BMS has been divided into two types: primary (no other evident disease) and secondary (oral burning due to a clinical abnormality).11 Primary BMS is idiopathic, in that the organic local/systemic causes cannot be identified; however, peripheral and central neuropathological pathways are potentially involved.9 Secondary BMS involves a local or systemic condition such as a mucosal disease (i.e., lichen planus, candidiasis), hormonal disturbances, psychosocial stressors, vitamin or nutritional deficiencies, diabetes, dry mouth, contact allergies, parafunctional habits, cranial nerve injuries, or medication side effects.1,11,25 Primary BMS treatments seek to alleviate symptoms; secondary BMS requires diagnosis and treatment of the underlying condition.11 There were substantial differences in burning symptom cessation with treatment; the patients who had secondary BMS improved if the underlying clinical abnormality was treated, whereas the primary BMS group rarely reported such positive results.11Meanwhile, the main accompanying medical conditions of BMS are xerostomia, dysgeusia, or psychological issues such as depression and anxiety.2,3 Thus, clinicians have attempted to manage BMS along with xerostomia, taste disturbance, and psychogenic issues. In general, clonazepam has been recognized as the most effective standard treatment, regardless of the accompanying symptoms or type of BMS;15–18 its therapeutic effect is mediated by the inhibition of pain signaling.16 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.12,26 Therefore, clonazepam may have the effect of reducing burning pain in the oral cavity. BMS is often accompanied by complaints of xerostomia, as reported by 25–40% of BMS patients in recent studies.1,11,27 Scala et al. reported that 46–67% of BMS patients claim to be experiencing xerostomia, regardless of whether the salivary flow rate is decreased; notably, dry mouth is often subjective, as opposed to any real decrease in salivary gland function.9,25 However, the response to clonazepam treatment for BMS in those with xerostomia is not clear, as only a few studies have examined this. In one of them, Silva reported that the therapeutic response of topical urea treatment (10% of concentration, applied to the oral cavity three to four times per day for 3 months) was 60% in patients with xerostomia, which was similar to the results obtained with the control group.28 In our present work, 10 patients (24.3%) out of 41 reported subjective xerostomia, and all 10 of these patients exhibited objective hyposalivation. Among the hyposalivation patients, 7 out of 10 (17%) responded to clonazepam in terms of a reduced BMS visual analogue score (VAS) score (mean VAS changed from 7.6 to 5.9); however, the response rate was lower than that (80%) of the normal group, which was not statistically significant. Previous studies have presented evidence suggesting that changes in the salivary flow rate may be associated with mucosal atrophy and/or subclinical inflammation, which may be accompanied by oral neuropathy in BMS patients.28–30 Lauria et al. also demonstrated oral neuropathy by examining the tongue epithelium of BMS patients and found fewer small-diameter nerve fibers, which may explain the thermal hypoesthesia symptoms and change in the pain thresholds. Considering the above, it is thought that dry mouth is closely related to BMS onset. In addition, it can be hypothesized that the effect of clonazepam may be reduced as chronic neural degeneration occurs extensively as the duration of dry mouth is extended. Therefore, we think that this study can provide some insight into predicting the treatment effects of BMS patients with xerostomia.
From the aspect of psychogenic factors, several studies have suggested that psychological factors cause BMS.1,11,13,14,31−33 Depressive mood, anxiety, somatization, and aberrant personality traits have frequently been reported in BMS patients, and much of the research has been devoted to the role of psychological factors in BMS,1,13,14,32 in which psychosocial disorders with a principal focus on anxiety and/or depression were examined. Several studies reported that up to 35% of BMS patients showed depressive mood and up to 50% of patients complained of anxiety.1,14,32 On the other hand, some controversy remains as to whether psychogenic pathological conditions occur primarily or are secondary to BMS. In general, psychological disorders may be associated with the modulation of pain perception, increasing nerve transmission by peripheral pain receptors, and altering of an individual’s perception of pain. Based on this, with the belief that the treatment effect for each BMS patient may differ depending on the accompanying psychogenic problem, some studies have shown that psychological problems are associated with worse prognoses.9,25,34 According to Ko's study, the reduction in burning pain caused by clonazepam was smaller in the psychiatric disease group than the control group (29% vs. 45%, respectively).25 Among our patients, depressive mood and anxiety trait were reported by 75.7% and 65.9%, respectively. Like other studies, our study found that the response rate with clonazepam therapy on burning pain was less in patients with psychiatric problems than in those without (in depressive mood: 74.2% vs. 90%; in anxiety trait: 77.7% vs. 78.5%, respectively). However, there was no significant improvement in the BMS VAS score, regardless of the Beck Depression Inventory or State Trait Anxiety Inventory (T/S) score. The small degree of pain reduction in patients with psychogenic problems may be explained by emotional and cognitive factors for chronic pain. Forssell et al. demonstrated that BMS patients with more intensive and interfering pain report more depressive and pain-related anxiety symptoms, compared to patients with less severe pain intensity;35 he explained this using a biopsychosocial model of chronic pain, showing that emotional and cognitive factors play a role in pain experience. Forssell also claimed that BMS patients with more intensive pain reported more depressive- and pain-related anxiety symptoms, and more hypervigilance to pain, compared to patients with less severe pain intensity.35 Excessive attention to pain or pain hypervigilance has been reported in association with a higher pain intensity, disability, and emotional distress in different pain patient populations.36 Such patients usually exaggerate their pain, thus they are likely to express a poor response to clonazepam.25 Also, patients with psychogenic symptoms are likely to take psychiatric medications. According to Ko's study, 23% of BMS patients had been taking psychiatric medications; these patients showed significantly reduced salivary flow rates because psychiatric medications may decrease salivary gland function and may result in a reduction of saliva’s protective capacity in the mouth.25 As described above, the treatment effect of clonazepam may be influenced by a change in salivary components and xerostomia induced by psychiatric medication.
A loss of taste inhibition by central structures that mediate oral pain has been proposed to explain BMS development.13 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.1 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.1,26,37 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.12 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.
There have been many studies reporting the prevalence of psychogenic conditions, xerostomia and taste disturbance in patients with BMS.25,38 However, studies on the therapeutic effect of clonazepam in the presence of these concomitant symptoms have been insufficient. Thus, we assessed the therapeutic effects according to psychological, dysgeusia, and hyposalivation status. We found no correlation of psychological or hyposalivation status with the therapeutic effect of clonazepam; however, taste disturbance was associated with a higher response rate and greater improvement in relieving the burning pain. The limitations of our work include the questionnaire-based retrospective design and the small cohort size. Nevertheless, we elucidated the pain reduction effect of clonazepam according to the accompanying symptoms, resulting in clonazepam significantly improving the burning pain in BMS patients with taste disturbances. Such information can be used in BMS patient counseling and in the prediction of therapeutic outcomes with clonazepam treatment.