Elucidating High Oral Fluid Exposure Mechanisms of Buprenorphine to Reduce Dental Caries

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SUMMARY Opioid use disorders (OUD) are having devastating and tragic effects in the USA. There are only three drugs available as a part of medication assisted treatment (MAT), and the newest drug is buprenorphine. Buprenorphine is mostly given as sublingual tablets and films. It is estimated that more than 1 million oral buprenorphine prescriptions were filled in 2018. Multiple reports suggest that buprenorphine is present in high concentrations in the oral fluids after oral (sublingual) buprenorphine administration, typically 10-100 folds higher than its plasma concentrations. The high oral fluid exposure to opioid analogs is well known and used to monitor the presence of opioids in people. Recently, a less known side effects of chronic oral buprenorphine use raised alarm. In January of 2022, FDA issued a warning stating that use of oral buprenorphine formulations (i.e., sublingual tablets and films) may cause serious harm to the teeth in significant percentages of patients who are taking these buprenorphine formulations. This is serious problem for OUD patients because the effective pharmacotherapy options for this population are limited. Without understanding the mechanism of this severe side effects that impact users' health and quality of life, it is difficult to develop effective pharmacological countermeasures. The mechanisms responsible for observed tooth damaging effects are unknown, but we suspected that it is caused by high concentrations of buprenorphine in the oral fluids. We hypothesize that mechanisms responsible for high oral fluid exposure to buprenorphine can be elucidated and oral fluid exposure to buprenorphine exposure can be significantly reduced by saliva stimulant without reducing their systemic exposure. Moreover, the reduced oral fluid drug exposure will lead to fewer dental caries in rodent models of caries. We also hypothesize that high accumulation of buprenorphine in salivary glands elevates oral fluid exposure to buprenorphine and inhibition of their accumulation in the salivary glands will reduce their oral fluid exposure. A mouse model of dental caries that are responsive to varying concentrations of buprenorphine will be established and use to evaluate the impact of high oral fluid exposure to buprenorphine on dental caries in mice. The study team has a rich experience in studying drug glucuronidation (buprenorphine is extensively glucuronidated), and transporter-mediated drug disposition, and is equipped with the proper dosage form (e.g., oral film) and expertise (LC-MS for bioanalysis and mass spectrometry) to understand how oral fluid exposure to buprenorphine could be reduced. Our efficacy study will be led by a dentist-scientist with expertise in studying the virulence of Streptococcus mutans, a primary cariogen. Our study aims to develop “pharmacologic approaches” using the current animal models to support drug discovery and/or repurposing for OUD pharmacotherapeutics with minimal or minor negative impact on dental health. In other words, our research may lead to future selection of drugs to reduce oral cavity concentrations of buprenorphine without negatively impacting the drug's systemic exposure and its intended use for medication assisted treatment in OUD.