A 2004 randomized controlled trial (N= 179) examined the use of buprenorphine treatment in patients with concomitant cocaine and opiate dependence. Double-blinded groups received daily sublingual buprenorphine doses of 2, 8, or 16 mg; 16 mg on alternate days; or placebo. After 13 weeks, patients were tested for opiate and cocaine metabolite presence and concentration in urine. During the study, patients who received daily buprenorphine doses of 8 mg or 16 mg showed statistically significant decreases in urine morphine levels (8 mg, p= 0.0135; 16 mg, p<0.001) and metabolite concentrations (8 mg, p= 0.0277; 16 mg, p= 0.006). During the withdrawal phase, all treatment groups except patients receiving 16 mg reported increased urine morphine concentration (16 mg, p= 0.15). For this reason, the authors suggest a loss of beneficial effects on opiate use with buprenorphine doses lower than 16 mg/day. No significant between-group differences were reported for adverse events or treatment retention. Based on the results, the use of buprenorphine 16 mg daily appears to be well-tolerated and effective in patients with concomitant cocaine and opiate dependence, although it should be of note that buprenorphine was administered as a sublingual alcoholic solution, which has greater bioavailability in comparison to its tablet counterpart and thus may not be entirely comparable. Results may not be applicable to use of buprenorphine/naloxone as buprenorphine was studied individually in this trial. [1]
A 2014 Cochrane review evaluated buprenorphine maintenance treatment versus placebo or methadone maintenance. A total of 31 randomized controlled trials and 5,430 patients were included with varying buprenorphine dose conditions: low (2 mg to 6 mg daily), medium (7 mg to 15 mg daily), and high (≥ 16 mg daily). Included trials also utilized differing formulations: sublingual solution, sublingual tablet, combined buprenorphine/naloxone sublingual tablet, and implant. At all doses examined, buprenorphine was superior to placebo in treatment retention (high quality of evidence), although only high-dose buprenorphine was more effective versus placebo in suppressing illicit opioid use (standardized mean difference [SMD] -1.17; 95% confidence interval [CI] -1.85 to -0.49; 3 studies, medium quality of evidence). However, there was no difference between buprenorphine prescribed at fixed doses (> 7 mg daily) or methadone prescribed at fixed doses (≥ 40 mg daily) in treatment retention or suppression of illicit opioid use. The authors noted that buprenorphine may have advantages in settings where it may be clinically preferred, due to its alternate dosing schedule and safety profile, over methadone, and that buprenorphine overall is highly effective for heroin dependence versus placebo, especially at higher doses. [2], [3]
A recently published retrospective cohort study (N= 6,499) evaluated whether higher doses of buprenorphine treatment for opioid use disorder (OUD) are associated with improved treatment retention due to the increased spread of fentanyl addiction. Data were extracted from the Rhode Island Prescription Drug Monitoring program for patients initiating buprenorphine treatment for OUD between October 1, 2016, and September 30, 2020. Patients were categorized based on their daily dose of buprenorphine: 2 mg (0 to <3 mg), 4 mg (3 to <6 mg), 8 mg (6 to <10 mg), 12 mg (10 to <14 mg), 16 mg (14 to <18 mg), 20 mg (18 to <22 mg), 24 mg (22 to <26 mg), 28 mg (26 to <30 mg), and 32 mg (≥30 mg). The analysis primarily focused on comparing 16 mg and 24 mg daily dosing, which are the recommended and upper limit daily doses, respectively, per the FDA-approved prescribing information. An exploratory analysis also compared 8 mg daily dosing with the 16 and 24 mg daily dosing. [4]
Among 6,499 patients included for analysis, Kaplan-Meier analyses found a significantly higher proportion of patients receiving 16 mg daily dosing discontinued treatment within 180 days compared to patients receiving 24 mg daily dosing (59% vs. 24%; p= 0.005). Cox regression analyses determined patients receiving 16 mg had a higher risk for treatment discontinuation compared to those prescribed 24 mg (adjusted hazard ratio 1.20; 95% CI 1.06 to 1.37). Exploratory analyses found similar time to treatment discontinuation among patients prescribed 8 mg and 16 mg. The authors posit that buprenorphine doses higher than current recommendations may hold merit with regard to treatment retention improvement. Of note, similar results for 16 and 8 mg daily dosing may not be observed with use of buprenorphine/naloxone, as this study solely evaluated use of buprenorphine alone. [4]
A 2020 systematic review examined the effect of buprenorphine dose in treatment of OUD to determine an optimal dose or dose-range. A total of 15 studies were included, utilizing both oral liquid and tablet formulations. Studies that included a dose of 16 mg or higher reported mixed results of the efficacy of lower doses in producing blockade effects; studies that reported doses found a dose ≥16 mg to be more effective generally included higher challenge doses of a μ-opioid-receptor agonist versus studies that reported doses under 16 mg to be effective. There was no clear correlation between buprenorphine dose and reported treatment retention, nor illicit opioid use during the study periods. There was no evidence that a daily dose higher than 16 mg confers additional benefit, and data were inconclusive regarding the comparative effectiveness of 8 mg versus 16 mg. The authors concluded that buprenorphine treatment should be individualized and subject to risk-benefit assessments, as data appears inconclusive with regards to relative effectiveness between dosages. [5]