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harms from fentanyl, the Food and Drug Administration's current recommendations on target dose and dose limit are outdated and causing harm.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.

Buprenorphine Dose and Time to Discontinuation Among Patients With Opioid Use Disorder in the Era of Fentanyl

“…The currently recommended dose of 16 mg was derived from studies conducted prior to the widespread availability of fentanyl, and our finding suggests that a higher dose may now improve retention in treatment. This interpretation is consistent with addiction specialist commentaries that have challenged the value of 16 mg as an optimal buprenorphine dose, as well as limited observational analyses suggesting that higher doses may potentially improve buprenorphine treatment effectiveness . The findings also support clinician accounts that higher than recommended buprenorphine doses are increasingly needed to suppress withdrawal and cravings …”

“…This interpretation is consistent with addiction specialist commentaries that have challenged the value of 16 mg as an optimal buprenorphine dose, [12][13][14] as well as limited observational analyses suggesting that higher doses may potentially improve buprenorphine treatment effectiveness. [20][21][22][23][24][25][26][27][28] The findings also support clinician accounts that higher than recommended buprenorphine doses are increasingly needed to suppress withdrawal and cravings. 16 Preclinical studies suggest that fentanyl downregulates mu opioid receptor expression to a higher degree than morphine and induces greater (or at least more rapid) tolerance to its effects.…”

“…33 Even at a 24 mg daily dose, 53% of patients in the present study discontinued buprenorphine treatment within 180 days of initiation. This is consistent with previous observational analyses suggesting dose-dependent benefits of daily doses up to 32 mg. [20][21][22][23][24][25][26][27][28] While some reasons for discontinuation may be unaffected by higher buprenorphine doses, 34 some patients who use fentanyl require buprenorphine doses greater than the FDA-approved 16 or 24 mg doses to control withdrawal and cravings. 35 We had hoped to examine doses higher than 24 mg in the current study, but an insufficient number of patients in Rhode Island were prescribed such doses during the study period.…”

“…19 Together, these findings perhaps explain why substitution therapy with a low-efficacy agonist like buprenorphine may require higher doses when treating patients exposed to fentanyl than those exposed to morphinan opioids (eg, heroin and oxycodone). Although observational analyses have also suggested higher buprenorphine doses may potentially improve treatment effectiveness, [20][21][22][23][24][25][26][27][28] the findings have not been confirmed in a large study using data from the fentanyl era that considers patients' daily dose throughout follow-up.…”

A Systematic Review of State Office-Based Buprenorphine Treatment Laws Effective During 2022: Counseling, Dosage, and Visit Frequency Requirements

“…Recent studies suggest that higher dosages of buprenorphine may result in longer retention 41 -45 ; and higher dosages of buprenorphine may be particularly useful at a time when fentanyl—a very potent opioid—is increasingly the cause of overdose. 46 Furthermore, high dosages are the norm in the Veterans Health Administration.…”