Association between dynamic dose increases of buprenorphine for treatment of opioid use disorder and risk of relapse

Abstract

Background and Aims: Dynamic, adaptive pharmacologic treatment for opioid use disorder (OUD) has been previously recommended over static dosing to prevent relapse, and is aligned with personalized medicine. However, there has been no quantitative evidence demonstrating its advantage. Our objective was to estimate the extent to which a hypothetical intervention that increased buprenorphine dose in response to opioid use would affect risk of relapse over 24 weeks of follow-up.Design: A secondary analysis of the buprenorphine arm of an open-label randomized controlled 24-week comparative effectiveness trial, 2014-17.Setting: Eight community addiction treatment programs in the United States.Participants: English-speaking adults with DSM-5 OUD, recruited during inpatient admission (n = 270). Participants were mainly white (65%) and male (72%).Intervention(s): Participants were treated with daily sublingual buprenorphine-naloxone (BUP-NX), with dose based on clinical indication, determined by the provider. We examined a hypothetical intervention of increasing dose in response to opioid use.Measurements: Outcome was relapse to regular opioid use during the 24 weeks of outpatient treatment, assessed in a survival framework. We estimated the relapse-free survival curves of participants under a hypothetical (i.e. counterfactual) intervention in which their BUP-NX dosage would be increased following their own subject-specific opioid use during the first 12 weeks of treatment versus a hypothetical intervention in which dose would remain constant.Findings: We estimated that increasing BUP-NX dose in response to recent opioid use would lower risk of relapse by 19.17 percentage points [95% confidence interval (CI) = −32.17, −6.18) (additive risk)] and 32% (0.68, 95% CI = 0.49, 0.86) (relative risk).The number-needed-to-treat with this intervention to prevent a single relapse is 6. Conclusions:In people with opioid use disorder, a hypothetical intervention that increases sublingual buprenorphine-naloxone dose in response to opioid use during the first 12 weeks of treatment appears to reduce risk of relapse over 24 weeks, compared with holding the dose constant after week 2.

Nonparametric causal mediation analysis for stochastic interventional (in)direct effects

“…The conclusions that may be drawn from our re-analysis using the stochastic interventional direct and indirect effects complement those previously reported in the investigations of Lee et al (2018), who evaluated the total effect of BUP-NX (versus XR-NTX) treatment on OUD relapse, and Rudolph et al (2020a), who used the interventional mediation analysis approach of (limited to static interventions on A) to examine differences in relapse risk between homeless and non-homeless participants. Importantly, our substantive conclusion -that dose increases directly lower the risk of relapse -agree generally with those of Rudolph et al (2020b), who found that dose increases directly lowered risk of OUD relapse when such dose increases followed opioid use. Notably, our proposed (in)direct effects and estimation approach differ from previous efforts in three important ways: (i) our causal effect definitions remain unaltered in the presence intermediate confounders affected by exposure and may be re-evaluated in randomized trials, (ii) the flexible estimators we introduce eschew restrictive modeling assumptions by incorporating state-of-the-art machine learning in the estimation of nuisance parameters, and (iii) our strategy provides an analog to a dose-response analysis by allowing for the risk of OUD relapse to be traced out across changes in the odds of exposure to a schedule in which BUP-NX dose is increased repeatedly early in treatment.…”

Higher First 30-Day Dose of Buprenorphine for Opioid Use Disorder Treatment Is Associated With Decreased Mortality

“…Higher TMbup doses have been associated with improved treatment retention and decreased relapse risk in some observational studies 11,15 . In addition to these reported associations, our findings suggest an association between higher first 30-day TMbup doses and decreased subsequent mortality.…”

“…11,13 Clinical guidelines vary on TMbup's target dose and how quickly it should be reached, but it is agreed that most patients reach stable maintenance daily doses between 4 mg and 24 mg, with 16 mg being a common target. 7,14 Despite prior findings suggesting that higher doses of buprenorphine (eg, >16 mg daily) may provide better treatment outcomes, such as decreased discontinuation and return to opioid use, 10,11,15 limited information is available about the associations between TMbup doses and subsequent risk of death.…”

“Macrodosing” Sublingual Buprenorphine and Extended-release Buprenorphine in a Hospital Setting: 2 Case Reports

“…High-dose bup/nal is an adaptive dosing protocol; the patient receives an additional bup/nal dose only if the Clinical Opiate Withdrawal Scale (COWS) score is 13 or above. Evidence suggests that higher doses and adaptive dosing are associated with reduced opioid use and increased treatment retention 8 …”

“…Evidence suggests that higher doses and adaptive dosing are associated with reduced opioid use and increased treatment retention. 8 Buprenorphine extended-release subcutaneous injection (buprenorphine ER) also has the potential to increase treatment retention rates. Buprenorphine ER produces a higher and more constant serum buprenorphine level than buprenorphine SL, and its duration of action is between 28 and 42 days, eliminating the need for daily medication use.…”