rate only in eCH treated with tcVNS | Well-tolerated |
| Open-label phase: response rates were similar in eCH and cCH cohort | ||||||||
| Goadsby et al. [52] (2018) | Cluster headache | Human, n = 102 | tcVNS | RCT | Three consecutive 120 s doses applied unilaterally | Randomized phase: 2 weeks | Randomized phase: a higher response rate with tcVNS than with sham in the eCH subgroup (p < 0.01) | Well-tolerated |
| Open-label phase: 2 weeks | ||||||||
| Lange et al. [53] (2011) | Fibromyalgia | Human, n = 14 | iVNS | Open-label observational cohort study | 250 μS 20 Hz pulses with 30 s ON and 5 min OFF. Current intensity: 0.75–2 mA | 3-month study of iVNS with follow-up at 5, 8, and 11 months after stimulation initiation | At the end of 3 months, 5 patients had become MCID+, 2 no longer meeting criteria for widespread pain or tenderness criteria for fibromyalgia | Chest pain Dyspepsia |
| Kutlu et al. [54] (2020) | Fibromyalgia | Human, n = 60 | taVNS | RCT | 30 min per day applied to both ears | 5 weekdays for 4 weeks | taVNS did not give additional benefit together with exercise | Well-tolerated |
| Muthulingam et al. [55] (2021) | Chronic pancreatitis | Human, n = 28 | tcVNS | RCT, crossover study | One 120 s doses applied bilaterally three times a day | 2-week tcVNS followed by 2-week sham stimulation or vice versa | No differences in pain scores were seen in response to 2 weeks tcVNS as compared to sham treatment | Acute pancreatitis Worsening of pain |
| Farmer et al. [56] (2020) | Esophageal pain | Human, study 1: n = 15 study 2: n = 18 | taVNS | RCT, crossover study | Study 1: 30 min tcVNS during acid infusion | 120 min after completion of the acid infusion | The development of acid-induced esophageal hypersensitivity was prevented and reversed with tVNS in comparison to sham | Well-tolerated |
| Study 2: 30 min tcVNS after acid infusion | ||||||||
| Shi et al. [57] (2021) | Irritable bowel syndrome | Human, n = 42 | taVNS | RCT | 30 min stimulation applied bilaterally twice a day | 4 weeks | taVNS decreased VAS pain score and improved anxiety and depression | Well-tolerated |
| Venborg et al. [58] (2021) | Polymyalgia rheumatica | Human, n = 15 | tcVNS | Open-label, proof-of-concept experimental pilot study | Day1–4: three consecutive 120 s doses applied bilaterally | 5 days | A 14% reduction in the pain score for the hips was shown on day 5 in comparison with baseline (p < 0.05), while global pain score had no change | None noted |
| Day 5: one 120 s stimulation | ||||||||
| Aranow et al. [59] (2021) | Systemic lupus erythematosus | Human, n = 18 | taVNS | RCT, pilot study | 5 min stimulation per day applied to the left ear for 4 consecutive days | 12 days | Subjects receiving taVNS achieved a significantly greater reduction in their pain compared with sham group | Well-tolerated |
cCH, chronic cluster headache; eCH, episodic cluster headache; iVNS, invasive vagus nerve stimulation; MCID, minimal clinically important difference; RCT, randomized controlled trial; taVNS, transauricular vagus nerve stimulation; tcVNS, transcervical vagus nerve stimulation.