Sublingual Buprenorphine Research Articles

Characteristics of patients who are initiated on long-acting buprenorphine (Buvidal®) in France: A retrospective cross-sectional study

The long-acting buprenorphine Buvidal® is a recent type of opioid agonist treatment (OAT) used for opioid use disorder (OUD). It was initially suggested to preferentially use Buvidal® for specific OUD populations, including people in prison, or patients in recovery and on sublingual buprenorphine. We conducted a national study to examine whether the profile of patients treated with Buvidal® in France matched these initial recommendations. A retrospective cross-sectional study was conducted in 13 national addiction centers (outside prison), using the individual medical records of patients initiated on Buvidal®. Baseline characteristics were collected and described, including sociodemographic features, comorbid medical conditions, concurrent substance use and prescription drug misuse, and OAT features before Buvidal® initiation, respectively. In total 101 patients (72.3% males, mean age 43.9±11.3years) were identified, which corresponded to one sixth of all patients treated with Buvidal® in France at the time of the study. Of them, 36 (36.4%) of them were professionally active, 35 (35.4%) were durably inactive, and the rest in an intermediary situation. Furthermore, 90 (90.0%) patients had at least one medical comorbidity (all types), and 83 (83.0%) at least one psychiatric comorbidity. Most frequent non-psychiatric comorbidities were chronic pain (n=20, 20.0%) and chronic viral infection (n=16, 17.8%). Current use of psychoactive substances included cocaine and crack (n=43, 42.6%), heroin (n=19, 18.8%), but also misuse of prescription drugs (n=20, 20%), mainly opioid analgesics. Moreover, 99 (98.0%) patients had an OAT before Buvidal® initiation, including 7 (8.1%) patients on methadone. The profile of patients initiated on Buvidal® in France was extremely similar to that of patients treated for OUD in France, either in terms of social or clinical features. While initial recommendations essentially underlined the interest of Buvidal® for some niche populations, the on-the-ground practice reveals a more widespread use, including for unrecovered patients, or patients treated with methadone.

Basal cortisol level modulates stress-induced opioid-seeking behavior

In preclinical studies and our human laboratory, the α2-noradrenergic autoreceptor antagonist yohimbine was found to promote drug-seeking behavior. This study evaluated effects of dose-combinations of yohimbine and the glucocorticoid receptor agonist hydrocortisone to model intensity-dependent effects of stimulating each neurochemical system, alone and together, on stress-reactivity and opioid-seeking. Twelve regular heroin-using participants diagnosed with opioid use disorder (OUD) were stabilized on sublingual buprenorphine (8-mg/day), then passed a hydromorphone 18-mg vs. placebo intramuscular reinforcement screen. Across 9 experimental conditions (3 × 3 within-subject, randomized crossover, placebo-controlled, double-blind design) during inpatient buprenorphine maintenance, combinations of oral pretreatment doses of yohimbine (0, 27, 54-mg; t = 0 min) then hydrocortisone (0, 20, 40-mg; t = 45 min) were administered. In each condition, subjective drug and mood effects, cardiovascular responses, and saliva cortisol and α-amylase levels were assessed to evaluate stress-reactivity, and participants completed a 12-trial choice progressive ratio task during which they could earn units of hydromorphone (1.5-mg intramuscular) and/or money ($2.00). Yohimbine dose-dependently increased blood pressure, α-amylase, and anxiety scores, and decreased opioid agonist symptoms; hydrocortisone dose-dependently increased cortisol levels. Yohimbine/hydrocortisone dose-combinations significantly shifted within-session responding from money to opioid-seeking among participants with lower basal cortisol levels. These findings replicate yohimbine effects on stress biomarkers and demonstrate that noradrenergic/glucocorticoid-potentiated opioid-seeking is modulated by basal cortisol level. In persons with OUD stabilized on buprenorphine, basal HPA-axis activity and acute stressors can enhance opioid relative reinforcing efficacy. These factors may limit OUD treatment efficacy and highlight the need for novel interventions that prevent stress-induced opioid-seeking.

Parenteral Buprenorphine for Opioid Withdrawal.

Buprenorphine is the standard of care for treatment of opioid withdrawal. However, when sublingual (SL) administration is not appropriate or practical, parenteral administration by the intravenous (IV) or intramuscular (IM) route may be a reasonable substitute. Although previously used intravenously for the treatment of pain, current practitioners have limited experience with parenteral use of buprenorphine. This is a case series using retrospective chart review of patients at an urban public hospital who received IV or IM buprenorphine for treatment of opioid withdrawal. A query of the electronic health record (EHR) was performed to identify patients who had received IV or IM buprenorphine from January 2020 to December 2021. Charts were reviewed for patient demographics, medical history, substance use history, urine drug screens, clinical scenario, indication for parenteral buprenorphine, dose of buprenorphine, vital sign trends, and any measure of change in withdrawal. Eight patients were identified. The most frequent initial dose of parenteral buprenorphine was 0.3 mg, and if buprenorphine needed to be re-dosed it was most commonly administered every six hours. The most common indications for use were delirium or intractable nausea and vomiting related to opioid withdrawal. Withdrawal improved in 6 of the 8 cases, and often allowed for subsequent use of SL buprenorphine. There were no adverse effects identified. Parenteral buprenorphine was successfully used to treat opioid withdrawal in a select group of patients. Further studies are needed to identify the optimal use parameters of parenteral buprenorphine.

Health service utilization, substance use treatment response, and death in patients with opioid use disorder and comorbid hepatitis C findings from prospective cohort study with administrative database linkage

BackgroundAmong patients with opioid use disorder (OUD), high rates of overdose and death have been reported in subgroups with Hepatitis C Virus (HCV). Evidence on the comorbid effect of HCV on clinical and substance use trajectories has been limited by small sample sizes, short follow-up, and heavy reliance on administrative data which lacks granularity on important prognostic factors. Additionally, few studies include populations on substance use treatment. AimTo establish the impact of HCV exposure (antibody positivity) on health care utilization patterns, substance use treatment response, and death in a cohort of patients with OUD on opioid agonist therapy (OAT). MethodsThis multi-center prospective cohort study recruited adult patients with OUD on OAT from 57 substance use treatment centers in Ontario, Canada. The study collected substance use outcomes, and classified patients with ≥50 % positive opioid urine screens over one year of follow-up as having poor treatment response. Additional data obtained via linkage with ICES administrative databases evaluated the relationship between HCV status, healthcare service utilization, and death over 3 years of follow-up. Multiple logistic regression models established the adjusted impact of HCV on various outcomes. ResultsAmong recruited participants (n = 3430), 44.10 % were female with a mean age of 38.64 years (Standard deviation: 10.96). HCV was prevalent in 10.6 % of the cohort (n = 365). Methadone was used most often (83.9 %, n = 2876), followed by sublingual buprenorphine (16.2 %, n = 554). Over the three-year follow-up, 5.3 % of patients died (n = 181). Unadjusted results reveal rates of hospitalization (all-cause, mental-health related, critical care) and emergency department visits (mental health-related), were significantly higher among HCV patients. Associations diminished in adjusted models. Active injection drug use exhibited the highest predictive risk for all outcomes. ConclusionA high degree of acute physical and mental illness and its resulting health service utilization burden is concentrated among patients with OUD and comorbid HCV. Future research should explore the role for targeted interventions and how best to implement integrated healthcare models to better address the complex health needs of HCV populations who inject drugs.

Perceptions of extended-release buprenorphine among people who received medication for opioid use disorder in jail: a qualitative study

BackgroundIncarceration provides an opportunity for health interventions, including opioid use disorder (OUD) treatment and prevention of opioid-related overdoses post-release. All FDA-approved forms of medication for OUD (MOUD) treatment were mandated in several Massachusetts jails in 2019, with some jails offering extended-release buprenorphine (XR-Bup). Little is known about patient perspectives on and experiences with XR-Bup in carceral settings.MethodsWe conducted semi-structured interviews in 2022 with community-dwelling people who received MOUD during a recent incarceration in a Massachusetts jail. We asked participants about their experiences with and perspectives on XR-Bup while in jail. Qualitative data were double-coded deductively and reviewed inductively to identify emergent themes, which were structured using the Theoretical Framework of Acceptability (TFA).ResultsParticipants (n = 38) had a mean age of 41.5 years, were 86% male, 84% White, 24% Hispanic, and 95% continued to receive MOUD at the time of their interview, including 11% receiving XR-Bup. Participants who viewed XR-Bup favorably appreciated avoiding the taste of sublingual buprenorphine; avoiding procedural difficulties and indignities associated with daily dosing in carceral settings (e.g., mouth checks, stigmatizing treatment from correctional staff); avoiding daily reminders of their addiction; experiencing less withdrawal; having extra time for other activities, such as work; and reduction of diversion of MOUD within the jail setting. Participants who viewed XR-Bup less favorably preferred to maintain their daily dosing routine; liked daily time out of their housing unit; wanted to know what was “going into my body everyday”; and feared needles and adverse events. Participants also reported that jail clinicians used XR-Bup for patients who were previously caught diverting sublingual buprenorphine, suggesting limited patient participation in decision-making around XR-Bup initiation in some jails.ConclusionPeople who received MOUD in Massachusetts jails had both favorable and unfavorable views and experiences with XR-Bup. Understanding these preferences can inform protocols in jails that are considering implementation of XR-Bup treatment.

Buprenorphine-Precipitated Withdrawal Among Hospitalized Patients Using Fentanyl

Buprenorphine treatment of opioid use disorder (OUD) is safe and effective, but opioid withdrawal during treatment initiation is associated with poor retention in care. As fentanyl has replaced heroin in the drug supply, case reports and surveys have indicated increased concern for buprenorphine-precipitated withdrawal (PW); however, some observational studies have found a low incidence of PW. To estimate buprenorphine PW incidence and assess factors associated with PW among emergency department (ED) or hospitalized patients. This retrospective cohort study at 3 academic hospitals in Philadelphia, Pennsylvania, included adults with OUD who underwent traditional or high-dose buprenorphine initiation between January 1, 2020, and December 31, 2021. Exclusion criteria included low-dose buprenorphine initiation and missing documentation of opioid withdrawal severity within 4 hours of receiving buprenorphine. Buprenorphine initiation with an initial dose of at least 2 mg of sublingual buprenorphine after a Clinical Opiate Withdrawal Scale (COWS) score of 8 or higher. Additional exposures included 4 predefined factors potentially associated with PW: severity of opioid withdrawal before buprenorphine (COWS score of 8-12 vs ≥13), initial buprenorphine dose (2 vs 4 or ≥8 mg), body mass index (BMI) (<25 vs 25 to <30 or ≥30; calculated as weight in kilograms divided by height in meters squared), and urine fentanyl concentration (0 to <20 vs 20 to <200 or ≥200 ng/mL). The main outcome was PW incidence, defined as a 5-point or greater increase in COWS score from immediately before to within 4 hours after buprenorphine initiation. Logistic regression was used to estimate the odds of PW associated with the 4 aforementioned predefined factors. The cohort included 226 patients (150 [66.4%] male; mean [SD] age, 38.6 [10.8] years). Overall, 26 patients (11.5%) met criteria for PW. Among patients with PW, median change in COWS score was 9 points (IQR, 6-13 points). Of 123 patients with confirmed fentanyl use, 20 (16.3%) had PW. In unadjusted and adjusted models, BMI of 30 or greater compared with less than 25 (adjusted odds ratio [AOR], 5.12; 95% CI, 1.31-19.92) and urine fentanyl concentration of 200 ng/mL or greater compared with less than 20 ng/mL (AOR, 8.37; 95% CI, 1.60-43.89) were associated with PW. In this retrospective cohort study, 11.5% of patients developed PW after buprenorphine initiation in ED or hospital settings. Future studies should confirm the rate of PW and assess whether bioaccumulated fentanyl is a risk factor for PW.

A Pharmacologic Evaluation of Buprenorphine in Pregnancy and the Postpartum Period.

The dosing regimen in the package insert for sublingual buprenorphine is similar for pregnant and nonpregnant people despite the physiologic changes seen during pregnancy. To compare plasma buprenorphine pharmacokinetics during and after pregnancy and relate buprenorphine concentration to the pharmacodynamic endpoints of pupil diameter, Clinical Opioid Withdrawal Scale (COWS), and craving scores. Prospective cohort of 22 pregnant people undergoing 33 pharmacologic studies (6-8 hours each) during pregnancy or postpartum. Participants were on a stable daily dose of 2-8 mg sublingual buprenorphine every 6 or 8 hours. The dosing frequency was selected by the participant. On study day, baseline measurements of plasma buprenorphine, pupil diameter, COWS, and craving scores were obtained, then the usual morning dose was taken, and measurements were repeated several times over 1 dosing interval. The dose-normalized area under the plasma buprenorphine concentration time curve was significantly (P = 0.036) lower during pregnancy (155 ± 52 ng × min/mL) than postpartum (218 ± 113 ng × min/mL). Buprenorphine trough concentrations were similar at the start (1.1 ± 0.7 ng/mL) and end of a dosing cycle (1.2 ± 0.8 ng/mL) regardless of dosing frequency. Pupillary diameter, COWS, and craving scores returned to baseline as buprenorphine concentrations approached ~1 ng/mL. Pregnant people require a higher dose of buprenorphine to achieve concentrations comparable to nonpregnant people. There is a temporal relationship between the plasma buprenorphine concentration and the pharmacodynamic markers of pupillary diameter, COWS, and craving scores. An average plasma concentration of ~1 ng/mL was associated with the lowest level of COWS and craving scores.

Inpatient initiation of long-acting injectable buprenorphine at a community hospital: A retrospective case series

Objectives Determine if long-acting injectable buprenorphine (LAIB) can be successfully and safely administered in the hospital with minimal sublingual buprenorphine lead-in and potentially improve follow-up engagement in care. Methods We performed a retrospective case series of 46 patients who received LAIB while hospitalized at a safety-net community hospital. We abstracted demographic information, details about substance use disorder treatment history, in-hospital buprenorphine initiation methods and follow-up data from inpatient and outpatient electronic medical records. Results In total, 46 hospitalized patients received LAIB during the study period. The majority of our patients were older Black adults with Medicaid who self-reported intranasal heroin use. A low-dose buprenorphine initiation protocol was used most commonly, either in sublingual or intravenous form, with only two cases of precipitated withdrawal occurring during the buprenorphine initiation process and no cases of precipitated withdrawal after the administration of LAIB. 87% (40) of the patients received LAIB after receiving either sublingual or IV buprenorphine for fewer than the recommended seven days. Of the 46 hospitalized patients who received LAIB, 23 (50%) attended a follow-up addiction medicine appointment within 30 days of discharge. Conclusions Hospital administration of LAIB could play an important role in retention in care after hospital discharge.

Comparative effectiveness of extended-release naltrexone and sublingual buprenorphine for treatment of opioid use disorder among Medicaid patients.

Extended-release naltrexone (XR-NTX) and sublingual buprenorphine (SL-BUP) are both approved for opioid use disorder (OUD) treatment in any medical setting. We aimed to compare the real-world effectiveness of XR-NTX and SL-BUP. This was an observational active comparator, new user cohort study of Medicaid claims records for patients in New Jersey and California, USA, 2016-19. The participants were adult Medicaid patients aged 18-64 years who initiated XR-NTX or SL-BUP for maintenance treatment of OUD and did not use medications for OUD in the 90 days before initiation. Our cohort included 1755 XR-NTX and 9886 SL-BUP patients. We examined two outcomes up to 180 days after medication initiation: (1) composite of medication discontinuation and death and (2) composite of overdose and death. In adjusted analyses, treatment with XR-NTX was more likely to result in discontinuation or death by the end of follow-up than treatment with SL-BUP: cumulative risk 75.9% [95% confidence interval (CI) = 73.9%, 77.9%] versus 62.2% (95% CI = 61.2%, 63.2%), respectively (risk difference = 13.7 percentage points, 95% CI = 11.4, 16.0). There was minimal difference in the cumulative risk of overdose or death by the end of follow-up: XR-NTX 3.9% (95% CI = 3.0%, 4.8%) versus SL-BUP 3.3% (95% CI = 2.9%, 3.7%); risk difference = 0.5 percentage points, 95% CI = -0.4, 1.5. Results were consistent across sensitivity analyses. Medicaid patients in California and New Jersey, USA, receiving treatment for opioid use disorder stayed in treatment longer on sublingual buprenorphine than on extended-release naltrexone, but the risk of overdose was similar. Most patients in this study discontinued medication within 6months, regardless of which medication was initiated.

Buprenorphine/naloxone – one formulation that doesn’t fit all: a case report

BackgroundSublingual buprenorphine, approved for treatment of opioid use disorder since 2002, is most commonly available in co-formulation with naloxone. Naloxone is an opioid antagonist minimally absorbed when sublingual (SL) buprenorphine/naloxone is taken as prescribed; it is thought to reduce potential for misuse via intravenous administration. However, growing data and clinical experience demonstrate that previously accepted assumptions about the pharmacokinetics of these medications may not apply to all patients.Case presentationWe present a patient whose adverse post-administration side effects on SL buprenorphine/naloxone resolved with transition to SL buprenorphine monoproduct.DiscussionNaloxone can be detected in nearly all patients taking SL buprenorphine/naloxone, though with apparent variability in clinical effect. In a minority of patients, naloxone can contribute to adverse and potentially treatment-limiting side effects. Furthermore, the naloxone component is commonly misunderstood by patients and providers and can foster mistrust in the therapeutic relationship if providers are perceived to be withholding a more tolerable formulation. Prescribers should have a low threshold to offer buprenorphine alone when clinically appropriate.

Extended-release buprenorphine induction in opioid non-tolerant incarcerated individuals

BackgroundBuprenorphine maintenance treatment remains unavailable in most jails in the US. We provide data on a four-day rapid sublingual buprenorphine (SL-B) induction strategy followed by a weekly dose of extended-release injectable buprenorphine (XR-B) with incarcerated individuals with opioid use disorder (OUD) who were not opioid tolerant. MethodsBetween October 2020 to April 2024, N = 65 individuals with an opioid use disorder in jails participating in a larger randomized, controlled trial received SL-B and XR-B prior to release. Primary outcomes included completing the proposed dose induction and any reported adverse events (AEs). ResultsSixty-five individuals received SL-B dose induction from our team’s medical staff, 53 (81.5 %) completed the four-day SL-B dose induction and received their first weekly XR‑B injection on day 5. Of the 65 individuals, 10 (15.38 %) participants reported AEs during the dosing period and/or in the week following the dosing period. All but one of the AEs were rated as mild. One participant experienced a serious adverse event in the week following dose induction. The study medical team determined that this was unlikely to be related to the intervention. DiscussionOverall, our study findings demonstrate the feasibility of implementing a four-day sublingual dose induction followed by a weekly XR-B injection with incarcerated individuals who are not opioid tolerant. This study provides important data to illustrate a dose induction strategy that might assist in reducing illicit diversion in jails, which is a main barrier to buprenorphine delivery cited by correctional administrators.

A case of severe opioid and methamphetamine use disorder in a 14 year old

We present the case of a 14-year-old who established care at our primary care clinic after hospitalization for unintentional fentanyl overdose. They were diagnosed with severe opioid use disorder (OUD) and stimulant use disorder (StUD) and initiated buprenorphine while inpatient. They were then transitioned to the only known outpatient primary care clinic in her county who was actively providing medications for opioid use disorder (MOUD) in adolescents.At the first visit, they reported a history of 20 overdoses, struggling with adherence to buprenorphine and continued opioid cravings. An overdose safety plan was reviewed with them and their parent including providing them naloxone kits, fentanyl test strips, and education handout sheets. Due to their significant overdose history and adherence challenges with sublingual buprenorphine, they were started on long-acting injectable buprenorphine (LAIB) with weekly provider visits and urine toxicology screening. In collaboration with the treatment team, they initiated behavioral treatment with contingency management (CM), with incentives for appointment completion, expected urine results, and successful medication administration. Over the next 19 months, and to date, they have increasingly engaged with care and have remained abstinent. LAIB may be an appealing alternative for adolescents with OUD to improve adherence and reduce risk of recurrent use and overdose. Adjunctive treatment with CM may improve retention in MOUD and have the benefit of treating StUD. There is a need for further research to explore innovative, community-based treatment for youth with OUD.

Efficacy and safety of sublingual buprenorphine in managing acute postoperative pain – A systematic review

Abstract Sublingual (SL) buprenorphine has been used as a modality of managing acute postoperative pain in many studies. This systematic review aimed to investigate the safety and efficacy of SL buprenorphine as an analgesic for various surgeries. After registering the protocol with PROSPERO, we searched PubMed, Cochrane Library, and Ovid databases with relevant keywords. The primary outcomes were 24-hour pain scores, and the secondary outcomes were postoperative nausea and vomiting, sedation scores, pruritus, rescue analgesia, and urinary retention. The risk of bias scale was used to identify the quality of evidence. From the 103 articles identified, four randomized-controlled trials fulfilled the inclusion criteria for qualitative analysis. The overall risk of bias was low. Most of the studies showed that the use of SL buprenorphine led to either better or comparable pain scores when compared to a control group with lesser or tolerable adverse events. There was a lot of heterogeneity across the studies in this systematic review in terms of the type of surgery performed, the comparison groups, doses of buprenorphine, and the outcomes that were assessed. Therefore, a quantitative meta-analysis was not performed. The results of this systematic review should be interpreted with caution due to heterogeneity in the methodology. Adequately powered studies with robust methodology should investigate the safety and efficacy of SL buprenorphine when used for postoperative analgesia.

Community buprenorphine continuation post-release following extended release vs. sublingual buprenorphine during incarceration: a pilot project in Maine

BackgroundThe aim of our study was to evaluate the post-release outcomes of incarcerated individuals with opioid use disorder (OUD) treated with extended-release buprenorphine (XRB) in a rural county jail. Administrative data were collected from a pilot program within a jail in Maine that introduced XRB treatment in 2022 and a comparable jail utilizing sublingual buprenorphine (SLB) during the same period to compare post-release outcomes. Log-binomial regression models were used to estimate the risk ratio (RR) and 95% confidence interval (CI) for jail use of XRB vs. SLB on post-release community buprenorphine continuation.ResultsFrom September 2022 to September 2023, 70 individuals who received XRB were released from the pilot jail and 130 individuals who received SLB were released from the comparison jail. After adjusting for age, sex, and buprenorphine use at entry to jail, individuals released from the pilot jail were almost 3 times (adjusted RR = 2.67, 95% CI 1.84, 3.88) as likely to continue community buprenorphine treatment post-release relative to the comparison jail. In addition, utilization of XRB allowed for expanded access to OUD treatment, was well tolerated, and reduced medication diversion.ConclusionsIn this pilot program in Maine, XRB treatment during incarceration was associated with higher post-release community buprenorphine continuation when compared to individuals treated with SLB. These findings provide strong evidence for the superiority of XRB vs. SLB for the treatment of OUD in jail settings.

Extended-Release Injection vs Sublingual Buprenorphine for Opioid Use Disorder With Fentanyl Use

Fentanyl has exacerbated the opioid use disorder (OUD) and opioid overdose epidemic. Data on the effectiveness of medications for OUD among patients using fentanyl are limited. To assess the effectiveness of sublingual or extended-release injection formulations of buprenorphine for the treatment of OUD among patients with and without fentanyl use. Post hoc analysis of a 24-week, randomized, double-blind clinical trial conducted at 35 outpatient sites in the US from December 2015 to November 2016 of sublingual buprenorphine-naloxone vs extended-release subcutaneous injection buprenorphine (CAM2038) for patients with OUD subgrouped by presence vs absence of fentanyl or norfentanyl in urine at baseline. Study visits with urine testing occurred weekly for 12 weeks, then 6 times between weeks 13 and 24. Data were analyzed on an intention-to-treat basis from March 2022 to August 2023. Weekly and monthly subcutaneous buprenorphine vs daily sublingual buprenorphine-naloxone. Retention in treatment, percentage of urine samples negative for any opioids (missing values imputed as positive), percentage of urine samples negative for fentanyl or norfentanyl (missing values not imputed), and scores on opiate withdrawal scales and visual analog craving scales. Of 428 participants, 123 (subcutaneous buprenorphine, n = 64; sublingual buprenorphine-naloxone, n = 59; mean [SD] age, 39.1 [10.8] years; 75 men [61.0%]) had evidence of baseline fentanyl use and 305 (subcutaneous buprenorphine, n = 149; buprenorphine-naloxone, n = 156; mean [SD] age, 38.1 [11.1] years; 188 men [61.6%]) did not have evidence of baseline fentanyl use. Study completion was similar between the fentanyl-positive (60.2% [74 of 123]) and fentanyl-negative (56.7% [173 of 305]) subgroups. The mean percentage of urine samples negative for any opioid were 28.5% among those receiving subcutaneous buprenorphine and 18.8% among those receiving buprenorphine-naloxone in the fentanyl-positive subgroup (difference, 9.6%; 95% CI, -3.0% to 22.3%) and 36.7% among those receiving subcutaneous buprenorphine and 30.6% among those receiving buprenorphine-naloxone in the fentanyl-negative subgroup (difference, 6.1%; 95% CI, -1.9% to 14.1%), with significant main associations of baseline fentanyl status and treatment group. In the fentanyl-positive subgroup, the mean percentage of urine samples negative for fentanyl during the study was 74.6% among those receiving subcutaneous buprenorphine vs 61.9% among those receiving sublingual buprenorphine-naloxone (difference, 12.7%; 95% CI, 9.6%-15.9%). Opioid withdrawal and craving scores decreased rapidly after treatment initiation across all groups. In this post hoc analysis of a randomized clinical trial of sublingual vs extended-release injection buprenorphine for OUD, buprenorphine appeared to be effective among patients with baseline fentanyl use. Patients with fentanyl use had fewer opioid-negative urine samples during the trial compared with the fentanyl-negative subgroup. These findings suggest that the subcutaneous buprenorphine formulation may be more effective at reducing fentanyl use. ClinicalTrials.gov Identifier: NCT02651584.

A Case-Based Curriculum on Buprenorphine for Treatment of Opioid Use Disorder Among Internal Medicine Residents

Background: As the mandatory X-waiver requirements for prescribing buprenorphine have recently been lifted, general practitioners are being relied on to fill the treatment gap in prescribing medications for opioid use disorder (MOUD). However, insufficient clinician education remains a major barrier to prescribing MOUD in both inpatient and outpatient settings. Objective: To evaluate the impact of a new MOUD curriculum on internal medicine (IM) residents’ attitudes, comfort, and knowledge of buprenorphine in the inpatient and outpatient settings. Methods: All second-year IM residents (n = 46) participated in a 90-minute curricular session between July and October 2022 during scheduled mandatory didactic blocks. The curriculum was structured as a small group, case-based session focused on how to initiate sublingual buprenorphine (traditional and low-dose initiation). Residents completed identical and anonymous pre- and post-session surveys. A Wilcoxon signed rank test was used to analyze the data. Results: Thirty-nine (84.4%) second-year IM residents participated in the evaluation. Residents reported increased importance of independently initiating buprenorphine for hospitalized patients with opioid withdrawal ( P &lt; .001). Residents were significantly more likely to endorse confidence in discussing MOUD with patients ( P &lt; .001), initiating buprenorphine in inpatient and outpatient settings ( P &lt; .001), and identifying patients who would benefit from low-dose buprenorphine initiation ( P = .002). There was a significant increase in the correct number of knowledge-based questions after the session (before = 1.55/4 vs after = 3.33/4; P value &lt; .001). Conclusions: A 90-minute buprenorphine training improved residents’ attitudes toward, perceptions of competency, and knowledge of buprenorphine delivery to patients with OUD in the inpatient and outpatient setting.

Provider Perceptions Toward Extended-Release Buprenorphine for Treatment of Opioid Use Disorder.

The persistence of the opioid crisis and the proliferation of synthetic fentanyl have heightened the demand for the implementation of novel delivery mechanisms of pharmacotherapy for the treatment of opioid use disorder, including injectable extended-release buprenorphine (buprenorphine-ER). The purpose of this study was to understand provider-level barriers to prescribing buprenorphine in order to facilitate targeted strategies to improve implementation for patients who would benefit from this novel formulation. Using an interview template adapted from the Consolidated Framework for Implementation Research (CFIR), we conducted structured focus group interviews with 20 providers in an outpatient addiction clinic across 4 sessions to assess providers' perceptions of buprenorphine-ER. Ninety-four unique comments were identified and deductively coded using standardized CFIR constructs. Providers expressed mixed receptivity and confidence in using buprenorphine-ER. Although providers could identify a number of theoretical advantages to the injectable formulation over sublingual buprenorphine, many expressed reservations about using it due to inexperience, negative patient experiences, uncertainties about patient candidacy, cost, and logistical constraints. Provider concerns about buprenorphine-ER may limit utilization. Some concerns may be mitigated through improved education, research, and logistical support. Given the putative benefits of buprenorphine-ER, future research should target barriers to implementation, in part based on hypotheses generated by these findings.

Development and Verification of a Full Physiologically Based Pharmacokinetic Model for Sublingual Buprenorphine in Healthy Adult Volunteers that Accounts for Nonlinear Bioavailability.

Sublingual buprenorphine is used for opioid use disorder and neonatal opioid withdrawal syndrome. The study aimed to develop a full physiologically based pharmacokinetic (PBPK) model that can adequately describe dose- and formulation-dependent bioavailability of buprenorphine. Simcyp (v21.0) was used for model construction. Four linear regression models (i.e., untransformed or log transformed for dose or proportion sublingually absorbed) were explored to describe sublingual absorption of buprenorphine across dose. Published clinical trial data not used in model development were used for verification. The PBPK model's predictive performance was deemed adequate if the geometric means of ratios between predicted and observed (P/O) area under the curve (AUC), peak concentration (Cmax), and time to reach Cmax (Tmax) fell within the 1.25-fold prediction error range. Sublingual buprenorphine absorption was best described by a regression model with logarithmically transformed dose. By integrating this nonlinear absorption profile, the PBPK model adequately predicted buprenorphine pharmacokinetics (PK) following administration of sublingual tablets and solution across a dose range of 2-32 mg, with geometric mean (95% confidence interval) P/O ratios for AUC and Cmax equaling 0.99 (0.86-1.12) and 1.24 (1.09-1.40), respectively, and median (5th to 95th percentile) for Tmax equaling 1.11 (0.69-1.57). A verified PBPK model was developed that adequately predicts dose- and formulation-dependent buprenorphine PK following sublingual administration. SIGNIFICANCE STATEMENT: The physiologically based pharmacokinetic (PBPK) model developed in this study is the first to adequately predict dose- and formulation-dependent sublingual buprenorphine pharmacokinetics. Accurate prediction was facilitated by the incorporation of a novel nonlinear absorption model. The developed model will serve as the foundation for maternal-fetal PBPK modeling to predict maternal and fetal buprenorphine exposures to optimize buprenorphine treatment for neonatal opioid withdrawal syndrome.

Inpatient Rotation from High-Dose Oral Methadone to Sublingual Buprenorphine in a Patient with Chronic Pain

Inpatient Rotation from High-Dose Oral Methadone to Sublingual Buprenorphine in a Patient with Chronic Pain

Dental Disorders Reported to the FDA Adverse Event Reporting System in Association with Buprenorphine: An Analysis by Ingredient Composition and Route of Administration.

Prior research has suggested buprenorphine-containing medications may be associated with an increased risk of dental disorders. However, published data describing adverse dental reactions in buprenorphine users by active ingredient composition and route of administration are limited. The purpose of this study was to evaluate the influence of formulation on spontaneous reporting of dental disorders among patients treated with buprenorphine. Adverse event reports submitted to the United States Food and Drug Administration Adverse Event Reporting System (FAERS) between 2015 and 2022 were analyzed. Reporting odds ratios (ROR) and 95% confidence intervals (CI) were calculated to measure disproportionality of dental disorder reporting as classified by 39 Medical Dictionary for Regulatory Activities preferred terms. Compared to pooled reports for all other drugs across FAERS, both buprenorphine monotherapy (ROR 3.09; 95% CI 2.61-3.66) and combination buprenorphine/naloxone (ROR 14.61; 95% CI 13.34-16.01) were associated with positive disproportionality signals. Signals of disproportionate dental disorder reporting were also detected for buprenorphine medicines administered by sublingual (ROR 20.03; 95% CI 18.04-22.24), buccal (ROR 4.46; 95% CI 3.00-6.61) and oral (ROR 7.17; 95% CI 5.03-10.22) routes, but not for other modalities. In considering active ingredient and route together, sublingual buprenorphine monotherapies (ROR 23.55; 95% CI 17.84-31.11) and sublingual buprenorphine/naloxone (ROR 19.47; 95% CI 17.39-21.80) were each associated with disproportionate reporting of dental disorders. Subject to the limitations of spontaneous adverse event data, this study identified significantly disproportionate reporting of dental disorders to FAERS among patients treated with buprenorphine- containing medications, including formulations administered by sublingual, buccal and oral routes. These findings are consistent with prior data and suggest that regular oral care and proper dental hygiene be emphasized for patients undergoing therapy with orally dissolving buprenorphine.