Search

High dose and long-acting opioid overdose reversal drugs can precipitate withdrawal in people who are opioid dependent. Products recently brought to market for community use in the United States (US) have drawn international concern because of their increased risk of withdrawal. At the March 18-19, 2024, Compassionate Overdose Response Summit & Naloxone Dosing Meeting, a panel of harm reduction experts issued the following call to action: 1) people who use drugs should be directly involved in decisions regarding the research, development, selection, and distribution of opioid overdose reversal products; 2) regulatory agencies and pharmaceutical manufacturers should carefully consider and communicate the risk and duration of withdrawal associated with higher dose and longer-acting opioid antagonists; 3) take-home naloxone kits should include at least two doses of an intramuscular (IM) product containing 0.4 mg or an intranasal (IN) product containing ≤4 mg; 4) At this time, high dose and long-acting opioid antagonists have no use in acute opioid overdose response; and, 5) overdose response educational materials, instructions on overdose response, and training should emphasize the restoration of breathing, avoiding withdrawal, and compassionate post-overdose support and care. High dose and long-acting opioid overdose reversal drugs were approved without testing for withdrawal and are often aggressively marketed despite decades of evidence from naloxone distribution programs worldwide that the ideal dose of naloxone is one that restores breathing without inducing withdrawal. Government agencies should direct resources to harm reduction programs to make standard dose take-home naloxone products widely available among people who use drugs. Lay bystanders, people who use drugs, their families, and professional first responders can learn and apply a compassionate approach to opioid overdose response., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: 1. Erin Russell discloses that Harm Reduction Therapeutics is a client of Health Management Associates. HRT is a nonprofit organization based in the United States that manufactures a 3 mg naloxone nasal spray product. 2. In the last three years, Joanne Neale has secured, through her university, research funding from Mundipharma Research Ltd (for research on naloxone) and Camurus AB (for research on long-acting injectable buprenorphine). She has also received honoraria from Indivior and Camurus AB for presentations and from Figure 8 Consultancy Ltd for research advice on a study of residential rehabilitation., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: In the United States, community overdose education and naloxone distribution (OEND) programs have demonstrated efficacy in reducing opioid-related mortality. OEND programs have expanded across San Diego County, California, but differential naloxone accessibility among people who use drugs (PWUD) has not been assessed. We examined factors that shape individual naloxone accessibility in San Diego., Methods: We employed a convergent parallel mixed methods design using surveys (n = 194) and qualitative interviews (n = 20). Ordinal logistic regression examined factors associated with individual naloxone accessibility (i.e., the frequency with which participants could access naloxone within five minutes, categorized as never, sometimes, or always). Qualitative interviews explored participant perceptions of naloxone accessibility and whether and how they maintained naloxone. We organized multilevel findings into a modified social-ecological model., Results: In quantitative and qualitative samples, participants were majority male (72 % and 70 % respectively), non-White race/ethnicity (55 % and 75 %), with an average age around 42 years. In the quantitative sample, 24 % never had personally accessible naloxone, 52 % sometimes did, and 24 % always did. Factors independently associated with individual naloxone accessibility were female gender (Adjusted Odds Ratio [AdjOR]: 2.51, 95 % Confidence Interval [CI]: 1.31-4.85), monthly income <$500 (AdjOR: 0.42, 95 %CI:0.19, 0.90), witnessing an overdose (AdjOR: 3.51, 95 %CI:1.67-7.55), and knowing where to get free naloxone (AdjOR: 3.44, 95 %CI: 1.79-6.75). Qualitative data suggested that naloxone was generally easy to acquire in San Diego due to community harm reduction outreach and mutual aid among peers, albeit community barriers including distance to harm reduction providers and frequent relocation/displacement for those experiencing homelessness. Individual attitudes toward overdose risk, naloxone, and community responsibility contributed to varied individual naloxone accessibility., Conclusions: This study highlights multilevel factors influencing individual naloxone accessibility among people who use drugs in San Diego, emphasizing the importance of harm reduction outreach and peer-to-peer support. We identified opportunities for interventions that address both individual attitudes and community-level barriers to improve naloxone accessibility., 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: Examining take-home naloxone (THN) uptake using a 'cascade of care' framework could help identify targets for increasing THN training and carriage among people who may witness or experience opioid overdose. We describe the THN cascade and factors associated with engagement among people who inject drugs., Methods: People aged ≥18 years in Australia who inject drugs were interviewed from 2020 to 2022, reporting lifetime THN awareness and acquisition and past-month carriage. We examined factors associated with engagement using multivariable logistic regression., Results: Of 2,149 participants (64 % men, mean age 44.5), 85 % had heard of naloxone, of whom 76 % were aware of THN programs. Of these, 72 % had ever participated in THN training/brief education, 92 % of whom had acquired THN. Of those who had ever acquired THN and reported past-month opioid use, 63 % always/often carried THN when using opioids. Past six-month opioid agonist treatment (OAT) (adjusted odds ratio [AOR] 2.55; 95 %CI 1.91-3.42) and ≥daily injecting (1.32; 1.01-1.73) were associated with awareness. OAT (1.79; 1.38-2.33), past-year opioid overdose (1.68; 1.18-2.42) and older age (1.02; 1.00-1.03) were associated with acquisition. Primarily injecting methamphetamine (versus heroin) in the past month was associated with lower awareness (0.43; 0.31-0.58) and acquisition (0.59; 0.44-0.78). Reporting no accommodation (squatting/sleeping rough) was associated with reduced odds of carriage (0.46; 0.24-0.88)., Conclusion: Participants reported high THN awareness and acquisition, with lower carriage. Future efforts should focus on improving THN access and reducing barriers to carriage, particularly for people experiencing homelessness or who primarily inject non-opioids., 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.)

Introduction: Rates of fatal overdose continue to rise in the United States, and most people with opioid use disorder (OUD) are not engaged in evidence-based treatment with medications. In Philadelphia, a city with one of the highest fatal overdose rates in the country, many residents face significant care access barriers. The COVID-19 pandemic - which destabilized the street drug supply and forced many clinics to limit services - worsened this crisis, but also led to regulatory changes that allowed for buprenorphine induction and maintenance visits via telehealth in the U.S. To increase access to buprenorphine across the Philadelphia area and reach individuals who struggle to access care, Penn Medicine developed the CareConnect Warmline in October 2021. CareConnect is embedded in an existing virtual urgent care practice. Staffed by advanced practice providers and substance use navigators (SUNs), CareConnect provides same-day buprenorphine bridge (i.e., short-term) prescriptions and linkage to longitudinal OUD care., Objective: To examine barriers and facilitators to implementing CareConnect from the perspective of key stakeholders, including CareConnect leadership, clinicians, and staff, and attitudes and beliefs about providing care for patients with OUD via this model., Methods: In this qualitative descriptive study, we interviewed 14 participants and used thematic analysis to analyze the data. The sample included CareConnect prescribing clinicians, SUNs, and administrative staff., Results: Our analysis yielded four themes: 1/ CareConnect is a unique program that fills an important care gap; 2/ Benefits of leveraging existing infrastructure; 3/ Importance of an interdisciplinary team; and 4/ Necessity of relationships with outside stakeholders. Prescribing clinicians and administrative staff - most of whom had little experience with OUD care before CareConnect - stressed how embedding the model within an existing virtual clinic and involving experienced SUNs increased their comfort prescribing buprenorphine. However, all participants highlighted how the program's effectiveness is contingent upon buy-in from outside stakeholders, including pharmacists who fill the prescriptions and longitudinal care providers in the community., Conclusions: Innovative delivery models can help expand OUD care access to individuals who are poorly served by traditional treatment infrastructure. Our findings provide valuable insight to improve and sustain CareConnect and can guide the development and implementation of future programs nationally., Competing Interests: Declaration of competing interest We have no competing interests to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Emergency medical services (EMS) systems are piloting interventions to respond to overdoses with additional services such as leave-behind naloxone and medication for opioid use disorder, but little is known about the perspectives of people who use drugs (PWUD) on these interventions being delivered by EMS during an overdose response., Methods: The Consolidated Framework for Implementation Research guided the development of data collection tools, the analytic strategy and the organisation of results. A community engaged method was used which included both academically trained researchers and community trained researchers who are also PWUD. This study used semi-structured interviews to gather data from 13 PWUD in King County, Washington in June 2022. Data were analysed using thematic analysis., Results: The people interviewed for this study viewed EMS distribution of leave-behind naloxone and field-based buprenorphine favourably. They viewed EMS facilitation of hepatitis C virus and HIV testing in the field less favourably and were concerned about stigmas associated with those results. Additional themes emerged regarding: the need for different approaches to post-overdose care; the need for new services, including post-overdose trauma counselling and an alternative destination to the emergency department; and the harms of law enforcement presence at overdose responses., Discussion and Conclusions: This study found strong support for leave-behind naloxone and field-initiated buprenorphine. Further training for EMS should include trauma-informed care and strategies to address burnout and increase compassion. Alternatives to the emergency department as a post-overdose destination are needed. These strategies should be considered by jurisdictions revising overdose response protocols., (© 2024 Australasian Professional Society on Alcohol and other Drugs.)

Naltrexone, an opioid antagonist that blocks the reinforcing properties of opioid agonists, is often prescribed to preclude relapse to opioid use disorder (OUD) following detoxification. However, few laboratory studies have directly investigated the ability of naltrexone to alter relapse-inducing effects of opioid agonists, including their priming strength in reinstatement studies and their impact in brain regions known to be involved in drug-induced reinforcement in MRI studies. Here we directly address this issue by investigating the effects of continuous exposure to naltrexone on 1) fentanyl-induced reinstatement of drug-seeking behavior, 2) fentanyl-induced patterns of blood oxygenation level dependent (BOLD) activation in the nucleus accumbens (NAcc), and 3) fentanyl-induced changes in NAcc functional connectivity (FC) in awake non-human primates that are engaged in ongoing opioid self-administration studies. We found that naltrexone antagonizes the priming strength of fentanyl as shown by a rightward shift in its reinstatement dose-effect curve and that naltrexone surmountably antagonizes the BOLD response induced by fentanyl. However, while naltrexone also countered fentanyl's effects on NAcc FC, the effects were not surmounted by a higher dose of fentanyl. Together, these data suggest that, in contrast to naltrexone's modulation of fentanyl's effects on behavior and BOLD responses, their interactive effects on FC between multiple brain regions do not reflect their receptor-mediated activity. Additionally, we demonstrated opposing effects in the absence and presence of naltrexone on NAcc FC at baseline (i.e., in the absence of any fentanyl prime) suggesting that naltrexone alters FC at baseline, even though naltrexone appears behaviorally silent in the absence of an agonist prime. Together these data provide additional insight into ways in which naltrexone interacts with opioid agonists, both behaviorally and in the brain. Further understanding the effects of opioid agonists on patterns of FC could help elucidate our understanding of the neural processes that contribute to the initiation of and relapse to opioid-seeking behavior in OUD., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/aims: In people with opioid use disorder (OUD), buprenorphine is a vital treatment to decrease opioid use and overdose. The US Food and Drug Administration's prescribing information for buprenorphine advises dosing up to 24 mg/day; however, doses of buprenorphine up to 32 mg have been shown to be safe and effective. We compared outcomes associated increased dosing from 24 to 32 mg/day., Design: Prospective cohort investigation., Setting: Low-barrier buprenorphine clinic in Washington, District of Columbia, USA., Participants: Participants in the ANCHOR study (people with hepatitis C virus (HCV), OUD, and active opioid misuse who were treated for HCV and offered buprenorphine) who received buprenorphine at doses of 24 and/or 32 mg/day. 72 participants were included in the analysis: 24 (33%) patients stabilized on 24 mg, and 48 (67%) patients stabilized on 32 mg. Patients were predominantly male (78%), Black (96%), unstably housed (57%), and used opioids by injection (93%)., Measurements: Patient-reported drug use, use frequency, triggers for use, and urine drug screens were collected at each visit. For analysis, the cohort was divided into individuals stabilized on 24 mg (24 mg cohort) or 32 mg (32 mg cohort). Drug use outcomes were assessed between cohorts at 24 mg dosing and at respective maximum dosing. Within the 32 mg cohort, outcomes were compared at 24 mg versus 32 mg dosing., Findings: Within the 32 mg cohort, increased dosing from 24 to 32 mg was associated with a decline in opioid use (68.5% [5.2%] at 24 mg vs 59.5% [5.6%] at 32 mg; P = 0.02), frequency of use per week (1.58 [0.19] at 24 mg vs. 1.15 [0.16] at 32 mg; P = 0.0002) and physiologic triggers for use (38.2% [6.0%] at 24 mg vs 7.0% [1.9%] at 32 mg; P < 0.0001). At the end of the study period, there were significantly more patients retained in the 32 mg cohort (78.7%) compared with the 24 mg cohort (50.0%, P = 0.02)., Conclusion: Higher buprenorphine dosing (32 mg/day) appears to improve outcomes in people with opioid use disorder, even in the absence of abstinence., (© 2024 Society for the Study of Addiction.)

Aims: To explore healthcare professionals' perceptions and experiences of take-home naloxone initiatives in acute care settings to gain an understanding of issues facilitating or impeding dispensing., Design: Systematic literature review., Data Sources: Cochrane, MEDLINE and CINAHL were searched from 15/03/2021 to 18/03/2021, with a follow-up search performed via PubMed on 22/03/2021. The years 2011 to 2021 were included in the search., Review Methods: A systematic literature review focused on qualitative studies and quantitative survey designs. Synthesis without meta-analysis was undertaken using a thematic analysis approach., Results: Seven articles from the United States of America (5), Australia (1) and Canada (1) with 750 participants were included in the review. Results indicate ongoing stigma towards people who use drugs with preconceived moral concerns regarding take-home naloxone. There was confusion regarding roles and responsibilities in take-home naloxone dispensing and patient education. Similarly, there was a lack of clarity over logistical and financial issues., Conclusion: Take-home naloxone is a vital harm reduction initiative. However, barriers exist that prevent the optimum implementation of these initiatives., Impact: What is already known: Deaths due to opioid overdose are a global health concern, with take-home naloxone emerging as a key harm reduction scheme. Globally, less than 10% of people who use drugs have access to treatment initiatives, including take-home naloxone. An optimum point of distribution of take-home naloxone is post-acute hospital care., What This Paper Adds: There is role confusion regarding responsibility for the provision of take-home naloxone and patient education. This is exacerbated by inconsistent provision of training and education for healthcare professionals. Logistical or financial concerns are common and moral issues are prevalent with some healthcare professionals questioning the ethics of providing take-home naloxone. Stigma towards people who use drugs remains evident in some acute care areas which may impact the use of this intervention. Implications for practice/policy: Further primary research should examine what training and education methods are effective in improving the distribution of take-home naloxone in acute care. Education should focus on reduction of stigma towards people who use drugs to improve the distribution of take-home naloxone. Standardized care guidelines may ensure interventions are offered equally and take-home naloxone 'champions' could drive initiatives forward, with support from harm reduction specialists., Reporting Method: This has adhered to the PRISMA reporting guidelines for systematic reviews., Patient or Public Contribution: No patient or public contribution., (© 2024 John Wiley & Sons Ltd.)

Background and Aims: Extended-release naltrexone (XR-NTX) and sublingual buprenorphine (SL-BUP) are both approved for opioid use disorder (OUD) treatment in any medical setting. We aimed to compare the real-world effectiveness of XR-NTX and SL-BUP., Design and Setting: This was an observational active comparator, new user cohort study of Medicaid claims records for patients in New Jersey and California, USA, 2016-19., Participants/cases: The participants were adult Medicaid patients aged 18-64 years who initiated XR-NTX or SL-BUP for maintenance treatment of OUD and did not use medications for OUD in the 90 days before initiation. Our cohort included 1755 XR-NTX and 9886 SL-BUP patients., Measurements: We examined two outcomes up to 180 days after medication initiation: (1) composite of medication discontinuation and death and (2) composite of overdose and death., Findings: In adjusted analyses, treatment with XR-NTX was more likely to result in discontinuation or death by the end of follow-up than treatment with SL-BUP: cumulative risk 75.9% [95% confidence interval (CI) = 73.9%, 77.9%] versus 62.2% (95% CI = 61.2%, 63.2%), respectively (risk difference = 13.7 percentage points, 95% CI = 11.4, 16.0). There was minimal difference in the cumulative risk of overdose or death by the end of follow-up: XR-NTX 3.9% (95% CI = 3.0%, 4.8%) versus SL-BUP 3.3% (95% CI = 2.9%, 3.7%); risk difference = 0.5 percentage points, 95% CI = -0.4, 1.5. Results were consistent across sensitivity analyses., Conclusions: Medicaid patients in California and New Jersey, USA, receiving treatment for opioid use disorder stayed in treatment longer on sublingual buprenorphine than on extended-release naltrexone, but the risk of overdose was similar. Most patients in this study discontinued medication within 6 months, regardless of which medication was initiated., (© 2024 Society for the Study of Addiction.)

Abstract: Naltrexone, buprenorphine, and methadone are Food and Drug Administration-approved medications for the treatment of opioid use disorder in the United States. Naltrexone, an opioid antagonist, can precipitate opioid withdrawal if administered too quickly after the use of full or partial opioid agonists for those with either dependence or use disorder. We describe a case of severe precipitated opioid withdrawal syndrome after reported buprenorphine extended-release (XR) administration, despite the patient having been stable on buprenorphine-XR for several years, with no missed doses or recent opioid use. Naltrexone levels were sent and helped to diagnose suspected inadvertent naltrexone-XR administration in this patient, which was likely the etiology of his precipitated opioid withdrawal syndrome. We suggest the use of high-dose buprenorphine, as well as adjunctive medications including benzodiazepines, as a treatment strategy for naltrexone-XR precipitated withdrawal in the setting of chronic buprenorphine-XR treatment., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 American Society of Addiction Medicine.)

Clinical reports suggest that the most effective strategies for managing opioid use disorder comprise a comprehensive treatment program of both pharmacological and nonpharmacological approaches. However, the conditions under which these combinations are most effective are not well characterized. This study examined whether the presence of an alternative reinforcer could alter the efficacy of Food and Drug Administration-approved opioid antagonist or agonist medications, as well as the nonopioid flumazenil, in decreasing oxycodone choice self-administration in nonhuman primates. Adult squirrel monkeys ( n = 7; four females) responded under concurrent second-order fixed-ratio (FR)-3(FR5:S);TO45s schedules of reinforcement for intravenous oxycodone (0.1 mg/kg) or saline on one lever and 30% sweetened condensed milk or water on the other. Doses of naltrexone (0.00032-1.0 mg/kg), nalbuphine (0.32-10 mg/kg), buprenorphine (0.0032-0.032 mg/kg), methadone (0.32-1.0 mg/kg), or flumazenil (1-3.2 mg/kg) were administered intramuscularly prior to oxycodone self-administration sessions that occurred with either milk or water as the alternative. Naltrexone, a μ -opioid receptor antagonist, was >30-fold more potent when milk was available compared with water and abolished oxycodone intake (injections/session) while concomitantly increasing milk deliveries at the highest dose tested. Pretreatment with the low-efficacy μ -agonist nalbuphine was most effective in the presence of milk compared with water, decreasing oxycodone preference to <50% of control values. The higher efficacy μ -agonists, methadone and buprenorphine, and the benzodiazepine antagonist flumazenil did not appreciably alter the reinforcing potency of oxycodone under either condition. These results suggest that antagonist medications used in combination with alternative reinforcers may be an effective strategy to curtail opioid abuse-related behaviors. SIGNIFICANCE STATEMENT: Clinical treatment programs for opioid use disorder use a combination of pharmacological and nonpharmacological approaches. However, the conditions under which these combinations are most effective have not been fully characterized. This study examined whether the effectiveness of μ -opioid medications to decrease oxycodone self-administration is altered in the presence of an alternative reinforcer. The results suggest that alternative reinforcers enhance the effects of antagonist or low-efficacy partial agonists, suggesting they may be a more effective strategy to curtail opioid use., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Opioids kill more people than any other drug. Naloxone is an opioid antagonist which can be distributed in take-home 'kits' for peer administration (take-home naloxone)., Aim: To determine the feasibility of carrying out a definitive randomised controlled trial of take-home naloxone in emergency settings., Design: We used Welsh routine data (2015-21) to test the feasibility of developing a discriminant function to identify people at high risk of fatal opioid overdose. We carried out a cluster randomised controlled trial and qualitative study to examine experiences of service users and providers. We assessed feasibility of intervention and trial methods against predetermined progression criteria related to: site sign-up, staff trained, identification of eligible patients, proportion given kits, identification of people who died of opioid poisoning, data linkage and retrieval of outcomes., Setting: This study was carried out in the emergency environment; sites comprised an emergency department and associated ambulance service catchment area., Participants: At intervention sites, we invited emergency department clinicians and paramedics to participate. We recruited adult patients who arrived at the emergency department or were attended to by ambulance paramedics for a problem related to opioid use with capacity to consent to receiving the take-home naloxone and related training., Interventions: Usual care comprised basic life support plus naloxone by paramedics or emergency department staff. The take-home naloxone intervention was offered in addition to usual care, with guidance for recipients on basic life support, the importance of calling the emergency services, duration of effect, safety and legality of naloxone administration., Discriminant Function: With low numbers of opioid-related deaths (1105/3,227,396) and a high proportion having no contact with health services in the year before death, the predictive link between death and opioid-related healthcare events was weak. Logistic regression models indicated we would need to monitor one-third of the population to capture 75% of the decedents from opioid overdose in 1-year follow-up., Randomised Controlled Trial: Four sites participated in the trial and 299 of 687 (44%) eligible clinical staff were trained. Sixty take-home naloxone kits were supplied to patients during 1-year recruitment. Eligible patients were not offered take-home naloxone kits 164 times: 'forgot' ( n  = 136); 'too busy' ( n  = 15); suspected intentional overdose ( n  = 3)., Qualitative Interviews: Service users had high levels of knowledge about take-home naloxone. They were supportive of the intervention but noted concerns about opioid withdrawal and resistance to attending hospital for an overdose. Service providers were positive about the intervention but reported barriers including difficulty with consenting and training high-risk opioid users., Health Economics: We were able to calculate costs to train staff at three sites (£40 per AS and £17 in Site 1 ED). No adverse events were reported. Progression criteria were not met - fewer than 50% of eligible staff were trained, fewer than 50% of eligible patients received the intervention and outcomes were not retrieved within reasonable timescales., Future Work: The take-home naloxone intervention needs to be developed and evaluated in emergency care settings, with appropriate methods., Limitations: The Take-home naloxone Intervention Multicentre Emergency setting study was interrupted by coronavirus disease., Conclusions: This study did not meet progression criteria for intervention or trial methods feasibility, so outcomes were not followed up and a fully powered trial is not planned., Trial Registration: This trial is registered as ISRCTN13232859., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/91/04) and is published in full in Health Technology Assessment ; Vol. 28, No. 74. See the NIHR Funding and Awards website for further award information.

Importance: Layperson-administered naloxone (LAN) is a powerful but incompletely characterized intervention to prevent opioid-related overdose mortality. LAN trends are relevant to policy and strategic planning in naloxone distribution initiatives., Objective: To assess the 2-year LAN trend for persons in the United States receiving naloxone during emergency medical services (EMS) activations., Design, Setting, and Participants: This retrospective cross-sectional study was conducted in the United States from June 2020 to June 2022 among 65 621 195 EMS activations from 911 responses, EMS standbys, or when EMS crews functioned in an ambulance intercept role or during mutual aid to another ambulance response. Activations within health care settings and interfacility or medical transports were excluded. Data are from the National Emergency Medical Services Information System (NEMSIS), the national EMS patient care record database. From June 2020 to June 2022, NEMSIS included more than 96 million EMS activations from nearly 14 000 agencies across 54 states and territories., Exposures: EMS clinician-reported LAN., Main Outcome and Measures: The primary outcome was the trend of receiving LAN, measured by EMS clinician documentation., Results: From June 2020 to June 2022, EMS reported 744 078 patients receiving naloxone, with 24 990 (3.4%) involving LAN. Patients were predominantly male (17 331 [69.4%]) and had a median (IQR) age of 42 (31-56) years, with the majority treated in urban homes or residences (21 692 [86.8%] urban; 13 223 [52.9%] in-home or residence). Of the total naloxone recipients, 243 985 patients (32.8%) had suspected drug overdose documentation as either the primary or secondary impression. Overall, the percentage change in naloxone administration rates decreased 6.1% over the study period (from 1140.1 [95% CI, 1135.1-1145.1] per 100 000 EMS activations to 1070.1 [95% CI, 1064.9-1075.3] per 100 000 EMS activations), while the percentage change of persons receiving LAN increased 43.5% (from 30.0 [95% CI, 29.2-30.8] per 100 000 EMS activations to 43.1 [95% CI, 42.0-44.1] per 100 000 EMS activations)., Conclusions and Relevance: In this cross-sectional study, the LAN rate increased from June 2020 to June 2022 as reported in the national EMS database. These findings help inform policies and practices aimed at mitigating the devastating impacts of the opioid epidemic and saving lives. Novel public health strategies are needed to measure the effects of this intervention nationally, evaluate approaches to expand naloxone distribution, and address naloxone usage barriers.

The purpose of the analysis was to evaluate if 10 mg naloxone, administered intramuscularly, could reverse or prevent opioid-induced respiratory depression (OIRD), including OIRD associated with the administration of lethal doses of high-potency opioids. A naloxone population pharmacokinetic (PK) model was generated using data from two naloxone auto-injector (NAI) clinical PK studies. Mechanistic OIRD PK-pharmacodynamic (PD) models were constructed using published data for buprenorphine, morphine, and fentanyl. Due to the lack of published carfentanil data in humans, interspecies allometric scaling methods were used to predict carfentanil PK parameters in humans. A PD model of a combined effect-compartment and receptor kinetics model with a linear relationship between ventilation and carbon dioxide was used to predict the respiratory depression induced by carfentanil. Model-based simulations were performed using the naloxone population PK model and the constructed mechanistic OIRD PK-PD models. Changes in ventilation were assessed after opioid exposure and treatment with 2 mg naloxone or one or two doses of 10 mg naloxone. A higher percentage of subjects recovered back to the rescue ventilation thresholds and/or had a faster recovery to 40% or 70% of baseline ventilation with 10 mg compared with 2 mg naloxone. A second dose of 10 mg naloxone, administered 60 min post-opioid exposure, expedited recovery to 85% of baseline ventilation and delayed time to renarcotization compared with a single dose. In addition, when 10 mg naloxone was administered at 5, 15, 30, or 60 min before fentanyl or carfentanil exposure, rapid and profound OIRD was prevented., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Naloxone is an effective antidote, but its short half-life means repeated doses, and infusions are often required. We investigated the effectiveness of adding intramuscular naloxone to titrated intravenous naloxone in opioid overdose in preventing recurrence of respiratory depression., Methods: This double-blinded randomised placebo-controlled trial was conducted in patients with suspected opioid poisoning and respiratory depression (respiratory rate <10 breaths/min or oxygen saturation <93%). Patients were randomised to receive either intramuscular naloxone 1,600 µg or saline placebo. All patients received titrated intravenous naloxone 100 µg and were managed on an opioid poisoning care pathway. The primary outcome was recurrence of respiratory depression within 4 h. Secondary outcomes were the proportion receiving naloxone infusions, number of naloxone boluses administered, reversal of respiratory depression at 10 min, and precipitation of opioid withdrawal (any symptom)., Results: Recurrence of respiratory depression within 4 h was less common in 28/69 (41%) patients receiving intramuscular naloxone versus 48/67 (72%) patients receiving placebo (difference 31%, 95% CI: 13-46%; P  < 0.001). Fewer naloxone infusions (5/69; 7% versus 25/67; 37%, difference 30%, 95% CI: 15 to 55%; P  < 0.001) and fewer naloxone doses were administered (median 2, IQR: 1 to 5, versus median 5, IQR: 2 to 8; P  = 0.001) in the intramuscular group. Reversal of respiratory depression at 10 min was similar between groups (51/69; 74% intramuscular naloxone versus 47/67; 70% placebo; P  = 0.703). Opioid withdrawal occurred in 35/69 (51%) given intramuscular naloxone compared to 28/67 (42%) in the placebo group (difference 9%; 95% CI: -8 to 27%; P  = 0.308)., Discussion: The favourable pharmacokinetics of intramuscular naloxone, particularly its longer duration of activity, likely explains the improved effectiveness with lower recurrence of respiratory depression., Conclusion: The addition of intramuscular naloxone 1,600 µg to titrated intravenous naloxone prolonged effective reversal of respiratory depression, with fewer naloxone doses and infusions given, and no significant difference in patients developing withdrawal.

Background: North America is grappling with an ongoing drug overdose crisis. While harm reduction measures like take-home naloxone kits, and supervised consumption sites, have helped reduce mortality, other strategies to address this public health emergency are required. Good Samaritan Laws (GSLs) offer legal protection for individuals who report overdoses, yet people who use substances (PWUS) may still hesitate to seek help due to concerns about existing legislation. This scoping review explores barriers preventing PWUS from calling emergency services for overdoses, along with potential solutions and facilitators to address this challenge., Methods: PRISMA-ScR was used as a guide to conduct this study. Health sciences librarians searched Medline, Embase, PsychINFO, CINAHL, and SCOPUS to identify relevant articles. Six reviewers contributed to screening and extracting the articles through Covidence. Two reviewers performed thematic analysis using NVivo software to identify key barriers and facilitators., Results: An initial search found 6275 articles for title and abstract screening, resulting in 48 studies meeting the inclusion criteria. The primary barrier to calling 911 pertained to concerns about police arrivng with other first responders, especially regarding their presence and involvement at the scene of overdose. This was followed by legal repercussions, including fear of arrest, incarceration, and fear of eviction, amongst others. Some studies noted the lack of knowledge or trust in GSLs as a deterrent to seeking medical assistance. Additional barriers included concerns about privacy and confidentiality, preference to manage an overdose alone/receive help from another peer, confidence in naloxone effectiveness, limited access to cell phones, peer pressure to not call for help, and identifying as Black, Indigenous, or a Person of Colour (BIPOC). Facilitators include increased GSL awareness among PWUS and law enforcement, expanded legal safeguards for 911 callers, reduced police intervention in overdose cases, and enhanced naloxone availability at key access points., Conclusion: Despite the good intentions of GSLs, PWUS continue to experience significant barriers to calling emergency services in the event of an overdose. Understanding these barriers and key facilitators is necessary to inform future drug policy and advocacy efforts., 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.)

Background: In addition to teaching overdose recognition and response, overdose education and naloxone distribution (OEND) trainings for emergency responders aim to improve trainee attitudes toward people who use drugs and toward naloxone. This study examines the training effectiveness long term, as well as the extent to which improvements are dependent on profession type or recent experience administering naloxone., Methods: A total of 774 emergency responders, consisting of law enforcement officers (LEOs) (n = 624, 81%) and emergency medical service (EMS) personnel (n = 150, 19%), attended OEND trainings and completed surveys immediately prior to ("pre") and following ("post") the training, as well as 6 months later ("follow-up"). Survey items assessed attitudes toward people who have overdosed, naloxone-related risk compensation (ie, "enabling") beliefs, and whether participants had administered naloxone since attending the training. Multiple regression and estimated marginal means were used to evaluate changes in scores., Results: Emergency responders showed improved attitudes (pre = 2.60, follow-up = 2.45, P  < .001) and risk compensation beliefs (pre = 2.97, follow-up = 2.67, P  < .001) 6 months following the training. Follow-up scores differed by profession, with LEOs endorsing worse attitudes (difference = 0.55, P  = .013) and more risk compensation beliefs (difference = 0.67, P  = .014) than EMS. In addition, having recently administered naloxone predicted more negative attitudes (EMS: difference = 0.55, P  = .01; LEO: difference = 0.54, P  = .004) and risk compensation beliefs (EMS = 0.73, P  = .006; LEO = 0.69, P  = .002) at follow-up., Conclusion: Six months after an OEND training, emergency responders' attitudes toward people who overdose, and their risk compensation beliefs remained improved. However, LEOs had more negative follow-up attitudes and beliefs compared to EMS. Emergency responders who had administered naloxone had worse attitudes and beliefs at follow-up than those who had not. Of note, our sample evidenced sizable attrition between pre and follow-up assessments, leaving room for selection bias. Future studies should investigate how to mitigate negative effects of administering naloxone on attitudes toward those who overdose, and belief that naloxone is "enabling.", 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: High-dose (≥24 mg) buprenorphine daily doses (BDD) may be important in treating patients with opioid use disorder (OUD) to improve retention and prevent overdose, particularly in the context of increased illicit fentanyl use. This study sought to: (1) identify trajectories for average BDD among patients initiating buprenorphine treatment for OUD and (2) assess patient characteristics associated with these identified trajectories., Methods: Buprenorphine treatment episodes among patients in the US Veterans Healthcare Administration (VHA) from federal fiscal years 2006 to 2020 were identified. Group-based trajectory modeling (GBTM) was used to identify BDD trajectories based on weekly averages of BDD over the 180 days after buprenorphine episode initiation., Results: A total of 79 303 buprenorphine treatment episodes among 44 583 patients were included in the analytic sample. GBTM identified 9 latent trajectories for BDD: (1) moderate dose, early discontinuation (10.1%), (2) moderate dose, delayed discontinuation (4.5%), (3) moderate dose, moderate-paced discontinuation (5.2%), (4) low-moderate dose, delayed discontinuation (7.0%), and (5) low-moderate dose, early discontinuation (21.1%), (6) low dose retention (9.6%), (7) low-moderate dose retention (16.7%), (8) moderate dose retention (18.6%), and (9) high dose retention (7.4%). Patient BDD can broadly be characterized as low [2-4 mg/day], low-moderate (6-8 mg/day), moderate (12-18 mg/day), and high dose (≥ 24 mg/day). Patients with episodes in the high BDD trajectory have the lowest social risk (eg, lowest rate of past-year history of homelessness) and the lowest diagnosed rate of physical and mental health-related comorbidities compared to those following other trajectories., Conclusions: BDD ranges widely and patient characteristics are significantly different between those episodes following differing BDD trajectories. Future research on the association between BDD and subsequent patient outcomes (eg, overdose) needs to carefully consider these differences in baseline characteristics., 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: 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: People who experience a nonfatal opioid overdose and receive naloxone are at high risk of subsequent overdose death but experience gaps in access to medications for opioid use disorder. The immediate post-naloxone period offers an opportunity for buprenorphine initiation. Limited data indicate that buprenorphine administration by emergency medical services (EMS) after naloxone overdose reversal is safe and feasible. We describe a case in which a partnership between a low-barrier substance use disorder (SUD) observation unit and EMS allowed for buprenorphine initiation with extended-release injectable buprenorphine after naloxone overdose reversal., Case: A man in his 40's with severe opioid use disorder and numerous prior opioid overdoses experienced overdose in the community. EMS was activated and he was successfully resuscitated with intranasal naloxone, administered by bystanders and EMS. He declined emergency department (ED) transport and consented to transport to a 24/7 SUD observation unit. The patient elected to start buprenorphine due to barriers attending opioid treatment programs daily. His largest barrier was unsheltered homelessness. His severe opioid withdrawal symptoms were successfully treated with 16/4 mg sublingual buprenorphine/naloxone and 300 mg extended-release injectable buprenorphine (XR-buprenorphine), without precipitated withdrawal. Two weeks later, he reported no interval fentanyl use., Discussion: We describe the case of a patient successfully initiated onto XR-buprenorphine in the immediate post-naloxone period via a partnership between an outpatient low-barrier addiction programs and EMS. Such partnerships offer promise in expanding buprenorphine access and medication choice, particularly for the high-risk population of patients who decline ED transport., 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.

According to the Centers for Disease Control and Prevention (CDC), 100,306 drug overdose deaths occurred in the US during a 12-month period ending in April 2021. Opioids were involved in 75% of these related deaths. Opioid Use Disorder (OUD) is a constantly evolving public health crisis with potentially lethal consequences. In 2017, 900 adolescents began to misuse opioids every day. Nearly 10% of high school seniors reported using opioids nonmedically. Additionally, the incidence for hospitalizations for adolescents among children 1-19 years of age increased nearly 2-fold from 1997 to 2012. This data emphasizes the dangers associated with the increasing accessibility of pharmaceutical and non-pharmaceutical opioids, particularly for adolescents. All three of the currently FDA approved medications for OUD have shown clear efficacy in decreasing all-cause mortality in adults. It is proposed that the same effects should be seen in adolescents but limited data is present. A recent study analyzed buprenorphine and naltrexone treatment amongst OUD in adolescents between 2001-2014; only 1 in 4 youth received any medication therapy within six months of diagnosis. Adolescents under 16 were the most likely to receive medications. However, even adolescents aged 17, for whom buprenorphine is FDA approved for, were less likely to receive therapy than adults over 18 years of age. The following case report aims to demonstrate how subcutaneous extended release buprenorphine treatment can be initiated effectively as an outpatient in an adolescent with OUD. It is critical that clinicians work to expand access to pharmacotherapy for adolescents struggling with OUD to ensure proper management and reduction of opioid-related overdoses.

Background: Understanding opioid overdose risk perception may inform overdose prevention strategies., Methods: We used baseline data from a randomized overdose prevention trial, in San Francisco, CA, and Boston, MA, among people who used nonprescribed opioids, survived an overdose in the past 3 years, and had received naloxone. Participants were asked how likely they were to overdose in the next 4 months. We combined "extremely likely" and "likely" (higher risk perception) and "neutral," "unlikely," and "extremely unlikely" (lower risk perception). We performed bivariate analyses and separate multivariable logistic regression models of risk perception across (1) sociodemographic, (2) substance use, and (3) overdose risk behavior measures. Covariates were selected a priori or significant in bivariate analyses., Results: Among 268 participants, 88% reported at least 1 overdose risk behavior; however, only 21% reported higher risk perception. The adjusted odds ratio (AOR) of higher risk perception was 2.41 (95% confidence interval [CI]: 1.10-5.30) among those unhoused in the past 4 months, 2.06 (95% CI: 1.05-4.05) among those using opioids in a new place, and 5.61 (95% CI: 2.82-11.16) among those who had overdosed in the past 4 months. Living in Boston was associated with higher risk perception in all 3 models (AOR = 2.00-2.46, 95% CI: 1.04-4.88)., Conclusions: Despite prevalent risk behaviors, a minority of participants perceived themselves to be at higher risk of overdose. Nonetheless, some known risk factors for overdose were appropriately associated with risk perception. Fentanyl has been prevalent in Boston for longer than San Francisco, which may explain the higher risk perception there., 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: Naldemedine, a peripherally acting opioid μ receptor antagonist, is effective for prevention of opioid-induced constipation (OIC); however, evidence on its use in children is limited. Objective: To evaluate the efficacy and safety of naldemedine in pediatric patients with OIC. Design, Setting/Subjects: Retrospective analysis of 32 pediatric patients with OIC treated with naldemedine in a single institution in Japan from June 2017 to March 2021. Measurements: Efficacy was evaluated in 13 evaluable patients with bowel movement (BM) response, defined as those with at least three BMs in the first 7 days after naldemedine initiation and an increase of at least one BM from baseline. Safety was evaluated by examining adverse events (AEs) based on the Common Terminology Criteria for AEs (v5.0). Results: BM response was recorded in 11 of the 13 patients (85%), and the number BMs per day significantly increased from 0.43 before naldemedine to 1.00 after naldemedine ( p = 0.025). The most common AE was diarrhea, observed in 16 of the 32 patients (50%), and all instances were grade 1 or 2. In three of the 16 patients, naldemedine was discontinued owing to worsening diarrhea. Conclusions: In pediatric patients, naldemedine resulted in a high rate of BM response and increased the BM frequency, indicating its efficacy. In some patients, grade 2 diarrhea required naldemedine discontinuation, suggesting that it should be used with caution in pediatric patients. Further studies are warranted to determine the optimal naldemedine dose in pediatric patients.

Background and Aims: A 12-week placebo-controlled, sequential parallel Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder (ADAPT-2) trial evaluated the effects of extended-release injectable naltrexone plus extended-release oral bupropion (NTX + BUPN) on methamphetamine (MA) use over two stages. This study reports on the previously unpublished stage 2 MA use in participants randomized at stage 1 to receive NTX + BUPN through both stages compared with those assigned to placebo., Design: This is a secondary analysis of the US National Institute on Drug Abuse (NIDA) ADAPT-2 network trial., Setting: The parent ADAPT-2 trial was carried out across multiple NIDA Clinical Trials Network (CTN) sites in the United States., Participants: This analysis includes 403 people with MA use disorder who participated in the ADAPT-2 CTN trial., Intervention and Comparator: NTX + BUPN was compared with placebo over the course of the trial., Measurement: MA use was measured by urine drug screens conducted twice weekly for 12 weeks, then once in week 13 and once in week 16 post-treatment follow-up., Findings: Participants on NTX + BUPN in stage 1 showed an additional 9.2% increase [95% confidence interval (CI), 0.09%-17.9%, P = 0.038] during stage 2 in their probability of testing negative for MA, with a total increase of 27.1% (95% CI, 13.2%-41.1%, P < 0.001) over the full 12 weeks of treatment. In contrast, participants on placebo in both stages increased in probability of testing MA-negative by a total of 11.4% (95% CI, 4.1%-18.6%, P = 0.002) over all 12 weeks. The 12-week increase among participants on NTX + BUPN was significantly greater-by 15.8% (95% CI, 4.5%-27.0%, P = 0.006)-than the increase among those on placebo., Conclusion: For people with methamphetamine (MA) use disorder receiving treatment with extended-release injectable naltrexone plus extended-release oral bupropion (NTX + BUPN), continued treatment with NTX + BUPN after 6 weeks is associated with additional reductions in MA use up to 12 weeks., (© 2024 Society for the Study of Addiction.)

Background: Poppy seed tea (PST) is a legally obtainable source of opiates made from the seeds of the opium poppy. Our large telehealth opioid use disorder (OUD) provider group has treated several patients with PST misuse., Methods: We retrospectively identified patients with primary PST use disorder treated with buprenorphine in a telehealth-only practice with first visits between January 2021 and December 2022. Patients were identified by having the word "poppy" in their enrollment note, and then charts were reviewed to determine which patients had primary PST misuse. Demographics, buprenorphine doses, and retention in treatment were recorded., Results: We identified 18 patients treated for PST use disorder. Fifteen (83.3%) identified as male, mean age was 40.4 (standard deviation 8.8) years, and patients resided in 10 different U.S. states. Median starting buprenorphine dose was 2 mg (interquartile range (IQR) 2-2.5 mg). Median stabilizing dose of buprenorphine was 16 mg daily (IQR 15-20.5 mg). As of June 2023, 5 patients (27.8%) were still in active treatment. Two patients (11.1%) had completed a planned, elective taper. Ten patients (55.6%) had unplanned discontinuation from treatment, and 3 patients (16.7%) discontinued for other reasons., Conclusions: To our knowledge, this is the largest case series describing PST misuse in the U.S., and the first to demonstrate its treatment in the telehealth setting. PST use disorder is treatable with buprenorphine with doses similar to treatment of other opioid use disorders. Clinicians who treat patients with OUD should be aware of PST use disorder and its treatment.

Introduction: Buprenorphine is used to treat opioid use disorder (OUD). However, therapy is often disrupted during acute pain episodes, and re-initiation is often deferred due to intolerable interruption in opioid analgesics. This case report describes a unique strategy for inducing buprenorphine without stopping opioid analgesics., Case: One patient with OUD and acute pain was initiated on buprenorphine using intravenous microdosing without precipitated withdrawal or pain exacerbation. Full agonist opioids were successfully weaned after discharge and the patient was linked with a community-based treatment program., Conclusion: This case describes use of intravenous buprenorphine to treat OUD and acute pain without adverse consequences.

Background and Aims: Alcohol use disorder (AUD) is a persistent public health concern, contributing significantly to mortality and morbidity. This study aims to evaluate the impact of in-hospital extended-release naltrexone (XR-NTX) administration on alcohol-related outcomes., Methods: This retrospective cohort study, conducted at an academic medical centre, included 141 adult patients with AUD who received XR-NTX between December 2020 and June 2021. Primary and secondary outcomes were assessed 90 days before and after XR-NTX administration to identify number of alcohol-related hospitalisations, emergency department (ED) visits and average length of hospital stay. Subgroup analyses assessed outcomes in high hospital utilisers and marginally housed or unhoused populations., Results: There was a significant decrease in ED visits and length of hospital stay post XR-NTX and no significant difference in the number of rehospitalisations. Subgroup analysis showed significant reduction in hospital readmissions and ED visits among high hospital utilisers. Our sample was a predominantly middle-aged, male and white patient population., Conclusions: In-hospital initiation of XR-NTX for AUD was associated with a significant decrease in ED visits and length of hospital stay. While no significant impact on the number of hospitalisations was observed overall, there was a substantial reduction in hospital readmissions and ED visits among high utilisers. Our findings suggest the potential benefits of in-hospital XR-NTX, emphasising the need for further research to establish causal relationships, assess cost-effectiveness and explore effectiveness across diverse patient populations. Effective in-hospital interventions, such as XR-NTX, hold promise for improving patient outcomes and reducing the healthcare burden associated with AUD., (© 2024 The Author(s). Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

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.

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).)

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

Importance: Higher buprenorphine doses may benefit the increasing number of individuals using fentanyl and other synthetic opioids, but there is little empirical evidence on the efficacy of such higher doses., Objective: To examine the association between higher buprenorphine doses (above 16 mg and 24 mg) and subsequent emergency department (ED) or inpatient service use among patients diagnosed with opioid use disorder., Design, Setting, and Participants: This cross-sectional study was a retrospective analysis of health data from Optum's deidentified Clinformatics Data Mart Database from 2016 to 2021 for commercially insured individuals aged 18 years or older diagnosed with opioid use disorder (OUD). Eligible participants initiated buprenorphine after at least 90 days of enrollment and were dispensed at least a 14-day supply of buprenorphine. Data were analyzed from September 2023 through February 2024., Exposures: Maximum buprenorphine dose received by a patient for 14 or more days: more than 24 mg, more than 16 mg to 24 mg, more than 8 mg to 16 mg, or 1 mg to 8 mg., Main Outcomes and Measures: Days from initiation of the maximum buprenorphine dose to an ED or inpatient visit for a behavioral health diagnosis, controlling for patient demographics, comorbid conditions, time to reaching maximum dose, buprenorphine discontinuation, and pre-buprenorphine health care utilization., Results: A total of 35 451 individuals with an OUD diagnosis who began buprenorphine treatment were identified (mean [SD] age, 46.2 [15.1] years; 20 983 male [59.2%]; 3326 Black [9.4%], 2411 Hispanic [6.8%], 26 712 White [75.3%]). The most common dose was more than 8 mg to 16 mg daily (14 802 patients [42.9%]), with 9669 patients (27.3%) in the 1 mg to 8 mg tier, 10 329 patients (29.1%) in the 8 mg to 16 mg tier, and 651 patients (1.8%) in the tier receiving more than 24 mg. Among all patients receiving buprenorphine, 12.5% experienced an ED or inpatient visit. Survival analysis shows patients receiving doses more than 24 mg and between 16 mg to 24 mg had longer times to ED or inpatient use than patients receiving from 8 mg to 16 mg (time ratio [TR], 1.11; 95% CI, 1.02 to 1.20) and more than 24 mg (TR, 1.37; 95% CI, 1.04 to 1.81). Findings for doses above 16 mg daily were consistent for observation windows as short as 365 days (more than 24 mg: TR, 1.48; 95% CI, 1.01-2.18; more than 16 mg to 24 mg: TR, 1.19; 95% CI, 1.06-1.32)., Conclusions and Relevance: These findings contribute to the sparse empirical research regarding potential benefits of higher-dose buprenorphine treatment of individuals with OUD. Clinicians should be aware of the potential effects of higher buprenorphine doses on health care utilization while policymakers work to ensure equitable access to individuals who could potentially benefit from higher doses.

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).)

This study examines the clinical efficacy of high-dose naloxone in comatose emergency patients, focusing on its ability to enhance brain metabolism and reduce oxidative stress. A total of 120 patients were randomly assigned to a control group, which received conventional naloxone doses and a study group, which received higher doses. Key outcomes measured included clinical efficacy, time to awakening, blood gas indices, inflammatory factors, consciousness level, neurological recovery and adverse effects. The study group showed a higher response rate (96.67% vs. 83.33%), regained consciousness more quickly and had better blood gas indices and glasgow coma scale (GCS) scores (p<0.05). Neurological function recovery was superior in the study group, with fewer adverse reactions (6.67% vs. 20.00%, p<0.05). These results suggest that high-dose naloxone significantly improves treatment outcomes, enhancing wakefulness, reducing inflammation and improving prognosis in emergency comatose patients, making it a promising option for clinical use.

Naltrexone is an μ opioid receptor antagonist that is used in alcohol and opiate use disorder. Naltrexone does not constitute tolerance and dependence, and cessation of the drug does not cause withdrawal symptoms. Sustained release form of naltrexone has been developed due to patient compliance issues. There is currently only one sustainedrelease form available in Turkey, which is inserted subcutaneously. In this case report, we present, a probable serious side effect of sustained release naltrexone implant. A 36 years old male with alcohol use disorder, developed a sudden clouding of consciousness one hour after the naltrexone implant application followed by anterograde amnesia in the next 8-10 hours. We were not able to detect any medical or neurological reasons for the altered mental status but after the removal of the naltrexone implant, the symptoms improved. To the best of our knowledge, this is the first case to report clouding of consciousness and anterograde amnesia after naltrexone implantation. Keywords: Naltrexone Implant, Side Effect, Alcohol Use Disorder, Lethargy, Consciousness.

Objectives: In 2022, the Drug User Liberation Front opened an unsanctioned compassion club in Vancouver where members could purchase illicit drugs that had been rigorously tested to ensure quality and a lack of potentially fatal contaminants. We sought to evaluate the impact of access to this novel safer supply intervention on non-fatal overdose., Methods: Data were obtained from 47 club members via surveys completed at 3-month intervals between August 2022 and October 2023. We conducted multivariable generalized estimating equations (GEE) analyses to examine the association between club enrolment and the outcomes of: (1) any non-fatal overdose; and (2) any non-fatal overdose involving naloxone administration., Results: The final sample, including 47 study participants, contributed a total of 225 observations and 44.4 person-years of follow-up during the study, and a median follow-up duration of 12.2 months (quartile 1 - 3: 10.4 - 14.7) per participant. In multivariable GEE analyses, enrolment in the compassion club was associated with reduced likelihood of non-fatal overdose (Adjusted Odds Ratio [AOR] = 0.51, 95% Confidence Interval (CI): 0.26 - 0.99) and non-fatal overdose involving naloxone administration (AOR = 0.37, 95% CI: 0.16 - 0.84) after adjusting for potential confounders., Discussion: In this study, enrolment in an unsanctioned compassion club was found to be associated with reductions in any type of non-fatal overdose and non-fatal overdose involving naloxone administration. These findings highlight the need for ongoing research on safer supply interventions, as well as the potential of non-medicalized compassion clubs to complement existing safer supply programming and reduce overdose events., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: The authors report no conflicts of interest.

Abstract: This case report highlights a 36-year-old male without history of psychiatric disease, chronic pain, or substance use disorder who developed severe substance use disorder per Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition criteria to kratom. He was successfully treated with sublingual buprenorphine after a 3-year period of intermittent withdrawal management and trials of oral and extended-release injectable naltrexone. After a period of abstinence from kratom, he was tapered from buprenorphine using 2 monthly injections of 100 mg extended-release buprenorphine. His case underscores some of the current uncertainties around kratom use disorder diagnosis and treatment., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 American Society of Addiction Medicine.)

Objectives: The persistence of the opioid crisis and the proliferation of synthetic fentanyl have heightened the demand for the implementation of novel delivery mechanisms of pharmacotherapy for the treatment of opioid use disorder, including injectable extended-release buprenorphine (buprenorphine-ER). The purpose of this study was to understand provider-level barriers to prescribing buprenorphine in order to facilitate targeted strategies to improve implementation for patients who would benefit from this novel formulation., Methods: Using an interview template adapted from the Consolidated Framework for Implementation Research (CFIR), we conducted structured focus group interviews with 20 providers in an outpatient addiction clinic across 4 sessions to assess providers' perceptions of buprenorphine-ER. Ninety-four unique comments were identified and deductively coded using standardized CFIR constructs., Results: Providers expressed mixed receptivity and confidence in using buprenorphine-ER. Although providers could identify a number of theoretical advantages to the injectable formulation over sublingual buprenorphine, many expressed reservations about using it due to inexperience, negative patient experiences, uncertainties about patient candidacy, cost, and logistical constraints., Conclusions: Provider concerns about buprenorphine-ER may limit utilization. Some concerns may be mitigated through improved education, research, and logistical support. Given the putative benefits of buprenorphine-ER, future research should target barriers to implementation, in part based on hypotheses generated by these findings., Competing Interests: Conflicts of interest: None., (Copyright © 2024 American Society of Addiction Medicine.)

Introduction: Major depression is a common, disabling mental health condition associated with the highest disease burden for any neuropsychiatric disorder worldwide, according to the WHO. Due to the imperfect efficacy and tolerability profiles of existing treatments, investigational compounds in novel treatment classes are needed. Opioid-receptor antagonists are a potential new class of treatments currently under investigation., Areas Covered: Major depressive disorder is first overviewed. Existing treatments, both their mechanisms of action and their place within the antidepressant space, are discussed herein. Then, the profile of Aticaprant and the wider context of kappa-opioid antagonism for depression are discussed in focus., Expert Opinion: Early evidence indicates that Aticaprant may possess desirable pharmacodynamic and pharmacokinetic properties. A lack of convincing efficacy data at the time of writing precludes any definitive statement on its potential as an antidepressant.

Introduction: Buprenorphine is a Food and Drug Administration-approved therapy for opioid use disorder, with proven efficacy in treatment retention and reduction in opioid use and mortality. Low-dose buprenorphine initiation or microinduction is a novel means of initiation that may allow for an easier transition in patients. Trauma patients have high rates of opioid use disorder and patient directed discharges (PDD). We hypothesized that patients initiated on a buprenorphine microinduction program would have increased protocol completion and fewer PDD compared with patients initiated historically on a traditional induction., Methods: Our retrospective cohort study compared buprenorphine microinduction and traditional induction in trauma patients at an urban level one trauma center between December 2020 and June 2022. Patients aged 18-89 y with traumatic injuries who received buprenorphine were included. Our primary outcome was in-hospital protocol completion, defined as reaching 16 mg of buprenorphine within 24 h or a documented stable dose. Statistical analysis was performed using chi-square for categorical variables and two sample t-tests for continuous variables., Results: Ninety-eight patients were included, with 46 initiating with microinduction and 52 initiating with traditional induction. There was no difference in protocol completion, (P = 0.29) and 83% of subjects who started an induction protocol completed it. Those who completed a protocol were more likely to be discharged home (P = 0.0002), had less PDD (P = 0.001), and had an increased likelihood of attending outpatient addiction clinic follow-up (P = 0.038)., Conclusions: Regardless of the protocol type, buprenorphine induction can be implemented in trauma patients with high protocol completion rates. In our population, those who complete a protocol had a higher likelihood of discharge home and postdischarge follow-up in addiction medicine clinic., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The pharmacokinetics (PK) of naloxegol were characterized in pediatric subjects, aged 6 months or older to less than 18 years who either have or are at risk of developing opioid-induced constipation following single dose administration. Subjects grouped as aged 12 years or older to less than 18 years, 6 months or older to less than 12 years, and 6 months or older to less than 6 years, received a single oral dose of naloxegol at doses that were estimated to achieve plasma exposures comparable to adult 12.5- or 25-mg doses. Intensive and sparse plasma naloxegol samples were collected to assess naloxegol concentrations. Data were combined with previously collected adult PK data and used to estimate PK parameters using population PK analyses. Naloxegol PK was described using a 2-compartment model with Weibull-type absorption. Neither age nor body weight was identified as a significant covariate indicating similar PK properties in adult and pediatric subjects. PK estimates in the youngest age group were approximately 80% less than those in adults (12.5-mg equivalent dose). Exposures in the other pediatric groups were similar to those in adult equivalent doses. The PK of naloxegol were characterized as linear over the dose range, with no clinically significant covariates and comparable PK characteristics in adults and pediatric subjects aged 6 months or older., (© 2024, The American College of Clinical Pharmacology.)

Rationale and Objective: Avoidance of opioid withdrawal plays a key role in human opioid addiction. Here, we present a procedure for studying operant negative reinforcement in rats that was inspired by primate procedures where opioid-dependent subjects lever-press to prevent naloxone infusions., Methods: In Experiment 1, we trained rats (n = 30, 15 females) to lever-press to escape and then avoid mild footshocks (0.13-0.27 mA) for 35 days (30 trials/d). Next, we catheterized them and implanted minipumps containing methadone (10 mg/kg/day) or saline. We then paired (4 times, single session) a light cue (20-s) with a naloxone infusion (20 µg/kg, i.v) that precipitated opioid withdrawal. Next, we trained the rats to escape naloxone injections for 10 days (30 trials/d). Each trial started with the onset of the opioid-withdrawal cue. After 20-s, the lever extended, and an infusion of naloxone (1 to 2.2 µg/kg/infusion) began; a lever-press during an 11-s window terminated the withdrawal-paired cue and the infusion. In Experiment 2, we trained rats (n = 34, 17 females) on the same procedure but decreased the footshock escape/avoidance training to 20 days., Results: All rats learned to lever-press to escape or avoid mild footshocks. In both experiments, a subset, 56% (10/18) and 33% (8/24) of methadone-dependent rats learned to lever-press to escape naloxone infusions., Conclusions: We introduce an operant negative reinforcement procedure where a subset of opioid-dependent rats learned to lever-press to escape withdrawal-inducing naloxone infusions. The procedure can be used to study mechanisms of individual differences in opioid negative reinforcement-related behaviors in opioid-dependent rats., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: A trial comparing extended-release naltrexone and sublingual buprenorphine-naloxone demonstrated higher relapse rates in individuals randomized to extended-release naltrexone. The effectiveness of treatment might vary based on patient characteristics. We hypothesized that causal machine learning would identify individualized treatment effects for each medication., Methods: This is a secondary analysis of a multicenter randomized trial that compared the effectiveness of extended-release naltrexone versus buprenorphine-naloxone for preventing relapse of opioid misuse. Three machine learning models were derived using all trial participants with 50% randomly selected for training (n = 285) and the remaining 50% for validation. Individualized treatment effect was measured by the Qini value and c-for-benefit, with the absence of relapse denoting treatment success. Patients were grouped into quartiles by predicted individualized treatment effect to examine differences in characteristics and the observed treatment effects., Results: The best-performing model had a Qini value of 4.45 (95% confidence interval, 1.02-7.83) and a c-for-benefit of 0.63 (95% confidence interval, 0.53-0.68). The quartile most likely to benefit from buprenorphine-naloxone had a 35% absolute benefit from this treatment, and at study entry, they had a high median opioid withdrawal score ( P < 0.001), used cocaine on more days over the prior 30 days than other quartiles ( P < 0.001), and had highest proportions with alcohol and cocaine use disorder ( P ≤ 0.02). Quartile 4 individuals were predicted to be most likely to benefit from extended-release naltrexone, with the greatest proportion having heroin drug preference ( P = 0.02) and all experiencing homelessness ( P < 0.001)., Conclusions: Causal machine learning identified differing individualized treatment effects between medications based on characteristics associated with preventing relapse., Competing Interests: Conflicts of Interest: None., (Copyright © 2024 American Society of Addiction Medicine.)

Background: Take home naloxone (THN) programmes are effective at reducing opioid related mortality, but require high levels of distribution, including to the general public. Mass media campaigns can be effective in improving public understanding of a topic and encouraging behavior change. Whilst mass media campaigns focusing on naloxone have been developed internationally, there is a lack of research on their potential impact. We investigated the effects of components of a recent national mass media campaign (Scotland, UK) designed to improve public awareness of drug related deaths, and readiness to intervene., Methods: We undertook a cross-sectional online experimental study with a randomized design, conducted with a nationally representative sample. Participants (N = 1551; 52.6% female; age 46.1±16.5 years) were assessed on overdose knowledge and readiness to intervene after presentation of eight combinations of campaign components., Results: Compared to a basic campaign description, exposure to all types of campaign component were associated with higher overdose knowledge (p < .001), but not knowledge of what to do in response to an overdose (p = .374), or readiness to intervene (p= .286). The greatest effects were associated with a media rich audio-visual resource (animated video with a popular song on the soundtrack, and narrated by a well-known actor)., Conclusion: Our data suggest that harm reduction is an appropriate topic for large-scale mass media campaigns. However, effects may be limited to knowledge and awareness raising in the general public, and may be related to the types of media used. Audience segmentation is important and more general messaging about drug related deaths may be more appropriate for the majority of audiences., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

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.)