(36) Human Laboratory Evaluation of Direct-to-Inject XR-Buprenorphine: Preliminary Results

Background & Introduction: A novel approach to buprenorphine induction is “direct-to-inject” (DTI)—administering extended-release buprenorphine (XR-bup) without first administering sublingual buprenorphine. Current recommendations are to use the weekly XR-Bup 24mg injection but wait for COWS of 4 or greater, since prior research suggests that administering with COWS < 4 is more likely to result in buprenorphine precipitated opioid withdrawal (BPOW), defined as reaching moderate or greater withdrawal severity within 4 hours of injection. It is unclear if the 16mg injection can be administered at these low COWS scores without precipitating withdrawal. In this NIH-funded human laboratory study, we aimed to determine the safety of administering varying doses of XR-Bup at low COWS scores. Here we provide preliminary results from our first three participants who enrolled in the trial and received the 16mg injection with COWS score of 0.

Methods: The study was funded by NIH (R21DA060411), registered (NCT06441604), and conducted at the Center for Clinical Investigation (CCI) at Brigham and Women’s Hospital, Boston, MA. Individuals with opioid use disorder actively using illicit fentanyl provided informed consent, then admitted to the CCI unit for 3 days. On day 1, participants received fentanyl IV 100-200µg for withdrawal as needed. At 9am on day 2, after confirming COWS of ≤3, participants received XR-Bup 16mg. Vital signs and COWS scores were monitored, and timed blood samples at baseline, and at 0.5, 1, 2, 4, 6, 8, 12 and 24 hours. After the XR-Bup, participants were offered comfort medications (e.g. clonidine, gabapentin, lorazepam) but not fentanyl. Plasma was isolated from samples via centrifugation, frozen at -80C, and analyzed by LC-MS/MS. Participants were discharged on the morning of day 3, referred to treatment, and scheduled for a follow-up within one week. Primary outcome was the incidence of BPOW defined as COWS≥13 within 4 hours of injection. Secondary outcomes included COWS and DEQ scores, comfort medications received, and pharmacokinetics (PK) of buprenorphine and fentanyl. Participants were compensated for their time. Mass General Brigham IRB approved the study, and received in-kind support from Braeburn to obtain Brixadi.

Results: A total of 52 individuals were screened, 6 passed the initial screening and were assessed in-person for eligibility, and 3 were enrolled (mean age 41, 33% female and 67% white/33% black). On average, fentanyl IV 367µg was administered after admission to treat opioid withdrawal prior to the XR-Bup injection. All three participants had a COWS of 0 at baseline just prior to receiving the XR-Bup. While no participant met the a priori definition of BPOW (COWS≥13 within 4 hours of injection), all three experienced increase in COWS scores following the injection. One participant experienced an increase to COWS of 10 within an hour and requested to be withdrawn from the study, then discharged 2.5 hours after the injection. In the other two, COWS scores increased to a maximum of 5 within 4 hours, but then returned to baseline. Both then experienced an additional increase in COWS scores starting in the early afternoon and evening (max of 9 at 8pm). Both requested and received comfort medications (i.e. clonidine, gabapentin, and lorazepam) with good effect. By 9am on day 3, COWS scores were either 0 or 1, and both were discharged in stable condition. The full PK analysis of buprenorphine and fentanyl is currently underway.

Conclusion & Discussion: This is the first human laboratory study of the DTI strategy to initiate buprenorphine among individuals actively using illicit fentanyl. Consistent with prior reports, participants in this study did experience a mild increase in withdrawal severity after receipt of XR-Bup but this did not meet the a priori definition of precipitated withdrawal. Nevertheless, one participant withdrew from the study soon after the injection, while the other two participants experienced a second increase in COWS scores later in Day 2 requiring additional comfort medications. While analysis of the PK data is still ongoing, the early increase in COWS likely represents the effects of buprenorphine displacing the fentanyl, while the later second increase in COWS may represent withdrawal from fentanyl itself. These preliminary results suggest that the 16mg dose may be safe to administer, but that the buprenorphine dose may be insufficient to prevent fentanyl withdrawal prior to reaching its Cmax. More research is needed to better characterize the safety and feasibility of DTI using XR-bup, and enrollment for the study is ongoing.

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