Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized primarily by abdominal pain or discomfort accompanied by changes in bowel habits (76). Its prevalence has been rising in recent years, with epidemiological studies indicating that approximately 7%–21% of the global population experiences IBS symptoms (77, 78). Although not directly life-threatening, this condition significantly impairs patients’ quality of life and imposes a substantial healthcare burden (79).

To investigate the efficacy and mechanisms of taVNS in alleviating abdominal pain and constipation in patients with constipation-predominant IBS (IBS-C), Shi et al. (80) conducted a randomized controlled trial. Forty-two IBS-C patients were assigned to either the taVNS group or a sham stimulation group for a 4-week intervention. Results demonstrated that taVNS not only significantly alleviated abdominal pain and increased weekly complete spontaneous bowel movements but also effectively improved patients’ quality of life and depression levels. Another study involving patients with persistent abdominal pain lasting over 6 months further indicated that a 20-day taVNS treatment significantly reduced abdominal pain and enhanced quality of life. Combined with electroencephalography technology, it enabled early prediction of treatment efficacy (81). These studies confirm that taVNS, as a non-invasive, highly safe, and well-tolerated neuromodulation technique, offers a novel treatment option for patients with gastrointestinal pain. It expands the application prospects of non-pharmacological therapies in the comprehensive management of chronic pain.

Through multi-node, multi-pathway synergistic effects, taVNS extensively modulates the central pain processing network, constituting its core mechanism for analgesic effects (59). fMRI studies confirm that a key target of taVNS is the periaqueductal gray (PAG) in the midbrain—a pivotal hub of the descending pain modulation system (86, 92). For instance, studies indicate that 1 Hz taVNS specifically enhances FC between the PAG and structures such as the medial cingulate cortex, anterior cingulate cortex, and anterior insula. This may represent the neural mechanism underlying the significant therapeutic efficacy of low-frequency stimulation in chronic migraine (61). In patients with chronic low back pain, taVNS has similarly been shown to remodel the PAG network, specifically by enhancing its FC with the amygdala and sensorimotor cortex. This suggests taVNS not only modulates pain intensity but also improves pain-related emotional and sensory dimensions (86).

More critically, the central regulatory effects of taVNS can be traced along the vagus nerve afferent pathway to the brainstem, where it exerts fundamental influence by modulating key neurochemical systems. The solitary tract nucleus, a primary relay station for vagal afferents, receives signals and further projects to the locus coeruleus and nucleus accumbens, thereby regulating noradrenergic and serotonergic systems. Huang et al. (60) found that following taVNS intervention, FC between the NTS and the hippocampus and prefrontal cortex weakened, potentially contributing to the alleviation of pain-related memory and anxiety. Simultaneously, FC between the raphe nucleus and basal ganglia increased, and this enhancement was significantly correlated with a reduction in migraine attack days. This provides compelling imaging evidence that taVNS suppresses pain perception by enhancing the brainstem-striatal serotonergic pathway. In summary, taVNS does not function through a single “analgesic switch,” but rather by precisely modulating the entire “pain matrix” spanning the brainstem, limbic system, and cortex. This restores the imbalanced endogenous pain regulation and reward system functions observed in chronic pain states.

Inflammation serves as the body's core defensive response to injury or infection, characterized pathologically by persistent infiltration of immune cells predominantly comprising monocytes and lymphocytes (18). This process involves complex cascade reactions mediated by multiple substances and is closely associated with the onset and progression of chronic pain (22). A 2021 bibliometric analysis revealed that research on the co-morbidity mechanisms of inflammation and pain has expanded approximately 192-fold over the past four decades, with neuropathic pain emerging as one of the most prominent research directions (23). This reflects the growing significance of this field within global scientific communities and clinical practice.

Among neuroimmunoregulatory strategies for inflammatory pain, taVNS demonstrates significant therapeutic potential by activating cholinergic anti-inflammatory pathways. Aranow et al. (71) conducted a randomized, double-blind, sham-controlled trial in systemic lupus erythematosus patients, demonstrating that just four days of taVNS intervention significantly reduced plasma levels of substance P—a neuropeptide with dual pro-inflammatory and pain-conducting functions. This reduction correlated positively with improvements in patients’ pain scores. Similarly, Bellocchi et al. (75) reported a 17.1% reduction in serum IL-6 levels in systemic sclerosis patients following one month of taVNS treatment, with its dynamic changes synchronized with improvements in pain scores. Collectively, these findings suggest taVNS may exert therapeutic effects in inflammatory pain management by modulating cholinergic anti-inflammatory pathways to suppress the release of key pro-inflammatory mediators like substance P and IL-6.

Beyond effectively regulating peripheral inflammation, taVNS also influences neuroinflammatory processes through central-peripheral synergistic mechanisms, particularly evident in neuropathic pain. Yang et al. (67) further elucidated that taVNS activates α7 nicotinic acetylcholine receptors to inhibit nuclear factor-κB signaling pathway activity, thereby reducing the release of proinflammatory cytokines such as IL-1β and TNF-α, effectively alleviating chemotherapy-induced peripheral neuropathy-related pain. Although plasma inflammatory cytokine levels showed no significant changes in this study, the reduction in pain intensity and overall improvement in sleep and quality of life suggest that taVNS may achieve systemic regulation and symptom relief in complex pain states through multi-level, multi-pathway neuro-immune interaction mechanisms.

From the perspective of autonomic regulation, taVNS effectively enhances parasympathetic activity and suppresses excessive sympathetic excitation by stimulating the vagus nerve branches in the ear, thereby restoring dynamic equilibrium in the autonomic nervous system (93). Studies indicate that taVNS significantly improves clinical symptoms closely related to autonomic function, particularly sleep disorders (62, 88, 90). For instance, in migraine patients, taVNS treatment led to a significant 21.2% reduction in Pittsburgh Sleep Quality Index (PSQI) scores, with improved sleep quality showing a clear correlation to reduced migraine attack frequency (62). In fibromyalgia patients, taVNS has also been demonstrated to improve sleep architecture, with the degree of sleep improvement showing a significant negative correlation to pain score reduction (90). Furthermore, research by Kutlu et al. (88) indicates that taVNS simultaneously modulates autonomic balance, improves emotional states, and promotes overall symptom relief in fibromyalgia. Collectively, these findings suggest taVNS provides a critical physiological basis for alleviating chronic pain and its associated sleep and emotional disturbances by restoring sympathetic-parasympathetic equilibrium.

At the level of brain function regulation, the mechanism of taVNS extends further to emotion- and cognition-related brain regions, particularly through functional modulation of the limbic system and prefrontal cortex, thereby directly alleviating pain-associated emotional disorders (94). Research indicates that taVNS can regulate activity in key limbic system nodes such as the amygdala and hippocampus, while enhancing the function of the dorsolateral prefrontal cortex (dlPFC), which is closely associated with cognitive control and emotional regulation (95). Asmaa et al. (91) found that compared to single interventions, combining taVNS with pain neuroscience education more effectively enhanced dlPFC activity and yielded greater clinical benefits, fully demonstrating taVNS's potential in regulating the prefrontal-limbic neural circuit. Thus, taVNS not only maintains homeostasis through peripheral autonomic pathways but also modulates emotional brain regions via central mechanisms, establishing a dual pathway for treating chronic pain and its emotional comorbidities.

TaVNS effectively improves abnormal pain processing by modulating FC within central pain-related networks. Multiple fMRI studies confirm that taVNS regulates neural activity at key nodes within the default mode network (DMN), sensorimotor network (SMN), and salience network (SN). For instance, Luo et al. (59) observed that a single taVNS intervention in patients with migraine without aura significantly reduced FC between the left amygdala and core DMN regions like the posterior cingulate cortex, while simultaneously attenuating abnormal FC with SMN regions such as the postcentral gyrus. This rapidly alleviated acute-phase pain processing abnormalities. Feng et al. (62) further demonstrated that after 4 weeks of taVNS treatment, amplitude of low frequency fluctuation values in the bilateral anterior cingulate cortex—a key DMN node—significantly decreased, with the reduction positively correlated to reduced migraine attack frequency. This suggests taVNS may restore normal DMN regulation by suppressing its hyperactivity.

Beyond regulating the DMN and SMN, taVNS significantly influences the salience network, which is closely associated with pain emotion and sensory integration. Cai et al. (81) combined taVNS with electroencephalogram studies in patients with persistent abdominal pain, revealing that taVNS markedly reduced functional connectivity strength in the thalamic-insular region within the delta band. This change effectively predicted improvements in patients’ pain scores. This finding suggests that taVNS may alleviate abnormal sensory integration processes in chronic pain by modulating the synchrony of high-frequency oscillations within the sensorimotor and salience networks. Thus, taVNS reshapes the functional architecture of central pain pathways through multi-network synergistic effects, providing robust imaging evidence for neuromodulatory therapies in chronic pain.

The development of chronic pain is closely associated with an imbalance between excitatory and inhibitory signals in the central and peripheral nervous systems (20). Under physiological conditions, inhibitory neurotransmitters such as serotonin, norepinephrine, and GABA form the basis of endogenous analgesia (29). In contrast, nociceptive neuropeptides like substance P act as excitatory modulators, promoting pain sensitization through mechanisms including enhanced synaptic transmission and induction of neurogenic inflammation (21). Therefore, restoring neurochemical equilibrium is a key strategy for intervening in the vicious cycle of chronic pain.

Aranow et al. (71) demonstrated that taVNS significantly reduced plasma substance P levels in systemic lupus erythematosus patients, with this change positively correlated with improved pain visual analog scale scores. This suggests taVNS may attenuate substance P's pro-pain role in central and peripheral pain transmission by inhibiting its release. Shi et al. (80) further discovered in patients with constipation-predominant irritable bowel syndrome that taVNS not only promotes colonic acetylcholine release and enhances vagal activity but also inhibits P substance release from intestinal nerve endings, thereby alleviating pain transmission in functional abdominal pain. Collectively, these studies reveal taVNS's pivotal role in pain regulation by modulating the dynamic equilibrium of neuropeptides and neurotransmitters. They provide crucial experimental evidence for understanding taVNS's function within the neuro-immune-pain axis and establish a mechanistic foundation for its clinical application in chronic pain management.

The core pathophysiological mechanism of chronic pain stems from a vicious cycle involving peripheral and central sensitization (2). Peripheral sensitization begins with local inflammation or nerve injury, leading to increased excitability and lowered thresholds in nociceptors, resulting in pain hypersensitivity (18). Persistent peripheral injury signals further induce central sensitization, manifested as plastic changes in spinal and cerebral pain pathways. Excessive glutamatergic signaling expands neuronal response fields, while the descending inhibitory system, which centers on the locus coeruleus and raphe nuclei, weakens. This ultimately amplifies and generalizes pain signals at the central level (19, 24).

Multiple clinical studies demonstrate that taVNS effectively suppresses peripheral and central sensitization processes through multi-level regulation of pain transmission pathways. At the peripheral level, Bellocchi et al. (75) found taVNS significantly increased the mechanical pain threshold in systemic sclerosis patients, accompanied by decreased serum IL-6 levels, suggesting it alleviates peripheral nerve terminal sensitization via anti-inflammatory mechanisms. At the central level, taVNS suppresses abnormal neuronal excitability by modulating functional connectivity in the brainstem and higher cortical regions. Huang et al. (60) found taVNS effectively suppressed abnormal discharges in the trigeminal spinal nucleus of migraine patients, improving sensitivity to light and sound stimuli. This effect was closely associated with enhanced functional connectivity between the nucleus accumbens and the putamen. Furthermore, Figueiredo et al. (85) observed in chronic low back pain studies that taVNS reduces excessive excitability in spinal dorsal horn neurons, with this effect positively correlated with enhanced FC along the locus coeruleus-nucleus accumbens pathway. These findings systematically elucidate the comprehensive analgesic mechanism of taVNS from peripheral to central pathways.

Currently, taVNS research lacks unified standards in several critical aspects, limiting the reliability and comparability of its results. Regarding treatment parameters, existing studies predominantly employ different frequencies such as 1 Hz, 20 Hz, or 25 Hz, with no consensus established. Future research should systematically compare the dose-response relationships among different parameters to determine the optimal stimulation protocol. Regarding stimulation site selection, the relative merits of the left concha versus bilateral stimulation remain unclear, necessitating standardized protocols and controlled studies. For control group design, common sham sites include the earlobe or non-innervated areas of the auricle. However, the simulation effectiveness and blinding reliability of these sites require further validation and standardization. Additionally, sample sizes are generally small, and follow-up periods are short. Existing clinical studies predominantly employ 4-week treatment cycles, lacking long-term follow-up data. Future research should prioritize large-scale, multicenter, and extended-duration studies to clarify the long-term efficacy and stability of taVNS.

Currently, the precise analgesic mechanism of taVNS remains incompletely elucidated. Existing research exhibits multiple limitations, such as: (1) unclear characterization of the specific neural circuits mediating analgesic effects; (2) lack of direct evidence for the dynamic processes of neuroimmune interactions; (3) insufficient exploration of the mechanistic heterogeneity across chronic pain conditions of different etiologies. Future research urgently requires integrating techniques such as multimodal neuroimaging, molecular imaging, and biomarker analysis to establish more robust connections between macro-network and micro-molecular levels, thereby systematically elucidating the analgesic mechanisms of taVNS.

Currently, the exploration of taVNS in the field of personalized and precision medicine remains in its early stages, directly limiting the optimization of its clinical efficacy and widespread application. First, there is a lack of stable, universally applicable biomarkers for predicting treatment outcomes. Although a few studies have attempted to correlate changes in brain network FC revealed by fMRI with clinical improvement (61), these imaging markers remain unstable and are costly to obtain, making them impractical as routine predictive tools. Recent research has identified several promising candidate biomarkers for taVNS response. For example, HRV, reflecting autonomic modulation, may predict pain reduction in fibromyalgia patients (90). Inflammatory markers such as IL-6 and substance P decrease after taVNS, correlating with clinical improvements in autoimmune-related pain (71, 75). Neuroimaging markers, including resting-state functional connectivity between the periaqueductal gray and limbic regions, also show predictive value for migraine outcomes (61). Electroencephalogram (EEG) signatures—especially theta and alpha band power changes—have been linked to acute analgesic responses in abdominal pain (81). While promising, the specificity, reproducibility, and clinical utility of these biomarkers require further validation in large prospective cohorts. Second, stimulation parameter settings lack individualized theoretical guidance. Current protocols predominantly employ uniform frequencies and fixed intensity adjustments based on sensory thresholds, failing to account for patients’ distinct pain etiologies, pathophysiological underpinnings, or specific clinical manifestations. Future research urgently requires the deep integration of multi-omics data, neurophysiological indicators, and clinical phenotypes. Leveraging advanced algorithms such as machine learning, decision support systems capable of precisely guiding patient selection, parameter optimization, and treatment plan formulation must be developed to ultimately maximize the clinical value of taVNS.

Although multiple studies have preliminarily confirmed the good safety and tolerability of taVNS as a monotherapy, its synergistic effects in combination therapy remain understudied. Currently, only a few studies have attempted to combine taVNS with other non-pharmacological therapies. For example, Abdel-Baset et al. (91) demonstrated that taVNS combined with PNE outperformed monotherapy in improving pain and mood in fibromyalgia patients. Conversely, Kutlu et al. (88) found that adding taVNS to structured exercise did not yield significant additional benefits. These inconsistent findings suggest that the efficacy of taVNS in combination therapy may be influenced by multiple factors, including disease type, treatment parameters, co-administered interventions, and patient characteristics. Future research requires well-designed, adequately powered randomized controlled trials to explore optimized combination regimens of taVNS with pharmacotherapy, physical therapy, psychological interventions, and other modalities. This will clarify synergistic mechanisms and establish personalized combination treatment strategies to enhance the overall efficacy and clinical applicability of taVNS in managing complex chronic pain.