Table 2.

Summary of clinical studies utilizing implantable or non‐invasive VNS delivery cited in this review

Reference	Indication studied	n	Stimulation schedule; location	Efficacy	Safety/tolerability
Schwartz et al. 27	Severe congestive heart failure	8	2–10 s on, 6–30 s off for 6 months; right cervical vagus nerve	Significant improvements in NYHA class (P < 0.01), QOL on Minnesota Living With Heart Failure questionnaire (P = 0.001), and left ventricular end systolic volume (P = 0.03)	Implantation‐related AE: voice alteration (hoarseness) Stimulation‐related AEs: cough; pain at stimulation site, mandible and ear; voice alteration
De Ferrari et al. 47	Chronic heart failure	32 (8 from feasibility phase 27 and 24 from multicenter international phase 47)	Duty cyclea ≤25% (e.g. maximum 10 s on, 30 s off) for 6 months; right cervical vagus nerve	At 3 and 6 months: 56% and 59% of patients improved by ≥1 NYHA class (P ≤ 0.001) At 6 months: significant improvements in 6‐min walk test (P = 0.0014), QOL on Minnesota Living with Heart Failure questionnaire (P = 0.0001), LVEF (P ≤ 0.0003) and LVESVI (P = 0.02)	Implantation‐related SAEs: acute pulmonary edema (1 event), surgical revision (1 event) Other possibly related SAEs: dehydration‐related syncope (2 events); syncope resulting from new‐onset atrial fibrillation and hypotension; atrial fibrillation (2 events; 1 was a return to atrial fibrillation after cardioversion) AEs: pain at site of stimulation (n = 6), cough (n = 5), dysphonia (n = 4), mandibular pain (n = 3) and ECG stimulus artifact (n = 1)
Ben‐Menachem et al. 57	Refractory focal epilepsy	5	12–15 months after implantation: amplitude was 1.5–2.0 mA, frequency was 20 Hz, duty cyclea was 30 s on, 1.8–3 min off (14.3%–20.3%) with a pulse width of 0.3 ms and a quasi‐trapezoidal pulse shape; left cervical vagus nerve	Seizure frequency reduction of 50% in 2 patients and 25% in 2 patients; rate unchanged in 1 patient	Cough and/or hoarseness not noted until stimulation of 2 mA reached
Stefan et al. 49	Pharmacoresistant epilepsy	10	3 times daily (1 h each) for 9 months; left auricular branch of vagus nerve	50% reduction threshold not reached; seizure frequency was reduced by 45% and 48% in 2 patients and increased in 2 patients	3 patients discontinued; AEs included hoarseness, headache and constipation
Busch et al. 50	Healthy volunteers	48	Stable stimulation duration of ~1 h; left auricular branch of vagus nerve	tVNS increased pain threshold and lowered pain sensitivity and pain ratings	No discontinuations or SAEs; AEs included stimulation site sensations of slight pain, pressure, prickling, itching or tickling in 39 patients with active stimulation
Hein et al. 58	Major depression	37	15 min once or twice daily, 5 day/week for 2 weeks; bilateral transauricular vagus nerve	Significant reduction (P < 0.0001) in Beck Depression Inventory (self‐report) but not in clinician‐rated Hamilton Depression Rating Scale between active and sham treatments	No vital sign changes; no unpleasant sensations or irritations
Nesbitt et al. 52, 53	Intractable CH	21	Acute stimulation of 2–4 cycles (90 s each) to abort CH attacks and twice daily as preventive; cervical vagus nerve, ipsilateral to pain	Overall improvement: estimated subjective improvement of 51% in 18 patients; no change in 3 patients Abortive treatment: 47% of acute attacks were terminated and 27% substantially improved in 15 min Preventive treatment: reduction in 24‐h attack frequency (4.68 ± 2.36 to 2.54 ± 2.12; P < 0.0005)	AEs included worsening of pain in 1 patient; skin irritation, local skin reaction to conductive gel
Goadsby et al. 4	Episodic migraine	30	Two 90‐s stimulations 15 min apart; right cervical vagus nerve	Pain relief noted at 2 h for 46 of 79 migraines (58%) treated by 26 patients; 2‐h pain free rate was 28%	AEs included transient muscle or local skin irritation and 2 reports of light‐headedness
Moscato and Moscato 55	Chronic migraine	19	Two 90‐s stimulations 15 min apart; location not reported	Reduction (P < 0.05) in mean pain scores in overall group at 2 h; 9 patients were pain free, 6 had reduced pain and 4 were unchanged at 2 h	2 brief episodes of paresthesia

AE, adverse event; CH, cluster headache; ECG, electrocardiogram; LVEF, left ventricular ejection fraction; LVESVI, left ventricular end systolic volume index; NYHA, New York Heart Association; QOL, quality of life; SAE, serious adverse event; tVNS, transcutaneous VNS; VNS, vagus nerve stimulation.

^aDuty cycle is the percentage of time that stimulation is on.