Title: Topical Clonazepam and Placebo Effect in Burning Mouth Syndrome
Description: Burning mouth syndrome (BMS) is a chronic pain condition reported to affect up to 7.9% of the general population, with associated detrimental impact on patients’ quality of life. Currently employed treatment regimens follow therapy for other neuropathic pain conditions. Very few placebo-controlled randomized trials (RCTs) have been conducted to evaluate the efficacy of these regimens, with a wide range of placebo responses documented. Low-dose clonazepam is considered first-line therapy for BMS, either in a topical or systemic mode of administration. An innovative formulation of topical clonazepam in the form of a compounded oral solution has been used at the Division of Oral Medicine and Dentistry at Brigham and Women’s Hospital (DOM-BWH) since 2008 for the management of BMS and other oral dysesthesias. An initial concentration of 0.5 mg/mL was used until 2012, when this was changed to a 0.1 mg/mL solution.

The objectives of this project were to 1) quantify the magnitude of placebo response in BMS, 2) evaluate the tolerability, safety, and efficacy of the two concentrations of topical clonazepam solution for the management of BMS, and 3) compare their effectiveness in improving burning symptoms.

We first conducted a systematic review of published randomized, blinded, placebo-controlled trials of therapies for BMS and evaluated the magnitude of the placebo response compared with the response to the treatment. Twelve RCTs were included. Ten studies (83%) reported at least some improvement in the symptomatology of patients receiving active treatment compared with baseline. In six of these studies (60%), there was also a positive response to placebo. On average, treatment with placebos produced a response that was 72% as large as the response to active drugs.

Next, we conducted a retrospective chart review of all patients with oral dysesthesia, including BMS, managed with topical clonazepam solution (0.1 mg/mL or 0.5 mg/mL) in DOM-BWH from 2008 to 2015. The relative safety of the two concentrations of the solution was evaluated in terms of occurrence of adverse drug reactions (ADRs) and occurrence of change to treatment plan secondary to ADRs. A total of 541 charts were reviewed. 162 subjects met the inclusion criteria, 84 patients in the 0.1 mg/mL cohort and 78 in the 0.5 mg/mL cohort, evaluated at a median follow-up of 6 weeks. Thirty-eight (23%) patients developed ADRs. The most frequently reported ADR was sedation (62% of ADRs), followed by altered mental status and dizziness (7% each). In total, dose adjustments were required in nine patients (6%), and treatment was discontinued in 13 patients (8%). ADRs were more frequently reported in the 0.5 mg/mL cohort, but no significant difference was found between the two concentrations, either in terms of occurrence of ADRs or change to treatment secondary to ADRs, or in terms of types of ADRs (p>0.05).

Finally, we conducted a retrospective chart review of all patients diagnosed specifically with BMS and managed with topical clonazepam solution (0.1 mg/mL or 0.5 mg/mL) from 2008 to 2015. The efficacy of the two concentrations in improving burning symptoms was compared using patient-reported outcome measures, including the percentage improvement in burning symptoms as reported at first follow-up, and the change from baseline to first follow-up in the worst burning severity over the week prior to evaluation, ranked on an 11-point numeric rating scale (NRS). The study included 57 subjects, with 32 patients in the 0.1 mg/mL cohort and 25 patients in the 0.5 mg/mL cohort, who were evaluated at a median follow-up of 7 weeks. The median overall percentage improvement associated with the 0.1 mg/mL solution was 32.5% (range 0-100%), not significantly higher than the commonly used 30% cut-off. Treatment with the 0.5 mg/mL solution was associated with median overall percentage improvement of 75% (range 0-100%), significantly higher than the more conservative 50% cut-off (p<0.01). The median reduction in NRS score was 6 points in the 0.5 mg/mL concentration, and 0.5 points in the 0.1 mg/mL concentration. Using either outcome measure, response to treatment with the 0.5 mg/mL solution was superior to that associated with the 0.1 mg/mL solution (p<0.01).

This thesis is the first to suggest a potentially considerable role for placebo effect in treatments for BMS. Our results suggest that treatment with topical clonazepam solution is generally safe and well-tolerated, with a similar safety profile for both concentrations. A 0.5 mg/mL concentration is highly effective in the management of burning dysesthesia in patients with BMS, significantly more than a 0.1 mg/mL concentration.