Decoding orofacial pain: a translational review of mechanisms and novel therapies

Abstract

Orofacial pain encompasses a diverse group of disorders that pose a significant clinical challenge, often progressing from acute to chronic conditions due to a disconnect between clinical diagnosis and underlying pathophysiology. This review provides a synthesis of the mechanisms driving this transition and evaluates emerging therapeutic strategies that target them. First, we dissect the pathophysiological mechanisms of acute pain, including peripheral sensitization and transient central sensitization; and then detail how these processes can become maladaptive, leading to chronic pain states sustained by a combination of persistent nociceptive input, neuropathic alterations, and nociplastic changes involving dysfunctional descending modulation and central network reorganization. Building on this mechanistic framework, we critically appraise novel therapeutic approaches, including targeted pharmacotherapies such as selective ion channel and endocannabinoid system modulators, alongside non-pharmacotherapeutic interventions that encompass neuromodulation techniques designed to regulate central neural plasticity and psychologically grounded therapies. By integrating molecular evidence with clinical presentations, this review offers a framework for advancing towards a more precise, mechanism-based management of orofacial pain.

Graphical abstract

Introduction

Orofacial pain (OFP) represents a significant global health burden, encompassing a diverse spectrum of conditions ranging from common dental pain to complex neuropathic disorders that affect millions worldwide [1]. The prevalence of these conditions is substantial; temporomandibular disorders (TMDs) alone are estimated to affect up to 31% of the adult population, while trigeminal neuralgia and acute pulpitis also contribute significantly to this burden [2–4]. Beyond the primary sensory experience, OFP frequently impairs essential functions such as mastication and speech and is often associated with significant psychological comorbidities, including anxiety and depression, thereby profoundly diminishing quality of life [5, 6]. To navigate this complexity, the International Classification of Orofacial Pain (ICOP) has provided crucial nosological framework, stratifying OFP into distinct etiologies such as odontogenic, musculoskeletal, and neuropathic subtypes [7]. However, despite refining clinical diagnosis, a fundamental disconnect persists between these symptomatic phenotypes and their underlying biological mechanisms.

This gap between classification and pathophysiology could be considered a primary driver of high treatment failure rates and the progression from acute, self-limiting pain to intractable chronic disease. Consequently, current therapeutic strategies remain largely empirical, relying on a “one-size-fits-all” approach guided by broad diagnostic labels rather than precise pathophysiology [8]. While standard analgesics like nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids have well-documented limitations, including ceiling effects and tolerance [9], the core issue could be the underlying mechanistic heterogeneity. This lack of mechanistic insight may contribute to frequent treatment failures, as therapies are applied without knowledge of whether a patient’s pain is sustained by persistent peripheral nociception, ectopic neuropathic activity, or centralized nociplastic alterations [10–12]. Therefore, resolving this mechanistic ambiguity is critical for preventing pain chronification and developing more effective, personalized therapeutic strategies.

Accordingly, this review aims to provide a synthesis that bridges contemporary understanding of OFP mechanisms with current and emerging therapeutic strategies. We will first dissect the pathophysiological continuum from acute to chronic pain by examining the key stages of maladaptive neuroplasticity: (1) the initial processes of peripheral and transient central sensitization in acute pain, and (2) the consolidation of these states in chronic pain through persistent nociception, neuropathic insults, and profound nociplastic changes within the central nervous system (CNS). Building on this mechanistic foundation, we will systematically dissect the key peripheral and central drivers, informing the development of novel therapeutic approaches. This includes a discussion of targeted pharmacotherapies, such as ion channel and endocannabinoid system (ECS) modulators, as well as non-pharmacotherapeutic interventions which include neuromodulation techniques designed to harness central neural plasticity and psychologically grounded therapies. By integrating clinical phenotyping with molecular and circuit-level evidence, this review provides an evidence-based framework to guide practitioners and researchers toward a future of precision medicine in OFP management.

Classification and clinical manifestations of OFP

Historically, the diagnosis and management of OFP was hampered by a fragmented and inconsistent nosology. The lack of standardized diagnostic criteria and overlapping terminologies posed significant challenges to both clinical practice and multicenter research, thereby impeding the development of evidence-based treatments. To address this, the International Headache Society released the ICOP in 2020 [7] providing the first comprehensive, evidence-based taxonomy for all clinically recognized forms of OFP and establishing a standardized language for clinicians and researchers worldwide.

A pivotal strength of the ICOP lies in its systematic organization of OFP into six major categories (Table 1), which provides a structured framework for differential diagnosis by integrating temporal features (acute vs. chronic): (1) Pain from disorders of dentoalveolar and related structures; (2) Myofascial orofacial pain; (3) Temporomandibular joint (TMJ) pain; (4) Pain due to lesion or disease of the cranial nerves; (5) Pains resembling primary headaches; and (6) Idiopathic orofacial pain. Each category is further subdivided, with explicit operational diagnostic criteria for each entity, including specific features, durations, and exclusions. Crucially, this classification is not merely topographical; it is fundamentally structured around pain-generating mechanisms, supplemented by anatomical location, clinical phenotype, and etiological evidence.

Table 1.

ICOP classification and main clinical manifestations

Category	Subcategory	Pain type	Clinical Manifestation	References
Orofacial pain attributed to disorders of dentoalveolar and anatomically related structures	Dental pain	Primarily acute pain	Pulpal Pain: originating from the dental pulp, this pain is typically provoked by thermal stimuli (hot or cold). It often manifests as spontaneous, paroxysmal episodes, may worsen at night, and can be exacerbated by occlusal pressure. Periodontal pain: Arising from the structures supporting the tooth and is characterized by tenderness to mastication and percussion. It is often associated with clinical signs like tooth mobility, gingival inflammation, or, in cases of pericoronitis, localized swelling and trismus.	[13, 14]
	Oral mucosal pain	Primarily acute pain	Caused by inflammatory, traumatic, infectious, or neoplastic lesions. It clinically presents as erosions or ulcerations accompanied by severe pain or dysesthesia that can significantly impede eating and speaking.	[15]
	Salivary gland pain	Primarily chronic pain	This pain is typically due to obstructive (e.g., sialolithiasis) or infectious (sialadenitis) processes. Obstruction causes post-prandial glandular swelling and pain, while infection presents with localized erythema, warmth, swelling, and often a purulent discharge from the ductal orifice, sometimes with systemic signs like fever.	[16]
	Jawbone pain	Primarily chronic pain	Precipitated by trauma, infection, or malignancy. It typically presents as severe, intractable pain. Associated signs may include regional swelling, malocclusion, loosening of teeth, or the formation of a draining fistula. Radiographic examination often reveals osteolytic changes.	[17–19]
Myofascial orofacial pain	Primary myofascial orofacial pain	Primarily chronic pain	Characterized by localized tender points within the masticatory musculature, exacerbated by muscle fatigue, and accompanied by palpable taut bands.	[20]
	Secondary myofascial orofacial pain	Primarily chronic pain	Encompasses the same clinical features but is further distinguished by masticatory fatigue, restricted mandibular excursion, and associated cephalalgia (commonly linked to nocturnal bruxism or diurnal clenching). Psychological comorbidities, most notably anxiety and depression, frequently intensify these symptoms.	[21]
Temporomandibular joint pain	Primary temporomandibular joint pain	Primarily chronic pain	Primary temporomandibular joint pain presents as arthralgia localized to the preauricular region, accompanied by restricted mandibular excursion, joint clicking or crepitus, and exacerbation during mastication; otologic symptoms such as tinnitus or ipsilateral headache may co-occur.	[22, 23]
	Secondary temporomandibular joint pain	Primarily chronic pain	Secondary temporomandibular joint pain is characterized by preauricular pain that intensifies with jaw opening or chewing, concomitant limitation of mouth opening, joint sounds or locking, and referred pain to the head, ear, or neck. Precipitating factors include traumatic or infectious synovitis; infectious cases may additionally exhibit regional erythema, swelling, fever, and systemic signs of toxicity.	[24, 25]
Orofacial pain attributed to lesion or disease of the cranial nerves	Trigeminal neuralgia	Primarily chronic pain	A classic neuropathic condition manifesting as sudden, paroxysmal attacks of lancinating or electric-shock-like pain. The pain is strictly confined to the distribution of one or more divisions of the trigeminal nerve, lasts from a fraction of a second to two minutes, and is often precipitated by innocuous stimuli in a specific “trigger zone”.	[26]
	Glossopharyngeal neuralgia	Primarily chronic pain	Presenting as paroxysmal, stabbing pain in the distribution of the glossopharyngeal nerve (throat, base of tongue, ear). Attacks can be triggered by swallowing, talking, or coughing.	[27]
Orofacial pains resembling presentations of primary headaches	Orofacial migraine	Primarily chronic pain	Presents as unilateral, pulsating pain in the face or oral cavity that meets the temporal and symptomatic criteria for migraine (lasting 4–72 h, associated with nausea, photophobia, and/or phonophobia). The pain is often exacerbated by routine physical activity.	[28]
	Tension-type orofacial pain	Primarily chronic pain	Characterized by bilateral, pressing or tightening, non-pulsating pain of mild to moderate intensity. It is not aggravated by routine activity and lacks features of migraine. The pain is often associated with pericranial muscle tenderness and psychosocial stress.	[29]
	Trigeminal autonomic orofacial pain	Primarily chronic pain	Characterized by attacks of severe, strictly unilateral pain in the trigeminal distribution. Its hallmark is the co-occurrence of prominent ipsilateral cranial autonomic symptoms during attacks, such as conjunctival injection, lacrimation, nasal congestion, and/or facial sweating.	[30]
	Neurovascular orofacial pain	Primarily chronic pain	Manifested as episodic, unilateral or bilateral orofacial pain that is typically dull, pressing, or throbbing and may shift from tooth to tooth. Associated features include photophobia, phonophobia, and autonomic signs such as lacrimation and conjunctival injection; symptoms are often aggravated by physical exertion.	[31, 32]
Idiopathic orofacial pain	Burning mouth syndrome	Primarily chronic pain	Characterized by a persistent intraoral burning or dysesthetic sensation. It recurs daily for more than 2 h per day over more than three months, in the absence of any clinically evident causative lesions on oral examination. It is frequently associated with comorbid anxiety, depression, and perceived taste disturbances.	[33]
	Persistent idiopathic facial pain	Primarily chronic pain	Defined as persistent or recurring facial pain that is poorly localized and has a dull, aching, or nagging quality. It occurs daily for more than 2 h per day over more than three months, without demonstrable neurological deficits or other identifiable cause.	[34, 35]
	Persistent idiopathic dentoalveolar pain	Primarily chronic pain	A form of PIFP localized to the dentoalveolar region (teeth and gums) where a tooth has often been endodontically treated or extracted, without any evidence of persistent pathology. The pain is deep, dull, and aching, and persists for months or years in a localized site.	[36]
	Constant unilateral facial pain with additional attacks	Primarily chronic pain	Presented with persistent dull pressure sensation and paroxysmal non-neuralgic attacks (10–30 min duration) in the same region, occurring 2–20 times daily during active phases. The attacks demonstrate no autonomic symptoms, sensory deficits, or imaging abnormalities.	[37]

This mechanistic foundation makes it imperative to consider the temporal dimension, as the underlying mechanisms of acute and chronic pain differ profoundly. The International Association for the Study of Pain (IASP) provides the essential mechanistic language for this distinction, classifying pain as nociceptive, neuropathic, or nociplastic [38, 39]. By integrating the ICOP’s clinical phenotypes with their typical duration and underlying IASP mechanism, we can construct a more precise diagnostic framework: (1) Primarily acute conditions: The category 1, pain from disorders of dentoalveolar and related structures, typically presents acutely. Conditions such as pulpitis, periapical abscess, or post-traumatic dental pain are classic examples of acute nociceptive signals directly linked to tissue injury, which are expected to resolve with healing. (2) Conditions with high propensity for chronification: Myofascial OFP (Category 2) and TMJ pain (Category 3) often begin as acute nociceptive musculoskeletal issues but frequently transition into chronic states. This chronification typically signals a maladaptive shift from a simple nociceptive driver to more complex nociplastic mechanisms. (3) Primarily Chronic Conditions: The remaining categories are predominantly chronic or recurrent by definition. Pain due to lesion or disease of the cranial nerves (Category 4), like trigeminal neuralgia, is a quintessential example of chronic neuropathic pain. Pains resembling primary headaches (Category 5) are characteristically chronic or episodic-chronic disorders. Finally, idiopathic OFP (Category 6), including persistent idiopathic dentoalveolar pain, is defined by its persistence beyond any identifiable cause, making it a primary chronic pain disorder. This integrated approach elucidates the pathophysiological basis of the clinical phenotype.

By integrating the clinical phenotype (ICOP), temporal trajectory (acute versus chronic), and mechanistic substrate (IASP), this approach establishes a coherent framework for both diagnosis and therapy. Building upon this foundation, the subsequent chapters will examine the core pathophysiological mechanisms of OFP at the molecular, cellular, and circuit levels.

Mechanisms of pain development

Pain is not a simple symptom, but a complex pathophysiological process driven by intricate neural mechanisms. Understanding its transition from an acute, protective response to a chronic, pathological disease is paramount for the precise diagnosis and treatment of OFP. Acute pain, lasting less than 3 months, serves as a physiological warning signal directly caused by identifiable tissue injury or disease. In contrast, chronic pain lasts for 3 months or more, often becoming decoupled from the initial injury and transforming from a symptom into a disease state itself [40, 41]. Inadequately controlled acute pain can progressively evolve into chronic pain through a convergence of overlapping mechanisms [38]. Acute pain pathogenesis primarily involves nociceptive mechanisms and peripheral sensitization, which under certain conditions can induce a transient form of central sensitization. The pathogenesis of chronic pain, however, encompasses a complex interplay of persistent nociceptive input, neuropathic changes, and nociplastic alterations.

Mechanisms of acute pain

Acute OFP is a physiological alarm system designed to detect and respond to actual or potential tissue damage [42]. Its development is not a single event but a dynamic cascade involving 3 principals, and often sequential, mechanisms: (1) initial nociceptive signal transduction from the periphery, (2) amplification of this signal at the periphery via peripheral sensitization, and (3) a transient, activity-dependent enhancement of signal processing within the central CNS known as transient central sensitization. These processes are normally reversible and tightly regulated by the body’s endogenous analgesic systems.

Nociceptive pain

Nociceptive pain represents the foundational component of the acute pain experience, serving as the initial alert to tissue injury. It arises when noxious stimuli activate high-threshold primary afferent neurons (nociceptors), and these signals are transmitted through an intact somatosensory pathway to the CNS, eliciting a well-localized pain response that is proportional to the stimulus intensity [43]. This direct signaling from the site of injury, often termed “peripheral pain”, serves a critical protective function by alerting the individual to prevent further harm and initiate repair. A classic example is acute pulpitis, where inflammatory mediators (e.g., prostaglandins, cytokines) released within the dental pulp directly activate trigeminal nociceptors. The resulting nociceptive signals are rapidly conveyed via Aδ fibers (mediating sharp, fast pain) and C fibers (mediating dull, slow pain) to the trigeminal nucleus, producing pain [44, 45].

Importantly, this afferent barrage is simultaneously modulated by a functional descending inhibitory system. Projections from cortical areas like the medial prefrontal cortex (mPFC) orchestrate the release of endogenous opioids and other neurotransmitters in the brainstem, which act to constrain neuronal excitability and prevent the nociceptive input from becoming excessive [46, 47].

Peripheral sensitization

While nociceptive signaling initiates the pain response, the persistence of tissue injury or inflammation rapidly triggers peripheral sensitization, a crucial mechanism that amplifies the initial alarm [48]. This process occurs at the terminals of nociceptors, lowering their activation threshold and increasing their responsiveness to stimuli. Consequently, a stimulus of the same or even lesser intensity elicits a magnified pain response, clinically manifesting as hyperalgesia (exaggerated pain from a noxious stimulus) and allodynia (pain from a non-noxious stimulus) [49–51].

This state is orchestrated by several synergistic molecular mechanisms: (1) Pro-inflammatory mediators (e.g., TNF-α, IL-1β) released at the injury site directly sensitize nociceptors by phosphorylating and enhancing the activity of key transducer ion channels, notably transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) [52, 53]. The sensitization of TRPV1, for instance, lowers its thermal activation threshold, providing a direct molecular explanation for the heat hyperalgesia observed in pulpitis [54]. (2) Nerve injury initiates a remodeling of voltage-gated sodium channels (Nav). The expression and accumulation of specific subtypes like Nav1.7 at nociceptor terminals significantly lowers the threshold for action potential generation, contributing to the ectopic, spontaneous, electric shock-like discharges that define this debilitating condition [55, 56].

(3) Local tissue acidosis, a hallmark of inflammation and injury, acts as a potent sensitizer. A drop in extracellular pH due to inflammatory metabolism and cytolysis activates acid-sensing ion channels (ASICs) on nociceptor terminals [57]. ASIC activation, especially ASIC1 and ASIC3, induces cation influx (mainly Na⁺ and Ca²⁺), leading to membrane depolarization [58]. This lowers the nociceptor firing threshold, increasing excitability and promoting hyperalgesia and allodynia. In pathogen-related inflammatory diseases, such as pulpitis, bacterial and inflammatory processes create an acidic microenvironment [59], establishing ASICs as central to persistent dental pain. (4) adenosine triphosphate (ATP) released from damaged cells acts as a potent “danger signal” via purinergic P2 × 3 receptors on nociceptors [60, 61]. In pulpitis, for example, ATP released by odontoblasts directly excites pulpal afferents via P2 × 3 receptors [62, 63], while in TMDs, ATP released from hypercontracting muscles can act in concert with IL-1β to upregulate P2 × 3 expression in the trigeminal ganglion (TG), exacerbating mechanical allodynia [64]. Peripheral sensitization can be long-lasting and, in some cases, persist even after the initial injury has healed, potentially contributing to the maintenance of chronic pain states.

Transient central sensitization

When the afferent barrage from sensitized peripheral neurons is sufficiently intense and sustained, it can induce a short-term, reversible state of hyperexcitability within the CNS. This phenomenon is an example of central sensitization. The IASP defines central sensitization as: An increase in the responsiveness of nociceptive neurons in the CNS to normal or sub-threshold incoming stimuli [39]. This state is not limited to synaptic alterations; it can result from any cause of neuronal hyperexcitability, including changes in ion channel function in central neurons. In the context of acute pain, this represents an incipient stage of centralized pain processing but crucially lacks the stable, long-term structural reorganization seen in chronic conditions [65].

One of the key mechanisms contributing to central sensitization is activity-dependent synaptic plasticity. At the trigeminal nucleus, high-frequency afferent input triggers the activation of N-methyl-D-aspartate (NMDA) receptors on second-order neurons. This initiates intracellular cascades that increase neuronal excitability and lead to the “wind-up” effect, a progressive amplification of neuronal output in response to repetitive C-fiber stimulation [66, 67]. Crucially, in the acute setting, this hyperexcitability is functionally adaptive and remains under the firm control of descending modulatory pathways. This regulation is evident in neuroimaging studies of healthy individuals, where brief noxious orofacial stimuli elicit only transient activation of pain-related cortical areas (e.g., anterior cingulate cortex, insula). This activation is effectively modulated by endogenous analgesic mechanisms and subsides promptly upon stimulus cessation, without engaging memory-related structures like the hippocampus or amygdala that are associated with chronic “memorized pain” [68, 69].

It is important to note that while central sensitization has been suggested as a mechanism potentially implicated in pain persistence after injury, it is not a defining characteristic of chronic pain, as the original work describing it utilized an acute pain model [70]. Therefore, in the context of acute OFP, transient central sensitization should be viewed as a controlled, reversible amplification of nociceptive signals that is designed to resolve as the initial injury heals.

In summary, the development for acute OFP is designed to be self-limiting, resolving as the initial injury heals (Fig. 1). However, significant knowledge gaps remain, particularly concerning the molecular determinants that govern the resolution of acute pain versus its transition to chronicity. While the roles of ion channels and inflammatory mediators in initiating pain are well-studied, it remains unclear which specific cellular and molecular events fail when acute pain becomes chronic. Future research should therefore focus on these critical areas. High-throughput techniques like single-cell RNA sequencing and spatial transcriptomics applied to the TG and injured orofacial tissues could reveal the dynamic cellular conversations between neurons, immune cells, and glial cells during the initiation and, crucially, the resolution phases of acute pain.

Fig. 1.

Key mechanisms in the development of acute pain. Acute pain develops through mechanisms involving (A) the initial activation of nociceptors, which leads to (B) peripheral sensitization at the terminals of nociceptors. Sustained afferent input can subsequently induce a state of transient central sensitization within the trigeminal nucleus (C). This figure was created by bio-GDP.com

Mechanisms of chronic pain

The transition from acute to chronic pain, conventionally defined by a duration exceeding 3 months, represents a fundamental shift from a physiological warning system to a pathological disease state [71]. This process is driven by maladaptive neuroplasticity across the somatosensory system. Chronic OFP is seldom attributable to a single mechanism; instead, it typically arises from a variable combination of persistent nociception, neuropathic processes, and centralized nociplastic changes.

Persistent nociceptive pain

Persistent nociceptive pain arises from unresolved peripheral tissue pathology, serving as a continuous driver for CNS modifications [65] (Fig. 2). In orofacial conditions such as chronic infectious diseases (e.g., periodontitis, apical periodontitis) or degenerative TMDs, the resulting non-healing tissue serves as a persistent reservoir for bacterial endotoxins (e.g., lipopolysaccharide, lipoteichoic acid) and inflammatory mediators (e.g., TNF-α, IL-6), thereby establishing a sustained inflammatory environment that maintains peripheral sensitization of trigeminal nociceptors [72–74]. Consequently, this provides a persistent afferent barrage to the trigeminal nucleus, which is critical for inducing durable neuroplastic changes. At the central level, this sustained input triggers transcriptional alterations (e.g., upregulated c-Fos), persistent NMDA receptor phosphorylation, and structural synaptic remodeling, such as increased dendritic spine density [75–77]. These events consolidate central sensitization, transitioning it from a transient, activity-dependent phenomenon to a stable, pathological state of neuronal hyperexcitability. While the origin of the pain signal is peripheral, its most significant consequence is the establishment of a self-perpetuating state of central dysfunction. For example, in the trigeminal nucleus, increased release of glutamate and substance P leads to excessive activation of NMDA receptors [66]. The subsequent calcium influx activates intracellular kinases like ERK, which phosphorylate multiple targets, leading to long-term potentiation of synaptic strength [67]. This is well-documented in chronic TMDs, where TMJ arthritis elevates the expression of the NMDA receptor subunit NR2B and increases phosphorylation of the NR1 subunit, heightening neuronal excitability and driving persistent pain [78].

Fig. 2.

Transition from peripheral injury to chronic central pain. Persistent nociceptive pain, sustained by unresolved peripheral pathology, generates a continuous afferent barrage that drives durable neuroplastic changes within the central nervous system, thereby facilitating pain chronification. This figure was created by bioGDP.com

Neuropathic pain​

Neuropathic OFP mainly stems from a primary lesion or disease within the trigeminal somatosensory system, leading to maladaptive signaling through mechanisms such as ectopic firing and neuro-immune interactions that contribute to and amplify central pain states [79, 80]. Conditions such as trigeminal neuralgia, postherpetic neuralgia, or post-surgical nerve trauma involve pathologies like demyelination or axonal injury [81]. This damage promotes ectopic action potential generation, often driven by the altered expression and function of ion channels (e.g., Nav1.7 and Nav1.8) in primary afferent neurons [82, 83]. In postherpetic neuralgia, for instance, spontaneous, electric shock-like pain can persist long after cutaneous healing due to underlying nerve damage. Concurrently, injury triggers the activation of resident glial cells, such as the satellite glial cells in the TG and microglia and astrocytes in the CNS. These activated glial cells release pro-inflammatory cytokines and chemokines, which further enhance neuronal excitability and contribute to the maintenance of central sensitization [84, 85]. Functional neuroimaging like using fMRI often reveals abnormal activation patterns in the trigeminal nucleus and somatosensory cortex, reflecting the central consequences of the peripheral nerve lesion [86, 87].

Nociplastic pain

Nociplastic pain is a relatively new classification introduced by the IASP. It describes a centralized pain state defined by altered nociception in the absence of clear peripheral tissue damage or somatosensory nerve lesion [39]. Nociplastic OFP represents the pinnacle of pain centralization and is the core manifestation of “brain network pain” and “memorized pain”. Its pathophysiology is characterized by top-down dysfunction of descending modulatory systems and bottom-up reorganization of brain networks involved in sensory, affective, and cognitive processing [88] (Fig. 3). This mechanism is central to conditions such as burning mouth syndrome (BMS) [89], fibromyalgia and TMDs [90]. The key features include:

Fig. 3.

Central mechanisms of nociplastic pain. The pathophysiology involves (A) impaired descending inhibitory control, and (B) aberrant connectivity and reorganization of central pain networks. This figure was created by bio-GDP.com

1. Dysfunctional descending modulatory control: A hallmark of nociplastic pain is the impairment of the brain’s endogenous analgesic systems. This dysfunction is primarily associated with structural alterations, such as reduced gray matter volume in the mPFC, and the disbalance in rostral ventromedial medulla (RVM), a key modulatory center [91]. The RVM not only contains both pain-facilitating “ON-cells” and pain-inhibiting “OFF-cells” but also serves as a major source of key neurotransmitters such as serotonin. Under chronic pain conditions, the balance within this region shifts toward dominance of ON-cells and suppression of OFF-cells, thereby facilitating the transmission of signals [92–94]. Serotonin primarily acts on 5-HT2A and 5-HT3 receptors to enhance the excitability of spinal neurons, lower pain thresholds, and ultimately promote pain perception [95].

   Furthermore, the endogenous opioid system becomes dysregulated. Positron-emission tomography studies in chronic TMDs patients revealed reduced µ-opioid receptor availability in the brain, suggesting an overactive yet ultimately inefficient compensatory system [96]. This is supported by findings that patients with TMDs show pathologically elevated pre-operative plasma β-endorphin levels, which normalize post-operatively as pain resolves, indicating that chronic pain drives a dysregulated hyper-compensatory state [96, 97].

2. Central network reorganization and pain memory: Nociplastic pain involves robust changes in brain connectivity. Hyperconnectivity is often observed within the medial pain system (e.g., anterior cingulate cortex, insula, amygdala, and hippocampus), which integrates the affective and emotional dimensions of pain [98, 99]. Therein, hyperactivity in the amygdala amplifies pain-related fear and anxiety, creating a vicious cycle of suffering, while the hippocampus is involved in encoding “pain memories”, enabling the perception of pain to be triggered internally, even without any peripheral stimulus [100, 101]. Therefore, these hyperconnectivity creates a maladaptive feedback loop between pain perception and negative affect. Neuroimaging studies in BMS patients support this model, showing lower gray matter volume in the bilateral ventromedial prefrontal cortex and increased functional connectivity between this region and the bilateral amygdala, with the degree of alteration often correlating with pain duration [102]. This reorganization in CNS explains the diffuse nature of nociplastic pain and its reduced responsiveness to peripherally targeted therapies.

In summary, the pathophysiology of chronic OFP is a multifactorial process underpinned by a combination of persistent peripheral nociceptive input, direct nerve injury, and profound central reorganization. These mechanisms are not mutually exclusive but rather coexist and interact, creating the complex and heterogeneous clinical presentations seen in patients. While this framework effectively describes the established chronic pain state, a critical knowledge gap remains: identifying the molecular and cellular determinants that govern why some individuals transition from acute to chronic pain while others recover. This requires a paradigm shift from characterizing the chronic state to prospectively investigating the transition itself, focusing on the failure of active pain resolution mechanisms. For example, investigation should move beyond the established role of glial cells to encompass the broader cellular ecosystem of the trigeminal system. The contributions of adaptive immune cells, such as T lymphocytes, and resident innate immune cells, like mast cells, are increasingly recognized for their capacity to modulate neuronal function and sustain a pro-inflammatory state [103, 104]. Characterizing how these cells interact with trigeminal neurons during the subacute phase post-injury could reveal novel targets for preventing pain chronification.

Therapeutic approaches

The intricate pathophysiology of OFP presents formidable therapeutic challenges, demanding a shift away from empirical, one-size-fits-all regimens. While traditional pharmacotherapies are constrained by systemic side effects, tolerance, and variable efficacy, and surgery carries risks of functional compromise, a new era of precision management is emerging. These range from novel pharmacotherapies targeting specific molecular pathways and the ECS, to the exploration of adjunctive therapies like zinc supplementation. Concurrently, advancements in neuromodulation techniques are offering precise interventions on central mechanisms, while the critical role of the CNS is further addressed through psychotherapy and therapeutic exercise. This chapter outlines the current standard of care guided by the ICOP framework and then critically appraises the emerging therapeutic landscape, charting a translational roadmap toward individualized OFP treatment.

Current clinical management strategies

Effective management of OFP hinges on an accurate diagnosis guided by the ICOP. This framework is essential for implementing a mechanism-targeted, multimodal, and preemptive therapeutic strategy. The key point of the treatment is to integrate the treatment with the underlying pathophysiology: controlling the source for inflammatory pain, suppressing aberrant neural activity for neuropathic pain, and restoring biomechanical function for musculoskeletal disorders. By intervening early and effectively, clinicians aim to disrupt the vicious cycle of pain and inflammation, thereby preventing the transition to chronic pain states. The following strategies are tailored to the major ICOP categories.

Type I OFP attributed to disorders of Dentoalveolar and anatomically related structures

For OFP driven by infection and inflammation (e.g., pulpitis and abscesses), the primary strategy is controlling the source of infection and implementing a stratified intervention strategy based on the severity of the infection. Treatment is stratified by severity, ranging from minimally invasive procedures like root canal therapy to relieve dental pulp cavity pressure in acute pulpitis, to surgical incision and drainage for maxillofacial abscesses [105]. Systemic antibiotics serve as crucial adjuncts to, but not substitutes for, procedural intervention, with choices guided by infection severity—from amoxicillin/metronidazole combinations to clindamycin for severe, spreading infections [106]. In critical cases like Ludwig’s angina, timely airway management via tracheotomy may be life-saving [107]. The definitive goal is to eradicate the inflammatory nidus before it establishes persistent peripheral and central sensitization.

Type II myofascial and type III TMJ pain

Management of musculoskeletal OFP is inherently multimodal, addressing both muscle hyperactivity (Type II) and TMDs pathology (Type III). For Myofascial Pain, the focus is on inactivating myofascial trigger points and reducing muscle parafunction. Key interventions include Botulinum Toxin A injections into masticatory muscles to inhibit acetylcholine release and decrease muscle hyperactivity [108], and physical therapies like dry needling to mechanically release trigger points [109]. Patient education and behavioral modification to eliminate habits like bruxism and clenching are fundamental to long-term success, and patients should be reminded to avoid detrimental behaviors such as unilateral chewing, eating hard foods, and excessive mouth opening [110, 111]. The clinical features of TMDs mainly include symptoms such as dull pain in the joint area, clicking sounds, and limited mouth opening. For TMJ pain and TMDs patients, treatment aims to restore biomechanical function and reduce joint loading. This includes occlusal splints to decompress articular structures, physical modalities like photo biomodulation [112] to reduce local inflammation, and minimally invasive procedures [113]. Intra-articular injections of hyaluronic acid can improve joint lubrication, while judicious use of corticosteroids can control acute synovitis [114, 115]. For refractory cases, particularly those with internal derangement, arthroscopic surgery offers a minimally invasive surgical option [116].

Type IV neuropathic pain attributed to cranial nerve lesions

Therapy for neuropathic pain, exemplified by trigeminal neuralgia, requires precise targeted blocking of pain conduction pathways. First-line pharmacotherapy consists of voltage-gated sodium channel blockers, primarily carbamazepine and oxcarbazepine, which directly target the source of aberrant discharges [117]. For patients who are intolerant or refractory, second-line agents like gabapentin and pregabalin are employed [118]. Interventional techniques, such as radiofrequency thermocoagulation of the TG, offer a durable alternative by creating a controlled lesion in the nociceptive pathway [119].

Type V headache-like and type VI idiopathic OFP

These conditions, including Persistent Idiopathic Facial Pain and pains resembling primary headaches, often involve dysfunctional central pain processing and are frequently comorbid with affective disorders. Treatment therefore targets central neurotransmitter systems to enhance descending inhibitory control. Tricyclic antidepressants like Amitriptyline and serotonin-norepinephrine reuptake inhibitors like duloxetine are the mainstay of treatment, leveraging their ability to modulate serotonergic and noradrenergic pathways [120, 121]. To be specific, Amitriptyline can inhibit the reuptake of 5-HT and NE, but attention should be paid to its potential risks to the cardiac conduction system and Duloxetine has a significant effect on improving pain-depression comorbidity [122, 123]. However, caution should be exercised against the occurrence of serotonin syndrome during its use [124]. In some cases, interventional approaches like stellate ganglion blocks may be used to modulate autonomic nervous system input and central pain perception [125].

While this ICOP-guided approach represents the current standard of care, many treatments primarily offer symptomatic control. The limitations of existing therapies underscore the urgent need for novel strategies that target the specific molecular mechanisms of OFP, moving beyond symptom management toward disease modification.

Novel pharmacotherapies and molecular targets

Ion channel modulators

Building on the pathophysiological understanding of OFP, targeting the specific ion channels that govern nociceptor excitability represents a rational and promising therapeutic strategy. Research is intensely focused on developing selective modulators for key channels implicated in OFP, notably voltage-gated sodium, transient receptor potential, and acid-sensing ion channel, with recent breakthroughs offering new hope for improved efficacy and safety.

Targeting Nav channels

As the principal mediators of action potential generation in nociceptors, Nav channels represent a primary therapeutic focus for OFP therapeutics. Within this family, Nav1.3, Nav1.7, Nav1.8, and Nav1.9 subtypes are critical determinants of the nociceptive threshold. These channels are preferentially expressed in peripheral sensory neurons, such as those in the TG, and have been directly implicated in trigeminal neuropathic pain, mechanical allodynia, and thermal hyperalgesia [83, 126]. Their established roles in conditions like trigeminal neuralgia and inflammatory pain make them prime therapeutic targets. Strategies to mitigate their pro-nociceptive functions include indirect modulation of channel expression and direct regulation of channel function.

1. Indirect modulation of channel expression. Regulating Nav subtype expression via upstream signaling pathways is a key therapeutic strategy in inflammation and nerve injury. For Nav1.7, which expression is tightly controlled by upstream signals. In inflammatory states, mediators like prostaglandin E2 upregulate Nav1.7, an effect that can be reversed by EP2 receptor antagonists (e.g., PF-04418948) or Cyclooxygenase-2 inhibitors like meloxicam to alleviate pain [127]. Similarly, hormones like progesterone can downregulate Nav1.7 expression, attenuating sodium currents and relieving allodynia in TMJ inflammation [128].

   Nav1.8 contributes to both inflammatory dental pain (e.g., pulpitis) and trigeminal neuropathic pain. In rodent models of oral peripheral inflammation (e.g., complete Freund’s adjuvant injection), Nav1.8 mRNA and protein levels are significantly upregulated in TG neurons, and its knockdown reduces pain behaviors[129]. Following nerve injury in the model of trigeminal neuropathy, Nav1.8 also redistributes to peripheral axons, which enhances Aδ-fiber signaling and increases axonal sensitivity to Nav1.8 selective blocker A-803467, highlighting its translational relevance[126].

   Nav1.3, an embryonic subtype normally silenced in adults, is re-expressed in TG neurons after trigeminal nerve injury (e.g., vascular compression in trigeminal neuralgia)[130]. For example, in trigeminal neuralgia patients, gingival tissue from affected trigeminal territories shows an upregulation of Nav1.3 mRNA compared to controls, with this reactivation linked to enhanced axonal excitability and ectopic action potentials[83]. This reactivation drives ectopic firing in demyelinated axons due to its rapid biophysical properties, thereby mediating neuropathic pain persistence.

2. Direct regulation of channel function. Beyond altering expression levels, directly modulating the function of Nav channels offers a more precise therapeutic avenue. This can be achieved through two primary strategies: regulating the channel’s activity via accessory proteins and post-translational modifications, or more directly, by selectively blocking the channel pore with subtype-specific antagonists.

   An example of the first strategy involves Collapse response regulatory protein 2 (CRMP2), a trafficking protein that interacts with Nav1.7. In chronic pain states, enhanced SUMOylation of CRMP2 boosts Nav1.7 channel activity. Consequently, inhibiting this process with novel agents like compounds 194 disrupts the CRMP2-Nav1.7 complex by inhibiting Ubc9-mediated CRMP2 SUMOylation, thereby functioning as a “gating brake” to reduce both inflammatory and neuropathic pain effectively [131].

   The second and more clinically advanced strategy is the selective blockade of channel activity. For Nav1.7, early antagonists like PF-05089771 [132] showed limited clinical efficacy. A subsequent paradigm shift revealed that analgesia in Nav1.7-deficient models stems not only from reduced peripheral excitability but also from enhanced endogenous opioid signaling in the dorsal horn [133]. This discovery has inspired novel approaches that combine selective Nav1.7 inhibitors with low-dose opioids to achieve synergistic analgesia while minimizing adverse effects [134].

   For Nav1.8, the therapeutic landscape has advanced significantly with the recent FDA approval of suzetrigine for the treatment of pain [135, 136]. As a highly selective Nav1.8 blocker, suzetrigine recapitulates the analgesic effects of Nav1.8 knockdown in preclinical models, attenuating orofacial hypersensitivity and reducing Aδ-fiber hyperexcitability by targeting axonally localized Nav1.8 [135, 137]. Its high specificity avoids the CNS and cardiac side effects associated with non-selective blockers like carbamazepine, positioning it as a landmark therapeutic agent for OFP.

   Nav1.9 also represents a critical target, primarily due to its unique functional properties rather than changes in its expression [138, 139]. Nav1.9 activates at near-resting membrane potentials and generates persistent sodium currents that are indispensable for initiating orofacial neuropathic pain, as demonstrated in knockout mouse models that fail to develop mechanical or thermal hypersensitivity [139]. This strong functional rationale is driving the ongoing preclinical development of selective antagonists for Nav1.9.

   To sum up, the Nav channel family, including subtypes Nav1.3, Nav1.7, Nav1.8, and Nav1.9, constitutes a multi-target therapeutic axis for OFP. Strategies range from indirect regulation of expression and direct modulation of function using FDA-approved selective blockers. Future research should focus on combinatorial approaches and the development of agents targeting Nav1.3 and Nav1.9 to address the full spectrum of OFP.

Targeting TRP channels

TRP channels, particularly TRPA1 and TRPV1, function as key polymodal sensors that detect a wide array of noxious thermal, mechanical, and chemical stimuli, thereby playing a crucial role in initiating pain signaling. Targeting these channels through direct antagonism, indirect modulation, or multi-target strategies can effectively inhibit mechanical and thermal hypersensitivity as well as neuroinflammation, offering synergistic analgesic effects for various OFP disorders.

Direct antagonism: The most straightforward approach is to directly block channel activation. For instance, the high-affinity TRPA1 antagonist ADM_12 provides rapid inhibition of nociceptor firing, significantly alleviating mechanical abnormal pain in rat facial models [140]. Direct blockade of TRPV1 is a valid strategy, though it presents unique challenges. While systemic TRPV1 antagonists have shown efficacy [141], their clinical development has been hampered by the on-target side effect of hyperthermia. Topical delivery elegantly circumvents this issue. A recent clinical trial of ACD440, a topical TRPV1 antagonist gel, demonstrated significant local analgesia without systemic side effects [142, 143]. Given the high density of TRPV1 in oral tissues, developing similar mucoadhesive formulations (e.g., gels or patches) for conditions like BMS or chemotherapy-induced oral mucositis represents a highly promising translational goal.

Indirect modulation: An alternative to direct blockade is to modulate channel activity by targeting upstream endogenous signaling pathways. This can be achieved in two primary ways: (1) Enhancing pro-resolving pathways. Endogenous lipid mediators that promote the resolution of inflammation can also suppress pain signaling. The pro-resolving mediator Maresin 1, for example, has been shown to suppress TRPV1-mediated currents and synaptic potentiation within the trigeminal nuclei, thereby mitigating hyperalgesia in models of TMJ inflammation [141]. (2) Counteracting Pro-nociceptive pathways. In many neuropathic pain states, including trigeminal neuralgia, excessive oxidative stress is a key driver of channel sensitization. Reactive oxygen species (ROS) directly activate TRPA1, contributing to pain. Instead of blocking TRPA1, a more fundamental approach is to reduce ROS levels. Enhancing the endogenous NRF2 antioxidant pathway with drugs like exemestane has been shown to effectively lower ROS and alleviate pain [144]. We suggest that this strategy works by removing the channel’s endogenous activator, offering an upstream alternative to direct channel blockade.

Multi-Target Strategies: Recognizing that OFP often results from the convergence of multiple pathological mechanisms, drug development is shifting from single-target agents to multimodal therapeutics. This approach leverages synergy and can address the complex nature of pain more effectively. For example, co-administration of sub-therapeutic doses of cannabidiol with the TRPV1 antagonist capsazepine synergistically attenuated trigeminal neuralgia-like pain more effectively than either agent alone [145]. Another example is the α-phellandrene/HPβCD inclusion complex, which simultaneously inhibits TRPV1 and TRPA1 while suppressing pro-inflammatory cytokine release (TNF-α, IL-1β) [146]. These dual ion-channel and anti-inflammatory activity underpins its efficacy across diverse orofacial nociceptive paradigms (formalin, cinnamaldehyde, glutamate). The primary advantage of such multi-target strategies lies in their potential to address the heterogeneity of pain pathophysiology among patients. By covering diverse bases, such as varying levels of inflammation, oxidative stress, and channel expression, multimodal therapies may reduce the risk of treatment failure inherent in single-target agents that rely on one specific mechanism.

Targeting ASIC

ASICs, particularly the ASIC3 subtype, are activated by the local acidosis accompanying tissue inflammation, contributing significantly to mechanical hyperalgesia [147]. Therapeutic strategies targeting these channels in OFP can be viewed from two perspectives: direct inhibition as a monotherapy and their role in synergistic combination therapies.

Firstly, the ASIC antagonist APETx2, a selective ASIC3 inhibitor, effectively reduces mechanical allodynia in context of orthodontic and TMJ pain [148]. This principle is further validated by studies on natural compounds. Curcumin, the active component of turmeric, directly inhibits ASIC function by reducing both channel current and protein expression. Crucially, its potential as a standalone treatment has been translated to a clinical setting. Studies have confirmed that in the formalin-induced OFP model, intraperitoneal injection of 50 mg/kg curcumin can bidirectionally inhibit hyperalgesia, and its mechanism involves directly reducing ASIC current amplitude and decreasing ASIC protein expression, thereby inhibiting ASIC-mediated inflammatory pain hypersensitivity [149]. A randomized controlled trial confirmed that curcumin monotherapy significantly reduced postoperative pain following third molar extraction, validating its feasibility as a clinical analgesic regimen [150]. Another alternative direct target strategy involves targeting pathways that regulate ASIC expression. Nerve growth factor (NGF), for example, upregulates ASIC3, mediating mechanical hyperalgesia in tooth movement models. Consequently, inhibiting the source of the upregulation via NGF-shRNA gene therapy not only alleviates pain but also downregulates ASIC3 expression, confirming that modulating the NGF-ASIC3 axis is a potent therapeutic approach [148]. These findings underscore that direct ASIC inhibition is a viable therapeutic strategy and pave the way for developing more potent and selective small-molecule inhibitors for inflammatory OFP.

While direct inhibition is effective, preclinical data strongly suggest that combining ASIC modulation with other mechanisms can produce superior analgesic effects, particularly in complex pain states. The efficacy of ASIC inhibitors can be significantly enhanced when paired with agents targeting different nociceptive pathways. For instance, while APETx2 alone shows limited effect in an occlusal interference model, its anti-hyperalgesic activity is dramatically potentiated when combined with a TRPV1 antagonist [151]. Similarly, curcumin produces a synergistic effect when co-administered with the classic NSAIDs diclofenac, which is a drug reported to inhibit ASIC in neurons and can produce a synergistic effect. In formalin-induced OFP model, combined administration enhancedpain relief on facial pain behaviors in both acute and chronic stages, and significantly potentiated the efficacy of sub-therapeutic doses of diclofenac sodium [150]. With the deepening of research on curcumin, we believe that future studies can further explore the potential targets of curcumin. Cryo-electron microscopy can be used to analyze the spatial conformation of the curcumin-ASIC complex, accurately locating its binding domains. Then, through molecular docking simulation and point mutation verification, the allosteric inhibition mechanism can be clarified, guiding the design of curcumin derivatives with high selectivity and stability (such as tetrahydro curcumin metal complexes) to improve their regulatory efficacy on ASIC subtypes.

In summary, ion channel modulators represent a frontier in precision pain medicine. They are amenable to direct inhibition for standalone pain relief and can be integrated into powerful multimodal strategies to achieve synergistic effects, either through combination with other analgesics or by targeting their regulatory pathways. However, significant hurdles remain for their clinical application in OFP, including achieving high target selectivity to avoid off-target effects, overcoming potential compensatory upregulation of other channel subtypes (e.g., Nav1.3 upregulation following Nav1.7 blockade) [55, 152], and designing effective local delivery systems to navigate the unique environment of the oral cavity.

Endocannabinoid system modulators

The ECS, composed of cannabinoid receptors (CB1R, CB2R), endogenous ligands such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and synthesis/metabolic enzymes (e.g., fatty acid amide hydrolase (FAAH)), is a key regulator of pain signal transduction by modulating neuronal excitability, inflammatory responses, and glial cell activation [153]. Therein, CB1R is predominantly distributed within the CNS, for example in the spinal trigeminal nucleus, where it reduces neuronal hypersensitivity by inhibiting presynaptic glutamate release [153]. CB2R, conversely, is enriched in peripheral immune cells such as gingival macrophages and alleviates inflammatory pain by suppressing the release of TNF-α and IL-6 [153]. Metabolic enzyme targets include FAAH and monoacylglycerol lipase (MAGL), which are responsible for degrading AEA and 2-AG, respectively; inhibitors of these enzymes elevate endocannabinoid levels, thereby achieving sustained analgesia [153]. Therapeutic strategies for OFP aim to leverage this system through two primary approaches: administering exogenous cannabinoids or enhancing the activity of endogenous cannabinoids.

Application of exogenous cannabinoids

Targeted ECS-based therapeutic strategies for OFP leverage the anatomical basis of widely distributed CB1R/CB2R in human fasciae and fascial fibroblasts [154]. Cannabidiol, a non-psychoactive phytocannabinoid, exerts analgesic and anti-inflammatory effects through modulation of CB1R/CB2R, thereby reducing cytokine release and modulating neurotransmitter transmission [155]. Clinical evidence supports its use in OFP. Randomized controlled trials have shown that topical cannabidiol ointments can reduce masseter muscle activity in patients with TMDs, ameliorating masseter muscle activity and masticatory function in patients. Furthermore, intramuscular cannabidiol injections, used as either monotherapy or in combination with other treatments, have been found to effectively alleviate myofascial pain without significant neurological side effects [156, 157]. Despite these promising results, the duration of efficacy varies across formulations, with gel-based topical delivery providing longer-lasting effects than short-term formulations [158]. Further high-quality research is required to establish optimal dosing, delivery formulations (e.g., gels, oral mucosal products), and long-term safety for cannabidiol as an adjunctive therapy for OFP.

Enhancing endogenous cannabinoids via enzyme Inhibition

This strategy aims to increase the local concentration and duration of action of the body’s own endocannabinoids by blocking their degradation, thereby enhancing ECS activity. (1) FAAH inhibitors. Compounds such as URB597 and URB937 sustain AEA levels by inhibiting the activity of its metabolic enzyme FAAH. Application of these agents can therefore significantly increase AEA concentration in cerebrospinal fluid, which primarily acts on CB1R to reduce neuronal hyperexcitability in pain-processing regions like the spinal trigeminal nucleus [159, 160]. (2) MAGL inhibitors. JZL184 and URB602 elevate 2-AG levels by blocking MAGL activity. In nitroglycerin-induced migraine rat models, these agents could revert hyperalgesia, reduce neuronal activation in the brain, and suppress neuroinflammatory responses by decreasing calcitonin gene-related peptide and pro-inflammatory cytokine expression [161, 162]. (3) Dual FAAH/MAGL inhibitors (e.g., JZL195). This synergistic approach inhibits the catabolism of both AEA and 2-AG, providing a more comprehensive enhancement of ECS tone. Dual inhibition has demonstrated significant efficacy in alleviating trigeminal hyperalgesia in nitroglycerin-induced migraine models, without inducing motor impairment or anxiety associated with direct CB1 agonists [163]. Further research is needed to validate their efficacy and safety across a broader spectrum of pain types and to assess their potential in clinical settings, ensuring that these compounds can be effectively harnessed for therapeutic purposes while minimizing adverse effects.

Collectively, ECS modulators provide a multi-target approach for managing OFP. The primary challenge moving forward is to refine target selectivity and develop strategies (such as peripherally restricted inhibitors) that maximize therapeutic benefits while minimizing potential CNS side effects.

Zinc supplementation as an adjunctive therapy

Recent evidence highlights the therapeutic value of zinc, an essential trace element, as an adjunctive treatment for various forms of OFP, particularly those involving mucosal inflammation and sensory dysfunction [164]. Zinc’s therapeutic effects are multifactorial: it acts as a potent antioxidant, modulates immune responses, inhibits matrix-degrading enzymes to preserve epithelial integrity, and is a critical cofactor for proteins involved in sensory perception, such as the taste-regulating protein Gustin [165–168].

The clinical application of zinc supplementation is most robustly established for inflammatory mucosal diseases such as oral lichen planus (OLP). As previously noted, clinical trials have revealed that oral zinc tablets (50 mg/day) combined with 0.1% triamcinolone acetonide (applied topically twice a day for 1 week) significantly outperformed steroid monotherapy. After 6 months of zinc supplementation and at 6-month follow-up, patients showed that the burning sensation in the cheek mucosa, gums and tongue, as well as the size of the lesion, all significantly decreased. Additionally, the histopathological examination showed a significant recovery of epithelial integrity [168, 169]. Systematic reviews and meta-analysis consolidate these findings, concluding that zinc supplementation is an effective adjunctive therapy for reducing the pain (measured by visual analogue scale scores) and clinical signs of OLP, especially in its erosive form [170]. Moreover, patients with recurrent aphthous stomatitis (RAS) often exhibit lower serum zinc levels [171]. Literatures have indicated that oral zinc supplementation (typically as zinc sulfate) can significantly reduce the frequency, duration, and severity of RAS episodes. It serves as a valuable prophylactic and therapeutic strategy for managing this painful condition [172].

In summary, zinc supplementation represents a simple, safe, and cost-effective adjunctive strategy for managing OFP. Its well-established role in mucosal healing and immune regulation makes it a strong candidate for treating inflammatory conditions like OLP and RAS.

Neuromodulation techniques

Non-invasive neuromodulation techniques, including repetitive transcranial magnetic stimulation (rTMS), transcutaneous auricular vagus nerve stimulation (taVNS), and photobiomodulation (PBM), offer innovative strategies for managing chronic OFP by targeting distinct levels of the nervous system. These techniques provide a spectrum of therapeutic options for managing chronic OFP, from modulating central brain networks to influencing local tissue environments.

rTMS operates by directly influencing brain activity. High-frequency rTMS applied over key cortical areas, such as the dorsolateral prefrontal cortex or the primary motor cortex, is thought to restore top-down pain inhibitory control. Double-blind randomized controlled trials have confirmed that a single session of active rTMS provides immediate, mild reductions in pain intensity and discomfort. The effects could last ≤ 7 days, and the side effects limited to only transient mild headache or fatigue [173]. Another randomized controlled trial demonstrates that repeated sessions of navigated high frequency rTMS (10 Hz/2400 pulses) targeting the functional facial motor cortex significantly reduced pain intensity in patients with chronic facial pain [174]. The efficacy of this technique is highly dependent on precision. Studies show that using numerical simulations based on functional magnetic resonance imaging and computer modeling to ensure stimulation coil positioning error be controlled within 10 mm dramatically improves therapeutic outcomes, with optimized placement increases stimulation volume in target areas by 60% [175].

taVNS targets the critical intermediate hub—the brainstem. By delivering low-level electrical stimulation to the auricular branch of the vagus nerve, it engages the nucleus tractus solitarius, locus coeruleus pathway, thereby suppressing C-fiber mediated responses within the spinal trigeminal nucleus caudalis [176]. This activation enhances endogenous descending pain inhibition, effectively dampening nociceptive signals within the spinal trigeminal nucleus. Clinically, taVNS not only elevates pain thresholds but also demonstrates a powerful synergistic effect with pharmacotherapy. A single 30-minute taVNS session significantly elevated pressure-pain thresholds and augmented conditioned pain modulation, indicating enhancement of descending inhibitory pain control in patients with trigeminal neuralgia [177]. Moreover, a study demonstrated that a taVNS treatment regimen, consisting of 12 sessions with stimulation delivered at a frequency of 1 Hz and a pulse width of 200 µs per session, significantly reduced the required dosage of carbamazepine while simultaneously improving scores on the McGill Pain Questionnaire and Facial Pain Rating Scale and alleviating pain-related anxiety and catastrophizing, thus achieving the therapeutic objective of “reducing medication while enhancing efficacy” [178].

PBM, also known as low-level laser therapy, acts directly on the site of injury and inflammation. By applying specific wavelengths of light, such as intra-oral red laser with an extra-oral infrared laser, PBM modulates cellular processes to reduce neuroinflammation and promote tissue repair and offers versatile therapeutic utility across multiple OFP conditions. A double-blind controlled trial following third molar surgery shows that single-session infrared laser application (808 nm, 100 mW) significantly reduces pain scores, facial edema, and trismus while decreasing analgesic consumption, with particularly marked effects observed on postoperative days 2 and 7 [179]. A meta-analysis of TMDs studies including a total of 40 patients demonstrated that PBM (wavelength 780–980 nm, energy density < 100 J/cm², ≥ 6 sessions) effectively reduces pain intensity and increases inter-incisal opening and pressure-pain thresholds. Therein, infrared lasers with output power ≤ 500 mW have been identified as the optimal modality [180]. At the molecular level, PBM has been shown to downregulate key neuroinflammatory mediators (e.g., TRPV1, substance P, and CGRP) and glial cell markers (e.g., GFAP, Iba-1) in trigeminal neuralgia models, providing a mechanistic basis for its analgesic effects [181].

In summary, these non-invasive neuromodulation techniques establish novel pathways for chronic OFP management through the targeted modulation of nociceptive and neuro-immune pathways. They operate on distinct but complementary levels: rTMS at the cortico-limbic network level, taVNS at the brainstem-autonomic axis, and PBM at the peripheral cellular level. This hierarchical approach moves beyond conventional analgesia, allowing for tailored interventions based on the underlying pain mechanism. Future efforts should focus on standardizing treatment parameters and exploring integrated protocols, which will accelerate the clinical translation of an individualized pain-management framework and ultimately deliver more refined and efficacious therapeutic options for OFP patients.

Psychotherapy and therapeutic exercise

The high prevalence of psychological comorbidities in chronic OFP, with 40–60% of TMDs patients, for instance, presenting with significant anxiety or depression [182], is not incidental but rather reflects the deep integration of sensory, emotional, and cognitive circuits in the brain [183]. Non-pharmacological interventions, particularly psychotherapy and therapeutic exercise, are evidence-based therapeutic pillars for managing chronic OFP. These approaches offer durable symptom relief and functional recovery by targeting the underlying neurobehavioral and sensorimotor mechanisms of pain.

Cognitive behavioral therapy (CBT) stands as the most well-validated psychotherapeutic intervention for chronic pain, addressing the intricate interplay of maladaptive cognitions (e.g., catastrophizing), behaviors (e.g., parafunction), and physiological arousal through methods like cognitive restructuring and relaxation [184]. Its efficacy is demonstrated across multiple OFP conditions, including TMDs, BMS, and myofascial pain, with studies confirming sustained improvements in pain, function, and emotional distress. A systematic review of high-quality randomized trials confirmed that CBT, either alone or with conservative care, yields both short- and long-term benefits in chronic TMD patients [185]. This is exemplified by a 6–8-week structured program that produced sustained reductions in pain and functional impairment over a 12-month follow-up [186]. The benefits of CBT extend to other OFP conditions. For instance, group-based CBT has achieved sustained pain and anxiety reduction in BMS for at least six month [187, 188], while in myofascial pain, its combination with postural correction improves pain-free mouth opening and daily function [189]. Furthermore, its utility in refractory cases is notable; when paired with biofeedback, CBT can achieve response rates as high as 70%, cementing its position as a first-line non-pharmacological treatment [190].

Therapeutic exercise offers a dual-pronged approach to OFP management, targeting both local neuromuscular dysfunction and central pain processing pathways. On a local level, a consensus of international experts supports individualized jaw exercises, such as controlled opening and resistance training, to improve function, mobility, and pain in patients with myalgia, restricted opening, or non-reducing disc displacement [186, 191]. Complementing this localized treatment, systemic aerobic exercise modulates central pathways. Its mechanisms extend beyond general synaptic plasticity [192]; preclinical models show that it can reverse the pathological expression of pain-related neuropeptides and cannabinoid receptors within trigeminal pathways, offering a specific neurochemical rationale for its analgesic effects [193]. Clinically, these two approaches converge in a synergistic multimodal strategy. Recent studies confirmed that combining aerobic exercise with manual therapy and other exercises yields superior short- and medium-term pain reduction and quality of life improvements compared to less comprehensive interventions, reinforcing the principle of combined therapy [194, 195].

In conclusion, CBT and therapeutic exercise are foundational treatments for chronic OFP. These approaches not only modulate pain perception and enhance physiological function but also facilitate long-term adaptive outcomes. By addressing both psychological and physical dimensions of pain, they transcend the limitations of the conventional biomedical model and underscore the central role of psychosomatic integration in modern pain medicine.

Conclusion and perspective

OFP represents a complex set of conditions that pose significant diagnostic and therapeutic challenges. While the introduction of the ICOP has provided an essential nosological framework, establishing standardized diagnostic criteria for clinicians. In parallel, recent years have witnessed significant therapeutic innovation. The development of novel pharmacotherapies, such as ion channel modulators and endocannabinoid-based agents, alongside non-pharmacological neuromodulation techniques like rTMS and taVNS, has expanded the therapeutic arsenal. However, a substantial gap persists between our mechanistic understanding and consistent clinical success. To bridge this gap and advance patient care, future research must pivot towards a more integrated, mechanism-based paradigm. We propose that future efforts should prioritize these pivotal areas: (1) elucidating the CNS mechanisms of pain chronification, (2) enhancing the translational validity of preclinical models, and (3) innovating and integrating comprehensive therapeutic strategies.

Elucidating the CNS mechanisms of pain chronification

A primary frontier is the investigation of CNS mechanisms. A compelling body of neuroimaging evidence indicates that chronic OFP conditions, such as TMDs and BMS, are not merely peripheral phenomena but are sustained by maladaptive plasticity within the brain [196]. In fMRI studies, for instance, have identified dysregulated functional connectivity between the salience network (SN) and the default mode network (DMN) as a cardinal neurobiological feature. In chronic pain states, SN hyperactivity leads to a persistent, draining allocation of attention to nociceptive signals, while altered DMN function is linked to the cognitive and affective comorbidities that define the patient experience [197, 198]. Therefore, a critical next step is to delineate the neurochemical substrates modulating these large-scale networks.

Future research should focus on how neurotransmitter systems, including the dopaminergic, endocannabinoid, serotonergic, and noradrenergic systems, govern this network dysfunction following key areas: (1) The dopaminergic system: Given its established role in regulating motivation, reward processing, and pain modulation, this system may offer insights into the high prevalence of anhedonia and depressive mood observed in chronic pain populations [199]. (2) The endocannabinoid system: As a critical endogenous neuromodulatory system involved in pain inhibition and mood regulation, the ECS represents a promising target for the development of non-opioid analgesic therapies [200]. (3) The serotonergic and noradrenergic systems: As primary components of the descending pain inhibitory pathway, these systems are the therapeutic target of many first-line analgesics, such as Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) [201]. An integrated approach combining functional neuroimaging with neurochemical assessment will be essential for developing targeted neuromodulation techniques and pharmacotherapies capable of recalibrating these dysfunctional central circuits.

Enhancing the translational relevance of preclinical models

The translational relevance of preclinical models must be enhanced. The validity of therapeutic discovery is contingent on animal models that faithfully recapitulate the human condition. Current research primarily employs three types of animal models: inflammatory pain models, neuropathic pain models, and functional pain models, each with distinct characteristics and challenges. (1) Inflammatory pain models (e.g., for periodontitis and TMDs). These models suffer from a lack of standardization, as different inducing agents (e.g., formalin, complete Freund’s adjuvant, and mustard oil) fail to consistently recapitulate the human condition [202]. To address this and better mirror the pathogenesis of OFP in humans, we propose specific inducers for animal models. For primary TMDs, intra-articular injection of either collagenase or mono-iodoacetate can be used to replicate cartilage degeneration and synovial inflammation [203, 204]. For myogenic TMDs, in contrast, repetitive intramuscular administration of acidified saline or NGF is suitable for modeling myofascial pain [205, 206]. (2) Neuropathic pain models (e.g., for trigeminal neuralgia). These models are limited by significant interspecies differences in trigeminal neurobiology between rodents and humans, such as the distribution of TG neuron subtypes and the expression of ion channels [207]. The development of human stem cell-derived TG organoids [208], offers a promising path forward, enabling the study of pain mechanisms in a more clinically relevant context. (3) Functional pain models (e.g., for orthodontic pain). These models are often compromised by technical inconsistencies in force application. The implementation of 3D-printed customized devices can provide the mechanical stability and precision needed to enhance the reliability and reproducibility of these models.

While progress has been made in standardizing inflammatory and neuropathic models, a critical flaw remains: the failure to adequately model the striking sex-based dimorphism in OFP. Many chronic OFP conditions, such as TMDs and BMS, are significantly more prevalent in females, with the highest incidence occurring during the reproductive years [209–211]. This disparity strongly implicates the role of sex hormones, particularly estrogen, in pain modulation. Mechanistically, estrogen exerts complex, often bidirectional, effects on the trigeminal nociceptive system, influencing neuronal excitability, inflammatory responses, and central pain processing [128, 212]. The general omission of these hormonal considerations in preclinical studies represents a profound gap in translational validity. It is therefore imperative that future models not only systematically include female animals but are also designed to account for hormonal status (e.g., estrous cycle tracking), enabling the development of sex-specific therapeutic strategies.

Innovating and integrating comprehensive therapeutic strategies

For pharmacotherapy, innovating drug delivery systems remains crucial. Effective therapy requires delivering sufficient drug concentrations to target sites while minimizing side effects. Advanced formulations such as mucoadhesive hydrogels and biomimetic microneedle patches [213, 214] are needed to overcome local challenges like salivary washout and provide sustained drug delivery to target sites, minimizing systemic side effects. For instance, to address salivary washout, materials can be engineered into bio-adhesive hydrogels by enhancing their adhesiveness to the mucosa; while for improving resistance to tongue movements, biomimetic microneedle patches can be designed.

However, pharmacological intervention is only one component of effective care. A genuinely mechanism-based approach must embrace the biopsychosocial nature of chronic pain, wherein non-pharmacological interventions like psychotherapy and therapeutic exercise are foundational. Therapeutic exercise, spanning localized jaw movements to systemic aerobic activity, complements this by targeting the sensorimotor domain, improving neuromuscular function, reducing peripheral sensitization, and modulating central pain processing pathways. Together, these integrated strategies provide a comprehensive treatment that addresses the multifaceted nature of chronic OFP.

In summary, the future of OFP management lies in a multidisciplinary, mechanism-driven approach. By integrating insights from central neurobiology, refining sex-specific preclinical research, and combining targeted drug delivery with essential non-pharmacological therapies like CBT and therapeutic exercise, we can move beyond symptom management towards personalized interventions. Forging a tighter collaboration between dentists, neurologists, pain specialists, and psychologists is essential to translate these scientific advances into tangible improvements in the quality of life for individuals suffering from OFP.

Abbreviations

AEA

Anandamide

ASICs

Acid-sensing ion channels

ATP

Adenosine triphosphate

BMS

Burning mouth syndrome

CBT

Cognitive behavioral therapy

CNS

Central nervous system

CRMP2

Collapse response regulatory protein 2

DMN

Default mode network

ECS

Endocannabinoid system

IASP

International Association for the Study of Pain

ICOP

International Classification of Orofacial Pain

IL-1β

Interleukin-1β

MAGL

Monoacylglycerol lipase

mPFC

Medial prefrontal cortex

Nav

Sodium channel

NGF

Nerve growth factor

NMDA

N-methyl-D-aspartate

NSAIDs

Nonsteroidal anti-inflammatory drugs

OFP

Orofacial pain

OLP

Oral lichen planus

PBM

Photobiomodulation

RAS

Recurrent aphthous stomatitis

ROS

Reactive oxygen species

RVM

Rostral ventromedial medulla

rTMS

Repetitive transcranial magnetic stimulation

SN

Salience network

taVNS

Transauricular vagus nerve stimulation

TG

Trigeminal ganglion

TMDs

Temporomandibular disorders

TMJ

Temporomandibular joint

TNF-α

Necrosis factor-alpha

TRPV1

Transient receptor potential vanilloid 1

TRPA1

Transient receptor potential ankyrin 1

2-AG

2-arachidonoylglycerol

Authors’ contributions

Yiyuan Kang: Conceptualization, Writing - original draft, Writing - review & editing, Funding acquisition. Yinyu Fu: Conceptualization, Writing - original draft, Writing - review & editing. Kehui Jian: Writing - review & editing. Jia Liu: Supervision, Conceptualization. Longquan Shao: Conceptualization. All authors reviewed the manuscript.

Funding

This Project was funded by the Natural Science Foundation of Guangdong Province (2025A1515010308), Young Talent Support Project of Guangzhou Association for Science and Technology (QT2024-031), Guangzhou Basic and Applied Basic Research Program (2025A04J3457).

Data availability

All the references data can be available on the Internet in the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

Competing interests The authors declare no competing interests.