The application of acupuncture in the management of neuropathic orofacial pain: a narrative literature review

2.1 Endogenous opioid release

Acupuncture stimulates the release of endogenous opioids, such as endorphins, enkephalins and dynorphins, which modulate pain perception by binding to opioid receptors in the central and peripheral nervous systems, thereby inhibiting pain signaling and producing analgesic effects [27, 28]. These neuropeptides bind to the μ (mu), δ (delta) and κ (kappa) opioid receptors located in key pain-processing areas such as the periaqueductal gray (PAG), thalamus and dorsal horn of the spinal cord [29]. The activation of these receptors by acupuncture inhibits nociceptive transmission, enhances descending pain inhibition, and reduces pain perception. Repeated acupuncture sessions have been shown to strengthen opioid-mediated pathways and induce neuroplastic changes that persist for long periods [30]. Such adaptations enhance the body’s ability to regulate pain and contribute to long-term analgesic effects. Evidence from animal models and human studies suggests that the release of opioids might also modulate the emotional and psychological aspects of pain, further supporting acupuncture’s holistic benefits in neuropathy pain management [31].

2.2 Neurotransmitter regulation

The effect of acupuncture on neurotransmitter dynamics in the CNS is significant, particularly regarding descending inhibitory pathways. It enhances the release of 5-hydroxytryptamine (5-HT) and norepinephrine, both of which are central mediators of descending pain modulation mechanisms [32]. By increasing the levels of these neurotransmitters, acupuncture inhibits endogenous pain signals in the spinal cord and reduces pain perception at various levels of the CNS. Additionally, acupuncture stimulates the activity of gamma-aminobutyric acid (GABA), which helps decrease neuronal excitability and hyperalgesia [33]. By promoting a balanced neurochemical environment, acupuncture not only alleviates pain but also addresses psychological comorbidities such as anxiety and depression, which are common in patients with NOP [34]. These neurochemical effects play a crucial for in breaking the cycle of chronic pain and emotional disturbance, ultimately providing both physical and emotional comfort [35].

2.3 Neuroinflammation and immune modulation

Neuroinflammation, resulting from the interactions between neurons, astrocytes and microglia in the CNS, is a hallmark of neuropathic pain. The event of nerve injury triggers inflammatory cascades that lead to the secretion of pro-inflammatory cytokines, such as IL-1β and TNF-α, along with excitatory mediators like glutamate and brain-derived neurotrophic factor (BDNF) [36, 37]. These molecules upregulate nociceptive signaling through the activation of N-methyl-D-aspartate (NMDA) receptors and extracellular signal-regulated kinase (ERK) phosphorylation (pERK), resulting in central sensitization [38]. Acupuncture modulates neuroinflammation by regulating glial cell activation through the Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway. By downregulating pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and upregulating IL-10, it suppresses excessive immune responses and promotes M2 microglial polarization [39]. TLR4 activation recruits myeloid differentiation primary response 88 (MyD88), triggering NF-κB translocation, which amplifies neuroinflammation [40]. Acupuncture inhibits TLR4/MyD88 signaling, reducing NF-κB-driven cytokine release and preventing pathological glial cross-talk. IL-10 further restrains NF-κB activation, reinforcing an anti-inflammatory state [41]. This modulation mitigates chronic neuroinflammation, supporting its therapeutic role in neuropathic pain (Fig. 1).

Fig. 1.Neuroinflammatory Pathways and Cellular Interactions in Nerve Injury-Induced Pain Signaling. Abbreviations: AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ATP: adenosine triphosphate; BDNF: brain-derived neurotrophic factor; Ca²⁺: calcium ion; CX3CR1: C-X3-C motif chemokine receptor 1; ERK: extracellular signal-regulated kinase; FKN: fractalkine; Gln: glutamine; GLS: glutaminase; IL-1β: interleukin-1 beta; IL-1RI: interleukin-1 receptor type I; Na⁺: sodium ion; NMDAR: N-methyl-D-aspartate receptor; NK1: neurokinin-1 receptor; p38: p38 mitogen-activated protein kinase; Perk: phosphorylated ERK; P2X4: purinergic receptor P2X, ligand-gated ion channel 4; SP: substance P; THR: tyrosine kinase receptor; TLR4: toll-like receptor 4; TNF-α: tumor necrosis factor-alpha; TNFR: tumor necrosis factor receptor.

2.4 Neuroplasticity and central sensitization

NOP is associated with maladaptive neuroplasticity and central sensitization, both of which are characterized by the increased activity of pain-processing pathways [42]. Functional magnetic resonance imaging (fMRI) studies indicate that acupuncture restores aberrant neural activities in important brain regions such as the anterior cingulate cortex (ACC), insula and somatosensory cortex [43]. This process involves the modulation of neural networks, allowing acupuncture to reduce hypersensitivity to pain and alleviate emotional distress associated with chronic pain [44]. These neuromodulatory effects not only influence pain perception but also contribute to improved emotional regulation and cognitive functioning, highlighting acupuncture’s multifaceted role in treating neuropathic pain [45].

2.5 Peripheral modulation

Acupuncture exerts its anti-inflammatory and analgesic effects through the activation of nociceptors and surrounding tissues [42]. It increases local blood flow, enhancing oxygenation and nutrient delivery to the affected area, which accelerates tissue repair and reduces nociceptor sensitization. Additionally, acupuncture promotes the clearance of pro-inflammatory mediators from the extracellular environment [46]. The neuromodulatory action of adenosine further contributes to localized pain relief, owing to its potent anti-inflammatory effects [47]. Adenosine inhibits nociceptive signaling through the A1 receptor, which enables immediate analgesic action and reduces peripheral sensitization [48]. These peripheral mechanisms complement the central effects of acupuncture, offering an integrated framework with both localized and systemic mechanisms contributing to the management of NOP.

3.1 Burning mouth syndrome

BMS is a chronic NOP condition characterized by a recurrent burning or dysesthetic sensation in the oral mucosa for over two hours daily and lasting more than three months, without detectable mucosal lesions or abnormal lab results [49]. Despite the absence of detectable physical causes or dental abnormalities, BMS is more prevalent among postmenopausal women and is considered a multifactorial disorder with neuropathic, psychogenic and systemic bases. This complexity, coupled with its uncertain etiology, makes clinical management particularly challenging, as pharmacological interventions often yield inconsistent outcomes. Studies indicate that acupuncture may alleviate BMS symptoms by stimulating specific acupoints, such as SI1 (Shaoze), TE1 (Guanchong), LI4 (Hegu), TW21 (Ermen), ST5 (Daying), ST6 (Jiache) and CV24 (Chengjiang) [49, 50, 51, 52, 53]. These points are selected based on their ability to modulate nociceptive pathways and optimize both local and systemic physiological responses [50, 51, 52, 53]. Mechanistically, acupuncture enhances oral microcirculation, promotes blood flow and restores vascular homeostasis, which links the dysfunction of circulation to BMS pathogenesis [54]. By modulating vasoreactivity, acupuncture may reduce localized neuroinflammation and improve tissue oxygenation. Furthermore, as BMS often involves psychological components such as anxiety and depression, which amplify pain perception and exacerbate the condition, acupuncture appears to improve patients’ emotional well-being [55]. Table 1 provides a concise summary of the pathogenesis and clinical symptoms associated with different subtypes of NOP. Franco et al. [56] emphasized that acupuncture combined with auricular therapy offers a dual benefit by addressing both the physical and emotional domains of the disorder. Recent evidence also suggests that acupuncture may influence immunity and hormonal balance, potentially alleviating the neuroinflammatory and neurodegenerative processes underlying BMS [57]. Gremeau-Richard et al. [58] conducted a randomized placebo-controlled study on topical clonazepam, demonstrating its effectiveness in reducing BMS symptoms. Heckmann et al. [59] performed a double-blind study on systemic clonazepam, which also showed significant symptom relief. Furthermore, Scardina et al. [52] reported that acupuncture improved oral microcirculation and alleviated burning symptoms in BMS patients. These studies, along with others, contribute to the growing body of evidence supporting different therapeutic approaches for BMS.

3.2 Trigeminal neuralgia

TN presents substantial clinical management challenges owing to its insidious onset and limitations of conventional pharmacotherapy. Although carbamazepine maintains its status as first-line treatment, its therapeutic utility is frequently constrained by dose-dependent adverse effects including dizziness, fatigue and cognitive impairment, which collectively compromise patients’ QoL [60]. Emerging evidence positions acupuncture as a promising therapeutic alternative, demonstrating statistically significant pain reduction and enhanced treatment response rates compared to conventional approaches.

A comprehensive network meta-analysis by Yin et al. [61], encompassing 58 randomized controlled trials (RCTs) with >4000 participants, revealed that combined EA and manual acupuncture protocols outperformed carbamazepine monotherapy in both pain intensity reduction (measured by visual analogue scale improvements) and achieving clinically meaningful response rates (defined as ≥50% pain relief). This therapeutic advantage was particularly evident when compared to sham acupuncture controls. Complementary findings by Gao et al. [60] further substantiate acupuncture’s multidimensional benefits, demonstrating concurrent improvements in cognitive function and QoL metrics alongside pain alleviation. The robustness of these conclusions is reinforced by multicenter studies from Edwards et al. [62] and Hu et al. [63], which confirmed consistent efficacy across varied acupuncture modalities including EA, traditional manual needling, and fire acupuncture techniques. Acupuncture also performed well in terms of safety, with few documented side effects across the studies [64, 65]. Yin et al. [61] specifically noted an absence of serious adverse events across analyzed trials, positioning acupuncture as a well-tolerated option for medication-intolerant patients. Clinical application in TN typically involves strategic stimulation of trigeminal nerve-associated acupoints: ST2 (Sibai), ST4 (Dicang), ST6 (Jiache) and ST7 (Xiaguan) for local neuromodulation, combined with distal points including LI4 (Hegu), GB20 (Fengchi) and DU26 (Renzhong) for systemic regulation [60, 61, 66, 67, 68]. This dual-target approach concurrently addresses peripheral nociceptive pathways and central pain processing mechanisms, potentially explaining its sustained therapeutic effects.

3.3 Temporomandibular disorders

TMD encompasses a spectrum of conditions affecting the temporomandibular joint (TMJ), masticatory muscles, and associated structures, often presenting with chronic orofacial pain, myofascial discomfort, and joint dysfunction [69]. Symptoms such as restricted jaw mobility, clicking or popping sounds, and persistent muscular pain significantly impair patients’ QoL [70]. While conventional treatments, including physical therapy, occlusal splints and pharmacological interventions, are widely utilized, their efficacy varies, and adverse effects or incomplete symptom relief often limit their applicability. This has driven growing interest in adjunctive therapies like acupuncture and EA, which have demonstrated potential in symptom relief, muscle relaxation and functional improvement of the TMJ [71]. Acupuncture and EA have been extensively studied for their capacity to reduce pain, regulate neuromuscular activity, and address the inflammatory mechanisms underlying TMD. Key acupoints used in treatment include SI18 (Quanliao), TW21 (Ermen), LI4 (Hegu), ST6 (Jiache), ST7 (Xiaguan), GV24 (Shenting), GV20 (Baihui), GV21 (Qianding), GV22 (Xinhui), ST36 (Zusanli), LI3 (Sanjian) and LI11 (Quchi) [72, 73, 74, 75, 76, 77, 78, 79, 80]. These points are chosen for their ability to alleviate pain, improve joint function and regulate neuromuscular activity. These acupoints are specifically selected for their roles in modulating pain pathways, improving joint mobility, and promoting neuromuscular coordination. Studies consistently report significant reductions in pain intensity and enhancements of jaw function when acupuncture or EA is employed, often outperforming sham acupuncture or standard care. For example, Liu et al. [80] demonstrated substantial reductions in pain scores and improvements in jaw mobility, with effects persisting for weeks post-treatment. Similarly, Sung et al. [76] found that EA combined with ultrashort wave therapy provided superior therapeutic outcomes, indicating a synergistic effect when acupuncture is integrated with other modalities.

The mechanisms underlying acupuncture’s efficacy in TMD are multifaceted, involving both peripheral and central processes. Acupuncture stimulates the release of endogenous opioids, such as β-endorphins, and modulates serotonergic and dopaminergic pathways, both of which are essential in pain regulation and perception [81]. Furthermore, acupuncture has been shown to attenuate inflammatory responses by downregulating cytokines such as TNF-α and IL-6, both of which contribute to TMD symptom severity [42]. EA amplifies these benefits by delivering electrical stimulation to acupoints, further improving nerve conduction, reducing muscular hyperactivity and facilitating localized blood flow [82]. Acupuncture’s impact extends beyond the physical symptoms of TMD, addressing the psychological dimensions of the disorder. Anxiety, depression and stress, which are prevalent among TMD patients, often exacerbate pain perception and complicate treatment outcomes. Acupuncture has been shown to modulate the hypothalamic–pituitary–adrenal (HPA) axis, reducing cortisol levels and promoting emotional regulation [83]. Jung et al. [77] observed that acupuncture not only alleviated muscle tension but also improved emotional function, highlighting its role in mitigating the both physical and psychological burden of TMD. These effects underscore the holistic potential of acupuncture in addressing both the somatic and psychological dimensions of the disorder. However, discrepancies in the reported efficacy of acupuncture persist. Wu et al. [84] and Laurence et al. [78] found mixed results, with limited evidence supporting acupuncture’s superiority over sham treatments in certain contexts. These inconsistencies can be attributed to methodological variability, including differences in diagnostic frameworks, acupoint selection, treatment protocols and study designs. Such heterogeneity underscores the need for rigorously designed, standardized studies to establish clearer evidence regarding acupuncture’s therapeutic role in TMD. Future research should prioritize randomized, sham-controlled trials with well-defined diagnostic criteria and standardized acupuncture protocols to ensure reliability and reproducibility. These findings collectively suggest that acupuncture and EA offer a multifaceted approach to TMD management, targeting not only localized pain and inflammation but also systemic and psychological factors.

3.4 Postherpetic neuralgia

PHN is a challenging form of chronic neuropathic pain that persists even after the remedy of herpes zoster infection [85]. It is often characterized by severe, localized pain along affected dermatomes. Treatment remains complex due to the intricate interplay of peripheral and central sensitization mechanisms, which allow symptoms to persist and intensify [86]. Conventional treatments encompass all the usual approaches, including anticonvulsants and topical treatments; unfortunately, they usually offer only partial relief, with scant benefits due to the side effects experienced and the continued persistence of some symptoms [9]. Acupuncture is thought to reduce PHN symptoms via a multifaceted modulation of neural and inflammatory pathways: its mechanism of action includes inhibiting peripheral sensitization by reducing the release of proinflammatory cytokines such as IL-6 and TNF-α, which are among the most critical mediators of nociceptive sensitization [42, 46]. Acupuncture also regulates the transient receptor potential vanilloid 1 (TRPV1) activity, which may help diminish nociceptive sensitivity in the dermatomes [87]. From a central perspective, acupuncture reduces dorsal horn hyperexcitability by downregulating NMDA receptor activation and enhancing opioid receptor-mediated analgesic pathways [20]. These effects are often exaggerated by releasing endogenous opioids (endorphins and enkephalins) and modulating GABAergic and serotonergic transmission, all of which contribute to altered pain perception [88]. By modulating sympathetic and parasympathetic responses, acupuncture harmonizes different functions of the autonomic nervous system and hence reduces the stress-induced exacerbation of pain [89]. Acupuncture for PHN involves the careful selection of acupoints to address both localized and systemic pathophysiological processes. Commonly used points include Ashi points (non-fixed points that are selected based on tenderness or pain), Jiaji (EX-B2), GB34 (Yanglingquan), LI4 (Hegu), ST36 (Zusanli), GB21 (Jianjing), LR3 (Taichong), SP6 (Sanyinjiao), BL15 (Xinshu), and PC6 (Neiguan) [64, 65, 66, 67, 68, 69]. Concisely, ashi points are chosen for diminishing localized inflammation and pain at affected dermatomes, while Jiaji (EX-B2), located near the spinal column, exerts its effects through modulation of central sensitization and autonomic balance [90]. Other systemic points, like ST36 (Zusanli) and LI4 (Hegu), are selected for their ability to enhance microcirculation, reduce systemic inflammation and promote neural repair, reflecting the integrative approach to acupuncture in PHN management [91].

Several acupuncture techniques have shown therapeutic efficacy in PHN, including EA, manual acupuncture, fire needling, moxibustion (a therapy that involves burning dried mugwort near the skin to stimulate acupoints), bloodletting-cupping (a method combining controlled bleeding and cupping to promote circulation and remove stagnation) and acupoint injection (the injection of medicinal substances into acupuncture points to enhance therapeutic effects) [65]. For instance, Pei et al. [92] reported significant pain relief and improved sleep quality with low-frequency EA [92]. Similarly, Wang et al. [93] found that fire needling demonstrated superior curative effects compared to other techniques, as it combines thermal stimulation with traditional needling methods [93]. Ashi points, treated by bloodletting cupping, have shown substantial pain relief although the risks of mild adverse effects (e.g., dizziness or bleeding) do increase a little [65]. Both moxibustion and acupoint injection promoted circulation and reduced inflammation through heat stimulation. Additionally, acupoint injection integrated acupuncture with pharmacological agents, such as vitamin B12, to enhance therapeutic effects [65, 94]. Improvements in pain scores and QoL continue to support acupuncture as a potentially safe and effective strategy for PHN. However, challenges remain in standardizing acupuncture protocols and confirming its long-term efficacy. As acupuncture becomes more integrated with conventional therapies, its therapeutic potential is expected to grow, providing a more comprehensive approach to managing this debilitating condition.

3.5 Clinical applications

Acupuncture has been widely studied for its effects on neuromodulation, pain regulation and neurovascular function, demonstrating clinical relevance in the management of NOP. The selection of acupoints is guided by anatomical and neurophysiological considerations, with research supporting their role in pain modulation and neural activity regulation. For instance, LI4 (Hegu) has been shown to influence pain perception by modulating neurotransmitter release and improving microcirculation, contributing to its effectiveness in conditions such as facial paralysis, TN and TMD [66, 95, 96]. Clinical studies suggest that LI4 stimulation enhances endogenous pain control mechanisms, reducing hyperalgesia and central sensitization [20]. Additionally, ST36 (Zusanli) and LI11 (Quchi) are frequently utilized due to their systemic effects on immune function, neural excitability and inflammatory response, making them valuable in broader neuropathic conditions [23, 97]. Acupoint selection is often tailored to specific conditions, aligning with pathophysiological mechanisms. For example, SI18 (Quan Liao) and TE21 (Er Men) are commonly employed in TMD treatment, aiding in neurovascular regulation and muscle function restoration [98]. Similarly, EX-HN5 (Taiyang) and DU26 (Ren Zhong) are frequently utilized in TN management, targeting cranial nerve dysfunction and neuropathic pain pathways [99]. Moreover, scalp acupuncture points, such as GV20 (Baihui) and GV24 (Shen Ting), have been investigated for their role in modulating cortical activity and cranial nerve function, making them relevant in neurological conditions involving central pain processing and neurovascular dysregulation [100]. These findings underscore the importance of precision in acupoint selection, ensuring that therapeutic interventions align with the underlying neurophysiological mechanisms of pain and dysfunction.

By integrating acupuncture with contemporary pain management strategies, clinicians can enhance therapeutic outcomes in NOP and associated neuropathic syndromes. The neuromodulatory effects of acupuncture, supported by functional anatomy and neurophysiological mechanisms, reinforce its role as a scientifically supported adjunct therapy in neuropathic pain management. While acupuncture shows promise as a non-pharmacological treatment, several barriers hinder its clinical implementation. The lack of standardized protocols leads to variability in practice, while inconsistent training requirements affect treatment quality. Patient adherence can also be challenging, as multiple sessions are often required for effectiveness. Additionally, limited insurance coverage and regulatory inconsistencies restrict accessibility. Addressing these issues through standardized guidelines, improved practitioner training, and policy support is essential for optimizing acupuncture’s clinical integration.

3.6 Limitations and future directions

Despite promising findings, the current body of evidence on the use of acupuncture for NOP remains limited primarily due to significant methodological shortcomings. Key issues include inconsistencies in acupoint selection, treatment frequency, session duration and study design, all of which compromise the reproducibility and comparability of findings. Additionally, short follow-up periods raise concerns about the reliability and broader applicability of reported outcomes. Furthermore, the lack of standardized protocols tailored to the various subtypes of NOP further complicates the development of precise clinical guidelines. Interpreting data from acupuncture trials is further challenged by difficulties in controlling placebo effects and the insufficient exploration of its long-term therapeutic benefits. Moreover, the limited research on combining acupuncture with other non-invasive therapies highlights a significant gap in the existing evidence, underscoring the need for future exploration of such integrative approaches [94, 101, 102]. To address these issues, future studies must prioritize the adaptation of standardized protocols and extend their duration to evaluate both the immediate and lasting effects of acupuncture. Advancing the field will require detailed mechanistic studies using tools such as functional MRI to investigate how acupuncture influences processes like central sensitization, neuroinflammation and neural plasticity. Comparative trials are also essential to assess the combined efficacy of acupuncture with established pharmacological and non-pharmacological treatments. The lack of comprehensive research in these domains underscores an unexploited opportunity to optimize acupuncture’s role in managing chronic pain conditions. By addressing these research priorities, the field can progress toward developing evidence-based guidelines, unlocking the full potential of acupuncture as a treatment for NOP.