Burning mouth syndrome (BMS) is a poorly understood chronic pain disorder characterized by an intraoral burning sensation in the absence of any identifiable organic cause according to the International Headache Society classification (ICHD-3) (1).

The prevalence of BMS in the population ranges from 0.7 to 15%, depending on the diagnostic criteria used, with postmenopausal women being more frequently affected (2). The average age of BMS patients is 61 years. It is assumed that there is a male-to-female ratio of 1:5–1:7, and the prevalence seems to increase with advancing age in both genders (3, 4).

According to the current ICHD-3 classification the burning pain is felt superficially in the oral mucosa, recurring daily for more than 2 h per day over more than 3 months. In the physical examination, the oral mucosa has a normal appearance and clinical findings including sensory testing are normal (1).

The painful sensation predominantly affects the tongue (67.9%), with the anterior two-thirds of the tongue being most commonly affected. However, it may also extend to other regions of the oral mucosa, including the floor of the mouth and the lips (5). The pain experienced typically ranges from moderate to severe intensity, quantified within a range of 3.1–5.11 on the Numeric Rating Scale (NRS) (5). The most frequently described accompanying symptoms are a dry mouth (xerostomia), described in 46–70% of cases, followed by taste disturbances (5). Psychosocial and psychological comorbidities manifest in 85% of cases, with anxiety disorders and depression being particularly common (2). BMS Patients often report a bad sleeping quality (6). The consumption of foods with high acidity, spiciness, or temperature exacerbates the discomfort. Chewing gum and mouth rinses use to alleviate the pain (5).

The etiology and pathophysiology of BMS remains mostly unknown. Pathophysiological concepts include peripheral and central mechanisms. Neurophysiological concepts include damage to the chorda tympani, damage to the lingual nerve (a branch of the trigeminal nerve that supplies the oral mucosa), peripheral small-fiber polyneuropathy, altered cortical networks involving the “pain matrix” and descending inhibitory pathways as well as impaired dopaminergic inhibition (1, 6). A biopsy study by Lauria et al. on 12 BMS patients demonstrated a significant reduction in epithelial and subpapillary nerve fibers in the lingual mucosa, which strengthens the hypothesis of small-fiber polyneuropathy (7). There also appears to be a strong interaction with psychological factors, especially depression and anxiety disorders (8, 9).

On the other hand, “secondary” BMS is attributed to identifiable local or systemic factors. Local factors include odontogenic diseases, mechanical and chemical irritants, viral, bacterial, or fungal infections, as well as hypersensitivity reactions. Systemic factors may be induced by drugs, anemia, vitamin B12 or folic acid deficiency, Sjögren’s syndrome, and diabetes mellitus (2). In this study, we adopted the ICHD-3 classification, in which BMS is diagnosed only after ruling out all potential local and systemic causes. BMS-like symptoms that can be attributed to the aforementioned factors should be labeled as symptomatic BMS and be treated with a targeted therapy for the causing factor (1).

A therapeutic strategy for BMS based on evidence from studies is missing. The treatment approaches can be differentiated into symptomatic and topical therapies. Topical treatments include capsaicin and benzodiazepines, systemic treatments pregabalin, gabapentin or tricyclic antidepressants like amitriptyline. Given the large psychiatric comorbidity, cognitive behavioral approaches complement pharmacologic treatments. Multimodal, multidisciplinary therapy with pharmaceutical and psychosocial approaches seems to be most effective. However, the evidence regarding the success of these treatment options is limited (2, 5). Cranial electrical stimulation (CES) is a non-invasive procedure involving transcutaneous application of pulsed, low amplitude (<1 mA) electrical voltage via electrodes to the earlobes. CES received FDA (Food and Drug Administration) approval in 1979 for the treatment of depression, anxiety disorder and insomnia (10). The exact mechanism of action of CES is unknown. Studies have shown that CES can affect the blood levels of various neurotransmitters, such as beta-endorphin or serotonin, and may act via the limbic system, the reticular ascending system (RAS) and the hypothalamus (11, 12). Changes in the EEG after CES use have been observed, including an increase in alpha and a decrease in beta and delta activity. These alterations indicate a possibly improved relaxation. CES also appears to influence the brain’s default mode network (DMN) (13), which is significantly activated by serotonin and whose connectivity is altered in depression, sleep disorders, anxiety disorders and pain (13, 14). Many studies have investigated the benefits and effectiveness of CES. Also, in randomized, double-blind, controlled clinical trials, a positive effect for CES on pain was shown in patients with fibromyalgia (15) and in neuropathic pain after spinal cord injury (12). There is also supporting evidence for the amelioration of psychological comorbidities, which are highly prevalent among individuals with BMS, through CES. In a randomized, double-blind, controlled clinical trial, Barclay and Barclay showed significant improvement after CES in patients with anxiety disorder and comorbid depression (11).

In Transcutaneous electrical nerve stimulation (TENS) electrical currents are delivered to the skin through surface electrodes for pain relief.

The precise mechanism of TENS is not fully understood. Its analgesic effect is believed to be complex, involving peripheral, spinal, and supraspinal mechanisms. Animal studies demonstrated that the analgesic effect was partly mediated by peripheral mechanisms like a decreased peripheral response to serotonin and changes in antinociceptive α2A-adrenergic receptors (16). A spinal effect for electrical stimulation was initially demonstrated by Melzack and Wall’s Gate Control Theory which suggests that afferent fibers can inhibit nociceptive activity in the dorsal horn of the spinal cord, resulting in reduced pain perception (17). Animal studies also indicate changes in neurotransmitter levels like GABA and Glycine associated with TENS (18, 19). Regarding central mechanisms, there is a suggestion that TENS stimulates descending inhibitory nerve pathways and increases the release of endorphins (20). Positive effects of TENS on pain have been demonstrated in patients with fibromyalgia (21) and neuropathic pain after spinal cord injury (22). Additionally, TENS has shown efficacy as a therapeutic option in trigeminal neuralgia, migraine, and cluster headache (23–27).

In this study we aimed to investigate the therapeutic effectiveness of CES in combination with local TENS as an adjunct therapy in patients with BMS compared to sham stimulation. We assessed the impact on pain intensity, sleep quality, and psychological comorbidities, such as somatic symptoms disorder, depression and anxiety disorders.

The process of patient recruitment is shown in Figure 2. At the onset of recruitment, there were 101 potential study participants with BMS. Out of these, 22 patients met the inclusion criteria and none of them discontinued the study. The average age of the entire group was 64 years, with 77% of the patients being female. Demographic and clinical characteristics of patients are summarized in Table 1.

CES represents a non-invasive treatment option with a low likelihood of severe adverse events. Over the study period, both groups experienced a significant reduction in pain. However, superiority of active stimulation over sham stimulation could not be demonstrated. Other studies have shown a significant reduction in pain intensity through CES in chronic pain syndromes, such as fibromyalgia or pain in Parkinson’s disease (15, 29, 30). TENS as well has demonstrated efficacy in individuals (21), neuropathic pain after spinal cord injury (22) and various types of headaches in clinical studies (23–27). As TENS and CES share similarities in their application, mechanisms, and effects, there is a potential for a synergistic analgesic effect. Additionally, there could be an additional local effect through the TENS stimulation directly on the tongue, where the main symptoms of BMS are located. However, in our study, the patients’ evaluation at the end of the study period indicates that the modest improvements were not significant enough to create a subjective sense of improvement for the majority of the patients. Many BMS patients had a long history of unsuccessful treatments, leading to a high burden of disease and therefore high hope for an improvement. When this improvement does not occur in the expected intensity, it can reinforce the already felt frustration. It is known that BMS patients tend to catastrophize (31). Catastrophizing has been defined as an exaggerated negative orientation toward pain stimuli and pain experience (32). It affects the modulation of pain stimulus, the way patients cope with their pain, and the response to the treatment (33). These aspects could have been a reason that the patients did not perceiving little changes and evaluated the stimulation rather negative. The subjects for the study were recruited via the Headache Centre and the Department of Oral and Maxillofacial Surgery at Rostock University Medical Centre, so that a selected clientele was probably included in the study. The patients were often severely affected and had remained refractory to previous treatment attempts.

Another factor that influenced the results is the placebo effect, which is often particularly strong in patients with pain and can pose a methodological problem in the control group, especially in stimulation studies. In other BMS studies, a significant placebo effect has been reported, ranging from 15 to 75% (34). Barcley et al. conducted a 5-week randomized, double-blind, placebo-controlled study to evaluate the efficacy of CES for various anxiety disorders and comorbid depression. Patients in the active group received 60 min of stimulation over the course of 5 weeks, and their symptoms were assessed using the HAMA and HAMD. They found a significant decrease of anxiety and comorbid depression scores in the active group. However, a significant increase of 28% in anxiety scores was also observed in the sham group. The authors attributed this result to the placebo effect (11).

Also in chronic migraine, another chronic pain condition with a similar spectrum of especially psychiatric comorbidities, a substantial placebo effect is often observed. The reported placebo effect in the acute treatment of migraine attacks is up to 47% and in migraine prophylaxis usually between 20 and 40% (35).

The choice of sham stimulation can pose a methodological problem, as shown in the study by Straube et al. who investigated the efficacy of transcutaneous stimulation of the auricular branch of the vagus nerve in chronic migraine patients. Active stimulation with a 1 Hz frequency was used in the control group, which surprisingly proved to be more effective than the stimulation at 25 Hz in the active group. The authors initially expected the 25 Hz stimulation to be more effective, and the 1 Hz frequency was primarily planned for blinding purposes only. It remains unclear whether this result was due to a placebo effect or if the frequency was already high enough to induce a therapeutic effect (36). Although we chose inactive devices for the control group to avoid this effect in our study, including a non-intervention group would have provided additional information for both studies. As it helps to evaluate whether the stimulation process itself induced the reduction in pain intensity or a placebo effect. As a secondary endpoint, our study investigated the impact of CES on psychiatric comorbidities and sleep. At the baseline a greater number of patients in the active group were utilizing antidepressants and pregabalin. Nevertheless, considering the limited potential for neuromodulation devices to interfere with concurrent treatments or associated comorbidities, this is expected to have a relatively modest effect (10, 37, 38). Despite the presence of high psychosomatic comorbidity in our study population, there was no significant decrease in depression and anxiety scores between the beginning and end of the study either. This differs from numerous other studies that have described CES as a good treatment option for psychiatric conditions (10, 39, 40). However, contradictory and heterogeneous results are also described in the literature. In a Cochrane Review, O'Connell et al. concluded that the evidence was insufficient to support the use of CES for depression due to the low quality of the studies (41). The FDA also reached a similar conclusion in December 2019 stating that effectiveness of CES for the treatment of depression was “unclear.” They noted significant limitations in the quality of available clinical studies and a lack of high evidence results regarding the use of CES in patients with depression or sleep disorders (42). In summary, the evidence regarding the effectiveness of CES for psychiatric conditions is heterogeneous and does not allow a definitive judgment. Kirsch and Gilula conclude in a meta-analysis on the use of CES for insomnia that CES is an excellent treatment option for patients with insomnia. The review examined 20 studies using CES for the treatment of patients with primary insomnia, as well as with insomnia occurring as a comorbidity with psychiatric and pain-related disorders (39). We observed an improvement in sleep quality in some patients. However, in comparison to other studies, the observed effect was small, and no advantage of active stimulation over sham stimulation could be observed.

This study aimed to investigate the therapeutic effectiveness of CES as an adjunct therapy in patients with BMS compared to sham stimulation. According to our study results, CES is a low-risk and easily applicable therapeutic option that led to an improvement in symptoms and reduced the burden of the disease in some BMS patients. Over the study period, both groups experienced a significant reduction in pain intensity, somatic symptoms and an improvement in sleep quality. Superiority of active stimulation over sham stimulation could not be demonstrated. To prove the high effectiveness of CES, further studies with strong evidence are necessary. Studies exploring the ethology of BMS are needed to develop therapeutic approaches, as well as clinical trials aimed at devising improved treatment strategies for BMS.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by the Ethics Committee of the University Medical Centre Rostock. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

AP: Data curation, Formal analysis, Investigation, Writing – original draft. TH: Formal analysis, Writing – review & editing. JL: Formal analysis, Writing – review & editing. BM: Formal analysis, Writing – review & editing. PK: Formal analysis, Writing – review & editing. TJ: Conceptualization, Formal analysis, Writing – review & editing. FR: Conceptualization, Formal analysis, Writing – original draft, Writing – review & editing.