HEAL Initiative: Oral Complications Arising from Pharmacotherapies to Treat Opioid Use Disorders

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  1. Goal
  2. Background
  3. Gaps and Opportunities
  4. Impact
  5. References

May 2022

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Goal

The NIH Helping to End Addiction Long-term (HEAL) initiative is a trans-agency effort to speed scientific solutions to stem the national opioid public health crisis. Through the initiative, NIH supports research to enhance pain management and improve treatment for opioid misuse and addiction. The NIDCR has been an active partner with the HEAL initiative since its inception in 2018.

The purpose of this concept is to solicit research to better understand the biology, natural history, and directionality of oral complications associated with pharmacotherapies used to treat opioid use disorders (OUDs). Further, this concept will support research to address access to care and other challenges that may contribute to dental and oral disease onset and progression in people with OUD, with a long-term goal of developing targeted preventive strategies for these individuals.

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Background

Medication-assisted treatment (MAT) is a comprehensive treatment program that involves the use of medications in combination with counseling and behavioral therapies to treat substance use disorders. The Food and Drug Administration (FDA) has approved three drugs to treat opioid dependence as part of a MAT: Buprenorphine, methadone, and intramuscular extended-release naltrexone. Buprenorphine is available in oral (buccal and sublingual film or tablet), subdermal, and extended-release injection formulations. Due to recent efforts to make MAT for OUD more accessible along with the ongoing opioid crisis, buprenorphine prescriptions have steadily increased in recent years. During 2017-2018, there were over 55,000 active buprenorphine prescribers, and over 1 million prescriptions were dispensed in 2018.

A recent FDA Drug Safety Communication report indicated oral complications arising from use of buprenorphine formulations that are dissolved in the mouth, resulting in dental caries, dental abscesses/infection, tooth erosion, and total tooth loss. Most cases were reported to the FDA Adverse Event Reporting System (FAERS) database, with over 40% of cases being classified as serious, over one-third reporting the problem as affecting two or more teeth, and approximately 8% of cases being reported in individuals with no history of dental issues. There is limited scientific literature to describe oral complications directly related to buprenorphine use, and different etiologies may contribute to these reported problems. One case series suggests that oral buprenorphine may alter the oral environment, indirectly decreasing the salivary pH, thereby leading to an acidic environment and contributing to erosion of tooth enamel. It is also speculated that dry mouth caused by buprenorphine may make individuals susceptible to dental caries since saliva has many protective properties, including buffering capacity. Other hypothesized mechanisms of action suggest the immunosuppressive effects of opioids (impaired antibody production, natural killer cell activity, cytokine expression, and phagocytic activity) may contribute to the reported complications. Alternatively, individuals with pre-existing oral disease may experience exacerbations or progression of the disease process after initiating buprenorphine due to a direct or indirect effect upon the oral environment, or possibly due to increased awareness of oral disease after having received treatment for OUD.

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Gaps and Opportunities

Sublingual/buccal administration of buprenorphine is the preferred route of administration because absorption is fast and there is a prolonged half-life. Other routes have poor bioavailability due to the first-pass effect, in which the liver and intestine break down the majority of the drug. Despite the reported oral complications, the benefits of buprenorphine clearly outweigh the risks. Given the important role of buprenorphine in treating OUDs and significant knowledge gaps regarding oral complications, it is critical to gain an understanding about the mechanism(s), clinical course, and directionality of the effect of buprenorphine upon the oral cavity to inform risk mitigation strategies and support its continued use.

To address these knowledge gaps, this concept would support basic science research to understand the local environment of the oral cavity during oral buprenorphine use and elucidate the role of microbial flora and salivary proteins and buffering capacity in contributing to the development and progression of reported oral complications. Drugs dissolved in the mouth that may induce a low pH oral environment and, along with prolonged exposure times to the dentition, may affect their physical integrity or undermine the natural physiology of the tooth, both directly and indirectly. In the mouth, changes in abundance or function of organisms within the oral microbiome can lead to dysbiosis and subsequent oral disease development after environmental, dietary, or host perturbations. Further, there is an opportunity for pharmacological development, such as drug discovery and repurposing, to identify OUD pharmacotherapeutics that may have less direct impact upon the oral cavity.

Examples of basic science research supported by this concept include, but are not limited to:

  • Elucidating the direct chemical effects of buprenorphine or components of the delivery product on perturbations of the tooth structures and associated tissues.
  • Identifying changes in critical oral cavity parameters and the physiology and interaction of the microbiome community with each other or host factors (e.g., diet, salivary protective factors, biochemical changes in the local oral environment) in the presence of buprenorphine or other pharmacotherapies for OUD.
  • Characterizing the interaction of the oral microbiome, host factors, biochemical processes, and alveolar bone in the oral cavity environment in individuals receiving treatment for OUD to understand the direct and indirect contribution to oral disease initiation and progression.
  • Delineating the effects of oral buprenorphine formulations on neuromodulation of metabolic (e.g., oral epithelial cell turnover, salivary production), neurotrophic, or other factors that lead to pathologic perturbations of the dental pulp and/or local oral environment, relative to other drug delivery formulations.
  • Developing pharmacological approaches including animal model development, to support drug discovery and repurposing for OUD pharmacotherapeutics with minimal direct impact upon the local oral environment.

In addition, this concept would support clinical studies to characterize the directionality, clinical course, and extent of oral disease development and progression in people undergoing OUD treatment, and factors that may predispose people receiving buprenorphine to the development and/or progression of oral complications. It is important to differentiate between de novo oral disease development and progression of pre-existing oral disease in the presence of OUD treatment. Further, a retrospective claims database study suggested that individuals receiving MAT for OUD did not increase dental utilization in the year after beginning MAT. Consequently, there is a need to address behavioral and psychosocial influences upon oral health and access to care challenges in individuals undergoing treatment for OUD. These individuals may have significant oral health and medical needs and encounter multiple levels of contextual influences that affect access to quality and affordable oral health care. Study designs may include cohort studies that provide longitudinal follow-up of individuals initiating treatment for OUD, case-control studies, and retrospective/prospective database analyses that include dental, medical, and pharmacy data.

Examples of clinical research supported by this concept include, but are not limited to:

  • Prospective studies of individuals initiating pharmacotherapy for OUD to improve our understanding about the directionality of the relationship between pharmacotherapy for OUD and oral disease development.
  • Clinical studies to identify direct etiologic factors in the oral environment that may contribute to the development and progression of oral complications in individuals receiving pharmacotherapy for OUD.
  • Clinical studies to assess the onset, extent, and rate of progression of oral complications in individuals receiving buprenorphine or other pharmacotherapies for OUD.
  • Research to identify barriers to and facilitators of oral health care in individuals with OUDs, taking into account multiple co-occurring contextual influences and their intersectionality.
  • Research to assess specific access to and quality of care challenges and how OUD treatment may impact dental care utilization.
  • Clinical studies to develop strategies to prevent dental and oral disease in individuals receiving treatment for OUD, including interactions with medical professionals to support continuity of medical and oral care needs.

Research supported by this concept may identify best practices and/or interventions to prevent dental, oral, and/or craniofacial disease in individuals receiving pharmacotherapies for OUD and/or tools to educate prescribers and patients being treated with buprenorphine about the potential for oral complications.

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Impact

An important aspect of the HEAL initiative is to enhance treatment options for OUD to promote long-term recovery in more patients. This concept aligns with the HEAL goal of developing new or improved prevention and treatment strategies for opioid addiction since buprenorphine is an important component of MAT. The HEAL research portfolio has supported research to assess the effects of pharmacotherapies for OUD on harm reduction. The discovery of oral complications associated with buprenorphine use provides an opportunity for the HEAL initiative to support research that will contribute to our understanding of and develop best practices for OUD management that includes patient-centered, whole-person care.

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References

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Last Reviewed
April 2024