Table 1.

Summary of clinical studies addressed to invasive cervical vagal nerve stimulation (iVNS) and primary headache disorders

Year, study design	Headache disorder	Primary indication	Patient no.	Outcome/parameter	Follow-up	Cyclic stimulation paradigm	Efficacy	Safety/tolerability
2000, rCS5 Class IV	CM	Seizure	1	Severity/frequency	10 years	30 sec on/1–5 min off 20 Hz, 200–250 µsec	R	Not reported
2002, pCS6 Class IV	CM	Seizure	1	Severity/frequency	2 months	Not reported	R	Not reported
2003, rCS7 Class IV	CM	Seizure	4	Severity/frequency	14 years	30 sec on/1–5 min off 20 Hz, 200–250 µsec	R-75%	Not reported
2005, pPS8 Class IV	CM/CCH/BM	Headache	6 3 CM 2 CCH 1 BM	Severity/frequency Functional impairment (MIDAS)	6 months	Not reported	R-66% (2 CM) R-100% (2 CCH)	Vomitus BM patient
2009, pPS9 Class IV	CM	Headache Depressive disorder	4	Severity/frequency Functional impairment (MIDAS/HRSD)	4–14 months	30 sec on/1–5 min off 1.25–2.5 mA, 30 Hz 500 µsec	R-100%	Voice alteration, dyspnea, cough
2017, rCS10 Class IV	CM	Seizure iVNS+SoC vs. SoC vs. HC	19 10 iVNS 9 SoC	Severity/frequency Affective/cognitive head pain perception (MIDAS, PASS-40, FSVA)	5–13 years	30 sec on/1–5 min off 0.5–2 mA, 20 Hz, 200–250 µsec	iVNS (VAS) 5.4 vs. SoC (VAS) 7.8, p=0.03 iVNS (PASS) 21 vs. SoC (PASS) 16, p=0.02	Voice disturbance Battery replacement

Abbreviations: BM, basilar migraine; CCH, chronic cluster headache; CH, cluster headache; CM, chronic migraine; FSVA, questionnaire for pain-associated vigilance and attention; HC, healthy control; HRSD, Hamilton Rating Scale for Depression; iVNS, surgically implanted cervical vagal nerve stimulation; MIDAS, Migraine Disability Scale; PASS, Pain Anxiety Symptoms Scale; pCS, prospective case series; pPS, prospective pilot study; R, responder (≥30%–50% reduction severity/frequency); rCS, retrospective case series; SoC, standard of care; VAS, visual analog scale.