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Journal of Central South University Medical Sciences logoLink to Journal of Central South University Medical Sciences
. 2025 Dec 28;50(12):2438–2448. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2025.250561

迷走神经刺激治疗慢性疼痛的研究进展

Research progress on vagus nerve stimulation in the treatment of chronic pain

LIU Qingqing 1,2, CHEN Bin 2, XU Cong 1, LIN Wanqing 3,✉
Editor: 吴 旭芳
PMCID: PMC12989421

Abstract

Chronic pain is a common clinical symptom that seriously affects patients’ quality of life. Traditional pharmacological treatments often have limited efficacy and are accompanied by many adverse effects. A large number of clinical and basic studies have focused on exploring the pathogenesis and therapeutic approaches of chronic pain, making it a research hotspot in clinical medicine. Increasing evidence indicates that the vagus nerve participates in pain signal transmission through multiple pathways, and the underlying mechanisms may involve neuroinflammation, the brain-gut axis, and central regulatory systems. As an emerging neuromodulation technique, vagus nerve stimulation has attracted considerable attention because of its unique therapeutic mechanisms and promising clinical application prospects. A systematic overview of the anatomical basis of vagus nerve involvement in pain modulation, the analgesic mechanisms of vagus nerve stimulation, current clinical applications, technological optimization, and future development directions may provide references for better clinical application of vagus nerve stimulation in the treatment of chronic pain.

Keywords: vagus nerve stimulation, chronic pain, neuroinflammation, brain-gut axis, neuropathic pain

慢性疼痛是指持续或反复发作超过3个月的疼痛，并伴有明显的情绪困扰和/或功能障碍，常见于慢性腰痛、慢性偏头痛、神经病理性疼痛等多种疾病[1-2]。慢性疼痛不仅严重干扰患者的生活和工作，还造成巨大的社会经济负担。传统的治疗方法主要包括药物治疗、物理治疗和心理干预等，但这些方法在某些情况下效果有限，且易产生依赖性、治疗效果难以持久等问题[3-5]。因此，寻找安全有效的替代疗法成为临床的迫切需求。

迷走神经(第X对脑神经)作为人体最长的脑神经，连接外周与中枢神经系统，在调节内脏功能、免疫反应和疼痛感知中发挥关键作用。迷走神经刺激(vagus nerve stimulation，VNS)作为一种新兴的神经调控技术，通过对迷走神经施加电刺激等方式，调节神经功能，VNS最初用于治疗癫痫和抑郁症[6-7]，近年来其治疗慢性疼痛的潜力逐渐受到关注[8]。VNS可通过多途径、多靶点的作用机制调节疼痛信号转导，为慢性疼痛治疗提供了新思路。本文回顾VNS治疗慢性疼痛的研究进展，探讨其作用机制、应用现状及未来发展方向，以期为相关研究和临床实践提供参考。

1. 迷走神经参与痛觉调节过程的解剖学基础

迷走神经作为副交感神经系统的主要组成部分，包含约80%的传入(感觉)纤维和20%的传出(运动)纤维。在解剖结构上，其感觉和运动核团与多个痛觉调控中枢存在直接或间接的纤维联系，构成复杂的痛觉调控网络。外周痛觉主要由迷走神经的内脏感觉纤维和躯体感觉纤维传入。内脏感觉纤维传递胸腹腔脏器(如心、肺、胃肠道)的伤害性信息，其初级传入纤维主要投射至延髓的孤束核(nucleus of the solitary tract，NTS)。躯体感觉纤维(如耳支)传递部分痛温觉，并投射至三叉神经脊束核(spinal nucleus of trigeminal nerve，Sp5)，后者是躯体-内脏痛觉信息整合的关键核团。NTS是迷走神经内脏痛觉信息的主要中继站，接收并整合来自内脏的伤害性信号[9]。Sp5不仅接受三叉神经的痛觉传入，还与迷走神经的耳支纤维存在交汇，参与头面部及部分外周的痛觉调控[10]。

从NTS和Sp5发出的神经纤维可进一步投射至蓝斑核(locus coeruleus，LC)等多个痛觉调控关键核团，形成复杂的下行抑制系统和上行调控系统，包括NTS-LC下行抑制通路、Sp5-LC-丘脑-皮质通路和NTS-网状结构-脊髓通路。在NTS-LC下行抑制通路中，NTS发出的纤维直接投射至LC，LC的去甲肾上腺素(norepinephrine，NE)能神经元进一步发出纤维至延髓头端腹内侧区(rostral ventromedial medulla，RVM)和脊髓背角，增强下行痛觉抑制，减少伤害性信号的上传[11]。在中枢神经系统中，大脑皮质、皮质下结构和小脑的多巴胺能神经支配主要源自中缝核(raphe nuclei，RN)，多巴胺能神经调节系统是参与调节疼痛体验的第2种神经递质系统[12]。VNS可以调节NTS-LC-RN通路，加强RN和尾状核/壳核之间的功能连接，调控疼痛体验。在Sp5-LC-丘脑-皮质通路中，Sp5的伤害性信息可直接影响LC的NE，调节觉醒和痛觉敏感性[13]。同时，Sp5和NTS的纤维可经LC/臂旁核(parabrachial nucleus，PB)投射至丘脑和杏仁核，影响痛觉的情绪传递[14]。在NTS-网状结构-脊髓通路中，延髓网状结构通过释放5-羟色胺(5-hydroxytryptamine，5-HT)和内啡肽，抑制脊髓背角的伤害性神经元，发挥镇痛作用[15-16](图1)。

图1.

图1

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迷走神经参与痛觉调节过程的解剖学基础

Figure 1 Anatomical basis for vagus nerve involvement in pain modulation

NTS: Nucleus tractus solitarius; Sp5: Spinal trigeminal nucleus; LC: Locus coeruleus; RN: Raphe nuclei; PB: Parabrachial nucleus; 5-HT: 5-Hydroxytryptamine.

迷走神经通过NTS和Sp5接收痛觉信息，并经由LC-NE能系统、RVM-5HT能系统和PBN-边缘系统等多条通路，形成下行抑制和上行调控网络，从而在外周、脊髓和大脑多个层面参与痛觉的调节。这一解剖学基础不仅解释了VNS的镇痛机制，也为慢性疼痛及慢性疼痛引起的情绪障碍的共病治疗提供了理论依据。

2. VNS调节痛觉的作用机制

2.1. 调控神经炎症

多项研究[17-19]发现，神经炎症是慢性疼痛发病机制的关键驱动因素，神经胶质细胞、免疫细胞和促炎性细胞因子与慢性疼痛状态有关。迷走神经参与炎症反应，VNS可通过减轻炎症来控制疼痛，其主要通过影响胆碱能抗炎通路(cholinergic anti-inflammatory pathway，CAP)与下丘脑-垂体-肾上腺轴(hypothalamic-pituitary-adrenal axis，HPA)，以及调控特异性炎症消退介质(specialized proresolving mediators，SPMs)来实现镇痛效果(图2)。

图2.

图2

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VNS调节痛觉的作用机制

Figure 2 Mechanisms of pain modulation by VNS

VNS: Vagus nerve stimulation; HPA: Hypothalamic-pituitary-adrenal axis; CAP: Cholinergic anti-inflammatory pathway; SPMs: Specialized proresolving mediators; ACh: Acetylcholine; α7nAChR: Alpha-7 nicotinic acetylcholine receptor; JAK2: Janus kinase 2; STAT3: Signal transducer and activator of transcription 3.

迷走神经传出纤维释放乙酰胆碱(acetylcholine，ACh)，通过作用于免疫细胞表面的α7烟碱型乙酰胆碱受体(alpha-7 nicotinic acetylcholine receptor， α7nAChR)，抑制单核细胞和巨噬细胞合成或释放肿瘤坏死因子α(tumor necrosis factor alpha，TNF-α)、白介素(interleukin，IL)-1β等促炎性细胞因子[20-21]。在此基础上，进一步研究[22-23]发现，急性与慢性神经病理性疼痛状态会对雄性小鼠脾脏辅助性T细胞2的免疫反应产生差异性调节，且迷走神经背侧运动核的ACh能神经元可直接支配脾脏。脾神经释放NE，作用于脾脏中表达胆碱乙酰转移酶(choline acetyltransferase，ChAT)的T细胞，促使这些T细胞释放ACh。ACh与巨噬细胞上的α7nAChR结合，激活Janus激酶2(Janus kinase 2，JAK2)信号转导及转录活化因子3(signal transducer and activator of transcription 3，STAT3)信号通路，隔离核因子κB(nuclear factor kappa-B，NF-κB)，并抑制促炎性细胞因子的产生，从而发挥镇痛作用[24-25]。NE还可作用于脾淋巴细胞的β2受体以释放ACh，ACh与脾巨噬细胞的α7nAChR结合以抑制这些巨噬细胞释放TNF-α[26]，迷走神经的这种抗TNF-α作用可用于治疗慢性炎症性肠病。

迷走神经的传入纤维刺激可以激活HPA轴，通过NTS将信号传递至下丘脑室旁核，诱导促肾上腺皮质激素释放激素的释放，进而促进垂体释放促肾上腺皮质激素，最终刺激肾上腺分泌糖皮质激素[27-28]。糖皮质激素具有强大的抗炎作用，能够抑制促炎性细胞因子的产生，从而减轻炎症反应。一项针对HPA功能与脊髓损伤相关性神经病理性疼痛的病例对照研究[29]发现，慢性脊髓损伤期间神经病理性疼痛的严重程度可能与HPA轴活性呈正相关。这也为探索VNS调节HPA轴减轻炎症反应，降低机体疼痛感提供了理论支撑。

VNS能够提高SPMs的水平。这些介质包括消退素、脂氧素、保护素和马雷辛等，是炎症消退阶段产生的脂质分子，它们通过作用于免疫细胞、胶质细胞和神经元上的受体调节炎症反应，促进炎症的消退[30-31]。Serhan等[32]用人离体迷走神经实验获得的结果表明，迷走神经可以产生促炎性类花生酸，如胡萝卜素和白三烯等；电刺激人离体迷走神经可降低肾上腺素和白三烯水平，增强消退素和其他SPMs水平，达到抗炎的效果。Tao等[33]的研究发现，电针耳迷走神经会增加消退素的产生，并抑制由紫杉醇注射诱导的化学治疗相关的周围神经病变模型小鼠的神经性疼痛。然而，VNS通过激活小鼠体内何种受体调控SPMs，以及不同SPMs介导生物学功能的信号通路，仍有待深入探究。

2.2. 调节脑-肠轴

迷走神经作为脑-肠轴(brain-gut axis，BGA)的重要组成部分，在肠道和大脑之间的交流中起至关重要的作用。它通过调节BGA来影响食物摄入、脂肪代谢和情绪，BGA与胃肠道、精神和新陈代谢相关疾病的发展密切相关[34]。近年来研究[35-36]发现BGA亦是慢性疼痛的关键调控通路，通过影响迷走神经、免疫反应、内分泌和微生物组等途径参与疼痛调控，尤其在功能性疼痛中的作用显著。

BGA和慢性疼痛间相互作用的关键机制包括微生物生态失调、迷走神经功能障碍和HPA轴调节失调，这些因素导致神经炎症和中枢致敏[37]。慢性疼痛患者肠道有益菌减少，促炎菌增多，菌群代谢物短链脂肪酸减少，削弱肠屏障功能并加剧神经炎症。肠黏膜通透性增加(“肠漏”)导致内毒素入血，激活全身免疫反应，释放IL-6、TNF-α等炎症因子，通过迷走神经或血脑屏障引发中枢敏化。HPA轴失调，慢性皮质醇升高加剧肠漏和神经炎症，形成“应激-疼痛”恶性循环[38]。

慢性疼痛发生时迷走神经传入纤维可以将肠道的机械信号和化学信号传递至LC、下丘脑和杏仁核，传出纤维通过CAP通路抑制脾脏巨噬细胞释放促炎性细胞因子，并调节肠道运动和分泌，维护菌群平衡[38-40]。Yue等[41]研究发现，在弗氏完全佐剂诱导的慢性炎症伴肠道菌群失衡的模型小鼠中，切断膈下迷走神经可阻断肠道炎症对中枢的影响。在功能性消化不良(functional dyspepsia，FD)模型小鼠中，慢性应激可导致皮质醇升高，加剧杏仁核基底外侧核神经元敏化和肠道通透性；而VNS可逆转杏仁核可塑性，减轻FD小鼠的内脏痛和焦虑[42]。迷走神经还可以通过肠神经系统和肠神经胶质细胞改变肠道通透性：肠神经胶质细胞在被激活时可分泌许多活性分子，其中一些可改善肠道屏障功能并限制黏膜炎症，因此具有屏障保护特性[43]。Costantini等[44]的研究表明，VNS可通过激活肠神经胶质细胞，在肠组织水平上调节对损伤的反应，来保护烧伤诱导的肠损伤，且这种肠保护效应不依赖脾脏细胞因子的参与。

2.3. 影响中枢神经通路

研究[45-46]表明，VNS可通过特定的神经通路级联反应调控疼痛信号转导。刺激迷走神经后，NTS、LC以及与其有纤维投射的相关脑区呈现时序性激活模式，人体功能性磁共振成像(functional magnetic resonance imaging，fMRI)可通过评估、对比这些脑区与静息状态下的功能连接变化，从而揭示VNS对中枢疼痛网络的调节机制。

在一项基于经耳迷走神经刺激(transcutaneous auricular vagus nerve stimulation，taVNS)对偏头痛患者迷走神经通路中脑干关键区域功能连接的调节作用的研究[47]中，研究者分别评估了NTS、LC及RN脑区的功能连接变化，fMRI结果显示，taVNS通过3条通路调控中枢疼痛网络：1)taVNS增强了NTS与双侧RN的功能连接，降低了NTS与双侧内侧前额叶皮层和双侧海马的功能连接，通过增强血清素能调节减少疼痛相关的情绪和记忆的产生；2)taVNS增强了LC与双侧丘脑的功能连接，降低了LC与双侧中央后回、顶上小叶和左侧前中央回的功能连接，通过调节丘脑痛觉信息传递，抑制体感区的疼痛输入； 3)taVNS促进了RN与双侧内侧前额叶皮层/前扣带回、左侧眶额叶皮层、左侧角回、右侧尾状核和豆状核的功能连接增加，降低了RN与双侧丘脑和右侧中央后回的功能连接，通过增强下行抑制和基底节调节通路，从而抑制痛觉和情绪认知传导。taVNS还可通过调节大脑边缘系统和基底节的活动，选择性地“关闭”疼痛体验中的情感部分，从而实现镇痛效果[48]。在一项taVNS治疗慢性腰痛(chronic low back pain，CLBP)的研究[49]中，fMRI揭示了taVNS通过增强下行疼痛调制系统与感觉皮层及边缘系统的连接，并调节奖赏网络与前扣带皮层、尾状核、中央前回的功能连接，从而同时抑制疼痛感觉和改善负面情绪，实现镇痛效果。

基于fMRI的研究[50]不仅揭示了taVNS通过改变不同脑区功能连接以缓解疼痛的机制，更清晰地展现了大脑不同区域在急性刺激期与刺激后延迟期具有不同的活动模式。大多数被taVNS激活的脑干区域(如NTS、黑质、背侧中缝核、底丘脑核等)不仅在刺激期间被显著激活，而且在刺激停止后的3 min内依然保持活跃。且不同脑区对taVNS的响应时间模式并不相同，NTS和背侧中缝核等核心节点表现出快速且持续的激活，黑质等一些中脑区域则显示出延迟响应，其最强激活出现在刺激停止之后。右侧RN表现为在刺激期激活，左侧RN则在刺激后延迟期激活。这表明taVNS对大脑的影响具有精细的时间和空间特异性，并非简单的全局激活。

3. VNS方式

VNS分为侵入性迷走神经刺激(implantable vagus nerve stimulation，iVNS)、经皮迷走神经刺激(transcutaneous cervical vagus nerve stimulation，tcVNS)和taVNS几种形式。iVNS主要通过外科手术将电极植入颈部迷走神经，连接到刺激器，刺激器通常植入胸部皮下。tcVNS通过皮肤电极刺激耳部或颈部迷走神经。taVNS通过刺激耳部迷走神经分支，影响中枢神经系统，耳甲艇可能是最佳刺激部位[51]。刺激参数包括电流强度、频率和脉冲宽度等，iVNS的电流强度一般在0.25~3.75 mA之间，而taVNS和tcVNS的电流强度取决于对应产品指定的参数。脉冲宽度的选择一般为100~500 μs，频率一般设置在20~30 Hz[52-53]。由于没有统一的参数标准，具体刺激参数因装备、研究和应用而异，或参考类似疾病的研究文献中报道的数值。目前，VNS参数与不同机制和疾病之间是否存在联系尚不清楚。在未来的研究中，应考虑探索VNS参数与机制之间的联系，以及不同疾病的最佳参数范围。

4. VNS在慢性疼痛中的临床应用

目前，VNS已被广泛应用于偏头痛、纤维肌痛(fibromyalgia，FM)、炎症性肠病(inflammatory bowel diseases，IBD)、CLBP、神经病理性疼痛等多种慢性疼痛疾病的治疗中。

4.1. VNS治疗偏头痛

偏头痛是一种致残性神经性头痛疾病，患者常常出现恶心、呕吐，以及对光、声音敏感等症状。一项动物实验[54]首次证明了VNS可以抑制急性硬膜内(偏头痛样)和三叉神经自主神经(群集样)头痛模型动物中三叉神经元的急性伤害性激活。屈箫箫等[55]研究发现taVNS可预防性治疗偏头痛，能够明显降低偏头痛发作天数及疼痛程度。Silberstein等[56]也发现持续预防性使用tnVNS可减少慢性偏头痛患者的头痛天数。一项纳入了tcVNS和taVNS治疗偏头痛的急性和预防性结局的荟萃分析[57]显示，2种刺激方式均可显著减少偏头痛的疼痛程度和天数，低频taVNS还可以显著降低头痛强度。但现有研究均存在观察样本过小、随访时间受限等问题，其远期疗效有待进一步研究。

4.2. VNS治疗FM

FM是一种常见的疾病，其主要特征是慢性广泛疼痛、极度疲劳和痛觉过敏，并涉及自主神经和免疫系统的失调[58]。其核心机制主要涉及交感-迷走神经失衡、中枢敏化和免疫-炎症异常等方面。研究[59]发现多次非侵入性VNS可以调节FM患者的交感-迷走神经张力，从而显著减轻疼痛强度。Kutlu等[60]发现taVNS联合运动能改善FM患者疼痛和生活质量，但该联合方案中taVNS的独立效应无法与运动干预的效应明确区分，需进一步剥离运动干预效应，并需要更长的随访时间和更多的患者样本量。此外，FM综合征作为一种应激相关疾病，存在CAP和HPA轴的过度激活，VNS对健康状态生理和心理方面的调节效应可对该疾病的控制起到一定作用。Dolcini等[61]的先导研究首次证实4周taVNS可显著改善FM患者的整体疾病严重程度和睡眠质量，且安全易耐受，但其镇痛效果无统计学意义。Lommano等[62]的研究发现，tcVNS使FM患者的自主神经功能、FM疼痛特征和中枢敏化显著改善。这是首个描述tcVNS是否能够调节自主神经功能，以及其是否能够改善FM患者中枢敏化和疼痛的研究。但该研究仅纳入25名女性患者，且缺乏对照试验，需要进行更大规模、有对照且随访时间更长的研究，更清晰地阐明tcVNS在FM中的治疗作用。

4.3. VNS治疗IBD

IBD是一种器质性疾病，临床上可分为克罗恩病(Crohn disease，CD)和溃疡性结肠炎(ulcerative colitis，UC)，症状表现为腹痛、腹泻、发烧、体重减轻及肠外(皮肤、眼睛、关节)表现等，其中腹痛是IBD的一个突出症状。在IBD患者的大型队列中，60%的患者报告有腹痛，30%~50%的IBD患者即使在疾病缓解时仍报告有显著疼痛[63]。当前对IBD患者疼痛的治疗以减轻并维持缓解为目标，但尚无法根治，停药后易复发[64]。VNS凭借“神经-免疫”双重抗炎机制，可在不依赖免疫抑制的情况下调节肠道炎症，可用作缓解慢性IBD患者腹痛的非药物疗法[65]。

VNS治疗IBD患者腹痛的潜在机制主要涉及CAP和BGA双向调节。最新动物实验[66]采用葡聚糖硫酸钠诱导的结肠炎模型证实，taVNS显著下调结肠及中枢促炎性细胞因子IL-1β、IL-6、TNF-α，同时上调抗炎细胞因子IL-10，并首次揭示taVNS通过“迷走神经-肠-脑轴”同步缓解肠道黏膜损伤与活化脑内小胶质细胞的作用，减轻结肠炎症与溃疡，并改善黏膜层肥厚，从而缓解疼痛。在临床探索方面，D’Haens等[67]完成的先导研究对12例中重度活动性CD患者进行iVNS干预治疗，第16周时CD活动指数、粪便钙卫蛋白、内镜下黏膜炎症及外周细胞因子均显著下降，提示VNS可通过CAP重塑免疫稳态、改善肠道异常活动、缓解腹痛症状，为IBD患者的腹痛治疗提供了一种新策略。

4.4. VNS治疗CLBP

CLBP是一种常见的肌肉骨骼系统疾病，其特征为腰部疼痛持续超过3个月，常伴随活动受限、生活质量下降及焦虑、抑郁等心理问题。一项概念验证性试点研究[68]证明，taVNS在减轻CLBP患者的疼痛、改善功能状态和生活质量方面是安全有效的。但该研究缺乏对照组，且样本量较小。与传统腰背康复治疗相比，VNS在改善疼痛和日常生活活动方面效果更好[69]。Li等[70]进行对照试验时，将刺激耳垂处耳大神经作为对照组，结果发现taVNS组与对照组患者在经过4周治疗后，其疼痛强度和疼痛对生活的干扰均得到显著缓解，2组疗效无明显差异。随后基于fMRI的研究[49]发现，taVNS通过增强导水管周围灰质(periaqueductal gray matter，PAG)与左杏仁核等边缘系统的连接发挥镇痛作用，而经皮耳大神经刺激则通过减弱PAG与右杏仁核等区域的连接来缓解疼痛，两者通过不同神经通路实现镇痛效果。当前研究的不足之处在于将一种具有独立镇痛机制和神经通路的主动治疗简单地设置为“对照组”，无法完全排除安慰剂效应等非特异性因素对结果的干扰，且评估多依赖于患者主观报告的疼痛相关结果，缺乏客观的生物学指标，这导致对VNS疗效的评估可信度降低。

4.5. VNS治疗神经病理性疼痛

神经病理性疼痛是一种直接由感觉系统受损、功能障碍或疾病引起的疼痛。其特征是存在持续性或复发性疼痛状态，表现为烧灼感、刺痛或麻木感[71-72]。动物实验[73]表明，在糖尿病肥胖大鼠坐骨神经慢性束缚损伤模型中，taVNS可显著减轻大鼠的热超敏反应，有效缓解其神经病理性疼痛。在坐骨神经结扎诱导的神经病理性疼痛模型小鼠中，taVNS可通过激活下行疼痛抑制通路上调小鼠脊髓背角的5-HT1A和5-HT3受体表达，显著缓解机械性痛觉过敏和冷痛觉异常[74]。一项探讨tcVNS是否可改善糖尿病自主神经病变患者的胃肠道功能的研究[75]发现，单次tVNS未能改善糖尿病自主神经病变患者的胃肠道动力、症状或自主神经功能。这可能是因为对慢性、严重的神经病变，单次刺激的剂量可能不足以逆转病理状态，需要进行长期、重复的刺激才能累积产生生理效应。随后一项研究[76]发现taVNS联合三叉神经颈复合体外周神经刺激能显著改善严重糖尿病疼痛型周围神经病变症状，两者联合疗效优于单一taVNS疗法。可见除了探索适宜的刺激强度和频率外，探索taVNS与其他治疗联合使用也是一种可行的思路。

化学治疗诱导的周围神经病变(chemotherapy-induced peripheral neuropathy，CIPN)是化学治疗药物的常见不良反应，表现为疼痛、感觉异常、麻木和刺痛感，神经炎症是介导CIPN的关键因素[77]。一项探讨VNS对紫杉醇诱导的CIPN的潜在治疗作用的动物实验研究[78]发现，VNS能够短暂减轻紫杉醇诱导的大鼠疼痛过敏，特别是在刺激后的第1天，大鼠对热和机械疼痛的敏感性显著降低，但在治疗7 d后并无明显变化。另一项动物研究[79]评估不同频率taVNS对CIPN的疗效，结果显示20 Hz的taVNS对CIPN疼痛的缓解效果最为显著。临床试验[80-81]结果表明，taVNS可在短期内缓解CIPN，改善患者的睡眠状态和生活质量。然而，目前动物实验与临床试验的研究中均只评估了VNS的短暂疗效，需要进一步探究慢性VNS是否能在CIPN中产生持久的保护作用。

VNS虽然在治疗慢性疼痛及疼痛导致的情绪共病中显示出良好的效果，但也存在一些常见的不良反应。iVNS可能导致声音嘶哑、声音改变，咳嗽、咽喉痛、喉咙发紧，呼吸困难、气短，以及心动过缓等情况，尤其在初始调整参数时，可能因喉部肌肉收缩导致气道感觉异常[82]。非侵入性VNS的不良反应通常表现为电极放置部位的皮肤出现刺痛、发红、瘙痒或轻微灼热感等症状[83]。这些症状通常在适应后或调整电极位置后消失。长期应用VNS治疗的安全性是临床关注的重点，应根据个人情况设定刺激强度，避免强刺激引发不适。在治疗期间可为患者配备心率检测仪，定期随访评估疗效与不良反应，及时调整治疗方案，提高治疗的安全性和有效性。

5. 结 语

VNS作为一种创新的神经调控疗法，通过多靶点、多机制作用为慢性疼痛治疗提供了新途径。大量基础和临床研究证实了其有效性和安全性，随着研究的深入和技术的进步，未来研究应重点关注以下几个方向：1)探索VNS与多模态干预及神经影像学验证的整合研究。现有的fMRI研究大多聚焦于中枢机制，未能同步监测和关联外周生理指标(如心率变异性、炎症因子水平等)。这种中枢与外周数据的分离，限制了对VNS的治疗途径的全面理解，并且多数研究的关注点侧重于急性和短期效应，缺乏对VNS长期效应的评估。未来研究需结合高时空分辨率技术对VNS作用机制进行更深层次的探索。2)深入研究VNS对于慢性疼痛共病的胃肠道疾病和情绪障碍的调节作用。慢性疼痛常与胃肠道功能障碍和情绪障碍共病，而迷走神经作为连接BGA的关键通路，其调控作用具有天然优势。相关研究中动物实验占多数，而临床转化研究仍处于初步阶段。动物实验通常在基因背景一致、病因单一的模型中展开，而慢性疼痛患者常伴有抑郁、焦虑、失眠等多种共病，其病理生理是多种机制交织的复杂网络。除了主观疼痛评分，还应整合客观生物标志物与神经影像学生物标志物等指标以增加研究的可靠性。 3)建立个体化、精准化的刺激方案。慢性疼痛病因复杂、表型多样，VNS的镇痛效应与刺激方式、参数及疾病亚型之间的量效关系仍不清晰，未来的研究需要更大样本、更严格的随机对照设计。

基金资助

国家自然科学基金(JCZX202307)；福建省自然科学基金(2023J01846)。This work was supported by the National Natural Science Foundation (JCZX202307) and the Natural Science Foundation of Fujian Province (2023J01846), China.

利益冲突声明

作者声称无任何利益冲突。

作者贡献

刘晴晴 论文设计、撰写与修改；陈斌 论文设计、指导与修改；徐聪 论文设计；林万庆 论文指导。全体作者阅读并同意最终的文本。

Footnotes

http://dx.chinadoi.cn/10.11817/j.issn.1672-7347.2025.250561

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2025122438.pdf

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