Duloxetine in the treatment of burning mouth syndrome refractory to conventional treatment: A case report

Abstract

Patients with burning mouth syndrome (BMS) report burning sensation and pain involving the tongue and oral mucosa without any apparent medical or dental cause. The pathogenesis of this syndrome remains unclear and there is currently no standard treatment. BMS is, therefore, often misdiagnosed and its management is complex. This lack of clinical expertise may result in decreased health-related quality of life and increased psychological distress among patients with BMS. The present case report involves a 77-year-old female patient with BMS refractory to conventional treatment with nerve block and medication, who was successfully treated with duloxetine. Duloxetine may become a new therapeutic option in the management of BMS.

Introduction

Burning mouth syndrome (BMS) is characterized by diffuse, persistent, and chronic painful burning sensations involving the tongue and oral mucosa. ¹ Other sites such as the hard palate, lips and floor of the mouth may also be involved. ² In patients with BMS, examination of the oral mucosa shows normal findings. Various treatment options have been proposed for BMS, however, there is currently no optimal approach.^3–5 Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor that has been shown to be effective in the treatment of pain associated with major depressive disorder. ⁶ Some reports have described the use of duloxetine as a first-choice medication for the treatment of BMS.^7,8 The present case report concerns a female patient diagnosed with BMS that was refractory to conventional treatment, but was successfully treated with duloxetine. Written informed consent to publish this case was obtained from the patient.

Case report

A 77-year-old female patient was transferred to the Department of Anaesthesiology and Pain Medicine, Wonkwang University Hospital, Ik-san, Republic of Korea in January 2012 from the Department of Oral Medicine in the same institute. She had complained of a burning sensation in her tongue and lower lip over the previous 2 years. Her medical history was unremarkable and she did not report any traumatic events. The patient described a severe burning sensation, with pain persisting throughout the day without any aggravating factors. Her level of pain was between 80 and 90 on a visual analogue scale (VAS) of 100 and she scored 40 of 45 on the short-form McGill Pain Questionnaire (SF-MPQ). ⁹ The patient had visited dentists, internists, neurologists and neuropsychiatrists at several other clinics, but no effective treatment had been proposed. Prior to transfer to the present clinic, she had been treated with up to 1200 mg gabapentin (oral, three times a day) and 0.5 mg topical clonazepam (applied to the tongue, three to four times a day) for one month. She initially reported a reduction in pain by 20% (VAS score), however, the improvement was short-lived and gabapentin caused side effects (dizziness).

The results of laboratory tests were normal, including assessments of haemoglobin level (12.9 g/d [normal range, 12–16 g/d]), platelet count (255 × 10³µl [normal range, 150–450 × 10³/µl]), white blood cell count (6.61 × 103/µl [normal, 4.10 × 10³ cells/µl]), erythrocyte sedimentation rate (3 mm/h [normal range, 0–10 mm/h]), and C-reactive protein level (0.62 mg/l [normal, 0–5 mg/l)]. Test results for liver function (aspartate transaminase, 18 IU/l [normal, 5–35 IU/l]; alanine transaminase, 12 IU/l [normal, 5–40 IU/l]) and thyroid function (tri-iodothyronine, 100.16 ng/dl [normal, 60–190 ng/dl]; thyroxine, 7.79 µg/dl [normal, 4.5–12.0 µg/dl]; thyroid stimulating hormone, 3.66 µlU/ml [normal, 0.2–5.0 µlU/ml]), electrolyte levels (sodium, 136 mEq/l [normal, 135–150 mEq/l]; potassium, 4.5 mEq/l [normal 3.5–5.5 mEq/l]), serum ferritin levels (41.97 µg/l [normal 13–150 µg/l]), total iron-binding capacity, percent transferrin saturation, serum vitamin B12 (74.66 µg/l [normal, 13–150 µg/l]) and folic acid levels (8.58 µg/l [normal, 4.6–18.7 µg/l]) were also normal. Brain magnetic resonance imaging did not show any abnormalities. Extra- and intraoral examinations performed at the Department of Oral Medicine yielded normal results, with no alteration of quality (viscosity, resting pH of unstimulated saliva) or flow in the salivary function test. The patient did not meet the Tenth Revision of the International Classification of Diseases and Related Health Problems (http://www.who.int/classifications/icd/en/) for any psychiatric disorder and had no history of depression on psychiatric consultation. The patient was also found to have a normal score on the Beck Depression Inventory, ¹⁰ which was completed while the clinical team took her full medical history; this finding indicated an absence of depression.

After diagnosing the patient with BMS, a nerve block was performed which comprised a stellate ganglion block (6 ml of 1% lidocaine) every 4 weeks and a lingual nerve block (4 ml of 1% lidocaine and 10 mg triamcinolone) bilaterally every 2 weeks, for a total of 4 weeks. The patient reported no side-effects. Her symptoms persisted, however, and treatment with 20 mg nortriptyline (oral, twice a day) and 600 mg carbamazepine (oral, three times a day) was administered for the following month. No beneficial clinical effects were observed, however, as the patient failed to adhere to the regimen because of somnolence. She was subsequently treated with an opioid (oxycodone/naloxone [Targin®]; Mundipharma Korea Ltd., Seoul, Korea) at a dose of 20 mg (oral, following breakfast) which increased to 40 mg (oral, twice a day), but no improvement in pain intensity was observed. Treatment with duloxetine was then initiated at a dose of 30 mg/day (oral, following breakfast) for 2 weeks followed by 60 mg/day (30 mg/oral, twice a day) for another 2 weeks. The patient’s symptoms gradually improved, and at 4 weeks of treatment her VAS pain score decreased to 50–60 and her SF-MPQ score decreased to 33. The patient continued to receive treatment for the following 3 months. At 4 months of treatment, her VAS score had decreased to 0–10 and her SF-MPQ to 6. The patient remained asymptomatic throughout a 16-month follow-up period.

Discussion

Burning mouth syndrome is a complex disease characterized by burning sensation and pain affecting the oral mucosa, including the tongue and lips, with no detectable abnormalities on physical examination or in laboratory tests. The disease is not fully understood and an accurate diagnosis is often challenging. Moreover, even if the condition is diagnosed correctly, treatment is not always effective. ¹¹ Most patients experience pain in the tongue, anterior portion of the soft palate, and lower lip. ³ Burning pain usually occurs by mid-morning or early afternoon, and maximum pain intensity is observed by early evening. ¹² Patients with BMS report difficulty falling asleep at night significantly more often than healthy subjects, but are usually not awakened by pain. ¹² In the present case, the patient complained of insomnia, but it might have been caused by the chronic nature of the pain and the unsuccessful treatment regimens, rather than the pain of burning mouth syndrome itself.

The pathogenesis of BMS remains unclear. One study reported a lower density of epithelial nerve fibres and reduced axonal degeneration in tongue biopsies in patients with BMS, suggesting a type of trigeminal sensory neuropathy. ¹³ Another study suggested reduced nigrostriatal dopamine levels as a pathophysiological factor in BMS, as observed in patients with anxiety or other forms of psychological distress. ¹⁴ An accurate diagnosis of BMS requires careful history taking, and other conditions (such as a disease of the oral mucosa, malnutrition, cerebral dysfunction or drug intoxication) need to be excluded. ⁶

No definitive treatment for BMS has been established, to date. The current approach combines medications, nerve block and supportive psychotherapy. ¹⁵ Treatment with low-dose clonazepam, chlordiazepoxide, and amitriptyline have been described, ⁶ and gabapentin and capsaicin have also been used in refractory patients. ¹⁶ In a randomized controlled crossover trial that assessed the efficacy of lingual nerve block by lidocaine in BMS, ¹⁷ Hospital Anxiety and Depression scores were shown to be higher in patients in whom lingual nerve block was less effective (that is, did not result in a decrease in VAS), compared with others. This led to the conclusion that there is a close relationship between BMS and psychological problems. It is generally known that patients with chronic pain do not respond to various treatments and might become more depressed and anxious, which, in turn, aggravates pain. It is not surprising therefore, that long-lasting and ineffective treatment of BMS is frequently associated with psychological disorders including anxiety and depression. ¹⁸

A report on BMS described a patient in which stellate ganglion block was effective, however, a mechanism was not proposed. ³ In the present case, treatment with conventional medication resulted in side-effects and did not yield satisfactory results. Stellate ganglion block and lingual nerve block did not result in side-effects or worsening of the psychological condition, but these treatments were not effective in treating the symptoms of BMS.

Duloxetine is a mixed serotonin and norepinephrine reuptake inhibitor used in the treatment of major depressive disorder, diabetic polyneuropathy and fibromyalgia. ⁸ It potently inhibits the neuronal reuptake of serotonin and norepinephrine, with similarly high affinity for transporter proteins such as serotonin transporter and norepinephrine transporter in brain and other tissues.^19,20 Since recent studies have shown a loss of function in descending inhibitory serotonergic and noradrenergic pathways in patients with BMS, duloxetine is expected to be a promising treatment option. ¹⁴ The efficacy of duloxetine might be due to its modulatory effect on serotonin and norepinephrine neurotransmission, even if no depression is diagnosed. There are only two other published reports on the efficacy of duloxetine as a first-choice treatment in patients with BMS.^7,8 Since there is insufficient evidence to confirm the efficacy of duloxetine in treating BMS, the authors propose its use as an alternative approach. In the present case the patient had experienced BMS that was refractory to treatment for 2 years and she was successfully treated with duloxetine. The authors therefore recommend duloxetine as an alternative medication in any case of BMS that is refractory to conventional treatment, although its mechanism of action and clinical dosage require more thorough investigation.