Introduction

Burning mouth syndrome (BMS) is characterized by a burning sensation in the intraoral mucosal membranes and perioral areas in the absence of clinical and laboratory findings to account for the pain.1–3 Diagnosis is often made on a clinical basis. Sensations associated with BMS have been variously described as “burning,” “annoying,” “granular or sandy,” or “dryness and swelling.”2 Frequently, patients do not report pain when eating, sleeping, or on waking, but the sensation gradually increases throughout the day to peak in late afternoon and early evening.1,2 Up to two-thirds of patients with BMS also complain of dysgeusia,4,5 described as the presence of a constant “foul,” bitter, or metallic taste sensation, which may be at least as disturbing as the burning pain itself.1

Prevalence

The prevalence of BMS has been reported to be between 0.7 and 5% in the general population (including Canadian studies1,6), with the variation probably due to study methodology (survey or clinical assessment) and location.1,6–8 BMS is most commonly reported by female patients in the fifth to seventh decade of life,4,9,10 and investigations have often focused on menopausal and post-menopausal populations.11–14 The high proportion of postmenopausal patients with BMS has led to interest in the role of estrogen in chronic orofacial pain,15 and whether changes in estrogen levels can precipitate BMS.

Etiology

There is an increasing consensus that BMS is an idiopathic neuropathic pain condition.9,16 However, there is no consensus on the etiology or whether developing BMS can be attributed to a single precipitating event.4,12 Recent evidence has suggested that both central17–20 and peripheral neuropathic changes10,21–23 are present in patients with BMS. A recent study by Lauria et al10 assessed superficial nerve changes on biopsy of the anterior two-thirds of the tongue in 12 patients diagnosed with BMS. Compared with control subjects, patients with BMS demonstrated a significantly lower density of unmyelinated epithelial nerve fibers and subpapillary nerve fibers, with evidence of diffuse axonal derangement in the patients with BMS.10 The changes were caused by a primary axonopathy rather than a neuronopathy. Like other small-fiber neuropathies, the severity of the symptoms did not correlate with the density of epithelial nerve fibers.10 Previous studies have shown that these epithelial nerve fibers synapse with the taste buds in the fungiform papillae, and such changes may be the basis for both the dysgeusia and the pain experienced by some patients with BMS.22,24,25

Most clinicians recognize the existence of secondary BMS—pain related to an organic cause such as a systemic disease—and primary BMS, which is the neuropathic phenomenon.26 An interesting question is whether there is overlap between the two: is the development of neuropathic changes associated with primary BMS related to a local or systemic disease? Suarez and Clark26 report that BMS is more frequent in women with systemic diseases. Recent literature on Sjögren syndrome, a common autoimmune disease affecting more women than men, indicates that peripheral neuropathies are among the most common non-gland manifestations.27 The prevalence of peripheral neuropathy is unknown, but has been estimated at 5 to 20%.27 Although the general prevalence of small-fiber neuropathy, such as that described by Lauria,10 is unknown, one study assessing skin biopsies found that mean intraepidermal nerve fiber innervation was considerably lower in patients with Sjögren syndrome than in age- and sex-matched controls.28 This is similar to the findings of reduced epithelial nerve density reported by Lauria et al10 Like treatment of BMS, treatment of neuropathy associated with Sjögren syndrome can include antiepileptic drugs (AED) and antidepressants used as adjuvant analgesics.27

Recent literature has also suggested that BMS may be caused by mast-cell activation disorder.29 However, it is likely that the study, based on three cases, describes secondary BMS rather than primary BMS, given that these cases did not respond to AED and antidepressant medication but responded dramatically to nonsteroidal anti-inflammatory drugs and histamineacting medications.29 Therefore, it is more likely that mast-cell disorders are part of the differential diagnosis for BMS rather than a cause for primary BMS.29

Another suggestion has been an association between zinc deficiency and the pathogenesis of BMS.30 Cho et al reported that zinc deficiency was present in ~27% of patients with BMS, and that pain scores in such patients who were treated with zinc replacement improved significantly compared with those of a control group.30 An animal model has suggested that zinc deficiency causes histological changes in the tongue, but it is uncertain how this is associated with neuropathy.30

It has been suggested that neuropathic pain begins peripherally and progresses to central sensitization. Jääskeläinen, who has done much of the quantitative sensory testing work in BMS, suggests that BMS encompasses changes in both the peripheral trigeminal nerve and in central pathways.18 While conventional imaging such as magnetic resonance imaging may fail to detect trigeminal pathology, it may be evident on sensory testing.18 On testing heat sensation thresholds and pain in BMS, changes were found in the mouth as well as distal locations, suggesting that BMS may be associated with disseminated small-fiber nerve changes.18 Centrally, blink-reflex testing suggests a role for the striatal dopaminergic system in BMS pain.18 Overall, sensory data suggest that both peripheral and central nervous system (CNS) changes are present, but do not pinpoint the location of specific changes in the somatosensory system.18,26

Taste Changes

Bartoshuk’s group have demonstrated the convergence of taste sensation and pain both clinically and experimentally.30,31 The chorda tympani nerve (cranial nerve VII) leaves the tongue with the lingual nerve (cranial nerve V) and travels through the pterygomandibular space. The inferior alveolar nerve (cranial nerve V), which conveys sensation from the lower teeth, also passes through this same space. Often, anesthesia of the inferior alveolar and lingual nerves required for dental procedures abolishes touch, pain, and also taste sensations on the injected side. The chorda tympani and lingual nerves separate and the chorda tympani passes through the middle ear. Researchers30,32–34 have demonstrated that anesthesia of the chorda tympani behind the tympanic membrane intensifies tastes from the area innervated by the glossopharyngeal nerve (cranial nerve IX)—the posterior aspect of the tongue on the opposite side—supporting a model of central inhibition between the chorda tympani and glossopharyngeal nerves. According to Bartoshuk’s group, reduced input into the CNS from one taste nerve releases inhibition of other tastes, resulting in these tastes being intensified.30

Tie et al35 found that anesthesia of the chorda tympani can intensify capsaicin-induced pain on the contralateral anterior tongue, suggesting the presence of central inhibitory interactions between taste and oral pain. Furthermore, the intensification of pain was found to be related to an individual’s genetic ability to taste 6-n-propylthiouracil (PROP), an extremely bitter compound, with the greatest intensification found in “super-tasters” (mainly females) who report the most bitter sensation from PROP testing.36

Based on these taste–pain interactions, it is believed that some cases of BMS could be the result of taste damage, to either the chorda tympani, with release of inhibition in the glossopharyngeal nerve (taste alterations, alterations in touch and pain), or the trigeminal nerve (changes in touch and pain). Consistent with this model, taste damage has been found in many patients with BMS. Notably, the intensity of peak oral pain was found to correlate with the density of fungiform papillae, with the greatest density being found in patients with BMS who were primarily supertasters.31,37

According to Bartoshuk’s group,30 if taste damage produces a sufficient loss of the inhibition normally exerted on central structures mediating oral pain, then centrally acting medications that are known to impact on pain, such as pregabalin, may ameliorate the loss of inhibition and relieve the pain of BMS.

Spatial Taste Testing

Taste on the tongue is innervated by the branches of the facial nerve (cranial nerve VII) and the glossopharyngeal nerve (cranial nerve IX), which serve different regions of the tongue. Often, changes to taste in patients with BMS may occur in one area but not another.7 As a result, taste damage presents as a regional phenomenon and rarely as a whole-mouth phenomenon.38

Therefore, spatial taste testing is performed to assess perceived taste intensity for sweet, sour, salty, and bitter solutions applied with cottons swabs, filter paper, or drops at the anterior tongue tip and the circumvallate papillae, on both left and right sides. Patients rate the quality and intensity of the stimuli using a validated psychometric scale, the general labeled magnitude scale—a modified numeric scale.39