Dental caries associated with medications for opioid use disorder: drug effects, formulation factors, or both?

Medications for opioid use disorder (MOUD) have reduced fentanyl-related mortality by approximately 20% over the past five years. However, MOUD-associated dental caries has become an important clinical concern that may negatively affect treatment adherence, patient quality of life, and long-term treatment outcomes as the number of patients receiving MOUD continues to rise. Two key questions remain unresolved: (1) Why are buprenorphine (BUP) and methadone (MTD) associated with dental complications, whereas naltrexone (NLX) carries a substantially lower risk? (2) Why do transmucosal BUP formulations, including sublingual and buccal products, appear to pose a greater risk of dental injury than other MOUD products? To address these questions, this review evaluates MOUD-associated dental problems from two perspectives: formulation-related factors and drug-related factors, with an emphasis on the role of drug administration routes. From the formulation perspective, acid excipients used in transmucosal formulations can directly alter the oral microenvironment by reducing local pH and saliva buffering capacity, leading to increased enamel demineralization. These acid excipients may also indirectly affect oral health by supporting cariogenic bacterial growth, altering bacterial metabolism, and facilitating biofilm formation. From the drug perspective, opioid receptor agonists or partial agonists may impair salivary secretion and alter oral fluid composition, whereas BUP may persist in oral fluid at high levels and accumulate in salivary glands following transmucosal dosing. Overall, MOUD-associated dental injury should be understood as a multifactorial process involving baseline oral-health vulnerability, the unique transmucosal delivery route, drug-related factors, and formulation-related factors. Importantly, comprehensive oral health care will improve patients' life quality, leading to better adherence, suggesting that understanding and preventing this adverse effect may improve adherence and long-term clinical outcomes. Among available MOUDs, transmucosal BUP provides a clinically relevant model for addressing current mechanistic gaps and developing preventive, formulation-based, and administration route-informed interventions.