Headaches and facial pain are highly prevalent diseases but are often difficult to treat. Though there have been significant advances in medical management, many continue to suffer from refractory pain. Neuromodulation has been gaining interest for its therapeutic purposes in many chronic pain conditions, including headaches and facial pain. There are many potential targets of neuromodulation for headache and facial pain, and some have more robust evidence in favor of their use than others.
Occipital Nerve |
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Author |
Study Type |
Condition |
Targeted Nerve(s) |
Number of Participants |
Type of Intervention |
Outcome |
Prospective |
Occipital Neuralgia |
Occipital |
13 |
PNS |
67% of patients with >75% pain relief; 33% of patients with >50% pain relief |
|
Case |
Occipital Neuralgia |
Occipital |
1 |
PNS |
0/10 pain scale at five- and twelve-month follow-ups |
|
Case |
Occipital Neuralgia |
Occipital |
3 |
PNS |
55% (range 25–90%) pain relief at nine (range 6–16 months) months |
|
Technical Report |
Occipital Neuralgia |
Occipital |
10 |
PNS (C1-3 paddle-style electrode) |
At one month, 80% patients with >90% pain reduction; 20% patients with 75–90% pain reduction; at six months, 78% patients with >90% pain reduction, 11% patients with 50–75% pain reduction |
|
Case-series |
Occipital Neuralgia |
Occipital |
6 |
PNS |
71% decrease in VAS and 72% decrease in pain disability index scores |
|
Retrospective |
Occipital Neuralgia |
Occipital |
14 |
PNS |
At mean follow-up of 22 months (range five-32 months), 50% patients pain-free, 30% with significant pain relief |
|
Retrospective |
Occipital Neuralgia |
Occipital |
60 |
PNS |
72.2% decrease in VAS and 72.7% decrease in number of headache days per month after one year |
|
Prospective |
Short-lasting Unilateral Neuralgiform Headache (SUNCT syndrome) |
Occipital (bilateral) |
31 |
PNS |
At mean follow-up of 44.9 months (range 13–89 monts), 69% decrease in mean daily attack frequency; 38.7% of patient pain-free at the final follow-up |
|
Crossover |
Hemicrania Continua |
Suboccipital |
6 |
PNS |
At median follow-up of 13.5 months (range 6–21 months), 67% patients with 80–95% improvement, 17% patients with 30% improvement, and 17% patients with worsening pain by 20% |
|
Retrospective |
Trigeminal Neuralgia |
Occipital |
7 |
PNS |
Mean follow-up of 59 months (range 2–106 months); mean pain relief of 86.7% (range 70–100%); at last follow-up, mean pain relief of 58% (range 0–100%) |
|
Prospective |
Cluster Headache |
Occipital |
10 |
PNS |
90% patients with improvement; mean overall improvement of 44% (range 20–90%) of attacks; 30% patients with up to 19 days of pain-free period |
|
Prospective |
Cluster Headache |
Suboccipital |
8 |
PNS |
Mean follow-up of 15.1 (range 3-22 months) months; 25% patients pain-free at 16 and 22 months, 38% patients with 90% attack frequency reduction, 25% patients with 40% improvement |
|
Prospective |
Cluster Headache |
Suboccipital |
15 |
PNS |
Mean follow-up of 36.82 months; 80% patients with 90% improvement in pain, 60% patients pain-free, 13% patients with no or mild improvement |
|
Monocentric, Open-Label |
Cluster Headache |
Occipital |
35 |
PNS |
Median follow-up of 6.1 (range 1.6–10.7 years) years; decrease in mean number of daily attacks from 5.7 to 2.4; 66.7% patients with >50% reduction in number of headache per day |
|
Prospective |
Cluster Headache |
Occipital (bilateral) |
14 |
PNS |
Median follow-up of 17.5 (range four-35 months) months; 71% patients with improvement in frequency, severity, or duration; 30% patients with 90% improvement, 30% patients with >40% improvement, 40% patients with 20–30% improvement |
|
Prospective |
Cluster Headache |
Occipital (bilateral) |
8 |
PNS |
Median follow-up of 20 (range eight-27 months) months; 75% patients with improvements; 25% patients with >90% improvement in attacks, 38% patients with >40% improvement, 13% patients with >25% improvement |
|
Cohort |
Cluster Headache |
Occipital (bilateral) |
13 |
PNS |
Mean follow-up of 14.6 (range three-34 months) months; 77% patients with improvements within a few days of implantation; eight patients with 68% decrease in mean attack frequency and 49% decrease in mean attack intensity on NRS at one-year follow-up |
|
Retrospective |
Cluster Headache |
Occipital |
17 |
PNS |
60% patients with complete remission, 100% patients with >80% decrease in attack frequency with a mean reduction of 42% in residual headache intensity |
|
Prospective |
Cluster Headache |
Occipital (bilateral) |
51 |
PNS |
Mean follow-up of 39.17 months; 52.9% patients with >50% decrease in daily attack frequency, 47.1% patients with six months of continuous pain relief; of 27 patients using preventive medications at baseline, four ceased all preventive medication use and 17 reduced use |
|
Prospective |
Cluster Headache |
Occipital (bilateral) |
67 |
PNS |
At three-month follow-up, 75% patients with >30% reduction in attack frequency; at 12 months follow-up, 64% patients with >30% reduction in attack frequency and 59% patients with >50% reduction |
|
Randomized Controlled Trial (multicenter, double-blind, phase 3) |
Cluster Headache |
Occipital |
131 |
PNS |
Ten-day run = in phase, 24-week treatment period; Decrease in median weekly mean attack frequency (MAF) from 7.38 to 5.21 after ONS onset; between weeks 21–24 and 45–48, about 50% of patients with >50% pain relief |
|
Case Series |
Migraine |
Occipital |
25 |
PNS |
Mean follow-up of 18.3 (range nine-36 months) months; Mean headache frequency reduction from 75.6 days to 37.5 days; mean severity on a NRS scale of 0–10 decreased from 9.32 to 5.72 |
|
Prospective |
Migraine |
Occipital |
10 |
PNS (C1-3 paddle electrode) |
At one-month follow-up, 90% patients with >90% pain reduction, 10% patients with 75–90% reduction in pain; at six-month follow-up, 78% patients with >90% pain reduction, 22% patients with 75–90% pain reduction |
|
Prospective |
Migraine |
Occipital |
41 |
PNS |
Mean follow-up of 9.4 years; VAS decrease by 4.9, the number of migraine days per month reduction by 59.2%; 13.9% patients with permanent implantation pain-free at last visits |
|
Prospective |
Migraine |
Occipital |
112 |
PNS |
At three-month follow-up, mean reported pain relief of 25.1% and 21.7% patients with >50% pain relief; at nine- and 12-month follow-ups, reported pain relief of 30.8%, and 28.5% patients with >50% relief |
|
Retrospective |
Migraine |
Occipital (eight bilateral; seven unilateral) |
15 |
PNS |
Mean follow-up of 17.8 (range 6–36 months) months; severity reduction from 6.75 to 4.5 on a 0–10 scale; MIDAS from 170 to 116; HIT-6 from 73 to 61; BDI-II from 19 to 11.5 |
|
Case Series |
Migraine |
Suboccipital (bilateral) |
8 |
PNS |
Mean follow-up of 1.5 years (range seven months to three years); 50% patients pain-free with only rare breakthrough headaches; 25% with very good responses with suppression of headaches |
|
Prospective, randomized cross-over |
Migraine |
Occipital |
34 |
PNS |
Trial period of 15–30 days; Average follow-up of 45 days (range 12 to 122 days); 9% patients with >50% reduction in the number of attacks, 22% patients with >50% reduction in the severity of attacks, 66% patients with >50% reduction in both number and severity |
|
Randomized Controlled Trial (double-blind) |
Migraine |
Occipital |
268 |
PNS |
157 subjects with permanent implantation; 59.5% patients > 30% reduction in headache days and/or pain intensity, 47.8% patients > 50% in headache days |
|
Randomized Controlled Trial |
Migraine |
Occipital |
75 |
PNS |
At three months follow-up, 39% of adjustable stimulation (AS) group, 6% of preset stimulation (PS) group, and 0% of medical management (MM) group with reduction of >50% in number of headache days per month |
|
Randomized Controlled Trial |
Migraine |
Occipital (bilateral) |
8 |
PNS |
No significant differences in improvement of VAS between “effective”, “subthreshold”, and “no” stimulation from the prior ONS |
|
Randomized Controlled Trial |
Migraine |
Occipital |
20 |
PNS |
Randomized to either active or no stimulation for 12 weeks, followed by 40 weeks of active simulation; after twelve week randomization period, 60% active group with >30% reduction in VAS, 20% control group with >30% reduction in VAS; at the end of 52 weeks/open phase, 60% patients with >30% reduction in VAS, 25% patients with >50% reduction in VAS |
|
Randomized Controlled Trial |
Migraine |
Occipital |
110 |
PNS |
Randomized into transcutaneous ONS (2 Hz, 100 Hz, 2/100 Hz, sham) and treatment with topiramate; only the 100 Hz tONS and topiramate groups with significant differences in reduction of headache days compared to sham |
|
Case |
Complicated Migraine, Occipital Neuralgia, combined (phophobia, temporary bilateral vision loss, slurred speech, ptosis, hemiplegia) |
Occipital, bilateral subcutaneous temporal region |
1 |
PNS |
At 24-month follow-up, 50% reduction in the onset of headache and resolution of neurologic deficits |
|
Prospective |
Primary Headache, combined |
Occipital |
9 |
PNS |
62.5% patients with excellent, 25% with fair, and 12.5% with poor responses; mean decrease of 28.5 in headache days, average decrease in headache severity score of 0.88 |
|
Prospective |
Craniofacial Pain |
Infraorbital |
30 |
PNS |
22/30 patients with 50% reduction in pain intensity, of whom three had infraorbital, four had supraorbital, 13 had occipital, and one had a combination of infraorbital and occipital, and one had a combination of supraorbital and occipital stimulations; mean follow-up of 35 months (range 1–77 months); 73% of 22 patients with implantation with >50% improvement in pain intensity and 13.5% with <50% improvement. |
|
Trigeminal Ganglion |
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Author |
Study Type |
Condition |
Targeted Nerve(s) |
Number of Participants |
Type of Intervention |
Outcome |
Case |
Trigeminal Neuropathy |
Trigeminal Ganglion |
2 |
PNS |
Total resolution of symptoms within weeks to months after implantation in both patients |
|
Prospective |
Trigeminal Neuropathy |
Trigeminal Ganglion |
34 |
PNS |
Of the group with permanent implantation, 53% patients with >50% pain relief |
|
Retrospective Case Series |
Trigeminal Neuropathy |
Trigeminal Ganglion |
59 |
PNS |
70% patients with positive results with a trial of trigeminal stimulation; history of oral surgery, facial trauma predictive of failure |
|
Kustermans et al. [6] |
Retrospective |
Trigeminal Neuropathy |
Trigeminal Ganglion |
22 |
PNS |
At the initial follow-up, 88% patients with >50% reduction of pain; at six-month follow-up, 93.8% patients with some level of pain relief; at 24 months, 46.7% patients with some level of pain relief |
Prospective |
Trigeminal Neuropathy |
Trigeminal Ganglion |
321 |
PNS |
At a long-term follow-up (range five to 25 years), 52% patients with >50% pain reduction, 82% patients with good or excellent analgesia |
|
Prospective |
Trigeminal Neuralgia |
Trigeminal Ganglion |
267 |
PNS |
48% patients with >50% long-term pain relief; patients with postherpetic neuralgia with low success rate of 10% |
|
Supraorbital/Supratrochlear Nerve |
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Author [Citation] |
Study Type |
Condition |
Targeted Nerve(s) |
Number of Participants |
Type of Intervention |
Outcome |
Case |
Postherpetic Neuralgia |
Supraorbital |
2 |
PNS |
Significant reduction in VAS score and discontinuation of opioid medication |
|
Prospective |
Postherpetic Neuralgia |
Supraorbital, Occipital, combined |
14 |
PNS |
Follow-up ranging from three to 60 months; 71% patients > 50% reduction in pain severity with mean VAS score reduction of 3.92 |
|
Prospective |
Postherpetic Neuralgia |
Supraorbital, Infraorbital |
10 |
PNS |
At the mean follow-up of 26.6 months post-transplantation, 70% patients with >50% reduction in pain and decreased medication use |
|
Case |
Cluster |
Supraorbital |
1 |
PNS |
Successful relief and resolution of symptoms after implantation |
|
Retrospective |
Cluster |
Supraorbital |
16 |
PNS |
Ten patients with permanent implantation; significant reduction in headache scores after five to seven days of stimulation, persisting up to thirty weeks; significant decrease in morphine equivalent required |
|
Prospective |
Cluster |
Supraorbital |
5 |
PNS |
VAS scores decreased from 8.9 to 1.6; reported improvement in frequency and intensity of attacks |
|
Prospective |
Cluster |
Supraorbital, Occipital, combined |
7 |
PNS |
Mean follow-up of 25.2 months; all patients with improvements in functional status, VAS, and frequency of headaches |
|
Randomized Controlled Trial (multicenter) |
Cluster |
Supraorbital |
67 |
PNS |
Significant decrease in mean number of migraine days, difference in 50% responder rate, monthly migraine attacks, monthly headache days, monthly acute anti-migraine drug intake |
|
Randomized Controlled Trial (multicenter, double-blind) |
Migraine |
Supraorbital, Supratrochler, combined |
106 |
PNS |
At one, two, and 24 h, mean change in pain score significantly reduced in the verum group compared to the sham; 29% of verum group pain-free, while 6% of sham group pain-free |
|
Prospective |
Migraine |
Supraorbital |
24 |
PNS |
81% patients with >50% reduction in migraine attacks, 75% patients with >50% reduction in migraine days per month |
|
Randomized Controlled Trial |
Migraine |
Supraorbital |
154 |
PNS |
At three-month follow-up, more pronounced reduction in days of migraine per month in the combination group of flunarizine with neurostimulation; 50% responder rate of 78.43% in combination group, 46.15% in flunarizine monotherapy, and 39.22% in supraorbital stimulation monotherapy |
|
Prospective |
Hemiplegic Migraine |
Supraorbital, Occipital, combined |
4 |
PNS |
Follow-up period running 6 to 92 months post-transplantation; mean headache frequency by 92% from 30 to 2.4 headache days per month; VAS reduction by 44% from 9.5 to 5.3; frequency of hemiplegic episode reduction by 96% from 7.5 to 0.25 |
|
Case |
Supraorbital Neuralgia, Traumatic |
Supraorbital |
1 |
PNS |
14-day trial resulting in improvement of VAS score; permanent implantation to discontinue medications |
|
Vagus Nerve |
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Author |
Study Type |
Condition |
Targeted Nerve(s) |
Number of Participants |
Type of Intervention |
Outcome |
Case |
Non-Specific/ Combination Primary Headache; history of epilepsy |
Vagus |
1 |
PNS |
Reduction in migraine attack frequency from three in one month to three in 13 months |
|
Case |
Migraine (4), Cluster (6) Headaches |
Vagus |
6 |
PNS |
33% patients with “excellent” response, 33% with “good” response to vagus nerve stimulation |
|
Prospective |
Short-Lasting Neuralgiform Headache Attacks with Autonomic Symptoms (SUNA) |
Vagus |
2 |
PNS |
At three-month follow-up, the patients with SUNA reported noticeable improvement |
|
Prospective |
Hemicrania Continua |
Vagus |
4 |
PNS |
At three-month follow-up, 50% of the patients with HC reported meaningful improvement; one patient with 72.7% decrease in headache exacerbations at three months |
|
Prospective |
Cluster Headache |
Vagus |
12 |
PNS |
At three-month follow-up, 8% of patients with >30% reduction in weekly CH frequency and reduction in oxygen use per week, 17% patients with slight improvement in weekly frequency, 25% patients with no changes to headache, and 50% with worsening of CH frequency |
|
Cohort, Open-Label |
Cluster Headache |
Vagus |
19 |
PNS |
Mean improvement in condition from baseline by 50%; a near 50% reduction in attack frequency in patients using nVNS preventively |
|
Retrospective |
Cluster Headache |
Vagus |
30 |
PNS |
53% patients used as preventive therapy, 3% patients used exclusively for acute, and 43% patients for both; mean follow-up of 7.6 (range 0.0 to 27.5 months) months; 10% patients free of attack |
|
Randomized Controlled Trial (double-blind) |
Cluster Headache |
Vagus |
150 |
PNS |
No significant differences in response rate, sustained treatment response rate, the percentage of patients who were responders, and of those who were pain relief for at least 50% of treated attacks |
|
Randomized Controlled Trial (double-blind) |
Cluster Headache |
Vagus |
102 |
PNS |
Randomized to a sham or active nVNS group for two weeks, then an open-label period for two weeks; significantly higher proportion of treated attacks that achieved pain-free status in nVNS than that of sham in the episodic CH group |
|
Randomized Controlled Trial (open-label) |
Cluster Headache |
Vagus |
97 |
PNS |
At four-week follow-up, statistically significant reduction in the number of attacks per week in nVNS group compared to the control (−5.9 vs. −2.1); during the randomized phase, 57% decrease in the frequency of abortive medication use in the treatment group |
|
Prospective |
Migraine |
Vagus |
23 |
PNS |
8.7% patients with >30% reduction of headache days, 17.4% with <30% reduction, 30.4% patients with worsening number of headache days, and 43.5% patients with no change |
|
Retrospective |
Migraine |
Vagus |
34 |
PNS |
Mean follow-up of 17 (range 4–36 months) months; 80% patients with >50% reduction in monthly frequency, in the first three month of placement |
|
Retrospective |
Migraine |
Vagus |
62 |
PNS |
25% patients with complete pain relief, 25% patients with mild pain relief, and 50% patients with a lot of pain relief; 100% patients with a dcrease in migraine frequency |
|
Open-Label, Single-Arm, Multiple Attack, Pilot |
Migraine |
Vagus |
30 |
PNS |
For the first attack, after two hours of treatment, 21% patients with baseline moderate or severe headache reported pain-free and 47% patients reported partial pain relief |
|
Prospective, Observational Cohort |
Migraine |
Vagus |
20 |
PNS |
Median pain VAS reduction from 8 (range 7.5 to 8) to 4 (range 3.5 to 5); mean number of headache days per month decreased by 39.5% in tota; migraine attacks per month decreased by 38.4%l |
|
Open-Label, Single-Arm, Multicenter |
Migraine |
Vagus |
50 |
PNS |
56.3% patients with >50% pain reduction at one hour, 62.9% of whom reported pain-free; 64.6% patients with >50% pain reduction at two hours, 61.3% of whom reported being pain-free |
|
Randomized Controlled Trial |
Migraine |
Vagus |
248 |
PNS |
At 120 min, statistically significant difference in pain-free responder rate in nVNS compared to sham; nVNS superior to sham in abortion of the first treated attack at 30 and 60 min, but not at 120 min |
|
Randomized Controlled Trial (prospective, multicenter, double-blind, parallel-group) |
Migraine |
Vagus |
477 |
PNS |
No statistically significant difference in the number of migraine days per month, percentage of patients with at least 50% reduction in number of migraine days, mean reductions in the number of headache days, nor reductions in the number of acute medication days |
|
Randomized Controlled Trial |
Migraine |
Vagus |
336 |
PNS |
After 12-week of double-blind period, nVNS group with statistically significant difference in the proportion of >50% reduction in the number of migraine days |
|
Prospective, Multicenter, Double-Blind, Sham-Controlled, Pilot |
Migraine |
Vagus |
73 |
PNS |
No statistically significant difference in the number of headache days during the randomized phase; statistically significant decrease in mean headache days after eight months in the nVNS group during the open-label phase |
|
Randomized Controlled Trial (Monocentric, Prospective, Double-Blind) |
Migraine |
Vagus |
46 |
PNS |
36.4% reduction in headache days in the 1 Hz group and 17.4% reduction in the 25 Hz group; 29.4% in the 1 Hz and 13.6% in the 25 Hz group reported >50% improvement in headache days |
|
Cervical Spinal Cord |
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Author |
Study Type |
Condition |
Targeted Nerve(s) |
Number of Participants |
Type of Intervention |
Outcome |
Prospective, Long-Term, Single-Center, Open-Label |
Migraine |
Cervical Spinal Cord |
20 |
SCS (10 kHz) |
At 52-week follow-up, 60% patients with >30% reduction in mean monthly migraine days (MMD) and 50% patients with >50% reduction in mean MMD |
|
Prospective |
Cluster Headache |
Cervical Spinal Cord |
7 |
SCS (high cervical epidural electrodes) |
Mean follow-up of 23 (range three to 78 months) months; decrease in attacks per day from 5.0 (range 1.7–10.0 attacks/day) to 1.4 (range 0–3.5 attacks/day); reduction in mean VAS from 7.4 to 4.5 |
|
Case |
Post-Traumatic Headache |
Cervical Spinal Cord |
1 |
SCS (cephalad end of C3–C4) |
80% improvement of neck pain and resolution of supraorbital pain |
|
Case |
Postherpetic Neuralgia |
Cervical Spinal Cord |
1 |
SCS (C1–C2; 40 Hz) |
Reduction in NRS score from 7–9 to 1–2 post-implantation |
|
Infraorbital Nerve |
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Author [Citation] |
Study Type |
Condition |
Targeted Nerve(s) |
Number of Participants |
Type of Intervention |
Outcome |
Case |
Cluster Headache |
Infraorbital |
1 |
PNS |
At 36-month follow-up, reduction in frequency of headache from three-to-four episodes per day to three-to-four episodes per month |
|
Great Auricular Nerve |
||||||
Author |
Study Type |
Condition |
Targeted Nerve(s) |
Number of Participants |
Type of Intervention |
Outcome |
Case |
Migraine |
Great Auricular |
1 |
PNS |
At six-month follow-up, significant alleviation of pain |
|
Case |
Post- Traumatic Headache |
Great Auricular |
1 |
PNS (C2-C3 branches) |
At six-month follow-up, >90% reduction in headache frequency |
|
Auriculotemporal Nerve |
||||||
Author |
Study Type |
Condition |
Targeted Nerve(s) |
Number of Participants |
Type of Intervention |
Outcome |
Case |
Migraine |
Auriculotemporal (bilateral) |
1 |
PNS |
At 16-month follow-up, MIDAS decreased from grade IV (severe disability) to grade II (mild disability), and average pain intensity from 8–9 to 5 on a 0–10 scale |
|
Prospective |
Chronic Headache |
Auriculotemporal |
20 |
PNS |
At three-month follow-up, reduction in mean total pain index (TPI) from 516 to 74.8 post-implantation |
|
Sphenopalatine Ganglion |
||||||
Author |
Study Type |
Condition |
Targeted Nerve(s) |
Number of Participants |
Type of Intervention |
Outcome |
Prospective |
Migraine |
Sphenopalatine Ganglion |
11 |
PNS |
Two patients with a complete resolution of migraine headaches within three minutes of stimulation, three patients with reduction in pain, and five patients with no response, and one not stimulated |
|
Open-Label Prospective |
Cluster Headache |
Sphenopalatine Ganglion |
33 |
PNS |
45% patients with >50% attacks, >50% reduction in attack frequency |
|
Double-Blind, Randomized Controlled Trial |
Cluster Headache |
Sphenopalatine Ganglion |
93 |
PNS |
62.46% of SPG stimulation group with pain relief, while 38.87% of control group with pain relief |
|
Case |
Facial Pain |
Sphenopalatine Ganglion (pteyrgopalatine fossa) |
1 |
PNS |
Complete discontinuation of opioid-based medication |