Clinical Psychopharmacology and Neuroscience 2019; 17(1): 139-142  
Effectiveness of Pregabalin for Treatment of Burning Mouth Syndrome
Saliha Yeter Amasyalı1, Aslı Akyol Gürses2, Osman Nuri Aydın3, and Ali Akyol4
1Department of Physical Medicine and Rehabilitation, Division of Algology, Adnan Menderes University Faculty of Medicine, Aydın, Turkey, 3Department of Anesthesiology, Division of Algology, Adnan Menderes University Faculty of Medicine, Aydın, Turkey, 4Department of Neurology, Adnan Menderes University Faculty of Medicine, Aydın, Turkey, 2Department of Neurology, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey
Correspondence to: Address for correspondence: Ali Akyol, MD, Department of Neurology, Adnan Menderes University Faculty of Medicine, Aydın 09100, Turkey, Tel: +90-5054549278, Fax: +90-256-2136064, E-mail: aakyol@adu.edu.tr, ORCID: https://orcid.org/0000-0002-3109-6573
Received: April 10, 2017; Revised: May 31, 2017; Accepted: June 1, 2017; Published online: February 28, 2019.
© The Korean College of Neuropsychopharmacology. All rights reserved.

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Treatment of burning mouth syndrome (BMS) is challenging because there is no consensus regarding pharmalogical or nonpharmalogical therapies. The use of anticonvulsants is controversial. We present nine patients BMS who respond to pregabalin. They were diagnosed secondary BMS except two. Etiologic regulations were made firstly in patients with secondary BMS but symptoms did not decrease. We preferred pregabalin in all patients and got good results. Furthermore the addition of pregabalin to the treatment of two patients who did not respond adequately to duloxetine provided good results. We are only aware that pregabalin may reduce symptoms as a result of case reports. We believe that the diagnosis of pathologic etiology with appropriate diagnostic tests will result in better outcomes in treatment.

Keywords: Burning mouth syndrome, Anticonvulsants, Pregabalin
INTRODUCTION

Burning mouth syndrome (BMS) is classified in ‘painful cranial neuropathies and other facial pains’ section (part 3) in the International Classification of Headache Disorders III-beta (ICHD-III-beta). In this classification it is defined as “an intraoral burning or dysesthetic sensation, recurring daily for more than 2 hours/day over more than 3 months, without clinically evident causative lesions.1) It has numerous different definitions belonging to several organizations such as the American Academy of Orofacial Pain, The International Association for the Study of Pain. In 2003, Scala et al.2) have suggested the definitions ‘primary (essential or idiopathic—there is no underlying cause) and secondary BMS (resulting from local or systemic precipitating factor)’. This classification was probably more pragmatic approach.2) This chronic idiopathic pain condition affects to range from 0.7% up to 15% of the population. It is more common in female than male and occurs in the fifth-seventh decade of life in general.2,3) We present nine patients who were diagnosed with BMS and successfully treated with pregabalin.

CASE

All patients who had complaint of dysesthesia or burning in the mouth were included from the outpatient clinic of Department of Neurology, Adnan Menderes University. The intensity, onset, duration, alleviating-aggravating factors of symptoms and medical history were evaluated. Thereafter intraoral-systemic exam and laboratory-imaging-electroencephalography (EEG) studies were performed. All patients fulfilled the International Headache Society diagnostic criteria (ICHD-III-beta version) for BMS (Table 1). Demographic data, predisposing factors or comorbidities, pain intensity according to numeric rating scale, treatment period and follow-up duration are summarized in Table 2. Seven patients were female, only two were male. There were hypertension, thyroid nodule, diabetes mellitus, sickle cell trait, hypertriglyceridemia, gastritis, migraine, tension type headache in their medical histories. The duration of symptoms was six months or longer in all patients. The complaints started in two patients after their teeth had been extracted. One patient with Parkinson disease was taking levodopa treatment. Laboratory work-up including blood urea nitrogen, creatinine, electrolytes, alanine amino transferase, aspartat amino transferase, cholesterol, tryglicerids, complete blood cell count, iron, ferritin, vitamin B12, erythrocyte sedimentation rate, albumin, total protein, tri-iodothyronine, thyroxine and thyroid stimulating hormone was conducted. All parameters were normal in all patients (including those with thyroid nodules) except hemoglobin A1c levels. Blood glucose control (increased hemoglobin A1c levels) was unfavorable in two patients with diabetes mellitus. No pathology was detected in the EEG that was performed to exclude partial epilepsy and cranial magnetic resonance imaging had also no features. They were diagnosed secondary BMS based on clinical and laboratory data except two patients.

DISCUSSION

BMS is an enigmatic disease characterized by intraoral discomfort such as burning, tingling, tender, scalding and numbness that reported in different sites of oral cavity. Most commonly affected areas are anterior part, dorsum and lateral borders of tongue, anterior facet of hard palate and labial mucosa of the lips in the mouth respectively.3)

The pathogenesis of BMS is still unclear. For this reason, recently it is considered that BMS has multifactorial etiology with enigmatic pathophysiology. Several hypotheses have been put forward with the reason of many findings revealed in the literature; neuropathic mechanism, hormonal alterations, psychologic mechanism. These findings in the literature are as follows: Lower density of epithelial and subpapillary nerve fibers of tongue reflecting trigeminal small fiber sensory neuropathy and axonopathy; changes in saliva composition, mucosal blood flow and cell morphology; intensely decreasing of neurosteroids following falls of systemic steroids; damage to any special sensory nerve responsible for taste sensation (glossopharyngeal, vagus, chorda tympani, greater petrosal nevre) and hence probably impairing central inhibitory activity on the trigeminal system; pathologic responses of blink reflexes again indicating subclinical trigeminal neuropathy; impairment in autonomic system findings which are similar to those found in Parkinson disease that exhibited by autonomic nervous function studies and reduction in dopamin levels in nigrostriatal neurons displayed by PET studies suggesting involvement of the central dopaminergic system; thalamic hypo-activation demonstrated by functional magnetic resonance imaging supporting that loss of central inhibitor mechanism, etc.38)

In conclusion, it appears that BMS implicate disturbance of the central and/or peripheral nervous system. Furthermore, psychological inconvenience and hormonal alterations may contribute to these neuronal changes. An increasing number of studies are on the way to establish the underlying pathological process/processes.

The diagnosis of primary BMS based on the exclusion of all possible systemic or local factors and is purely clinical. All possible causes of secondary BMS must be excluded.5,6) If an underlying cause is detected, it should be regulated or removed firstly according to determined pathology. Some of the local and systemic factors that may cause burning mouth are as follows: oral infections (bacterial, viral or fungal); mechanical and chemical irritations; thermal injury; hyposalivation; parafunctional habits; oral mucosal lesions; allergic contact stomatitis; nutritional deficiencies involving iron, zinc, folate and vitamin B1, B2, B6, B12; autoimmune, gastrointestinal and endocrine-hormonal deficiencies disorders (connective tissue disorders, diabetes, hypothyroidism); drug induced conditions that possibly causing hyposalivation/xerostomia as side effect (tricyclics, antipsychotics, anti-hypertensives such as angiotensin-converting enzyme inhibitors, opioids etc). A thorough evaluation is needed when BMS is suspected and the diagnosis of BMS remains a major challenge in general.3,5,6)

First of all, we organized underlying causes (disorder or deficiencies) that identified in the etiologic investigation. For example, iron and vitamin B12 deficiencies were replaced in the patient 4 and 5, respectively or uncontrolled glucose levels were detected in patient 4 and 6, so they were consulted to Department of Endocrinology and the treatments were rearranged. Although HbA1C levels were normal after three months, the complaints of the patients continued. Also these patients (patient 4 and 6) were taking duloxetin treatment at 60 mg/day when they applied to our outpatient clinic. Levodopa which is known to cause hyposalivation/xerostomia side effect was stopped in patient 7 with Parkinson disease. Treatment of this patient was resumed with dopa agonist (pramipexol). Patient 1 and 8 were consulted to the department of dental surgery since the complaints did not resolve despite the completion of wound healing period of tooth extraction. However there was no additional recommendation. Mild mood disturbance scores which were assessed by the Beck Depression Inventory were detected in these patients who were thought to be secondary BMS. Also the anxiety scores which were assessed with the Beck Anxiety Inventory were found mild levels in three patients (patient 4, 5 and 7). Patient 9 was taking amlodipine for hypertension treatment and also had thyroid nodule but thyroid function tests were normal. Nonetheless, this patient was regarded as secondary BMS. In our series, the comorbidities were not considered as underlying cause in two patients (patient 2 and 3) so they were diagnosed as primary BMS.

Treatment of BMS is challenging because there is no consensus regarding pharmalogical, nonpharmalogical (cognitive behavioral therapy, complementary and alternative medicine, acupuncture, etc) and interventional therapies (lingual nerve block, topical anesthetic dyclonine). Clonazepam, topical benzydamine, systemic capsaicin, trazodone, amisulpride, paroxetin, sertralin, alpha lipoic acid (ALA) are studied in a few randomized controlled trial in the literature. Gabapentin, nortriptyline and pregabalin commonly used but there is no randomized controlled study except gabapentin. Nonetheless distinct recommendations are scarce and the optimal approach is not yet satisfactory in patients with BMS.6,7,9)

The pathophysiological evidence related to neuropathic mechanisms has increased recently. However, a consensus concerning treatment for BMS has not been attained. Furthermore the use of anticonvulsants is controversial in the literature. White et al.10) reported that gabapentin has favorable results in BMS patient, but Heckman et al.11) did not support their findings. In 2009, López et al.12) reported a case with BMS that improved with pregabalin treatment. Thereafter, in their randomized double blind placebo controlled study, López-D’alessandro and Escovich13) reported that the use of combination ALA and gabapentin was useful than gabapentin alone or plasebo and also gabapentin alone was beneficial than placebo. In another study related to anticonvulsants, Ito et al.9) proposed pregabalin may become treatment option for BMS patients who are not responsive to serotonin-norepinephrine reuptake inhibitors.

We administered immediately pregabalin treatment to two patients with primary BMS diagnosis whereas other seven patients diagnosed with secondary BMS received the same treatment after the etiologic evaluation or corrections. It is known that we usually treat comorbidities such as depression, anxiety, insomnia, cognition deficit besides the therapy of pain and neuropathies. Pregabalin has antiepileptic, analgesic and anxiolytic effects and also perfect effect at allodinia and hyperalgesia. Its action appears to be alpha 2-delta subunit of voltage dependent calcium channels widely distributed throughout the peripheral and central nervous system. It modulates the excessive release of excitatory neurotransmitters by reducing depolarization-induced calcium influx. It has highly predictable and linear pharmacokinetics, good bioavailability, dose-proportional plasma concentrations.1416) For this reasons pregabalin was used as the first choice agent and also by considering the existence of both central and peripheral neuropathic mechanisms in BMS. Therefore pregabalin was initiated 2×50 mg/day. After one week the doses of pregabalin were increased to 2×150 mg/day. In three patients who did not respond adequately, it was increased to 2×225 mg/day (patient 4, 5, 6). Dizziness and impaired balance was observed in three patients, hypersomnia in one patient and constipation in two patients as a side effect. None of the patients terminated their treatment due to these side effects.

We considered two patients as primary BMS and the remaining as secondary. However there is still diagnostic dilemma to distinguish primary and secondary cases.17) This present report demonstrated that good results were obtained with pregabalin treatment in both primary and secondary types. There were no patients presenting with a new episode after pregabalin was discontinued. Topics such as drug choice, individualization of treatment, duration of treatment are not yet clear. We believe that further randomized controlled trials are needed to confirm the clinical algorithm.

Tables

Demographic data and clinical characteristics of patients with burning mouth syndrome

No.Age (yr)SexComorbidity/predisposition stateAffected region in the mouthBDI scoresBAI scoresNRS baselineNRS endpointTreatment periodFollow-up duration
149MTooth extraction historyHard palate mucosa117836 mo6 mo
222MMigraineSoft palate mucosa87726 mo6 mo
360FGastritisTongue106831 yr1 yr
454FDiabetes mellitus
Iron deficiency
Thyroid nodule
Palate mucosa, dorsum lingua1515912 yr1 yr
561FPeripheral facial paralysis
Vitamin B12 deficiency
Hypertri glyceridemia
All of the oral mucosa, lingual margins1314802 yr1 yr
652FDiabetes mellitus
Sickle cell trait
Thyroid nodule
Hypertri glyceridemia
Labial mucosa of the lips167922 yr1 yr
793FParkinson’s disease
Hypertension
All of the oral mucosa1215713 yr2 yr
870FTooth extraction history
Hypertension
Tongue, hard palate mucosa125801 yr1 yr
955FHypertension
Thyroid nodule
Tension type headache
Lower lip136823 yr2 yr

BDI, Beck Depression Inventory; BAI, Beck Anxiety Inventory; NRS, Numeric Rating Scale; M, male; F, female.

International Headache Society diagnostic criteria for burning mouth syndrome

13.10 Burning mouth syndrome (BMS)
A. Oral pain fulfilling criteria B and C
B. Recurring daily for >2 hours per day for >3 months
C. Pain has both of the following characteristics:
  • Burning quality

  • Felt superficially in the oral mucosa

D. Oral mucosa is of normal appearance and clinical examination including sensory testing is normal
E. Not better accounted for by another ICHD-III-beta diagnosis.

ICHD, International Classification of Headache Disorders.

References
  1. Headache Classification Committee of the International Headache Society (IHS) (2013). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 33, 629-808.
    Pubmed CrossRef
  2. Scala, A, Checchi, L, Montevecchi, M, Marini, I, and Giamberardino, MA (2003). Update on burning mouth syndrome: overview and patient management. Crit Rev Oral Biol Med. 14, 275-291.
    Pubmed CrossRef
  3. Klasser, GD, Grushka, M, and Su, N (2016). Burning mouth syndrome. Oral Maxillofac Surg Clin North Am. 28, 381-396.
    Pubmed CrossRef
  4. López-Jornet, P, Camacho-Alonso, F, Andujar-Mateos, P, Sánchez-Siles, M, and Gómez-Garcia, F (2010). Burning mouth syndrome: an update. Med Oral Patol Oral Cir Bucal. 15, e562-e568.
    CrossRef
  5. Gurvits, GE, and Tan, A (2013). Burning mouth syndrome. World J Gastroenterol. 19, 665-672.
    Pubmed KoreaMed CrossRef
  6. Nasri-Heir, C, Zagury, JG, Thomas, D, and Ananthan, S (2015). Burning mouth syndrome: current concepts. J Indian Prosthodont Soc. 15, 300-307.
    CrossRef
  7. Ducasse, D, Courtet, P, and Olie, E (2013). Burning mouth syndrome: current clinical, physiopathologic, and therapeutic data. Reg Anesth Pain Med. 38, 380-390.
    Pubmed CrossRef
  8. Jääskeläinen, SK (2012). Pathophysiology of primary burning mouth syndrome. Clin Neurophysiol. 123, 71-77.
    CrossRef
  9. Ito, M, Tokura, T, Yoshida, K, Nagashima, W, Kimura, H, and Umemura, E (2015). Five patients with burning mouth syndrome in whom an antidepressant (serotonin-noradrenaline reuptake inhibitor) was not effective, but pregabalin markedly relieved pain. Clin Neuropharmacol. 38, 158-161.
    Pubmed CrossRef
  10. White, TL, Kent, PF, Kurtz, DB, and Emko, P (2004). Effectiveness of gabapentin for treatment of burning mouth syndrome. Arch Otolaryngol Head Neck Surg. 130, 786-788.
    Pubmed CrossRef
  11. Heckmann, SM, Heckmann, JG, Ungethüm, A, Hujoel, P, and Hummel, T (2006). Gabapentin has little or no effect in the treatment of burning mouth syndrome - results of an open-label pilot study. Eur J Neurol. 13, e6-e7.
    Pubmed CrossRef
  12. López, V, Alonso, V, Martí, N, Calduch, L, and Jordá, E (2009). Marked response of burning mouth syndrome to pregabalin treatment. Clin Exp Dermatol. 34, e449-e450.
    Pubmed CrossRef
  13. López-D’alessandro, E, and Escovich, L (2011). Combination of alpha lipoic acid and gabapentin, its efficacy in the treatment of Burning Mouth Syndrome: a randomized, double-blind, placebo controlled trial. Med Oral Patol Oral Cir Bucal. 16, e635-e640.
    CrossRef
  14. Ben-Menachem, E (2004). Pregabalin pharmacology and its relevance to clinical practice. Epilepsia. 45, 13-18.
    Pubmed CrossRef
  15. Gajraj, NM (2005). Pregabalin for pain management. Pain Pract. 5, 95-102.
    CrossRef
  16. Ceyhan, M, and Tan, E (2008). A new anticonvulsant pregabalin: pre-clinical data. Turk J Neurol. 14, 161-171.
  17. Aggarwal, A, and Panat, SR (2012). Burning mouth syndrome: a diagnostic and therapeutic dilemma. J Clin Exp Dent. 4, e180-e185.
    Pubmed KoreaMed CrossRef


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