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Extended-release buprenorphine (XRB), a monthly injectable long-acting opioid use disorder (OUD) treatment, has not been studied for use in corrections facilities. To compare treatment retention following release from jail among adults receiving daily sublingual buprenorphine-naloxone (SLB) vs those receiving XRB. This open-label, randomized comparative effectiveness study included 52 incarcerated adults in New York City observed for 8 weeks postrelease between June 2019 and May 2020. Participants were soon-to-be-released volunteers from 1 men's and 1 women's jail facility who had OUDs already treated with SLB. Follow-up treatment was received at a primary care clinic in Manhattan. Data were analyzed between June 2020 and December 2020. XRB treatment was offered prior to release and continued monthly through 8 weeks after release. SLB participants continued to receive daily directly observed in-jail SLB administration, were provided a 7-day SLB supply at jail release, and followed up at a designated clinic (or other preferred clinics). Buprenorphine treatment retention at 8 weeks postrelease. A total of 52 participants were randomized 1:1 to XRB (26 participants) and SLB (26 participants). Participants had a mean (SD) age of 42.6 (10.0) years; 45 participants (87%) were men; and 40 (77%) primarily used heroin prior to incarceration. Most participants (30 [58%]) reported prior buprenorphine use; 18 (35%) reported active community buprenorphine treatment prior to jail admission. Twenty-one of 26 assigned to XRB received 1 or more XRB injection prior to release; 3 initiated XRB postrelease; and 2 did not receive XRB. Patients in the XRB arm had fewer jail medical visits compared with daily SLB medication administration (mean [SD] visits per day: XRB, 0.11 [0.03] vs SLB, 1.06 [0.08]). Community buprenorphine treatment retention at week 8 postrelease was 18 participants in the XRB group (69.2%) vs 9 in the SLB group (34.6%), and rates of opioid-negative urine tests were 72 of 130 tests in the XRB group (55.3%) and 50 of 130 tests in the SLB group (38.4%). There were no differences in rates of serious adverse events, no overdoses, and no deaths. XRB was acceptable among patients currently receiving SLB, and patients had fewer in-jail clinic visits and increased community buprenorphine treatment retention when compared with standard daily SLB treatment. These results support wider use and further study of XRB as correctional and reentry OUD treatment. ClinicalTrials.gov Identifier: NCT03604159.

Opioid-induced respiratory depression driven by ligand binding to mu-opioid receptors is a leading cause of opioid-related fatalities. Buprenorphine, a partial agonist, binds with high affinity to mu-opioid receptors but displays partial respiratory depression effects. The authors examined whether sustained buprenorphine plasma concentrations similar to those achieved with some extended-release injections used to treat opioid use disorder could reduce the frequency and magnitude of fentanyl-induced respiratory depression. In this two-period crossover, single-centre study, 14 healthy volunteers (single-blind, randomized) and eight opioid-tolerant patients taking daily opioid doses ≥90 mg oral morphine equivalents (open-label) received continuous intravenous buprenorphine or placebo for 360 minutes, targeting buprenorphine plasma concentrations of 0.2 or 0.5 ng/mL in healthy volunteers and 1.0, 2.0 or 5.0 ng/mL in opioid-tolerant patients. Upon reaching target concentrations, participants received up to four escalating intravenous doses of fentanyl. The primary endpoint was change in isohypercapnic minute ventilation (VE). Additionally, occurrence of apnea was recorded. Fentanyl-induced changes in VE were smaller at higher buprenorphine plasma concentrations. In healthy volunteers, at target buprenorphine concentration of 0.5 ng/mL, the first and second fentanyl boluses reduced VE by [LSmean (95% CI)] 26% (13-40%) and 47% (37-59%) compared to 51% (38-64%) and 79% (69-89%) during placebo infusion (p = 0.001 and < .001, respectively). Discontinuations for apnea limited treatment comparisons beyond the second fentanyl injection. In opioid-tolerant patients, fentanyl reduced VE up to 49% (21-76%) during buprenorphine infusion (all concentration groups combined) versus up to 100% (68-132%) during placebo infusion (p = 0.006). In opioid-tolerant patients, the risk of experiencing apnea requiring verbal stimulation following fentanyl boluses was lower with buprenorphine than with placebo (odds ratio: 0.07; 95% CI: 0.0 to 0.3; p = 0.001). Results from this proof-of-principle study provide the first clinical evidence that high sustained plasma concentrations of buprenorphine may protect against respiratory depression induced by potent opioids like fentanyl.

Patient-reported outcomes in the treatment of opioid dependence may differ between subcutaneously administered depot buprenorphine and daily sublingual buprenorphine. To compare patient satisfaction between depot buprenorphine and sublingual buprenorphine in adult outpatients with opioid dependence. This open-label, randomized clinical trial was conducted among adult patients with opioid dependence at 6 outpatient clinical sites in Australia from October 2018 to September 2019. Data analysis was conducted from October 2019 to May 2020. Participants were randomized to receive treatment with weekly or monthly depot buprenorphine or daily sublingual buprenorphine over 24 weeks. The primary end point was the difference in global treatment satisfaction, assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4 (range, 0-100; higher score indicates greater satisfaction) at week 24. Secondary end points included other patient-reported outcomes, including quality of life, treatment burden, and health-related outcomes, as well as measures of opioid use, retention in treatment, and safety. A total of 119 participants (70 [58.8%] men; mean [SD] age, 44.4 [10.5] years) were enrolled, randomized to, and received either depot buprenorphine (60 participants [50.4%]) or sublingual buprenorphine (59 participants [49.6%]). From the initial sample of 120, a participant (0.8%) in the sublingual buprenorphine group withdrew consent and did not receive study treatment. All participants were receiving sublingual buprenorphine when enrolled. The mean TSQM global satisfaction score was significantly higher for the depot group compared with the sublingual group at week 24 (mean [SE] score, 82.5 [2.3] vs 74.3 [2.3]; difference, 8.2; 95% CI, 1.7 to 14.6; P = .01). Improved outcomes were also observed for several secondary end points after treatment with depot buprenorphine (eg, mean [SE] treatment burden assessed by the Treatment Burden Questionnaire global score, on which lower scores indicate lower burden: 13.2 [2.6] vs 28.6 [2.5]; difference, -15.4; 95% CI, -22.6 to -8.2; P < .001). Thirty-nine participants (65.0%) in the depot buprenorphine group experienced 117 adverse drug reactions, mainly injection site reactions of mild intensity following subcutaneous administration, and 12 participants (20.3%) in the sublingual buprenorphine group experienced 21 adverse drug reactions. No participants withdrew from the trial medication or the trial due to adverse events. In this study, participants receiving depot buprenorphine reported improved treatment satisfaction compared with those receiving sublingual buprenorphine. The results highlight the application of patient-reported outcomes as alternative end points to traditional markers of substance use in addiction treatment outcome studies. anzctr.org.au Identifier: ANZCTR12618001759280.

Buprenorphine extended-release monthly formulation (BUP-XR, SUBLOCADE ) is approved for treatment of moderate-to-severe opioid use disorder (OUD) following subcutaneous injection in the abdomen. This open-label pharmacokinetic study assessed three alternative injection locations (upper arm, thigh, buttocks) to offer additional flexibility considering the chronic nature of the disease and patient preferences. Following stabilization on 12/3 mg/day of sublingual buprenorphine/naloxone for ≥ 7 days, participants with moderate-to-severe OUD were randomized to receive a single 300-mg BUP-XR injection in the upper arm, thigh, buttocks, or abdomen (reference). Serial blood samples were taken to measure buprenorphine plasma concentrations over 28 days and assess buprenorphine relative bioavailability. Safety evaluations included treatment-emergent adverse events and assessments of injection site pain, tenderness, erythema, induration, and swelling. A total of 88 participants received a single subcutaneous injection of 300-mg BUP-XR in the upper arm (N = 21), thigh (N = 23), buttocks (N = 22), or abdomen (N = 22); 81/88 (92%) completed the study. Buprenorphine plasma exposure (area under the plasma concentration-time curve over 28 days) was comparable across injection site groups with mean buprenorphine plasma concentrations sustained at approximately 2 ng/mL (therapeutic target concentration) or above. Buprenorphine maximum plasma concentration (C ) was approximately 39% and 52% higher after injection in the upper arm and thigh, respectively, versus the abdomen, while comparable between buttocks and abdomen. Higher C values were not associated with an increased incidence of adverse events. Safety and injection site tolerability were comparable across injection groups. These pharmacokinetic and safety findings support BUP-XR injection into the upper arm, thigh, and buttocks. Clinicaltrials.gov: NCT05704543.

Background For nearly two decades, it has been widely recognized that individuals in jail settings have a high prevalence of opioid use disorders (OUD) and are highly susceptible to fatal overdose upon their release. This setting provides a public health opportunity to address OUD with Medication for Opioid Use Disorders (MOUDs). Yet, 56% of jails do not provide MOUD, creating a pressing need for better implementation approaches in jail and the hand-off to the community. Two successful implementation strategies, NIATx external coaching and the Extension for Community Healthcare Outcomes (ECHO) case management telementoring model, were compared to address this persistent treatment gap. Methods This 2 × 2 design compared high ( n  = 12) and low ( n  = 4) dose coaching with and without ECHO in a 12-month intervention and 12 M sustainability period. The national trial included 25 jails and 13 community-based partners. MOUD trends for buprenorphine, methadone, injectable naltrexone, and combined MOUD between the study arms were assessed. Results Jail sizes ranged from 24% with < 100 and 24% with > 500 daily population, and community-based treatment providers ranged from 63% with < 50 and 7% with > 500 average monthly OUD intakes. New patient counts were found to significantly increase across the intervention phase for buprenorphine ( p  < .01) and combined MOUD ( p  < .01). Injectable naltrexone and methadone showed no consistent, significant gains. For sites with low coaching without ECHO, new patient counts for combined MOUD were predicted to increase by 47.44% during the intervention phase and 7.30% during the sustainability phase. ECHO demonstrated that MOUD use did not significantly increase compared to coaching across MOUDs in the intervention phase ( p  = .517). High- and low-dose coaching showed no significant differences in MOUD use during the intervention phase ( p  = .124). Conclusions Coaching emerged as a more effective implementation strategy than ECHO for increasing buprenorphine use in jail settings. In practice, ECHO sessions offered considerable overlap with coaching strategies. While high-dose coaching had greater gains for MOUDs overall than low-dose coaching, those gains were statistically insignificant, suggesting low-dose coaching to be more economical. To increase MOUD use in jail settings, jurisdictions should focus on new MOUDs so all three MOUDs are available and enhance the post-incarceration continuum of care. Trial registration Name of registry: ClinicalTrials.gov. Trial registration number: NCT04363320. Date of registration: 2020–07-30. URL of trial registry record: https://clinicaltrials.gov/study/NCT04363320?term=molfenter&rank=7 .

Abstract Objective Acute pain management in opioid-dependent persons is complicated because of tolerance and opioid-induced hyperalgesia. Very high doses of morphine are ineffective in overcoming opioid-induced hyperalgesia and providing antinociception to methadone-maintained patients in an experimental setting. Whether the same occurs in buprenorphine-maintained subjects is unknown. Design Randomized double-blind placebo-controlled. Subjects were tested on two occasions, at least five days apart, once with intravenous morphine and once with intravenous saline. Subjects were tested at about the time of putative trough plasma buprenorphine concentrations. Setting Ambulatory. Subjects Twelve buprenorphine-maintained subjects: once daily sublingual dose (range = 2–22 mg); no dose change for 1.5–12 months. Ten healthy controls. Methods Intravenous morphine bolus and infusions administered over two hours to achieve two separate pseudo-steady-state plasma concentrations one hour apart. Pain tolerance was assessed by application of nociceptive stimuli (cold pressor [seconds] and electrical stimulation [volts]). Ten blood samples were collected for assay of plasma morphine, buprenorphine, and norbuprenorphine concentrations until three hours after the end of the last infusion; pain tolerance and respiration rate were measured to coincide with blood sampling times. Results Cold pressor responses (seconds): baseline: control 34 ± 6 vs buprenorphine 17 ± 2 (P = 0.009); morphine infusion-end: control 52 ± 11(P = 0.04), buprenorphine 17 ± 2 (P > 0.5); electrical stimulation responses (volts): baseline: control 65 ± 6 vs buprenorphine 53 ± 5 (P = 0.13); infusion-end: control 74 ± 5 (P = 0.007), buprenorphine 53 ± 5 (P > 0.98). Respiratory rate (breaths per minute): baseline: control 17 vs buprenorphine 14 (P = 0.03); infusion-end: control 15 (P = 0.09), buprenorphine 12 (P < 0.01). Infusion-end plasma morphine concentrations (ng/mL): control 23 ± 1, buprenorphine 136 ± 10. Conclusions Buprenorphine subjects, compared with controls, were hyperalgesic (cold pressor test), did not experience antinociception, despite high plasma morphine concentrations, and experienced respiratory depression. Clinical implications are discussed.

Context/background The high prevalence of opioid use among jailed adults offers an unmatched opportunity to identify and treat those with opioid use disorder (OUD), a population that is at a substantial risk for post-release overdose. From a public health perspective, jails are critical touchpoints, as these facilities typically admit more than 7 million adults per year. One clinical consideration is whether pre-trial detainees with OUD would benefit from early induction onto extended-release buprenorphine (XRB). Methods/study design In this 3-year randomized controlled trial, we will identify and recruit 200 incarcerated adults with OUD who are receiving sublingual buprenorphine (SLB) or tolerate a SLB test dose and randomize them to receive extended release buprenorphine (XRB) ( n  = 100) or to remain on SLB ( n  = 100) while in custody. Study participation will continue through their pre-trial time in jail (up to 6 months) or until they are sentenced or released. Community treatment will then be tracked for 90 days following release. In addition to collecting data on XRB uptake in jail, we will assess (1) the percentage of XRB and SLB study participants leaving jail with a clinically active dose of buprenorphine in their system, (2) 90- day post-release MOUD continuation, (3) levels of buprenorphine diversion while in custody, and (4) recidivism and death (90 days). “Clinically active” is defined as receiving XRB within the past 28 days or SLB in the past 24 h. Discussion Findings from this study will demonstrate the feasibility and outcomes of inducting pre-trial adults with OUD onto XRB, as well as offer practical clinical and policy guidelines for best practices for treating this high risk and understudied population.

RationaleOpioid injection drug use (IDU) has been linked to a more severe pattern of use (e.g. tolerance, overdose risk) and shorter retention in treatment, which may undermine abstinence attempts.ObjectivesThis secondary data analysis of four human laboratory studies investigated whether current opioid IDU modulates subjective abuse liability responses to high-dose hydromorphone during intermediate-dose buprenorphine stabilization (designed to suppress withdrawal but allow surmountable agonist effects), and whether hydromorphone response magnitude predicts latency of return to opioid use during buprenorphine dose-tapering.MethodsRegular heroin users not currently seeking treatment (n = 54; 29 current injectors, 25 non-injectors) were stabilized on 8-mg/day sublingual buprenorphine and assessed for subjective responses (e.g. ‘liking’, craving) to hydromorphone 24-mg intramuscular challenge (administered 16-hr post-buprenorphine) under randomized, double-blinded, controlled conditions. A subgroup (n = 35) subsequently completed a standardized 3-week outpatient buprenorphine dose-taper, paired with opioid-abstinent contingent reinforcement, and were assessed for return to opioid use based on thrice-weekly urinalysis and self-report.ResultsDuring buprenorphine stabilization, IDU reported lower ‘liking’ of buprenorphine and post-hydromorphone peak ‘liking’, ‘good effect’ and ‘high’ compared to non-IDU. Less hydromorphone peak increase-from-baseline in ‘liking’ (which correlated with less hydromorphone-induced craving suppression) predicted significantly faster return to opioid use during buprenorphine dose-tapering.ConclusionsIn these buprenorphine-stabilized regular heroin users, IDU is associated with attenuated ‘liking’ response (more cross-tolerance) to buprenorphine and to high-dose hydromorphone challenge and, in turn, this cross-tolerance (but not IDU) predicts faster return to opioid use. Further research should examine mechanisms that link cross-tolerance to treatment response.

Buprenorphine, a partial μ-receptor agonist, is approved for the management of moderate to severe pain, but it has low oral bioavailability. Two open-label studies were performed to determine the pharmacokinetic profile of buprenorphine from buccal film formulations of buprenorphine. Both studies enrolled healthy volunteers, aged 18 to 55 years, who received concurrent oral naltrexone to reduce adverse events (AEs); subjects with a history or evidence of substance abuse or current use of any product affecting cytochrome P450 3A4 activity were excluded. The first study (n = 25) was a 5-period crossover trial with 4 single doses (75 and 300 and 300 and 1200 μg) of 2 formulations (F14 and F24) of buccal buprenorphine (BBUP) and a 300-μg intravenous dose of buprenorphine with a 7-day washout between periods. In the second study, each subject (n = 10) received 6 doses of 4 BBUP strengths (60, 120, 180, and 240 μg BID) in a dose-escalation design. Plasma concentrations of buprenorphine and norbuprenorphine were assayed, and pharmacokinetics were summarized with descriptive statistics and analyzed by using a linear mixed effects model (single-dose study). AEs were recorded. In the single-dose study, the 2 formulations exhibited comparable bioavailability of 46% to 51% that was independent of dose, with a single buprenorphine peak concentration from each BBUP dose occurring at 2.5 to 3 hours. The mean buprenorphine Cmax across the doses ranged from 0.17 ng/mL for the 75-µg dose to 1.43 ng/mL for the 1200-µg dose. AUC0–∞, AUC0–last, and Cmax were proportional to the dose of BBUP administered. Cmax of norbuprenorphine after BBUP administration was approximately one tenth that of buprenorphine Cmax. In the multiple-dose study, steady state was reached within 3 days of BID dosing. There was a linear increase in exposure across the dose range from 60 to 240 μg BID. Treatment-emergent AEs in both studies were consistent with those reported with opiate administration to healthy volunteers. The absolute bioavailability of BBUP was 46% to 51% across a 16-fold dose range, with dose-proportional increases in systemic exposure. Apparent steady-state conditions occurred within 3 days of dosing. These pharmacokinetic results suggest that therapeutic buprenorphine plasma concentrations can be obtained with BBUP across a wide dose range in a shorter time than other (eg, transdermal) dosage forms.

Background. This study examined drug interactions between buprenorphine, a partial opioid agonist used for opioid dependence treatment and pain management, and the protease inhibitors (PIs) darunavir-ritonavir and fosamprenavir-ritonavir. Methods. The pharmacokinetics of buprenorphine and its metabolites and symptoms of opioid withdrawal or excess were compared in opioid-dependent, buprenorphine-naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (11 for darunavir-ritonavir and 10 for fosamprenavir-ritonavir) before and after 15 days of PI administration. PI pharmacokinetics and adverse effects were compared between the buprenorphine-maintained participants and an equal number of sex-, age-, race-, and weight-matched, healthy, non-opioid-dependent volunteers who received darunavir-ritonavir or fosamprenavir-ritonavir but not buprenorphine. Results. There were no significant changes in buprenorphine or PI plasma levels and no significant changes in medication adverse effects or opioid withdrawal. Increased concentrations of the inactive metabolite buprenorphine-3-glucuronide suggested that darunavir-ritonavir and fosamprenavir-ritonavir induced glucuronidation of buprenorphine. Conclusions. Dose adjustments are not likely to be necessary when buprenorphine and darunavir-ritonavir or fosamprenavir-ritonavir are coadministered for the treatment of opioid dependence and HIV disease.