Topical Clonazepam and Placebo Effect in Burning Mouth Syndrome

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

Pathogenesis of Oral Toxicities Associated with Targeted Therapy and Immunotherapy

Targeted therapy and immunotherapy have redefined cancer treatment. While they have enhanced tumor response and improved survival rates in many cancer types, toxicities continue to occur, and these often involve the oral cavity. Broadly reported as "mucositis" or "stomatitis," oral toxicities induced by targeted therapies differ clinically and mechanistically from those associated with conventional chemotherapy. Manifesting primarily as mucosal lesions, salivary gland hypofunction, or orofacial neuropathies, these oral toxicities may nonetheless lead to significant morbidity and impact patients' quality of life, thereby compromising clinical outcomes. We conclude that familiarity with the spectrum of associated toxicities and understanding of their pathogenesis represent important areas of clinical research and may lead to better characterization, prevention, and management of these adverse events

Pathogenesis of Oral Toxicities Associated with Targeted Therapy and Immunotherapy

Targeted therapy and immunotherapy have redefined cancer treatment. While they have enhanced tumor response and improved survival rates in many cancer types, toxicities continue to occur, and these often involve the oral cavity. Broadly reported as “mucositis” or “stomatitis,” oral toxicities induced by targeted therapies differ clinically and mechanistically from those associated with conventional chemotherapy. Manifesting primarily as mucosal lesions, salivary gland hypofunction, or orofacial neuropathies, these oral toxicities may nonetheless lead to significant morbidity and impact patients’ quality of life, thereby compromising clinical outcomes. We conclude that familiarity with the spectrum of associated toxicities and understanding of their pathogenesis represent important areas of clinical research and may lead to better characterization, prevention, and management of these adverse events

World workshop on oral medicine VIII: development of a core outcome set for dry mouth: a systematic review of outcome domains for xerostomia

Objective The purpose of this study was to identify all outcome domains utilized in clinical studies of xerostomia, i.e. subjective sensation of dry mouth. This study is part of the extended project ‘World Workshop on Oral Medicine Outcomes Initiative for the Direction of Research (WONDER)’ to develop a core outcome set (COS) for dry mouth. Study design A systematic review was performed on MEDLINE, EMBASE, CINAHL and Cochrane Central Register of Controlled Trials databases. All clinical and observational studies that assessed xerostomia in human subjects from 2001 to 2021 were included. Information on outcome domains was extracted and mapped to the Core Outcome Measures in Effectiveness Trials (COMET) taxonomy. Corresponding outcome measures were summarized. Results From a total of 34,922 records retrieved, 688 articles involving 122,151 persons with xerostomia were included. There were 16 unique outcome domains and 166 outcome measures extracted. None of these domains or measures was consistently utilized across all the studies. Severity of xerostomia and physical functioning were the two most frequently assessed domains. Conclusion There is considerable heterogeneity in outcome domains and measures reported in clinical studies of xerostomia. This highlights the need for harmonization of dry mouth assessment in order to enhance comparability across studies and facilitate synthesis of robust evidence for the management of patients with xerostomia

World Workshop on Oral Medicine VIII: Development of a core outcome set for dry mouth: The Patient Perspective

We conducted a qualitative study on patients’ perspectives of dry mouth outcomes to explore their personal experiences and investigate what outcomes are most important to them. This work was part of the WONDER initiative (World Workshop on Oral Medicine Outcomes Initiative for the Direction of Research) exploring Core Outcome Measures in Effectiveness Trials (COMET). Study Design This was a qualitative study based on digitally recorded, semi-structured interviews using a study-specific topic guide incorporating focus groups of patients with dry mouth secondary to Sjögren syndrome, and head and neck radiotherapy. The interviews were performed until data saturation is achieved, all transcripts were evaluated for accuracy and then anonymized. Results Two focus groups consisting of four participants per group identified four distinct themes: (1) impact on oral health and function; (2) social isolation and withdrawal; (3) frustrations with dry mouth management; and (4) limited knowledge of the medical community and lack of understanding of family and friends. Conclusions The diversity of self-reported outcomes and the complexity of patients’ perceptions identified in our work may represent additional barriers to successful dry mouth management that should be considered in the design of future clinical trials

World workshop on oral medicine VIII: Development of a core outcome set for dry mouth: A systematic review of outcome domains for salivary hypofunction

Objective To identify all outcome measures used to assess salivary gland hypofunction (i.e.: objective measures used to determine actual changes in saliva quantity or to assess response to treatment of salivary gland hypofunction) and to group these into domains. Study Design A systematic review including clinical trials, and prospective or retrospective observational studies involving human participants with dry mouth, with any type of intervention where objective assessment of salivary gland hypofunction was described. Results Five hundred fifty-three studies involving 31,507 participants were identified. The majority assessed both salivary gland hypofunction and xerostomia (68.7%), whilst 31.3% assessed salivary gland hypofunction alone. The majority of studies investigated ‘amount of saliva’ and the highest number of outcome measures was within the domain ‘clinical/objective signs of salivary gland hypofunction’. Conclusions Seven domains encompassing 30 outcome measures were identified, confirming the diversity in outcomes and outcome measures used in research regarding salivary gland hypofunction. Identified items will be used in conjunction with those identified regarding xerostomia to create a COS for dry mouth quantification for use in future clinical trials, with the overall goal of improving the standardization of reporting, leading to the establishment of more robust evidence for the management of dry mouth and improving patient care

World Workshop on Oral Medicine VIII: Development of a core outcome set for dry mouth: A Consensus Study

Objective To develop a consensus-based core outcome set (COS) to be used in clinical trials assessing dry mouth interventions. Study design Through two systematic reviews of the literature and interviews with dry mouth patients we identified relevant outcome domains for dry mouth assessment. A Delphi survey was presented to health care providers attending the American Academy of Oral Medicine annual meeting in Memphis, Tennessee, USA, May 2022 (n = 104) and ten dry mouth patients at Cork University Dental School and Hospital, Republic of Ireland. Outcome domains for which no consensus was reached were subsequently discussed in a second consensus process led by a virtual Special Interest Group (SIG) of 11 oral medicine experts from the World Workshop on Oral Medicine VIII dry mouth working group. Results After the two-step consensus process, consensus was reached for 12 dry mouth outcome domains (salivary gland flow, signs of hyposalivation, mucosal moisture/wetness, severity of xerostomia, duration of xerostomia, overall impact of xerostomia, impact on physical functioning, impact of hyposalivation on general health, impact on social activities, quality of life, economic impact of dry mouth, patient satisfaction) to be included in the final COS. Conclusion We propose a consensus-based COS to assess dry mouth interventions in clinical trials. This COS includes the minimum, but mandatory set of domains that all clinical trials evaluating dry mouth treatments should assess