Burning mouth syndrome: updates on pathogenesis and diagnostic algorithms

1. Introduction

Burning mouth syndrome (BMS), is a multifaceted idiopathic orofacial disorder characterized by persistent, chronic, and spontaneous pain. Patients often describe this discomfort as an oral burning sensation, lasting for over three months, without any identifiable local or systemic pathological changes. Although the tongue is frequently affected, any intraoral site may experience these distressing sensations [1]. Historically, this condition has been referred to by various terms, such as stomatodynia, glossodynia, burning tongue, oral dysesthesia, and complex oral sensitivity disorder—reflecting the broad spectrum of symptoms experienced by patients [2, 3, 4]. Moreover, individuals with BMS generally present with a range of additional intra-oral and extra-oral symptoms, further complicating and delaying the diagnostic process [5].

In recent years, a significant conceptual shift has emerged regarding the classification of BMS. While traditionally labeled as a “syndrome” due to its heterogeneous symptomatology—including burning sensations, xerostomia, dysgeusia, and other additional oral symptoms—this terminology has been increasingly questioned. The term “syndrome” implies a consistent cluster of clinical features that recur across most patients, yet in BMS, only the burning sensation appears to be reliably present, while other associated symptoms vary widely in intensity and presence. This inconsistency has prompted several experts in the field to advocate for a redefinition of BMS as a “disorder” rather than a “syndrome”. A recent Delphi consensus among international orofacial pain specialists supported the adoption of the term Burning Mouth Disorder (BMD) to more accurately reflect the clinical and pathophysiological complexity of the condition [6]. This terminology emphasizes the chronic neuropathic nature of the pain and the exclusion of other identifiable causes, aligning with the latest International Classification of Diseases (ICD-11) classification which categorizes BMS under “chronic primary pain” conditions [7].

Concurrently, an expanded diagnostic framework has been proposed to encompass patients presenting with dysaesthetic symptoms (such as tingling, taste disturbance, xerostomia, numbness, and itching) and perceptual symptoms (such as intraoral foreign body sensation, altered perception of tongue size or color, and sialorrhea), but without burning sensations, yet sharing key clinical features with BMS. The term Oral Dysaesthetic and Perceptual Disorder (ODPD) has been introduced to define this under-recognized subgroup, underscoring the need to broaden diagnostic criteria to better capture and manage such phenotypes [8].

In this review, we retain the term BMS for consistency. However, we fully acknowledge the evolving nosology that favors the more precise designation of BMD and the recognition of emerging categories such as ODPD. These developments have important implications for improving diagnostic accuracy, guiding future research, and optimizing clinical management.

Despite ongoing research, the pathogenesis of BMS remains elusive. Current evidence suggests the involvement of central and peripheral neuropathy [9, 10], along with potential contributions from endocrinological and psychosocial factors [11, 12, 13], in the development and perpetuation of this enigmatic condition. Recognizing the intricate interplay of these factors is essential in developing effective strategies for diagnosis, treatment, and management.

This review aims to comprehensively present the multifaceted nature of BMS, exploring its clinical manifestations, potential underlying mechanisms, and the challenges encountered in both diagnosis and treatment. A pivotal focus of this review is on proposing and discussing specific diagnostic approaches to assist clinicians in differential diagnosis, and in the formulation personalized treatment plans for BMS patients. By synthesizing existing knowledge and presenting a structured approach to understanding and addressing BMS, this review endeavors to deepen the understanding of this complex affection and enhance clinical practices.

2. Epidemiology: prevalence, age, and sex distribution

The worldwide prevalence of BMS is estimated at 1.7% in the general population, rising to 7.7% among dental patients in clinical settings. However, precise prevalence data can vary significantly due to differences in populations, geographic regions, and diagnostic criteria [14]. Additionally, a population-based study by Kohorst et al. [15] reported a prevalence of 0.11% for BMS, with a higher incidence observed in women over the age of 60. In the general population, BMS prevalence is higher in Europe (5.5%) and North America (1.1%), and lower in Asia (1%). Conversely, in clinical settings, the prevalence is higher in Asia (8.9%) compared to South America (6.1%) and Europe (6.5%). These variations highlight the impact of geographic location on BMS prevalence [14].

Gender-specific analysis revealed a prevalence of 1.1% in females, significantly higher than the 0.38% observed in males in the general population. Consequently, the female-to-male ratio is approximately 3:1 in population-based studies, whereas in clinical settings it may reach 6:1 to 9:1, highlighting a notable gender disparity in BMS prevalence. This disparity may be related to physiological and behavioral differences [14].

Interestingly, recent large cohort studies suggest a shift in the onset of BMS towards older ages, with the disease manifesting predominantly around 65 years, emphasizing the evolving landscape of BMS epidemiology in the context of an aging population [14]. An age-specific analysis indicated a higher incidence of BMS among individuals aged 50 and above (3.31%) compared to those under 50 (1.92%). This trend may be attributed to various factors that differ across the countries, including hormonal changes, nutritional deficiencies, differences in socioeconomic and medical conditions or the cumulative effects of environmental factors over time (Table 1, Ref. [14]). This also highlights important methodological differences across studies.

3. Aetiopathogenesis

3.1 Neuropathological insight

The pathogenesis of BMS remains an enigma and is not fully understood. Nevertheless, there is a widespread consensus that the etiology of BMS is intricate and multifactorial, with different patients exhibiting various combinations of triggers and perpetuating factors [16, 17]. Neurological, psychological, and hormonal factors are extensively recognized as potential contributors to the development of this condition [12, 18, 19]. Additionally, local factors, systemic conditions, and certain medications have been implicated in provoking secondary burning sensations in the oral cavity [20, 21]. A comprehensive understanding of these diverse factors, their distinct characteristics, and interactions is imperative for accurate diagnosis and, subsequently, for developing more effective treatment strategies.

The trigeminal nerve transmits nociceptive sensory information to various regions of the central nervous system, which process both the sensory-discriminative and affective-emotional aspects of orofacial pain [22] (Fig. 1). Recent neuroimaging advancements have significantly enhanced our comprehension of the pathophysiological mechanisms underlying BMS [23, 24]. These studies have provided consistent evidence that BMS is a neuropathic disorder involving both the peripheral (PNS) and central nervous systems (CNS), highlighting the role of the trigeminal nerve in transmitting abnormal pain signals in BMS patients [25, 26]. In this scenario, both peripheral and central sensitization, characterized by an increased responsiveness of peripheral neurons and an enhanced excitability of central neurons may further contribute to persistent pain [27] (Fig. 2).

Fig. 1.Anatomy of the trigeminal nerve, sensory nuclear complex, and ascending pain pathways. The fifth pair of cranial nerves (V), known as the trigeminal nerve, is divided into three main branches: ophthalmic (V1), maxillary (V2), and mandibular (V3). Nociceptive sensory information from the areas innervated by the trigeminal nerve is transmitted via trigeminal afferents to second-order neurons in the trigeminal sensory nuclear complex (TSNC) located in the brainstem and the upper cervical spinal cord (C1–C2). The TSNC comprises the principal sensory nucleus (PSN) and the spinal trigeminal nucleus (SpTN), which is functionally divided into three subnuclei: oralis (Or), interpolaris (Ip), and caudalis (Ca). The trigeminal nuclei are considered equivalent to the dorsal horn of the spinal cord for orofacial pain. The Ca and C1–C2 regions are primary sites for synaptic integration of sensory inputs from craniofacial tissues. Three main areas of the central nervous system (CNS) receive nociceptive input from the SpTN and C1–C2 regions: the ventral posteromedial thalamic nucleus (VPM), the medial thalamic nuclei (MTN), and the parabrachial nucleus (PBN). Nociceptive neurons in the VPM, which receive input from the orofacial region, send axons to neurons in the primary (S1) and secondary (S2) somatosensory cortices. These neurons are involved in the sensory-discriminative perception of pain (intensity and localization). In contrast, those in the MTN and PBN project first to limbic cortices, such as the anterior cingulate cortex (ACC) and insula (I), and subsequently to the S2, and are involved in the affective and emotional aspects of pain. OrN: Nucleus Oralis; IpN: Nucleus Interpolaris; CaN: Nucleus Caudalis; VPMTN: Ventral Posteromedial Thalamic Nucleus; IC: Insular Cortex; CSS: Somatosensory Cortex; MSC1/C2: Mesencephalic Nucleus 1 and 2.

Fig. 2.Peripheral and central sensitization of pain. Damage to the trigeminal nerve or inflammation can induce hyperexcitability of primary afferent neurons of the trigeminal system, which release excitatory neurotransmitters (glutamate (Glu), substance P (SP), calcitonin gene-related peptide (CGRP), brain-derived neurotrophic factor (BDNF), and ATP) that activate normally silent glutamate receptors (NMDA receptors) present on second-order neurons. In this context, C fibers and A-delta fibers play crucial roles. C Fibers: These unmyelinated fibers are responsible for transmitting slow, dull, and aching pain. They release excitatory neurotransmitters such as substance P and CGRP, which contribute to the development of hyperalgesia by promoting inflammation and sensitizing neurons. A-Delta Fibers: These thinly myelinated fibers are involved in transmitting fast, sharp pain. They release neurotransmitters like glutamate, which can activate NMDA receptors on second-order neurons and contribute to central sensitization. Additionally, tissue damage or inflammation activates the release of ATP, chemokines, and fractalkine from primary afferent neurons, which in turn activate satellite glial cells (microglia and astrocytes). Activated microglia (M1) release a range of cytokines such as TNFα, IL-1β, IL-6, NGF, and BDNF, while activated astrocytes release CCL2, glutamine, and NF-κB, further contributing to neuronal hyperexcitability by increasing the expression of pain receptors TRPV1, TRPA1, and P2X3. Under normal conditions, inhibitory interneurons continuously release GABA to decrease the excitability of nociceptive neurons and modulate nociceptive transmission (inhibitory tone). Following damage or inflammation, this inhibition can be lost (disinhibition), resulting in hyperalgesia. ATP: Adenosine Triphosphate; TNFα: Tumor Necrosis Factor-alpha; NGF: Nerve Growth Factor; IL-1β: Interleukin-1β; IL-6: Interleukin-6; CCL2: Chemokine CCL2; NF-κB: Nuclear Factor Kappa; TRPV1: Transient Receptor Potential Vanilloid 1; TRPA1: Transient Receptor Potential Cation Channel A1; P2X3: Purinergic Receptor P2X3; NK1R: Neurokinin 1 Receptor; GABA: Gamma-Aminobutyric Acid; Ca++: Calcium Ions; Cl−: Chloride Ions; NC: Caudal Nucleus; MS-C1C2: Upper Cervical Spinal Cord.

Understanding the involvement of the trigeminal nerve and its pathways in the CNS is crucial for developing targeted treatments for the sensory and emotional dimensions of BMS. BMS can be defined as a nociplastic pain because it is characterized by altered nociception in the absence of clear evidence of actual or threatened tissue damage that would activate peripheral nociceptors or indicate a disease or lesion of the somatosensory system causing the pain. This classification underlines the absence of visible signs or detectable disorders that typically accompany other types of pain, thereby situating BMS within the realm of conditions where the pain arises primarily from dysfunctions in the pain processing systems. Studies have shown that BMS is associated with dysfunction of the pain modulatory system, particularly the descending pain inhibition, where altered brain function can be demonstrated through neurophysiological tests and imaging, revealing an atypical response to painful stimuli without the usual physical causes [28, 29].

3.2 Central neuropathy

Central neuropathy in BMS involves several key alterations in the CNS, including structural and functional changes that indicate brain hypoactivity, impacting pain modulation and sensory processing [23, 24, 26, 30].

3.2.1 Striatal dopamine, substantia Nigra and midbrain raphe alterations

Striatal dopamine dysfunction, particularly depletion in the putamen, impairs pain inhibition in the trigeminal brainstem complex. Transcranial sonography reveals unique abnormalities, such as hypoechogenicity in the substantia nigra and midbrain raphe, suggesting nigrostriatal dopaminergic hypofunction. Indeed, a hypofunction in the nigrostriatal dopaminergic pathway, particularly in the basal ganglia and sensory cortex, has been suggested as a cause of reduction of endogenous pain inhibitory control. Specifically, the increased availability of dopamine D2 receptors, reflecting dopamine depletion, may contribute to chronic neuropathic pain within the trigeminal distribution [31, 32].

3.2.2 Brain activation and connectivity

Advanced neuroimaging techniques, such as functional Magnetic Resonance Imaging (fMRI), have revealed a spectrum of changes affecting both structural and connectivity aspects of the brain’s pain matrix in BMS patients. These patients exhibit decreased activation, especially in the thalamus, alongside an expansion in hippocampal grey matter volume (GMV) and a reduction in the medial prefrontal cortex [33]. Further supporting this, studies have established a correlation between pain intensity and reductions in grey matter concentration (GMC) and GMV in BMS patients compared to control groups. Specifically, these reductions are observed in the thalamus, cingulate gyrus, cerebellar lobules, insula/frontal operculum, inferior temporal area, primary motor cortex, and medial and dorsolateral prefrontal cortex [24, 34]. Similar reductions in GMV in the prefrontal cortex have been documented in various chronic pain conditions, such as back pain, trigeminal neuralgia, temporomandibular disorder, and functional dyspepsia, as well as in depression (D) and anxiety (A) [35].

Moreover, BMS patients show distinct brain activation patterns, including increased connectivity in the left insula, right amygdala, and right lateral orbitofrontal cortex, and decreased connectivity between the bilateral medial prefrontal cortex and the amygdala. These changes, which correlate with BMS duration, along with reduced thalamic activity, underscore the thalamus’s critical role in pain signal transmission and BMS pathogenesis [30]. Furthermore, reductions in cerebral blood flow in the middle temporal gyrus and insula have been documented, highlighting the role of altered neurovascular dynamics in BMS [35].

3.2.3 White matter hyperintensities

Recent research has identified an elevated incidence of White Matter Hyperintensities (WMHs) in specific brain regions of BMS patients, particularly in the frontal, parieto-occipital, and temporal areas. These WMHs, visible on MRI through T2-weighted or Fluid Attenuated Inversion Recovery (FLAIR) sequences, are early indicators of brain vulnerability and may signify accelerated brain aging (Fig. 3).

Fig. 3.White matter hyperintensities in a burning mouth syndrome (BMS) patient. Axial T2-weighted fluid-attenuated inversion recovery (FLAIR) images from a 63-year-old male BMS patient. (A) Axial image at supraventricular level shows multiple hyperintense gliotic foci predominantly in the frontal and parietal white matter. (B) Axial image at the level of the temporal lobes highlights hyperintense foci (white arrows) in the temporal white matter, particularly involving the mesial temporal structures.

They are associated with cerebral small vessel arteriolosclerosis and potential links to vascular dementia and neurodegenerative diseases like Alzheimer’s. The connection between chronic orofacial pain, including BMS, and WMHs remains debated, with uncertainty about whether WMHs contribute to the onset of chronic pain or exacerbate BMS symptoms [36]. A recent study by Kato et al. [23] used Diffusion Tensor Imaging (DTI) and Neurite Orientation Dispersion and Density Imaging (NODDI) to evaluate white and gray matter abnormality in BMS. The study included 14 BMS patients and 11 healthy controls, analyzing various metrics such as fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), intracellular volume fraction (ICVF), and isotropic volume fraction (ISO). Results showed that BMS patients exhibited higher FA and ICVF and lower MD and RD in widespread white matter areas, as well as higher ISO and lower MD and RD predominantly in the amygdala. These findings suggest microstructural changes in both white and grey matter, indicating alterations in myelination, astrocytic hypertrophy, and neuroinflammation, reflecting the complex pathology of BMS [23].

4. Stress and neuromodulation

Stress plays a significant role in the pathogenesis and symptom modulation of BMS. Beyond immediate adaptive responses via catecholamines and cortisol, chronic stress induces long-term neuroendocrine, immune, and epigenetic changes that affect pain perception. These include the release of pro-inflammatory cytokines, altered neural plasticity, and modulation of gene expression through mechanisms like DNA methylation and microRNAs, potentially facilitating central sensitization and hyperalgesia. Experimental studies have shown that prolonged stress can suppress dopaminergic activity in the nucleus accumbens (NAc) and alter tyrosine hydroxylase expression in the ventral tegmental area (VTA), impairing dopamine synthesis and signaling in regions involved in orofacial pain, such as the NAc, dorsal striatum, and amygdala [49]. This highlights the bidirectional relationship between stress and pain processing in BMS. Moreover, BMS patients appear particularly vulnerable to stress-induced hyperalgesia. During the COVID-19 pandemic, they exhibited increased symptom severity and distress compared to controls, including higher levels of intrusive cognitions and emotional dysregulation. Chronic stress also affects neuroendocrine biomarkers: elevated salivary cortisol and α-amylase levels have been observed in BMS patients, with reductions correlating with symptom improvement. These markers may serve as objective indicators of stress-related exacerbation in BMS.

5. Interplay of mood disorders and burning mouth syndrome

It is widely acknowledged that a dynamic interplay of psychological and neurological mechanisms plays a crucial role in the syndrome’s onset and progression, as suggested by the biopsychosocial model (Fig. 4).

Fig. 4.The biopsychosocial model of pain. This figure illustrates the integration of biological, psychological, and social factors in understanding the experience of pain. The model emphasizes that pain is influenced by a complex interplay between physiological processes (biological factors), mental and emotional states (psychological factors), and social contexts including relationships, socioeconomic status, and cultural influences (social factors). The interconnected circles represent how each dimension impacts and interacts with the others, highlighting the need for a comprehensive approach to patient care and intervention.

Mood disorders (MDs), such as A and D, and certain aberrant personality traits are often linked with conditions like fibromyalgia, irritable bowel syndrome, chronic fatigue, and notably, BMS. A pivotal study by Taiminen et al. [50] revealed that over half of the patients with BMS had experienced at least one Axis I psychiatric disorder during their lifetime, with major D being the most prevalent. Notably, a significant proportion of these psychiatric conditions preceded the onset of BMS symptoms, suggesting a potential contributory role in the pathogenesis of the syndrome. Additionally, a considerable number of patients exhibited Axis II personality disorders, particularly those within cluster C, characterized by anxious and fearful behaviors. These findings underscore the importance of comprehensive psychiatric evaluation in patients presenting with BMS symptoms [50].

6. Hormonal imbalance in BMS

Hormonal dysregulation, especially involving sex steroids, has been considered a possible contributing factor in BMS largely based on its higher prevalence in peri- and postmenopausal women. While early studies suggested that reduced estrogen may impact peripheral nerve sensitivity and salivary function, recent data remain inconclusive. For example, a recent prospective case-control study found no significant differences in salivary estrogen levels between BMS patients and healthy controls [63], while other investigations have reported reduced salivary estradiol in symptomatic postmenopausal women [68]. Experimental research has also proposed that menopause-related estrogen decline could increase pain sensitivity through upregulation of TRPV1 and NGF pathways, potentially sensitizing peripheral nerves [69]. However, such mechanisms remain largely theoretical and need further validation in clinical settings. Regarding adrenal steroids, data on dehydroepiandrosterone (DHEA) are inconsistent. Some studies suggest lower salivary DHEA levels in BMS patients, possibly reflecting chronic stress or adrenal fatigue, but other investigations have failed to confirm this association [70]. Overall, while hormonal fluctuations—particularly related to menopause—may contribute to BMS susceptibility, current evidence is mixed, and hormone replacement therapy has shown inconsistent results, suggesting that hormonal factors are likely part of a broader multifactorial etiology.

7. Association of systemic comorbidities and BMS

BMS patients frequently encounter a higher incidence of simultaneous medical comorbidities and consume more medications than controls. This scenario often results in an overall poorer health status, which can, in turn, intensify the symptoms and potentially accelerate the progression of BMS itself. MD, hypertension, hypercholesterolemia, hyperhomocysteinemia, hypothyroidism, and gastroesophageal reflux disease (GERD) are the most frequent comorbidities associated with BMS. Concerning co-occurring pain conditions, a systematic review by Moisset et al. [71] demonstrated that such comorbidities are relatively uncommon among individuals with BMS, thereby supporting the hypothesis that BMS may involve distinct pathophysiological mechanisms compared to other chronic pain disorders. Understanding the multifaceted nature of these comorbidities and their interactions with BMS is essential for developing a comprehensive and tailored treatment plan. This involves not only addressing the primary symptoms of BMS but also managing any underlying or concurrent conditions that may be contributing to the patient’s overall health challenges.

7.6 BMS in the COVID-19 pandemic

The emergence of the COVID-19 pandemic, caused by the SARS-CoV-2 virus, has introduced new complexities in understanding BMS. COVID-19 is known to affect various bodily systems and has the potential to lead to neurological symptoms, including those related to taste disturbance and burning sensation [92, 93]. Although some COVID-19 patients have reported these symptoms, establishing a direct link between the virus and BMS continues to be a subject of ongoing research. Nevertheless, it is known that the COVID-19 pandemic has notably impacted the mental and overall health of individuals, leading to increased psychological stress and limited access to healthcare services [94]. This is particularly relevant for BMS, whose symptoms can intensify under psychological stress. The constrained access to healthcare during the pandemic may have resulted in delayed diagnosis and treatment of BMS, potentially exacerbating the condition. Indeed, Candela et al. [95] reported an increase in A, worsened sleep quality, and heightened pain intensity in BMS patients. Furthermore, a study by Ottaviani et al. [96] involving 100 BMS patients and 100 healthy controls from five Italian centers highlighted significant deep loneliness in BMS patients. This loneliness correlated with factors like age, higher education, stress, lower satisfaction in relationships, and perceived social support [96]. Moreover, during the pandemic, BMS patients exhibited increased post-traumatic stress symptoms, particularly intrusive thoughts, compared to healthy controls. These patients also showed lower levels of resilience and post-traumatic growth, indicating a reduced capacity to find positive meaning and personal growth following stressful life events [96]. This suggests that BMS patients may lack adaptive coping strategies and a positive mindset, making them more vulnerable to the negative effects of future traumas. Overall, comorbidities such as mood disorders (A, D, sleep disorders) and cardiovascular risk factors (hypertension, hypercholesterolemia, hyperhomocysteinemia) alongside the emerging impact of SARS-CoV-2 infection significantly contribute to brain aging in BMS patients. These factors, particularly cardiovascular risks, lead to microvascular injury, endothelial damage, and reduced cerebral blood flow, resulting in neuroinflammation, WMHs, and cerebral atrophy. These brain alterations may further increase chronic pain, creating a detrimental cycle. Chronic pain and WMHs serve as biomarkers of brain frailty, promoting progressive brain aging, reducing neuroplasticity, and exacerbating pain perception and mood disorders (Fig. 5).

Fig. 5.Conceptual model of the interaction between comorbidities, brain aging, and central mechanisms of pain chronification in Burning Mouth Syndrome (BMS). This figure illustrates potential pathways linking common comorbidities—including cardiovascular risk factors (hypertension, hypercholesterolemia, hyperhomocysteinemia), mood and sleep disorders, and the emerging effects of SARS-CoV-2 infection—to functional and microstructural brain changes. The resulting cycle of pain and brain vulnerability may further exacerbate neuroplasticity decline and mood disturbances, promoting progressive brain aging. HTN: Hypertension; HCh: Hypercholesterolemia; HHCys: Hyperhomocysteinemia; WMHs: White Matter Hyperintensities.

8. Classification system of ICOP 2020; ICHD-3, ICD-11, and DSM-V

In the last years, the conceptualization and categorization of BMS have undergone significant changes shaped by its clinical manifestations and treatment outcomes. Multiple classification systems have been introduced to refine its definition and differentiate it from oral burning sensations linked to various local or systemic factors. These classification systems have been developed not only for accurate disease identification but also to enhance patient understanding and acceptance of their condition [77]. Establishing universally accepted diagnostic standards has been crucial for clinicians for precise disease identification and treatment strategies and for patients to benefit from a clear diagnosis framed within a globally recognized system, aiding in their understanding and acceptance of the disease.

Although there is no consensus regarding the use of a universal and unique classification for BMS, the most used classifications are:

- The International Classification Headache Society (ICHD-3) [97];

- The International Classification of Orofacial Pain (ICOP-2020) [1];

- The International Association for the Study of Pain (IASP) for the International Classification of Diseases (ICD-11) [7] (Table 2, Fig. 6).

Fig. 6.Classification and coding of burning mouth syndrome. The most used classifications for BMS with relative codes include: International Classification Headache Society (ICHD-3 beta version); International Classification of Orofacial Pain (ICOP-2020); International Association for the Study of Pain (IASP) for the International Classification of Diseases (ICD-11). BMS: Burning Mouth Syndrome; DSM-V: Diagnostic and Statistical Manual of Mental Disorders (5th Edition).

Each offers distinct perspectives on categorizing BMS based on clinical evidence and research advancements. Moreover, the ongoing updates to these classifications, readily available online, permit clinicians to evaluate changes across time.

The ICHD-3 includes BMS under the classification of “Painful Cranial Neuropathies and Other Facial Pains”. This classification defines BMS as intraoral burning or dysaesthetic sensation, recurring daily for >2 hours/day for >3 months, without clinically evident causative lesions. The pain is generally burning in character and felt superficially in the oral mucosa but the mucosa appears normal at clinical examination, and sensory testing is normal. The pain is usually bilateral; the most common site is the tip of the tongue, and it may be associated with subjective dryness of the mouth, dysaesthesia, and altered taste. Laboratory investigations and brain imaging may indicate changes in central and peripheral nervous systems. Whether secondary BMS attributed to a local (candidiasis, lichen planus, hyposalivation) or systemic disorder (medication-induced, anemia, deficiencies of vitamin B12 or folic acid, Sjogren’s syndrome, diabetes) should be considered as an entity [98].

The ICOP 2020 includes BMS in idiopathic orofacial pain and offers a more detailed and inclusive classification system for orofacial pain, aimed at improving diagnosis, treatment, and research. Differently from ICHD-3, ICOP 2020 recommends conducting somatosensory assessments to further classify BMS into subgroups based on the presence or absence of somatosensory alterations. QST is often abnormal (differentiating the two subtypes), whereas clinical sensory examination very rarely reveals slight sensory deficits however, QST currently has no definitive diagnostic value in BMS. Similarly, to ICHD-3, BMS is defined as an intraoral burning or dysaesthetic sensation, recurring daily for >2 hours/day for >3 months, without evident causative lesions on clinical examination and investigation. The pain primarily affects the tongue but may also involve other areas of the oral mucosa, such as the lips, gums, and palatal regions. Although in most patients burning is usually bilateral, on rare occasions, it is unilateral differently from ICHD-3 where all patients who reported unilateral symptoms are included in atypical facial pain. Pain/burning is associated with additional oral symptoms in two-thirds of cases such as xerostomia, dysaesthesia and altered taste. BMS is diagnosed only when all local and systemic causes have been excluded (hence, previously, primary BMS). The diagnosis of BMS in the ICOP 2020 framework requires a thorough patient history, clinical examination, and the exclusion of other possible causes of the symptoms through appropriate investigations. These may include blood tests to check for nutritional deficiencies, glycemic control, and thyroid function, as well as oral cultures and possibly imaging studies. The ICOP 2020 may also consider the impact of the disease on the patient’s quality of life and functional status and the role of psychological comorbidities frequently associated to pain, differently from ICHD-3. Moreover, this classification underscores the importance of a multidisciplinary approach to diagnosing and managing a complex condition such as BMS, which may require contributions from various healthcare professionals, including dentists, oral medicine specialists, neurologists, and psychologists, to achieve optimal patient care [1].

The IASP has contributed to the development of pain-related diagnoses in the International Classification of Diseases, 11th Revision (ICD-11), which was adopted by the World Health Organization (WHO). The ICD-11 provides a modern standard for identifying health trends and statistics globally and contains significant updates to the classification and criteria of various conditions, including chronic pain conditions like BMS. One of the pivotal advancements in ICD-11 is its refined approach to chronic pain, now recognized both as a symptom and as a distinct disease entity, complete with a supportive coding framework. A groundbreaking feature of ICD-11 is the concept of “multiple parenting”, which allows diagnostic entities to be classified under more than one category. This multifaceted approach aligns more closely with the interdisciplinary nature of medical practice, bridging gaps between specialties such as oral medicine and neurology.

According to ICD-11, BMS is classified under secondary chronic headaches (MG30.62) and more specifically coded as DA0F.0, “sensory disturbances involving the orofacial region” (Foundation ID: 618998878 in the ICD-11 browser). In this classification, BMS is characterized by an intraoral burning or dysaesthetic sensation that recurs for more than two hours per day on 50% of the days over more than three months, without evident causative lesions on clinical investigation and examination. It is characterized by significant emotional distress (A, anger/frustration, or depressed mood) or interference with orofacial functions such as eating, yawning, speaking, etc. The diagnosis is appropriate independently of identified biological or psychological contributors unless another diagnosis would better account for the presenting symptoms. It is possible to include additional codes that specify the intensity of pain/burning; the presence of psychosocial factors and the interference of pain [7].

The analysis of ICOP 2020, ICHD-3, and ICD-11 underscores the critical role of psychosocial components. Consequently, many authors have advocated for the integration of these classifications with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). This integration is particularly relevant for BMS within the framework of Somatic Symptom Disorder (SSD), as classified in the DSM-5 [99]. The DSM-5 code for SSD, 300.82 (F45.1), relates to conditions where individuals experience an intense focus on physical symptoms. These symptoms, such as the chronic burning pain characteristic of BMS, lead to substantial health-related A, disproportionate concerns about the symptoms, and significant distress or functional impairment. In the case of BMS, the emphasis on the subjective experience of distress and the extensive psychological impact, including health-related A and concern over symptoms, aligns with the SSD criteria. The persistent nature of BMS symptoms can perpetuate a cycle of distress and functional impairment, reflecting the SSD framework [99]. This alignment highlights the importance of a holistic approach to diagnosing and treating BMS. Such an approach should address not only the physical symptoms but also the psychological and social dimensions of the condition, emphasizing the integral role of psychosocial factors in the experience and management of BMS.

9. Diagnosis of BMS

The diagnosis of BMS presents a significant clinical challenge, as it requires the exclusion of other systemic or local disorders that could contribute to oral cavity pain. To accurately diagnose and treat this condition, clinicians should consider patients’ characteristics and pain characteristics at the same time [17].

Firstly, a detailed examination of the oral cavity, and extensive analysis of socio-demographic characteristics, habits, body mass index (BMI), and medical history including current medications, any history of mood disorders, systemic diseases, and familiarity with psychiatric and cognitive impairment is required for every patient (Table 3).

An extensive clinical examination should investigate signs of parafunctional habits, erythema, irritation, glossitis, atrophy of oral mucosa or tongue, mucosal ulceration or other abnormalities.

Medical history of the patients and laboratory investigation are also essential to exclude any possible local and systemic conditions causing oral burning [1]. For instance, there is a range of medications acting as potential triggers for BMS-like symptoms, such as antihypertensive drugs, particularly angiotensin-converting enzyme (ACE) inhibitors or antiretrovirals [100, 101]. It is possible to perform challenge, dechallenge, and rechallenge to determine if a medication has caused the burning sensation. This procedure is useful for establishing a causal relationship between the intake of a specific medication and the onset of burning symptoms, providing a structured methodology for identifying pharmacological triggers. A thorough medical history is necessary to assess if the burning sensation started after the introduction of a new medication, and if so, to proceed with this methodology. A detailed analysis of the pain’s characteristics—such as its onset, duration, location, and any factors that may exacerbate or alleviate it—and the presence of extraoral symptoms (medically unexplained extraoral physical symptoms) is crucial. This analysis should employ both qualitative and quantitative pain assessment tools (Table 4).

The quality of pain is often described as burning, tender, tingling, hot, stinging, scalding, numbness, discomfort, raw, unpleasant, or annoying. The intensity of pain varies from mild to severe. BMS presents as a predominantly burning, neuropathic pain with a diurnal increase in intensity, and while initially challenging, it can be successfully managed in most cases through a collaborative, empathetic approach involving the other medical colleagues [29, 102]. BMS patients generally report oral burning/pain that diffuse to the entire oral mucosa or restricted to the tongue, but it can also affect buccal mucosa, lip, floor of the mouth, gingiva, and palate or rarely burning may be unilateral. When pain is unilateral, it is essential to differentiate BMS from other orofacial pain conditions, such as persistent idiopathic facial pain (PIFP), persistent idiopathic dentoalveolar pain (PIDAP), and trigeminal neuralgia (TN) (Table 5, Ref. [1]).

The early onset of the disease is characterized by a less severe symptomatology in the morning, getting worse during the day, although generally alleviated by eating and drinking, but in a long-standing disease these criteria may be not respected [1]. Frequently, most patients report additional symptoms, such as xerostomia, alteration in taste perception, phantom taste, alteration in sensory perception, globus, and others that may differ between patients, resulting in a varying clinical presentation [5, 10, 36]. The characteristics of symptomatology are reported in Table 4. The additional symptoms frequently complicate the disease and contribute to diagnostic delay because many instrumental exams and evaluations by other specialists are required to exclude possible related local and systemic conditions with the same symptoms. Therefore, BMS may remain under-recognized and under-appreciated by both dental and medical professionals for a long time. It took an average of 30 months from the onset of symptoms until a definitive diagnosis of BMS was achieved and every patient consulted almost three specialists, receiving several misdiagnoses before a proper diagnosis [5]. Additionally, the somatosensory screening tests may be considered to assess sensory nerve dysfunction in BMS patients. A thorough assessment should also include the metabolic profile evaluation through hematological tests, to rule out the nutritional, hormonal, autoimmune, and thrombophilia conditions that may underlie or contribute to symptoms. The laboratory tests required in BMS patients are available in (Table 6).

Comprehensive diagnostic screening for nutritional deficiencies and anemia is imperative because deficits in ferritin, iron, vitamin B12, folate, and zinc are often present in iron-deficiency anemia and vitamin B12-deficiency anemia. These conditions can lead to a secondary form of oral burning. Therefore, when deficiencies are identified, targeted treatment to correct them is crucial. This typically involves supplementation and dietary modifications to replenish the deficient micronutrients [92]. Upon correcting these deficiencies, a careful reassessment of the patient’s symptoms is necessary to determine whether the oral burning has resolved or improved. This step is important as it can help differentiate between a secondary burning related to nutritional deficits and BMS, where the symptoms may not respond to nutritional supplementation.

Similarly, hyperhomocysteinemia is a condition frequently observed in patients with BMS. It is often associated with folate deficiency, as well as vitamins B6 and B12, all of which are necessary for homocysteine metabolism [103]. Management of hyperhomocysteinemia includes supplementation with these vitamins, and it’s critical to monitor the patient’s response to treatment because hyperhomocysteinemia is a risk factor for various neurodegenerative and vascular brain pathologies, including increased stroke risk, cognitive decline, dementia, and mood disorders through mechanisms such as oxidative stress, endothelial dysfunction, excitotoxicity, and impaired methylation processes [104, 105, 106, 107]. Specifically, testing for mutations in the Methylenetetrahydrofolate Reductase (MTHFR) gene (C677T and A1298C) is advised in patients with hyperhomocysteinemia exhibiting suboptimal responses to vitamin B supplementation. Such mutations can affect the metabolism of homocysteine and, by extension, influence the patient’s response to treatment.

Additionally, when an MRI of the brain reveals a high burden of WMHs that cannot be accounted for by common risk factors, such as hypertension or aging, genetic testing may uncover a predisposition to vascular disorders that impair cerebral blood flow. This is particularly relevant in patients with a history of deep vein thrombosis, pulmonary embolism, pre-eclampsia, or recurrent miscarriages, where an underlying thrombophilic condition might exist.

In all cases, genetic tests should be considered as part of a comprehensive evaluation that includes a detailed clinical examination, patient’s medical history, and if necessary, genetic counseling. It is crucial to interpret the results within the overall clinical context of the patient and not in isolation. A Comprehensive Evaluation of Coagulation Parameters in the context of BMS is meticulously detailed in the Tables 6 and 7, with a particular focus on the modifications of test results in patients who are undergoing treatment with antiplatelet agents and blood thinners, which are commonly prescribed for individuals with BMS.

Recently, Kishore and collaborators have proposed using NSE as a novel biomarker for peripheral neuropathies. Found in neurons and neuroendocrine cells, NSE plays a crucial role in glycolysis. Its utility in clinical diagnostics lies in its ability to indicate neuronal damage, making it a valuable tool for assessing various neuropathic conditions. Incorporating NSE measurement into the screening process for peripheral neuropathies allows clinicians to detect early signs of neuronal damage, thereby facilitating timely intervention and management [47].

Clinicians should perform an electrocardiogram (ECG) before starting pharmacological treatment, especially when prescribing psychotropic drugs. The ECG helps to identify cardiovascular risks, such as prolonged QT interval, conduction disorders, or cardiac ischemia, which may affect treatment decisions. QTc prolongation (normal: <430 ms in men, <450 ms in women; borderline: 430–450 ms in men, 450–470 ms in women; prolonged: >450 ms in men, >470 ms in women) is often drug-induced and is a known risk factor for torsades de pointes, a potentially fatal arrhythmia [108].

Many psychiatric drugs, including some antipsychotics and antidepressants, are known to potentially cause QT interval prolongation. A baseline ECG can establish whether the patient has a prolonged QT interval before treatment initiation, allowing the physician to make informed decisions regarding the prescription. The incidence of this adverse event is unpredictable, but a common observation is that most patients have at least one identifiable risk factor in addition to antidepressants exposure, such as female gender, age older than 60 years, hypokalemia, and a previous diagnosis of cardiovascular disease [109]. Therefore, the Food and Drug Administration recommends evaluating periodic ECG monitoring in all patients who begin treatment with these drugs with monitoring of the electrolytes, especially potassium [110]. Following this initial assessment, imaging techniques, particularly MRI of the brain, the brain stem, and the maxillofacial area should be employed as supplementary tools. MRI of the brain and brain stem can help identify any central nervous system pathology, such as WMHs [36] or space-occupying lesions [111] which are vital for a comprehensive understanding of the patient’s condition.

For cases presenting with unilateral and localized burning sensations on the gingiva, orthopantomography (OPT) and Cone Beam Computed Tomography (CBCT) of the jaw are recommended. These imaging modalities are essential for ruling out dental causes of pain, including local infections of the jaw, which might mimic or exacerbate BMS symptoms. Further, in the assessment of BMS, particularly when patients report symptoms of dry mouth, it is crucial to include comprehensive immunological testing as part of the diagnostic workup. The assessment should encompass Antinuclear Antibodies (ANA), Extractable Nuclear Antigen Antibodies (ENA; anti-SSA: Anti-Sjögren’s-syndrome-related antigen A; anti-SSB: Anti-Sjögren’s-syndrome-related antigen B), and C-reactive protein (CRP) levels. Elevated levels of these markers can be instrumental in unveiling underlying immunological conditions, notably Sjogren’s Syndrome. Routine ANA testing is not recommended in BMS patients without xerostomia or other clinical signs suggestive of systemic autoimmune disease. Targeted ANA testing may be considered in selected patients with additional risk factors or symptoms [112]. The presence of these antibodies, alongside raised CRP levels, points to an autoimmune process that may be contributing to the patient’s symptoms, necessitating further evaluation. Imaging studies of the salivary glands, such as sialography, scintigraphy, salivary gland ultrasonography, or MRI of the salivary glands, become essential in this context. These imaging modalities offer valuable insights into glandular structure and functionality, helping to distinguish between objective xerostomia—where there is a quantifiable decrease in salivary flow—and subjective xerostomia, where patients perceive dryness without a measurable reduction in saliva production [113, 114].

In patients that report globus or exhibit erythematous lesions of the soft palate or dental erosions, these may indicate an underlying GERD. In such cases, a consultation with a gastroenterologist is mandatory to address and manage the potential reflux contributing to BMS [81, 85]. By adhering to this structured diagnostic approach, healthcare professionals can ensure a comprehensive evaluation of BMS, addressing both the primary symptoms and any underlying or contributing conditions. This meticulous attention to detail ensures that treatment strategies are well-informed and tailored to the individual needs of the patient, thereby improving outcomes and patient satisfaction.

10. Multidimensional clinical assessment of BMS: insights from IMMPACT

In the early 2000s, the international pain research community identified a critical gap: the lack of standardized outcome measures in chronic pain studies. This led to the establishment of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) [115], which introduced a set of core outcome domains designed to capture the multidimensional nature of pain—including its intensity, as well as its physical, emotional, and social impacts. While IMMPACT recommendations were originally developed for clinical trials, they can also guide and enrich the clinical evaluation of complex pain conditions such as BMS, promoting a more comprehensive understanding of each patient’s experience and needs.

This is not intended as a recommendation to routinely administer all the listed questionnaires to every patient. Rather, it encourages clinicians to adopt a flexible, patient-centered approach, choosing appropriate tools based on clinical judgment and the patient’s presentation. Table 8 summarizes validated instruments used in research and selectively applicable in clinical settings to deepen the assessment of BMS-related impairment.

IMMPACT recommends evaluating chronic pain patients across six core domains: pain intensity, physical functioning, emotional well-being, participant ratings of improvement and satisfaction with treatment, adverse events, and participant disposition (including adherence and reasons for treatment withdrawal). This framework is particularly relevant to BMS, where symptoms extend beyond pain intensity and may affect multiple aspects of life.

Suggested tools for each domain include:

• Pain Intensity (Domain 1): Numerical Rating Scale (NRS), Visual Analog Scale (VAS).

• Physical Functioning (Domain 2): Multidimensional Pain Inventory (MPI), Brief Pain Inventory (BPI), Pain Disability Index (PDI), which assess the impact of pain on activity, mood, relationships, sleep, and quality of life.

• Emotional Functioning (Domain 3): Hospital Anxiety and Depression Scale (HADS), Beck Depression Inventory (BDI), Profile of Mood States (POMS).

• Global Improvement and Satisfaction (Domain 4): Patient Global Impression of Change (PGIC).

• Symptoms and Adverse Events (Domain 5): Typically captured through clinical interviews and patient reports.

• Participant Disposition (Domain 6): Information on treatment adherence and reasons for discontinuation, gathered via structured interviews or questionnaires.

IMMPACT also highlights the importance of additional domains such as sleep disturbances, fatigue, and the emotional burden of chronic pain, which—although not part of the core domains—are highly relevant for BMS patients. Moreover, emerging evidence suggests a potential link between cognitive impairment and BMS, supporting the integration of cognitive screening into the clinical evaluation. Instruments such as the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) provide valuable screening for cognitive deficits and can guide the need for more comprehensive neuropsychological evaluation when indicated. Incorporating selected IMMPACT-based assessments and cognitive screening into routine BMS management fosters a holistic understanding of the condition, enabling more personalized treatment planning and improving quality of life.

11. Conclusions

BMS is a painful condition that necessitates careful evaluation for accurate diagnosis. It is essential to differentiate BMS from other orofacial pain conditions particularly when the pain is unilateral. Additionally, it is crucial to distinguish primary BMS from secondary forms of burning sensations. This distinction is vital as each of these conditions may require different therapeutic approaches. An accurate diagnosis involves considering a range of diagnostic tools including MRI of the brain, blood tests, and cognitive and psychological assessments. These evaluations help to provide a comprehensive understanding of the patient’s condition, leading to appropriate treatment, improved pain management, and enhanced quality of life.

Availability of data and materials

The data are contained within this article.

Author contributions

FC and DA—conception and design, acquisition of data. GO and GS—analysis and interpretation of data. EC, NGA and MDM—been involved in drafting the manuscript or revising it critically for important intellectual content. GO—agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors given final approval of the version to be published. All authors should have participated sufficiently in the work to take public responsibility for appropriate portions of the content.

Ethics approval and consent to participate

Not applicable.

Acknowledgment

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Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest.