Burning Mouth Syndrome

Etiology

The etiology behind BMS is not well understood. Multiple theories exist regarding the underlying etiology, and most believe the condition to be multifactorial. As previously stated, the disease has a higher prevalence in peri- and postmenopausal women, which supports the theory that estrogen plays a role in the underlying process.[8] Decreased estrogen levels can lead to the atrophy of oral mucosal tissue, which may leave the area more susceptible to inflammatory change and the development of symptoms of BMS. In some cases, the infection may precede the development of symptoms, and certain pathogens are more commonly found in patients actively suffering from BMS, including Candida, Enterobacter, Fusospirochetal, Helicobacter pylori, and Klebsiella.[8] Diabetes mellitus and associated peripheral neuropathy may also cause symptoms related to BMS, although the underlying mechanism is neuropathy in this case.

There is an association with certain irritants, including dental materials such as mercury, amalgam, methyl methacrylate, cobalt chloride, zinc, and benzoyl peroxide.[9] Also, certain food allergies, including peanuts, sorbic acid, chestnuts, and cinnamon, have been related to BMS.[10] As previously stated, there is a connection with patients with neuropsychiatric conditions such as major depression, chronic anxiety, and mood disorders. The most common association is with a major depressive disorder, and it may follow acute symptoms or share an association with a comorbid condition at some point in the patient's life.[3] Other causes include orthodontic appliances, possible prescription drug adverse effects, increased bradykinin, and comorbid dermatologic conditions.[4]

Epidemiology

BMS is much more common in females than males, with 3 to 7 times higher occurrence. It has a strong association with advancing age in both sexes. The highest prevalence in females occurs in the perimenopausal and postmenopausal periods. The condition is non-existent in children and rarely seen in those under 30. Occurrence in males is rare before the fifth decade. Overall, the prevalence of BMS is not well documented but is thought to be around 4%.[8]

Pathophysiology

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 also show changes in taste perception and hot and cold sensation, which may have reflex hyperfunction to closely related nerve hypofunction. One study showed a link with the chorda tympani hypofunction, resulting in reduced taste while hyperstimulating the lingual nerve and causing symptoms. Other theories include mechanisms similar to phantom limb syndrome and small fiber neuropathy. Xerostomia in BMS is thought to be related more to neuropathy than a glandular issue. Mechanical damage from bruxism, clenching, and tongue thrusting may initiate symptoms, and psychiatric conditions most likely exacerbate symptoms.[11]

Toxicokinetics

BMS symptoms may correlate with certain medications, specifically angiotensin-converting enzyme (ACE) inhibitors and angiotensin blockers, resulting in increased bradykinin in a similar mechanism to the development of secondary angioedema. Although the mechanism is poorly understood, increased kallikrein levels (an active molecule in the kinin pathway) may be elevated in the saliva of patients with BMS and lead to inflammation. Other drugs that were linked to BMS include antiretrovirals such as efavirenz and nevirapine, as well as levothyroxine and topiramate. However, the underlying mechanisms are not fully understood. Irritation to tissue and nerves via contact dermatitis or direct nerve irritation may partially explain the mechanism.[12]

History and Physical

BMS is a diagnosis of exclusion. When taking a history, clinicians should rule out organic causes of oral pain and investigate the onset and duration of symptoms and associated medical conditions, medications, and history of oral prostheses. The absence of oral lesions is mandatory to diagnose BMS.[1]. The lack of consensus regarding BMS makes its diagnosis a difficult matter. Scala et al suggested 5 clinical criteria to diagnose BMS:

1. Deep and bilateral burning pain is reported daily.
2. Burning pain lasts for at least 4 to 6 months.
3. Constant or increasing severity throughout the day.
4. No worsening but improvement with eating and drinking.
5. No sleep interference.[13] 

Additional criteria include taste disorder, xerostomia, sensory or chemosensory alterations, and mood or psychological disorders.[13] Most patients experience taste disorders such as perceiving a metallic or bitter taste.[14]

Evaluation

In a review of the diagnostic and therapeutic approach to BMS, R. Aravindhan, Santhanam Vidyalakshmi et al suggest a series of steps to diagnose the condition:

1. Taking a careful history and quantifying the burning pain.
2. Examining oral mucosa to rule out local and systemic causes of oral pain.
3. Asking for information about psychological well-being.
4. Measuring salivary rate and taste function with objective methods.
5. Performing neurological examination and imaging to rule out degenerative disorders or other neurological pathologies.
6. Taking oral cultures to rule out suspected bacterial, fungal, or viral infections.
7. Performing allergy patch tests for allergic patients.
8. Investigating for gastric reflux disease.
9. Ruling out hormonal, autoimmune, and nutritional anomalies.

It is worth noting that if the tongue looks normal during the examination, no biopsy is required - it is only indicated when a lesion is seen.[1][8]

Treatment / Management

Only after ruling out local and systemic causes of burning symptoms can the patient be considered as having BMS.[4] The management of such patients is complex, and more than 1 treatment modality is often required. Importantly, the patient should be aware that complete resolution of symptoms is not always possible. The current management options include topical and systemic medications and a newer approach: cognitive behavioral therapy. Despite the need for standardized guidelines, laser therapy has also reduced symptoms.(B3)

Topical Medications

Capsaicin is an analgesic used as a desensitizing agent that acts on the sensory afferent neurons to manage neuropathic pain.[15] Capsaicin has proven to improve burning symptoms compared to placebo groups in 3 studies.[16] However, increased burning sensation after its application, dyspepsia, and toxicity may limit its use.[1][4][1] Topical clonazepam successfully improves BMS symptoms.[17] It is applied by sucking a 1 mg tablet 3 times per day for 2 weeks [18]; however, symptoms may come back if the medication is discontinued, and it can cause dependence.[17] Dry mouth and fatigue are other possible side effects.[4] Interestingly, unconventional topical agents, including a mouth rinse of tabasco sauce with water [1] or hot pepper and water [19] have reduced burning symptoms. Also, 70% aloe vera gel was applied 3 times per day in combination with a tongue protector, effectively decreasing the tongue's burning symptoms.[20] Due to its short-term effect, topical anesthesia, like lidocaine, is not considered an effective treatment option.[1](A1)

Systemic Medications

Low doses of clonazepam (0.5 mg per day) are frequently prescribed for treating BMS pain.[1] Systemic clonazepam relieves BMS pain but does not improve taste dysfunction, xerostomia, or mood.[21] It is a good option for short-term treatment since the chronic use of systemic clonazepam has not been deeply evaluated yet in this regard.[16] Systemic capsaicin can improve BMS symptoms but should be prescribed with caution because of its side effects, including gastric pain.[1]The regime consists of capsaicin 0.25% capsules 3 times daily for 4 weeks.[1](A1)

Even though they contribute to xerostomia symptoms, tricyclic antidepressants – amitriptyline, desipramine, clomipramine, imipramine, and nortriptyline – can also be used in managing patients with BMS.[1] The regime consists of an initial 5 to 10 mg daily dose, gradually increasing to 50 mg daily.[1]. Furthermore, selective serotonin reuptake inhibitor antidepressants such as sertraline, paroxetine, and duloxetine result in a significant improvement in oral burning symptoms.[22][1][22] Antipsychotic drugs like amisulpride and levosulpiride show good patient compliance in short-term treatments and are proven to reduce patients’ burning symptoms (24-week course of 50 mg daily).[1] A study reported a complete resolution of symptoms after supplementation with vitamins BC, B12, folic acid, and minerals [23], which decreased mean serum homocysteine levels and increased hemoglobin levels in the blood.[23][1][23] Finally, hormone replacement therapy has been used to decrease oral burning symptoms in peri- and post-menopausal women.[24][1][24](B3)

Behavioral Modulation

Relaxation and cognitive restructuring are 2 cognitive-behavioral therapy (CBT) techniques for BMS treatment. Patients learn focused breathing and muscle relaxation to alleviate pain using the relaxation technique.[25] Cognitive restructuring targets eliminating destructive thoughts – in the case of BMS, it aims at reducing pain catastrophizing [25], analyzing harmful automatic thoughts, and replacing them with more helpful ones.[25]

Low-level Laser Therapy

Low-level laser therapy stimulates the production and secretion of serotonin and β-endorphins and decreases bradykinin secretion, alleviating burning symptoms.[25] Low-level lasers also inhibit the depolarization of C fibers, which are responsible for transmitting pain and heat stimuli.[26] Standardized treatment guidelines are needed and are yet to be developed.[26](A1)

Differential Diagnosis

Multiple conditions may cause similar symptoms as BMS, including:

• Stomatitis,
• Atypical facial pain,
• Atypical odontalgia,
• Idiopathic facial arthromyalgia
• Pemphigoid
• Pemphigus
• Oral neoplastic lesions
• Acoustic neuroma
• Failed denture design or tooth restoration
• Herpes simplex
• Herpes zoster
• Post-surgical trauma to the lingual or mandibular nerve[27][13][8] 

Prognosis

The prognosis is variable and based on the underlying mechanism and comorbidity. While some cases are transient and resolve with symptomatic treatment and time, symptoms can persist for months to years or never resolve. The disease is not progressive or known to cause further damage.

Complications

BMS is a chronic condition that can remit spontaneously, improve moderately, or even worsen with time. Patients with BMS suffer from chronic burning pain, sometimes accompanied by xerostomia and taste disorders, significantly impairing their quality of life. The etiopathogenesis of the condition is yet to be understood; therefore, treatment is challenging, and no individual approach can fully resolve symptoms, frustrating patients and clinicians.