Perspectives of key interest groups regarding supervised Consumption sites (SCS) and novel virtual harm reduction services / overdose response hotlines and applications: a qualitative Canadian study.

BACKGROUND: Supervised consumption sites (SCS) and overdose prevention sites (OPS) have been implemented across Canada to mitigate harms associated with illicit substance use. Despite their successes, they still contend with challenges that limit their accessibility and uptake. Overdose response hotlines and apps are novel virtual technologies reminiscent of informal "spotting" methods that may address some of the limitations. Here, we strove to qualitatively examine the factors that may encourage or deter utilization of these virtual services and SCS. METHODS: A total of 52 participants across Canada were recruited using convenience and snowball sampling methods. These included people with lived and living experience of substance use, family members of people with lived experience, healthcare providers, community harm reduction workers, and virtual harm reduction operators. Semi-structured telephone interviews were conducted and inductive thematic analysis was performed to identify the themes pertaining to SCS and virtual harm reduction. RESULTS: Participants viewed overdose response hotline and apps as an opportunity to consume substances without being hindered by logistical barriers (e.g., wait times), fear of law enforcement, invasion of privacy, and more. They also noted that these virtual services provided more flexibility for clients who opt for routes of consumption that are not supported by SCS, such as smoking. Overall, SCS was perceived to be better than virtual services at facilitating social connection, providing additional resources/referrals, as well as prompt response to overdose. CONCLUSION: In sum, participants viewed SCS and virtual services as filling different needs and gaps. This study adds to a growing body of literature which informs how virtual harm reduction services can serve as useful adjunct to more standard harm reduction methods.

Reported Xylazine Use Among Adults Aged ≥18 Years Evaluated for Substance Use Treatment - United States, July 2022-September 2023.

Xylazine has been increasingly detected in illegally manufactured fentanyl (IMF) products and overdose deaths in the United States; most xylazine-involved overdose deaths involve IMF. A convenience sample of U.S. adults aged ≥18 years was identified from those evaluated for substance use treatment during July 2022-September 2023. Data were collected using the Addiction Severity Index-Multimedia Version clinical assessment tool. Among 43,947 adults, 6,415 (14.6%) reported IMF or heroin as their primary lifetime substance-use problem; 5,344 (12.2%) reported recent (i.e., past-30-day) IMF or heroin use. Among adults reporting IMF or heroin as their primary lifetime substance-use problem, 817 (12.7%) reported ever using xylazine. Among adults reporting recent IMF or heroin use, 443 (8.3%) reported recent xylazine use. Among adults reporting IMF or heroin use recently or as their primary lifetime substance-use problem, those reporting xylazine use reported a median of two past nonfatal overdoses from any drug compared with a median of one overdose among those who did not report xylazine use; as well, higher percentages of persons who reported xylazine use reported other recent substance use and polysubstance use. Provision of nonjudgmental care and services, including naloxone, wound care, and linkage to and retention of persons in effective substance use treatment, might reduce harms including overdose among persons reporting xylazine use.

Mobile addiction treatment and harm reduction services as tools to address health inequities: a community case study of the Brockton Neighborhood Health Center mobile unit.

Opioid overdose deaths continue to increase in the US. Recent data show disproportionately high and increasing overdose death rates among Black, Latine, and Indigenous individuals, and people experiencing homelessness. Medications for opioid use disorder (MOUD) can be lifesaving; however, only a fraction of eligible individuals receive them. Our goal was to describe our experience promoting equitable MOUD access using a mobile delivery model. We implemented a mobile MOUD unit aiming to improve equitable access in Brockton, a racially diverse, medium-sized city in Massachusetts. Brockton has a relatively high opioid overdose death rate with increasingly disproportionate death rates among Black residents. Brockton Neighborhood Health Center (BNHC), a community health center, provides brick-and-mortar MOUD access. Through the Communities That HEAL intervention as part of the HEALing Communities Study (HCS), Brockton convened a community coalition with the aim of selecting evidence-based practices to decrease overdose deaths. BNHC leadership and coalition members recognized that traditional brick-and-mortar treatment locations were inaccessible to marginalized populations, and that a mobile program could increase MOUD access. In September 2021, with support from the HCS coalition, BNHC launched its mobile initiative - Community Care-in-Reach® - to bring low-threshold buprenorphine, harm reduction, and preventive care to high-risk populations. During implementation, the team encountered several challenges including: securing local buy-in; navigating a complex licensure process; maintaining operations throughout the COVID-19 pandemic; and finally, planning for sustainability. In two years of operation, the mobile team cared for 297 unique patients during 1,286 total visits. More than one-third (36%) of patients received buprenorphine prescriptions. In contrast to BNHC's brick-and-mortar clinics, patients with OUD seen on the mobile unit were more representative of historically marginalized racial and ethnic groups, and people experiencing homelessness, evidencing improved, equitable addiction care access for these historically disadvantaged populations. Offering varied services on the mobile unit, such as wound care, syringe and safer smoking supplies, naloxone, and other basic medical care, was a key engagement strategy. This on-demand mobile model helped redress systemic disadvantages in access to addiction treatment and harm reduction services, reaching diverse individuals to offer lifesaving MOUD at a time of inequitable increases in overdose deaths.

Physiologic oxygen responses to smoking opioids: an observational study using continuous pulse oximetry at overdose prevention services in British Columbia, Canada.

BACKGROUND: In British Columbia, Canada, smoking is the most common modality of drug use among people who die of opioid toxicity. We aimed to assess oxygen saturation (SpO2) while people smoked opioids during a pilot study that introduced continuous pulse oximetry at overdose prevention services (OPS) sites. METHODS: This was an observational cohort study, using a participatory design. We implemented our monitoring protocol from March to August 2021 at four OPS. We included adults (≥ 18 years) presenting to smoke opioids. A sensor taped to participants' fingers transmitted real-time SpO2 readings to a remote monitor viewed by OPS staff. Peer researchers collected baseline data and observed the timing of participants' inhalations. We analyzed SpO2 on a per-event basis. In mixed-effects logistic regression models, drop in minimum SpO2 ≤ 90% in the current minute was our main outcome variable. Inhalation in that same minute was our main predictor. We also examined inhalation in the previous minute, cumulative inhalations, inhalation rate, demographics, co-morbidities, and substance use variables. RESULTS: We recorded 599 smoking events; 72.8% (436/599) had analyzable SpO2 data. Participants' mean age was 38.6 years (SD 11.3 years) and 73.1% were male. SpO2 was highly variable within and between individuals. Drop in SpO2 ≤ 90% was not significantly associated with inhalation in that same minute (OR: 1.2 [0.8-1.78], p = 0.261) or inhalation rate (OR 0.47 [0.20-1.10], p = 0.082). There was an association of SpO2 drop with six cumulative inhalations (OR 3.38 [1.04-11.03], p = 0.043); this was not maintained ≥ 7 inhalations. Demographics, co-morbidities, and drug use variables were non-contributory. CONCLUSIONS: Continuous pulse oximetry SpO2 monitoring is a safe adjunct to monitoring people who smoke opioids at OPS. Our data reflect challenges of real-world monitoring, indicating that greater supports are needed for frontline responders at OPS. Inconsistent association between inhalations and SpO2 suggests that complex factors (e.g., inhalation depth/duration, opioid tolerance, drug use setting) contribute to hypoxemia and overdose risk while people smoke opioids.

Co-located Heroin Assisted Treatment within primary care: A preliminary analysis of the implications for healthcare access, cost, and treatment delivery in the UK.

BACKGROUND: The UK is experiencing its highest rate of drug related deaths in 25 years. Poor and inconsistent access to healthcare negatively impacts health outcomes for people who use drugs. Innovation in models of care which promote access and availability of physical treatment is fundamental. Heroin Assisted Treatment (HAT) is a treatment modality targeted at the most marginalised people who use drugs, at high risk of mortality and morbidity. The first service-provider initiated HAT service in the UK ran between October 2019 and November 2022 in Middlesbrough, England. The service was co-located within a specialist primary care facility offering acute healthcare treatment alongside injectable diamorphine. METHODS: Analysis of anonymised health records for healthcare costs (not including drug treatment) took place using descriptive statistics prior and during engagement with HAT, at both three (n=15) and six (n=12) months. Primary outcome measures were incidents of wound care, skin and soft tissue infections (SSTIs), overdose (OD) events, unplanned overnight stays in hospital, treatment engagement (general and within hospital care settings) and ambulance incidents. Secondary outcome measures were costs associated with these events. RESULTS: A shift in healthcare access for participants during HAT engagement was observed. HAT service attendance appeared to support health promoting preventative care, and reduce reactive reliance on emergency healthcare systems. At three and six months, engagement for preventative wound care and treatment for SSTIs increased at the practice. Unplanned emergency healthcare interactions for ODs, overnight hospital stays, serious SSTIs, and ambulance incidents reduced, and there was an increase in treatment engagement (i.e. a reduction in appointments which were not engaged with). There was a decrease in treatment engagement in hospital settings. Changes in healthcare utilisation during HAT translated to a reduction in healthcare costs of 58% within six months compared to the same timeframe from the period directly prior to commencing HAT. CONCLUSION: This exploratory study highlights the potential for innovative harm reduction interventions such as HAT, co-located with primary care services, to improve healthcare access and engagement for a high-risk population. Increased uptake of primary healthcare services translated to reductions in emergency healthcare use and associated costs. Although costs of HAT provision are substantial, the notable cost-savings in health care should be an important consideration in service implementation planning.

Feeling safer: effectiveness, feasibility, and acceptability of continuous pulse oximetry for people who smoke opioids at overdose prevention services in British Columbia, Canada.

BACKGROUND: Smoking is the most common mode of unregulated opioid consumption overall and implicated in fatal overdoses in British Columbia (BC). In part, perception of decreased risk (e.g., fewer who smoke carry naloxone kits) and limited smoking-specific harm reduction services contribute to overdose deaths. Overdose prevention services (OPS) offer supervised settings for drug use. Continuous pulse oximetry, common in acute care, allows real-time, remote oxygen monitoring. We evaluated the effectiveness of a novel continuous pulse oximetry protocol aimed at allowing physical distancing (as required by COVID-19, secluded spaces, and to avoid staff exposure to vaporized opioids), its feasibility, and acceptability at OPS for people who smoke opioids. METHODS: This was a mixed methods survey study. We developed a continuous pulse oximetry protocol in collaboration with clinical experts and people with lived/living experience of substance use. We implemented our protocol from March to August 2021 at four OPS in BC permitting smoking. We included adults (≥ 18 years) presenting to OPS to smoke opioids. Peer researchers collected demographic, health, and substance use information, and conducted structured observations. OPS clients participating in our study, OPS staff, and peer researchers completed post-monitoring surveys. We analyzed responses using a thematic inductive approach and validated themes with peer researchers. RESULTS: We included 599 smoking events. OPS clients participating in our study had a mean age of 38.5 years; 73% were male. Most (98%) reported using "down", heroin, or fentanyl; 48% concurrently used other substances (32% of whom reported stimulants); 76% reported smoking alone in the last 3 days; and 36% reported an overdose while smoking. Respondents reported that the protocol facilitated physical distancing, was easy to use, high satisfaction, improved confidence, improved sense of safety, and that they would use it again. CONCLUSIONS: Continuous pulse oximetry allowed safe physical distancing, was feasible, and acceptable in monitoring people who smoke opioids at OPS.

Correlates of Stimulant Use among People Who Use Heroin Undergoing Treatment in Out-Patient Facilities in France, 2010-2020.

Background: Polydrug use has been implicated in driving a "fourth wave" of the overdose crisis in North America, specifically through concurrent use of stimulants and opioids, especially fentanyl. In France, however, heroin has historically been and remains the easiest-to-access opioid, accounting for most drug treatment demand. Whether similar polydrug use is increasing in Western Europe remains understudied, despite severe health implications and potential inadequate public health responses.Methods: We take advantage of a nation-wide dataset containing information on all patients serviced in treatment centers in France from 2010 to 2020. We conduct Poisson regression to determine the main predictors of stimulant use among people who use heroin (PWUH) and opioids (PWUO) generally.Results: Heroin remains the primary opioid within drug treatment in France. A decreasing number of out-patients seeking treatment for heroin use has been accompanied by an increasing trend of stimulant use over time, most commonly with powder cocaine. Our results suggest a significant increase of crack cocaine use among the most vulnerable PWUH. Concurrent use of stimulants among PWUH was positively associated with use of alcohol, cannabis, unprescribed psychotropics and hallucinogens, and negatively with tobacco. Similar results were found for all in-treatment PWUO.Conclusions: Our results uncover heterogeneity in the profiles of PWUH that should be fully acknowledged to ensure better efficiency in substance use clinical practices and policy, while simultaneously drawing attention to trends in concurrent opioid-stimulant use outside North America. We advocate for an extension of the generalized risk framework and its implementation in prevention programs.

Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease.

INTRODUCTION: Paracetamol is one of the most used medicines worldwide and is the most common important poisoning in high-income countries. In overdose, paracetamol causes dose-dependent hepatotoxicity. Acetylcysteine is an effective antidote, however despite its use hepatotoxicity and many deaths still occur. AREAS COVERED: This review summarizes paracetamol overdose and toxicity (including mechanisms, risk factors, risk assessment, and treatment). In addition, we summarize the epidemiology of paracetamol overdose worldwide. A literature search on PubMed for poisoning epidemiology and mortality from 1 January 2017 to 26 October 2022 was performed to estimate rates of paracetamol overdose, liver injury, and deaths worldwide. EXPERT OPINION: Paracetamol is widely available and yet is substantially more toxic than other analgesics available without prescription. Where data were available, we estimate that paracetamol is involved in 6% of poisonings, 56% of severe acute liver injury and acute liver failure, and 7% of drug-induced liver injury. These estimates are limited by lack of available data from many countries, particularly in Asia, South America, and Africa. Harm reduction from paracetamol is possible through better identification of high-risk overdoses, and better treatment regimens. Large overdoses and those involving modified-release paracetamol are high-risk and can be targeted through legislative change.

An observational study of the extent of naloxone furnishing in California Central Valley community pharmacies.

BACKGROUND: California has sought to expand medication access and improve public health by authorizing pharmacists in California to prescribe certain medications since 2014. Medications with pharmacist-initiated prescribing, or furnishing, include naloxone, hormonal contraception, postexposure prophylaxis/preexposure prophylaxis, and nicotine replacement therapy. In light of the United States' opioid epidemic, naloxone, an opioid antagonist, this study considered furnishing rates in urban areas of California. Research from 2020 found 42.5% of pharmacies furnished naloxone. However, there has been limited study of furnishing outside of urban areas. OBJECTIVE: This study assessed pharmacist furnishing rates of naloxone in California's Central Valley and identified barriers and facilitators to implementation. METHODS: From April to May 2022, the researchers first conducted a cross-sectional, observational study of community and mail-order pharmacies in California's largely rural Central Valley, then collected interview data from a subset of pharmacists in stores that indicated they furnished naloxone. RESULTS: Forty-three percent of Central Valley pharmacies reported that they furnished naloxone. Interview respondents reported that barriers to furnishing included time restrictions, cost to patients, stigma, and language barriers. CONCLUSIONS: Furnishing rates in the Central Valley were slightly higher (43.4%) than those reported in previous research focusing on urban areas of California (42.5%). Identified barriers to furnishing were consistent with those identified in previous research. These findings suggest that further policy interventions may be needed to reduce out-of-pocket costs, establish stronger pharmacist-provider relationships, and provide education combatting stigma against opioid users to increase naloxone furnishing.

Patient, family members and community pharmacists' views of a proposed overdose prevention intervention delivered in community pharmacies for patients prescribed high-strength opioids for chronic non-cancer pain: An explorative intervention development study.

INTRODUCTION: Despite opioid prescribing for chronic non-cancer pain (CNCP) having limited therapeutic benefits, recent evidence indicates significant increases in the prescribing of high-strength opioids for individuals with CNCP. Patients prescribed opioids for CNCP have overdose risk factors but generally have low opioid overdose awareness and low perceptions of risk related to prescribed opioids. Currently, there are few bespoke overdose prevention resources for this group. METHODS: This qualitative study investigated views on a naloxone intervention for people prescribed high-strength opioids for CNCP delivered via community pharmacies. The intervention included overdose risk awareness and naloxone training and provision. Interviews were conducted with eight patients, four family members and two community pharmacists. Participants were convenience sampled and recruited through networks within the Scottish pain community. The Framework approach was used to analyse findings. RESULTS: All participants had positive attitudes towards the intervention, but patients and family members considered risk of overdose to be very low. Three themes were identified: potential advantages of the intervention; potential barriers to the intervention; and additional suggestions and feedback about the intervention. Advantages included the intervention providing essential overdose information for CNCP patients. Barriers included resource and time pressures within community pharmacies. DISCUSSION AND CONCLUSION: While patients had low overdose knowledge and did not see themselves as being at risk of opioid overdose, they were receptive to naloxone use and positive about the proposed intervention. A feasibility trial is merited to further investigate how the intervention would be experienced within community pharmacy settings.

"It's just not the same": Exploring PWUD' perceptions of and experiences with drug policy and SCS services change in a Canadian City.

BACKGROUND AND AIMS: Shifting political contexts can significantly alter drug policy approaches and available supports for People Who Use Drugs (PWUD). The purpose of this study was to explore how shifts in provincial drug policy approaches, specifically the replacement of a Safe Consumption Site (SCS) with a smaller mobile Overdose Prevention Site (OPS) in Lethbridge, Alberta Canada, impacted PWUD' access to and experiences with harm reduction services. METHODS: We conducted semi-structured interviews with 50 PWUD in the City of Lethbridge, Canada. Through traditional fieldwork, we recruited participants within, and just outside of, downtown Lethbridge. Using a standardized general prompt guide to begin interviews, participants were asked a variety of questions about their experiences with and perceptions of SCS access and changes to SCS provisions. Interviews were audio recorded, then transcribed, coded, and analyzed. RESULTS: Participants reported regular and frequent access and overall positive experiences with the SCS, despite also noting certain operational barriers (e.g., long wait times). By contrast, participants reported more limited use of the new OPS compared to the SCS because of three main reasons: (1) concerns about location; (2) smoking room elimination; and (3) lack of social space and activities. Overall, changes to SCS provision produced a range of negative consequences for PWUD in Lethbridge. These relate to perceived increases in drug-related harms (e.g., increased overdoses) as well as negative social impacts (e.g., lack of place to meet other people). CONCLUSION: Findings from this study provide preliminary indications of the importance of understanding how contextual and locally-specific elements (location, limits on permitted route administration, and social aspects) can work together to facilitate SCS uptake and even overcome traditional SCS barriers. Conversely, the absence of such elements can hinder SCS uptake. Results show that the value of SCS might differ across locations, pointing to the need for further locally-grounded examinations of harm reduction service uptake and experience.

Expanding the accessibility of harm reduction services in the United States: Measuring the impact of an automated harm reduction dispensing machine.

BACKGROUND: In 2021, approximately 107,622 Americans died from drug overdose in the United States. With overdose deaths rising rapidly, it is imperative that prevention efforts focus on expanding proven, evidence-based strategies to curb overdose death rates such as targeted naloxone distribution and syringe service programs (SSPs). The COVID-19 pandemic placed additional strain on SSPs, increasing the need for programs that minimize direct contact and potential COVID-19 exposure. The purpose of this study is to evaluate the impact of an automated harm reduction dispensing machine on the local accessibility of harm reduction services. OBJECTIVES: The primary outcome of the study is the number of harm reduction supplies distributed to the community by the dispensing machine in its first year compared to the number of supplies distributed by the same organization in the previous year. Secondary outcomes include the countywide incidence of fatal drug overdose and human immunodeficiency virus (HIV) compared to previous years. METHODS: The machine is located outside, in the same location as a once weekly, in-person SSP. Clients register with the program over the phone with a harm reduction coordinator. Each client is connected to products and services such as naloxone, sharps containers, safer injection/smoking kits, pregnancy tests, HIV tests, substance use disorder treatment, and more. RESULTS: Since installation, 637 individuals registered with the program, 12% of whom had never reportedly used harm reduction services before. Within its first year of use, the machine dispensed 3360 naloxone doses and 10,155 fentanyl test strips, more than any other SSP in the county. CONCLUSION: The implementation of an automated harm reduction dispensing machine led to an increased accessibility of harm reduction products and services and was associated with a lower countywide incidence of unintentional overdose death and HIV. The association with decreased overdose death and HIV incidence should be further investigated to assess causality.

Knowledge, attitudes, and behaviors related to the fentanyl-adulterated drug supply among people who use drugs in Oregon.

INTRODUCTION: Nonpharmaceutical fentanyl has reconfigured the U.S. illicit drug market, contributing to a drastic increase in overdose drug deaths. While illicit fentanyl has subsumed the drug supply in the Northeast and Midwest, it has more recently reached the West. For this study, we explored knowledge, attitudes, and behaviors among people who use drugs in Oregon in the context of the emergence of fentanyl in the drug supply. METHODS: We conducted in-depth interviews by phone with 34 people who use drugs in Oregon from May to June 2021. We used thematic analysis to analyze transcripts and construct themes. RESULTS: People who use drugs knew about fentanyl, expressed doubt that fentanyl could be found in methamphetamine; believed those who were younger or less experienced were at higher risk for harm; and received information about fentanyl from drug dealers, syringe service programs, or peers (other people who use drugs). Preference for fentanyl's presence in drugs like heroin or methamphetamine was mixed. Some felt that their preference was irrelevant since fentanyl was unavoidable. Participants reported engaging in harm reduction practices, including communicating about fentanyl with dealers and peers, testing for fentanyl, using smaller quantities of drugs, switching from injecting to smoking, and using naloxone. CONCLUSION: People who use drugs are responding to the rise of fentanyl on the West Coast and are concerned about the increasing uncertainty and hazards of the drug supply. They are willing and motivated to adopt harm reduction behaviors. Harm reduction promotion from syringe service programs and public health agencies is essential to reduce injury and death from nonpharmaceutical fentanyl.

More Than a Pipe Dream? The Need to Adapt Safer Opioid Supply Programs for People Who Smoke Drugs.

Safer opioid supply programs are being expanded in select Canadian cities as interventions to provide alternatives to the toxic drug supply. Programs primarily provide tablet hydromorphone for patients to consume orally, intranasally, or intravenously. However, in the Canadian province of British Columbia, smoking is the most common mode of consumption among those who have died from illicit drug overdoses. There is a need for these programs to provide smokable opioid alternatives in order to attract and retain those most at risk of overdose mortality.

Towards an International Consensus on the Prevention, Treatment, and Management of High-Risk Substance Use and Overdose among Youth.

Background and Objectives: Now more than ever, there is an obvious need to reduce the overall burden of disease and risk of premature mortality that are associated with mental health and substance use disorders among young people. However, the current state of research and evidence-based clinical care for high-risk substance use among youth is fragmented and scarce. The objective of the study is to establish consensus for the prevention, treatment, and management of high-risk substance use and overdose among youth (10 to 24 years old). Materials and Methods: A modified Delphi technique was used based on the combination of scientific evidence and clinical experience of a group of 31 experts representing 10 countries. A semi-structured questionnaire with five domains (clinical risks, target populations, intervention goals, intervention strategies, and settings/expertise) was shared with the panelists. Based on their responses, statements were developed, which were subsequently revised and finalized through three iterations of feedback. Results: Among the five major domains, 60 statements reached consensus. Importantly, experts agreed that screening in primary care and other clinical settings is recommended for all youth, and that the objectives of treating youth with high-risk substance use are to reduce harm and mortality while promoting resilience and healthy development. For all substance use disorders, evidence-based interventions should be available and should be used according to the needs and preferences of the patient. Involuntary admission was the only topic that did not reach consensus, mainly due to its ethical implications and resulting lack of comparable evidence. Conclusions: High-risk substance use and overdoses among youth have become a major challenge. The system's response has been insufficient and needs substantial change. Internationally devised consensus statements provide a first step in system improvement and reform.

Improving the performance of Bayesian logistic regression model with overdose control in oncology dose-finding studies.

An accurately identified maximum tolerated dose (MTD) serves as the cornerstone of successful subsequent phases in oncology drug development. Bayesian logistic regression model (BLRM) is a popular and versatile model-based dose-finding design. However, BLRM with original overdose control strategy has been reported to be safe but "excessively conservative." In this article, we investigate the reason for conservativeness and point out that a major reason could be the lack of appropriate underdose control. We propose designs that balance overdose and underdose control to improve the performance over the original BLRM. Simulation results reveal that the new designs have better accuracy and treat more patients at MTD.

Naloxone Co-Dispensing with Opioids: a Cluster Randomized Pragmatic Trial.

BACKGROUND: Although naloxone prevents opioid overdose deaths, few patients prescribed opioids receive naloxone, limiting its effectiveness in real-world settings. Barriers to naloxone prescribing include concerns that naloxone could increase risk behavior and limited time to provide necessary patient education. OBJECTIVE: To determine whether pharmacy-based naloxone co-dispensing affected opioid risk behavior. Secondary objectives were to assess if co-dispensing increased naloxone acquisition, increased patient knowledge about naloxone administration, and affected opioid dose and other substance use. DESIGN: Cluster randomized pragmatic trial of naloxone co-dispensing. SETTING: Safety-net health system in Denver, Colorado, between 2017 and 2020. PARTICIPANTS: Seven pharmacies were randomized. Pharmacy patients (N=768) receiving opioids were followed using automated data for 10 months. Pharmacy patients were also invited to complete surveys at baseline, 4 months, and 8 months; 325 survey participants were enrolled from November 15, 2017, to January 8, 2019. INTERVENTION: Intervention pharmacies implemented workflows to co-dispense naloxone while usual care pharmacies provided usual services. MAIN MEASURES: Survey instruments assessed opioid risk behavior; hazardous drinking; tobacco, cannabis, and other drug use; and knowledge. Naloxone dispensings and opioid dose were evaluated using pharmacy data among pharmacy patients and survey participants. Intention-to-treat analyses were conducted using generalized linear mixed models accounting for clustering at the pharmacy level. KEY RESULTS: Opioid risk behavior did not differ by trial group (P=0.52; 8-month vs. baseline adjusted risk ratio [ARR] 1.07; 95% CI 0.78, 1.47). Compared with usual care pharmacies, naloxone dispensings were higher in intervention pharmacies (ARR 3.38; 95% CI 2.21, 5.15) and participant knowledge increased (P=0.02; 8-month vs. baseline adjusted mean difference 1.05; 95% CI 0.06, 2.04). There was no difference in other substance use by the trial group. CONCLUSION: Co-dispensing naloxone with opioids effectively increased naloxone receipt and knowledge but did not increase self-reported risk behavior. TRIAL REGISTRATION: Registered at ClinicalTrials.gov ; Identifier: NCT03337100.