Abstract
Data sources
Cochrane Oral Health's Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), Medline Ovid, Embase Ovid, US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform. Handsearch of the proceedings from the British Society for Oral Medicine (BSOM), British Society for Dental Research (BSDR) and the International Association for Dental Research (IADR).
Study selection
All included studies were randomised placebo controlled trials comparing a treatment to placebo with no language or year of publication restrictions. Symptom relief and changes in quality of life were considered primary outcomes.
Data extraction and synthesis
Teams of two authors independently screened for inclusion, extracted data using an ad-hoc tool and assessed the risk of bias using the Cochrane's tool. Outcomes were analysed for <3 months (short term) and ≥3 to ≤6 months (long term). For single studies with multiple interventions, the number of participants in the control group was adjusted to half before combining the results. For crossover studies without washout periods, the first period was analysed. RRs (risk ratios) and 85% confidence intervals were calculated for dichotomous outcomes and MDs (mean differences) and 95% confidence intervals for continuous data.
Results
A total of 23 studies encompassing 1121 patients were included. One study was considered as having overall low risk of bias, four unclear and the rest as high risk of bias. The interventions were grouped into: antidepressants and antipsychotics, anticonvulsants, benzodiazepines, cholinergics, dietary supplements, electromagnetic radiation, physical barriers, psychological therapies and topical treatments. Short-term symptom relief was demonstrated by: energy waves (one study, 58 participants) MD −30.36, 95% CI −44.22 to −16.50, physical barriers (one study, 50 participants) MD −1.1 95% CI −2.14 to 0.06, the anticonvulsant gabapentin (one study, 100 participants) RR 4.00, 95% CI 2.09 to 7.67 and topical benzodiazepine (two studies, 111 participants) MD −1.89 95% CI −2.19 to −1.59. Long term symptom relief was achieved with topical benzodiazepine (one study, 66 participants) MD −1.39 95% CI −1.96 to 0.83
Conclusions
From studies mostly classified as high risk of bias, there is insufficient evidence to support or refute the use of any particular intervention for the management of BMS.
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Commentary
Burning mouth syndrome is a diagnosis of exclusion used for oral mucosal burning or pain without identifiable dental or medical causes. It has been considered a syndrome because patients may also experience xerostomia and altered taste or smell. Recent studies have demonstrated that several neuropathic mechanisms (both central and peripheral changes) contribute to the pathophysiology of BMS. Anxiety, depression and personality disorders are often co-morbid psychiatric diagnoses in these patients. BMS is a common chronic condition that occurs more often in women. It has been shown to negatively affect quality of life, necessitating the need for studies investigating effective interventions.
This is an update of a previously reported review in 2005 that included nine trials. This review consists of 23 randomised controlled trials comparing any treatment against placebo. The authors were careful to review only studies that included patients with ruled-out identifiable causes of oral mucosal burning. A total of 1061 women (83%) and 221 men (17%) are reported to have participated in these studies.
The primary outcomes measured were symptom relief and changes in quality of life. The VAS scale as a measure of pain or burning was used in 17 of the studies. Other measures were used in the remaining studies. Only four studies directly assessed changes in quality of life, while three studies assessed depression or anxiety as secondary markers of quality of life. Since anxiety, depression and personality disorders are often co-morbid with BMS, it may be unrealistic to expect changes in quality of life in studies without psychological therapy, but it may help elucidate the relationship of pain to the psychological conditions.
The secondary outcomes evaluated were changes in taste, changes in dryness and adverse effects. Only two studies assessed changes in taste. There were no studies with quantitative data for changes in feeling of dryness.
The review categorises the treatment interventions into: antidepressants, antipsychotics, anticonvulsants, benzodiazepines, cholinergics, dietary supplements, electromagnetic radiation, physical appliance, psychotherapy and topical treatments. Most of the interventions studied were selected based on treatments used for other types of neuropathic pain (clonazepam, gabapentin, alpha lipoic acid), Some interventions targeted increasing salivary flow (bethanachol, lactoperoxidase rinse, topical urea).
The authors suggest that one limitation of all of the studies reviewed was that other drugs within the same class as the drug investigated were not used as a comparison. It needs to be considered that some drugs used for the treatment of neuropathic pain are unique in their class. Gabapentin is an anticonvulsant that is commonly used to treat neuropathic pain, clonazepam is a benzodiazepine that is commonly used to treat neuropathic pain and capsaicin is a topical treatment for desensitization of peripheral nerves for the treatment of neuropathic pain. Alpha lipoic acid is a dietary supplement that has been previously been studied for the treatment of diabetic neuropathy. If BMS is a neuropathic pain it would necessitate studies of interventions that have been shown to be effective in other types of neuropathic pains. The authors even suggest in their conclusion that treatments that are established in the management of neuropathic pain conditions and psychological therapies should be considered for clinical trials in BMS.
Only placebo-controlled studies were included in this review. While such trials limit bias, placebo may also be a limitation when studying pain and could be the reason why there were only four long-term studies, none with systemic medications. According to the reviewers, about half of the studies had a high risk of attrition and selective reporting.
The review found some evidence of a benefit (very low quality) in short-term symptom relief for electromagnetic radiation, topical benzodiazepines, physical barriers and anticonvulsants. From the long-term effect data available, the review found some evidence for symptom relief (very low quality) from psychological therapies, capsaicin oral rinse (topical) and topical benzodiazepines.
Of the little data available for quality of life, the review found some evidence of short-term improvement from electromagnetic radiation. Findings for changes in taste and feeling of dryness were inconclusive. There was a low quality of evidence for adverse events for antidepressants and alpha lipoic acid, and insufficient evidence of adverse events for anticonvulsants and benzodiazepines. Adverse events were poorly or under reported for cholinergics, psychological therapies and electromagnetic radiation.
Overall the quality of the evidence assessed was very low for all interventions except physical barriers, which was assessed as low.
Ideally long term RCTs are needed to evaluate the effectiveness of neuropathic pain medications and psychological therapies for BMS. Long-term studies may be challenging and perhaps unethical when requiring retention of placebo-controlled patients who have been experiencing long term pain.
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Additional information
Address for correspondence: Luisa Fernandez Mauleffinch, Managing Editor, Cochrane Oral Health Group, School of Dentistry, The University of Manchester, JR Moore Building, Oxford Road, Manchester, M13 9PL, UK. E-mail: luisa.fernandez@manchester.ac.uk
McMillan R, Forssell H, Buchanan JA, Glenny AM, Weldon JC, Zakrzewska JM. Interventions for treating burning mouth syndrome. Cochrane Database Syst Rev 2016; 11: Art. No. CD002779. DOI:10.1002/14651858.CD002779.pub3.
This paper is based on a Cochrane Review published in the Cochrane Library 2016, issue 11 (see www.thecochranelibrary.com for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and the Cochrane Library should be consulted for the most recent version of the review.
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Fischoff, D., Spivakovsky, S. Little evidence to support or refute interventions for the management of burning mouth syndrome. Evid Based Dent 18, 57–58 (2017). https://doi.org/10.1038/sj.ebd.6401244
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DOI: https://doi.org/10.1038/sj.ebd.6401244
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