Therapeutic strategies that act on the peripheral nervous system in primary headache disorders

Figures & data

Table 1. Peripheral neurostimulation methods in drug-resistant primary headache disorders.

Invasive		Non-invasive
Method	Indications	Method	Indications
Implantable ONS	Intractable chronic migraine Intractable chronic cluster headache Intractable SUNCT and SUNA Intractable hemicrania continua	Transcutaneous ONS	Drug-refractory episodic migraine Drug-refractory custer headache
Implantable SONS+ONS	Intractable chronic migraine	Transcutaneous SONS (The Cefaly® device)	Drug-refractory episodic migraine
Implantable cervical branch VNS	Epileptic patients with headache	Transcutaneous cervical VNS (the gammaCore® device) Transcutaneous auricular VNS (the NEMOS® device)	Drug-refractory episodic and chronic migraine Drug-refractory episodic and chronic cluster headache Drug-refractory SUNA Drug-refractory hemicrania continua Drug-refractory chronic migraine
Implantable SPG stimulation (The Pulsante SPG Microstimulator System®)	Intractable episodic and chronic cluster headache

Abbreviations: ONS = occipital nerve stimulation; SONS = supraorbital nerve stimulation; SPG = sphenopalatine ganglion; SUNA = short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms; SUNCT = short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing; VNS = vagal nerve stimulation.

Table 2A. Data of the occipital nerve neurostimulation (ONS) studies in drug-refractory primary headache disorders.

	Migraine		Cluster headache (CH)		Other TACs
Study design	Episodic migraine (EM)	Chronic migraine (CM)	Episodic CH	Chronic CH	SUNHA	Hemicrania continua
Non-invasive (transcutaneous) occipital nerve stimulation (ONS)
RCT (for prevention) (2017) [7]	n = 110 E = 40.91% (at 100 Hz) versus 4.55% (sham) AEs = no serious AEs
Invasive (implantable) occipital nerve stimulation (ONS)
RCT (long-term) (2015) [46]		n = 125 (intractable CM) E: headache days reduced by 7.7 (±8.7) days AEs: lead migration, persistent pain, and/or numbness
RCT (2015) [47]		n = 15 E: suprathreshold vs. subthreshold stimulation (1.98 ± 1.56 vs. 5.65 ± 2.11) AEs: none
RCT (2012) [48]		n = 157 E: failed AEs: persistant implant side pain, lead migration
Prospective RCT (the ICON study) (2013) [115]				ongoing
Open-label prospective long-term uncontrolled observational (2017) [49]		n = 37 E: VAS decreased by 4.9 ± 2.0 AEs: none
Open-label prospective cohort (2018) [50]		n = 35 E: 28,5% of the patients AEs: not mentioned
Open-label prospective cohort (2018) [50]				n = 33 E: 54.5% of the patients AEs: not mentioned
Open-label monocentric long-term (2017) [117]				n = 35 E: 66.7% of the patients AEs: battery depletion, electrode migration
Open-label long-term prospective (2013) [143]					n = 9 E: 8 out of 9 of the pateints AEs: lead migration, muscle pain
Open-label long-term follow-up prospective (2017) [144]						n = 16 E: 75% of the patients AEs: none
Cross-over prospective randomized (2012) [51]		n = 30 E: 54–60% of patients AEs: infection, lead migration
Single-center combined ONS and SONS (2013) [52]		n = 14 E: 71% of patients AEs: lead migration
Long-term functional outcome combined ONS and SONS (2016) [53]		n = 16 E: 50% of patients AEs: lead migration, supraorbital lead allodynia, infection
Long-term retrospective (2013) [54]		n = 25 E: 53% of patients AEs: lead displacement, local infection
Single-center observational (2014) [55]		n = 17 E: NRS = 9.8 + 0.7 (at baseline), 5.0 ± 1.6 (at 3 months); 5.7 ± 2.6 (at 12 months) AEs: lead migration
Single-center prospective long-term (2013) [118]				n = 24 E: 89% of the patients AEs: local pain, local infections
Single-center long-term follow-up (2017) [119]				n = 16 E: 75% of the patients AEs = electrode migration, battery replacement, infection
Observational prospective (2017) [120]				n = 67 E: 59% of the patients AEs: early battery depletion
Literature review (2017) [149]					n = 7 E: 100% of the patient AEs: none

Abbreviations: AE = adverse event; CH = cluster headache; E = effectiveness (at least 50% improvement in headache frequency and/or intensity); GON = greater occipital nerve; n = number of the randomized patients; NRS = numeric rating scale; RCT = randomized multicenter double-blind controlled trial; SON = supraorbital nerve; SUNHA = short-lasting unilateral neuralgiform headache attacks; TAC = trigeminal autonomic cephalalgia; VAS = Visual Analogue Scale.

Table 3. Data of the non-invasive (transcutaneous) and invasive (implantable) supraorbital nerve stimulation (SONS) studies in intractable primary headache disorders.

	Migraine		Cluster headache (CH)		Other TACs
Study design	Episodic migraine (EM)	Chronic migraine (CM)	Episodic CH	Chronic CH	SUNHA	Hemicrania continua
RCT of transcutaneous SONS (the Cefaly® device) (The PREMICE study) (2013) [13]	n = 67 E = 38.1% of the patients AEs = none
RCT of transcutaneous SONS (the Cefaly® device) (2013) [14]	n = 2313 E = 54.4% of the patients AEs = local paresthesia
RCT of transcutaneous SONS (the Cefaly® device) (2018) [15]	n = 109 E = 59% of the patients AEs = no serious AEs
Single-center combined implantable ONS and implantable SONS (2013) [52]		n = 14 E = 71% of patients AEs = lead migration
Long-term functional outcome combined implantable ONS and implantable SONS (2016) [53]		n = 16 E = 50% of the patients AEs = lead migration, supraorbital lead allodynia, infection

Abbreviations: AE = adverse event; E = effectiveness (at least 50% improvement in headache frequency and/or intensity); n = number of the randomized patients; ONS = occipital nerve stimulation; RCT = randomized multicenter double-blind controlled trial; SUNHA = short-lasting unilateral neuralgiform headache attacks; TAC = trigeminal autonomic cephalalgia; VAS = Visual Analogue Scale.

Table 4. Data of the non-invasive vagus nerve stimulation (VNS) studies in drug-refractory primary headache disorders.

	Migraine		Cluster headache (CH)		Other TACs
Study design	Episodic migraine (EM)	Chronic migraine (CM)	Episodic CH	Chronic CH	SUNHA	Hemicrania continua
The gammaCore® device (cervical branch of the vagus nerve)
RCT (for acute and preventive treatment) (the PREVA study) (2016) [19]				n = 97 E = 40% of the patients AEs = headache, nasopharyngitis, dizziness, oropharyngeal pain, neck pain
RCT (for acute treatment) (the ACT1 study) (2016) [108]			n = 38 E = 34.2% of the patients AEs = burning, tingling, soreness, stinging, lip, or facial drooping	n = 22 E = failed AEs = burning, tingling, soreness, stinging, lip, or facial drooping
RCT (for acute treatment) (the ACT2 study) (2018) [109]			n = 27 E = 48% AEs = not relevant	n = 65 E = 5% AEs = not relevant
RCT prospective pilot (for prevention) (the EVENT study) (2016) [31]		n = 59 E = 9.1% (at 2 month) E = 46.7% (at 8 month) AEs = eye twitch, facial pain/numbness, gastrointestinal symptoms, upper respiratory tract infection
RCT (for acute treatment) (the PRESTO study) (2018) [32]	n = 248 E = at 30 min: 12.7% versus 4.2%; at 60 min: 21.0% versus 10.0%; at 120 min: 30.4% versus 19.7% AEs = no serious AEs
Open-label single-arm multicenter (for acute treatment) (2015) [20]		n = 36 (high-frequency EM n = 14) E = 51% (at 2 h after treatment) AEs = stingling and pricking sensation
Open-label single-arm multiple-attack pilot (for acute treatment) (2014) [33]	n = 30 E = 22% (pain-free rate) AEs = neck twitching, raspy voice, redness at the device site
Open-label preliminary single-arm safety (for acute treatment) (2017) [34]	n = 9 E = 46.8% of the treated migraine attacks AEs = none
Open.label menstrual/menstrually-related mini-prophylaxis (2016) [35]	n = 56 E: 39% of patients AEs: no serious AEs
Open-label real-world prospective clinical audit (2018) [145]		n = 23 E: 2 out of 23 patients (at least 30% reduction in headache days/episodes) AEs = no serious AEs		n = 12 E: 1 out of 12 patients (at least 30% reduction in headache days/episodes) AEs = no serious AEs	n = 2 E: none of the patients AEs = no serious AEs	n = 4 E: 2 out of 4 patients (at least 30% reduction in headache days/episodes) AEs = no serious AEs
Single-center prospective observational cohort (for acute and preventive treatment) (2015) [36]	n = 10 E = VAS = 8 (at baseline) versus VAS = 3.5 (at 3 month post-treatment) E = headache days: 11.3 (at baseline) versus 5.7 (at 3 month post-treatment) AEs = no serious AEs	n = 10 E = VAS = 8 (at baseline) versus VAS = 5 (at 3 month post-treatment) E = headache days: 18.1 (at baseline) versus 8.1 (at 3 month post-treatment) AEs = no serious AEs
Single-center (2017) [146]						n = 9 E = 78% of the patients AEs = no serious
The NEMOS® device (auricular branch of the vagus nerve)
Single-center sandomized parallel-group double-blind (for prevention) (2015) [38]		n = 46 E = 29.4% of the patients (at 1 Hz); 13.3% of the patients (at 25 Hz) AEs = pain, paresthesia, pruritus, erythema, ulcer, or scab

Abbreviations: AE = adverse event; CH = cluster headache; E = effectiveness (at least 50% improvement in headache frequency and/or intensity); n = number of the randomized patients; RCT = randomized multicenter double-blind controlled trial; SUNHA = short-lasting unilateral neuralgiform headache attacks; TAC = trigeminal autonomic cephalalgia; VAS = Visual Analogue Scale.

Table 2B. Data of the greater occipital nerve (GON) blockade studies in intractable primary headache disorders.

	Migraine		Cluster headache (CH)		Other TACs
Study design	Episodic migraine (EM)	Chronic migraine (CM)	Episodic CH	Chronic CH	SUNHA	Hemicrania continua
Greater occipital nerve (GON) blockade with chemical agents
RCT (bupivacaine) (2017) [58]		n = 44 E = frequency: 21.0 (at baseline) versus 6.3 (at 3 month); intensity: 8.9 (at baseline) versus 6.3 (at 3 month) AE = local pain, vertigo, nausea
RCT (bupivacaine) (2017) [59]		n = 36 E = number of headache days: 4.9 (pretreatment) to 3.4 (post-treatment) AE = stinging sensation, presyncope
RCT prospective pilot (bupivacaine) (2015) [60]		n = 23 E = pain intensity: VAS: 3.93 (pre-injection) versus VAS: 1.55 (post-injection) AE = no serious AE
RCT (bupivacaine) (2015) [61]		n = 84 E = headache days: from 18.1 (at baseline) to 8.8 (at 1 month); VAS = from 8.4 (at baseline) to 5.3 (at 1 month) AEs = local pain, vertigo
RCT (bupivacaine plus methylprenisolone) (2015) [64]	n = 70 E = 30% of the active and placebo groups AEs = pain at injection side
RCT (lidocaine plus saline versus lidocaine plus triamcinolone) (2014) [65]	n = 48 E = pain intensity: 5.46 (lidocaine plus triamcinolone group) versus 5.29 (lidocaine plus saline group) at week 8; headache frequency: 8.38 versus 9.42 at week 8 AEs = no serious AEs
RCT prospective (bupivacaine) (2018) [66]	n = 60 E = pain scale score from 9 to 1 (in GON block group) AEs = no serious AEs
RCT (pulsed RF versus depomethylprednisolone) (2015) [63]	n = 9	n = 20 E = headache frequency from 3.140 (at baseline) to 1.810 (at 6 week) in steroid injection group; from 3.640 (at baseline) to 1.708 (at 6 week) in pulsed RF group AE = no serious AEs
RCT (long- and rapid acting salts of betamethasone) (2005) [129]			n = 16 E = 85% of the patients AEs = transient pain at the injection site	n = 7 E = 85% of the patients AEs = transient pain at the injection site
Open-label (bupivacaine) (2016) [67]	n = 78 E = attack frequency: from 15.73 (at baseline) to 4.52 (at month 3) in group GON blockade versus from 13.76 to 3.28 in group GON blockade + prophylactic medication; headache severity: from 8.26 to 5.16 (in group GON blockade) versus from 8.80 to 5.96 (in group GON blockade + prophylactic medication) AEs = no serious AEs
Open-label (bupivacaine) (2017) [59]	n = 18 patients (22 aura symptoms) E = 86% of the aura symptoms AEs = no serious AEs
Open-label retrospective (bupivacaine) (2017) [68]		n = 41 E = headache frequency: unilateral GON block: from 20.0 (at baseline) to 9.9 (at 3 month post-treatment) versus bilateral GON block: from 20.44 to 12.00; pain intensity: unilateral GON block: from 7.05 to 5.11 versus bilateral GON block: from 6.84 to 5.91 AEs = no serious AEs
Open-label observational case series (high volume lidocaine+triamcinolone) (2018) [130]				n = 10 E = 100% of the patients (for mean of 65.1 days post-treatment pain-free period) AEs = no serious AEs
Open-label prospective (methylprednisolone) (2014) [131]				n = 83 E = 57% of the patients AEs = tenderness at the injection site, neck stiffness, dizziness
Open-label case series (GON and/or SON or trochlear area) (bupivacaine plus mepivacaine) (2012) [150]						n = 22 E = 100% of the patients (reduction in pain intensity) AEs = no serious AEs
Retrospective cohort study (bupivacaine, lidocaine) (2018) [69]	n= 562 E = 58% of the patients AEs = vasovagal symptoms, burning feeling at the injection site
Retrospective analysis (betamethasone) (2012) [133]			n = 31	n = 29 E = 64.8% of the patients (after first injection) AEs = local pain, facial oedema, insomnia, acne, bradycardia, syncope
Prospective observational (triamcinolone plus bupivacaine) (2017) [134]			n = 61	n= 40 E = 83.2% of the patients AEs = no serious AEs
Single-center retrospective comparative (GON blockade with methylprednisolone versus oral steroid with prednisone and dexamethasone) (2018) [132]			n = 29	n = 12 E = 82.7% of oral steroid encounters (n = 81) and 64.4% of GON injection encounters (n = 59) AEs = no AEs were recorded

Abbreviations: AE = adverse event; CH = cluster headache; E = effectiveness (at least 50% improvement in headache frequency and/or intensity); GON = greater occipital nerve; n = number of the randomized patients; NRS = numeric rating scale; RCT = randomized multicenter double-blind controlled trial; SON = supraorbital nerve; SUNHA = short-lasting unilateral neuralgiform headache attacks; TAC = trigeminal autonomic cephalalgia; VAS = Visual Analogue Scale.

Table 5. Data of the sphenopalatine ganglion (SPG) stimulation and blockade studies in drug-refractory primary headache disorders.

Study design		Migraine		Cluster headache (CH)		Other TACs
		Episodic migraine (EM)	Chronic migraine (CM)	Episodic CH	Chronic CH	SUNHA	Hemicrania continua
Electrical stimulation of SPG
Multicenter RCT (the PATHWAY CH-I study) (2013) [126]					n = 32 E = 68% of the patients AEs = loss of sensation in the maxillary nerve region
Long-term open-label follow-up of the PATHWAY CH-I study (attack remission) (2016) [123]					n = 33 E = 30% of the patients at least one episode of complete attack remission AEs = no serious AEs
Long-term open-label follow-up of the PATHWAY CH-I study (effectiveness) (2017) [127]					n = 33 E = 61% of the patients AEs = no serious AEs
The PATHWAY R-1 register study (2018) [128]				n = 7 E = 71.4% (frequency) AEs = not detailed	n = 78 E = 65% AEs = 73% postoperative sequelae
Radiofrequency (RF) ablation of SPG
Prospective open-label follow-up (pulsed RF) (2016) [137]				n = 13 E = 85% AEs = no seriousAEs	n = 3 E = 33% AEs = no serious AEs
Case series (2015) [138]					n = 3 E = 2 out of 3 patients no pain relief after pulsed RF; 3 out of 3 patients pain-free after continuous RF + SPG blockade
Ganglion (SPG) blockade with chemical agents
RCT pilot (bupivacaine) (2015) [74]			n = 41 E = 4.20 versus 2.85 NRS score AE = lacrimation, nasal irritation, mouth numbness, bad taste
Long-term RCT pilot (bupivacaine) (2015) [75]			n = 41 E = 17.44 versus 22.82 headache days at 1 month post-treatment AE = lacrimation, taste disturbances, oral numbing
Prospective open-label uncontrolled (onabotulinumtoxinA) (2017) [139]			n = 10 E = 80% AE = local discomfort in the face and jaw
Retrospective open-label uncontrolled (lidocaine) (2018) [77]			n = 55 E = 78.2% of the patients AEs = no serious AEs
Prospective open-label uncontrolled (onabotulinumtoxinA) (2016) [139]					n = 10 E = 50% AE = epistaxis, accomodation problem
Retrospective single-center open-label (absolute alcohol) (2014) [140]				n = 14 E = 76.5% AE = no serious AE
Case report (bupivacaine) (2016) [151]							n = 1 E = frequency: from 7/7 (baseline) to 2/7 (at week 4) and 0/7 (at week 6); intensity: VAS = 6/10 (at baseline) to 1/10 (at week 4) and 0/10 (at week 6) AE = no serious AE

Abbreviations: AE = adverse event; E = effectiveness (at least 50% improvement in headache frequency and/or intensity); n = number of the randomized patients; NRS = numeric rating scale, RCT = randomized multicenter double-blind controlled trial; RF = radio frequency; SPG = sphenopalatine ganglion; SUNHA = short-lasting unilateral neuralgiform headache attacks; TAC = trigeminal autonomic cephalalgia; VAS = Visual Analogue Scale.

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