Conditioned pain modulation (CPM) is a quantitative estimation of the capacity for endogenous pain modulation. Reduced CPM enables chronic painful event development or exacerbates pre-existing pain symptoms. Emerging reports indicate that patients with trigeminal neuralgia (TN) have dysregulated endogenous pain modulation. Transauricular vagus nerve stimulation (taVNS) is known to alleviate both acute and chronic pain symptoms. Its role in modulation or management of TN remains unknown. Here, we evaluated the taVNS efficacy in modulating CPM among TN patients. Conclusions from this investigation may facilitate establishment of novel non-invasive adjunctive approaches to treating TN patients.
Methods
All research work was conducted at the First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital). In all, we recruited 62 study participants, 31 TN patients and 31 healthy volunteers, for a 2-day experimental test. At the beginning of the experiment (Day 1), all subjects received 30 min of active taVNS. On Day 2, they received sham taVNS with the same duration and intensity. Meanwhile, technicians documented participant pressure pain thresholds (PPT) and CPM values at baseline, and at 15 and 30 min post-active or sham taVNS.
Results
A 30-min active taVNS exposure substantially elevated the PPT and CPM effect (P < 0.05) among TN patients, and we also observed a notable rise in the PPT and CPM effect (P < 0.05) among healthy controls. Additionally, there were no serious adverse events from the administered treatment.
Conclusion
Exposure to 30 min of active taVNS strongly augmented the CPM effect and elevated the PPT among TN patients and healthy controls. These effects were not observed with sham stimulation. Despite the limitations inherent to survey studies, such as duration and compliance biases, we consider that taVNS is a promising, safe, and cost-effective therapy. In future investigations, we recommend assessment of long-term taVNS application and its effects on CPM and clinical pain.
Patients with chronic pain often exhibit diminished conditioned pain modulation (CPM), which exacerbates their primary pain symptoms or increases the likelihood of additional painful episode emergence. Trigeminal neuralgia (TN) is a commonly occurring neuropathic pain condition that significantly impacts patients' quality of life.
To date, there has been limited research on the underlying mechanism associated with transauricular vagus nerve stimulation (taVNS) for pain relief, despite its potential application in pain treatment.
This study aims to investigate the taVNS-mediated regulation of CPM among TN patients by comparing CPM before and after intervention.
Findings from this research may provide strong supporting evidence of taVNS usage as an effective strategy in managing pain among TN patients. This has significant implications in improving patients' pain conditions and healthcare, offering potential benefits for both individuals and society as a whole.
Introduction
Conditioned pain modulation (CPM), otherwise called diffuse noxious inhibitory control, is a robust endogenous analgesic mechanism that suppresses pain signal transmission via activation of specific neural networks [1]. CPM is a well-established advanced psychophysical measure with significant clinical relevance for assessment of an individual's pain modulation ability as well as susceptibility to developing new pain disorders [2]. Owing to its intricate relationship with pain-induced central pain inhibitory network activation, CPM is frequently employed in clinical pain research for evaluation of deficiencies in endogenous pain modulation [3]. It is reported that, in comparison to those without pain, patients with chronic pain, such as fibromyalgia [4], temporomandibular disorders [5], and irritable bowel syndrome [6], also exhibit reduced CPM. Therefore, these patients may have suppressed ability to modulate incoming pain signals, which may, in turn, exacerbate existing pain or promote development of chronic pain disorders.
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Trigeminal neuralgia (TN) is a persistent facial pain disorder that significantly impacts quality of life of affected individuals. Innocuous stimuli, such as light touch, eating, shaving, and even a light breeze, can induce intense electric shock-like unilateral pain across the face, thereby making daily tasks difficult to manage [7]. Once patients are diagnosed with TN, the preferred treatment is drug therapy. However, many patients find that medication alone is insufficient for pain control, and may thus require surgical therapy, such as microvascular decompression of the trigeminal nerve. However, this procedure may lead to complications, including facial paralysis, impaired hearing, and intracranial infection. Additionally, there is a risk of reoperation. It is therefore imperative to identify an effective adjunctive treatment for pain alleviation, with a preference for non-invasive options before considering surgical intervention. Prior investigations reported that TN patients have substantially reduced CPM [8]. Therefore, enhancing CPM among TN patients, in conjunction with other available therapies, may offer sufficient pain relief.
Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive practice of vagal nerve stimulation involving pulsed electrical signal delivery to the vagal nerve branches in the external auditory canal. This method can effectively increase cortical activity and induce favorable alterations in neurotransmitters among humans [9]. Based on emerging evidences, taVNS is highly efficacious in treating acute and prophylactic migraine as well as cluster headaches [10]. Therefore, it has great potential in treating patients with chronic or episodic pain conditions. Additionally, taVNS has also been reported to significantly diminish pain severity, thereby enhancing overall patient quality of life [11]. This underscores its highly advantageous holistic effects, which may be related to vagus nerve stimulation. Of note, a recent investigation revealed that vagal nerve stimulation can successfully alleviate pain sensation by stimulating downstream pain inhibitory mechanisms, a mechanism that may be akin to taVNS [12]. In this report, we explored the effect and possible mechanism of taVNS influence on CPM among TN patients.
Methods
Participants
Between December 2023 and April 2024, we recruited 62 subjects, namely, 31 typical TN patients and 31 healthy controls, between the ages of 20 and 60 years, from the Department of Anesthesiology of the First Affiliated Hospital of the University of Science and Technology of China. This study received ethical approval from the relevant committee at the participating location (ethics: 2023-ky271 (F1)), and informed consent was collected from all individuals prior to participation in the study. This clinical trial was registered on December 1, 2023, at www.Chictr.org.cn (code: ChiCTR2300078673). Details of the specific inclusion and exclusion criteria are provided in Table 1.
Table 1
Inclusion and exclusion criteria for study participants
Inclusion criteria
Exclusion criteria
Patients with a confirmed diagnosis of typical trigeminal neuralgia (TN) by an experienced physician, based on the International Classification of Headache Disorders guidelines [13]
History of psychiatric disorders, diabetes, cardiovascular disease, inflammatory disorders, and Raynaud's syndrome
Patients with TN undergoing carbamazepine or pregabalin treatment who had difficulty controlling pain with medication and were scheduled for microvascular decompression (MVD) of the trigeminal nerve
Contraindications to wearing transcutaneous auricular vagus nerve stimulation (taVNS), such as abrasions of the left ear or allergy to metal
Subjects with no history of auriculotherapy or ear acupuncture
Those who refused to participate in the study
Healthy volunteers were selected based on an absence of complaints or pain syndrome diagnosis at the time of recruitment; the volunteers were age- (± 5 years) and sex-matched with the selected TN patients
Concurrent pain or diagnosis of other painful conditions (including pulpal and periodontal pain, fibromyalgia, widespread chronic pain, and irritable bowel syndrome)
Sample Size
Our preliminary findings defined the test level as 0.80, with an allowable error of 0.05. Using the G-Power software, we thus selected a sample size of 28 patients per group, accounting for a drop-off rate of 10%. Ultimately, we recruited 62 patients (31 typical TN patients and 31 healthy controls) for analysis.
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Study Design
All sessions were conducted under the same regulated conditions, such as, temperature, humidity, and timing (i.e., morning). All participants were asked to avoid alcohol and perform strenuous exercise during the 12 h prior to the experiment. The experiment began with a set of questionnaires for the participant, which included demographic information, the pain catastrophizing scale (PCS), and the Pittsburgh Sleep Quality Index (PSQI). Thereafter, the subjects took a 10-min seated rest, followed by a 30-min active taVNS exposure. The following day, all participants received sham taVNS of the same duration and intensity. Pressure pain thresholds (PPT) and CPM effects were measured, with data routinely recorded at baseline, and at 15 and 30 min post-treatment. Participants were blinded to the purpose of the study. A flowchart involving all participants is presented in Fig. 1.
The weighted needle pinprick sensory thresholds apparatus (MRC Systems®, Heidelberg, Germany) is commonly used in outpatient clinics to conduct sensory testing. The PinPrick Stimulator Set repeatedly applies tactile or mechanical stimulation to multiple areas of the human skin [14]. This device contains 7 punctate mechanical probes, with distinct weights and pressures (8 mN, 16 mN, 32 mN, 64 mN, 128 mN, 256 mN, 512 mN). A pinprick pain threshold is typically measured by applying weighted pinprick stimulators carrying a flat contact area of 0.2 mm diameter and force ranging between 8 and 512 mN on the right volar forearm. Here, we employed the up-down method, and the geometric mean of a 5 up-down series was computed to determine PPT [15].
The CPM Paradigm
CPM assessment was initiated 1 min post-PPT measurement. The aforementioned PPT score was recorded as unconditioned PPT. To provide the conditioning stimulus, we immersed the left hand in cold water for 2 min in a procedure called the cold pressor test (CPT) [16], which is commonly employed for CPM evaluation under experimental conditions [17]. During this procedure, PPT was measured again to obtain conditioned PPT scores. The final CPM value was computed as the difference between the conditioned and unconditioned PPT scores.
TaVNS
TaVNS (tVNS501®, RISHENA, China) is typically administered by adjusting specific parameters to achieve desired results. Transcutaneous electrical nerve stimulation (TENS) and taVNS share similarities. However, the major difference between the two is the specific nerves targeted for stimulation. In particular, taVNS has a more distinct stimulus target relative to TENS. Here, we administered a active taVNS over 30 min, using a pulse width of 200 ms. The most comfortable stimulus intensity was chosen based on subject feedback, with gradual elevation until an optimal, non-painful level was reached. We also utilized banner prompts on the device to adjust stimulus intensity. All stimulation parameters, namely, duration, intensity, and pulse frequency, were identical between the active taVNS and sham taVNS, apart from the placement of electrodes: left earlobes were used for sham taVNS and the left auricular region for active taVNS (Fig. 2).
Fig. 2
Schematic of the active and sham transcutaneous auricular vagus nerve stimulation (taVNS) sites and instrumentation. Stimulation was delivered through two electrodes located in the left-ear headphone, targeting the auricular branch of the vagus nerve
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Statistical Analyses
All data analyses were carried out on SPSS 25 (IBM®, Armonk, NY, USA). Significance was indicated at two-tailed p < 0.05. Data are presented as group mean standard error of the mean (SEM), unless specified otherwise. Time impact (baseline, taVNS15min, taVNS30min) within individual cohort was assessed using repeated measures ANOVA with post hoc Bonferroni correction. Active and sham taVNS effects were evaluated using mixed mode ANOVA integrating type of stimulation (active or sham stimulation) and treatment duration (baseline, taVNS15min, taVNS30min). In presence of interactions, post hoc analyses were used with independent repeated measures ANOVA per group.
Results
Two participants withdrew from the study. Therefore, we analyzed data from the remaining 60 subjects. Table 2 summarizes the demographics of all analyzed participants. Overall, we observed no discernible differences in participant age, weight, and sex between the two cohorts. TN patients exhibited enhanced PCS (P = 0.000) and PQSI scores (P = 0.028) relative to healthy volunteers. Additionally, taVNS intensity was found to be significantly higher in healthy controls compared with TN patients (P = 0.049).
Table 2
General characteristics of patients with TN and healthy controls
Healthy (n = 30)
TN (n = 30)
P value
Age (years)
51.60 ± 8.59
51.63 ± 9.66
n.s
Male: Female
13:17
13:17
n.s
BMI
23.35 ± 2.99
24.75 ± 3.19
n.s
PCS
14.07 ± 2.38
23.00 ± 7.89
0.000
PSQI
6.07 ± 2.55
7.90 ± 3.64
0.028
Stimulus intensity (Hz)
25.53 ± 6.75
22.50 ± 4.76
0.049
Supplementary information: Clinical information on patients with TN
Pain location (left: right)
9:21
Pain severity
Severe to very severe
Carbamazepine dose range (mg/day)
800–1200
Pregabalin dose range (mg/day)
75–150
Comorbidity (yes:no)
14:16
Pain duration (months)
55.76 ± 45.66
Trigger point (yes:no)
13:17
BMI body mass index, PCS Pain Catastrophizing Scale, PSQI Pittsburgh Sleep Quality Index
Active taVNS (F[2, 57] = 4.003, P = 0.024, partial η2 = 0.123) enhanced CPM in both cohorts, with no interaction effect (F[2, 57] = 1.902, P = 0.159, partial η2 = 0.063). At 30 min post-taVNS, the CPM effect of TN patients was augmented, relative to controls (P = 0.042) (Fig. 3). Notably, there were no marked differences in CPM during sham taVNS between the two cohorts. Additionally, both cohorts produced a marked effect under various stimulation modes (F[1,28] = 13.417, P = 0.001, partial η2 = 0.316) and stimulation durations (F[1,28] = 5.461, P = 0.010, partial η2 = 0.281). At 30 min post-taVNS, both cohorts exhibited markedly elevated CPM in the active stimulation mode relative to the sham stimulation mode (P < 0.05) (Fig. 4).
Fig. 3
The effects of conditioned pain modulation (CPM) at baseline and after active transcutaneous auricular vagus nerve stimulation (taVNS) task sessions in healthy controls and patients with trigeminal neuralgia (TN); *p < 0.05, error bars represent SEM
Fig. 4
Effects of conditioned pain modulation (CPM) after active or sham transcutaneous auricular vagus nerve stimulation (taVNS) task sessions in patients with trigeminal neuralgia (TN) (a) and healthy controls (b); *p < 0.05, ***P < 0.001, error bars represent SEM
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Upon active taVNS, we recorded a total of 6 PPT measurements. TN patients revealed substantial PPT differences in the 1st, 4th, 5th, and 6th measurements. Likewise, healthy volunteers also revealed strong PPT variances in the measurements (P < 0.05). Healthy volunteers also demonstrated higher PPT at baseline than TN patients (P = 0.012). Furthermore, PPTs were elevated among healthy volunteers following cold water immersion (P = 0.006). However, no alterations were present among TN patients in PPT1 versus PPT2 (Fig. 5).
Fig. 5
Pressure pain threshold (PPT) values measured at baseline, after cold water immersion, and following active transcutaneous auricular vagus nerve stimulation (taVNS) in patients with trigeminal neuralgia (TN) (a) and healthy controls (b). PPT1 baseline pressure pain threshold, PPT2 pressure pain threshold during cold water immersion, PPT3 pressure pain threshold after 15 min of taVNS, PPT4 pressure pain threshold during cold water immersion, PPT5 pressure pain threshold after 30 min of taVNS, PPT6 pressure pain threshold during cold water immersion; *p < 0.05, ***P < 0.001, error bars represent SEM
×
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Discussion
Our objective was to evaluate the impact of taVNS on endogenous pain modulation among TN patients.
Here, we demonstrated a marked post-taVNS rise in the CPM effect and PPT among both TN patients and healthy controls. These findings suggest that taVNS may promote endogenous pain modulation. Furthermore, taVNS could potentially strengthen the effects of CPM and raise the pain threshold, ultimately providing pain relief for patients suffering from TN. This has significant clinical implications. Additionally, long-term taVNS may delay the onset of TN or lead to a reduction in anticonvulsant intake. Straube et al. reported that 3 months of taVNS reduced the frequency of migraine attacks [18]. Similarly, Shi et al. found that 3 weeks of taVNS led to improvements in constipation and abdominal pain [19]. However, determining whether taVNS can replace drug therapy may necessitate multi-center, large-scale, and long-term studies for verification.
In their study of the taVNS effect on CPM among healthy individuals, Pacheco-Barrios et al. also reported a strong taVNS-mediated rise in CPM [20]. Additionally, Yang, Y et al. revealed the short-term alleviation of chemotherapy-induced neuropathic pain using taVNS [21]. Busch et al. examined the taVNS-mediated effects on pain thresholds among healthy individuals, and noted a considerable rise in both mechanical and PPTs, alongside a reasonable decline in mechanical pain sensitivity [22]. Such evidence corroborates our results in that taVNS has a positive impact on pain threshold and CPM. To date, however, there have been no clear reports on the underlying mechanism behind this taVNS-mediated regulation of pain threshold and CPM. Major neurotransmitters, namely, noradrenaline, serotonin, and dopamine are intricately associated with the neurophysiological effects of taVNS involving the afferent pathway of the vagus nerve [23]. These components elicit either anti- or pronociceptive influences using the descending pain network [24]. Furthermore, taVNS interventions often direct attention away from painful stimuli, and electric stimulation can also augment pain thresholds by stimulating a placebo effect. Based on imaging reports, distraction during painful stimuli reduces activation of the upstream pain pathway. Hoegh et al. also demonstrated that distraction during painful stimuli augments CPM [25]. Therefore, attention may be a crucial component of the taVNS-mediated effect on CPM and pain threshold. Additionally, the discrepancies in findings may result from psychological factors that reduce the influence of taVNS on CPM effectiveness and pain thresholds. It has been observed that the influence of taVNS on CPM efficacy was markedly reduced in individuals prone to anxiety and fear compared to those with a more optimistic outlook. As demonstrated in this study, patients suffering from TN exhibited markedly higher distress scores and lower sleep quality in comparison with the control group. Together, the aforementioned studies offer potential explanations for the taVNS-based effects on CPM and PPT. In addition, we have revealed that 30 min post-taVNS, the TN patients demonstrated a strong improvement in CPM, relative to healthy controls. Hence, based on this evidence, taVNS may elicit a stronger influence on TN patients, and holds incredible promise as an intervention tool for chronic pain-suffering patients.
In contrast to our findings, other investigations have suggested that noninvasive vagus nerve stimulation has no impact on CPM. This discrepancy may be due to variations in the site and intensity of stimulation. Yap et al. examined the cervical branch of the vagus nerve, while, in this study, we targeted the auricular branch, which is typically considered to be the most effective in terms of surface vagal nerve stimulation [26]. In addition, our sham stimulation targeted the earlobe site, which is widely recognized in the literature as the optimal site for controlling vagus nerve stimulation [27]. Here, we have clearly demonstrated that taVNS of the auricular region strongly enhanced the CPM effect relative to earlobe stimulation. In the Johnson et al. study, high-intensity stimulation activated the small-diameter afferent nerves, which triggered opioid peptide release via the downstream inhibitory networks, which, in turn, enhanced CPM effects and regulated pain pathways [28]. The superior taVNS performance in our study may be attributed to the adequate stimulus intensity and site that promptly activated the downstream pain regulatory system. Rampazo et al. reported that individuals with augmented PPT may require stronger stimulation to achieve comparable results relative to individuals with reduced pain thresholds [29]. This is further supported by the conclusion of this study. Additionally, we revealed that following 15 min of taVNS, there was no significant impact on both cohorts. However, a marked alterations was evident after 30 min of taVNS. Based on these results, the duration of taVNS is critical in determining the success of the intervention.
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Prior investigations indicated pain-induced hypoesthesia among TN patients, as well as a strong link between chronic pain and reduced CPM [30]. In this study, there was no decline in baseline CPM among TN patients. The important consideration is the continued medication usage by TN patients is reported to modulate pain processing sufficiently in the dorsal horn, thereby mitigating central sensitization. As a result, CPM may increase or remain unchanged in chronic pain [31]. We were unable to independently verify the impact of taVNS on CPM in patients with TN. The discontinuation of medication in favor of taVNS alone could elevate the risk of pain in patients, raising ethical concerns. However, the significance of drug influence in the efficacy of taVNS in patients with TN cannot be overlooked. Furthermore, we revealed that TN patients did not exhibit marked alterations in PPT during ice water immersion. In contrast, healthy controls showed notable changes in PPT values. Based on these evidences, there may not be a complete CPM in TN patients. The findings from this study are in stark contrast to a previous investigation that reported an intact CPM effect among typical TN patients. This discrepancy may be due to the disparity between conditioning and test stimuli employed in this study. In particular, our conditioning stimulus was a cold pressor test at 4 °C, whereas prior authors utilized a water bath at 10 °C. In addition, we employed the subject’s PPT as an objective measure for pain inhibition determination rather than rely on subjective ratings. We utilized the mechanical pain threshold used in acupuncture in the Quantitative Sensory Test (QST) to evaluate the CPM effect. However, we did not include measurements for cold, heat, or touch sensation in QST. Therefore, further investigation is needed to fully understand the influence of taVNS on other sensory experiences.
Strengths and Limitations
This study possesses several notable strengths, namely, rigorous sham stimulation controls, a double-blind crossover design, and a precise vagus nerve stimulation apparatus. It employed the CPM effect to examine downstream pain suppression and to explore the taVNS influence on CPM in both TN patients and healthy controls. Of note, no earlier reports have investigated this particular intervention among TN patients.
This study has certain limitations. Firstly, this investigation lacked direct evidence demonstrating successful vagus nerve stimulation, for example, monitoring of heart rate, blood pressure, and pupil diameter. Secondly, relying solely on CPM may not comprehensively evaluate endogenous pain modulation. Thirdly, although we evaluated CPM at the wrist of TN patients, we did not assess CPM at the trigeminal nerve region among the same patients. Emerging evidences suggest regional differences in endogenous pain inhibition. Additionally, this study only examined the short-term effects of single taVNS and the washout duration was regarded as being insufficient. Lastly, the sample population was recruited from a single center, and the findings may, therefore, not be representative of the overall global population. Given these limitations, we recommend additional investigations involving large multi-center-based sample populations to validate our outcomes.
Conclusions
TaVNS augmented the CPM effect and enhanced PPT among TN patients and healthy controls. This non-invasive therapy was not only effective but also well tolerated among all cohorts. Therefore, it is a promising candidate for adjunct therapy of TN patients, as well as in pain-alleviating drug therapy and physical pain management.
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Acknowledgements
The authors thank all the participants of the study, including patients and our colleagues.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Medical Writing
The authors would like to thank all the editors and reviewers who participated in the review, as well as MJEditor (www.mjeditor.com) for providing English editing services during the preparation of this manuscript.
Declarations
Ethical Approval
The trial follows the principles of the Declaration of Helsinki. The study has been approved by the Ethics Committee of the First Affiliated Hospital of USTC, approval No. of the Ethic Committee: 2023-ky271 (F1). The researchers will follow GCP principles and the approved protocol to implement clinical research and protect the health and rights of each patient. All participants will sign an informed consent before starting the study.
Conflict of Interest
Yu Zhang, Yiyuan Luo, Qixing Wu, Mingming Han, Haitao Wang and Fang Kang declare that they have no financial or other conflict of interest.
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