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A machine learning-assisted 3D-printed conducting microneedle-based electrochemical sensing platform was developed for wireless, efficient, economical, and selective determination of buprenorphine. The developed microneedle array-based sensing platform used 3D printing and air spray coating technologies for rapid and scalable manufacturing of a conducting microneedle surface. Upon optimization and understanding of the electrode stability, redox behavior, and electrochemical characteristics of as-prepared conducting microneedle array, the developed electrochemical platform was investigated for monitoring different levels of buprenorphine in the artificial intestinal fluid and found to be highly sensitive and selective towards buprenorphine for a wide detection range from 2 to 140 μM, with a low limit of detection of 0.129 μM. Furthermore, to make the sensing platform user accessible, the experimentally recorded sensing data was used to train a machine learning model and develop a web application for the numerical demonstration of buprenorphine levels at the point of site. Finally, the proof-of-concept study demonstrated that by advancing our prevailing 3D printing and additive manufacturing techniques, a low-cost, user-accessible, and compelling wearable electrochemical sensor could be manufactured for minimally invasive determination of buprenorphine in interstitial fluid., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background and Objectives: There are high rates of comorbidity between posttraumatic stress disorder (PTSD) and opioid use disorder (OUD). Evidence-based trauma-focused psychotherapies such as Cognitive Processing Therapy (CPT) are a first-line treatment for PTSD. Veterans with OUD are treated primarily in substance use disorder (SUD) clinics where the standard of care is drug counseling; they often do not have access to first-line PTSD treatments. This study tested whether CPT can be conducted safely and effectively in veterans with comorbid OUD treated with buprenorphine., Methods: This 12-week, 2-site, randomized clinical trial (RCT) included open-label randomization to two groups: (a) CPT versus (b) Individual Drug Counselling (IDC) in veterans with PTSD and comorbid OUD who were maintained on buprenorphine (N = 38)., Results: Veterans randomized to either IDC (n = 18) or CPT (n = 20) showed a significant reduction in self-reported PTSD symptoms over time as measured by the PTSD checklist (PCL-5) but there were no treatment group differences; there was some indication that reduction in PTSD symptoms in the CPT group were sustained in contrast to the IDC group. Recruitment was significantly impacted by COVID-19 pandemic, so this study serves as a proof-of-concept pilot study., Discussion and Conclusions: Veterans with OUD and PTSD can safely and effectively participate in evidence-based therapy for PTSD; further work should confirm that trauma-focused treatment may be more effective in leading to sustained remission of PTSD symptoms than drug counseling., Scientific Significance: This is the first study to evaluate CPT for PTSD in the context of buprenorphine treatment for OUD., (© 2024 The American Academy of Addiction Psychiatry (AAAP).)

Background: Treatment-seeking people with opioid use disorder (OUD) who are capable of pregnancy need accurate information about the potential impact of medication to treat OUD (MOUD) on fertility to make informed choices about treatment that are consistent with their reproductive wishes. There is a dearth of research on fertility associated with MOUD receipt in birthing people with OUD., Objective: To estimate the association between treatment with MOUD and odds of conception among birthing people using national administrative claims., Design: Retrospective case-crossover study using multi-state US administrative data (2006-2016). Dates of conception were estimated from delivery dates and served as "case" days for which MOUD exposures were compared to those on all other ("control") days of insurance enrollment., Participants: Treatment-seeking people with OUD with a delivery during the observation period., Main Measures: Odds ratios for conception from within-person fixed effects models were modeled as a function of exposure to MOUD (buprenorphine, methadone, extended-release depot naltrexone, or oral naltrexone) using conditional logistic regression., Key Results: A total of 21,928 births among 19,133 people with OUD were identified. In the sample, 5873 people received buprenorphine, 1825 methadone, 486 extended-release naltrexone, and 714 oral naltrexone. Participants could receive more than one type of MOUD. Mean age was 28.2 years (SD = 2.2; range = 16-45), with 76.2% having Medicaid. vs. commercial insurance. Compared to no MOUD, periods of methadone (aOR = 0.55 [95% CI = 0.48-0.63]) or buprenorphine receipt (aOR = 0.84 [0.77-0.91]) were associated with fewer conceptions. Treatment periods with extended-release depot naltrexone compared to no medication were associated with higher odds of conception (aOR = 1.75 [1.22-2.50]) and there was no significant difference in conception with oral naltrexone (aOR = 1.02 [0.67-1.54])., Conclusions: The association between MOUD and odds of conception among birthing people varied by type of MOUD, with extended-release naltrexone associated with higher odds of conceiving compared to no treatment. Clinical studies are urgently needed to investigate these findings further., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Abstract: Opioid use disorder remains an epidemic in the United States. Buprenorphine is a Food and Drug Administration-approved medication for opioid use disorder that is associated with decreased opioid-related mortality and morbidity. Until recently, providers had to have a specialized wavier, a Drug Enforcement Agency (DEA) X, to prescribe buprenorphine for opioid use disorder. The 2023 Consolidated Appropriations Act, signed into law by President Biden, removed X waiver requirements and implements new training requirements for all new and renewing DEA registrants. This brief report outlines the history of buprenorphine prescribing regulation, reviews the recent regulatory changes and their implications for nurse practitioner buprenorphine prescribing, and concludes by considering the importance of promoting buprenorphine access., Competing Interests: Competing interests: The author has no conflicts of interest to disclose., (Copyright © 2023 American Association of Nurse Practitioners.)

Objective: Medication for opioid use disorder (MOUD) is an effective, evidence-based treatment, but significant gaps in implementation remain. We evaluate one novel approach to address this gap: a Hub and Spoke model to increase buprenorphine access and management., Methods: This outcome evaluation was guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework using secondary data analysis of clinical and administrative data to characterize program outcomes for program Reach, Effectiveness, Adoption, and Maintenance. Implementation was assessed through a chart review of provider progress notes and through key informant interviews with program staff to understand why this site was able to introduce a novel approach to MOUD., Results: Nearly half of patients with opioid use disorder (45.48%, n=156) were reached by the program over 2 years. Of those, 91.67% had 1 or more program visits after an initial intake appointment, and 78.85% had a buprenorphine prescription. Patients in the program were 2.44 times more likely to have a buprenorphine prescription than those in comparator site that did not have a Hub and Spoke program (95% CI: 1.77-3.37; P <0.001). There was significantly greater program reach in year 1 than year 2, suggesting rapid initial uptake followed by modest program growth. Key informant interviews illustrated several themes regrading program implementation, including the importance of process champions, the beneficial impact of MOUD for patients, and addressing facility performance metrics. A supportive organizational culture and a receptive climate were also key factors for implementation., Conclusions: This program led to rapid improvement in MOUD uptake across the facility. Future efforts should focus on improving program maintenance, including supporting the exchange of patients from the hub to appropriate spokes., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Buprenorphine is a partial agonist at the µ-opioid receptor and an antagonist at the delta and kappa opioid receptors. It has high affinity and low intrinsic activity at the µ-opioid receptor. Buprenorphine demonstrates no ceiling effect for clinical analgesia, but demonstrates this for respiratory depression and euphoria. It may provide effective analgesia while producing less adverse effects, making it a promising opioid analgesic. A systematic review and meta-analysis were performed to examine the analgesic efficacy of buprenorphine for patients with chronic noncancer pain., Methods: PubMed, MEDLNE, Embase, and the Cochrane Library were searched up to January 2022. Randomized controlled trials were included if they compared buprenorphine versus placebo or active analgesic in patients with chronic noncancer pain, where pain score was an outcome. Nonrandomized controlled trials, observational studies, qualitative studies, case reports, and commentaries were excluded. Two investigators independently performed the literature search, study selection, and data collection. A random-effects model was used. The primary outcome was the effect of buprenorphine on pain intensity in patients with chronic noncancer pain based on standardized mean difference (SMD) in pain score. Quality of evidence was assessed using the Grade of Recommendations Assessment, Development, and Evaluation (GRADE) approach., Results: Two separate literature searches were conducted for patients with and without opioid use disorder (OUD). Only one study met the search criteria for those with OUD. Fourteen randomized controlled trials were included for those without OUD. Buprenorphine was associated with reduced pain score (SMD = -0.368, P < .001, I 2 = 89.37%) compared to placebo or active analgesic. Subgroup meta-analyses showed statistically significant differences in favor of buprenorphine versus placebo (SMD = -0.404, P < .001), for chronic low back pain (SMD = -0.383, P < .001), when administered via the transdermal route (SMD = -0.572, P = .001), via the buccal route (SMD = -0.453, P < .001), with length of follow-up lasting <12 weeks (SMD = -0.848, P < .05), and length of follow-up lasting 12 weeks or more (SMD = -0.415, P < .001). There was no significant difference when compared to active analgesic (SMD = 0.045, P > .05). Quality of evidence was low to moderate., Conclusions: Buprenorphine was associated with a statistically significant and small reduction in pain intensity compared to placebo. Both the transdermal and buccal routes provided pain relief. There was more evidence supporting its use for chronic low back pain., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

Introduction: The introduction of depot buprenorphine for the treatment of opioid dependence allows for reduced dosing frequency compared with conventional treatments, such as oral methadone and sublingual buprenorphine-naloxone. Reduced dosing frequency is perceived to reduce issues such as high out-of-pocket costs, frequent attendance to pharmacies, stigmatisation and the risk of diversion for unsanctioned opioid use. This study aims to explore the experiences of patients receiving depot buprenorphine from an Australian publicly operated drug and alcohol service., Methods: Participants were recruited from the service over a 5-week period in 2021. Twenty-eight participants consented to be involved in a mixed methods quantitative verbal survey and qualitative interview process., Results: The majority of participants reported satisfaction with depot buprenorphine across the domains of efficacy, convenience and global satisfaction. Participants perceived benefits as increased convenience, reduced stigmatisation and the inability to 'skip' daily Medication Assisted Treatment for Opioid Dependence (MATOD) doses. There were mixed experiences with the ability for depot buprenorphine to 'hold' participants throughout the dosing interval. Reduced contact and disconnection from healthcare services were reported as an issue for some participants when initiating depot buprenorphine., Discussion and Conclusions: Patient perceptions of depot buprenorphine appear to be deeply rooted in prior experience with 'conventional' MATOD treatments. Depot buprenorphine is seen to be beneficial socially, personally, and financially by the majority of patients interviewed. The potential for disconnection from services and mixed experiences of efficacy throughout the dosing period may negatively influence patient experience., (© 2023 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

Aims: Although opioid-related harms have reached new heights across North America, the size of the gap in opioid agonist therapy (OAT) delivery for opioid-related health problems is unknown in most jurisdictions. This study sought to characterize the gap in OAT treatment using a cascade of care framework, and determine factors associated with engagement and retention in treatment., Design: A population-based retrospective cohort study., Setting: Ontario, Canada., Participants: Individuals who sought medical care for opioid-related health problems or died from an opioid-related cause between 2005 and 2019., Measurements: Monthly treatment status for buprenorphine/naloxone or methadone OAT between 2013 and 2019 (i.e. 'off OAT', 'retained on OAT < 6 months', 'retained on OAT ≥ 6 months')., Findings: Of 122 811 individuals in the cohort, 97 516 (79.4%) received OAT at least once during the study period. There was decreasing 6-month treatment retention over time. Model results indicated that males had higher odds of being on OAT each month [odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.23-1.28] but lower odds of OAT retention (OR = 0.90, 95% CI = 0.88-0.92), while the reverse was observed for older individuals (monthly: OR = 0.76 per 10-year increase, 95% CI = 0.76-0.77; retention: OR = 1.36 per 10-year increase, 95% CI = 1.34-1.38) and individuals with higher neighbourhood income (e.g. highest income quintile, monthly: OR = 0.79, 95% CI = 0.77-0.82; highest income quintile, retention: OR = 1.15, 95% CI = 1.11-1.20). Individuals residing in rural areas and with a history of mental health diagnoses had poorer outcomes overall, including lower odds of being on OAT each month (rural: OR = 0.75, 95% CI = 0.73-0.78; mental health: OR = 0.89, 95% CI = 0.87-0.92) and OAT retention (rural: OR = 0.79, 95% CI = 0.77-0.82; mental health: OR = 0.81, 95% CI = 0.78-0.83), as well as higher risk of starting/stopping OAT [rural, starting OAT: hazard ratio (HR) = 1.07, 95% CI = 1.05-1.10; mental health, starting OAT: HR = 1.20, 95% CI: 1.18-1.23; rural, stopping OAT: HR = 1.24, 95% CI: = 1.22-1.26; mental health, stopping OAT: HR = 1.11, 95% CI = 1.09-1.13]. Individuals with a history of mental health diagnoses also had a higher risk of death, regardless of OAT status (off OAT death: HR = 1.49, 95% CI = 1.33-1.66; on OAT death: HR = 1.20, 95% CI = 1.09-1.31)., Conclusions: Factors influencing engagement and declining retention in treatment with opioid agonist therapy in Ontario's health system include age, sex and neighbourhood income, as well as mental health diagnoses or residing in rural regions., (© 2022 His Majesty the King in Right of Canada. Addiction © 2022 Society for the Study of Addiction. Reproduced with the permission of the Minister of Health.)

Introduction and Objective: Receipt of opioid agonist treatment during early and late pregnancy for opioid use disorder may relate to varying perinatal risks. We aimed to assess the effect of time-varying prenatal exposure to opioid agonist treatment using buprenorphine or methadone on adverse neonatal and pregnancy outcomes., Methods: We conducted a retrospective cohort study of pregnant women with opioid use disorder using Rhode Island Medicaid claims data and vital statistics during 2008-16. Time-varying exposure was evaluated in early (0-20 weeks) and late (≥ 21 weeks) pregnancy. Marginal structural models with inverse probability of treatment weighting were applied., Results: Of 400 eligible pregnancies, 85 and 137 individuals received buprenorphine and methadone, respectively, during early pregnancy. Compared with 152 untreated pregnancies with opioid use disorders, methadone exposure in both periods was associated with an increased risk of preterm birth (adjusted odds ratio [aOR]: 2.52; 95% confidence interval [CI] 1.07-5.95), low birth weight (aOR: 2.99; 95% CI 1.34-6.66), neonatal intensive care unit admission (aOR, 5.04; 95% CI 2.49-10.21), neonatal abstinence syndrome (aOR: 11.36; 95% CI 5.65-22.82), respiratory symptoms (aOR, 2.71; 95% CI 1.17-6.24), and maternal hospital stay > 7 days (aOR, 14.51; 95% CI 7.23-29.12). Similar patterns emerged for buprenorphine regarding neonatal abstinence syndrome (aOR: 10.27; 95% CI 4.91-21.47) and extended maternal hospital stay (aOR: 3.84; 95% CI 1.83-8.07). However, differences were found favoring the use of buprenorphine for preterm birth versus untreated pregnancies (aOR: 0.17; 95% CI 0.04-0.77), and for several outcomes versus methadone., Conclusions: Methadone and buprenorphine prescribed for the treatment of opioid use disorder during pregnancy are associated with varying perinatal risks. However, buprenorphine may be preferred in the setting of pregnancy opioid agonist treatment. Further research is necessary to confirm our findings and minimize residual confounding., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Buprenorphine, a novel opioid with complex pharmacology, is effective for treating pain and is qualitatively safer than high-dose full agonist opioid therapy; but transitioning to buprenorphine can be technically complex and carries some risk of precipitated withdrawal. We report our clinic's experience converting 36 patients with sickle cell disease (SCD) from full agonist opioids to buprenorphine using a method developed in the past 10 years. Thirty of these patients were induced using a standard outpatient protocol and six were induced during medical admissions. Typically, patients were on high-dose chronic opioid therapy (COT) with inadequate response, and often with very high acute care utilization. Unlike prior case series, the method of induction, dosing, and management of withdrawal are detailed, as are post-induction adverse events. There were seven adverse events in the first 3 days following standard induction, and two of which were judged to be definitely related to the induction but none with any lasting sequelae. At 6 months follow-up, five participants had discontinued buprenorphine (16.67%), and overall acute care visits dropped from a mean of 10.50 (SD 11.35) in the 6 months pre-induction to 2.89 (SD 3.40) in the 6 months post-induction. In an appropriately interdisciplinary care setting, buprenorphine shows promise as a safe alternative to COT with early evidence of benefit for high-utilizing patients with SCD., (© 2022 Wiley Periodicals LLC.)

Background: Hospitalizations related to opioid use disorder (OUD) are rising. Addiction consultation services (ACS) increasingly provide OUD treatment to hospitalized patients, but barriers to initiating and continuing medications for OUD remain. We examined facilitators and barriers to hospital-based OUD treatment initiation and continuation from the perspective of patients and healthcare workers in the context of an ACS., Methods: In this qualitative study, we sought input using key informant interviews and focus groups from patients who received care from an ACS during their hospitalization and from hospitalists, pharmacists, social workers, and nurses who work in the hospital setting. A multidisciplinary team coded and analyzed transcripts using a directed content analysis., Findings: We conducted 20 key informant interviews with patients, nine of whom were interviewed following hospital discharge and 12 of whom were interviewed during a rehospitalization. We completed six focus groups and eight key informant interviews with hospitalists and hospital-based medical staff (n = 62). Emergent themes related to hospital-based OUD treatment included the following: the benefit of an ACS to facilitate OUD treatment engagement; expanded use of methadone or buprenorphine to treat opioid withdrawal; the triad of hospitalization, self-efficacy, and easily accessible, patient-centered treatment motivates change in opioid use; adequate pain control and stabilization of mental health conditions among patients with OUD contributed to opioid agonist therapy (OAT) continuation; and stable housing and social support are prerequisites for OAT uptake and continuation., Conclusion: Modifiable factors which facilitate hospital-based OUD treatment initiation and continuation include availability of in-hospital addiction expertise to offer easily accessible, patient-centered treatment and the use of methadone or buprenorphine to manage opioid withdrawal. Further research and public policy efforts are urgently needed to address reported barriers to hospital-based OUD treatment initiation and continuation which include unstable housing, poorly controlled chronic medical and mental illness, and lack of social support., (© 2021. The Author(s) under exclusive licence to Society of General Internal Medicine.)

Objectives: When initiated in the Emergency Department (ED), medication for addiction treatment (MAT) with buprenorphine improves outcomes, increases engagement in addiction treatment and decreases the use of inpatient addiction treatment services. Unfortunately, initiating MAT in the ED is not yet standard practice. We assessed the impact of the addition of a multipart behavioral science-based intervention to increase opioid use disorder (OUD)-related treatments prescribed in the ED., Methods: Our ED initiated a campaign to help ED faculty obtain their DEA-X waiver required to prescribe buprenorphine. In parallel, we implemented 2 ED-initiated buprenorphine treatment pathways. We then conducted a two-stage qualitative process informed by behavioral science to identify key barriers to physician use of the MAT protocol. Using these insights, we developed 4 behavioral science-based interventions. To assess the impact of the interventions on the number of OUD-related treatments per day among patients meeting the inclusion criteria we compared the number of OUD-related treatments per day before versus after the interventions began using t tests. Then, in our primary model, we estimated the causal effect of the behavioral interventions using a regression discontinuity in time approach., Results: Across the entire year study period, there is an increase in OUD-related treatment after the interventions begin, driven by greater use of ambulatory referral orders. The unadjusted mean difference in any OUD treatments per day pre- versus post-intervention increased by 0.80 (95% confidence interval [CI]: 0.04, 1.56; P = 0.039) whereas the number of ambulatory referral orders placed increased by 0.82 (95% CI: 0.48,1.16; P < 0.001). Using the 120-day study window and an ordinary least squares regression discontinuity in time model, the 4-part intervention increased the number of patients receiving any opioid treatment in the ED by 1.6 additional treatments per day (95% CI: 0.04, 3.19; P = 0.045)., Conclusions: To support our protocol and increase the provision of ED-MAT, we implemented 1 patient-facing and 3 provider-facing interventions rooted in behavioral science principles. Our results show that this pack of behavioral science interventions increased the likelihood that ED providers offer MAT to patients with OUD., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 American Society of Addiction Medicine.)

Abstract: Long-term opioid use in patients with chronic noncancer pain (CNCP) can lead to opioid use disorder (OUD) and has been associated with hyperalgesia and reduced quality of life (QoL). Studies suggest antihyperalgesic properties of buprenorphine, and buprenorphine or naloxone (BuNa) has shown beneficial effects on QoL in patients with OUD without CNCP. This study investigated the added value of BuNa in patients with CNCP with OUD on self-reported pain, pain thresholds, pain tolerance, and QoL. In the current study, 43 outpatients with CNCP and OUD were included for inpatient conversion from full μ-receptor agonist opioids to BuNa. Self-reported pain, pain thresholds, pain tolerance, and QoL were determined at baseline and after 2 months of follow-up, using, respectively, a Visual Analogue Scale (VAS-pain and VAS-QoL), quantitative sensory testing, and EuroQol-5 dimensions. In total, 37 participants completed the protocol, and their data were analyzed. The mean VAS-pain score decreased from 51.3 to 37.2 (27.5%, F = 3.3; P = 0.044), whereas the pressure pain threshold and electric pain threshold or tolerance increased after substitution (F = 7.8; P = 0.005 and F = 44.5; P < 0.001, respectively), as well as QoL (EuroQol-5 dimensions questionnaire: F = 10.4; P = 0.003 and VAS-QoL: F = 4.4; P = 0.043). We found that conversion of full μ-receptor agonists to BuNa, in patients with CNCP with OUD, was accompanied with lower self-reported pain, higher pain thresholds, higher pain tolerance, and improved QoL. Despite several study limitations, these data suggest that BuNa might be of value in patients with CNCP with OUD. Future studies should investigate long-term effects of BuNa in randomized trials., (Copyright © 2021 International Association for the Study of Pain.)

Introduction: Emergency department (ED) initiated opioid use disorder (OUD) care is effective; however, real-world predictors of patient engagement are lacking., Objective: This program evaluation examined predictors of ED-based OUD treatment and subsequent engagement., Method: Program evaluation in Boston, MA. Adult patients who met criteria for OUD during an ED visit in 2019 were included. Patients were included if a diagnosis of OUD or opioid-related overdose was associated with the ED visit or if they met previously validated criteria for OUD within the previous 12 months. We assessed predictors of ED-OUD treatment receipt and subsequent engagement, using Healthcare Effectiveness Data and Information Set definition of initial encounter within 14 days of discharge and either 2 subsequent encounters or a subsequent buprenorphine prescription within 34 days of the initial encounter. We used generalized estimating equations for panel data., Results: During 2019, 1946 patients met criteria for OUD. Referrals to Bridge Clinic were made for 207 (11%), buprenorphine initiated for 106 (5%), and home induction buprenorphine kits given to 56 (3%). Following ED discharge, 237 patients (12%) had a visit within 14 days, 122 (6%) had ≥2 additional visits, and 207 (11%) received a subsequent buprenorphine prescription. Young, White, male patients were most likely to receive ED-OUD care. Patients who received ED-OUD care were more likely to have subsequent treatment engagement (adjusted rate ratio: 2.30, 95% confidence intervals: 1.62-3.27). Referrals were made less often than predicted for Black (-49%) or Hispanic/Latinx (-25%) patients., Conclusions: Initiating treatment for OUD in the ED was associated with increased engagement in outpatient addiction care., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 American Society of Addiction Medicine.)

Purpose: We examined the impact on geographic distribution of medications to treat opioid use disorder (MOUD) in Oregon after the Comprehensive Addiction and Recovery Act (CARA) was implemented in February 2017 to include nurse practitioner (NP) prescribers., Methods: We conducted interrupted time series analysis with linear regression on prescriptions dispensed for buprenorphine used for MOUD in the Oregon Prescription Drug Monitoring Database written by physician (MD/DO) and NP prescribers January 1, 2016, to December 31, 2018. We analyzed total prescriptions by prescriber type and pharmacy ZIP Code using STATA 16.1., Findings: From January 1, 2016, to December 31, 2018, 420,765 eligible prescriptions were written by waivered MD/DO and/or NP prescribers. Prior to CARA, buprenorphine use was increasing steadily at 140 prescriptions per month (95% CI: 78-201; P < .01). Following CARA, dispensing increased by 88 prescriptions per month (95% CI: 23-152; P = .01). The absolute number increased in rural areas immediately after CARA implementation (368 prescriptions; 95% CI: 124-613; P < .01). NP contribution to total buprenorphine prescribing increased significantly in both urban and rural areas (0.44% per month [95% CI: 0.30%-0.57%; P < .01] and 0.74% per month [95% CI: 0.62%-0.85%; P < .01]). The contribution of NPs had a particularly large impact for very rural (frontier) areas, where NPs provided 36% of all buprenorphine prescriptions by the end of 2018., Conclusion: Changes in federal law regarding MOUD had a positive impact on both supply and geographic distribution in Oregon, particularly in frontier areas comprising 10 of 36 counties (27%)., (© 2020 National Rural Health Association.)

Background and Aim: To address the widespread severe problems with opioid use disorder, buprenorphine-naloxone treatment provided by primary care physicians has greatly expanded treatment access; however, treatment is often provided with minimal or no behavioral interventions. Whether or which behavioral interventions are feasible to implement in various settings and improve treatment outcomes has not been established. This study aimed to evaluate two behavioral interventions to improve buprenorphine-naloxone treatment., Design: A 2 × 2 factorial, repeated-measures, open-label, randomized clinical trial., Settings: General medical practice offices in Muar, Malaysia., Participants: Opioid-dependent individuals (n = 234)., Interventions: Participants were randomly assigned to one of four treatment conditions and received study interventions for 24 weeks: (1) physician management with or without behavioral counseling and (2) physician management with or without abstinence-contingent buprenorphine-naloxone (ACB) take-home doses., Measurements: The primary outcomes were proportions of opioid-negative urine tests and HIV risk behaviors [assessed by audio computer-assisted AIDS risk inventory (ACASI-ARI)]., Findings: The rates of opioid-negative urine tests over 24 weeks of treatment were significantly higher with [68.2%, 95% confidence interval (CI) = 65-71] than without behavioral counseling (59.2%, 95% CI = 56-62, P < 0.001) and with (71.0%, 95% CI = 68-74) than without ACB (56.4%, 95% CI = 53-59, P < 0.001); interaction effects between and among behavioral interventions and time were not statistically significant. Scores on ACASI-ARI decreased significantly from baseline across all treatment groups (P < 0.001) and did not differ significantly with or without behavioral counseling (P = 0.099) or with or without ACB (P = 0.339)., Conclusions: Providing opioid-dependent patients in Muar, Malaysia with buprenorphine-naloxone and physician management plus behavioral counseling or abstinence-contingent buprenorphine-naloxone (ACB) resulted in greater reductions of opioid use compared with providing buprenorphine-naloxone and physician management without behavioral counseling or ACB., (© 2021 Society for the Study of Addiction.)

An ambient method for rapid monitoring and quantitation of drugs of abuse in dried blood spots was developed using paper spray tandem mass spectrometry (PS-MS). [ABSTRACT FROM AUTHOR]

Objectives: Efforts to improve buprenorphine access for opioid use disorder have focused on increasing the number of waivered providers. However, it is unknown how efforts to increase initial prescribing result in a sustained pool of prescribers. We examine the prevalence of year-to-year provider-level buprenorphine prescribing, and provider- and state-level factors associated with provider continuity., Methods: Providers prescribing buprenorphine/naloxone within the Medicare Part D claims database were evaluated from 2013 to 2017 with prescriber continuity measured as prescriptions made in consecutive years from the same provider (N = 14,222 unique providers; 6670 in 2013)., Results: The number of providers prescribing buprenorphine/naloxone within Medicare Part D increased from 2013 to 2017. The majority of providers prescribed buprenorphine/naloxone to 10 or fewer beneficiaries. Approximately 84% of providers prescribing buprenorphine/naloxone in 1 year prescribed it in the following year. Continuous prescribing from 2013 to 2017 was 59.4%, which was 86% the rate of a comparator chronic health medication (ie, lisinopril). Survival analyses indicated that female providers (adjusted hazard ratios [AHR] = 1.30, P < 0.001) and clinical neuroscience specialties such as psychiatry (AHR = 1.21, P < 0.001) exhibited greater discontinuation rates, whereas those with higher buprenorphine/naloxone beneficiary loads (AHR = 0.50, P < 0.001) and in states with a greater increase in overdose mortality rates (AHR = 0.88, P < 0.05) showed lower discontinuation rates., Conclusions: These data support evidence that providers who begin prescribing buprenorphine continue prescribing, although short of maximum capacity. Efforts to help providers become waivered, understand the impact of overdose fatalities in their area, and prescribe to multiple patients are likely to generate an enduring positive contribution to the number of treated patients., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2020 American Society of Addiction Medicine.)

Purpose: Buprenorphine and methadone are international gold standards for managing opioid use disorders. Although they are efficacious in treating opioid dependence, buprenorphine and methadone present risks, especially during pregnancy, causing neonatal abstinence syndrome and adverse obstetrical outcomes. Buprenorphine and methadone are also abused during pregnancy, and identifying their use is important to limit unprescribed prenatal exposure. Previous studies have suggested that concentrations of buprenorphine, but not methadone markers in unconventional matrices may predict child outcomes, although currently only limited data exist. We reviewed the literature on concentrations of buprenorphine, methadone, and their metabolites in unconventional matrices to improve data interpretation., Methods: A literature search was conducted using scientific databases (PubMed, Scopus, Web of Science, and reports from international institutions) to review published articles on buprenorphine and methadone monitoring during pregnancy., Results: Buprenorphine and methadone and their metabolites were quantified in the meconium, umbilical cord, placenta, and maternal and neonatal hair. Methadone concentrations in the meconium and hair were typically higher than those in other matrices, although the concentrations in the placenta and umbilical cord were more suitable for predicting neonatal outcomes. Buprenorphine concentrations were lower and required sensitive instrumentation, as measuring buprenorphine glucuronidated metabolites is critical to predict neonatal outcomes., Conclusions: Unconventional matrices are good alternatives to conventional ones for monitoring drug exposure during pregnancy. However, data are currently scarce on buprenorphine and methadone during pregnancy to accurately interpret their concentrations. Clinical studies should be conducted with larger cohorts, considering confounding factors such as illicit drug co-exposure.

Objectives: To assess the rates of sleep disturbances in male patients with opioid dependence maintained on buprenorphine and to assess the factors associated with sleep disturbances in this population., Methods: Observational, cross-sectional study. Male patients with opioid dependence aged 18 years and older, and started on buprenorphine at least 6 months before were screened. Those with history of comorbid psychiatric illnesses (except sleep disorders), on any other substance in high-risk category (based on WHO-Alcohol Smoking Substance Involvement Screening Test (ASSIST)), or on any other psychotropic medications (in addition to OAT with buprenorphine) were excluded. Sleep was assessed using the Pittsburgh Sleep Quality Index (PSQI), Sleep-50, and Epworth Sleepiness Scale (ESS). Each participant was interviewed in a single session lasting 60 minutes., Results: One hundred six participants were included. Their mean age was 41.1 (SD 14.3) years. The participants had been on OAT with buprenorphine for a median duration of 60 months (IQR 17-120), with excellent adherence rate in past 1 month. The mean current dose of buprenorphine was 10.2 (SD 3.8) mg per day. The mean subjective total sleep time was 403.5 minutes (SD 94.8) and the median sleep latency was 35 minutes (IQR 18.8-62.5). The mean PSQI score was 6.6 (SD 3.4). Nearly 63% (n = 67) participants had PSQI scores more than 5 (PSQI > 5) suggesting sleep problems. Sociodemographic, substance use, and treatment variables were compared between participants who scored more than 5 and those who scored less than 5 on PSQI. No significant difference was found between the 2 groups., Conclusions: Substantial proportion of male patients with opioid dependence maintained on buprenorphine have sleep problems. The sleep problems in buprenorphine-maintained patients seem to be independent of substance use and treatment-related attributes.

Abstract: Background: The use of non‐human primates (NHPs) in research remains a major societal concern with public expectations that appropriate anaesthetics and analgesics are used to minimize any pain or distress caused to animals undergoing invasive procedures. A literature review was conducted to examine the reporting of anaesthesia and analgesia methods used in non‐human primates undergoing surgical procedures, with recovery from anaesthesia. Methods: A total of 397 papers from peer‐review journals published between 2010 and 2015 were examined. Results: Only 25.9% of papers reported the analgesic regimen used, with carprofen and buprenorphine the 2 most widely used agents. Reporting of the anaesthetic regimens was included in 49.9% of papers. Ketamine and isoflurane were the most frequently used anaesthetic agents. Conclusions: Anaesthetic and analgesic regimens administered to NHPs remain poorly reported. This lack of detailed descriptions of protocols does little to reassure the public or regulatory authorities that appropriate high standards of perioperative care are employed. [ABSTRACT FROM AUTHOR]

Introduction: The ongoing opioid epidemic in the United States has resulted in a substantial increase in overdose deaths and related morbidity and mortality. Given that emergency departments (ED) frequently serve as the initial point of contact for individuals experiencing opioid overdose or seeking treatment for opioid use disorder (OUD), ED clinicians have a pivotal role to play in providing prompt and effective treatment for OUD. While ED clinicians routinely administer sublingual and other transmucosal formulations of buprenorphine, extended-release buprenorphine (BUP-XR) remains underutilized in the ED., Case Report: We present a case involving the successful administration of BUP-XR in the ED to a patient experiencing spontaneous opioid withdrawal. The patient tolerated test dosing of sublingual buprenorphine (BUP-SL) and subsequently received BUP-XR in the ED. Following this intervention, the patient was referred to the hospital-affiliated substance use disorder outpatient clinic, where he has since demonstrated successful follow-up and retention in treatment., Conclusion: Our report adds to the existing limited literature on the administration of BUP-XR in the ED and highlights the need for more comprehensive clinician teaching and guidance, as well as the establishment of in-hospital protocols for BUP-XR. Despite these challenges, our case indicates that initiating BUP-XR could be a viable and effective option for ED patients with OUD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Challenges to engagement and retention on buprenorphine undermine treatment of individuals with opioid use disorder (OUD). Under the OUD Cascade of Care framework, we sought to identify patient characteristics and treatment response associated with superior clinical outcomes., Methods: A retrospective cohort study of specialty buprenorphine treatment patients entering treatment (n=19,487) based on EHR records from a large multi-state buprenorphine treatment network (2011-2019). Person-level care episodes were evaluated across treatment intake, engagement (i.e. 2+ visits in the month following intake), and retention at 6, 12, and 24 months. Time to achieving 90 days of continuous opioid abstinence was assessed using Cox proportional hazards regressions models and also assessed as a predictor of long-term retention., Results: Most patients engaged (82.4 %), but retention steadily declined over 6-month (38.7 %), 12-month (26.2 %), and 24-month (17.1 %) timepoints. Opioid-positive baseline tests were associated with lower hazards of achieving continuous abstinence for both buprenorphine-positive (aHR=0.33, p<.001) and buprenorphine-negative (aHR=0.49,p<.001) intakes. Opioid abstinence was associated with buprenorphine-positive baseline testing (aHR=1.59,p<.001), especially for those testing opioid-negative (aHR=1.82,p<.001). Patients who achieved and sustained abstinence at 6 months in care were 4.1 and 5.5 times as likely to achieve 12-month and 24-month retention, respectively, compared to patients with intermittent opioid use., Conclusion: Treatment discontinuation was concentrated early in care and buprenorphine and opioid status at intake were prognostic of achieving and sustaining abstinence. Early abstinence was associated with higher likelihood of subsequent stage progression. Implementing interventions to support early clinical stability for high-risk patients is critical to improve clinical outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Long-acting injectable buprenorphine (LAI-bup) formulations have advantages over transmucosal buprenorphine (TM-bup), but barriers may limit their utilization. Several policies shifted during the COVID-19 pandemic to promote buprenorphine access. The federal government expanded telemedicine treatment for opioid use disorder and Kentucky (KY) Medicaid lifted prior authorization requirements (PAs) for LAI-bup (i.e., Sublocade®). This retrospective cohort study evaluated changes in LAI-bup access, utilization, and retention before and after these policy changes in KY., Methods: Individual-level TM-bup and LAI-bup dispensing record data from KY's prescription drug monitoring program examined LAI-bup utilization and retention, without a >30-day gap in coverage, for patients starting a new episode of LAI-bup treatment. Two key time periods were examined: pre-policy changes (Apr 1, 2019 - Dec 31, 2019) and post-policy changes (Apr 1, 2020 - Dec 31, 2020). Data on PA requests among Medicaid managed care organizations and availability of LAI-bup Risk Evaluation and Mitigation Strategy (REMS)-certified pharmacies were also obtained. A multivariable Cox proportional hazard regression model analysis compared pre- versus post-policy period treatment discontinuation., Results: The number of patients initiating LAI-bup increased from 211 to 481 over the two periods. By the end of the post-policy period, 24.3 % of eligible patients were retained on LAI-bup, versus 12.5 % in the pre-policy change period. The adjusted hazard ratio, comparing discontinuation during the post- versus pre-policy change periods, was 0.70 (95 % confidence interval: 0.55-0.89). There were also more REMS-certified pharmacies and providers in the post-policy change period., Conclusions: LAI-bup access, utilization, and retention increased after several policy changes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sharon Walsh reports financial support was provided by National Institutes of Health and the Substance Abuse and Mental Health Services Administration. Lindsey Hammerslag reports administrative support and data access were provided by Kentucky Cabinet for Health and Family Services (KASPER Data Access). Michelle Lofwall reports a relationship with Berkshire Biomedical that includes: consulting or advisory. Michelle Lofwall reports a relationship with Braeburn Pharmaceuticals Inc. that includes: consulting or advisory. Michelle Lofwall reports a relationship with Journey Colab that includes: consulting or advisory. Sharon Walsh reports a relationship with Braeburn Pharmaceuticals Inc. that includes: consulting or advisory. Sharon Walsh reports a relationship with Astra Zeneca that includes: consulting or advisory. Sharon Walsh reports a relationship with Cerevel Therapeutics Inc. that includes:. Sharon Walsh reports a relationship with Opiant Pharmaceuticals Inc. that includes: consulting or advisory. Sharon Walsh reports a relationship with Pocket Naloxone that includes: consulting or advisory. Sharon Walsh reports a relationship with Titan Pharmaceuticals that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Persons receiving prescription buprenorphine for opioid use disorder experience high rates of comorbid conditions such as chronic pain and depression, which present barriers to buprenorphine care retention. This paper describes the protocol of the TOPPS (Treating Opioid Patients' Pain and Sadness) study, which compares a values-based, behavioral activation intervention with a health education contact-control condition, with the aim of decreasing chronic pain and depression, and increasing buprenorphine care retention for persons with opioid use disorder., Methods: This randomized controlled trial (RCT) enrolls and randomizes up to 250 participants currently being treated with buprenorphine to receive three months of either TOPPS, a six-session phone-based behavioral intervention, or a health education (HE) control condition. We compare the TOPPS intervention to HE on the following outcomes: 1) pain interference and pain severity over the 3-month treatment phrase; 2) depressive symptoms over the 3-month treatment phase; and 3) sustained improvements in pain interference, depressive symptoms, and buprenorphine treatment retention over the 12-month study period. We also examine mechanisms by which the intervention may reduce pain interference., Discussion: This RCT explores a novel intervention to address chronic pain and depression for individuals receiving buprenorphine in office-based settings. TOPPS may lead to improved pain, depression, and substance use outcomes, and can utilize providers available within buprenorphine programs, broadening the disseminability of this intervention and heightening its public health impact., Clinical Trial: #NCT03698669., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Risa Weisberg is currently the Chief Clinical Officer for RealizedCare, a digital therapeutics-based healthcare company. RealizedCare manufactures and sells behavioral health products including those for chronic pain and opioid use., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Medications for opioid use disorder (MOUD) including methadone (MMT), buprenorphine (BUP), and naltrexone (NTX) are safe and effective. However, there are significant negative perceptions surrounding MOUD, creating barriers to uptake. While research on MOUD stigma has largely focused on provider and patient experiences, fewer studies have explored MOUD perceptions among the general public. Given that MOUD stigma expressed by social ties surrounding individuals with OUD can influence treatment choices, we assessed MOUD perceptions among U.S. adults to determine how beliefs impacted treatment preference. We further explored how MOUD perceptions may be amplified among racialized groups with histories of experiencing drug-related discrimination., Methods: The study collected survey data from a diverse sample of U.S. adults (n = 1508) between October 2020 and January 2021. The survey measured knowledge of MOUD and non-medication treatments, relative agreement with common MOUD perceptions, and treatment preferences. Multinomial logistic regression analysis tested associations with treatment preference, stratified by race/ethnicity., Results: Descriptive results indicated that across groups, many respondents (66.8 %) had knowledge of MOUD, but believed MOUD was a "substitute" for opioids and had some degree of concern about misuse. Multivariable results showed knowledge of non-medication treatments was positively associated with MOUD preference among White (MMT OR = 3.16, 95 % CI = 1.35-7.39; BUP OR = 2.69, CI = 1.11-6.47), Black (MMT OR = 3.91, CI = 1.58-9.69), and Latino/a (MMT OR = 5.12, CI = 1.99-13.2; BUP OR = 3.85, CI = 1.5-9.87; NTX OR = 4.51, CI = 1.44-14.06) respondents. Among White respondents, we identified positive associations between MOUD experience and buprenorphine preference (OR = 4.33, CI = 1.17-16.06); non-medication treatment experience and preference for buprenorphine (OR = 2.86, CI = 1.03-7.94) and naltrexone (OR = 3.17, CI = 1.08-9.28). Concerns around misuse of methadone were negatively associated with methadone preference among White (OR = 0.65, CI = 0.43-0.98) and Latino/a (OR = 0.49, CI = 0.34-0.7), and concerns around misuse of buprenorphine was negatively associated with preference for MOUD among White (MMT OR = 0.62, CI = 0.39-0.99; BUP OR = 0.48, CI = 0.3-0.77; NTX OR = 0.6, CI = 0.36-0.99) and Latino/a (BUP OR = 0.59, CI = 0.39-0.89) respondents., Conclusions: This analysis offers critical insights into treatment perceptions beyond the patient population, finding that negative beliefs around MOUD are common and negatively associated with preferences for medication-based treatment. These findings highlight implications for public support of evidence-based treatment and lay the groundwork for future interventions addressing public stigma toward MOUD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pooja Lagisetty reports financial support was provided by National Institute on Drug Abuse. Amy Bohnert reports financial support was provided by Blue Cross Blue Shield of Michigan. Amy Bohnert reports financial support was provided by Michigan Department of Health and Human Services. Amy Bohnert reports a relationship with State of Michigan that includes: paid expert testimony. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Despite Medicaid's outsized role in delivering and financing medications for opioid use disorder (MOUD), little is known about the extent to which buprenorphine prescriber networks vary across Medicaid health plans, and whether network characteristics affect quality of treatment received. In this observational cross-sectional study, we used 2018-2019 Medicaid claims in Oregon to assess network variation in the numbers and types of buprenorphine prescribers, as well as the association of prescriber and network characteristics with quality of care., Methods: We describe prescribers (MD/DOs and advanced practice providers) of OUD-approved buprenorphine formulations to patients with an OUD diagnosis, across networks. For each patient who initiated buprenorphine treatment during 2018, we assigned a "usual prescriber" and assessed four measures of quality in the 180d following initiation: 1) continuous receipt of buprenorphine; 2) receipt of any behavioral health counseling services; 3) receipt of any urine drug screen; and 4) receipt of any prescription for a benzodiazepine. We used multivariable linear regressions to examine the association of prescriber and network characteristics with quality of buprenorphine care following initiation., Results: We identified 645 providers who prescribed buprenorphine to 20,739 eligible Medicaid enrollees with an OUD diagnosis. The composition of buprenorphine prescriber networks varied in terms of licensing type, specialty, and panel size, with the majority of prescribers providing buprenorphine to small panels of patients. In the 180 days following initiation, a third of patients were maintained on buprenorphine; 69.9 % received behavioral health counseling; 88.4 % had a urine drug screen; and 11.3 % received a benzodiazepine prescription. In regression analyses, while no single network characteristic was associated with higher quality across all examined measures, each one unit increase in prescriber-to-enrollee ratio was associated with a 1.18 p.p. increase in the probability of continuous buprenorphine maintenance during the 180 days following initiation (95 % confidence interval = [0.21, 2.15], p = 0.017)., Conclusions: Medicaid plans may be able to leverage their networks to provide higher quality care. Our findings, which should be interpreted as descriptive only, suggest that higher prescriber-to-enrollee ratio is associated with increased buprenorphine maintenance. Future research should focus on isolating the causal relationships between MOUD prescribing network design and patient outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jane Zhu reports financial support was provided by National Institute of Mental Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Coleman Drake reports financial support from the National Institute on Drug Abuse. No other competing financial interests are declared., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Buprenorphine may be safer and better-tolerated than full mu opioid receptor (MOR) agonists. Whether it effectively controls cancer-related pain is unclear. A prior review (Cochrane 2015) did not support prioritizing buprenorphine over full MOR agonists for cancer-associated pain., Purpose/hypothesis: We conducted an updated systematic review of buprenorphine's effect on cancer- related pain including both new studies and additional study designs. Procedures/data/observations: We searched Cochrane, OVID Medline, EMBASE, EBSCO and Web of Science for studies published in any language up to May 2023 for studies that examined buprenorphine's impact upon pain severity/intensity in patients with active cancer. Risk of bias and study quality were assessed using the Cochrane Collaboration tool for randomized controlled trials (RCTs), and the Newcastle-Ottawa Scale for cohort and casecontrol studies. Data were synthesized using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria., Conclusions/applications: 2322 publications were identified and 42 studies were included (14 RCTs, 10 pre-post uncontrolled, 5 cohort, and 2 case-control studies). All had moderate-high risk of bias. One RCT showed buprenorphine was superior to placebo. 11 RCTs (12 papers) showed buprenorphine was as effective as full MOR agonists for cancer pain. 10-30 percent of cancer patients trialing buprenorphine did not achieve adequate response.

Objectives: Buprenorphine is an effective evidence-based medication for opioid use disorder (OUD). Yet premature discontinuation undermines treatment effectiveness, increasing the risk of mortality and overdose. We developed and evaluated a machine learning (ML) framework for predicting buprenorphine care discontinuity within 12 months following treatment initiation., Methods: This retrospective study used United States (US) 2018-2021 MarketScan commercial claims data of insured individuals aged 18-64 who initiated buprenorphine between July 2018 and December 2020 with no buprenorphine prescriptions in the previous six months. We measured buprenorphine prescription discontinuation gaps of ≥30 days within 12 months of initiating treatment. We developed predictive models employing logistic regression, decision tree classifier, random forest, extreme gradient boosting, Adaboost, and random forest-extreme gradient boosting ensemble. We applied recursive feature elimination with cross-validation to reduce dimensionality and identify the most predictive features while maintaining model robustness. For model validation, we used several statistics to evaluate performance, such as C-statistics and precision-recall curves. We focused on two distinct treatment stages: at the time of treatment initiation and one and three months after treatment initiation. We employed SHapley Additive exPlanations (SHAP) analysis that helped us explain the contributions of different features in predicting buprenorphine discontinuation. We stratified patients into risk subgroups based on their predicted likelihood of treatment discontinuation, dividing them into decile subgroups. Additionally, we used a calibration plot to analyze the reliability of the models., Results: A total of 30,373 patients initiated buprenorphine and 14.98% (4551) discontinued treatment. C-statistic varied between 0.56 and 0.76 for the first-stage models including patient-level demographic and clinical variables. Inclusion of proportion of days covered (PDC) measured after one month and three months following treatment initiation significantly increased the models' discriminative power (C-statistics: 0.60 to 0.82). Random forest (C-statistics: 0.76, 0.79 and 0.82 with baseline predictors, one-month PDC and three-months PDC, respectively) outperformed other ML models in discriminative performance in all stages (C-statistics: 0.56 to 0.77). Most influential risk factors of discontinuation included early stage medication adherence, age, and initial days of supply., Conclusion: ML algorithms demonstrated a good discriminative power in identifying patients at higher risk of buprenorphine care discontinuity. The proposed framework may help healthcare providers optimize treatment strategies and deliver targeted interventions to improve buprenorphine care continuity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The relationship between opioid craving and opioid use is unclear. We sought to determine to what extent craving mediated the relationship between opioid agonist therapy and changes in opioid use., Methods: Data came from a pragmatic, 24-week, pan-Canadian, multi-centric, open-label, randomized controlled trial comparing flexible buprenorphine/naloxone take-home doses to standard supervised methadone models of care for the treatment of prescription-type opioid use disorder. Participants were randomly allocated to buprenorphine/naloxone or methadone models of care. 270 people with prescription-type opioid use disorder were included in analyses. There were 93 women (34.4%) and 2 transgender (0.7%) participants. Most participants were white (67.4%), 45.9% reported unstable living conditions, and 44.8% had psychiatric comorbidities. Generalized linear mixed models followed by mediation analysis estimated the direct effect of treatment group on Timeline Followback-reported next-week opioid use and the indirect effect through past 24-hour opioid craving measured using the Brief Substance Craving Scale at week 2, 6, 10, 14, 18 and 22., Results: Upon mediation analysis, the average direct effect of treatment on opioid use was 0.465 (95 % CI = 0.183 to 0.751, p < 0.001). The average causal mediated effect was 0.144 (95 % CI = 0.021 to 0.110; p < 0.001). Craving accounted for 23.6 % of the effect of treatment on opioid use (p < 0.001)., Conclusions: Past 24-hour craving was associated with increased next-week opioid use; however, craving only partially mediated the effect of buprenorphine/naloxone and methadone on next-week opioid use. Research is needed to develop a comprehensive understanding of factors mediating opioid use during opioid agonist therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

OPRM1 gene encoding mu-opioid receptor (MOR) is the primary candidate gene for buprenorphine (BUP) pharmacogenetics. OPRM1 undergoes alternative splicing leading to multiple MOR subtypes. Thus, in the current study 2 SNPs (rs1799972 and rs562859) were selected due to evidence for their contribution to alternative splicing of OPRM1. The effects of 2 SNPs of OPRM1 gene on plasma buprenorphine and norbuprenorphine levels in a sample of 233 OUD patients receiving BUP/naloxone were examined. Polymorphisms were analyzed by PCR and RFLP. BUP and norbuprenorphine concentrations in plasma were measured by LC-MS/MS. OPRM1 rs2075572 GC + CC (0.12 ng/ml) had significantly higher plasma BUP level compared to GG (0.084 ng/ml) (p = 0.043). Although there was not a statistically significant difference between OPRM1 rs562859 genotypes (p = 0.46), patients with OPRM1 rs562859 CT + TT had higher plasma BUP and BUP-related values as compared to those with CC. In conclusion, the effect of OPRM1 rs2075572 on BUP levels in opioid users' plasma was shown in a Caucasian population for the first time. On the other hand, OPRM1 rs562859 seems not to influence the BUP pharmacology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Chronic pain affects tens of millions of US adults and continues to rise in prevalence. Nonpharmacologic behavioral pain treatments are greatly needed and yet are often inaccessible, particularly in settings where medication prescribing is prioritized., Objective: This study aims to test the feasibility of a live-instructor, web-based 1-session pain relief skills class in an underserved and potentially at-risk population: people with chronic pain prescribed methadone or buprenorphine either solely for pain or for comorbid opioid use disorder (OUD)., Methods: This is a national, prospective, single-arm, uncontrolled feasibility trial. The trial is untethered from medical care; to enhance participants' willingness to join the study, no medical records or drug-monitoring records are accessed. At least 45 participants will be recruited from outpatient pain clinics and from an existing research database of individuals who have chronic pain and are taking methadone or buprenorphine. Patient-reported measures will be collected at 6 time points (baseline, immediately post treatment, 2 weeks, and months 1-3) via a web-based platform, paper, or phone formats to include individuals with limited internet or computer access and low literacy skills. At baseline, participants complete demographic questions and 13 study measures (Treatment Expectations, Body Pain Map, Medication Use, Pain Catastrophizing Scale [PCS], Patient-Reported Outcomes Measurement Information System [PROMIS] Measures, and Opioid Craving Scale). Immediately post treatment, a treatment satisfaction and acceptability measure is administered on a 0 (very dissatisfied) to 10 (completely satisfied) scale, with 3 of these items being the primary outcome (perceived usefulness, participant satisfaction, and likelihood of using the skills). At each remaining time point, the participants complete all study measures minus treatment expectations and satisfaction. Participants who do not have current OUD will be assessed for historical OUD, with presence of OUD (yes or no), and history of OUD (yes or no) reported separately. Feasibility threshold is set as an overall group treatment satisfaction rating of 8 of 10. In-depth qualitative interviews will be conducted with about 10 participants to obtain additional data on patient perceptions, satisfactions, needs, and wants. To assess preliminary efficacy, we will examine changes in pain catastrophizing, pain intensity, pain bothersomeness, sleep disturbance, pain interference, depression, anxiety, physical function, global impression of change, and opioid craving at 1 month post treatment., Results: This project opened to enrollment in September 2021 and completed the recruitment in October 2023. The data collection was completed in February 2024. Results are expected to be published in late 2024., Conclusions: Results from this trial will inform the feasibility and preliminary efficacy of Empowered Relief in this population and will inform the design of a future randomized controlled trial testing web-based Empowered Relief in chronic pain and comorbid OUD., Trial Registration: ClinicalTrials.gov NCT05057988; https://clinicaltrials.gov/study/NCT05057988., International Registered Report Identifier (irrid): DERR1-10.2196/53784., (©Morgan R Klein, Beth D Darnall, Dokyoung S You. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 06.06.2024.)

Objective: To get information on subcutaneous extended-release buprenorphine as opioid maintenance treatment during pregnancy, we compared it to orally administered buprenorphine and buprenorphine-naloxone treatments. We hypothesized that maternal and neonatal outcomes do not differ between the treatment groups. Study design In this population-based cohort study, 60 pregnant individuals receiving non-changed opioid maintenance treatment for opioid use disorder with a buprenorphine product from the time before conception to the time after delivery and their newborns were included. They were divided into three groups based on the pharmacotherapy with subcutaneous extended-release buprenorphine, sublingual buprenorphine, or buprenorphine-naloxone. Statistical analyses were conducted using Fischer's exact tests, ANOVA tests, and Kruskal-Wallis tests. All the statistical tests were two-tailed., Results: The frequency of pregnancy or delivery complications did not significantly differ between the group receiving extended-release buprenorphine and the other groups. During pregnancy, 38 % of the women used illicit drugs concomitantly, with equal frequency in the extended-release buprenorphine group and the other groups. Of the neonates, 93 % were born full-term and 90 % got at least eight Apgar points in one minute age, without significant differences between the groups (p = 0.57). The need for pharmacotherapy for neonatal opioid withdrawal syndrome was the lowest in the extended-release buprenorphine group (25 %) and highest in the sublingual buprenorphine group (67 %). Still, the difference between the treatment groups did not reach statistical significance (p = 0.17). Among all neonates, the breastfed infants were less likely to receive pharmacotherapy for withdrawal symptoms than the formula-fed ones (p = 0.048)., Conclusions: Extended-release buprenorphine with steady drug concentration seems to be a promising pharmacotherapy option during pregnancy for mothers. Maternal health during pregnancy may contribute to the well-being of newborns. Larger trials are urgently needed to confirm these results.., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: We sought to answer the question of how adolescents (ages 12-17 years old) with opioid-related presentations are currently managed in the ED. The two main outcomes were the proportion of visits where naloxone and buprenorphine were both used and prescribed, and the rate of revisits to the emergency department in the six months following ED presentation., Methods: This was a multi-center retrospective cross-sectional study. We studied patients presenting to the ED who were 12-17 years old with an opioid-related presentation., Results: Two-hundred and thirty-one patients were identified out of 571 encounters screened. Of these presentations, 77/231 (33%) were girls and 154/231 (67%) were boys. The majority of patients were Latino (64%; n=147); 26% were white (n=59), 6% were middle eastern or Arab (14), and 4% were black (10). Incidence of opioid use disorder per 100,000 presentations increased by 2800% from 2014 to 2022 (21/100,000 +/- 10 [2014] to 600/100,000 +/- 50 [2022]). A plurality of cases was related to opioid withdrawal (42%; 97). On discharge from the ED, 29% of patients received naloxone. For patients in withdrawal, 4% received a prescription for buprenorphine. Twenty-nine percent of patients had a return to the ED in the six months following initial visit., Conclusions: Adolescent opioid-related presentations to the ED are rapidly increasing. Increasing ED presentations, compounded by a high 6-month revisit rate, pose a management challenge amid limited outpatient resources for this population. Opioid agonist therapy and naloxone are not routinely provided. Increasing the use of both are two ways to improve the quality of care for this population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Until the end of 2022, a special registration, known as the X-waiver, was required to prescribe buprenorphine in the US. Before its removal, US federal regulations trialed an X-waiver exemption, initiated on April 28, 2021, which permitted buprenorphine prescribing for up to 30 patients without additional training. We aimed to understand if these regulatory changes impacted buprenorphine dispensing., Methods: We conducted an interrupted time series analysis to understand changes in buprenorphine dispensing during the 26 weeks after the X-waiver exemption compared to the expected baseline trend established in the 26 weeks before using the IQVIA Longitudinal Prescription claims database. The primary outcome was number of new buprenorphine prescribers nationwide (defined as no prior buprenorphine prescription dispensed in the last 26 weeks). Segmented regression estimated relative changes in buprenorphine dispensing at 1, 13, and 26 weeks post-X-waiver change., Results: A total of 15,517,525 prescriptions filled for 1,328,172 patients (43.4 % female) ordered by 62,312 providers were included for analysis. At 26 weeks post-X-waiver change, there was no change in the number of new prescribers compared to the expected baseline trend (-2.7 % [95 % CI:-8.3,2.9]). The number of new (15.2 % [4.6,25.8]) and existing (1.7 % [0.9,2.4]) patients and patients per prescriber (4.3 % [3,5.6]) increased. Buprenorphine prescriptions reimbursed by Medicaid increased (7.5 % [6.6,8.4]) while commercial fills decreased (-3.4 % [-5.3,-1.5])., Conclusions: The number of new prescribers did not increase six months post-X-waiver exemption while new patients continued to enter treatment at higher-than-expected rates. These findings suggest that additional interventions beyond the recent X-waiver removal may be needed to increase access to buprenorphine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: The difference in infant health outcomes by maternal opioid use disorder (OUD) status is understudied. We measured the association between maternal OUD during pregnancy and infant mortality and investigated whether this association differs by infant neonatal opioid withdrawal syndrome (NOWS) or maternal receipt of medication for OUD (MOUD) during pregnancy., Methods: We sampled 204,543 Medicaid-paid births from Wisconsin, United States (2010-2018). The primary exposure was any maternal OUD during pregnancy. We also stratified this exposure on NOWS diagnosis (no OUD; OUD without NOWS; OUD with NOWS) and on maternal MOUD receipt (no OUD; OUD without MOUD; OUD with <90 consecutive days of MOUD; OUD with 90+ consecutive days of MOUD). Our outcome was infant mortality (death at age <365 days). Demographic-adjusted logistic regressions measured associations with odds ratios (OR) and 95% confidence intervals (CI)., Results: Maternal OUD was associated with increased odds of infant mortality (OR 1.43; 95% CI 1.02-2.02). After excluding infants who died <5 days post-birth (i.e., before the clinical presentation of NOWS), regression estimates of infant mortality did not significantly differ by NOWS diagnosis. Likewise, regression estimates did not significantly differ by maternal MOUD receipt in the full sample., Conclusions: Maternal OUD is associated with an elevated risk of infant mortality without evidence of modification by NOWS nor by maternal MOUD treatment. Future research should investigate potential mechanisms linking maternal OUD, NOWS, MOUD treatment, and infant mortality to better inform clinical intervention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) in children often causes cognitive and mental dysfunctions, as well as acute and chronic pain. Adult hippocampal neurogenesis plays a key role in cognition, depression, and pain. Adult hippocampal neurogenesis can be modulated by genetic and environmental factors, such as TBI and opioids. Buprenorphine (BPN), a semisynthetic opioid, is commonly used for pain management in children, however, the effects of BPN on adult hippocampal neurogenesis after pediatric TBI are still unclear. This study investigated the sex-specific effects of BPN on adult hippocampal neurogenesis during acute phase after pediatric TBI. Male and female littermates were randomized on postnatal day 20-21(P20-21) into Sham, TBI+saline and TBI+BPN groups. BPN was administered intraperitoneally to the TBI+BPN mice at 30 min after injury, and then every 6-12 h (h) for 2 days (d). Bromodeoxyuridine (BrdU) was administered intraperitoneally to all groups at 2, 4, 6, and 8-h post-injury. All outcomes were evaluated at 3-d post-BrdU administration. We found that TBI induced significant cognitive impairment, depression, and reduced adult hippocampal neurogenesis in both male and female mice, with more prominent effects in females. BPN significantly improved adult hippocampal neurogenesis and depression in males, but not in females. We further demonstrated that differential expressions of opioid receptors, transcription factors and neuroinflammatory markers at the neurogenic niche might be responsible for the differential effects of BPN in males and females. In conclusion, this study elucidates the effects of BPN on adult hippocampal neurogenesis and behavioral outcomes at the acute phase after pediatric TBI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To identify individual and site-related factors associated with frequent emergency department (ED) buprenorphine/naloxone (BUP) initiation. BUP initiation, an effective opioid use disorder (OUD) intervention, varies widely across Canadian EDs., Methods: We surveyed emergency physicians in 6 Canadian provinces from 2018 to 2019 using bilingual paper and web-based questionnaires. Survey domains included BUP-related practice, demographics, attitudes toward BUP, and site characteristics. We defined frequent BUP initiation (the primary outcome) as at least once per month, high OUD prevalence as at least one OUD patient per shift, and high OUD resources as at least 3 out of the following 5 resources: BUP initiation pathways, BUP in ED, peer navigators, accessible addiction specialists, and accessible follow-up clinics. We excluded responses from sites with <50% participation (to minimize non-responder bias) and those missing the primary outcome. We used univariate analysis to identify associations between frequent BUP initiation and factors of interest, stratifying by OUD prevalence., Results: We excluded 3 responses for missing BUP initiation frequency and 9 for low response rate at one ED. Of the remaining 649 respondents from 34 EDs, 374 (58%) practiced in metropolitan areas, 384 (59%) reported high OUD prevalence, 312 (48%) had high OUD resources, and 161 (25%) initiated BUP frequently. Age, gender, board certification and years in practice were not associated with frequent BUP initiation. Site-specific factors were associated with frequent BUP initiation (high OUD resources [OR 6.91], high OUD prevalence [OR 4.45], and metropolitan location [OR 2.39],) as were individual attitudinal factors (willingness, confidence, and responsibility to initiate BUP.) Similar associations persisted in the high OUD prevalence subgroup., Conclusions: Individual attitudinal and site-specific factors were associated with frequent BUP initiation. Training to increase physician confidence and increasing OUD resources could increase BUP initiation and benefit ED patients with OUD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 MacKinnon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Regular counseling and frequent drug testing are common requirements for patients with opioid use disorder in buprenorphine treatment. State policies throughout the United States often reinforce these high-threshold practices, as was the case with Michigan, USA., Methods: We sought to explore the association between counseling requirements, drug testing practices, and buprenorphine treatment termination rates through administering a survey to buprenorphine prescribers in Michigan., Results: In our sample of 377 prescribers, we found associations between high-threshold practices like drug testing at every clinical visit and requiring counseling and buprenorphine treatment termination rates. Relative to prescribers who randomly drug tested, drug tested at fixed intervals, or did not require any drug testing, prescribers who drug-tested patients at every visit were 38% more likely to terminate treatment. Prescribers who required counseling were 33% more likely to terminate treatment than those who did not require counseling., Conclusion: With the elimination of the USA Drug Enforcement Administration X-waiver in December 2022, state policies need to minimize high-threshold practices that reduce buprenorphine treatment continuity and undermine an effective response to the overdose crisis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)