Neuromodulation for Craniofacial Pain and Headaches

Neuromodulation for Craniofacial Pain and Headaches: History

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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.

headache
facial pain
stimulation
neuralgia
migraine
cluster
neuromodulation

1. Introduction

Headaches are a common complaint, with an estimated lifetime prevalence of 95% and a general prevalence of 48.9% ^[1]. They are classified based on their characteristics as outlined in the International Classification of Headache Disorders (ICHD); primary headaches are classified as migraine, tension-type, trigeminal autonomic cephalgia (e.g., cluster headache), or other primary headache disorders. Secondary headaches or other facial pain have a larger differential, including trauma to the head and/or neck, cranial or cervical vascular disease, nonvascular intracranial disorders, substance use or withdrawal, infection, a disorder of homeostasis, other structural disorder, psychiatric disorders, or other. As one might expect from the terminology, primary headaches have no known underlying cause, while secondary headaches result from another condition that may cause traction or inflammation of pain-generating structures, such as the trigeminal nerve ^[2]. Primary headaches constitute nearly 98% of all headaches, but secondary headaches are important to recognize as they may often be a consequence of life-threatening disorders ^[1].

Facial pain may be classified according to reported symptoms and history. The differential diagnosis is broad, including pain of musculoskeletal origin, dental pain, primary headache, neuralgia, neuropathy, etc. ^[3]^[4]^[5]^[6]^[7].

Though most headaches may not be life-threatening, they are still a source of significant discomfort for patients, and so treatment is an important consideration for physicians. Primary headache management varies depending on type but generally includes some type of abortive medication, as well as preventive if frequency is high enough. For example, in the case of migraines, a patient may use acetaminophen, an NSAID, or triptan (or some combination thereof) as an abortive and take a daily amitriptyline for prevention. There are a few procedures that are also used for headaches. OnabotulinumtoxinA, commonly known as “Botox” and nerve blocks (specifically of the greater occipital nerve) are also treatment options for migraine prophylaxis ^[1]^[2].

Neuromodulation has been gaining significant interest and popularity in the treatment of various chronic pain disorders, including neuropathic and back pain. It refers to a technique that uses pulsed electrical energy near a nerve or spinal cord, using leads implanted into a nearby space. This technique is based on the gate control theory of pain, initially proposed by Melzac and Wall in 1965. The conventional understanding of how neuromodulation works to reduce pain is that by stimulating larger A-beta fibers, pain signals carried by smaller C- and A-delta fibers may be interrupted ^[8]^[9]. It is stated that the first reported clinical application of spinal cord stimulation was two years later, but its popularity has been increasing significantly since ^[10]. The first reported case in the management of intractable headaches was in the late 1990s ^[11].

2. Neuromodulation for Craniofacial Pain and Headaches

The results of neurostimulation in the context of headaches and facial pain are promising, especially in patients with pain refractory to other treatment modalities. In addition, given the significant suffering that patients with these conditions may deal with, neuromodulation is a way to provide significant relief to many patients who suffer from these conditions. The use of neurostimulation may also help reduce or eliminate the need for preventive medications in patients as well as improve disability, quality of life, mood, and sleep. However, many of the studies published as of the writing of this entry are uncontrolled studies or case reports, which raise concerns for placebo effect and bias. This is in part due to practical considerations, such as the difficulty in blinding when many treatments elicit paresthesia and the relative rarity of some headache disorders, which was recognized by several authors. The crossover study design does mitigate this somewhat and, for this reason, many trials have exploited it in their studies.

There is also a question of the long-term efficacy of neuromodulation. Many studies do show promise in some patients up to a few months out from implantation, but some do appear to experience the recurrence of headaches after some time. However, this may be secondary to technical failures, as some studies found that effective stimulation was not being delivered at the time of follow-up. Interestingly, there appear to be several patients reported in the cited studies who had had the exact opposite and found that they were able to explant permanent stimulators due to significant pain relief. A summary of cited studied are provided in Table 1.

Table 1. Summary of cited articles categorized by targeted nerves.

Occipital Nerve
Author	Study Type	Condition	Targeted Nerve(s)	Number of Participants	Type of Intervention	Outcome
Weiner et al. ^[12]	Prospective	Occipital Neuralgia	Occipital	13	PNS	67% of patients with >75% pain relief; 33% of patients with >50% pain relief
Rajat et al. ^[13]	Case	Occipital Neuralgia	Occipital	1	PNS	0/10 pain scale at five- and twelve-month follow-ups
Salmasi et al. ^[14]	Case	Occipital Neuralgia	Occipital	3	PNS	55% (range 25–90%) pain relief at nine (range 6–16 months) months
Oh et al. ^[15]	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
Kapural et al. ^[16]	Case-series	Occipital Neuralgia	Occipital	6	PNS	71% decrease in VAS and 72% decrease in pain disability index scores
Slavin et al. ^[17]	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
Raoul et al. ^[18]	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
Miller et al. ^[19]	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
Pascual et al. ^[20]	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%
Balossier et al. ^[21]	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%)
Mueller et al. ^[22]	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
Magis et al. ^[23]	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
Magis et al. ^[24]	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
Leone et al. ^[25]	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
Burns et al. ^[26]	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
Burns et al. ^[27]	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
Fontaine et al. ^[28]	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
Garcia-Ortega et al. ^[29]	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
Miller et al. ^[30]	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
Tepper et al. ^[31]	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
Wilbrink et al. ^[32]	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
Popeney et al. ^[33]	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
Oh et al. ^[15]	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
Rodrigo et al. ^[34]	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
Ashkan et al. ^[35]	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
Schwedt et al. ^[36]	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
Matharu et al. ^[37]	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
Serra et al. ^[38]	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
Silberstein et al. ^[39]	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
Saper et al. ^[40]	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
Slotty et al. ^[41]	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
Mekhail et al. ^[42]	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
Liu et al. ^[43]	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
Deshpande et al. ^[44]	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
Trentman et al. ^[45]	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
Slavin et al. ^[46]	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
Author	Study Type	Condition	Targeted Nerve(s)	Number of Participants	Type of Intervention	Outcome
Logghe et al. ^[47]	Case	Trigeminal Neuropathy	Trigeminal Ganglion	2	PNS	Total resolution of symptoms within weeks to months after implantation in both patients
Taub et al. ^[48]	Prospective	Trigeminal Neuropathy	Trigeminal Ganglion	34	PNS	Of the group with permanent implantation, 53% patients with >50% pain relief
Texakalidis et al. ^[49]	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
Mehrkens et al. ^[50]	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
Holsheimer et al. ^[51]	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
Author [Citation]	Study Type	Condition	Targeted Nerve(s)	Number of Participants	Type of Intervention	Outcome
Dunteman et al. ^[52]	Case	Postherpetic Neuralgia	Supraorbital	2	PNS	Significant reduction in VAS score and discontinuation of opioid medication
Hann et al. ^[53]	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
Johnson et al. ^[54]	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
Narouze et al. ^[55]	Case	Cluster	Supraorbital	1	PNS	Successful relief and resolution of symptoms after implantation
Amin et al. ^[56]	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
Vaisman et al. ^[57]	Prospective	Cluster	Supraorbital	5	PNS	VAS scores decreased from 8.9 to 1.6; reported improvement in frequency and intensity of attacks
Reed et al. ^[58]	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
Schoenen et al. ^[59]	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
Chou et al. ^[60]	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
Russo et al. ^[61]	Prospective	Migraine	Supraorbital	24	PNS	81% patients with >50% reduction in migraine attacks, 75% patients with >50% reduction in migraine days per month
Jiang et al. ^[62]	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
Reed et al. ^[63]	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
Asensio-Samper et al. ^[64]	Case	Supraorbital Neuralgia, Traumatic	Supraorbital	1	PNS	14-day trial resulting in improvement of VAS score; permanent implantation to discontinue medications
Vagus Nerve
Author	Study Type	Condition	Targeted Nerve(s)	Number of Participants	Type of Intervention	Outcome
Sadler et al. ^[65]	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
Mauskop et al. ^[66]	Case	Migraine (4), Cluster (6) Headaches	Vagus	6	PNS	33% patients with “excellent” response, 33% with “good” response to vagus nerve stimulation
Trimboli et al. ^[67]	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
Trimboli et al. ^[67]	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
Trimboli et al. ^[67]	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
Nesbitt et al. ^[68]	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
Marin et al. ^[69]	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
Silberstein et al. ^[70]	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
Goadsby et al. ^[71]	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
Gaul et al. ^[72]	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
Trimboli et al. ^[67]	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
Lenaerts et al. ^[73]	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
Hord et al. ^[74]	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
Goadsby et al. ^[75]	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
Kinfe et al. ^[76]	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
Barbanti et al. ^[77]	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
Tassorelli et al. ^[78]	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
Diener et al. ^[79]	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
Najib et al. ^[80]	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
Silberstein ^[81]	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
^[82]	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
Author	Study Type	Condition	Targeted Nerve(s)	Number of Participants	Type of Intervention	Outcome
Al-Kaisy et al. ^[83]	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
Wolter et al. ^[84]	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
Dario et al. ^[85]	Case	Post-Traumatic Headache	Cervical Spinal Cord	1	SCS (cephalad end of C3–C4)	80% improvement of neck pain and resolution of supraorbital pain
Zhao et al. ^[86]	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
Author [Citation]	Study Type	Condition	Targeted Nerve(s)	Number of Participants	Type of Intervention	Outcome
Mammis et al. ^[87]	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
Elahi et al. ^[88]	Case	Migraine	Great Auricular	1	PNS	At six-month follow-up, significant alleviation of pain
Elahi et al. ^[89]	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
Simopoulos et al. ^[90]	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
Zhou et al. ^[91]	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
Tepper et al. ^[92]	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
Jürgens et al. ^[93]	Open-Label Prospective	Cluster Headache	Sphenopalatine Ganglion	33	PNS	45% patients with >50% attacks, >50% reduction in attack frequency
Goadsby et al. ^[94]	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
Elahi et al. ^[95]	Case	Facial Pain	Sphenopalatine Ganglion (pteyrgopalatine fossa)	1	PNS	Complete discontinuation of opioid-based medication

In 2013, the European Headache Federation released a position on the use of neuromodulation for chronic headaches. Based on the available evidence at the time, it had recommended neurostimulation only in cases of chronic, medically intractable headaches. In the treatment of cCH, it recommended SPG or ONS prior to other forms of neurostimulation, such as DBS and in the management of CM, it stated that ONS may be acceptable. It did acknowledge that RCTs were scarce and that further trials may change the position on their use ^[96]. In 2021, the American Headache Society also stated that patients with intractable migraines or those with poor tolerability or contraindications with medications should be considered for a trial with FDA-approved neuromodulatory devices. For preventive treatment, they stated that all patients should be considered for a trial as an adjunct to the existing treatment plans ^[97].

A meta-analysis conducted in 2022 analyzed 45 studies studying preemptive treatments for refractory cCH, most focusing on neuromodulation. Consistent with the European Headache Federation’s recommendation years prior, the authors note that ONS appeared to be promising for the treatment of cCH. They also noted that DBS showed promise but had more heterogeneous results and a higher risk of complications ^[98]. Another meta-analysis analyzing 38 articles focused on acute or preventive treatment of migraines also noted the efficacy of ONS in terms of preventive migraine treatment ^[99].

3. Complications

Taking the cited studies into consideration, the most common complications are hardware-related, of which the majority are lead migration or battery depletion, but also include the malfunction of the electrodes. Though not as common as hardware complications, biologic events, commonly pain at the site of the implantable pulse generator (IPG) site or infections can also occur ^[14]^[16]^[17]^[20]^[21]^[24]^[25]^[29]^[30]^[31]^[32]^[34]^[35]^[37]^[38]^[39]^[41]^[81].

A retrospective analysis of a prospective, multicenter, double-blind controlled study on ONS for the management of chronic migraine aimed to analyze adverse event incidence rate’s relationship with device characteristics, surgical techniques, and IPG placement was carried out. The researchers noted that IPG pocket locations closer to the lead and more experienced implanters were associated with lower complication rates ^[95].

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11123328

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