Characterized by unilateral, paroxysmal, electric shock-like, pricking and relapsed pain attacks with sudden onset and sudden termination, trigeminal neuralgia (TN) is a debilitating neuropathic facial pain syndrome affecting the sensory distribution of one or more divisions of the fifth cranial nerve—trigeminal nerve, particularly at the innervation area of the three trigeminal nerve branches, when triggered by innocuous stimuli (1). Studies from animal models showed that persistent external stimulation was transmitted from the affected trigeminal nerve branches into the trigeminal ganglion (TG), resulting in the activation of the TG neurons, which is one of the leading reasons for the occurrence and maintenance of hyperalgesia in these patients (2). TN can be classified as (i) classical TN, which has no apparent cause other than neurovascular compression (NVC) of the trigeminal nerve at the root entry zone (REZ) (3); (ii) idiopathic TN, which shows no significant abnormalities assessed by electrophysiological tests or MRI; and (iii) secondary TN, which is caused by underlying diseases such as brain tumor or multiple sclerosis (MS) (4). The REZ is where the trigeminal nerve enters the brainstem and represents a transition zone from peripheral Schwann cell-mediated myelination to central oligodendrocyte-mediated myelination, which makes this area very susceptible to pressure-induced lesions (5). TN overall affects 0.07% (6) to 0.3% (7) of the general population, with a slight female predominance (approximately 1.5 to 2.1 ratio for male to female) (8, 9). Commonly seen above 50 years of age, its general incidence climbed with age (9). Moreover, the incidence of TN in systemic sclerosis and MS is significantly higher than that in general populations (10), and it has also been associated with other inflammatory diseases such as myositis, arthritis and interstitial lung disease (10). Pathophysiologically, compression from the blood vessel focal accounts for the main cause of TN, leading to demyelination in REZ of the primary sensory trigeminal afferents (11). Surprisingly, changes in the trigeminal nerve has been observed not only on the side with NVC, but also contralaterally, suggesting that individuals with TN may have preexisting abnormalities in the white matter with neuroinflammation and oedema (12). The chronic neuroinflammation of the TG is caused by the persistent constriction of blood vessels in abnormal positions, leading to the development of demyelination in TN patients (13). Indeed, a pivotal role of inflammation in the etiology and progression of TN has been highlighted previously, which demonstrate elevation of multiple inflammatory biomarkers in different samples of TN patients, such as serum and cerebrospinal fluid (CSF) (14).

This literature review aims to summarize current clinical and laboratory findings along the perioperative timeline to find out biomarkers for clinical use, and discuss underlying molecular mechanisms for a better understanding of the role of inflammation in TN and directions for future clinical trials and basic research.

A search of published articles was performed through PubMed database using strategy (trigeminal neuralgia[Title/Abstract]) AND (inflammatory[Title/Abstract]), and a search of registered clinical trials was performed through Cochrane Central Register of Controlled Trials (CENTRAL) database using ‘trigeminal neuralgia’ as key word, with a date range of 2000 to 2025. A total of 142 English articles was acquired from PubMed, and a total of 95 clinical trials registered on clinicaltrials.gov was acquired for further screening. Original articles of both human and animal studies related to ‘trigeminal neuralgia’, ‘surgical intervention’ and ‘inflammatory biomarkers’, as well as registered trials related to ‘trigeminal neuralgia’ and ‘surgical intervention’ were included, whereas articles in the format of reviews, systematic reviews and/or meta-analyses, case reports or case series, commentaries, editorials, letters, as well as articles irrelevant to or not fully covering (e.g., comparing the surgical interventions without analyzing inflammatory biomarkers, or studying inflammatory biomarkers in non-surgical scenarios) this topic were excluded.

For recurrent cases and patients refractory to pharmacotherapies, surgical treatments may be contemplated. Typical surgical treatments for TN include peripheral neurectomy, microvascular decompression (MVD), percutaneous balloon compression (PBC) and stereotactic radiosurgery (SRS).

Since inflammation plays a critical role in the pathogenesis and progression of TN, understanding how inflammatory factors change in biological specimens from clinical patients before and after surgical interventions may help us to determine the severity of disease, efficacy of surgical treatment and long-term follow-up for safety and prognosis. In addition, targeting these cytokines and chemokines may be capable of suppressing activation of glial cells and alleviating chronic neuropathic pain including TN (32). Currently, only limited number of clinical studies have been established, and therefore, results from animal studies could assist us in digging out the molecular mechanisms to explain these alterations. The promising findings in large-scaled clinical trials and repeatably verified conclusions may allow the development of trustful biomarkers for clinical use. The perioperative alterations in these inflammatory biomarkers are summarized in Table 1.

Notably, inflammatory response triggered by foreign materials is often seen in patients receiving surgical treatments. Traditional decompressive methods for TN patients involve placing foreign material (most often Teflon) between the affected nerve and the compressive blood vessel to maintain distance between the two structures. However, inflammatory reactions related to the foreign material have been reported in numerous papers, resulting in granuloma formation and recurrence of pain (61–63). Therefore, the tentorial slinging technique without using foreign material has been developed as an alternative decompressive method to minimize the inflammatory response and lower the rate of trigeminal pain recurrence over time (64). Postoperative changes of inflammatory factors have been explored by several studies, with results sometimes being contradicting, partially due to heterogeneities among these limited number of studies.

The pro-inflammatory cytokines, such as IL-1β, IL-6 and TNF-ɑ, are essential for the persistent activation of microglia and astrocytes in the spinal trigeminal nucleus, which is important in the establishment and maintenance of TN (57). The release of these inflammatory factors observed in patients with TN may be caused by focal nerve demyelination and vascular compression of the trigeminal nerve roots, as verified by evidence obtained from TN animal models (68, 69). At molecular level, the significant increases of these pro-inflammatory cytokines and chemokines have been associated with the up-regulated phosphorylation of the mitogen-activated protein kinases (MAPKs), which includes extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase (JNK; Figure 1). These singling molecules may be activated in the TG neurons to participate in the regulation of TN-related pain (39, 70, 71), and antagonizing them could be a practical strategy to reverse the pain (58, 72). For instance, in the injured trigeminal nerve of the CCI-ION model, it was shown that stem cells from human exfoliated deciduous teeth transplantation at the lesion site led to reduced inflammatory cell infiltration and pro-inflammatory cytokine release (TNF-ɑ and IL-1β). Moreover, the administration of resveratrol reversed the activation of astrocytes and microglia by downregulating the phosphorylated MAPKs in an adenosine monophosphate activated protein kinase (AMPK)-dependent manner (73). The MAPK signaling may partially be mediated by the polyubiquitinated TNF receptor-associated factor 6 (TRAF6), which also facilitates the activation of transcriptional factor nuclear factor-κB (NF-κB). Meanwhile, TRAF6 may also aggravate neuropathic pain by activating the c-Jun/NF-κB signaling pathway (74). The polyubiquitination of TRAF6 was attenuated by bovine lactoferrin inhibitors in a trigeminal nerve injury rat model (71). However, the clinical evidence for treatment efficacy of these MAPK-related antagonists in TN patients was very limited, only dilmapimod (a p38MAPK inhibitor) has been reported as a promising compound in neuropathic pain control (75). In addition to the MAPK-associated signaling pathways, the increased release of the pro-inflammatory factors (TNF-ɑ and IL-1β) could also be modulated by the activation of the colony-stimulating factor 1 (CSF1) - colony-stimulating factor 1 receptor (CSF1R) pathway, which regulates pain development in TG (44). Furthermore, the IL-1β maturation was promoted, the IL-1β released by microglia was increased, and the neuroinflammatory response and neuropathic pain in TN models was developed through the activation of P2X7/NLRP3/IL-1β or the P2X7/p38/IL-1β pathways (38, 76, 77), which could be blocked by brilliant blue G (BBG) (38) and lidocaine (77), respectively, both are inhibitors of the P2X7 receptor. Several P2X7R antagonists, e.g., AstraZeneca’s AZD9056 and Pfizer’s CE-224535 for rheumatoid arthritis, GlaxoSmithKline’s GSK-1482160 for chronic inflammatory pain have been tested in clinical trials but none have reached final approval due to lack of efficacy. Newly developed compounds, such as JNJ-55308942 and JNJ-54175446, may be more promising antagonists due to their ability of BBB penetration (78, 79). These signaling pathways might be novel targets for the treatment of TN, in either pharmacological or non-pharmacological way. Various mechanisms have been suggested based on animal findings, yet gaps still remain on translation from animal studies to human ones, partially due to less heterogeneities in these animal models. The greater heterogeneity in human requires validation in multi-centered larger cohorts. In addition, the insufficiency in replicating the full breadth of etiological factors reported in corresponding clinical studies of TN, including the absence of discovered TN-related human channel mutations in animal models, as well as reduced levels of substance P and calcitonin gene-related peptide (CGRP) in medullary dorsal horn of animal models following trigeminal nerve compression, have been detailedly discussed in a previous review (80).

By searching randomized controlled trials (RCTs) registered on clinicaltrials.gov through the CENTRAL database, we noticed that the number of registered trials testing surgical treatments for TN was low (Table 2). Most of these RCTs were designed for pharmacological treatments or radiofrequency therapies. Surprisingly, no registered trial involved inflammatory biomarkers as one of the outcome measurements. They predominantly focused on the improvement in main symptoms, such as pain and numbness. Due to the important role inflammation plays in the progression of TN, and based on the current findings of the alterations of inflammatory biomarkers in TN patients who are submitted to surgical treatments, we suggest to include the measurement of inflammatory factors in the design of future clinical studies. Given the dynamic change of these potential biomarkers with time, determination of the best observation window for these biomarkers was needed in future studies. Additionally, clinical evidence is also required for surgical interventions other than MVD and PBC, such as peripheral neurectomy and SRS, both before and after the surgical treatments, to build up the solid knowledge whether and which biomarkers are suitable ones to use in clinical practice. Longer follow-up period and further clinical investigation on other inflammatory biomarkers are also required in future research.

By reviewing the previously reported work on changes in inflammatory factors in TN patients submitted to typical surgical treatments include peripheral neurectomy, MVD, PBC and SRS, as well as the results from TN animal models, this narrative review revealed that pro-inflammatory cytokines and chemokines, such as IL-1β, IL-6, TNF-ɑ reached high levels in serum, CSF or saliva specimens from TN patients, which could be reversed by PBC, but not always by MVD. The elevated preoperative level of TRAIL was reversable by MVD, but the elevated preoperative level of TNF-β was not (Figure 2). Such different patterns responding to different surgical interventions are of research interest and require further investigations.

Currently, only a limited number of registered RCTs testing the application of surgical interventions in TN patients are being performed, and none of them have incorporated inflammatory biomarkers as endpoints (Table 2). The gap between inflammatory biomarkers and surgical outcomes need to be filled in future trial design. The results discussed in this review provided valuable information for further exploration and would need to be verified in larger-scaled clinical studies. Of note, the timing and intervals for sampling varied across studies, leading to heterogeneities among studies. Observation of dynamic changes of these markers after surgery in the future would contribute to standardization of timing and interval of postoperative samplings. Pain relief may compose major observation outcome, but other parameters may also be explored. In addition, the analytical platforms and statistical approaches also need to be more standardized for biomarkers that have been tested and shown changes in human studies such as IL-1β, IL-6, TNF-ɑ, TRIAL and TNF-β, as well as MAPK or P2X7 pathway-associated proteins in future studies. Furthermore, comparisons of peripheral blood, CSF and saliva are also needed to optimize sample selections. The alterations in these inflammatory biomarkers were modulated by a variety of signaling pathways, including MAPK- or P2X7-associated pathways, a better understanding of these underlying molecular mechanisms may help in the development of novel treatments for patients with TN.