Materiały źródłowe

• #1 Burning Mouth Syndrome: Aetiopathogenesis and Principles of Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5664327/

  Burning mouth syndrome (BMS) is a chronic debilitating oral condition characterised by a burning sensation of the oral mucosa in an otherwise apparently normal person. Its aetiology and pathogenesis are obscure, but both psychogenic factors and peripheral and central neuropathies appear to be implicated. […] In order to improve treatment outcomes, a better understanding of the pathogenesis of this syndrome might provide a basis for the development of more effective management strategies. […] In the pathogenesis of BMS, apart from psychogenic factors, both peripheral and central neuropathies appear to play a role, but the balance between central and peripheral neuropathies varies from case to case. […] It is probable that genetic and environmental factors play an important role in determining individual differences in the experience of pain.

• #2 Burning Mouth Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK519529/

  Burning mouth syndrome (BMS) is characterized by burning pain in normal-appearing oral mucosa lasting at least four to six months. The condition is idiopathic, and the underlying pathophysiology is not well understood. […] The pathophysiology behind BMS is poorly understood and may be related to psychogenic and neuropathic pathways. Disruptions in circadian rhythm, chronic anxiety, disruptions in the hypothalamic-pituitary-adrenal axis, irritants, infection, and diabetes mellitus are thought to contribute to its development. The underlying type of pain conduction is likely throughout the trigeminal distribution, and there is evidence of histopathologic changes in nociceptive nerves in patients displaying symptoms. […] Studies have shown an association of BMS with Axis I and Axis II psychiatric disorders, psychiatric illness, structural and functional changes in the nervous system, and disruption of the circadian rhythm. Disruptions in the circadian rhythm affect pain perception and mood and can disrupt the hypothalamic-pituitary-adrenal axis.

• #2 Burning Mouth Syndrome: Aetiopathogenesis and Principles of Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5664327/

  In persons with BMS who are anxious or depressed and who do not have immediate relief after local anaesthetic regional nerve block, or after topical treatment with capsaicin or with clonazepam, central neuropathy is probably the dominant mechanism of the pain. […] Several neuronal dysfunctions are linked to BMS pain. The lingual mucosa exhibits a decreased number of small-diameter nerve fibres; the remaining small-diameter nerve fibres show upregulation of the transient receptor potential subfamily member V 1 (TRPV1) ion channel, and upregulation of the P2X3 receptors and of nerve growth factor (NGF). These explain the role of trigeminal small-fibre sensory neuropathy in the pathogenesis of BMS. […] It has been further proposed that downregulation of central dopaminergic pain-inhibitory pathways also plays a role in the pathogenesis of BMS, particularly in persons with anxiety or depression, which are both associated with dysregulation of central mood-mediating dopaminergic pathways.

• #3 Is Burning Mouth Syndrome Based on a Physiological Mechanism which Resembles that of Neuropathic Pain?

  https://www.redalyc.org/journal/4995/499566080003/html/

  Burning mouth syndrome (BMS) is a chronic intraoral pain state that has been described as burning pain, tingling or numbness in the oral mucosa, in the absence of any organic disease. […] Relevant studies links BMS to a peripheral neuropathy and BMS patients have revealed distinct abnormalities within the trigeminofacial large and small fiber systems and the trigeminal brainstem complex. […] Recent studies using several relevant, objective neurophysiologic or psychophysical methods, such as blink reflex (BR) and thermal quantitative sensory testing (tQST) as well as neuropathological, neurobiological, and functional brain imaging techniques, have provided convincing evidence for neuropathic involvement in the pathophysiology of primary BMS. […] Evidence in the literature links BMS to a peripheral neuropathy.

• #3 Is Burning Mouth Syndrome Based on a Physiological Mechanism which Resembles that of Neuropathic Pain?

  https://www.redalyc.org/journal/4995/499566080003/html/

  Regarding peripheral neuropathic mechanisms, blink reflex recordings with stimulation of the distal branches of the third trigeminal division in primary BMS patients have revealed distinct abnormalities within the trigeminofacial large and small fiber systems and the trigeminal brainstem complex. […] Although BMS pathophysiology may involve hormonal and psychosocial factors, it is considered a neuropathic pain state. […] We can conclude that overall, BMS patients display brain activations patterns similar to those of patients with neuropathic pain conditions.

• #4 Neuropathic and Psychogenic Components of Burning Mouth Syndrome: A Systematic Review

  https://www.mdpi.com/2218-273X/11/8/1237

  The pathophysiology of primary burning mouth syndrome (BMS) has been extensively debated but is poorly understood despite a large number of hypotheses attempting to explain its etiopathogenic mechanisms. […] In recent decades, it has been shown that several neuropathic mechanisms may contribute to the primary BMS pathophysiology. Indeed, neurophysiologic, psychophysical and functional imaging studies have suggested pathophysiological alterations at different levels of the neuraxis, and BMS is currently considered to be a neuropathic pain affecting the central and peripheral nervous systems. […] The peripheral nervous system seems to be implicated in BMS development, as shown by Laurie et al., Yilmaz et al., Penza et al. and Puhakka et al., where the analysis of tongue biopsies showed that patients with BMS had a significantly lower intraepidermal and epithelial nerve fibre density than healthy subjects, suggesting small fibre neuropathies.

• #4 Neuropathic and Psychogenic Components of Burning Mouth Syndrome: A Systematic Review

  https://www.mdpi.com/2218-273X/11/8/1237

  fMRI studies have explored the implications of the central nervous system and support the hypothesis of a neuropathic aetiology of BMS; indeed, patients with BMS display structural and functional deficits in key brain regions associated with pain perception and they frequently show morphofunctional changes, suggesting a neurogenic basis of BMS, but some also show markers of depression. […] Moreover, some authors explored the neuropathic component with studies based on neuropathic pain questionnaires (PainDETECT, DN4, and DN4i) and found arguments in favour of neuropathic pain. […] Both neurogenic and psychogenic components may be involved in the pathophysiology of BMS.

• #5 Burning Mouth Syndrome: Aetiopathogenesis and Principles of Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5664327/

  In persons with BMS who are anxious or depressed and who do not have immediate relief after local anaesthetic regional nerve block, or after topical treatment with capsaicin or with clonazepam, central neuropathy is probably the dominant mechanism of the pain. […] Several neuronal dysfunctions are linked to BMS pain. The lingual mucosa exhibits a decreased number of small-diameter nerve fibres; the remaining small-diameter nerve fibres show upregulation of the transient receptor potential subfamily member V 1 (TRPV1) ion channel, and upregulation of the P2X3 receptors and of nerve growth factor (NGF). These explain the role of trigeminal small-fibre sensory neuropathy in the pathogenesis of BMS. […] It has been further proposed that downregulation of central dopaminergic pain-inhibitory pathways also plays a role in the pathogenesis of BMS, particularly in persons with anxiety or depression, which are both associated with dysregulation of central mood-mediating dopaminergic pathways.

• #5 Burning Mouth Syndrome: Aetiopathogenesis and Principles of Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5664327/

  Thus, central sensitization characterised by structural and functional neural plasticity results in increased excitability and increased tonic activity of central nociceptive neurons, playing an important role in the pathogenesis of BMS. […] This suggests that the neural pathogenic mechanisms of BMS are distinct, probably localised somewhere in the trigeminal nerve pathway.

• #6 Burning mouth syndrome

  https://www.wjgnet.com/1007-9327/full/v19/i5/665.htm

  Burning mouth syndrome is a debilitating medical condition affecting nearly 1.3 million of Americans. Its etiology is largely multifactorial, and associated medical conditions may include gastrointestinal, urogenital, psychiatric, neurologic and metabolic disorders, as well as drug reactions. Its pathophysiology has not been fully elucidated and involves peripheral and central neuropathic pathways. The pathophysiology of BMS has not been fully elucidated. Various studies have shown significant differences in thermal and nociception thresholds of patient with BMS compared to control subjects. Thus, a neuropathic mechanism for BMS is currently favored. However, controversy remains over whether a peripheral or central dysfunction is responsible for BMS. Evidence in the literature links BMS to a peripheral neuropathy. Superficial biopsies of the anterolateral tongue from BMS patients showed a significantly lower density of epithelial and subpapillary nerve fibers than controls. Morphologic changes were consistent with axonal degeneration. This supports a trigeminal small-fiber sensory neuropathy or axonopathy. Moreover, Borelli et al found increased levels of nerve growth factor, a neuropeptide vital to nociceptive function in adults, in the saliva of BMS subjects. Other histopathologic studies of patients with BMS have shown increased density of TRPV1 ion channels and P2X3 receptors on scattered nerve fibers, a finding previously linked to hypersensitivity and neuropathic pain symptoms in various models of human pain conditions. Additionally, dysfunction of the chorda tympani branch of the facial nerve may be involved in the pathogenesis of BMS. Patients with BMS will report improved symptoms with eating, suggesting that stimulation of the gustatory system decreases pain sensation. Finally, increased excitability or inhibition of the trigeminal system has been implicated as patients with BMS have greater alterations in blink reflexes compared to normal subjects. However, recent evidence indicates that dysfunction in the central nervous system can also cause BMS. Albuquerque et al showed that BMS patients process thermal and pain stimulation in the brain differently than pain-free individuals as demonstrated by functional magnetic resonance imaging of the thalamus. Additionally, the dysregulation of the nigrostriatal dopaminergic system has been implicated in BMS. As evident from these studies, the pathophysiology of BMS is highly complex, likely involving neural pathways at different levels of neuraxis. A recent double blind, randomized cross-over study of postmenopausal women showed heterogeneity of the response of BMS symptoms to lingual nerve block with lidocaine. If fact, it may lead to an effective increase, decrease, or an unchanged burning pain in patients, an effect attributed to variation in central, peripheral, or combined neurological pathways in pathogenesis of BMS. The symptoms of BMS can result from subclinical insults at various points in the nervous system, presenting with instant or gradual bilateral distribution. Recent classification suggests a possible overlap of three distinct subclasses in BMS: a peripheral oral small fiber neuropathy (50%-60% of cases), subclinical major trigeminal neuropathy (20%-25%), and central deficiency in dopaminergic top-down inhibition (20%-40%).

• #7 Treatment for Burning Mouth Syndrome: A Clinical Review

  https://www.journalomp.org/view.html?uid=1228&&vmd=Full

  Burning mouth syndrome (BMS) is a chronic idiopathic orofacial pain. BMS is currently classified as a neuropathic pain condition, but it is difficult to pinpoint the precise neuropathic mechanisms involved in each patient. […] From the great advances in the understanding of the etiology and pathogenesis of BMS, it is accepted that BMS is neuropathic pain. Chronic anxiety, menopause, neurotoxic agents, and genetic susceptibility such as dopamine D2 receptor polymorphism have all been implicated as causes of BMS. Many studies have indicated that peripheral and central neuropathic mechanisms are involved in the genesis of BMS. Large myelinated A afferent damage in the trigeminal nerve or its brainstem circuits, as well as decreased A fiber signaling with relatively normal C fiber function, are linked to taste changes and ongoing burning pain in BMS. Tongue biopsy revealed that peripheral sensitization was caused by increased expression of nerve growth factor, transient receptor potential vanilloid 1, and P2X3 receptor. Central neuropathic mechanisms in BMS are associated with hypofunction of the central dopaminergic system in the basal ganglia and decreased endogenous inhibitory control. Patients of BMS with central neuropathic mechanisms often seem to have associated psychiatric disorders such as depression and anxiety.

• #8 Treatment for Burning Mouth Syndrome: A Clinical Review

  https://www.journalomp.org/journal/view.html?doi=10.14476/jomp.2023.48.1.11

  Burning mouth syndrome (BMS) is a chronic idiopathic orofacial pain. BMS is currently classified as a neuropathic pain condition, but it is difficult to pinpoint the precise neuropathic mechanisms involved in each patient. […] From the great advances in the understanding of the etiology and pathogenesis of BMS, it is accepted that BMS is neuropathic pain. Chronic anxiety, menopause, neurotoxic agents, and genetic susceptibility such as dopamine D2 receptor polymorphism have all been implicated as causes of BMS. Many studies have indicated that peripheral and central neuropathic mechanisms are involved in the genesis of BMS. Large myelinated A afferent damage in the trigeminal nerve or its brainstem circuits, as well as decreased A fiber signaling with relatively normal C fiber function, are linked to taste changes and ongoing burning pain in BMS.

• #8 Treatment for Burning Mouth Syndrome: A Clinical Review

  https://www.journalomp.org/journal/view.html?doi=10.14476/jomp.2023.48.1.11

  Central neuropathic mechanisms in BMS are associated with hypofunction of the central dopaminergic system in the basal ganglia and decreased endogenous inhibitory control. Patients of BMS with central neuropathic mechanisms often seem to have associated psychiatric disorders such as depression and anxiety.

• #9 Burning Mouth Syndrome: Practice Essentials, Anatomy and Physiology, Pathophysiology

  https://emedicine.medscape.com/article/1508869-overview

  A study by Tan et al found neurologic differences between patients with burning mouth syndrome (BMS) and controls. […] The investigators suggested that an association exists between such connectivity, as well as between the VMPFC gray matter volume, and the number of years a patient has had burning mouth syndrome (BMS). […] One small study proposed that unilateral chorda tympani (taste) hypofunction results in lingual nerve (somatosensory) hyperfunction by disruption of a centrally mediated equilibrium between the two. […] It would tend to account both for pain and for gustatory disturbances in burning mouth syndrome (BMS). […] Studies focusing on trigeminal nerve alterations have found both hypersensitivity and hyposensitivity as well as large and small fiber neuropathy. […] These studies suggest that burning mouth syndrome (BMS) may have multiple etiologies producing similar symptoms.

• #9 Burning Mouth Syndrome: Practice Essentials, Anatomy and Physiology, Pathophysiology

  https://emedicine.medscape.com/article/1508869-overview

  Xerostomia in burning mouth syndrome (BMS) is likely related to neuropathy, rather than glandular dysfunction. […] Burning mouth syndrome (BMS) has been associated with oral parafunctional habits such as bruxism, clenching, and tongue thrusting. […] Although psychogenesis is no longer regarded as the primary cause, it may exacerbate symptoms. […] Burning mouth syndrome (BMS) is also associated with a higher incidence of gastrointestinal and urogenital disease, the significance of which is still unclear.

• #10 Burning Mouth Syndrome | AAFP

  https://www.aafp.org/pubs/afp/issues/2002/0215/p615.html

  Supertasters would be more likely to be affected by burning pain syndrome because of their higher density of taste buds, each of which is surrounded by a basket-like collection of the pain neurons of the trigeminal nerve. […] It has been suggested that damage to taste might also be associated with loss of central inhibition of trigeminal-nerve afferent pain fibers, which can lead to oral burning symptoms.

• #11 Burning Mouth Syndrome – Indian Journal of Palliative Care

  https://jpalliativecare.com/burning-mouth-syndrome/

  Central neuropathic mechanisms have been demonstrated following thermal stimulation of the trigeminal nerve in patients with BMS. Patients with BMS show patterns of cerebral activity similar to those that appear in other neuropathic pain disorders, suggesting that the cerebral hypoactivity could be an important element in the pathogenesis of BMS. […] The possible theories behind the cause of BMS are enlisted here: Abnormal interaction between the sensory functions of facial and trigeminal nerves. According to this theory, certain individuals labeled as supertasters (mainly females) due to the high density of fungiform papilla present on the anterior aspect of tongue, are at risk of developing burning pain. […] Sensory dysfunction associated with small and/or large fiber neuropathy. Forssell et al. found that almost 90% of individuals with BMS had some form of altered sensory threshold and/or blink reflex reaction. Immunohistochemical and microscopic observations revealed axonal degeneration of epithelial and subpapillary nerve fibers in the affected epithelium of the oral mucosa.

• #11 Burning Mouth Syndrome – Indian Journal of Palliative Care

  https://jpalliativecare.com/burning-mouth-syndrome/

  Centrally mediated alteration in the modulation of nociceptive processing. This theory explains the fact that resulting in reduced central pain suppression in BMS individuals. […] Disturbances in the autonomic innervation and oral blood flow. […] Chronic anxiety or stress results in the alteration of gonadal, adrenal, and neuroactive steroid levels in skin and oral mucosa.

• #12 Central mechanisms in burning mouth syndrome involving the olfactory nerve: a preliminary study | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-central-mechanisms-in-burning-mouth-S1807593222015095

  Burning mouth syndrome (BMS) is characterized by a continuous sensation of burning or heat in the oral cavity, mainly on the tongue, palate and/or gingiva, in the absence of a primary cause. […] There is no defined etiology for BMS other than precipitating causative factors, and it is still considered idiopathic. One of the most widely accepted theories is that the partial or total loss of chorda tympani (facial) nerve function disinhibits the trigeminal nerve, resulting in pain along trigeminal pathways, as both taste and pain systems are regulated by interneurons of the central nervous system (CNS). […] This study presents evidence that supports the theory that the neuropathic mechanisms underlying BMS involve the somatosensory, gustative and olfactory pathways. […] Thus, these findings support the notion that central sensitization is involved in the physiopathology of this disease.

• #12 Central mechanisms in burning mouth syndrome involving the olfactory nerve: a preliminary study | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-central-mechanisms-in-burning-mouth-S1807593222015095

  The pathophysiology is complex because of the overlapping of cortical areas that receive afferents with trigeminal and gustative inputs. […] It is possible that in BMS, there is a malfunction in warmth detection that leads to a pain sensation and, when it becomes chronic, induces other somatosensory, gustative and olfactory disturbances through central mechanisms, including neuroplasticity at the cortical areas responsible for sensory interaction. […] In conclusion, this preliminary study shows evidence of abnormal thresholds for pain, tactile, warmth perception, olfaction and gustation. Given these results and previous results in the literature, we propose a phantom heat sensation involving central pathophysiology as a mechanism in BMS.

• #13 An updated review on pathophysiology and management of burning mouth syndrome with endocrinological, psychological and neuropathic perspectives. – International Association for the Study of Pain (IASP)

  https://www.iasp-pain.org/publications/pain-research-forum/papers-of-the-week/paper/112783-updated-review-pathophysiology-and-management-burning-mouth-syndrome-endocrinological/

  Burning mouth syndrome (BMS) is a chronic orofacial pain disorder of unknown cause. […] Atrophy of small nerve fibers in the tongue epithelium has been reported, and potential neuropathic mechanisms for BMS are now widely investigated. […] Neuroprotective steroids and glial cell line-derived neurotrophic factor family ligands may have pivotal roles in the peripheral mechanisms associated with atrophy of small nerve fibers. […] With regard to the central mechanism of BMS, depletion of neuroprotective steroids alters the brain network related mood and pain modulation. […] Peripheral mechanistic studies support the use of topical clonazepam and capsaicin for the management of BMS, and some evidence supports the use of cognitive behavioral therapy. […] Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) may have important benefits, and well-designed controlled studies are expected.

• #14 Effectiveness of Pregabalin for Treatment of Burning Mouth Syndrome

  https://www.cpn.or.kr/journal/view.html?doi=10.9758/cpn.2019.17.1.139

  Burning mouth syndrome (BMS) is classified in painful cranial neuropathies and other facial pains section (part 3) in the International Classification of Headache Disorders III-beta (ICHD-III-beta). In this classification it is defined as an intraoral burning or dysesthetic sensation, recurring daily for more than 2 hours/day over more than 3 months, without clinically evident causative lesions. The pathogenesis of BMS is still unclear. For this reason, recently it is considered that BMS has multifactorial etiology with enigmatic pathophysiology. Several hypotheses have been put forward with the reason of many findings revealed in the literature; neuropathic mechanism, hormonal alterations, psychologic mechanism. These findings in the literature are as follows: Lower density of epithelial and subpapillary nerve fibers of tongue reflecting trigeminal small fiber sensory neuropathy and axonopathy; changes in saliva composition, mucosal blood flow and cell morphology; intensely decreasing of neurosteroids following falls of systemic steroids; damage to any special sensory nerve responsible for taste sensation (glossopharyngeal, vagus, chorda tympani, greater petrosal nevre) and hence probably impairing central inhibitory activity on the trigeminal system; pathologic responses of blink reflexes again indicating subclinical trigeminal neuropathy; impairment in autonomic system findings which are similar to those found in Parkinson disease that exhibited by autonomic nervous function studies and reduction in dopamin levels in nigrostriatal neurons displayed by PET studies suggesting involvement of the central dopaminergic system; thalamic hypo-activation demonstrated by functional magnetic resonance imaging supporting that loss of central inhibitor mechanism, etc.

• #15 Dopamine agonist responsive burning mouth syndrome: Report of eight cases

  https://www.wjgnet.com/2307-8960/full/v9/i23/6916.htm

  Burning mouth syndrome (BMS) is characterized by burning sensation of the oral mucosa in the absence of clinically apparent mucosal alterations, and it mainly affects the tongue. According to recent studies, the prevalence of BMS ranges from 1.0% to 3.7%, and it is more common in women, with the highest prevalence in postmenopausal women. BMS causes great harm to the physical and mental health of patients; however, there is a lack of rapid and effective treatment due to the unclear pathogenesis. […] In recent years, a special subtype of BMS has been reported, in which oral burning is mild in the morning and severe in the evening, and alleviated or even relieved after chewing, speaking, and other oral activities. Some patients also suffer from restless legs syndrome (RLS), and are sensitive to dopaminergic drugs. The researchers concluded that the subtype of BMS was a variant of RLS after summarizing its characteristics and therapeutic effects.

• #16 Dopamine agonist responsive burning mouth syndrome: Report of eight cases

  https://www.wjgnet.com/2307-8960/full/v9/i23/6916.htm

  BMS that is sensitive to dopaminergic drugs has the clinical characteristics of both BMS and RLS. The underlying reason is that BMS and RLS share some of the same pathogenesis. In recent years, a number of studies have shown that a variety of oral discomfort in patients with BMS is related to central nervous system lesions, among which the deficiency of dopamine inhibition function plays a prominent role. […] The results of these two studies suggest that the loss of striatal dopamine system inhibition is related to the occurrence of BMS. Similarly, a large number of studies have shown that dopamine neurotransmitter reduction or dopamine receptor dysfunction play a key role in RLS. […] Therefore, abnormal dopaminergic system plays an important role in the occurrence and development of both BMS and RLS.

• #17 “Burning mouth syndrome in Parkinson’s disease: dopamine as cure or cause?” Letter to the Editor Reply | The Journal of Headache and Pain | Full Text

  https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1007/s10194-012-0487-9

  We appreciate Drs. Fortuna and Pollios interest in our case report describing a woman with Parkinsons disease who developed burning mouth syndrome (BMS) with carbidopa/levodopa therapy that resolved after its discontinuation and initiation of a dopamine agonist. […] The intent of reporting our case was not to define the syndrome, but instead to contribute anecdotal evidence to the hypothesis that the pathophysiology of BMS is related to dopamine dysregulation. […] Our speculation is that carbidopa/levodopas central action led to the neurophysiological manifestations of BMS. […] The value in our case is related to deeper consideration of the underlying pathogenesis of BMS.

• #18 Therapeutic effects of clonazepam in patients with burning mouth syndrome and various symptoms or psychological conditions | Scientific Reports

  https://www.nature.com/articles/s41598-023-33983-6

  Clonazepam significantly improved burning pain in BMS patients who had taste disturbances. […] Clonazepam is known as an agent for the inhibitory neurotransmitter gamma-amino butyric acid (GABA), and GABA receptors are distributed in the oral pain and taste signaling pathways. Therefore, clonazepam may have the effect of reducing burning pain in the oral cavity. […] A loss of taste inhibition by central structures that mediate oral pain has been proposed to explain BMS development. Repetitive nociceptive inputs against a background of peripheral neuropathy eventually elicit central sensitization and other changes. Grushka proposed that BMS reflects the persistent breakdown of an intrinsic equilibrium caused by a reduction in corda tympani function; subsequently, lingual nerve inhibition and central sensitization tend to occur. Multiple studies have revealed damage to the innervation areas of the corda tympani and glossopharyngeal nerves in BMS patients; these areas control bitter taste. Such selective inhibition may reflect the loss of central pain inhibition. Among our patients with taste disturbances, most of them showed changes in bitter taste; these patients responded best to treatment, supporting the selective inhibition hypothesis described above. Although the role of taste in terms of oral burning syndrome is complex, clonazepam is an agonist of the inhibitory neurotransmitter GABA, which is active in the oral mucosa, mandible, palate, and salivary gland. Above all, it can be noted that it also acts on the taste pathway. If burning causes taste disturbances that result in the loss of normal inhibition of a central structure that mediates oral pain, GABA-specific agents may relieve such pain. We found that the pain VAS scores improved significantly after treatment in patients with taste disturbances. Based on the contents described above, we assume that when taste change accompanies the treatment response, there is a better effect on pain improvement.

• #18 Therapeutic effects of clonazepam in patients with burning mouth syndrome and various symptoms or psychological conditions | Scientific Reports

  https://www.nature.com/articles/s41598-023-33983-6

  Burning mouth syndrome (BMS) is a complex disorder, usually present in older women (1.55.5% of older women), and is characterized by pain and a burning sensation in the mouth but no visible mucosal abnormality. The principal symptom is pain, often accompanied by oral dryness (xerostomia) and dysgeusia. Further, BMS is often associated with psychological issues (depression or anxiety), hormonal changes, local effects (lichen planus or candidiasis), and systemic dysfunctions. Although many authors have studied BMS pathogenesis, the etiology remains unclear but is probably multifactorial, involving complex interactions between local, systemic, and/or psychogenic factors. BMS has been divided into two types: spontaneous (or primary) BMS, and Secondary BMS may be caused by complex interactions between local factors (e.g., hyposalivation) or systemic/psychogenic factors, but a clear definition of secondary BMS remains elusive. Based on recent findings, primary BMS is now believed to be a form of neuropathic pain. With respect to secondary BMS, there are findings for local or systemic factors. Among them, many studies have focused on psychologic issues, hyposalivation, and disturbance of the taste sensory pathway as causes of BMS. Depressive mood (in up to 35% of patients) or anxiety trait (in up to 50% of patients) have been reported frequently in BMS patients. In addition, approximately 25% of BMS patients exhibit xerostomia, and two-thirds of patients report taste disturbances. However, the exact cause has not been proven to date. Thus, diagnosis and management remain challenging, and the responses to various treatments have been inconsistent and limited. In the meantime, several studies have been conducted on the treatment of BMS; representative examples include clonazepam therapy, which has demonstrated relatively consistent therapeutic effects. However, compared to the frequent accompaniment of xerostomia and taste change or psychogenic factors in BMS patients, studies on the therapeutic effect of clonazepam in the presence of these medical conditions or comorbidities have not been well studied. Here, we investigated the effects of clonazepam on xerostomia, taste disturbances, dysgeusia, and psychogenic conditions.

• #19

  https://journals.lww.com/jpbs/fulltext/2014/06001/burning_mouth_syndrome__a_review_on_its_diagnostic.7.aspx

  Centrally mediated alteration in the modulation of nociceptive processing. […] Disturbances in the autonomic innervation and oral blood flow. […] Chronic anxiety or stress results in the alteration of gonadal, adrenal and neuroactive steroid levels in skin and oral mucosa. […] The exact cause of BMS is currently unknown. The etiology is presumed to be multifactorial involving the interaction between neurophysiological mechanisms and psychological factors.

• #20 Salivary biomarkers and burning mouth syndrome: a systematic review and meta-analysis of the literature | Journal of Oral Medicine and Oral Surgery

  https://www.jomos.org/articles/mbcb/full_html/2023/03/mbcb230062/mbcb230062.html

  Burning Mouth Syndrome (BMS) is defined by a burning sensation or intraoral dysesthesia without obvious causal lesion. […] Although the etiopathogenesis of burning mouth syndrome is not clearly identified, BMS is favoured by several factors: local, systemic and psychological. […] However, some studies have found changes in salivary composition, viscosity or salivary flow in BMS patients. […] The evaluation of the salivary biochemical characteristics of patients with BMS could then make it possible to understand the pathogenesis of this disease and identification of salivary biomarkers could open up new avenues of treatment. […] This meta-analysis nevertheless confirms all the interest of focusing on salivary biomarkers in BMS patients; the measurement of cortisol and/or salivary IgA could be a line of research for the establishment of a standardized biological assessment. […] The lack of standardized protocols for the collection of saliva samples is finally what emerges from this work, it therefore appears essential to set up a precise collection technique to obtain significant results.

• #21 Burning mouth syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Burning_mouth_syndrome

  As most people with BMS are postmenopausal women, one theory of the cause of BMS is of estrogen or progesterone deficit, but a strong statistical correlation has not been demonstrated. […] Another theory is that BMS is related to autoimmunity, as abnormal antinuclear antibody and rheumatoid factor can be found in the serum of more than 50% of persons with BMS, but these levels may also be seen in elderly people who do not have any of the symptoms of this condition. […] While salivary flow rates are normal and there are no clinical signs of a dry mouth to explain a complaint of dry mouth, levels of salivary proteins and phosphate may be elevated and salivary pH or buffering capacity may be reduced. […] Depression and anxiety are strongly associated with BMS. […] It is not known if depression is a cause or result of BMS, as depression may develop in any setting of constant unrelieved irritation, pain, and sleep disturbance.

• #22 Burning Mouth Syndrome: An Overview and Future Perspectives

  https://www.mdpi.com/1660-4601/20/1/682

  The complexity of the BMS patients requires a multidisciplinary approach with a strong collaborative relationship between orofacial pain specialist, physician, psychiatrist, and neurologist. […] Despite there being no evidence of the efficacy of specific medications or agreement between the authors, various neuropathic medications such as Clonazepam, Gabapentin, Tricyclics, Cannabinoids have been proposed for the treatment of BMS. […] Recently, Vortioxetine, a multimodal antidepressant, has demonstrated its efficacy in the pain relief, anxiety, depression, and sleep disturbance in BMS.

• #23 Is Burning Mouth Syndrome Based on a Physiological Mechanism which Resembles that of Neuropathic Pain?

  https://www.medigraphic.com/cgi-bin/new/resumenI.cgi?IDARTICULO=94158

  Burning mouth syndrome (BMS) is a chronic intraoral pain state that has been described as burning pain, tingling or numbness in the oral mucosa, in the absence of any organic disease. […] Relevant studies links BMS to a peripheral neuropathy and BMS patients have revealed distinct abnormalities within the trigeminofacial large and small fiber systems and the trigeminal brainstem complex. […] Therefore, treatment approach should involve a multidisciplinary character similar to the treatment for neuropathic pain including factors that might also play a role on the BMS etiology and pathophysiology.

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