Search

Background: Incarceration 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., Methods: We 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)., Results: Participants (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., Conclusion: People 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., (© 2024. The Author(s).)

Importance: Buprenorphine combined with naloxone is commonly used to treat opioid use disorders outside of pregnancy. In pregnancy, buprenorphine alone is generally recommended because of limited perinatal safety data on the combination product., Objective: To compare perinatal outcomes following prenatal exposure to buprenorphine with naloxone vs buprenorphine alone., Design, Settings, and Participants: Population-based cohort study using health care utilization data from Medicaid-insured beneficiaries in the US from 2000 to 2018. The cohort was restricted to pregnant individuals linked to their liveborn infants, with maternal Medicaid enrollment from 3 months before pregnancy to 1 month after delivery and infant enrollment for the first 3 months after birth, unless they died sooner., Exposure: Use of buprenorphine with naloxone vs buprenorphine alone during the first trimester based on outpatient dispensings., Main Outcomes and Measures: Outcomes included major congenital malformations, low birth weight, neonatal abstinence syndrome, neonatal intensive care unit admission, preterm birth, respiratory symptoms, small for gestational age, cesarean delivery, and maternal morbidity. Confounder-adjusted risk ratios were calculated using propensity score overlap weights., Results: This study identified 3369 pregnant individuals exposed to buprenorphine with naloxone during the first trimester (mean [SD] age, 28.8 [4.6] years) and 5326 exposed to buprenorphine alone or who switched from the combination to buprenorphine alone by the end of the first trimester (mean [SD] age, 28.3 [4.5] years). When comparing buprenorphine combined with naloxone with buprenorphine alone, a lower risk for neonatal abstinence syndrome (absolute risk, 37.4% vs 55.8%; weighted relative risk, 0.77 [95% CI, 0.70-0.84]) and a modestly lower risk for neonatal intensive care unit admission (absolute risk, 30.6% vs 34.9%; weighted relative risk, 0.91 [95% CI, 0.85-0.98]) and small for gestational age (absolute risk, 10.0% vs 12.4%; weighted relative risk, 0.86 [95% CI, 0.75-0.98]) was observed. For maternal morbidity, the comparative rates were 2.6% vs 2.9%, respectively, and the weighted relative risk was 0.90 (95% CI, 0.68-1.19). No differences were observed with respect to major congenital malformations overall, low birth weight, preterm birth, respiratory symptoms, or cesarean delivery. Results were consistent across sensitivity analyses., Conclusions and Relevance: There were similar and, in some instances, more favorable neonatal and maternal outcomes for pregnancies exposed to buprenorphine combined with naloxone compared with buprenorphine alone. For the outcomes assessed, compared with buprenorphine alone, buprenorphine with naloxone during pregnancy appears to be a safe treatment option. This supports the view that both formulations are reasonable options for the treatment of opioid use disorder in pregnancy, affirming flexibility in collaborative treatment decision-making.

Background: Opioid use disorder (OUD) poses a global health challenge, and despite medications for opioid use disorder (MOUD) and psychosocial interventions, relapse remains a significant concern. Comorbid psychiatric disorders, including attention deficit hyperactivity disorder (ADHD), are one of the major factors associated with poor OUD treatment outcome. We aimed to estimate the frequency of probable ADHD (in childhood and in adulthood) in patients with OUD; to assess the factors associated with this comorbidity; and to explore the factors that mediate the relationship between ADHD and OUD treatment outcome., Methods: We conducted an observational study using a sample of 229 patients aged 18 years and older who were diagnosed with OUD and had received MOUD for at least six months. Participants were assessed through a structured interview and self-report questionnaires. Multivariate logistic regressions and a mediation analysis were performed., Results: Almost half of the participants reported probable ADHD in childhood, and ADHD persisted into adulthood among two-thirds of the patients. The factors associated with poor OUD treatment outcome included earlier onset of OUD, lower education, and greater impulsivity. There was no direct effect of probable ADHD in childhood on OUD treatment outcome, but there was an indirect effect through negative urgency, the tendency to respond impulsively to negatively connoted emotional experiences., Conclusions: The findings suggest that ADHD symptoms, particularly impulsivity, may contribute to vulnerability in opioid use and play a crucial role in treatment outcomes for this population., Trial Registration: ClinicalTrials identifier NCT01847729., (© 2024. The Author(s).)

Importance: Individuals with opioid use disorder (OUD) and criminal justice system involvement experience high rates of overdose death. Historical data point to limited use of medications for opioid use disorder (MOUD) in criminal justice system-referred treatment for OUD as playing a role. However, how MOUD use among those referred to treatment by the criminal justice system has changed relative to other referral sources over time is still unclear, as well as how it varies across states., Objective: To examine disparities in the use of MOUD between individuals referred to treatment by the criminal justice system compared to other referral sources over time., Design, Setting, and Participants: This cross-sectional study included admissions to specialty substance use treatment facilities for OUD in the national Treatment Episodes Dataset-Admissions from 2014 to 2021. Logistic regression models were used to examine trends in the probability of MOUD use among individuals with and without criminal justice referrals for OUD treatment, as well as any differential trends by state. The data were analyzed from September 2023 to August 2024., Main Outcome and Measure: The main outcome was the probability that treatment for individuals with OUD included MOUD., Results: A total of 3 235 445 admissions were analyzed in the study data. Among individuals referred to OUD treatment by the criminal justice system, the probability that treatment included MOUD increased by 3.42 percentage points (pp) (95% CI, 3.37 pp to 3.47 pp) annually from 2014 to 2021. This was faster than the increase in the probability of MOUD use for noncriminal justice-referred admissions (2.49 pp [95% CI, 2.46 pp to 2.51 pp) and reduced, but did not eliminate, disparities in MOUD use between individuals with and without criminal justice system-referred treatment. In 2021, only 33.6% of individuals in criminal justice system-referred treatment received MOUD, 15.6 pp lower than for individuals referred to treatment by other sources. Trends in the probability of MOUD use varied substantially for individuals in criminal justice system-referred treatment across states, but very few experienced enough growth to eliminate this disparity., Conclusions and Relevance: The results of this cross-sectional study suggest that targeted efforts to address persistent disparities in MOUD use among those with OUD and criminal justice system involvement are needed to address the poor health outcomes experienced by this population.

Background: Switching from methadone to buprenorphine in patients receiving opioid maintenance therapy often requires inpatient care with a gradual tapering of methadone and an opioid-free day with challenging withdrawal symptoms. This case report describes and discusses a gentle outpatient approach without the opioid-free day., Case Presentation: A patient with a 15-year history of opioid maintenance therapy reduced his methadone dose from 80 mg to 50 mg due to concurrent use of other sedative substances and a significant risk of overdose. A week-long switch to buprenorphine 16 mg subcutaneous depot formulation was then undertaken using a microinduction approach in the outpatient setting., Interpretation: In line with earlier reports on microinduction, the switch from methadone to buprenorphine was carried out with no opioid withdrawal symptoms or complications. Microinduction offers a smooth and more patient-friendly approach to switching from full opioid agonists to partial agonists. Randomised controlled trials are, however, needed for a systematic evaluation of this method.

Opioid use disorder (OUD) has been linked to macroscopic structural alterations in the brain. The monthly injectable, extended-release formulation of μ-opioid antagonist naltrexone (XR-NTX) is highly effective in reducing opioid craving and preventing opioid relapse. Here, we investigated the neuroanatomical effects of XR-NTX by examining changes in cortical thickness during treatment for OUD. Forty-seven OUD patients underwent structural magnetic resonance imaging and subjectively rated their opioid craving ≤1 day before (pre-treatment) and 11 ± 3 days after (on-treatment) the first XR-NTX injection. A sample of fifty-six non-OUD individuals completed a single imaging session and served as the comparison group. A publicly available [¹¹C]carfentanil positron emission tomography dataset was used to assess the relationship between changes in cortical thickness and μ-opioid receptor (MOR) binding potential across brain regions. We found that the thickness of the medial prefrontal and anterior cingulate cortices (mPFC/aCC; regions with high MOR binding potential) was comparable between the non-OUD individuals and the OUD patients at pre-treatment. However, among the OUD patients, mPFC/aCC thickness significantly decreased from pre-treatment to on-treatment. A greater reduction in mPFC/aCC thickness was associated with a greater reduction in opioid craving. Taken together, our study suggests XR-NTX-induced cortical thickness reduction in the mPFC/aCC regions in OUD patients. The reduction in thickness does not appear to indicate a restoration to the non-OUD level but rather reflects XR-NTX's distinct therapeutic impact on an MOR-rich brain structure. Our findings highlight the neuroplastic effects of XR-NTX that may inform the development of novel OUD interventions., (© 2024. The Author(s).)

Background: Opioid related overdose morbidity and mortality continue to significantly impact rural communities. Nationwide, emergency departments (EDs) have seen an increase in opioid use disorder (OUD)-related visits compared to other substance use disorders (SUD). ED-initiated buprenorphine is associated with increased treatment engagement at 30 days. However, few studies assess rural ED-initiated buprenorphine implementation, which has unique implementation barriers. This protocol outlines the rationale and methods of a rural ED-initiated buprenorphine program implementation study., Methods: This is a two-year longitudinal implementation design with repeated qualitative and quantitative measures of an ED-initiated buprenorphine program in the rural Mountain West. The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework outlines intervention assessments. The primary outcome is implementation measured by ED-initiated buprenorphine protocol core components. Reach, adoption, and maintenance are secondary outcomes. External facilitators from an academic institution with addiction medicine and prior program implementation expertise partnered with community hospital internal facilitators to form an implementation team. External facilitators provide ongoing support, recommendations, education, and academic detailing. The implementation team designed and implemented the rural ED-initiated buprenorphine program. The program includes OUD screening, low-threshold buprenorphine initiation, naloxone distribution and administration training, and patient navigator incorporation to provide warm hand off referrals for outpatient OUD management. To address rural based implementation barriers, we organized implementation strategies based on Expert Recommendations for Implementing Change (ERIC). Implementation strategies include ED workflow redesign, local needs assessments, ED staff education, hospital leadership and clinical champion involvement, as well as patient and community resources engagement., Discussion: Most ED-initiated buprenorphine implementation studies have been conducted in urban settings, with few involving rural areas and none have been done in the rural Mountain West. Rural EDs face unique barriers, but tailored implementation strategies with external facilitation support may help address these. This protocol could help identify effective rural ED-initiated buprenorphine implementation strategies to integrate more accessible OUD treatment within rural communities to prevent further morbidity and mortality., Trial Registration: ClinicalTrials.gov National Clinical Trials, NCT06087991. Registered 11 October 2023 - Retrospectively registered, https://clinicaltrials.gov/study/NCT06087991 ., (© 2024. The Author(s).)

In the midst of the opioid crisis in the US, efforts to mitigate overdose risks have become paramount, leading some states to introduce mandates for coprescribing the life-saving overdose reversal drug naloxone. These mandates were designed to specifically address people receiving opioid analgesics who had an elevated risk for overdose. This included people receiving high opioid dosages, those concurrently using benzodiazepines, or those with a history of substance use disorder or overdose. Using a nationally representative, multipayer cohort of patients receiving prescription opioids, we investigated how naloxone codispensing rates changed at the state level from 2016 to 2021 among patients with an elevated risk for overdose. Then we used controlled interrupted time series analyses to assess mandates' longitudinal impact on naloxone codispensing in ten states that implemented mandates. We observed an immediate and significant increase in the naloxone codispensing rates in eight states after the implementation of mandates. Nevertheless, in five of these states, the codispensing rates exhibited a subsequent downward trend after the initial increase. State mandates show potential for improving naloxone codispensing; however, mandates alone might not be adequate for sustained change. Further research is needed to identify strategies complementing and enhancing the impact of mandates in combating the overdose crisis.

Background and Objectives: Recent increases in methamphetamine use among people seeking treatment for opioid use disorder (OUD) has created significant demand for effective approaches to support this clinical population. This study assessed the extent to which office-based opioid treatment (OBOT) patients, who were diagnosed with methamphetamine use disorder (MUD), engaged with providers., Methods: A retrospective analysis was conducted of adult patients (n = 470) seeking treatment for OUD who attended at least one visit between March 2020 and March 2023 at a rural regional OBOT provider. Approximately one quarter (28.7%) of patients were diagnosed with MUD in addition to receiving an OUD diagnosis. Bivariate methods and multivariate negative binomial regression models were estimated to examine the associations between clinical measures and the numbers of office visits, peer visits, and telehealth visits., Results: Regression results indicated patients who met criteria for MUD in addition to OUD attended a higher rate of peer visits (incidence rate ratio [IRR] = 2.63, p = .036) when compared to patients who did not meet criteria for MUD. In contrast, patients with MUD and OUD diagnoses displayed significantly lower (IRR = 0.68, p < .001) engagement rates through fewer office visits relative to those who did not meet MUD criteria., Discussion and Conclusions: Patients seeking treatment for OUD who meet criteria for MUD are more likely to engage through peer support specialists rather than office visits., Scientific Significance: This study demonstrates the ways patients who meet criteria for OUD and MUD engage with providers to receive treatment., (© 2024 The American Academy of Addiction Psychiatry (AAAP).)

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).)

Loperamide is an over-the-counter peripheral mu-opioid agonist commonly used to manage diarrhoea. When taken in an excessive dose, loperamide's penetration of the central nervous system increases, leading to euphoria, respiratory depression and other opioid effects. A health warning was released in the United States in 2016 with increased reports of excessive loperamide use leading to cardiac conduction abnormalities such as ventricular tachycardia, prolonged QTc and Torsades des Pointes. The growing number of cases is likely due to the increased restrictions on other opioids. Loperamide use disorder has been managed effectively in the United States and the United Kingdom using buprenorphine. In Australia, there have been recent opioid restrictions limiting easy access to opioids. We describe the case of a 28-year-old male who was admitted to hospital on multiple occasions with symptoms relating to loperamide use disorder. Buprenorphine was used to manage withdrawal symptoms in the hospital and maintain abstinence from loperamide in the community through an opioid agonist treatment program. To our knowledge, this is the first case study to describe the successful management of loperamide use disorder with buprenorphine within Australia. Our findings suggest that buprenorphine can be used to manage patients with loperamide associated withdrawal and help them remain abstinent upon discharge. Extramedical use of over-the-counter opioid medication may be becoming an emerging trend in Australia, and increased monitoring is warranted to prevent detrimental health outcomes., (© 2024 Australasian Professional Society on Alcohol and other Drugs.)

Background: For patients with opioid use disorder (OUD), primary care can serve as a pathway to medication for OUD (MOUD). No community-based studies have examined whether people with OUD engaged in primary care are more likely to a) initiate or b) continue MOUD., Methods: Data were collected 2014-2020 from two subsamples of the AIDS Linked to the Intravenous Experience (ALIVE) cohort, a community-recruited cohort of people from Baltimore who have injected drugs: 1) people who reported past-six-month illicit opioid use and no MOUD (360 participants, 789 study visits), and 2) people who reported MOUD and no illicit opioid use in the past six months (561 participants, 2027 visits). Logistic regression was used to estimate associations of past six-month self-reported primary care engagement, respectively, with a) initiating MOUD, b) continuing MOUD, and c) cessation from illicit opioid use without initiating MOUD., Results: Among 360 persons not on MOUD treatment (28 % female, 26 % under 50, 59 % actively injecting drugs), primary care engagement was not associated with either cessation from illicit opioid use or initiating MOUD. Similarly, among persons on MOUD (40 % female, 22 % under 50, 6 % actively injecting drugs) primary care engagement was not associated with continued treatment., Conclusions: Our findings implicate missed opportunities to initiate and maintain buprenorphine treatment in primary care settings., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024. Published by Elsevier B.V.)

The management of cancer-related pain in patients with opioid use disorder (OUD) remains complex and often challenging for clinicians and patients. There is currently a paucity of data to guide best practices, and the evidence that exists is variably applied. In this hospital-based questionnaire, we sought to understand the variation in practice patterns among clinicians in palliative medicine, addiction medicine, and hospital medicine, in caring for this complex patient population. Sixty-two questionnaire responses were analyzed and variation was found in management of pain, as well as initiation or titration of buprenorphine and methadone. There was also a significant difference in postdischarge subspecialty follow-up. Furthermore, the findings suggest that buprenorphine and methadone may be underutilized in this population. Patients and clinicians may benefit from additional support and standardization of practices to best manage coexisting cancer-related pain and OUD.

Importance: Medications for opioid use disorder (MOUD) are highly effective, but only 22% of individuals in the US with opioid use disorder receive them. Hospitalization potentially provides an opportunity to initiate MOUD and link patients to ongoing treatment., Objective: To study the effectiveness of interprofessional hospital addiction consultation services in increasing MOUD treatment initiation and engagement., Design, Setting, and Participants: This pragmatic stepped-wedge cluster randomized implementation and effectiveness (hybrid type 1) trial was conducted in 6 public hospitals in New York, New York, and included 2315 adults with hospitalizations identified in Medicaid claims data between October 2017 and January 2021. Data analysis was conducted in December 2023. Hospitals were randomized to an intervention start date, and outcomes were compared during treatment as usual (TAU) and intervention conditions. Bayesian analysis accounted for the clustering of patients within hospitals and open cohort nature of the study. The addiction consultation service intervention was compared with TAU using posterior probabilities of model parameters from hierarchical logistic regression models that were adjusted for age, sex, and study period. Eligible participants had an admission or discharge diagnosis of opioid use disorder or opioid poisoning/adverse effects, were hospitalized at least 1 night in a medical/surgical inpatient unit, and were not receiving MOUD before hospitalization., Interventions: Hospitals implemented an addiction consultation service that provided inpatient specialty care for substance use disorders. Consultation teams comprised a medical clinician, social worker or addiction counselor, and peer counselor., Main Outcomes and Measures: The dual primary outcomes were (1) MOUD treatment initiation during the first 14 days after hospital discharge and (2) MOUD engagement for the 30 days following initiation., Results: Of 2315 adults, 628 (27.1%) were female, and the mean (SD) age was 47.0 (12.4) years. Initiation of MOUD was 11.0% in the Consult for Addiction Treatment and Care in Hospitals (CATCH) program vs 6.7% in TAU, engagement was 7.4% vs 5.3%, respectively, and continuation for 6 months was 3.2% vs 2.4%. Patients hospitalized during CATCH had 7.96 times higher odds of initiating MOUD (log-odds ratio, 2.07; 95% credible interval, 0.51-4.00) and 6.90 times higher odds of MOUD engagement (log-odds ratio, 1.93; 95% credible interval, 0.09-4.18)., Conclusions: This randomized clinical trial found that interprofessional addiction consultation services significantly increased postdischarge MOUD initiation and engagement among patients with opioid use disorder. However, the observed rates of MOUD initiation and engagement were still low; further efforts are still needed to improve hospital-based and community-based services for MOUD treatment., Trial Registration: ClinicalTrials.gov Identifier: NCT03611335.

Introduction: Low-threshold substance use treatment programs may help overcome barriers for marginalized individuals. The aims of this study were to 1) describe participant characteristics and treatment outcomes for a multi-site, Philadelphia-based mobile program providing street-based buprenorphine initiation, stabilization, and referral to ongoing care and 2) examine associations between patient characteristics and successful linkage., Methods: We conducted a retrospective cohort study of patients receiving buprenorphine through Prevention Point Philadelphia's mobile overdose response program from 9/2020-12/2021. We abstracted electronic medical record data, including patient characteristics, mobile program treatment, and care linkage. We used descriptive statistics to characterize the sample and assessed the association between patient characteristics and successful care linkage using multi-variable logistic regression., Results: Two hundred thirty-seven patients initiated buprenorphine in the program across six sites. Mean age was 46. Participants were majority men (67 %); 59 % identified as Black, 33 % identified as White, and 15 % reported Hispanic ethnicity. Most were publicly insured (74 %) and 30 % were unstably housed. Basedline engagement in primary care (32 %), psychiatric treatment (5 %), and counseling (2 %) were low. Most participants reported heroin or fentanyl use at intake (87 %), with high rates of IV drug use (37 %)., and co-occurring substance use and prior buprenorphine treatment experience were common.. 86 % completed ≥1 mobile follow-up visit, and 69 % completed ≥4 mobile program visits. 51 % of patients attended at least one visit at an outside site, and 30 % had ≥2 visits for buprenorphine prescriptions at an outside site. 35 % of the referrals were internal, meaning they went to University-based practices staffed by the mobile unit physicians. In a multivariable logistic regression model, internal referral was associated with significantly increased odds of effective care linkage (aOR 2.47, 95 % CI 1.20-5.09)., Conclusions: Targeted community outreach with low-threshold substance use care facilitated treatment access among marginalized individuals. Participants showed high levels of engagement with the mobile program, but rates of outside care linkage, while comparable to retention in other low-threshold models, were lower. The only predictor of effective care linkage was referral to brick-and-mortar clinics staffed by mobile unit physicians. These findings support the importance of outreach beyond traditional health care settings to engage high-risk patients with OUD., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Prior studies suggest cost-sharing decreases buprenorphine dispensing. However, these studies used databases that only report prescriptions filled by patients, not those that were "abandoned." Consequently, the studies could not calculate the probability of buprenorphine prescription abandonment or evaluate whether cost-sharing is associated with abandonment., Objective: To evaluate the association between cost-sharing and buprenorphine prescription abandonment., Design: Cross-sectional analysis of the IQVIA Formulary Impact Analyzer, a pharmacy transaction database representing 63% of U.S. retail pharmacies. The database includes transaction records ("claims") for prescriptions even if they are not filled., Participants: Buprenorphine claims in 2022 among commercially insured and Medicare patients., Main Measures: We evaluated the association between cost-sharing per 30-day supply and abandonment using logistic regression, controlling for patient characteristics, product type, and buprenorphine use in the prior 180 days. We assessed for effect modification by prior buprenorphine use., Key Results: Analyses included 2,346,994 and 1,242,596 buprenorphine prescription claims for commercially insured and Medicare patients, respectively. Among these claims, mean (SD) cost-sharing per 30-day supply was $28.1 (46.4) and $8.4 (20.2), and 1.5% and 1.2% were abandoned. Each $10 increase in cost-sharing per 30-day supply was associated with a 0.09 (95% CI: 0.09, 0.10) and 0.09 (95% CI: 0.08, 0.10) percentage-point increase in abandonment among commercially insured and Medicare patients. Among commercially insured and Medicare patients without prior buprenorphine use, respectively, a $10 increase in cost-sharing per 30-day supply was associated with a 0.12 (95% CI: 0.11, 0.14) and 0.13 (95% CI: 0.07, 0.18) percentage-point higher increase in the probability of abandonment compared with patients with > 90 days of prior buprenorphine use., Conclusions: Among commercially insured and Medicare patients, buprenorphine prescription abandonment is rare and only minimally associated with cost-sharing. Findings suggest elimination of buprenorphine cost-sharing should only be one component of a larger, multi-faceted campaign to increase buprenorphine dispensing., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

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.)

Introduction: Mobile health units (MHUs) provide a variety of low-barrier services to populations that face systemic barriers to healthcare access. However, MHUs are not a common delivery method for medications to treat opioid use disorder (MOUD), and, of these, there is no consensus regarding MHU targeted objectives and outcomes. This scoping review seeks to summarize the state of the literature examining the delivery of MOUD by MHUs in the United States., Methods: A search of PubMed, PsycInfo, and CINAHL on February 21, 2023, found 223 articles. Two authors completed title and abstract and full text reviews and extracted data relevant to intervention and study design, program objectives, and study outcomes. Ten articles fit the study's inclusion criteria (nine total interventions)., Results: Of the 10 studies, six were cohort designs, three were cross-sectional (one with qualitative interviews), and one study conducted qualitative interviews only. Most studies were located in the Northeastern United States. MHU interventions primarily aimed to provide MOUD and to retain populations in treatment. Two interventions aimed to engage patients and then transfer them to fixed-site MOUD providers. Across four interventions that provided buprenorphine, 1- and 3-month retention rates varied from 31.6 % to 72.3 % and 26.2 % to 58.5 %, respectively. Qualitative interviews found that MOUD delivery from the MHU was characterized by less stigma/judgment and greater privacy compared to fixed-site, and it was flexible and low-barrier. MHUs were reportedly underutilized by the target populations, suggesting a lack of awareness from community members with opioid use disorder., Conclusions: MHUs that deliver MOUD are both under-provided and -utilized. Future research should continue to assess MOUD provision from MHUs with an emphasis on robust study design, application to other formulations of MOUD, and evaluation of outcomes such as participant satisfaction and key informant perceived challenges., Registration: Submitted to Open Science Framework (OSF) Repository on February 6, 2023., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The gut-brain axis mediates the interaction pathway between microbiota and opioid addiction. In recent years, many studies have shown that molecular hydrogen has therapeutic and preventive effects on various diseases. This study aimed to investigate whether molecular hydrogen could serve as pharmacological intervention agent to reduce risks of reinstatement of opioid seeking and explore the mechanism of gut microbiota base on animal experiments and human studies. Morphine-induced conditioned place preference (CPP) was constructed to establish acquisition, extinction, and reinstatement stage, and the potential impact of H 2 on the behaviors related to morphine-induced drug extinction was determined using both free accessible and confined CPP extinction paradigms. The effects of morphine on microbial diversity and composition of microbiota, as well as the subsequent changes after H 2 intervention, were assessed using 16 S rRNA gene sequencing. Short-Chain Fatty Acids (SCFAs) in mice serum were detected by gas chromatography-mass spectrometry (GC-MS). Meanwhile, we also conducted molecular hydrogen intervention and gut microbiota testing in opioid-addicted individuals. Our results revealed that molecular hydrogen could enhance the extinction of morphine-related behavior, reducing morphine reinstatement. Gut microbes may be a potential mechanism behind the therapeutic effects of molecular hydrogen on morphine addiction. Additionally, molecular hydrogen improved symptoms of depression and anxiety, as well as gut microbial features, in individuals with opioid addiction. This study supports molecular hydrogen as a novel and effective intervention for morphine-induced addiction and reveals the mechanism of gut microbiota., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All the authors approved the final version of the manuscript., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Compared with the Finnegan Neonatal Abstinence Scoring System (FNASS), the Eat, Sleep, Console (ESC) approach reduces pharmacotherapy and length of stay (LOS) for neonatal opioid withdrawal syndrome (NOWS) infants. The independent outcome contribution of ESC is unknown as the approach combines ESC assessment with additional management changes. Our objective was to evaluate ESC assessment's independent impact on outcomes compared with FNASS. We conducted a retrospective cohort study of in utero opioid-exposed infants ≥35 weeks gestation managed with FNASS versus ESC. Outcomes included pharmacotherapy initiation, LOS, length of pharmacotherapy, and emergency department visit/readmissions. Among 151 FNASS and 100 ESC managed infants, pharmacotherapy initiation ( P = .47), LOS for all infants ( P = .49), and LOS for pharmacologically treated infants ( P = .68) were similar. Length of pharmacotherapy did not differ ( P = .84). Emergency department evaluation/NOWS readmission was equally rare ( P = .65). Using equivalent models of care, comparison of ESC and FNASS assessment tools showed no difference in NOWS outcomes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Opioid and alcohol use disorders are increasingly being addressed in primary care, yet how medications to treat these disorders are prescribed in rural regions is unknown., Methods: We determined prevalence, types, and duration of medication prescription for opioid and/or alcohol use disorder among adult patients in rural primary clinics. The sample included 1874 adult patients who visited one of six rural primary care sites in the Northeastern and Northwestern United States at least once from October 2019 to January 2021 and had a diagnosis code for opioid use disorder (OUD), alcohol use disorder (AUD), or co-occurring opioid and alcohol use disorder (OUD + AUD) during that time., Results: Patients with OUD + AUD were more likely to be prescribed medication for at least one of these disorders (85.3 %) than patients with OUD only (63.7 %) or AUD only (10.3 %). Further, the OUD + AUD group had the highest number of days on medication (M = 264.7), followed by OUD only (M = 220.5), then the AUD only group (M = 62.5). Only 8.8 % of patients with OUD + AUD were prescribed naltrexone or medication for OUD + AUD to treat both substance use disorders., Conclusions: Medications for treating AUD as well as OUD are available, but few patients with OUD + AUD and even fewer with AUD received pharmacological treatment for AUD. The current work highlights the need for rural clinicians to consider medications for AUD as an important treatment method for patients with AUD only or OUD + AUD., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Opioid use disorder (OUD) is a serious health problem that may lead to physical dependence, in addition to affective disorders. Preclinical models are essential for studying the neurobiology of and developing pharmacotherapies to treat these problems. Historically, chronic morphine injections have most often been used to produce opioid-dependent animals, and withdrawal signs indicative of dependence were precipitated by administering an opioid antagonist. In the present studies, we have developed and validated a model of dependence on oxycodone (a widely prescribed opioid) during spontaneous withdrawal in male and female C57BL/6J mice. Dependence was induced by chronically administering oxycodone through osmotic minipumps at different doses for 7 days. Somatic withdrawal signs were measured after 3, 6, 24, and 48 h following minipump removal. Additionally, sensitivity to mechanical, thermal, and cold stimuli, along with anxiety-like behavior, were also measured. Our results indicated that spontaneous withdrawal following discontinuation of oxycodone produced an increase in total withdrawal signs after 60 and 120 mg/kg/day regimens of oxycodone administration. These signs were reversed by the administration of clinically approved medications for OUD. In general, both female and male mice showed similar profiles of somatic signs of spontaneous withdrawal. Spontaneous withdrawal also resulted in mechanical and cold hypersensitivity lasting for 24 and 14 days, respectively, and produced anxiety-like behaviors after 2 and 3 weeks following oxycodone removal. These results help validate a new model of oxycodone dependence, including the temporally distinct emergence of somatic, hyperalgesic, and anxiety-like behaviors, potentially useful for mechanistic and translational studies of opioid dependence., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Medications for opioid use disorder (MOUD) including buprenorphine are effective, but underutilized. Rural patients experience pronounced disparities in access. To reach rural patients, the US Department of Veterans Affairs (VA) has sought to expand buprenorphine prescribing beyond specialty settings and into primary care., Objective: Although challenges remain, some rural VA health care systems have begun offering opioid use disorder (OUD) treatment with buprenorphine in primary care. We conducted interviews with clinicians, leaders, and staff within these systems to understand how this outcome had been achieved., Design: Using administrative data from the VA Corporate Data Warehouse (CDW), we identified rural VA health care systems that had improved their rate of primary care-based buprenorphine prescribing over the period 2015-2020. We conducted qualitative interviews (n = 30) with staff involved in implementing or prescribing buprenorphine in these systems to understand the processes that had facilitated implementation., Participants: Clinicians, staff, and leaders embedded within rural VA health care systems located in the Northwest, West, Midwest (2), South, and Northeast., Approach: Qualitative interviews were analyzed using a mixed inductive/deductive approach., Key Results: Interviews revealed the processes through which buprenorphine was integrated into primary care, as well as processes insufficient to enact change. Implementation was often initially catalyzed through a targeted hire. Champions then engaged clinicians and leaders one-on-one to "pitch" the case, describe concordance between buprenorphine prescribing and existing goals, and delineate the supportive role that they could provide. Sites were prepared for implementation by developing new clinical teams and redesigning clinical processes. Each of these processes was made possible with the active, instrumental support of leadership., Conclusions: Results suggest that rural systems seeking to improve buprenorphine accessibility in primary care may need to alter primary care structures to accommodate buprenorphine prescribing, whether through new hires, team development, or clinical redesign., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Competing Interests: The author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research ® editors and board members are on file with the publication and can be viewed on request.

Background and Aims: Ukraine's Ministry of Health released urgent COVID-19 guidelines, allowing for early implementation of take-home dosing (THD) for opioid agonist therapies (OAT) such as methadone. Enrollment in OAT and retention in the program are the most effective HIV prevention strategies for people who inject drugs (PWID). This study aimed to evaluate the impact of Ukraine's COVID-19 emergency guidance on OAT treatment enrollment, retention on treatment and mortality., Design and Setting: Using Ukraine's national OAT registry for 252 governmental clinics across 25 regions, we conducted a 12-month comparative prospective cohort survival analysis. This study compared newly enrolled methadone patients within the initial 6 months following the COVID-19 guidance (COVID) with patients from the preceding year (pre-COVID) in a country with high adult HIV prevalence (1.2%) that is concentrated in PWID., Participants: In the nation-wide sample of newly enrolled PWID in Ukraine, comprising 2798 individuals, 1423 were in the COVID cohort and 1375 were in the pre-COVID cohort. The majority were male (86.7%), with an average age of 39.3 years., Measurements: Primary outcomes were average monthly enrollment per cohort, treatment retention and mortality, with internal time-dependent predictors, including THD and optimal (> 85 mg) methadone dosing., Results: Relative to the pre-COVID period, the monthly average patient enrollment was statistically significantly higher during the COVID period (283.7 versus 236.0; P < 0.0001), where patients were more likely to transition to THD and achieve optimal dosing earlier. Significant differences were observed in the proportions of person-months on THD (41 versus 13%, P < 0.0001) and optimal dosing (38 versus 31%, P < 0.0001) between the COVID and pre-COVID cohorts. Predictors of treatment retention, expressed as adjusted hazard ratios (aHR), included early THD [aHR = 1.90, 95% confidence interval (CI) = 1.47-2.45], early optimal dosing (aHR = 1.71, 95% CI = 1.37-2.13) and prior methadone treatment (aHR = 1.39, 95% CI = 1.15-1.68). These factors persisted, respectively, in the pre-COVID (aHR = 2.28, 95% CI = 1.41-3.70; aHR = 1.84, 95% CI = 1.32-2.56; and aHR = 1.36, 95% CI = 1.06-1.74) and COVID (aHR = 1.91, 95% CI = 1.40-2.59; aHR = 1.61, 95% CI = 1.20-2.16; and aHR = 1.49, 95% CI = 1.08-1.94) cohorts. Survival did not differ significantly between the two prospective cohorts., Conclusion: Ukraine's prompt adoption of early take-home dosing for opioid agonist therapies, such as methadone, following the emergency COVID-19 guidance appears to have increased enrollment into methadone and improved treatment retention for people who inject drugs without adverse effects on patient survival., (© 2024 Society for the Study of Addiction.)

Since April 2019, CA Bridge has worked with emergency departments (EDs) in diverse geographic and emergency care settings across California to scale up low-threshold buprenorphine access, patient navigation programs, harm reduction services, and take-home naloxone. Between April 2019 and June 2023, 268 (81.0%) of 331 acute care hospitals in California received funding and technical assistance from CA Bridge and completed data reporting. These hospitals provided navigation services during 279 025 patient encounters and gave patients buprenorphine in 89 549 ED visits. ( Am J Public Health . 2024;114(9):874-878. https://doi.org/10.2105/AJPH.2024.307710).

Background: Prescribing of gabapentinoids and Z-drug-hypnotics has increased in the population and among people receiving opioid-agonist treatment (OAT) for opioid dependence. Evidence is mixed on whether co-prescribing of sedatives such as gabapentinoids and Z-drugs during OAT increases risk of drug-related death (DRD)., Methods: We conducted a retrospective cohort study of individuals prescribed OAT between 2011 and 2020 in Scotland. Prescribing records were linked to mortality data and other healthcare datasets (sociodemographic, comorbidity). We identified episodes of treatment with gabapentinoids/Z-drugs and used multivariable quasi-Poisson regression to model associations between co-prescription and DRD risk., Results: Among 46,602 individuals with 304,783 person-years of follow-up, we found that co-prescription was common, with 25 % and 34 % ever being co-prescribed gabapentinoids and Z-drugs, respectively. Gabapentinoid exposure was strongly associated (adjusted hazard ratio (aHR)=2·18, 95 % CI=1·92, 2·46) and Z-drug exposure moderately associated (aHR=1·39, 95 % CI=1·15, 1·66) with elevated risk of DRD. Gabapentinoid exposure was associated with DRD risk on and off OAT; Z-drug exposure was less strongly associated with DRD risk when on OAT., Conclusions: Co-prescription of gabapentinoids and Z-drugs is common among OAT patients. However, co-prescription is associated with increased risk of DRD. Alternatives to prescribing sedative medications to OAT patients and/or greater monitoring - if prescribed - are needed., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: There is uncertainty about whether criminal legal involvement (CLI) impacts the effectiveness of medications for opioid use disorder (MOUD). We aimed to determine whether CLI modifies the association between buprenorphine-naloxone (BUP-NX) vs. extended-release naltrexone (XR-NTX) and MOUD treatment outcomes., Methods: We conducted a secondary analysis of X:BOT, a 24-week multi-center randomized controlled trial comparing treatment outcomes between BUP-NX (n = 287) and XR-NTX (n = 283) in the general population. We used baseline Additional Severity-Index Lite responses to identify patients with recent CLI (n = 342), defined as active CLI and/or CLI in the past 30 days, and lifetime incarceration (n = 328). We explored recent CLI and lifetime incarceration as potential effect modifiers of BUP-NX vs. XR-NTX effectiveness on relapse, induction, and overdose. We conducted both intention-to-treat and per-protocol analyses for each outcome., Results: In intention-to-treat analyses, recent CLI modified the effect of BUP-NX vs. XR-NTX on odds of successful induction (p = 0.03) and hazard of overdose (p = 0.04), but it did not modify the effect on hazard of relapse (p = 0.23). All participants experienced lower odds of successful induction with XR-NTX compared to BUP-NX, but the relative likelihood of successful induction with BUP-NX was lower than XR-NTX among individuals with recent CLI (OR: 0.25, 95 % CI: 0.13-0.47, p < 0.001) compared to those without recent CLI (OR: 0.04, 95 % CI: 0.01-0.19, p < 0.001). Participants with recent CLI experienced similar hazard of overdose with XR-NTX and BUP-NX (HR: 1.12, 95 % CI: 0.42-3.01, p = 0.82), whereas those without recent CLI experienced greater hazard of overdose with XR-NTX compared to BUP-NX (HR: 12.60, 95 % CI: 1.62-98.03, p = 0.02). In per-protocol analyses, recent CLI did not modify the effect of MOUD on hazard of overdose (p = 0.10) or relapse (p = 0.41). Lifetime incarceration did not modify any outcome., Conclusions: Compared to individuals without recent CLI, individuals with recent CLI experienced decreased relative effectiveness of BUP-NX compared to XR-NTX for induction and overdose outcomes. This highlights the importance of considering the impact of recent CLI on opioid use disorder treatment outcomes. Future research should explore the mechanisms through which recent CLI modifies MOUD effectiveness and aim to improve MOUD effectiveness for individuals with recent CLI., Competing Interests: Declaration of competing interest The authors have no declared conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The number of persons using opioids has increased worldwide in the last decade, particularly the use of opioid analgesics in North America and Africa. In Germany, the prevalence of heroin addiction has remained relatively stable., Method: Narrative review of the literature., Results: Opioid-assisted maintenance treatment (OMT) with the established substances methadone, levomethadone, slow-release morphine and buprenorphine is recommended as the first-line treatment for heroin dependence. The OMT reduces the use of heroin, mortality and individual suffering and improves the quality of life and physical health. A diamorphine and heroine-assisted treatment is an option for people who do not benefit from conventional OMT. An alternative to the use of diamorphine could be treatment with hydromorphone hydrochloride. The regulations on carrying out maintenance treatment in the Controlled Substances Prescription Act and the guidelines of the Federal Medical Association in Germany have been loosened based on the experiences of the COVID-19 pandemic, for example with respect to take-home prescriptions. There is an ongoing intensive discussion on how to deal with the decreasing number of outpatient clinics offering OMT., Conclusion: The first-line treatment for opioid addiction is opioid-assisted substitution treatment, including diamorphine and heroin-assisted treatment. Long-acting depot medications and implants still play a subordinate role., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Introduction: Attentional bias (AB) is believed to be an important factor in the development and maintenance of both opioid use disorder (OUD) and chronic pain. Cannabis and its main psychoactive constituent, delta-9-tetrahydrocannabinol (THC), produce analgesic effects via processes that are potentially relevant to AB and is commonly used by persons with OUD. This exploratory study investigated if THC influences AB towards pain and opioid cues individuals with OUD., Methods: Using a within-subject, crossover design, 27 adults receiving methadone were randomly assigned to receive single doses of oral THC (10 mg, 20 mg administered as dronabinol) or placebo across three, 5-h sessions. During each session, a visual probe task was used to measure AB to pain and opioid cues at baseline and 120 min post-THC administration., Results: Mixed-effects models examined main effects of THC dose, time, and their interaction across all participants; findings were then stratified by methadone dose (low dose <90 mg/day and high dose ≥90 mg/day). Among individuals receiving high doses of methadone, a significant interaction was observed such that AB towards opioids increased following 10 mg THC administration and decreased following 20 mg THC administration. Additionally, participants receiving low doses of methadone showed significant increases in the variability of opioid-related AB post THC administration., Conclusion: We provide preliminary evidence showing that THC may cause dose-dependent effects on selective attention for opioid cues among methadone patients. These results underscore the need for further clinical investigation into the effects of cannabinoids and other substances with potential analgesic and addictive properties among persons with OUD., Competing Interests: Declaration of competing interest None. Funding Statement This work was supported by the Robert E. Leet and Clara Guthrie Patterson Mentored Clinical Research Award and by the VISN-1 Mental Illness Research, Education, and Clinical Center (MIRECC) Pilot Award Program. Joao P. De Aquino is supported by Grants K23DA052682 and R21DA057240 from the National Institute on Drug Abuse (NIDA). R. Ross MacLean is supported by a Development Career Development Award 1IK2CX002286 from VA Clinical Science Research and Development (CSR&D). Other than providing funding, the Patterson Trust, the VA and NIDA had no role in the conception and conduction of this project or in the interpretation or reporting of its findings., (Published by Elsevier Ltd.)

The treatment landscape for opioid use disorder (OUD) faces challenges stemming from the limited efficacy of existing medications, poor adherence to prescribed regimens, and a heightened risk of fatal overdose post-treatment cessation. Therefore, there is a pressing need for innovative therapeutic strategies that enhance the effectiveness of interventions and the overall well-being of individuals with OUD. This study explored the therapeutic potential of nor-Levo-α-acetylmethadol (nor-LAAM) to treat OUD. We developed sustained release nor-LAAM-loaded poly (lactic-co-glycolic acid) (PLGA) microparticles (MP) using a hydrophobic ion pairing (HIP) approach. The nor-LAAM-MP prepared using HIP with pamoic acid had high drug loading and exhibited minimal initial burst release and sustained release. The nor-LAAM-MP was further optimized for desirable particle size, drug loading, and release kinetics. The lead nor-LAAM-MP (F4) had a relatively high drug loading (11 wt%) and an average diameter (19 μm) and maintained a sustained drug release for 4 weeks. A single subcutaneous injection of nor-LAAM-MP (F4) provided detectable nor-LAAM levels in rabbit plasma for at least 15 days. We further evaluated the therapeutic efficacy of nor-LAAM-MP (F4) in a well-established fentanyl-addiction rat model, and revealed a marked reduction in fentanyl choice and withdrawal symptoms in fentanyl-dependent rats. These findings provide insights into further developing long-acting nor-LAAM-MP for treating OUD. It has the potential to offer a new effective medication to the existing sparse armamentarium of products available to treat OUD., Competing Interests: Declaration of competing interest The nor-LAAM-MP technology described in this publication has been filed as a patent application through Virginia Commonwealth University (VCU). Qingguo Xu, Matthew Banks, Diane Ingabire, Chaolong Qin, Tuo Meng, and Aji Alex Moothedathu Raynold are the co-inventors who are subject to certain rules and restrictions under VCU policy. The terms of this arrangement are being managed by VCU in accordance with its conflict-of-interest policies., (Copyright © 2023. Published by Elsevier B.V.)

Purpose of Review: We apply the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria for substance use disorders (SUDs) to the herbal product kratom. Similarities and differences between kratom use disorder (KUD) and other SUDs are explored, along with assessment, diagnostic, and therapeutic recommendations for KUD., Recent Findings: Literature reports of "kratom addiction" or KUD rarely specify the criteria by which patients were diagnosed. Individuals meeting DSM-5 KUD criteria typically do so via tolerance and withdrawal, using more than intended, and craving, not functional or ​psychosocial disruption, which occur rarely. Most clinicians who use medication to treat patients with isolated KUD select buprenorphine formulations, although there are no controlled studies showing that buprenorphine is safe or efficacious in this patient population. Diagnosis and treatment decisions for KUD should be systematic. We propose an algorithm that takes into consideration whether KUD occurs with comorbid opioid use disorder., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Little is known about how use patterns of medications for opioid use disorder (MOUDs) evolve from pre-incarceration to post-incarceration among incarcerated individuals with opioid use disorder. This article describes pre- and post-incarceration MOUD receipt during a period when naltrexone was the only type of MOUD offered in a state prison system, the Massachusetts Department of Correction (MADOC)., Methods: A retrospective cohort study of individuals with opioid use disorder who had an incarceration episode in MADOC during January 2015 to March 2019. The data source was the Massachusetts Public Health Data Warehouse, a multi-sector data platform that links individual-level data from multiple statewide datasets. We described patterns of MOUD receipt during the four weeks prior to and after an incarceration episode. Multivariable logistic regression models characterized predictors of post-incarceration MOUD receipt., Results: In the male sample (n=691 incarcerations), from the pre- to post-incarceration periods, receipt of buprenorphine increased (14.3 % to 18.3 %), naltrexone increased (5.0 % to 10.5 %), and methadone decreased (4.7 % to 1.7 %). Similarly, in the female sample (n=892 incarcerations), from the pre- to post-incarceration periods, receipt of buprenorphine increased (10.3 % to 12.3 %, naltrexone increased (4.5 % to 9.3 %), and methadone decreased (5.0 % to 2.9 %). Much of the post-release naltrexone receipt occurred among participants in MADOC's pre-release naltrexone program., Conclusions: MOUD receipt was low but increased slightly in the post-incarceration period. This change was driven by increases in buprenorphine and naltrexone and despite decreases in methadone., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Benjamin Bovell-Ammon reports financial support was provided by National Institute on Drug Abuse. Benjamin Bovell-Ammon reports financial support was provided by National Institute of Allergy and Infectious Diseases. Peter Friedmann reports financial support was provided by National Institute on Drug Abuse. Elizabeth Evans reports financial support was provided by National Institute on Drug Abuse. Alexander Walley reports a relationship with Massachusetts Department of Public Health that includes: employment. 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 Elsevier B.V. All rights reserved.)

Background: Comorbid major depressive disorder (MDD) and opium use disorder (OUD) are known to increase the risk of suicide. The purpose of this study was to compare the efficacy and safety of adjunctive therapy with either ketamine or buprenorphine in patients with comorbid MDD and OUD., Methods: This was a randomized double-blind controlled trial in adults admitted to a hospital in Iran. Sixty-six participants were enrolled and received either ketamine or buprenorphine, along with current antidepressant therapy. The primary outcome was change in depressive symptoms assessed using the Beck Depression Inventory (BDI) after 2 hours, 24 hours, and 7 days following initiation of treatment. Secondary outcomes included changes in suicidal ideation, evaluated by the Beck Scale for Suicidal Ideation (BSSI)., Results: Both groups experienced a significant decrease in the severity of depression following the interventions ( p < .05). However, there was no significant difference in the between-group comparison ( p > .05). Both groups also exhibited a significant reduction in suicidal ideation compared to before the study, with the decrease in severity being over 85% in both groups ( p < .05)., Conclusion: Both ketamine and buprenorphine appear to be equally effective in reducing symptoms of depression and suicidal ideation among individuals with MDD and OUD., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Many people with opioid use disorder who stand to benefit from buprenorphine treatment are unwilling to initiate it due to experience with or fear of both spontaneous and buprenorphine-precipitated opioid withdrawal (BPOW). An effective means of minimizing withdrawal symptoms would reduce patient apprehensiveness, lowering the barrier to buprenorphine initiation. Ketamine, approved by the FDA as a dissociative anesthetic, completely resolved BPOW in case reports when infused at a sub-anesthetic dose range in which dissociative symptoms are common. However, most patients attempt buprenorphine initiation in the outpatient setting where altered mental status is undesirable. We explored the potential of short-term use of ketamine, self-administered sublingually at a lower, sub-dissociative dose to assist ambulatory patients undergoing transition to buprenorphine from fentanyl and methadone., Methods: Patients prescribed ketamine were either (1) seeking transition to buprenorphine from illicit fentanyl and highly apprehensive of BPOW or (2) undergoing transition to buprenorphine from illicit fentanyl or methadone and experiencing BPOW. We prescribed 4-8 doses of sublingual ketamine 16 mg (each dose bioequivalent to 3-6% of an anesthetic dose), monitored patients daily or near-daily, and adjusted buprenorphine and ketamine dosing based on patient response and prescriber experience., Results: Over a period of 14 months, 37 patients were prescribed ketamine. Buprenorphine initiation was completed by 16 patients, representing 43% of the 37 patients prescribed ketamine, and 67% of the 24 who reported trying it. Of the last 12 patients who completed buprenorphine initiation, 11 (92%) achieved 30-day retention in treatment. Most of the patients who tried ketamine reported reduction or elimination of spontaneous opioid withdrawal symptoms. Some patients reported avoidance of severe BPOW when used prophylactically or as treatment of established BPOW. We developed a ketamine protocol that allowed four of the last patients to complete buprenorphine initiation over four days reporting only mild withdrawal symptoms. Two patients described cognitive changes from ketamine at a dose that exceeded the effective dose range for the other patients., Conclusions: Ketamine at a sub-dissociative dose allowed completion of buprenorphine initiation in the outpatient setting in the majority of patients who reported trying it. Further research is warranted to confirm these results and develop reliable protocols for a range of treatment settings., (© 2024. The Author(s).)

Opioids have been utilized for both medical and recreational purposes since their discovery. Primarily recognized for their analgesic properties, they are also associated with the development of tolerance and dependence, contributing to a significant public health concern worldwide. Sex differences in opioid use disorder reveal that while men historically exhibit higher rates of abuse, women may develop dependence more quickly and are more susceptible to the addictive nature of opioids. This narrative review explores sex differences in opioid response in both clinical and experimental models, focusing on opioid receptor mechanisms, pain modulation, and hormonal influences. Additionally, it discusses the complexities of opioid addiction and withdrawal, highlighting sex-specific responses and the role of opioid replacement therapies. Diverse experimental outcomes, together with observational data, underscore the need for further research into sex-specific opioid biological mechanisms in a wider context, including demographic, cultural, and health-related factors. A comprehensive understanding of these complexities holds the potential to enhance personalized opioid therapies.

Background: In the United States, there has been a concerning rise in the prevalence of opioid use disorders (OUD) among transition-age (TA) adults, 18 to 25-years old, with a disproportionate impact on individuals and families covered by Medicaid. Of equal concern, the treatment system continues to underperform for many young people, emphasizing the need to address the treatment challenges faced by this vulnerable population at a pivotal juncture in their life course. Pharmacotherapy is the most effective treatment for OUD, yet notably, observational studies reveal gaps in the receipt of and retention in medications for opioid use disorder (MOUD), resulting in poor outcomes for many TA adults in treatment. Few current studies on OUD treatment quality explicitly consider the influence of individual, organizational, and contextual factors, especially for young people whose social roles and institutional ties remain in flux., Methods: We introduce a retrospective, longitudinal cohort design to study treatment quality practices and outcomes among approximately 65,000 TA adults entering treatment for OUD between 2012 and 2025 in New York. We propose to combine data from multiple sources, including Medicaid claims and encounter data and a state registry of substance use disorder (SUD) treatment episodes, to examine three aspects of OUD treatment quality: 1) MOUD use, including MOUD option (e.g., buprenorphine, methadone, or extended-release [XR] naltrexone); 2) adherence to pharmacotherapy and retention in treatment; and 3) adverse events (e.g., overdoses). Using rigorous analytical methods, we will provide insights into how variation in treatment practices and outcomes are structured more broadly by multilevel processes related to communities, treatment programs, and characteristics of the patient, as well as their complex interplay., Discussion: Our findings will inform clinical decision making by patients and providers as well as public health responses to the rising number of young adults seeking treatment for OUD amidst the opioid and polysubstance overdose crisis in the U.S., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Aleksanyan 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: Federal deregulation of opioid agonist therapies are an attractive policy option to improve access to opioid use disorder care and achieve widespread beneficial impacts on growing opioid-related harms. There have been few evaluations of such policy interventions and understanding effects can help policy planning across jurisdictions., Methods: Using health administrative data from eight of ten Canadian provinces, this study evaluated the impacts of Health Canada's decision in May 2018 to rescind the requirement for Canadian health professionals to obtain an exemption from the Canadian Drugs and Substance Act to prescribe methadone for opioid use disorder. Over the study period of June 2017 to May 2019, we used descriptive statistics to capture overall trends in the number of agonist therapy prescribers across provinces and we used interrupted time series analysis to determine the effect of this decision on the trajectories of the agonist therapy prescribing workforces., Results: There were important baseline differences in the numbers of agonist therapy prescribers. The province with the highest concentration of prescribers had 7.5 more prescribers per 100,000 residents compared to the province with the lowest. All provinces showed encouraging growth in the number of prescribers through the study period, though the fastest growing province grew 4.5 times more than the slowest. Interrupted time series analyses demonstrated a range of effects of the federal policy intervention on the provinces, from clearly positive changes to possibly negative effects., Conclusions: Federal drug regulation policy change interacted in complex ways with provincial health professional regulation and healthcare delivery, kaleidoscoping the effects of federal policy intervention. For Canada and other health systems such as the US, federal policy must account for significant subnational variation in OUD epidemiology and drug regulation to maximize intended beneficial effects and mitigate the risks of negative effects., (© 2024. The Author(s).)

Introduction: Supervised injectable opioid treatment (SIOT) is an evidence-based intervention targeting opioid-dependent people for whom existing treatments have been ineffective. This project will primarily assess the feasibility and the acceptability of time-limited SIOT using injectable hydromorphone delivered in an existing Australian public opioid treatment programme, with secondary outcomes of safety, cost, changes in drug use and other health outcomes. If feasible, the goal is to scale up the intervention to be more widely available in Australia., Methods and Analysis: Between 20 and 30 participants will be offered two times per day hydromorphone to inject under direct observation, in addition to their current opioid agonist treatment (OAT), for up to 2 years. At the end of 2 years of supervised hydromorphone treatment, participants will be continued on standard OAT only. Informed consent will be obtained from all participants included in the study. This is a single-site, uncontrolled, open-label study where quantitative and qualitative interview data will be collected at baseline, 12 months and lastly at 3 months following their final hydromorphone dose. The main outcome measures are feasibility, as assessed by recruitment, retention and participation in treatment, and acceptability to participants, clinic staff and other stakeholders assessed by qualitative interviews. Secondary outcome measures of safety, as assessed by adverse events, and cost will also be assessed, as well as a range of other drug and health outcomes., Ethics and Dissemination: This study received ethical approval from the St Vincent's Hospital Human Research Ethics Committee (2019/ETH00418). This will be the first study of time-limited SIOT in the Australian setting. All results will be submitted to peer-reviewed journals, scientific conferences and local practice meetings. A preliminary report on outcomes will also be presented to local health policy makers. A consumer and community forum will also be held to feedback results to a broader audience., Trial Registration Number: ACTRN12621001729819., Competing Interests: Competing interests: JS, through his university, has worked with several pharmaceutical companies to identify new or improved treatments and his employer (King’s College London) has received grants, travel costs and/or consultancy payments. None of these is related to the FOpIT study described in this paper. NL has received funding for independent research from Indivior and Camurus for work unrelated to this project. KJS and NE have received funding from the Australian Department of Health and Aged Care, and is employed by the University of New South Wales and St Vincent’s Hospital, Sydney. WvdB has worked with several pharmaceutical companies to identify new or improved treatments and received speaker fees, travel costs and/or consultancy payments. None of these is related to the FOpIT study described in this paper., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Despite the proliferation of pharmacy standing-order naloxone dispensing across many US states before the change to over-the-counter status, few policy analyses have evaluated the implementation of pharmacy naloxone standing orders in addressing opioid overdose fatality among communities., Objective: To determine whether the implementation of pharmacy standing-order naloxone was associated with lower opioid fatality rates compared with communities without pharmacies with standing-order naloxone., Design, Setting, and Participants: This retrospective multisite study was conducted with an interrupted time series analysis across 351 municipalities in Massachusetts over 24 quarters (from January 1, 2013, through December 31, 2018). Standing-order naloxone dispensing data were collected from 2 sources for all major chain pharmacies and many independent pharmacies, covering 70% of retail pharmacies in Massachusetts. Municipalities had various standing-order naloxone implementation inceptions during the study period. Data were analyzed from December 2021 to November 2023., Exposure: The main exposure was measured by the first quarter with standing-order naloxone dispensation as the actual implementation inception., Main Outcomes and Measures: The primary study outcome was municipal opioid fatality rate per 100 000 population obtained from the Massachusetts Registry of Vital Records and Statistics., Results: The median (IQR) population size across 351 municipalities was 10 314 (3635 to 21 781) people, with mean (SD) proportion of female individuals was 51.1% (2.8 percentage points). Pharmacies from 214 municipalities (60.9%) reported dispensing standing-order naloxone over the study period. At the baseline of the first quarter of 2013, municipalities that eventually had standing-order naloxone had greater quarterly opioid fatality rates compared with those that never implemented standing-order naloxone (3.51 vs 1.03 deaths per 100 000 population; P < .001). After adjusting for municipal-level sociodemographic and opioid prevention factors, there was significant slope decrease of opioid fatality rates (annualized rate ratio, 0.84; 95% CI, 0.78-0.91; P < .001) following standing-order naloxone dispensing, compared with the municipalities that did not implement standing-order naloxone. There were no significant level changes of opioid fatality rates in the adjusted models. Sensitivity analyses yielded similar and significant findings., Conclusions and Relevance: These findings suggest that community pharmacy dispensing of naloxone with standing orders was associated with a relative, gradual, and significant decrease in opioid fatality rates compared with communities that did not implement the standing-order naloxone program. These findings support the expansion of naloxone access, including over-the-counter naloxone as part of a multifaceted approach to address opioid overdose.

Background and Aim: In British Columbia, Canada, clinical guidelines for the treatment of opioid use disorders (OUD) were updated in 2017, during a period in which the potency and composition of the illicit drug supply changed rapidly. We aimed to describe changes in opioid agonist treatment (OAT) prescribing practices at the population level in a setting in which fentanyl and its analogs have become the primary illicit opioid of use., Design, Setting and Participants: This was a population-based retrospective cohort study using three linked health administrative databases in British Columbia (BC), Canada. All individuals with at least one OAT dispensation in BC between 1 January 2014 and 31 August 2021 took part., Measurements: To assess changes in OAT prescribing practices over time, we calculated initiation doses, dose titration intervals, maintenance doses and take-home dosing intervals stratified by medication [methadone, buprenorphine-naloxone and slow-release oral morphine (SROM)] according to recommended guidelines., Findings: A total of 265 410 OAT episodes (57.5% on methadone, 34.5% on buprenorphine-naloxone and 8.0% on SROM) were initiated during the study period. Compared with the guideline recommendation, observed initiation doses were higher among all medications from 2014 (2017 for SROM) to 2021 (buprenorphine-naloxone: 14-29%; methadone: 53-66%; SROM: 26-55%). Titration intervals were shorter for all medications, consistent with guidelines for buprenorphine-naloxone (26-49%), but shorter than recommended for methadone or SROM (28-51% and 12-41%, respectively). Higher maintenance dosing was observed for methadone (68-78%) and SROM (3-21%). Take-home allowances extending beyond the recommended guideline length increased across medications (buprenorphine-naloxone: 18-35%; methadone: 50-64%; SROM: 34-39%). Changes in prescribing patterns were similar for first-time OAT initiators., Conclusion: In British Columbia, Canada, from 2014 to 2021, prescribers of opioid agonist treatment (OAT) appeared to initiate both new and experienced OAT clients at higher doses than guideline recommendations, titrate them more rapidly and maintain clients at higher doses. Take-home dose allowances also gradually increased., (© 2024 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Objective: Dose optimization plays a key role in determining clinical outcomes in patients on opioid agonist treatment (OAT). The objective of this study was to identify the variables independently associated with buprenorphine/naloxone (B/N) dose adequacy in patients with opiate use disorder (OUD)., Method: Cross-sectional study of a convenience sample of patients with OUD treated with B/N (n = 315) in four regions in Spain. The Opiate Dosage Adequacy Scale (ODAS) was used to determine B/N dose adequacy. The ODAS evaluate the six components of the "dose adequacy" construct, as follows: continued use of heroin; narcotic blockade or crossed tolerance; objective opioid withdrawal symptoms (OWS); subjective OWS; craving for heroin; and overmedication. A binomial logistic regression analysis was performed to identify the variables associated with the condition "ODAS Adequate B/N dose". Participants completed a battery of instruments to assess sociodemographic, substance use, clinical, and treatment variables., Results: The B/N dose was considered adequate in 231 of the 315 participants (73.3 %). Two variables, satisfaction with B/N as a medication (OR=5.764, 95 % CI=2.211-15.030) and patient-perceived participation in B/N dose decisions (OR=1.790, 95 % CI=1221-2623), were independently, significantly, and positively associated with the "ODAS Adequate B/N dose" condition. While the severity of heroin dependence was significantly associated with buprenorphine dose adequacy in the bivariate analyses, significance was lost in the full regression model., Conclusion: Satisfaction with B/N as a medication and patient-perceived involvement in the dose decision are associated with clinician-assessed dose adequacy. In the context of good clinical practice, it is important to take into account both of these variables to individualize the prescribed dose through a shared decision-making process., Competing Interests: Declaration of competing interest Francisco Gonzalez-Saiz and José Pérez de los Cobos have received grant support for research and educational activities from Reckitt-Benckiser. All other authors declare no financial interests or potential conflicts of interest related directly or indirectly to this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Opioid overdose death is significantly increased immediately following incarceration. Evidence-based medications are underutilized in rural jails and detention centers. We have reported our efforts to address this gap through telemedicine-based medications for opioid use disorder treatment (tele-MOUD) for incarcerated patients. Staff acceptance and perceptions are critically important factors in the assurance of program validation. We assessed tele-MOUD acceptability and perceptions of effectiveness and stigma in one detention center. Overall, we found that jail staff's general acceptability of the program was rather low, as was perceived effectiveness of MOUD, while stigmatizing beliefs were present. Furthermore, tele-MOUD acceptability was positively correlated with perceptions of MOUD effectiveness and negatively correlated with stigmatizing notions of MOUD ( p ' s < 0.001). Findings suggest the need for educational interventions. Future research investigating the potential moderating effects of training on staff acceptability of jail-based tele-MOUD will support the implementation and sustainability of these life-saving programs.

Background: Patients with opioid use disorder (OUD) have increased emergency and hospital utilization. The PROUD trial showed that implementation of office-based addiction treatment (OBAT) increased OUD medication treatment compared to usual care, but did not decrease acute care utilization in patients with OUD documented pre-randomization (clinicaltrials.gov/study/NCT03407638). This paper reports secondary emergency and hospital utilization outcomes in patients with documented OUD in the PROUD trial., Methods: This cluster-randomized implementation trial was conducted in 12 clinics from 6 diverse health systems (March 2015-February 2020). Patients who visited trial clinics and had an OUD diagnosis within 3 years pre-randomization were included in primary analyses; secondary analyses added patients with OUD who were new to the clinic or with newly-documented OUD post-randomization. Outcomes included days of emergency care and hospital utilization over 2 years post-randomization. Explanatory outcomes included measures of OUD treatment. Patient-level analyses used mixed-effect regression with clinic-specific random intercepts., Results: Among 1988 patients with documented OUD seen pre-randomization (mean age 49, 53 % female), days of emergency care or hospitalization did not differ between intervention and usual care; OUD treatment also did not differ. In secondary analyses among 1347 patients with OUD post-randomization, there remained no difference in emergency or hospital utilization despite intervention patients receiving 32.2 (95 % CI 4.7, 59.7) more days of OUD treatment relative to usual care., Conclusions: Implementation of OBAT did not reduce emergency or hospital utilization among patients with OUD, even in the sample with OUD first documented post-randomization in whom the intervention increased treatment., Competing Interests: Declaration of Competing Interest All authors reviewed and approved the final article. Jennifer F. Bobb has no disclosures. Andrea Altschuler has no disclosures. Hongxiang Qiu has no disclosures. Abigail G. Matthews has no disclosures. Jennifer McCormack has no disclosures. Dr. Campbell has received support managed through her institution from the Industry PMR Consortium, a consortium of companies conducting post marketing studies required by the Food and Drug Administration that assess risks related to opioid analgesic use. Outside of this study, Paige Wartko received funding in the past year from a contract awarded to the Harvard Department of Population Medicine from GlaxoSmithKline to assess medication use in pregnancy and funding from a research contract awarded to Kaiser Permanente Washington Health Research Institute from Syneos Health to conduct Food and Drug Administration-mandated post-marketing research on the risks of opioid analgesic use. Dr. Saxon has received an honorarium from Indivior, Inc., travel support from Alkermes, Inc., and royalties from UpToDate. Onchee Yu received research grant funded by Bayer. Jeffrey Samet has no disclosures. Dr. Boudreau previously received funding from a research contract awarded to Kaiser Permanente Washington Health Research Institute (KPWHRI) from Syneos Health to conduct Food and Drug Administration-mandated post-marketing research on the risks of opioid analgesic use. Dr. Boudreau was an employee of KPWHRI at the time the study was conducted but is now an employee of Genentech, Inc. Amy K. Lee has no disclosures Dr. Glass reports that Pear Therapeutics Inc provided digital therapeutic prescriptions at no cost to Kaiser Permanente Washington during a quality improvement pilot study that he led. Kathrine A. Bradley has no disclosures., (Copyright © 2024 Elsevier B.V. All rights reserved.)