Burning mouth syndrome is a rare but impactful condition affecting mainly post-menopausal women resulting in constant pain and significant daily difficulty with eating, drinking and daily function. The aetiology of BMS remains an enigma. Recent evidence suggests a likely neuropathic cause the cause of which remains unknown. There is no cure for tis condition and the unfortunate patients remain managed on a variety of neuropathic pain analgesics, salivary substitutes and other non-medical interventions that help the patient ‘get through the day’.

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The dental team will recognise patients presenting with burning mouth syndrome. They are difficult patients to manage and are often referred to secondary care and ultimately with their general medical practitioners for pain management. Some simple startegies can assist both clinician and patient manage this debilitating condition.

This paper aims to provide an overview of the relevant management strategies for BMS and highlight how to overcome some management challenges.

Introduction

Burning mouth syndrome (BMS) is a chronic and intractable pain condition which predominantly affects postmenopausal women in their 5th-7th decade. The International Association for the Study of Pain (IASP)1 has identified BMS as a ‘distinctive neuropathic entity’ characterized by bilateral burning oral mucosal pain, usually affecting the anterior two thirds of the tongue that may comply with the anatomy of peripheral nerves. There is a lack of any visible signs of mucosal pathology and the symptoms usually last for more than 6 months.2The International Headache Society (IHS)3 defines BMS as ‘an intraoral burning sensation for which no medical or dental cause can be found.’ The IHS diagnostic criteria state the need for constant pain, normal appearance of the oral mucosa and exclusion of any local/systemic diseases. The pain intensity ranges from moderate to severe throughout the day, may vary during the day, and may last several years.4,5

Traditionally, BMS was thought to be purely psychogenic,6 especially due to the absence of any visible clinical pathology. Although there is likely to be a psychological component to the condition, in common with most chronic pain conditions, 4, 7-9  increasing evidence indicates that the aetiology of BMS is likely to be more complex. Possible peripheral neuropathic involvement has been suggested 10-14 and upstream effects of any peripheral changes within the central nervous system are likely.15-18

A recent review article on BMS17 summarises that recent neurophysiologic, psychophysical, neuropathological, and functional imaging studies may have elucidated multiple neuropathic mechanisms, mostly subclinical, acting at different levels of the neuroaxis and contributing to the pathophysiology of primary BMS. As in neuropathic pain, decreased brain activation to heat stimuli has been demonstrated with fMRI in BMS patients 18

Some authors conclude that the clinical diagnosis of primary BMS may encompass three distinct, subclinical neuropathic pain states that may overlap in individual patients. 11-16

  • Subgroup 1 (50-65%) is characterized by peripheral small diameter fibre neuropathy of intraoral mucosa.
  • Subgroup 2 (20-25%) consists of patients with subclinical lingual, mandibular, or trigeminal system pathology that can be dissected with careful neurophysiologic examination but is clinically indistinguishable from the other two subgroups.
  • Subgroup 3 (20-40%) fits the concept of central pain that may be related to hypofunction of dopaminergic neurons in the basal ganglia.

The neurogenic factors acting in these subgroups differ, and will require different treatment strategies. In the future, with proper use of diagnostic tests, BMS patients may benefit from interventions specifically targeted at the underlying pathophysiological mechanisms.

Despite such ongoing research, central and peripheral pain mechanisms in BMS are still not understood in their entirety. Questions remain regarding the possibility of a dominating nervous system driving the condition or a more complex network of central, peripheral and psychological aspects impacting on a susceptible patient, with a possible genetic involvement (Diagram 1).

Epidemiology

Epidemiological data available on BMS is very limited. The lack of strict diagnostic criteria has lead to publication of many studies reporting on the symptom of oral burning rather than the syndrome specifically.19 As a result, the quoted prevalence of BMS within the general population varies from 0.7% to 15%.20

The prevalence of BMS increases with age, predominantly affecting women, with a female to male ratio of 3:1, varying between 0.6% in the 30-39 year old women, increasing to 12.2% by their seventh decade.21

Aetiology 

The precise aetiology of BMS is unclear.  Several studies have suggested various local, systemic and psychological precipitating factors, however, there is a lack of general agreement due to poor quality prospective studies and case reports. As stated by a Cochrane review, it is important to diagnose BMS only on exclusion of any such aetiological factors.22 These factors include:

1. Oral candidiasis- candidal infections have been shown to induce a burning sensation (Grushka, 1987).  It is important to note, however, that treatment of the candidal infection has failed to relieve burning symptoms.19

2. Xerostomia (Dry Mouth) - Prevalence of xerostomia in BMS patients varies ranging from 34% (Klasser et al., 2008) to over 60%.23 Some studies have failed to show a difference in saliva production compared with controls. 24Drug induced xerostomia is known to be a cause of dry mouth.  Reduced saliva production in BMS patients taking antidepressants would be an understandable finding.  In addition, BMS patients are known to have higher anxiety and depression scores, increasing the chances of a dry mouth,19 however, xerostomia itself has not been shown to be a cause of BMS.

3. Nutritional neuropathy- Grushka4 investigated the role of deficiencies of iron, folate, serum ferritin and vitamin B12 in 72 age and sex matched BMS patients with 43 controls and showed no significant differences between both groups.  Some studies, however, report significant lower levels of vitamin B12 in BMS patients.25-28 There have also been suggestions of deficiencies of vitamins B1, B2 and B6 causing BMS.26,27,29-31 More recently, deficiency in zinc levels have been demonstrated in BMS patients with replacement therapy causing a decrease in pain, although not curing it completely.32

4. Dysgeusia- Femiano et al., reported up to two thirds of BMS patients with complaints of taste disturbances, especially persistent bitter and/or metallic tastes.33 Significantly different taste acuity in BMS patients has also been shown.34 

5. Mechanical factors- Poorly fitting prostheses causing local irritation and microtrauma have been suggested as a cause for BMS like symptoms.35   Conversely, it has been shown that denture replacement did not always relieve the symptoms, as is the case with supposedly allergic reactions to acrylic dentures.25,36

6. Parafunctional habits- parafunctional activity is commonly seen in patients with increased levels of anxiety.  There have been suggestions of such habits predisposing to BMS, but there have not been any controlled studies to support this.19

7. Endocrine disorders- Certain systemic conditions have been implicated with BMS. Diabetes mellitus has been linked to BMS possibly due to reports of glossodynia in diabetics and also the risk of peripheral neuropathies, such as burning feet,37,38. Some studies suggest it is poorly controlled diabetes that can lead to BMS 27,39  and better glycaemic control can improve symptoms.40 Hypothyroidism has also been implicated in predisposing patients to BMS. 33

With BMS being more common in post-menopausal women, a decrease in oestrogen levels has been a suggested cause for burning symptoms. 23, 41,42 This has not been confirmed however, due to the lack of improvement following oestrogen replacement therapies.43Salivary cortisol levels have been investigated in BMS patients. Although they followed the same circadian cycle, salivary levels were generally higher in BMS than controls.44 Chronic anxiety in BMS has also been related to a dysregulation in the production of adrenal steroids.45

8. Psychological disorders- BMS is stated to be ‘conceptualized as a psychogenic physical continuum’ 8 and over 50% of patients have been associated with psychological factors.7 Bergdhal et al.,9 demonstrated a significantly higher score on the somatic anxiety, muscular tension and psychoasthenia scales in the BMS cohort and lower socialisation scores, compared to controls.21 Conversely, studies such as Carlson et al., have shown there to be no significant prevalence of psychiatric symptoms in BMS patients.46 It is important to note that patients with chronic pain commonly have psychologic dysfunction and this may be a result of the ongoing pain itself.23

9. Helicobacter Pylori (H.pylori) and gastrointestinal disease - Recent studies have suggested a correlation between the presence of H.pylori and burning sensations within the oral cavity.47 When tested for this bacterium, higher levels were found in BMS patients compared to controls.48,49  In 2006, Brailo et al., found 51.3% of BMS patients had gastritis and 12.3% showed evidence of H.pylori. In addition, BMS patients were found to be 3.2 times more likely to suffer from gastrointestinal disease.25 When all factors possibly contributing to BMS were analysed, gastrointestinal problems were most common in BMS patients.50

10.  Autoimmune - The role of various cytokines in BMS have been suggested in the past. Simcic et al., found salivary interleukins 2 and 6 (IL-2 and IL-6) to be elevated in correlation to the severity of the symptoms of BMS.51 Conversely, other studies have demonstrated a significant decrease in IL-2 52 and IL-6 which was negatively correlated to chronic pain levels.53 More recently, no difference was found in salivary interleukin levels in BMS patients.54

11. Contact Hypersensitivity- Studies using patch testing on BMS patients has shown contact allergy not to play a significant role in its aetiology55 Levels of IgE have also been investigated with no evidence to support its role56 In addition, contact dermatitis has not been shown in BMS patients.57

12. Exclusion of other causes of peripheral neuropathy- Various secondary causes for peripheral neuropathies have been implicated and it is important to exclude these when diagnosing BMS.  These causes include: diabetic peripheral neuropathy, inherited neuropathies, idiopathic small fibre sensory neuropathy, peripheral neuropathies associated with connective tissue disease, acquired amyloid polyneuropathy, neuropathy with renal failure, hereditary sensory autonomic neuropathy, sarcoid polyneuropathy, arsenic neuropathy, Fabry’s disease, Coeliac’s disease, HIV-related neuropathy, paraneoplastic sensory neuropathy, post traumatic peripheral sensory neuropathy, post herpetic neuropathy and demyelination in multiple sclerosis.

Diagnostic screening therefore should include exclusion of: nutritional neuropathies (serum Fe, Ferritin, Vit B1, B6, B12, Folate and Zinc), blood dyscrasias (FBC, WBC, RBC, MCV, ESR), liver disease (LFTs), renal disease (Renal function test), candidal infection (candida count), diabetes (fasted blood glucose or HbA1C), autoantibody profile (ENAs and ANAs), hormone imbalance (FSH, Oestradiol, TSH, FT3, FT4) and if the clinical history indicates; gastrointestinal disease (antibodies to H.pylori), allergy (serum total IgE, patch test for dental materials) and xerostomia (salivary flow rate). This would ensure BMS is diagnosed correctly, as a diagnosis of exclusion (Table 2).

Pathogenesis

BMS was originally thought to be purely psychogenic in origin, however, growing evidence suggests it is in fact a much more complex condition involving multiple factors (Diagram 1). Studies have now shown BMS to be neuropathic in origin,10,-14,58,; with a recent study demonstrating a significantly lower density of epithelial nerve fibres in oral mucosa of BMS patients with morphological differences in the nerve fibres themselves13 and a significantly lower number of fibres penetrating the epithelium in oral mucosa of BMS patients .59More specifically, some peripheral pain receptors have been shown to be upregulated after analysis of tongue biopsies of patients suffering from BMS in comparison to controls.58 These changes in the peripheral nervous system suggest BMS to be (at least in part) a small fibre trigeminal neuropathic condition.

Upstream effects of any peripheral change are expected within the central nervous system 15and evidence is beginning to indicate a role for the central nervous system in BMS.16-18 A recent study suggested irreversible neuropathic degeneration both peripherally and centrally.45 This study demonstrated a different response to blockade of peripheral sensory input causing attenuation of pain in one subgroup, alleviation of pain in another and no change at all in the third group, illustrating the complex relationship between peripheral and central nervous systems. Grushka et al., found that the tolerance of pain in BMS patients was significantly reduced.4The question still remains whether this is due to changes within the peripheral or central nervous system.

A psychological element to chronic pain conditions is often reported 7-9, 23Behavioural studies involving patient questionnaires are being carried out to complete the understanding of this debilitating condition and help suggest appropriate multidisciplinary management of these patients.

Investigating peripheral pain mechanisms not only advances our understanding of BMS, but is also essential for the development of new therapeutic drugs. The majority of the orofacial tissues are supplied by the trigeminal nerve and BMS has been shown to involve trigeminal neuropathies.13,59 The trigeminal primary afferent nerve fibres (A delta and C fibres) tend to be the non-specialised peripheral nerve endings that act as nociceptors and are responsible for eliciting pain.60 Once these nerve endings are activated, action potentials are conducted to the sensory cortex. Activation of these peripheral nerves involves several factors and chemicals. Chemical mediators released due to tissue damage such as, prostaglandins can excite the peripheral nerves and translate as pain and damage to adjacent tissues due to an inflammatory response releases substances such as 5-hydroxytryramine (5-HT) and cytokines which again activate these nerve endings.61 With neuropathic pain, such as BMS, damage to or pathology of the peripheral nerve endings themselves can lead to an increase in excitability and aberrant firing causing chronic pain conditions.62 A wide range of mediators and receptors have been suggested to be involved in neuropathic pain, such as calcitonin gene-related peptide (CGRP), somatostatin, nerve growth factors and substance P.61 In addition, voltage gated sodium (Nav) channels are known to play a key role in elicitation of action potentials in neurons, including nociceptors.63 Our recent study demonstrated voltage gated sodium channel Nav1.7 to be maintained in BMS and upregulated in pulpitis, indicating further that BMS is a neuropathic condition rather than inflammatory.58

Expression of various receptors has been shown on afferent nerve endings including purinergic, serotonergic, opiate, cholinergic, anandamide, bradykinin, histamine, prostaglandin, adrenoreceptors, transient vanilloid receptor V1, ionotropic glutamate receptors, neurokinin receptors, acid-sensitive receptors and gamma-aminobutyric acid (GABA) receptors.61,64Research is currently being carried out to determine which specific receptors are involved in BMS which will help towards identifying a therapeutic goal. Recently we have shown purinergic receptor P2X3 to be significantly upregulated in BMS.61

Following investigation of the peripheral nervous system in BMS, the question still remains if this is purely a peripherally driven condition.  A growing body of evidence is beginning to indicate a role for the central nervous system in BMS and being a chronic pain condition we would expect to see central changes, especially as it is known chronicity of pain leads to alterations within the central nervous system.15-18(Moseley, 2003).

Pain is a complex multi-dimensional experience produced by nerve impulses being generated within the brain, for example following stimulation of peripheral pain receptors.65 The neurones involved in translating this peripheral input as pain is known as the pain neuromatrix.15

The pain neuromatrix was first described by Melzack in 1996.65 The huge network of neurons within the brain contributes to the many ‘pain centres’ and collectively are known as the pain neuromatrix.  Typically, this includes the thalamus, sensorimotor cortex, insular cortex, frontal cortex, premotor cortex and anterior cingulate cortex (Moseley, 2003).  This pain neuromatrix is thought to be genetically determined within each individual and refined by various sensory inputs over time.65  

BMS is a chronic pain condition and within the central nervous system, chronicity of pain is thought to lead to changes within the brain including the pain neuromatrix where sensitivity of neurones is increased. As a result, less sensory input, if at all, is required for activation of pain.15 Neuroimaging studies have furthered our understanding of the central representation of pain, both in experimental and clinical pain, and central changes within the pain neuromatrix can now be investigated. The use of these various imaging techniques have demonstrated the complexity of subjective pain perception and suggested a more invidualised ‘cerebral pain signature’ rather than a rigid neuromatrix.67 The previously named ‘pain centre’ is also seen as a grossly simplified term for the complex interactions involved in pain perception. 68

Novel functional neuroimaging techniques are providing us with a unique method of evaluating pain mechanisms in real time whilst the patient can report the quality and quantity of the pain they are experiencing.69 Our group is currently using functional magnetic resonance imaging to analyse the central representation of BMS and help to localise areas of the brain involved in chronic orofacial pain (Image 1).

Psychologial factors

Patients with chronic pain commonly have psychological dysfunction and this may be a result of the ongoing pain itself.70BMS is a chronic pain condition and we can expect these patients to have a psychological aspect to their condition. Studies have reported over 50% of BMS patients to be associated with a range of psychological factors7 and show a significantly higher score on the somatic anxiety, muscular tension and psychoasthenia scales and a lower score on the socialization scale.9

Clinical features

Eliciting a good clinical history from the patient is helpful in diagnosing burning mouth syndrome. Most patients report an increase in pain intensity from morning to night, similar to other neuropathic pain conditions. Most patients report a decreased pain with eating, oral dryness that waxes and wanes with the burning, and the frequent presence of taste disturbances.71

In over 50% of patients with burning mouth syndrome, the onset of pain is spontaneous, with no identifiable precipitating factor. Thirty percent of patients cite onset caused by dental procedure, recent illness or medication course (including antibiotic therapy). Regardless of the nature of pain onset, once the oral burning starts, it often persists for many years.4

The burning sensation affects more than one oral site in most cases, with the anterior two thirds of the tongue, the anterior hard palate and the mucosa of the lower lip most frequently involved.72 extra oral sites are not affected however, other mucosal sites may be concomitantly affected (vulvadynia).

In many patients with neuropathic pain, pain is absent during sleep but occurs at a mild to moderate level in morning. Again similar to other neuropathic pain conditions the pain increases throughout the day, with maximum intensity late in the day.4 The pain is moderate to severe and  may prevent onset of sleep and may alter mood changes, including irritability, anxiety and depression.4,73

There is a sparcity of evidence on the natural course of burning mouth syndrome with no identified factors indicative of recovery. Spontaneous partial recovery within six to seven years after onset has been reported in up to two thirds of patients, with recovery often preceded by a change from constant to episodic burning.5 .

Most studies have found that oral burning is frequently accompanied by other symptoms, including dry mouth and altered taste.4Alterations in taste occur in as many as two thirds of patients and often include complaints of persistent tastes (bitter, metallic, or both) or changes in the intensity of taste perception. Dysgeusic tastes accompanying oral burning are often reduced by stimulation with food.4,5 In contrast, application of a topical anesthetic may increase oral burning while decreasing dysgeusic tastes.

Current Management

Currently, there are multiple treatment modalities for the management of BMS, all of which are unsatisfactory (Table 3). Cognitive behavioural therapy (CBT) is at present the only evidence based treatment for BMS and this is still not always available for patients in some hospitals.

Medical treatment of burning mouth syndrome is similar to the medical management of other neuropathic pain conditions (Table 3).45,70-74 Studies generally support the use of low dosages of clonazepam (Klonopin),45 chlordiazepoxide (Librium)13 and tricyclic antidepressants (e.g., amitriptyline [Elavil]).27 Evidence also supports the utility of a low dosage of gabapentin (Neurontin).28Studies have not shown any benefit from treatment with selective serotonin reuptake inhibitors or other serotoninergic antidepressants (e.g. trazodone [Desyrel].29.)

Although benzodiazepines might exert their effect on oral burning by acting as a sedative-hypnotic, this possibility appears to be unlikely because the maximal effect of clonazepam is usually observed at lower dosages.45 The beneficial effects of tricyclic antidepressants in decreasing chronic pain indicate that, in low dosages, these agents may act as analgesics.30

Topical capsaicin has been used as a desensitizing agent in patients with burning mouth syndrome.70 However, capsaicin may not be palatable or useful in many patients. 74

Conclusion

There is no doubt that current research is beginning to unravel the mystery of BMS, previously thought to be purely psychogenic in origin, and prove that it is a complex condition requiring a multidisciplinary management approach. The importance of a correct diagnosis in the first instance is key to preventing patients from being labelled with this debilitating condition, which is still not completely understood and currently difficult to manage.  Referral of these patients to specialist pain centres will ensure correct diagnoses are made and optimum management is provided involving a multidisciplinary team.

TABLE 1
Possible Causes and Management of Burning Mouth Symptoms (Taken from Grushka et al 20028

table1

Table 2: Screening tests required to diagnose BMS: a diagnosis of exclusion.

table2

If indicated by clinical history:

table2.1

TABLE 3
Medical Management of Burning Mouth Syndrome

table3

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