(35) Assessing the Effects of Sublingual Buprenorphine on Dental Caries

Background & Introduction: Sublingual buprenorphine medications have proven to be highly effective in preventing withdrawal and relapse in patients suffering from Opioid Use Disorder (OUD). In 2022, an FDA warning was released following mounting clinical and epidemiological evidence that sublingual forms of buprenorphine are associated with severe dental caries and tooth loss[1,2], yet the reason for this association is poorly understood. Dental caries is a chronic polymicrobial biofilm-based disease initiated from an adherent biofilm composed of highly acidogenic (“acid-producing”) and aciduric (“acid-thriving”) microorganisms[3]. Microbial organic acid production, primarily via metabolism of carbohydrates, promotes demineralization of the enamel that can ultimately result in clinical cavitation. Untreated dental caries may lead to severe pain and potentially life-threatening odontogenic infections. Severe dental caries commonly results in tooth extraction leading to partial or full edentulism which negatively impacts one’s psychological well-being and risk for other chronic illnesses[4]. Dental caries is a multifactorial disease, with the oral microbiome and physiochemical properties of saliva being two of the most critical factors affecting caries pathogenesis. Thus, we designed a cross-sectional pilot study to assess caries prevalence, salivary parameters, and the levels of two of the most important caries-associated microorganisms (CAMs), Streptococcus mutans and Candida, in patients receiving sublingual buprenorphine treatment.

Methods: In this cross-sectional pilot clinical study, we recruited eleven subjects diagnosed with OUD who received sublingual buprenorphine for at least one year. Subjects were recruited from addiction medicine clinics in the surrounding area of Gainesville, Florida. This study was approved by the University of Florida Institutional Review Board. Eight of these subjects were regularly prescribed sublingual films while three were regularly prescribed sublingual tablets. Additionally, seven age and sex matched subjects from the general population were enrolled. All subjects completed verbal and written informed consent and a comprehensive questionnaire assessing general medical history, dental history, oral hygiene practices, and dietary consumption. Oral examination and caries scores were conducted by a calibrated dentist. Dental plaque was collected from a healthy enamel surface and from a carious site when present. Unstimulated saliva samples were collected to determine resting pH, buffering capacity, and flow rate. Saliva and plaque isolates were plated on selective agar media to determine levels of CAMs. Buprenorphine subjects were asked to self-administer their medication, and the pH of saliva and plaque samples were monitored at set intervals up to 30 minutes post-administration. Statistical analyses were conducted using GraphPad Prism 10.

Results: The primary outcome of dental caries as determined by the number of decayed, missing, or filled teeth (DMFT) or tooth surfaces (DMFS) were significantly higher in subjects receiving buprenorphine treatment relative to age and sex matched controls, with film and tablet subjects having a mean DMFT of 22.4 and 25.3, respectively. The control group had a mean DMFT score of 10.4, which was slightly greater than the national average DMFT of 8.6 for adults in the same age range[5]. The levels of highly cariogenic bacteria were significantly elevated in subjects receiving buprenorphine as the ratio of colony-forming units (CFUs) of Mutans streptococci to total cultivatable bacteria from saliva samples were over 7-fold greater relative to age- and sex-matched controls. Intriguingly, all buprenorphine subjects were Candida-positive in at least one of collected matrices whereas only 14.3% of the control group was positive for Candida. While there were no significant differences in salivary flow rate or buffering capacity between subjects receiving buprenorphine and our control group, resting salivary pH was significantly lower in buprenorphine subjects. Additionally, all buprenorphine subjects were ranked categorically as either having a low or very low buffering capacity. Saliva pH rapidly declined following administration of sublingual buprenorphine, with tablets exhibiting a more potent and sustained drop even after visual confirmation that the drug product fully dissolved. The average pH minima and time under the critical pH at which enamel demineralizes (pH 5.7) was greater in subjects receiving the tablet relative to subjects receiving the film.

Conclusion & Discussion: The results of this study suggest that subjects receiving sublingual buprenorphine have an increased prevalence of dental caries relative to age- and sex-matched individuals as determined by DMFT/S analysis. Our findings suggest that a reduced salivary pH and potentially impaired buffering capacity are likely contributory factors to the increase in caries and may suggest either a direct or indirect effect of buprenorphine on salivary gland physiology. Additionally, elevated levels of CAMs indicate a shift in the oral microbiome towards a more acidogenic and aciduric community, enhancing caries pathogenesis. However, future studies performing metagenomic analysis are necessary to further characterize the microbial community to explore this hypothesis. Furthermore, saliva was unable to effectively buffer the acid released following disintegration of either drug product, with administration of tablets increasing exposure below the critical pH of enamel, suggesting demineralization as a direct result of sublingual administration. This may in part explain why DMFT/S indices trend higher in subjects receiving tablets versus films. While this study comes with limitations such as small sample size and lack of control for indication, these findings support the FDA’s warning and provide a foundation for future longitudinal investigations evaluating a causal relationship of sublingual buprenorphine on dental caries.

References: 1. FDA warns about dental problems with buprenorphine medicines dissolved in the mouth to treat opioid use disorder and pain. (FDA) (2022).
2. Etminan M, Rezaeianzadeh R, Kezouh A, Aminzadeh K. Association Between Sublingual Buprenorphine-Naloxone Exposure and Dental Disease. JAMA. Dec 13 2022;328(22):2269-2271. doi:10.1001/jama.2022.17485
3. Pitts NB, Zero DT, Marsh PD, et al. Dental caries. Nat Rev Dis Primers. May 25 2017;3:17030. doi:10.1038/nrdp.2017.30
4. Li X, Kolltveit KM, Tronstad L, Olsen I. Systemic diseases caused by oral infection. Clin Microbiol Rev. Oct 2000;13(4):547-58. doi:10.1128/CMR.13.4.547
5. Centers for Disease Control and Prevention. Oral Health Surveillance Report: Dental Caries, Tooth Retention aE, United States, 2017–March 2020. U.S. Dept of Health and, https://www.cdc.gov/oral-health/php/2024-oral- HS, health-surveillance-report/index.html.