Table 2.

Non-Invasive Neuromodulation Devices FDA-Cleared for use in Primary Headache Disorders

	Remote electrical neuromodulation (REN)	Noninvasive vagus nerve stimulation (nVNS)	Single-pulse transcranial magnetic stimulation (sTMS)	External trigeminal nerve stimulation (eTNS)	External concurrent occipital and trigeminal nerve stimulation (eCOT-NS)	External trigeminal nerve stimulation (eTNS)
Brand Name	Nerivio®	GammaCore™	SAVI dual™, eNeura Inc. SpringTMS®	Cefaly®	Relivion®	HeadaTerm1, HeadaTerm2
Cost (as of 06/2024)	$49 for 18 uses first device, afterwards $89 per device	$600 every 3 months	$395 monthly subscription	$421+ one-time cost	$150 for 60 days, total $650 after, or $75 per month	HeadaTerm1: $49 one-time cost HeadaTerm2: $99.99 one-time cost
Device Wearability	Armband adhesive (latex- free)	Handheld, used with electroconductive gel (depending on the brand, may or may not contain latex)	Handheld; no adhesive	Forehead adhesive (latex free)	Headband with water-based electrodes	Forehead adhesive (non-latex)
Stimulation Type	Electric	Electric	Magnetic	Electric	Electric	Electric
Target and Therapeutic Effect	Nociceptive receptors of the upper arm Induction of conditioned pain modulation (CPM) in the brainstem via peripheral nerves	Vagus nerve (right or left) Modulation of the autonomic nervous system, inhibition of cortical spreading depression, and alteration of nociceptive trigeminovascular neurotransmission, as well as descending pain pathways [28–30]	Occiput Modulates cortical spreading depression, neurotransmission of GABAergic circuits, and thalamocortical activity [50, 51]	Ophthalmic Nerve (V1)- Supraorbital and Supratrochlear Branches Therapeutic effect is unclear	Supraorbital and supratrochlear nerves, greater occipital nerves Neurotransmission of trigeminal and occipital inputs to the trigeminocervical complex in the brainstem [70]	Ophthalmic Nerve (V1)- Supraorbital and Supratrochlear Branches Therapeutic effect is unclear
Mechanism of Action	Electrical signal of a symmetrical biphasic square pulse with a modulated frequency of 100‐120 Hz, a pulse width of 400 μs, and an output current up to 40 mA [17]	Electrical signal comprising a 5-kHz sine wave burst lasting for 1 ms (5 sine waves, each lasting 200 μs), with such bursts repeated once every 40 ms (25 Hz), generating a 24-V peak voltage and 60-mA peak output current	Single pulse of magnetic stimulation	Rectangular biphasic compensated impulses with an electrical mean equal to zero, 250 µS impulse width, 60 Hz frequency, maximum intensity of 16 mA with a progressive slope from 1 to 16 mA over 14 min	Electrical signal comprising a phase width 100 [micro]s, a pulse frequency 0.33 Hz, trigeminal stimulation intensity up to 5 mA, and occipital stimulation intensity up to 7 mA	Pulse repetition frequency of 50 Hz, a pulse width of 125 μs, and an impulse amplitude of 60 V
FDA Indication(s) for Adults	Acute treatment of migraine for ages 12 + [17, 21] Preventive treatment of EM and CM [20, 74]	EM preventive, acute [31, 32] cCH preventive [37] eCH acute [36] HC and PH acute [43, 44]	Preventive treatment of migraine [54] Acute treatment of migraine [52]	Preventive treatment of migraine [66] Acute treatment of migraine [64, 65]	EM acute [70] CM acute [70]	Acute treatment of migraine [68]
Adverse Effects	Paraesthesias and dysesthesias, warmth, muscle spasms, temporary numbness, pain in the arm, shoulders or neck	Application site discomfort Muscle twitching, Pain in face, head, teeth	Transient light headedness Scalp discomfort or tingling Tinnitus Dizziness	Stimulation-induced paresthesia or dysesthesias Sleepiness Skin irritation Nausea	Paraesthesias and dysesthesias, temporary numbness, skin irritation and erythema,	None listed
Safety Considerations	Not evaluated in persons with congestive heart failure, severe cardiac or cerebrovascular disease Should be applied over dry, healthy skin with normal physical sensation and without any metallic implants or in proximity to cancerous lesions	Not evaluated in patients with carotid artery atherosclerosis, cervical vagotomy, clinically significant hyper/hypotension or brady/tachycardia Not evaluated in patients with metallic devices implanted at/near neck (stent, bone plate/screw)	Long-term effects of sTMS are unknown	Not evaluated in patients who have received supraorbital nerve blocks or Botox treatment in the prior 4 months	Not evaluated in patients with suspected or diagnosed heart disease or epilepsy	None listed
Contraindications	Uncontrolled Epilepsy Any active implanted electrical device	Any implanted electronic medical device Simultaneous use of another portable electronic device	Conductive metal implants in the head and neck	Metallic or electric devices implanted in the head Cardiac pacemaker or implanted or wearable defibrillator Pain of unknown origin	Metal implants or shrapnel in the head (except dental implants) Recent (< 3 months) brain or facial trauma Skin abrasions on the forehead or occiput at the contact area Implanted neurostimulators or any implanted metallic or electronic device in the head Cardiac pacemaker or an implanted or wearable defibrillator	None listed
Evidence for safety during pregnancy	Retrospective case control study of 140 women (59 REN, 81 controls) did not show a difference in pregnancy outcomes [23] Daily TENS usage on the abdomen in pregnant mice showed no teratogenic effects [24] An RCT for the use of TENS device for pregnancy-related pelvic pain in 30 patients did not reveal any negative impact during pregnancy [25] RCT of acupuncture vs. TENS device use for pelvic girdle pain during pregnancy in 113 women did not show negative related birth outcomes [26]	One retrospective review of invasive VNS in 44 pregnancies did not reveal birth defects or developmental complications [48] A cohort study looking at use invasive VNS treatment during pregnancy, showed increased obstetrical complications but no teratogenicity [49] Invasive VNS stimulation in pregnant rats 6–7 days before delivery showed that neither pup viability nor number of cells labeled for pro-inflammatory cytokines in the nucleus tractus solitarii or hypoglossal motor nucleus was impaired by VNS [46] Invasive VNS can potentially have a protective effect in pregnant rats with pre-eclampsia model [47]	Repetitive TMS for the treatment of anxiety/depression during pregnancy was not associated with poor cognitive or motor development outcomes for the fetus [57–59] A case control study of 30 pregnant patients who received rTMS vs. controls did not show a difference in motor or cognitive outcomes of their children at ages 18–62 months [57] Exposure to MRI (without contrast) during the first trimester of pregnancy was not associated with increased risk of harm to the fetus [60]	Not evaluated previously, but e-TNS device used for depression in one case [69]	Not evaluated previously, but e-TNS device used for depression in one case [69] Two cases two patients with invasive occipital stimulation during pregnancy resulted in 4 healthy pregnancies [72, 73]	Not evaluated previously, but e-TNS device used for depression in one case [69]
Level of evidence in safety during pregnancy (using Sackett criteria [75])	Level III	Level IV	Level III	Level U	Level U	Level U

Six non-invasive FDA-cleared devices for primary headache, mainly for migraine, include two devices using external trigeminal stimulation (A-B), transcranial magnetic stimulation (C) non-invasive vagal nerve stimulation (D), remote electrical neuromodulation (E) and combined trigeminal and occipital neuromodulation (F). Level of safety evidence of the neuromodulatory devices during pregnancy was calculated using Sackett criteria. Other relevant safety data was included, which encompasses other devices with similar functionality to the devices depicted above and/or used for different indications, as well as animal studies, and fetal outcomes