Evidence on Buprenorphine Dose Limits: A Review

Abstract

Objectives: As overdose deaths from fentanyl continue to increase, optimizing use of medications for opioid use disorder has become increasingly important. Buprenorphine is a highly effective medication for reducing the risk of overdose death, but only if a patient remains in treatment. Shared decision making between prescribers and patients is important to establish a dose that meets each patient's treatment needs. However, patients frequently face a dose limit of 16 or 24 mg/d based on dosing guidelines on the Food and Drug Administration's package label.

Methods: This review discusses patient-centered goals and clinical criteria for determining dose adequacy, reviews the history of buprenorphine dose regulation in the United States, examines pharmacological and clinical research results with buprenorphine doses up to 32 mg/d, and evaluates whether diversion concerns justify maintaining a low buprenorphine dose limit.

Results: Pharmacological and clinical research results consistently demonstrate buprenorphine's dose-dependent benefits up to at least 32 mg/d, including reductions in withdrawal symptoms, craving, opioid reward, and illicit use while improving retention in care. Diverted buprenorphine is most often used to treat withdrawal symptoms and reduce illicit opioid use when legal access to it is limited.

Conclusions: In light of established research and profound harms from fentanyl, the Food and Drug Administration's current recommendations on target dose and dose limit are outdated and causing harm. An update to the buprenorphine package label with recommended dosing up to 32 mg/d and elimination of the 16 mg/d target dose would improve treatment effectiveness and save lives.

Figure 1

Drug liking versus plasma buprenorphine concentration. VAS represents the strength of patient drug “liking” of a high-dose challenge (18 mg) of intravenous hydromorphone, as a function of buprenorphine plasma concentration achieved with XR-BUP. A steady-state buprenorphine exposure of greater than 3.3 ng/mL (equivalent to plasma concentration with 32 mg/d after 12 hours with once-daily dosing; see Fig. 2) was required to suppress the rewarding opioid effect (red bar), the red shaded area indicates susceptibility to reward at lower concentrations. Each participant was measured at multiple exposure levels. Individual subject scores are shown as filled triangles without buprenorphine (a concentration of 0 ng/mL) and as open circles with different buprenorphine plasma concentrations. There is wide variability among subjects. VAS, visual analog scale; XR-BUP, extended-release buprenorphine. Source: Highlights of prescribing information. Sublocade (buprenorphine extended-release) injection, for subcutaneous use, CIII. FDA; 2022 (p. 30). https://www.sublocade.com/Content/pdf/prescribing-information.pdf.

Figure 2

Buprenorphine plasma concentration versus time at different doses. Plasma concentration of buprenorphine over a 24-hour blood sampling period after once-daily dosing in 5 heroin-dependent volunteers maintained on 0, 2, 16, and 32 mg/d buprenorphine. The thick line at 3 ng/mL is at the level required to suppress drug “liking” of a high-dose hydromorphone challenge and the red shaded area indicates concentrations where such drug “liking” occurs (Fig. 1). Adapted with permission from Greenwald et al.