Role of Vagus Nerve Stimulation in the Treatment of Chronic Pain

Chronic pain persists beyond the normal time that tissues take to heal following an injury and is not simply an accompanying symptom of other diseases [1]. Chronic pain is often resulted from peripheral tissue damage and persistent inflammation or pathological adaptations in the peripheral or central nervous system [2]. Unfortunately, current pain management interventions are unsatisfactory, causing inadequate pain relief and multiple individual and societal burdens [3‒6]. At present, oral analgesics are usually the first treatment given and play a vital role in chronic pain management. Commonly used drugs include nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antidepressants, and antiepileptics. However, side effects need to be taken seriously as the drugs are used longer or at higher doses, especially in the elderly. NSAIDs can increase the risk of gastrointestinal toxicities and serious thrombotic cardiovascular events [7]. Long-term use of codeine carries an increased risk of cardiovascular events in older patients [8]. Respiratory depression, nausea, sedation, cognitive impairment, and addictive potential are also concerns with chronic opioid use. Antidepressants and antiepileptics can induce dizziness, somnolence, and cognitive dysfunction as well. Recently, a growing number of interventional pain procedures have been used, such as block injections, denervation surgery, implantable drug delivery systems, and spinal cord stimulation. Nevertheless, block injections can be used only a limited number of times per year. Other surgical treatments are risky and expensive, and all require strict indications. Therefore, it is necessary to explore more effective treatments for chronic pain conditions with fewer adverse effects.

The vagus nerve (VN, cranial nerve X) is the longest and most widely distributed cranial nerve, which courses from the medulla to the distal third of the colon. The VN regulates multiple systems including cardiovascular, respiratory, immune, endocrine, and autonomic systems, and hence plays an important role in maintaining homeostasis [9]. VN stimulation (VNS) is a neuromodulatory therapy by electrical stimulation of the VN, which has been an effective treatment of refractory epilepsy and depression. In the past 2 decades, it has also demonstrated pain-inhibitory efficacy in multiple preclinical and clinical studies [10‒13]. Mechanistically, VNS may control pain by alleviating inflammation and modulating activities of neurons in the pain pathways.

Compared with the broad and multidisciplinary indications mentioned in the previous literature, the review presented here focuses exclusively on the application of VNS in the field of chronic pain. Thus, in this narrative review, we aimed to give an up-to-date review of animal and clinical research studies, supporting the utility of VNS for the treatment of multiple chronic pain conditions. Furthermore, we illustrate the anatomic features of the VN and the history of developing VNS technology. Finally, potential mechanisms which may underlie VNS-induced pain inhibition will be discussed.

We performed a comprehensive literature search of PubMed/MEDLINE database to retrieve articles published in English language using a combination of keywords such as “vagus nerve stimulation” or “electrical auricular puncture” or “chronic pain” or “pain management” or “headache.” All types of studies were included in this review such as systematic review, randomized trials, descriptive and analytic studies, review articles, and protocols.

The VN arises from the lateral aspect of the medulla and exits the skull through the jugular foramen with its field of distribution extending beyond the head and neck to the thorax and abdomen. It is a mixed nerve and consists of sensory, motor, and parasympathetic fibers and contains approximately 80% afferent fibers and 20% efferent fibers [14, 15]. There are three types of VN fibers which vary in myelination, size, and conduction speed. Each type of fiber has its own special physiological property. Specifically, myelinated A-fibers are composed of small and large fibers. The small fibers are visceral afferent fibers and the large are both afferent and efferent somatic fibers [16]. B-fibers provide efferent sympathetic and parasympathetic preganglionic innervation. Small unmyelinated C-fibers, making up approximately 70% of all vagal fibers, convey visceral information from various visceral organs. It has been demonstrated that vagal C-fibers afferents are important for the antinociception effect produced by VNS in animal models [17].

The VN has four related nuclei in the medulla: the spinal nucleus of the trigeminal nerve, the nucleus of the solitary tract (NTS), the dorsal motor nucleus, and the nucleus ambiguous. The spinal nucleus of the trigeminal nerve receives sensory inputs from the external auditory meatus, the posterior fossa meninges, the larynx, and the upper esophagus. As the main target of VNS, NTS receives sensory inputs from the pharynx, epiglottis, and most visceral organs. The dorsal motor nucleus is the origin of general visceral efferent preganglionic parasympathetic fibers innervating most thoracic and abdominal organs. The nucleus ambiguous gives rise to efferent fibers innervating the stylopharyngeus muscle and the striated muscles of the palate, larynx, and pharynx.

The afferent pathway of VN starts from the vagal afferents innervating the cervical, thoracic, and abdominal organs, mainly passes through the NTS, and then terminates in higher brain regions. Many brain areas in this pathway are involved in pain processing, including the thalamus, hypothalamus, parabrachial nucleus, the periaqueductal gray (PAG), the amygdala, and locus coeruleus (LC) [18‒21]. The descending vagal efferent fibers then convey regulatory information to various organs.

VNS devices are available in both implanted invasive and noninvasive forms and operate under various stimulation parameters including current intensity, frequency, pulse width, stimulation ON-time and OFF-time.

Implantable VNS (iVNS) was first developed by Jake Zabara in the 1980s and demonstrated promising antiepileptic effects in canine models [22]. With the success in increasing number of animal and clinical studies, iVNS was approved by the US Food and Drug Administration (FDA) for management of refractory epilepsy in 1997 [23‒25]. Interestingly, it was found that epileptic patients also showed mood improvement after iVNS treatment, and iVNS was later approved to treat refractory depression in 2005 [26, 27]. More recently, the potential utility of iVNS has been extended to a diverse array of diseases including heart failure, rheumatoid arthritis, sepsis, obesity, and chronic pain [28‒30]. Despite being well-established, this method remains expensive and has been associated with severe implantation complications such as nerve injuries. Moreover, stimulation is not restricted to afferent fibers of the cervical VN but may extend to efferent fibers of the VN as well, causing adverse effects such as bradycardia, cough, voice alteration, and hoarseness [31, 32].

To avoid surgical complications associated with iVNS, noninvasive form of transcutaneous VNS and minimally invasive form of percutaneous VNS were developed. Similar to iVNS, the transcervical VNS (tcVNS) stimulates VN fibers in the carotid sheath. The most widely used tcVNS device (gammaCore, electroCore LLC, Basking Ridge, NJ, USA) has received FDA approval for the treatment of acute cluster headache in 2017 and for acute migraine treatment and adjunctive cluster headache prevention in 2018. The transauricular VNS (taVNS) stimulates the auricular branch of the VN, which innervates the cavity of conchae and exclusively supplies the cymba conchae. The auricular branch of the VN joins the main bundle of the VN projecting to the NTS [33]. The NEMOS device (Cerbomed, Erlangen, Germany), one of the most widely used taVNS devices, received European certification as a treatment for epilepsy and depression in 2010, for chronic pain in 2012, and for anxiety in 2019 [34]. Commonly observed adverse events of noninvasive VNS (nVNS) are relatively mild, including local discomfort, skin irritation, transient muscle stiffness, and pain [35]. The percutaneous auricular VNS (paVNS) has features similar to acupuncture and can be performed with 2–3 miniature needle electrodes penetrating the skin in the vagally innervated regions of the out ear. Compared with the diffuse stimulation fields of taVNS, paVNS can precisely and specifically stimulate the local afferent auricular branch VN endings due to the small size of needle electrodes. The paVNS has been demonstrated to alleviate chronic pain, acute postoperative pain, and peripheral arterial disease [36, 37]. Minor side effects of paVNS mainly include local skin irritation and inadvertent bleeding [38].

Acupuncture is an established adjuvant analgesic method for the treatment of chronic pain and electrical stimulation of acupuncture points can enhance analgesic efficacy [36, 39, 40]. Almost all specific auricular acupuncture points used to treat pain conditions are situated in areas of external auricle receiving exclusively or mixed innervation by the auricular branch of the VN and cervical nerves. Consequently, the analgesic effects of auricular acupuncture may be explained by stimulation of the auricular branch of VN [41].

Over the past few decades, some animal and clinical studies have suggested that VNS may exert analgesic effects using certain defined parameters [11, 12, 39, 40, 42]. Recently, due to the convenience of using nVNS, an increasing number of studies have focused on the role of VNS in pain management as shown in Table 1.

The primary aim of treatment for chronic headache disorders was to prevent acute attack. The first-line treatment is pharmacological therapy. Onabotulinumtoxin A and topiramate are the only currently available therapies with high-quality evidence for the preventive therapy of chronic migraine [60]. As for chronic cluster headache, verapamil, lithium, and topiramate are effective in reducing the frequency of attacks. However, drugs have adverse effects and contraindications. Ideal therapy providing rapid symptom relief with minimal adverse events needs further investigat. There is evidence in support of the use of VNS for the acute and preventive treatment in chronic headache.

iVNS: during clinical trials of VNS for epilepsy treatment, many patients reported a reduction in headache frequency and intensity. For example, Kirchner found that 1 patient with a long history of chronic tension-type headache showed an 80% reduction of pain severity after VNS [11]. Later, several small case series also demonstrated significant improvements in chronic migraine and chronic cluster headache after VSN treatment [61, 62]. However, since both epilepsy and antiepileptic medications may affect pain thresholds, it was difficult to ascertain and generalize the VNS effects on primary headache at that time [63, 64]. The first study that focused on using VNS for headache treatment was conducted in 2003 and yielded promising results. Seven patients with migraine unresponsive to pharmacological treatments were treated with iVNS. Six months later, 1 patient reported a greater than 50% reduction in headache frequency, duration, and severity; 4 patients showed a 75% or greater improvement on the migraine disability assessment questionnaire scale [10]. To date, as refractory epilepsy and depression remain the primary indication for iVNS, the randomized controlled study of iVNS for headache treatment has not yet been carried out.

tcVNS: owing to the convenience and good safety profile, a growing number of studies have been conducted to evaluate the utility of nVNS in headache management. For migraine attack, Goadsby et al. [43] enrolled 30 participants to assess the effect of tcVNS for acute treatment of migraine and the pain-free rate at 2 h after tcVNS treatment for all moderate or severe attack was 22%. Barbanti et al. [44] found that the pain relief rate (≥50% reduction in visual analog scale [VAS] score) was 64.6% and 39.6% of patients achieved pain-free status at 2 h after treatment in their multicenter study. Interestingly, the tcVNS also had a prophylactic effect in chronic migraine. Silberstein et al. [45] conducted the first double-blinded, randomized controlled pilot trial to study the prophylactic effect of tcVNS on chronic migraine. After 2-months randomized phase, tcVNS failed to significantly decrease headache days compared to baseline and the mean reduction of headache days did not significantly differ between sham and tcVNS groups. However, patients in tcVNS group showed less headache days after 6-months open-label phase. Previous studies also suggested that the longer VNS treatment was associated with greater therapeutic effects [48, 65, 66]. Most recently, Najib et al. [46] conducted a multicenter trial to evaluate the efficacy and safety of tcVNS for migraine prevention and mean reduction in monthly migraine days were also similar in two groups. Nevertheless, the percentage of participants with a ≥50% reduction in migraine days was greater in tcVNS group and patients with aura responded preferentially.

VNS is also practical and effective as an acute and preventive treatment in chronic cluster headache. Silberstein et al. [51]and Goadsby et al. [52] both found that tcVNS induced the significantly higher response rate of episodic cluster headache, but the acute treatment was not effective for chronic cluster headache during randomized phase. However, findings after the 3-month open-label phase in the study of Silberstein et al. [51] showed that the response rate was similar between these two cohorts, indicating further benefit with continued use of tcVNS. Nesbitt et al. [47] studied 19 patients with cluster headache treated with tcVNS and found that 15 patients reported an overall improvement in their condition from baseline. Importantly, prophylactic use of tcVNS significantly reduced the mean 24-h attack frequency from 4.5 to 2.6 h. Gaul et al. [48] also conducted a large randomized trial to determine if adjunctive prophylactic tcVNS is effective for chronic cluster headache. Compared to the standard treatment alone, combining tcVNS with the treatment induced a significantly greater reduction in the number of attacks per week. Prophylactic tcVNS was also associated with a significantly decreased consumption of abortive medications and a greater improvement of life quality. Subsequently, they further demonstrated that adding tcVNS to standard treatments led to rapid, significant, and sustained reduction of attack frequency within 2 weeks [67].

In a recent meta-analysis, Lai et al. [68] analyzed six randomized controlled trials on the effects of tcVNS on primary headache disorders and showed that tcVNS is effective for acute relief of both migraine and cluster headache. The gammaCore device has received FDA approval for the treatment of acute cluster headache treatment in 2017 and for acute migraine treatment and adjunctive cluster headache prevention in 2018.

taVNS: there are only a few clinical studies examining the effects of taVNS on headache. Straube et al. [49] included 46 patients with chronic migraine treated with 1 Hz or 25 Hz of the taVNS. Both groups showed significant decreases in the number of headache days. Interestingly, 1 Hz taVNS induced a significant greater headache days reduction than 25 Hz stimulation did, which is the most frequently used VNS frequency. Headache intensity was not significantly changed, and there were no group differences. In a functional magnetic resonance imaging (fMRI) study, Zhang et al. [50] reported that the migraine patients showed a significant reduction in migraine days, migraine attack times, and pain intensity 4 weeks after taVNS.

In summary, VNS has demonstrated reproducible inhibitory effects on primary headache disorders. More randomized controlled trials are needed to further explore the optimal stimulation parameter for each type of nVNS to inhibit primary headache disorders.

VNS was also shown to modulate nociception and other clinical pain conditions. Chronic widespread pain is defined as pain involving three or more body quadrants and axial bones, accompanied by significant affective disorders and dysfunction [69]. Fibromyalgia is the most common chronic widespread pain and characterized by fatigue, sleep disorders, cognitive dysfunction, and depression. The pathogenesis of fibromyalgia has been linked to central sensitization and other factors, such as inflammatory, genetic, and psychosocial factors. Current therapies include pharmacotherapy (anticonvulsants, serotonin and norepinephrine [NE] reuptake inhibitors, tricyclics) and non-pharmacological therapies (education, exercise, cognitive behavioral therapy).

Since the stimulation of vagal afferents may reduce pain through modulating descending serotonergic and noradrenergic neurons which play an important role in central sensitization, Lange et al. [53] conducted the first open-label study to assess the efficacy, safety, and tolerability of iVNS in 14 fibromyalgia patients. Most patients tolerated implantation well, and the adverse effects of iVNS were comparable to those reported in using iVNS to treat other diseases. Importantly, 5 patients no longer met the diagnostic criteria for fibromyalgia after 11 months of treatment. The invasive nature of iVNS limited conducting further research in a larger cohort. Accordingly, Kutlu et al. [54] examined the impact of taVNS in conjunction with exercise on pain intensity and life quality in 60 patients with fibromyalgia. Combined use of taVNS significantly reduced the VAS score averages, but there is a no significant difference between the control (exercise only) and treatment group. Veterans with Gulf War illness treated with tcVNS also reported no improvement in either widespread pain or migraine frequency or severity relative to veterans who received sham tcVNS [70]. Further studies in larger sample size and with other stimulation parameters are needed to investigate the effects of nVNS on chronic widespread pain.

Chronic abdominal pain is the primary symptom of chronic pancreatitis. It has been demonstrated that chronic pancreatitis patients have abnormal pain processing in central nervous system [71]. Sustained pancreatic nociceptive afferent inputs can lead to central sensitization over time. This may help explain why patients respond inadequately to therapies directed against pathophysiological changes of the pancreas [72]. Currently, the use of analgesics for chronic pancreatitis pain is still based on the 1986 World Health Organization analgesic ladder for cancer pain. Antioxidants and pregabalin may also have some benefits to pain relief [73, 74].

In a small randomized crossover study, Muthulingam et al. [55] evaluated the effects of 2-week tcVNS treatment on pain symptoms and quality of life in patients with chronic pancreatitis. Both tcVNS and control groups induced significant improvements in pain scores when compared to their baselines, respectively. However, no significant difference was found between the two groups, and no change in the cardiac vagal tone was observed. The negative results may be partial due to insufficient activation of parasympathetic nervous system and treatment time. Later, Muthulingam et al. [75] conducted another trial using fMRI in chronic pancreatitis patients to investigate if tcVNS changes functional connections of limbic structures. Compared with sham treatment, 2 weeks of tcVNS reduced functional connection of limbic structures, suggesting a brain modulatory effect by tcVNS which may partially underlie the beneficial effect of tcVNS in these patients.

Symptomatic treatment of abdominal pain of functional gastrointestinal disorders may be accomplished with several classes of medication, including antispasmodics, peppermint oil, tricyclic antidepressants, and selective serotonin reuptake inhibitors [76]. Cognitive behavioral therapy and exercise also help patients reduce and manage pain symptoms [77, 78].

Visceral hypersensitivity is an important cause of chronic abdominal pain in functional gastrointestinal disorders [79]. Increased parasympathetic tone played an important role in visceral and esophageal pain hypersensitivity. Physiologically increasing of parasympathetic tone with deep breathing prevented the development of esophageal pain hypersensitivity, and this effect was antagonized by atropine [80]. In a randomized crossover trial, Farmer et al. [56] found that taVNS prevented the development and even reversed the established hypersensitivity in an acid-induced esophageal pain model by increasing parasympathetic tone. Correspondingly, the decreased pain thresholds at 60 min and 120 min after acid infusion were increased by taVNS treatment.

Irritable bowel syndrome is another common functional gastrointestinal disorder characterized by abdominal pain and altered bowel habits in the absence of demonstrable organic disease. In a randomized trial of 42 patients with irritable bowel syndrome, 4 weeks of taVNS substantially ameliorated abdominal pain and constipation. Compared with sham stimulation, the VAS pain score was decreased by 64% after taVNS treatment. In addition, taVNS decreased the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and serotonin (5-HT) in circulation and enhanced vagal activity assessed by the spectral analysis of heart rate variability. The vagal nerve activity was negatively correlated with the VAS score. These interesting findings suggested the autonomic and immune modulation involved in the improvement symptoms with the taVNS [57].

Trigeminal neuralgia is characterized by touch-evoked brief shock-like paroxysmal pain in one or more divisions of the trigeminal nerve. First-line treatment is sodium channel blockers, either carbamazepine or oxcarbazepine. Patients who fail medical management due to persistent pain or unacceptable side effects have options like open surgery and radiotherapy.

Oshinsky et al. [81] explored the effect of tcVNS for treatment of chronic trigeminal allodynia in a rat model induced by repeatedly infusing prostaglandin E2 onto the dura. They showed that periorbital sensitivity significantly decreased for up to 3.5 h after 2 min of tcVNS. Additionally, tcVNS blocked or even reversed the increased level of extracellular glutamate in the trigeminal nucleus caudalis. There was no significant difference in the levels of the inhibitory neurotransmitter gamma aminobutyric acid, 5-HT, and NE. Mechanistically, the suppression of increased glutamate level in the trigeminal nucleus caudalis induced by glyceryl trinitrate may be an important mechanism for nVNS to inhibit trigeminal allodynia. Clinical studies are needed to validate these preclinical findings of nVNS in patients with trigeminal neuralgia.

Painful neuropathy is a frequent comorbidity of diabetes, and the pathophysiology is not yet fully elucidated and the treatment remains unsatisfactory. Current treatments are purely symptomatic and the most commonly recommended first-line agents include anticonvulsants (gabapentin and pregabalin), serotonin-noradrenaline reuptake inhibitors, and tricyclic antidepressants. Unfortunately, the therapeutic effect may offset by intolerable adverse effects.

Previous animal study showed that 30 min taVNS per day for consecutive 5 weeks exerted an antidiabetic effect in Zucker diabetic fatty (ZDF, fa/fa) rats and triggered the secretion of melatonin, suggesting a potentially beneficial effect of taVNS in diabetic neuropathy [82]. Wang et al. [83] found that 30 min taVNS treatment per day for consecutive 28 days elevated plasma melatonin concentration, upregulated the expression of melatonin receptors in the amygdala, and alleviated thermal hyperalgesia in ZDF rats. Intraperitoneally injected luzindole, a melatonin receptor antagonist, attenuated the pain inhibitory effects of taVNS. Accordingly, the mechanisms of taVNS on inhibiting neuropathic pain may involve the release of extrapineal melatonin and increased expression of central melatonin receptors. Li et al. [84] also showed that similar taVNS treatment inhibited pain hypersensitivity in ZDF rats as detected by both thermal hyperalgesia and mechanical allodynia in the hind paw. Importantly, this pain inhibitory effect of taVNS was found to be due to an elevated plasma 5-HT concentration and increased expression of central 5-HT receptor type 1A (5-HT1AR) in the hypothalamus. 5-HT1AR plays an important role in descending pain inhibitory pathway. Both 5-HT1AR and melatonin receptor type 1 are expressed in the ventromedial hypothalamic nucleus. In addition, both 5-HT and melatonin are biochemically derived from tryptophan and were elevated by taVNS. It is possible that they may work synergistically in mediating pain inhibition from VNS. At present, there is a lack of clinical study to determine whether nVNS can alleviate pain in diabetic patients.

Chronic musculoskeletal pain is defined as persistent or recurrent pain that arises as part of a disease process directly affecting bones, joints, muscles, or related soft tissues [85]. For the treatment of chronic musculoskeletal pain, it is necessary not only to treat symptomatically but also to actively treat the primary diseases. Commonly used analgesics include NSAIDs, muscle relaxants, anticonvulsants, antidepressants, and opioids. Non-pharmacological therapies, including exercise, physical therapy, and interventional procedures, can alleviate pain to some extent.

Frøkjaer et al. [86] found that combined taVNS and physiological modulation (deep breathing) of vagal tone could reduce somatic pain sensitivity and increase musculoskeletal pain thresholds in healthy subjects. The anti-inflammatory of VNS may also contribute to its promising effect in chronic musculoskeletal pain.

Rheumatoid arthritis is a chronic autoimmune, inflammatory disease characterized by inflammation in the musculoskeletal joints, resulting in cartilage and bone degradation. Preclinical data confirmed that vagotomy exacerbated arthritis in mice [87]. Koopman et al. [29] first found that iVNS could improve patient’s assessment of pain. Polymyalgia rheumatica is an inflammatory rheumatic disease of unknown etiology, characterized by chronic muscle pain and morning stiffness in the shoulders, pelvic girdle, and neck. Venborg et al. [58] conducted an open-label, proof-of-concept pilot study to investigate the effect of acute (20 min) and chronic (5 days) tcVNS. A significant reduction of VAS pain score in the hip from baseline was found on day 5, but the global VAS score showed no significant change. tcVNS induced a significant increase in cardiac vagal tone at 20 min after initial stimulations compared with baseline. VNS has also been considered for treatment of systemic lupus erythematosus, a chronic autoimmune inflammatory disease characterized by musculoskeletal pain and fatigue [59]. Subjects receiving taVNS for 4 consecutive days achieved a significantly greater reduction in their pain and fatigue, and these effects remained during the whole study period of 12 days. Interestingly, the change of reported pain from baseline correlated significantly with the change in fatigue.

Krusche-Mandl et al. [88] found electrical auricular acupuncture significantly decreased pain scores and increased the pain-free walking time in patients with knee osteoarthritis. Patients in their study received continuous low-frequency electrical auricular acupuncture for 96 h per week and the treatment lasted 6 weeks. Moreover, acupuncture showed a continuing effect and pain scores further decreased during follow-up. Accordingly, taVNS may also be a potential non-pharmacological strategy for this disease.

The abnormalities of elements comprising the lumbar spine (e.g., soft tissue, vertebrae, zygapophyseal and sacroiliac joints, intervertebral discs, and neurovascular structures) can contribute to low back pain. The management of chronic low back pain is extremely challenging. Pharmacological treatments should begin with NSAIDs or muscle relaxants, and then tramadol or duloxetine for next step. Opioids are recommended to use only for low back pain refractory to other treatments [89]. Non-pharmacological approaches such as exercise and physical therapy are beneficial. However, this patient group has only small functional improvements from the use of the medication [90]. Some interventional procedures including radiofrequency and spinal nerve stimulation may be effective, but the invasive and risky nature limits their use.

Sator-Katzenschlager et al. found continuous auricular electroacupuncture (48 h per week for 6 weeks) relieves pain more effectively than conventional manual auricular acupuncture in chronic low back pain patients treated with standardized analgesic therapy and the effect lasted for 3 months after the treatment ended [36]. One pilot study found taVNS combined with mindful mediation also improved back pain severity and pressure pain threshold, especially for those with greater negative affect [91]. Thus, VNS may be a promising treatment strategy for chronic low back pain.

The experience of pain depends on peripheral sensory inputs, spinal transmission, and brain processing. Though the exact mechanisms by which VNS inhibits chronic pain remain to be determined, investigators have proposed several working hypotheses based on findings in animal studies and clinical trials.

VNS was shown to inhibit the spinal nociceptive transmission as suggested by its inhibitory effect on responses of spinal nociceptive neurons in the spinothalamic tract and spinoreticular tract [92‒96]. Chandler et al. [97] showed that VNS inhibited the spinothalamic tract neurons below C3 spinal level, but excited neurons between C1 and C3, indicating that neurons in high cervical segments may play a critical role in VNS-induced pain inhibition. Moreover, Lyubashina et al. [98] found that continuous cervical VNS suppressed electrically evoked firing rates in 48% spinal trigeminal neurons, and more than 80% of responders showed a carryover inhibition at 5 min after terminating VSN in an animal model of headache.

VNS modulates pain through multiple pain-processing structures in the brain (shown in Fig. 1). Animal experiments using local anesthetics to inhibit neuronal activities in NTS, nucleus raphe magnus, LC, and PAG suggested that these structures play important roles in the pain-inhibitory effects of VNS [99‒102]. An increasing number of clinical trials using fMRI also confirmed this notion. For example, migraineurs treated with 1 Hz taVNS showed a significant deactivation of signals at the LC, parabrachial nucleus, and NTS. Moreover, taVNS increased resting state functional connectivity between the LC and left secondary somatosensory cortex, mygdala, anterior cingulate cortex, and hippocampus. The increased resting state functional connectivity between the left LC and left secondary somatosensory cortex was negatively associated with the frequency of migraine attacks [103]. Compared with 20 Hz, 1 Hz taVNS produced greater increases of connections between PAG and middle cingulate cortex, left insula, and anterior cingulate cortex [104]. Zhang et al. [50] also found that taVNS increased the connectivity between the thalamus subregion and anterior cingulate cortex in migraine patients.

VNS can activate the descending pain inhibition system. The intrathecal administration of opioid receptor antagonist naloxone attenuated cervical VNS-produced inhibition of the tail flick reflex. Intrathecal injection of both phentolamine and methysergide also significantly attenuated inhibition of tail flick reflex by cervical VNS [39]. Collectively, these results suggest that cervical VNS activated spinal opioidergic system and descending serotonergic and noradrenergic systems to inhibit spinal nociceptive processing. Intravenous injection of 5-HT also stimulated vagal afferents and inhibited the tail flick reflex by activating descending inhibitory systems [105]. Hu et al. [106] provided evidence of activation of δ-opioid receptors in mediating the therapeutic action of iVNS in headache. Recently, Laura et al. [107] tested the effects of short-term tcVNS on the descending pain inhibitory system, quantified by the nociceptive flexor (RIII) reflex in twenty-seven healthy subjects. However, they did not observe the activation of the descending pain inhibition pathway during and up to an hour after tcVNS. Conversely, De Icco et al. [108] found a statistically significant increase of RIII reflex threshold at 5 and 30 min after 4 min of tcVNS in healthy participants. Descending pain inhibition may be a possible mechanism for pain control of VNS, further studies are needed to provide more details, especially the effects of long-term VNS on descending pain modulation system.

Cortical spreading depression (CSD) was suggested to be the main mechanism underlying migraine aura and a trigger for headache [109]. Both iVNS and tcVNS significantly suppressed spreading depression susceptibility in the occipital cortex in rats. The electrical stimulation threshold to evoke the CSD was elevated by more than 2-fold, and this effect could persist for more than 3 h [110]. VNS may suppress CSD through inhibition of glutamate release, the neurotransmitter critical for CSD initiation and spread [111]. Morais found that VNS inhibited CSD through central mechanisms which involve NTS and subcortical neuromodulatory centers that provide serotonergic and norepinephrinergic innervations to the cortex. Most recently, Liu reported that tcVNS suppressed CSD susceptibility in an intensity-dependent manner, with two 2-min nVNS applied at 5 min apart being the most effective paradigm [112]. Accordingly, central mechanisms including spinal and supraspinal modulation may be a key factor in pain control by VNS.

Inflammation exerts a pivotal role in pain perception with glial, immune cells, and pro-inflammatory cytokines implicated in chronic pain states [113]. Multiple studies have discovered that the VN was involved in the inflammatory response, and VNS may control pain through alleviating inflammation and neuroinflammation [114]. The tcVNS can cause a greater decrease of cytokines levels (TNF, IL-1β, IL-8), as well as a larger increase of IL-10 in healthy volunteers [115]. Chaudhry et al. [116] found that adjunctive tcVNS significantly reduced the IL-1β plasma levels and the number of severe attacks per month in migraineurs. Although the precise anti-inflammatory mechanism of VNS is not fully elucidated, it may achieve the effect through the cholinergic anti-inflammatory pathway (CAP), hypothalamic-pituitary-adrenal axis pathway, and the release of specialized proresolving mediators (SPMs) (shown in Fig. 2).

Increasing experimental evidence suggested that VNS might modulate the immune response and systemic inflammation through the CAP [117‒120]. The classical CAP modulates inflammatory responses through splenic nerve of the celiac ganglia to release NE. Then, NE bounds to the β2 adrenergic receptor on the T lymphocytes and the release of acetylcholine (Ach) increased. ACh then binds to the alpha7 nicotinic Ach receptor (α7nAChR), and inhibits the release of pro-inflammatory cytokines such as TNF-α from macrophages in the spleen. Later, Matteoli et al. [121] showed that the anti-inflammatory effect of VN in the intestine is through muscularis resident macrophages expressing α7nAChR, which is independent of the spleen and T cells. Rawat et al. [122] found that taVNS upregulated the CAP by increasing the expression of α7nAChR. Except for peripheral regulation, VNS can exert the anti-inflammatory effect through central α7nAChR-dependent mechanism [123, 124]. Wang et al. [125] demonstrated that taVNS reversed the downregulated expression of α7nAChR on the hippocampus to relieve neuroinflammation. Jiang et al. [126] showed that iVNS significantly decreased the levels of TNF-α, IL-1β, and IL-6 through elevating the expression of α7nAchR on microglia.

SPMs, including lipoxins, resolvins, protectins, and maresins, are endogenous lipid mediators generated during the resolution phase of inflammation [127]. Due to their potent proresolving and anti-inflammatory effects, several studies examined the effects of SPMs in inhibiting inflammatory pain and neuropathic pain in rodent models. Intrathecal injection of resolvin D1 attenuated chronic pancreatitis-induced mechanical allodynia and reduced the expressions of TNF-α, IL-1β, and IL-6 in thoracic spinal dorsal horn [128]. Intraplantar pretreatment of mice with resolvin E1 reduced carrageenan-induced neutrophil infiltration, paw edema, and pro-inflammatory cytokine expression and relieve the inflammation pain [129]. Intrathecal administration of lipoxin A4 decreased the pro-inflammatory cytokines (TNF-α, IL-1β), increased the expression of anti-inflammatory cytokines (IL-10), and alleviated neuropathic pain in the rat model with low back pain [130]. Recently, Serhan et al. [131] found that VNS could increase SPMs including resolvins 1, protectins 1/neuroprotectin 1, maresins 1, and resolvins 5 in human. Although the pain-inhibitory effect of SPMs is also related to other mechanisms, its direct anti-inflammatory action still plays a vital role [132]. VNS may increase plasma levels of adrenocorticotropic hormone and corticosterone through the hypothalamic-pituitary-adrenal axis pathway, which could also mediate some of its pain inhibitory and anti-inflammatory effects [133].

As an alternative, non-pharmacological intervention with fewer side effects, VNS is a promising neuromodulation method to treat chronic pain syndromes. However, there exits several limitations in current VNS studies for chronic pain management. First, most of the studies were conducted for a short period of time, leading to negative results in some studies during the randomized phase [45, 51]. A longer intervention may have more pronounced therapeutic effect. By the way, with the extension of treatment time, one thing that needs to be noted is therapeutic compliance of patients. The second problem is the small sample size, especially in clinical trials for chronic pain conditions other than headaches. Third, very few studies have been done to explore the characteristics of suitable populations for VNS.

Therefore, it is necessary to conduct more preclinical and clinical trials in the future. To begin with, current conclusions about the use of VNS for chronic pain syndromes mentioned above need to be validated in more and larger randomized controlled studies. Other types of chronic pain such as chronic cancer pain and postoperative pain may also benefit from this technique. Additionally, the relationship between stimulation schedule or stimulation parameters and therapeutic effects needs to be elucidated, which will help optimize the use of VNS in individual pain condition. Equally important is the selection of patients who are likely to respond better to this autonomic intervention. More research studies are needed to determine the optimal indication. At last, although several hypotheses of analgesic effects of VNS have been proposed, the precise mechanism is still unclear and the exact neural pathway needs further investigation.

The VN represents the most extensive neural system connecting organs and the brain and plays a critical role in homeostats and maintaining our physiology under a balanced condition. VN exerts an anti-nociceptive and anti-inflammatory effect within the viscera. Current preclinical and clinical VNS studies have demonstrated clinical beneficial effects for the use of VNS in primary headache disorders. With its good safety profile and demonstrated efficacy in previous trials, extending VNS in management of other clinical pain conditions is promising.

The authors have declared that no competing interest exists.

This work was supported by grants from the National Natural Science Foundation of China (81771181, 81571065, 82171217); the Beijing Natural Science Foundation (7202053).

Y.W. defined the topic of review. P.S. prepared the manuscript, and HL created the figures. J.J., Y.G., and X.C. aided in manuscript review and figure design. All authors read and approved the final manuscript.