Abstract
This study examines the association of sublingual buprenorphine/naloxone and dental adverse events using the IQVIA health claims database.
Oral buprenorphine is a key therapy for the treatment of opioid use disorder. In January 2022, the US Food and Drug Administration1 alerted health professionals of the potential risk of dental adverse events (dental caries or tooth loss) with long-term use of sublingual or buccal formulations of buprenorphine (usually combined with naloxone). The alert was based on data from case reports, which might be prone to selection bias. We undertook a pharmacoepidemiologic study of sublingual buprenorphine/naloxone and dental adverse events.
Methods
We used the PharMetrics database (IQVIA),2 which captures patient-level data including prescriptions dispensed in the US as well as inpatient and outpatient physician diagnoses (through the International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision). We used a random sample of patients from 2006 to 2020, with patients required to have 1 year of health care contact (physician contact or prescription drug use) before cohort entry. Ethics approval was obtained by the University of British Columbia’s clinical research ethics board with a waiver of informed consent.
We created a cohort of new users of sublingual buprenorphine/naloxone and 2 active comparator groups (used for opioid use disorder)—new users of either transdermal buprenorphine or oral naltrexone. We created a 1-year look back from cohort entry, excluding patients with previous use of the 3 study drugs in the prior year. Cohort members were followed up from the first prescription to the first occurrence of a dental adverse event, defined as any disease of the teeth, gums, or pulp. A secondary outcome of dental caries or tooth loss was also examined. Cohort members were followed up to the occurrence of an event, termination of health coverage, switch to a competing study drug, or end of follow-up (October 2020).
Cox regression models were constructed to compute hazard ratios (HRs) comparing dental adverse events with sublingual buprenorphine/naloxone vs transdermal buprenorphine and vs oral naltrexone, stratifying for exact age and adjusting for covariates (Table 1). We also examined confounding by indication3 by performing sensitivity analyses restricting the analysis to patients without opioid or alcohol use, illicit drug use, diabetes, or smoking. Because some patients can also use sublingual buprenorphine/naloxone for chronic pain (as an off-label use), we repeated the analysis in patients with previous opioid use or chronic pain. To control for exposure misclassification, we examined the risk in sublingual buprenorphine/naloxone users with at least 3 prescriptions. HRs were considered statistically significant if the 95% CI for that estimate did not cross 1.0. All analyses were performed using SAS, version 9.4 (SAS Institute Inc).
Table 1. Baseline Characteristics of Users of Sublingual Buprenorphine (BPN)/Naloxone, Transdermal BNP, and Oral Naltrexone.
| Characteristics | No. (%) | ||
|---|---|---|---|
| Sublingual BPN/naloxone (n = 21 404) | Transdermal BPN (n = 5385) | Naltrexone (n = 6616) | |
| Age, mean (SD), y | 35.6 (12.6) | 53.0 (15.6) | 43.2 (14.4) |
| Sex | |||
| Men | 13 144 (61.4) | 1913 (35.5) | 3365 (50.9) |
| Women | 8260 (38.6) | 3472 (64.5) | 3251 (49.1) |
| Follow-up, mean (SD), y | 2.2 (2.4) | 2.3 (2.1) | 2.6 (2.7) |
| Comorbidities | |||
| Sjögren syndrome | 44.9 (0.21) | 93.2 (1.73) | 23.2 (0.35) |
| Inflammatory bowel disease | 278.3 (1.3) | 150.8 (2.8) | 115.1 (1.74) |
| Diabetes | 1586 (7.41) | 1361.9 (25.29) | 705.9 (10.67) |
| HIV | 51.4 (0.24) | 7 (0.13) | 11.2 (0.17) |
| Xerostomia | 30 (0.14) | 52.2 (0.97) | 15.2 (0.23) |
| Smoking | 1406.2 (6.57) | 626.8 (11.64) | 449.9 (6.8) |
| Alcohol use | 10 098.4 (47.18) | 1580 (29.34) | 4133 (62.47) |
| Tricyclic antidepressant use | 355.3 (1.66) | 315 (5.85) | 84 (1.27) |
| Previous opioid use | 11 714.4 (54.73) | 710.8 (13.2) | 1411.2 (21.33) |
| Chronic pain | 1628.8 (7.61) | 1407.1 (26.13) | 136.3 (2.06) |
| Illicit drug usea | 969.6 (4.53) | 18.8 (0.35) | 265.3 (4.01) |
| Dentist visits, mean (SD) | 0.38 (2.10) | 0.20 (1.51) | 0.19 (1.38) |
Previous use of heroin or cocaine.
Results
A total of 21 404 new users of sublingual buprenorphine/naloxone, 5385 users of transdermal buprenorphine, and 6616 users of oral naltrexone were identified. The groups differed on age, sex, and a number of comorbidities (Table 1). The incidence of any dental adverse event was 21.6 per 1000 person-years with sublingual buprenorphine/naloxone, 12.2 per 1000 person-years with transdermal buprenorphine, and 10.9 per 1000 person-years with oral naltrexone. The adjusted HRs were 1.42 (95% CI, 1.17-1.73) for sublingual buprenorphine/naloxone vs transdermal buprenorphine and 1.67 (95% CI, 1.41-1.98) for sublingual buprenorphine/naloxone vs oral naltrexone. The incidence of dental caries or tooth loss was 8.2 per 1000 person-years with sublingual buprenorphine/naloxone, 3.5 per 1000 person-years with transdermal buprenorphine, and 3.8 per 1000 person-years with oral naltrexone. For dental caries or tooth loss, the HRs were 1.57 (95% CI, 1.11-2.23) for sublingual buprenorphine/naloxone vs transdermal buprenorphine and 1.71 (95% CI, 1.29-2.27) for sublingual buprenorphine/naloxone vs oral naltrexone. Results were generally similar for the different sensitivity analyses (Table 2).
Table 2. Hazard Ratios for Dental Adverse Events and Dental Caries or Tooth Loss Among Different Risk Categories.
| Outcome | Incidence per 1000 person-years | Cases, No. | Hazard ratio | |
|---|---|---|---|---|
| Crude | Adjusted (95% CI)a | |||
| Dental adverse eventsb | ||||
| Transdermal BPN | 12.2 | 150 | 1 | 1 [Reference] |
| Sublingual BPN/N | 21.6 | 1033 | 1.8 | 1.42 (1.17-1.73) |
| Naltrexone | 10.9 | 187 | 1 | 1 [Reference] |
| Sublingual BPN/N | 1033 | 1.91 | 1.67 (1.41-1.98) | |
| Dental caries or tooth loss | ||||
| Transdermal BPN | 3.5 | 44 | 1 | 1 [Reference] |
| Sublingual BPN/N | 8.2 | 393 | 2.31 | 1.57 (1.11-2.23) |
| Naltrexone | 3.8 | 66 | 1 | 1 [Reference] |
| Sublingual BPN/N | 393 | 1.99 | 1.71 (1.29-2.27) | |
| Sensitivity analysesc | ||||
| Including those receiving 3 prescriptions | ||||
| Transdermal BPN | 60 | 1 | 1 [Reference] | |
| Sublingual BPN/N | 763 | 1.84 | 1.76 (1.30-2.38) | |
| Naltrexone | 51 | 1 | 1 [Reference] | |
| Sublingual BPN/N | 763 | 2.08 | 1.97 (1.46-2.66) | |
| Excluding those with opioid use, alcohol use, diabetes, smoking, and illicit drug use | ||||
| Transdermal BPN | 50 | 1 | 1 [Reference] | |
| Sublingual BPN/N | 221 | 1.68 | 1.54 (0.89-2.66) | |
| Naltrexone | 50 | 1 | 1 [Reference] | |
| Sublingual BPN/N | 221 | 1.64 | 1.74 (1.25-2.43) | |
| Including those with history of opioid use | ||||
| Transdermal BPN | 31 | 1 | 1 [Reference] | |
| Sublingual BPN/N | 644 | 1.5 | 1.41 (1.15-1.72) | |
| Naltrexone | 54 | 1 | 1 [Reference] | |
| Sublingual BPN/N | 644 | 1.65 | 1.70 (1.43-2.02) | |
| Including those with history of chronic pain | ||||
| Transdermal BPN | 46 | 1 | 1 [Reference] | |
| Sublingual BPN/N | 96 | 1.91 | 1.42 (1.17-1.73) | |
| Naltrexone | 5 | 1 | 1 [Reference] | |
| Sublingual BPN/N | 96 | 1.88 | 1.67 (1.41-1.98) | |
Abbreviations: BPN/N, buprenorphine/naloxone; HR, hazard ratio.
Adjusted for variables in Table 1 and stratified by exact age.
Include tooth, gum, and pulp-related conditions and defined with 1 prescription.
For the primary outcome of dental adverse events only.
Discussion
This study found an increase in the risk of adverse dental outcomes associated with sublingual buprenorphine/naloxone compared with transdermal buprenorphine and oral naltrexone. Sublingual buprenorphine/naloxone is acidic in nature.4 Patients are instructed to hold the tablet under the tongue for 5 to 10 minutes to maximize absorption.5 Thus, prolonged acidic exposure of the drug in the mouth might lead to tooth damage. Study limitations include lack of information on patient oral hygiene, possible unmeasured confounding, capture of only dental events serious enough to be reported to a physician, and inability to fully ascertain the indication for the medications. Clinicians might consider drugs other than sublingual buprenorphine/naloxone in patients with previous dental problems. These patients might also benefit from regular oral health examinations by their dentist.
Section Editors: Jody W. Zylke, MD, Deputy Editor; Kristin Walter, MD, Senior Editor.
References
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