1. Introduction 

Headaches are one of the most common medical complaints worldwide, with a prevalence rate of 46% in the general population [1]. A majority of headaches are of the migraine, tension, and cluster subtype, but many other forms exist. The healthcare burden of this is profound, as headaches consistently rank as the fourth or fifth most common reason for emergency-department visits in the United States, and they make it into the top 10 most disabling conditions according to the World Health Organization (WHO) [2]. There is also a significant economic impact from the burden of disease and the often-high cost of treatment. Unfortunately, diagnosis can be difficult, due in part to the complexity of its classification, contributions of referred pain from the spine, and presence of craniofacial pain syndromes. As our knowledge of the nervous system and pathophysiology of headaches and craniofacial pain has advanced, therapeutics have steadily moved towards directly targeting nerves of interest. After conservative measures have been exhausted, peripheral nerve stimulation (PNS) and field stimulation (PNFS) have emerged as a novel therapy for intractable headaches. Given the relatively recent advent of neuromodulation, this rentryview seeks to help clinicians better understands the efficacy of PNS for headaches,. We hope to summarize the high-yield evidence for the physician caring for these patients and provide an evidence-based overview of treatment strategies.

2. Classification

Headache disorders and craniofacial pain are often difficult to treat due to the confluence of the spine and both ascending/descending neural pathways in the region. Based on the International Classification of Headache Disorders (ICHD), headaches are generally classified as primary (migraine, tension-type, and cluster headaches) and secondary (caused by underlying systemic or neurologic conditions, trauma, medication overuse, substance withdrawal, and others) (Table 1) [3]. The location, duration, intensity, and characteristics of headache, along with associated symptoms, such as photophobia, phonophobia, nausea, and vomiting, are important in establishing a suitable diagnosis. Craniofacial pain includes lesions of specific nerves, such as the trigeminal, occipital, or vagus, which can lead to neuropathic pain. This overlap complicates the ability to tease out specific diagnoses from history alone, as presentations are often complex. Increasingly, physicians have utilized interventional techniques like PNS to treat all categories of headache disorders [4]. While some have shown promise, further data are needed to determine their true efficacy.

Table 1. Classification of headaches.

* SUNCT: short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. ** SUNA: short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms.

3. Conventional Management

Due to the complexity in etiology and presentation of headaches and craniofacial pain, treatment can be challenging. Typically, the first step in management is to explore and avoid known triggers, often in the form of caffeine, stress, poor sleep hygiene, and aspartame [5]. If pain continues despite this, the next step is typically pharmacological treatment in the form of oral medications, due to their relatively safe side-effect profile and simplicity of use.

Typically trialed in a stepwise fashion, escalations in management are made if no improvement in symptoms is seen. These are often measured by pain scoring (visual or otherwise) and by measures of disability, including days off work and days with symptoms. Oral pain medications are typically classified as either preventative (prior to an acute episode) or abortive (during an attack) [6]. While specific pharmaceuticals are used for the different headache subtypes, nonsteroidal anti-inflammatory drugs, anticonvulsants, selective serotonin reuptake inhibitors, tricyclic antidepressants, triptans, and corticosteroids are typically used as abortive medications ^[6][7][6,7]. Conversely, preventative therapies often include beta blockers, calcium channel blocks, and other anticonvulsants.

Despite multimodal approaches in management, many refractory cases resistant to conventional treatments subsist. Interestingly, medication overuse headaches have become increasingly prevalent, leading to a need for non-pharmacological interventions. Novel treatments pioneered and trialed in recent years include botulinum injections, nerve blocks, acupuncture, physical therapy, trigger-point injections, deep brain stimulation, and facet joint radiofrequency ablation for cervicogenic headaches ^[4][7] [4,7]. While a thorough discussion of the evidence behind the techniques is outside the scope of this review, it is clear that there is no one-size-fits-all approach. Increasingly, PNS has been utilized as a minimally invasive intervention for these complex disorders. Evidence for its use is the primary focus of this review.

4. Peripheral Nerve Stimulation

While specific guidelines are sparse, the use of PNS has generally been indicated for chronic neuropathic pain disorders originating from specific peripheral nerves. The source of pain should logically follow that of a specific nerve distribution. While the exact mechanism of pain relief is unclear, it is thought to involve activation of central endogenous pain-modulation pathways [8]. As with any other pain modality, the success of PNS relies largely on patient selection. A typical patient for PNS is one who has failed conventional medical treatments and one for whom surgery has been deemed inappropriate [9]. After establishing a diagnosis and exhausting conservative treatment measures, patients are typically referred to a specialist for further discussion of symptoms, physician examination, and review of relevant imaging. Comorbid psychological illnesses should also be explored, as these can significantly reduce intervention success rates ^[10][11][12][10,11,12]. PNFS indications are even more nebulous, as these involve targeted stimulation of smaller mostly unnamed nerves at the site of pain [11]. Various targets and techniques are outlined below, in addition to the high-yield evidence for each.

There are generally few absolute contraindications for PNS. These typically include medical allergies, local infections, coagulopathies, immunocompromised status, comorbidities preventing fluoroscopic needle guidance, and patient refusal ^[11][13][11,13]. As these are peripheral procedures, the risk of permanent damage is relatively low. Complications are also similarly mild, but they can include headaches, muscle cramping, subcutaneous hematomas, seromas, and local skin infections [8]. Other common complications, along with their incidence seen in literature, are highlighted in Table 2 below. One of the most common themes in preventing success of treatment is improper lead placement or post-operative migration, causing displacement of electrodes from their target nerves [14]. While correctable, this is often frustrating for the patient and can worsen outcomes.

5. What Does the Evidence Suggest?

One of the most well-studied targets for neurostimulation is the occipital nerve ( Table 3 ). The occipital nerves are a group of nerves that originate from the C2/C3 spinal nerves and innervate a significant portion of the scalp, ear, and other nearby structures. The three major occipital nerves include the greater occipital nerve (GON), lesser (or small) occipital nerve (LON), and third (least) occipital nerve (TON) [75,76]. Common pathologies treated by occipital nerve stimulation include occipital neuralgia, chronic migraines, and cluster headaches ( Table 4 ).

VAS = pain visual analog scale, PDI = pain disability index, MIDAS = migraine disability assessment score, Zung = pain and distress score (PAD), SF-36 short form health surgery (measure of quality of life).

The trigeminal nerve carries sensory components for much of the head and innervates muscles in the lower jaw. It then divides into the ophthalmic (V1), maxillary (V2), and mandibular (V3) branches [77]. The ophthalmic further divides into the supraorbital nerve and the supratrochlear nerve, while the auriculotemporal nerve is a branch of the mandibular nerve.

Jiang et al. completed a RCT evaluating the combination of flunarizine and transcutaneous supraorbital neurostimulation (tSNS) on episodic migraines on patients randomized to flunarizine only, tSNS only, or both flunarizine and tSNS [57]. They found that while monthly migraine days was decreased in all three groups, pain reduction by >50% was greatest (78%) in the combination therapy group than either flunarizine (46%) or tSNS (39%) alone, showing the efficacy of pharmacological and interventional therapies in treating migraines (Table 5).

Table 5. Summary of studies reviewed regarding trigeminal nerve stimulation.

tSNS = transcutaneous supraorbital neurostimulation.

In 2019, Chou et al. conducted a multicenter RCT with 109 patients evaluating the efficacy of tSNS for acute migraine attacks. They found that one hour of tSNS treatment resulted in a 59% decrease in VAS versus a 30% decrease with sham [56]. Overall, these studies help support the efficacy of external neuromodulation as viable treatment for migraine headaches.

Several studies have also been conducted on the efficacy of neuromodulation on multiple concurrent nerve targets (Table 6). The first RCT to show the effectiveness of non-invasive supraorbital and supratrochlear PNS for migraines was completed by Schoenen et al. in 2013 [59]. In this study, 67 patients with at least two migraine attacks per month were randomized to either sham or stimulation with daily sessions of tSNS with Cefaly device. After 3 months of treatment, the stimulation group experienced a significant reduction in the average number of migraine days, with 38% achieving a >50% response. This study overall demonstrated a 26% therapeutic gain, which is within the range of those reported for other commonly used migraine treatments.

Table 65. Summary of studies reviewed regarding cotrigembined PNSinal nerve stimulation.

tSNS = transcutaneous supraorbital neurostimulation.

Table 6. Summary of studies reviewed regarding combined PNS.

The vagus nerve plays a major role in the autonomic nervous system, regulating metabolic homeostasis, control of various organs/glands/muscles in the body, and mediating the transfer of sensory information throughout the body [80]. Historically, neuromodulation of this nerve has played a role in treating epilepsy and depression. In more recent years, there has been a movement towards both invasive and noninvasive methods of vagus nerve stimulation for the treatment of migraine and cluster headaches (Table 7).

nVNS = noninvasive vagus nerve stimulation.

Gaul et al. conducted a large multicenter PREVA RCT in the UK, evaluating the use of noninvasive VNS as an adjunct to standard of care (oxygen and triptans) for chronic cluster headaches [71]. As one of the largest RCTs with a total of 97 patients, this study found a significantly greater reduction in the mean number of attacks per month (5.9 vs. 2.1) compared to standard of care. In addition, 40% of patients with the adjunct nVNS reported a greater than 50% reduction in pain as compared to just 8.3% for the control. Overall, this study suggests that nVNS has a beneficial role as an adjunct to standard of care for cluster headaches.

Silberstein et al. conducted the multicenter double-blinded RCT called ACT1 to evaluate the use of nVNS on acute treatment of episodic and chronic cluster headaches [75]. Interestingly, the study found a significantly higher response rate (pain relief based on scoring) for episodic cluster headaches versus the sham, but not for the chronic cohort. Goadsby et al. conducted a similar study on the European population and found comparable results^[72] [72]. This suggest that nVNS is more effective at treating episodic cluster headache than chronic cluster headache.

Subsequently, Silberstein completed the EVENT RCT to assess the use of nVNS for chronic-migraine prevention [69]. Patients were randomized to nVNS or sham, with treatments administered personally at a specific time of the day. Overall, they found no statistically significant difference at the 2-month follow-up. Following this, a small subset of patients completed a further 6 months of open-label treatment, where statistical significance (decreased headache days) was achieved. While limited, this suggests that continued nVNS use may have a benefit for chronic-migraine prevention.

Finally, Tassorelli et al. completed the PRESTO RCT to evaluate nVNS as an acute treatment for migraines [76]. Overall, this found that nVNS was superior to the sham in aborting the first treated attack of acute migraine at 30 and 60 min, with repeat-measures testing supporting superiority in pain freedom from 30 to 120 min. The pain-free response rate at 120 min was also similar to those achieved by oral triptans and NSAIDs, suggesting their usefulness for acute migraines.

 Table 7. Summary of studies reviewed regarding vagus nerve stimulation.

Peripheral nerve field stimulation involves the placement of electrodes near the area of the pain without direct contact to a specific peripheral neve ^[82] [84]. While research in this area is relatively new, several observational studies have been completed to evaluate this treatment’s efficacy. Verrills et al. evaluated ^[83]83 patients who had undergone PNFS targeting the occipital, supraorbital, and infraorbital nerves for chronic daily headache, chronic migraines, and occipital neuralgia [20]. Overall, they found a mean NRS decrease of 4.8, with 68% of the patients experiencing >50% reduction in pain. Furthermore, 23/35 of the patients at follow-up reported a moderate-to-extreme decrease in analgesic use at follow-up, highlighting its possibility for headache treatment.

In 2018, Ishiyama et al. applied C2 PNFS, using electroacupuncture for primary headache^[81] [85]. In this observational study of 54 patients, significant decreases in NRS pain was found with C2 PNFS use, alongside decreases in HIT-6 and SDS (self-rating depressing scale), and decreases in monthly headache days. While more research needs to be done for PNFS, this remains a safe and exciting field for further study.

Remote electrical neuromodulation (REN) is a novel technique for the treatment of acute migraine. The device is placed on the upper arm and stimulates peripheral nerves in the region to induce conditioned pain modulation. Yarnitsky et al. published a randomized, double-blinded, sham-controlled multicenter study across 12 sites with 252 adults to evaluate pain relief at 2 h post-stimulation ^[81][86]. They found that active stimulation was more effective in pain relief at 2 h versus the sham, sustained up to 48 h after treatment. While further research remains, this suggests REN can be an effective treatment for acute migraines.

6. Conclusion

Peripheral nerve stimulation offers promising treatments for intractable headaches. Their success relies on accurate diagnosis and appropriate patient selection. While high-quality evidence does exist regarding its use, additional research is needed in the field. For the physician wishing to utilize PNS in practice, the strongest up-to-date evidence for its use is ONS for treatment of chronic migraines, transcutaneous supraorbital nerve stimulation for migraines, and nVNS for cluster headaches. Preliminary evidence also suggests that interventional therapies may be beneficial as adjuncts to standard-of-care therapies (oxygen, triptans, etc.), thus forming a potential area of study. Looking towards the future, much work remains to bring PNS into the mainstream for headache intervention.