Rapid Initiation of Injection Naltrexone for Opioid Use Disorder: A Stepped-Wedge Cluster Randomized Clinical Trial.

Importance: Injectable extended-release (XR)-naltrexone is an effective treatment option for opioid use disorder (OUD), but the need to withdraw patients from opioid treatment prior to initiation is a barrier to implementation. Objective: To compare the effectiveness of the standard procedure (SP) with the rapid procedure (RP) for XR-naltrexone initiation. Design, Setting, and Participants: The Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone study was an optimized stepped-wedge cluster randomized trial conducted at 6 community-based inpatient addiction treatment units. Units using the SP were randomly assigned at 14-week intervals to implement the RP. Participants admitted with OUD received the procedure the unit was delivering at the time of their admission. Participant recruitment took place between March 16, 2021, and July 18, 2022. The last visit was September 21, 2022. Interventions: Standard procedure, based on the XR-naltrexone package insert (approximately 5-day buprenorphine taper followed by a 7- to 10-day opioid-free period and RP, defined as 1 day of buprenorphine at minimum necessary dose, 1 opioid-free day, and ascending low doses of oral naltrexone and adjunctive medications (eg, clonidine, clonazepam, antiemetics) for opioid withdrawal. Main Outcomes and Measures: Receipt of XR-naltrexone injection prior to inpatient discharge (primary outcome). Secondary outcomes included opioid withdrawal scores and targeted safety events and serious adverse events. All analyses were intention-to-treat. Results: A total of 415 participants with OUD were enrolled (mean [SD] age, 33.6 [8.48] years; 205 [49.4%] identified sex as male); 54 [13.0%] individuals identified as Black, 91 [21.9%] as Hispanic, 290 [69.9%] as White, and 22 [5.3%] as multiracial. Rates of successful initiation of XR-naltrexone among the RP group (141 of 225 [62.7%]) were noninferior to those of the SP group (68 of 190 [35.8%]) (odds ratio [OR], 3.60; 95% CI, 2.12-6.10). Withdrawal did not differ significantly between conditions (proportion of days with a moderate or greater maximum Clinical Opiate Withdrawal Scale score (>12) for RP vs SP: OR, 1.25; 95% CI, 0.62-2.50). Targeted safety events (RP: 12 [5.3%]; SP: 4 [2.1%]) and serious adverse events (RP: 15 [6.7%]; SP: 3 [1.6%]) were infrequent but occurred more often with RP than SP. Conclusions and Relevance: In this trial, the RP of XR-naltrexone initiation was noninferior to the standard approach and saved time, although it required more intensive medical management and safety monitoring. The results of this trial suggest that rapid initiation could make XR-naltrexone a more viable treatment for patients with OUD. Trial Registration: ClinicalTrials.gov Identifier: NCT04762537.

Effects of perioperative low-dose naloxone on the immune system in patients undergoing laparoscopic-assisted total gastrectomy: a randomized controlled trial.

BACKGROUND: Low immune function after laparoscopic total gastrectomy puts patients at risk of infection-related complications. Low-dose naloxone (LDN) can improve the prognosis of patients suffering from chronic inflammatory diseases or autoimmune diseases. The use of LDN during perioperative procedures may reduce perioperative complications. The purpose of this study was to examine the effects of LDN on endogenous immune function in gastric cancer patients and its specific mechanisms through a randomized controlled trial. METHODS: Fifty-five patients who underwent laparoscopic-assisted total gastrectomy were randomly assigned to either a naloxone group (n = 23) or a nonnaloxone group (n = 22). Patients in the naloxone group received 0.05 µg/kg-1.h- 1naloxone from 3 days before surgery to 5 days after surgery via a patient-controlled intravenous injection (PCIA) pump, and patients in the nonnaloxone group did not receive special treatment. The primary outcomes were the rates of postoperative complications and immune function assessed by NK cell, CD3+ T cell, CD4+ T cell, CD8+ T cell, WBC count, neutrophil percentage, and IL-6 and calcitonin levels. The secondary outcomes were the expression levels of TLR4 (Toll-like receptor), IL-6 and TNF-α in gastric cancer tissue. RESULTS: Compared with the nonnaloxone group, the naloxone group exhibited a lower incidence of infection (in the incision, abdomen, and lungs) (P < 0.05). The numbers of NK cells and CD8+ T cells in the naloxone group were significantly greater than those in the nonnaloxone group at 24 h after surgery (P < 0.05) and at 96 h after surgery (P < 0.05). Compared with those in the nonnaloxone group, the CD3 + T-cell (P < 0.05) and CD4 + T-cell (P < 0.01) counts were significantly lower in the naloxone group 24 h after surgery. At 24 h and 96 h after surgery, the WBC count (P < 0.05) and neutrophil percentage (P < 0.05) were significantly greater in the nonnaloxone group. The levels of IL-6 (P < 0.05) and calcitonin in the nonnaloxone group were significantly greater at 24 h after surgery. At 24 h following surgery, the nonnaloxone group had significantly greater levels of IL-6 (P < 0.05) and calcitonin than did the naloxone group. Compared with those in the naloxone group, the expression levels of TLR4 (P < 0.05) in gastric cancer tissue in the naloxone group were greater; however, the expression levels of IL-6 (P < 0.01) and TNF-α (P < 0.01) in the naloxone group were greater than those in the nonnaloxone group. CONCLUSION: Laparoscopic total gastrectomy patients can benefit from 0.05 ug/kg- 1. h- 1 naloxone by reducing their risk of infection. It is possible that LDN alters the number of cells in lymphocyte subpopulations, such as NK cells, CD3 + T cells, and CD4 + T cells, and the CD4+/CD8 + T-cell ratio or alters TLR4 receptor expression in immune cells, thereby altering immune cell activity. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry on 24/11/2023 (ChiCTR2300077948).

A case of naltrexone-induced acute eosinophilic pneumonia.

Acute eosinophilic pneumonia (AEP) is a rare cause of acute respiratory failure. Clinical presentations can range from dyspnoea, fever and cough, to rapidly progressive and potentially fulminant respiratory failure. While its exact cause is often unknown, associations with inhalational injuries and exposures to new medications have been described.We report a case of a middle-aged, non-smoking man with a history of alcohol use disorder. He presented with 4 days of shortness of breath that started hours after taking injectable naltrexone (Vivitrol). The patient had rapidly worsening hypoxaemia, necessitating emergent bronchoscopy with transbronchial biopsies and bronchoalveolar lavage which showed 66% eosinophils. The patient was intubated for the procedure and unable to get extubated due to worsening hypoxaemic respiratory failure with high fractional inspired oxygen requirements. Chest radiograph showed worsening lung infiltrates and with a high index of suspicion for AEP, he was started empirically on methylprednisolone. He had rapid improvement in his respiratory status and was extubated on day 5 of admission then discharged on day 8. Histopathological examination confirmed acute/subacute eosinophilic pneumonia. A 3-week post-discharge follow-up chest radiograph confirmed the full resolution of pulmonary infiltrates.Naltrexone-induced AEP is rare, with only six other cases reported in the literature. Careful history taking and prompt evaluation for AEP are important given the potential for rapid progression to acute hypoxic respiratory failure and the excellent response to steroid treatment.

Using quality improvement approaches to increase emergency department provider engagement in research participant enrollment during COVID-19 and opioid overdose public health emergencies.

PURPOSE: We utilized quality improvement (QI) approaches to increase emergency department (ED) provider engagement with research participant enrollment during the opioid crisis and coronavirus disease (COVID-19) pandemic. The context of this work is the Evaluating Microdosing in the Emergency Department (EMED) study, a randomized trial offering buprenorphine/naloxone to ED patients through randomization to standard or microdosing induction. Engaging providers is crucial for participant recruitment to our study. Anticipating challenges sustaining long-term engagement after a 63% decline in provider referrals four months into enrollments, we applied Plan-Do-Study-Act (PDSA) cycles to develop and implement an engagement strategy to increase and sustain provider engagement by 50% from baseline within 9 months. METHODS: Our engagement strategy was centered on Coffee Carts rounds: 5-min study-related educational presentations for providers on shift; and a secondary initiative, a Suboxone Champions program, to engage interested providers as study-related peer educators. We used provider referrals to our team as a proxy for study engagement and report the percent change in mean weekly referrals across two PDSA cycles relative to our established referral baseline. RESULTS: A QI approach afforded real-time review of interventions based on research and provider priorities, increasing engagement via mean weekly provider referrals by 14.5% and 49% across two PDSA cycles relative to baseline, respectively. CONCLUSIONS: Our Coffee Carts and Suboxone Champions program are efficient, low-barrier, educational initiatives to convey study-related information to providers. This work supported our efforts to maximally engage providers, minimize burden, and provide life-saving buprenorphine/naloxone to patients at risk of fatal overdose.

RéSUMé: BUT: Nous avons utilisé des approches d'amélioration de la qualité (AQ) pour accroître l'engagement des fournisseurs des services d'urgence (SU) avec l'inscription des participants à la recherche pendant la crise des opioïdes et la pandémie de maladie à coronavirus (COVID-19). Le contexte de ce travail est l'étude Evaluating Microdosing in the Emergency Department (EMED), un essai randomisé offrant de la buprénorphine/naloxone aux patients aux urgences par randomisation à l'induction standard ou au microdosage. L'engagement des fournisseurs est crucial pour le recrutement des participants à notre étude. En anticipant les difficultés à maintenir un engagement à long terme après une baisse de 63 % des recommandations de fournisseurs quatre mois après les inscriptions, nous avons appliqué le Plan-Do-Study-Act (PDSA) cycles d'élaboration et de mise en œuvre d'une stratégie d'engagement visant à accroître et à maintenir l'engagement des fournisseurs de 50 % par rapport au niveau de référence dans les neuf mois. MéTHODES: Notre stratégie de mobilisation était axée sur les tournées de Coffee Carts : des présentations éducatives de cinq minutes sur l'étude pour les fournisseurs sur le quart de travail; et une initiative secondaire, un programme Suboxone Champions, pour mobiliser les fournisseurs intéressés en tant que pairs éducateurs liés à l'étude. Nous avons utilisé les recommandations des fournisseurs à notre équipe comme indicateur de la participation à l'étude et nous avons signalé le pourcentage de changement dans les recommandations hebdomadaires moyennes pour deux cycles PDSA par rapport à notre base de référence établie. RéSULTATS: Une approche d'AQ a permis d'examiner en temps réel les interventions en fonction des priorités de la recherche et des fournisseurs, ce qui a augmenté l'engagement par l'intermédiaire des recommandations hebdomadaires moyennes des fournisseurs de 14,5 % et de 49 % au cours de deux cycles de PDSA par rapport au niveau de référence, respectivement. CONCLUSION: Notre programme Coffee Carts and Suboxone Champions est une initiative éducative efficace et peu contraignante qui permet de transmettre aux fournisseurs des renseignements sur les études. Ce travail a appuyé nos efforts visant à mobiliser au maximum les fournisseurs, à réduire au minimum le fardeau et à fournir de la buprénorphine/naloxone vitale aux patients à risque de surdose mortelle.

Low-dose naltrexone for post-COVID fatigue syndrome: a study protocol for a double-blind, randomised trial in British Columbia.

INTRODUCTION: A significant proportion of individuals suffering from post COVID-19 condition (PCC, also known as long COVID) can present with persistent, disabling fatigue similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-viral fatigue syndromes. There remains no clear pharmacological therapy for patients with this subtype of PCC, which can be referred to as post-COVID fatigue syndrome (PCFS). A low dose of the opioid antagonist naltrexone (ie, low-dose naltrexone (LDN)) has emerged as an off-label treatment for treating fatigue and other symptoms in PCC. However, only small, non-controlled studies have assessed LDN in PCC, so randomised trials are urgently required. METHODS AND ANALYSIS: A prospective, randomised, double-blind, parallel arm, placebo-controlled phase II trial will be performed to assess the efficacy of LDN for improving fatigue in PCFS. The trial will be decentralised and open to eligible individuals throughout the Canadian province of British Columbia (BC). Participants will be recruited through the province-wide Post-COVID-19 Interdisciplinary Clinical Care Network (PC-ICCN) and research volunteer platform (REACH BC). Eligible participants will be 19-69 years old, have had a confirmed or physician-suspected SARS-CoV-2 infection at least 3 months prior and meet clinical criteria for PCFS adapted from the Institute of Medicine ME/CFS criteria. Individuals who are taking opioid medications, have a history of ME/CFS prior to COVID-19 or history of significant liver disease will be excluded. Participants will be randomised to an LDN intervention arm (n=80) or placebo arm (n=80). Participants in each arm will be prescribed identical capsules starting at 1 mg daily and follow a prespecified schedule for up-titration to 4.5 mg daily or the maximum tolerated dose. The trial will be conducted over 16 weeks, with assessments at baseline, 6, 12 and 16 weeks. The primary outcome will be fatigue severity at 16 weeks evaluated by the Fatigue Severity Scale. Secondary outcomes will include pain Visual Analogue Scale score, overall symptom severity as measured by the Patient Phenotyping Questionnaire Short Form, 7-day step count and health-related quality of life measured by the EuroQol 5-Dimension questionnaire. ETHICS AND DISSEMINATION: The trial has been authorised by Health Canada and approved by The University of British Columbia/Children's and Women's Health Centre of British Columbia Research Ethics Board. On completion, findings will be disseminated to patients, caregivers and clinicians through engagement activities within existing PCC and ME/CFS networks. Results will be published in academic journals and presented at conferences. TRIAL REGISTRATION NUMBER: NCT05430152.

High-dose naloxone formulations are not as essential as we thought.

Naloxone is an effective FDA-approved opioid antagonist for reversing opioid overdoses. Naloxone is available to the public and can be administered through intramuscular (IM), intravenous (IV), and intranasal spray (IN) routes. Our literature review investigates the adequacy of two doses of standard IM or IN naloxone in reversing fentanyl overdoses compared to newer high-dose naloxone formulations. Moreover, our initiative incorporates the experiences of people who use drugs, enabling a more practical and contextually-grounded analysis. The evidence indicates that the vast majority of fentanyl overdoses can be successfully reversed using two standard IM or IN dosages. Exceptions include cases of carfentanil overdose, which necessitates ≥ 3 doses for reversal. Multiple studies documented the risk of precipitated withdrawal using ≥ 2 doses of naloxone, notably including the possibility of recurring overdose symptoms after resuscitation, contingent upon the half-life of the specific opioid involved. We recommend distributing multiple doses of standard IM or IN naloxone to bystanders and educating individuals on the adequacy of two doses in reversing fentanyl overdoses. Individuals should continue administration until the recipient is revived, ensuring appropriate intervals between each dose along with rescue breaths, and calling emergency medical services if the individual is unresponsive after two doses. We do not recommend high-dose naloxone formulations as a substitute for four doses of IM or IN naloxone due to the higher cost, risk of precipitated withdrawal, and limited evidence compared to standard doses. Future research must take into consideration lived and living experience, scientific evidence, conflicts of interest, and the bodily autonomy of people who use drugs.

Is a randomised controlled trial of take home naloxone distributed in emergency settings likely to be feasible and acceptable? Findings from a UK qualitative study exploring perspectives of people who use opioids and emergency services staff.

OBJECTIVE: Distribution of take-home naloxone (THN) by emergency services may increase access to THN and reduce deaths and morbidity from opioid overdose. As part of a feasibility study for a randomised controlled trial (RCT) of distribution of THN kits and education within ambulance services and Emergency Departments (EDs), we used qualitative methods to explore key stakeholders' perceptions of feasibility and acceptability of delivering the trial. METHODS: We undertook semi-structured interviews and focus groups with 26 people who use opioids and with 20 paramedics and ED staff from two intervention sites between 2019 and 2021. Interviews and focus groups were recorded, transcribed verbatim and analysed using Framework Analysis. RESULTS: People using opioids reported high awareness of overdose management, including personal experience of THN use. Staff perceived emergency service provision of THN as a low-cost, low-risk intervention with potential to reduce mortality, morbidity and health service use. Staff understood the trial aims and considered it compatible with their work. All participants supported widening access to THN but reported limited trial recruitment opportunities partly due to difficulties in consenting patients during overdose. Procedural problems, restrictive recruitment protocols, limited staff buy-in and patients already owning THN limited trial recruitment. Determining trial effectiveness was challenging due to high levels of alternative community provision of THN. CONCLUSIONS: Distribution of THN in emergency settings was considered feasible and acceptable for stakeholders but an RCT to establish the effectiveness of THN delivery is unlikely to generate further useful evidence due to difficulties in recruiting patients and assessing benefits.

Model of negative affect induced by withdrawal from acute and chronic morphine administration in male mice.

Opioid use disorder (OUD) is a chronic relapsing disorder that is a major burden for the lives of affected individuals, and society as a whole. Opioid withdrawal is characterized by strong physical symptoms, along with signs of negative affect. Negative affect due to opioid withdrawal is a major obstacle to recovery and relapse prevention. The mechanisms behind negative affect due to either spontaneous or antagonist-precipitated opioid withdrawal are not well known, and more animal models need be developed. Here, we present behavioral models of negative affect upon naloxone-precipitated morphine withdrawal in adult male mice. Social, anxiety, and despair-like deficits were investigated following naloxone administration in mice receiving morphine under three dosing regimens; acute, chronic constant dose and chronic escalating doses. Social behaviour in the three-chamber social preference test was decreased following withdrawal from chronic and escalating but not acute morphine. Anxiety-like behaviour in the open field was increased for all three treatments. Despair-like behaviour was increased following withdrawal from chronic and escalating but not acute morphine. Altogether, these animal models will contribute to study behavioural and neuronal circuitries involved in the several negative affective signs characterizing OUD.

Clinical Pharmacokinetics and Pharmacodynamics of Naloxone.

Naloxone is a World Health Organization (WHO)-listed essential medicine and is the first choice for treating the respiratory depression of opioids, also by lay-people witnessing an opioid overdose. Naloxone acts by competitive displacement of opioid agonists at the µ-opioid receptor (MOR). Its effect depends on pharmacological characteristics of the opioid agonist, such as dissociation rate from the MOR receptor and constitution of the victim. Aim of treatment is a balancing act between restoration of respiration (not consciousness) and avoidance of withdrawal, achieved by titration to response after initial doses of 0.4-2 mg. Naloxone is rapidly eliminated [half-life (t1/2) 60-120 min] due to high clearance. Metabolites are inactive. Major routes for administration are intravenous, intramuscular, and intranasal, the latter primarily for take-home naloxone. Nasal bioavailability is about 50%. Nasal uptake [mean time to maximum concentration (Tmax) 15-30 min] is likely slower than intramuscular, as reversal of respiration lag behind intramuscular naloxone in overdose victims. The intraindividual, interindividual and between-study variability in pharmacokinetics in volunteers are large. Variability in the target population is unknown. The duration of action of 1 mg intravenous (IV) is 2 h, possibly longer by intramuscular and intranasal administration. Initial parenteral doses of 0.4-0.8 mg are usually sufficient to restore breathing after heroin overdose. Fentanyl overdoses likely require higher doses of naloxone. Controlled clinical trials are feasible in opioid overdose but are absent in cohorts with synthetic opioids. Modeling studies provide valuable insight in pharmacotherapy but cannot replace clinical trials. Laypeople should always have access to at least two dose kits for their interim intervention.

Buprenorphine dispensing before and after the April 2021 X-Waiver exemptions: An interrupted time series analysis.

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

Adverse Effects After Prehospital Administration of Naloxone by Bystanders: A Preliminary Study.

OBJECTIVE: Opioid use disorder is a cause of significant morbidity and mortality. In order to reverse opioid overdose as quickly as possible, many institutions and municipalities have encouraged people with no professional medical training to carry and administer naloxone. This study sought to provide preliminary data for research into the rates of adverse effects of naloxone when administered by bystanders compared to Emergency Medical Services (EMS) personnel, since this question has not been studied previously. METHODS: This was a retrospective cohort study performed at an urban, tertiary, academic medical center that operates its own EMS service. A consecutive sample of patients presenting to EMS with opioid overdose requiring naloxone was separated into two groups based on whether naloxone was administered by bystanders or by EMS personnel. Each group was analyzed to determine the incidence of four pre-specified adverse events. RESULTS: There was no significant difference in the rate of adverse events between the bystander (19%) and EMS (16%) groups (OR = 1.23; 95% CI, 0.63 - 2.32; P = .499) in this small sample. Based on these initial results, a study would need a sample size of 6,188 in order to reach this conclusion with 80% power. Similarly, there were no significant differences in the rates of any of the individual adverse events. Secondary analysis of patients' demographics showed differences between the two groups which generate hypotheses for further investigation of disparities in naloxone administration. CONCLUSIONS: This preliminary study provides foundational data for further investigation of naloxone administration by bystanders. Adverse events after the prehospital administration of naloxone are rare, and future studies will require large sample sizes. These preliminary data did not demonstrate a statistically significant difference in adverse event rates when comparing naloxone administration by bystanders and EMS clinicians. This study provides data that will be useful for conducting further research on multiple facets of this topic.

Characterizing acute and postsurgical pain management in patients receiving buprenorphine or buprenorphine/naloxone.

BACKGROUND: There is currently a clinical dilemma in treating acute pain in patients receiving long-term buprenorphine products. METHODS: This is a retrospective cohort review involving patients receiving long-term buprenorphine therapy who either underwent a surgical procedure or presented to an emergency department (ED) for acute pain between January 1, 2012 and January 1, 2022. Patients were excluded if opioids were prescribed 30 days before the index date. Chart reviews were conducted to characterize buprenorphine treatment strategies and the addition of new pain medications. Chart review revealed (1) incidence of opioid use disorder (OUD) relapse, (2) hospital re-presentation for pain or OUD, (3) fatal and non-fatal overdose, and (4) all-cause mortality and suicidality. Descriptive statistics were used to analyze results. RESULTS: A total of 70 of 259 screened patients met inclusion criteria. The mean (±SD) age was 50.3 ± 13 years, 92.9% male, 64.3% White, and 78.6% had an OUD diagnosis. While 84.3% presented to the ED, 15.7% underwent surgical procedures. For the primary endpoint, the total daily dose of buprenorphine or buprenorphine/naloxone from index date to discharge was continued in 90.0%, increased in 2.9%, decreased in 1.4%, and discontinued in 5.7% of cases. At discharge, 46.2% were prescribed an additional pain medication. A total of 7.1% re-presented for pain or OUD relapse, 15.7% experienced an OUD relapse, 1.4% experienced new-onset suicidality, and 1.4% experience all-cause mortality within 90 days of the index date. No fatal or non-fatal opioid overdoses were observed. CONCLUSION: The most commonly observed practice was continuing buprenorphine doses in patients with acute or postsurgical pain, which was effective and safe. Although further data is necessary to fully elucidate these findings, the data herein may suggest that clinicians can safely continue buprenorphine doses in the acute pain setting in patients receiving these products chronically.

Tinkering with care: Implementing extended-release buprenorphine depot treatment for opioid dependence.

We examine how extended-release buprenorphine depot (BUP-XR) is put to use and made to work in implementation practices, attending to how care practices are challenged and adapted as a long-acting technology is introduced into service in opioid agonist treatment (OAT) in Australia. Our approach is informed by ideas in science and technology studies (STS) emphasising the irreducible entanglement of care practices and technology, and in particular the concept of 'tinkering' as a practice of adaptation. To make our analysis, we draw on qualitative interview accounts (n = 19) of service providers involved in BUP-XR implementation across five sites. Our analysis considers the disruptive novelty of BUP-XR. Tinkering to make a novel technology work in practice slows down the expectation of implementation in relation to transformative innovation, despite the promise of dramatic or rapid change. Tinkering allowed for more open relations, for new care practices that departed from the routine and familiar, opening potential for how BUP-XR could be put to use and made to work in its new situation, and as its situation evolved along-with its implementation. Flexibility and openness of altering relations was, however, at times, held in tension with inflexibility and closure. This analysis identifies a concern for what is made present and what is made absent in the altered care network affected by BUP-XR, with the multiple effects of supervised daily dosing practices thrown into relief as they become absented. Tinkering to implement BUP-XR locally connects with a broader assemblage of trial and movement in the constitution of treatment. The introduction of long-acting technologies prompts new questions about embedded implementation practices, including supervised dosing, urinalysis, the time and place of psychosocial support, and how other social aspects of care might be recalibrated in drug treatment.

Naloxone Accessibility by Standing Order in North Carolina Community Pharmacies.

BACKGROUND: According to a standing order in North Carolina (NC), naloxone can be purchased without a provider prescription. OBJECTIVE: The objective of this study is to examine whether same-day naloxone accessibility and cost vary by pharmacy type and rurality in NC. METHODS: A cross-sectional telephone audit of 202 NC community pharmacies stratified by pharmacy type and county of origin was conducted in March and April 2023. Trained "secret shoppers" enacted a standardized script and recorded whether naloxone was available and its cost. We examined the relationship between out-of-pocket naloxone cost, pharmacy type, and rurality. RESULTS: Naloxone could be purchased in 53% of the pharmacies contacted; 26% incorrectly noting that naloxone could be filled only with a provider prescription and 21% did not sell naloxone. Naloxone availability by standing order was statistically different by pharmacy type (chain/independent) (χ2 = 20.58, df = 4, P value < 0.001), with a higher frequency of willingness to dispense according to the standing order by chain pharmacies in comparison to independent pharmacies. The average quoted cost for naloxone nasal spray at chain pharmacies was $84.69; the cost was significantly more ($113.54; P < 0.001) at independent pharmacies. Naloxone cost did not significantly differ by pharmacy rurality (F2,136 = 2.38, P = 0.10). CONCLUSION: Approximately half of NC community pharmacies audited dispense naloxone according to the statewide standing order, limiting same-day access to this life-saving medication. Costs were higher at independent pharmacies, which could be due to store-level policies. Future studies should further investigate these cost differences, especially as intranasal naloxone transitions from a prescription only to over-the-counter product.

Naloxone access in perinatal substance use disorder.

BACKGROUND: Risk of fatal drug overdose is higher in pregnant and postpartum people with substance use disorder (SUD) than for nonpregnant women of reproductive age. It is recommended that naloxone is prescribed for pregnancies complicated by opioid or stimulant use disorder. OBJECTIVE: The purpose of this study was to assess the rates of naloxone coprescribing with buprenorphine in a perinatal SUD (PSUD) specialty clinic and identify opportunities for pharmacist-led interventions to improve communication and documentation surrounding naloxone access to achieve a rate of 100% coprescribing of naloxone with buprenorphine. PRACTICE DESCRIPTION: A clinical pharmacist practitioner is embedded on the Project CARA (Care that Advocates Respect/Resilience/Recovery for All) team, which provides outpatient SUD care integrated with perinatal care in Western North Carolina. PRACTICE INNOVATION: The clinical pharmacist practitioner assessed baseline rates of naloxone coprescribing with medications for opioid use disorder. Interventions to improve rates of coprescribing include provider education, electronic health record (EHR) documentation templates, and direct patient outreach. EVALUATION METHODS: Baseline rates of naloxone coprescribing were assessed and then re-evaluated after different interventions to measure pharmacist impact. RESULTS: Each intervention improved rates of naloxone coprescribing in a PSUD clinic. EHR documentation templates had the largest impact on baseline efforts, although the long-term benefits derived from these efforts have not yet been demonstrated. Substantial time investment from the pharmacist was required to address patients' barriers to obtaining naloxone after their visits. CONCLUSION: Further process improvement should address barriers to naloxone access for both patients and providers. This may include proactive identification of patients in need of naloxone and a "meds-to-beds" pilot to assist patients in navigating logistical challenges.

Pharmacokinetic-pharmacodynamic analysis of drug liking blockade by buprenorphine subcutaneous depot (CAM2038) in participants with opioid use disorder.

Buprenorphine is used to treat opioid use disorder (OUD). Weekly and monthly subcutaneous long-acting buprenorphine injections (CAM2038) provide more stable buprenorphine plasma levels and reduce the treatment burden, misuse, and diversion associated with sublingual transmucosal buprenorphine formulations. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship, a maximum inhibition (Imax) model was developed relating CAM2038 buprenorphine plasma concentration to drug liking maximum effect (Emax) visual analog scale (VAS; bipolar) score after intramuscular hydromorphone administration. Data included time-matched observations of buprenorphine plasma concentration and drug liking Emax VAS score after hydromorphone 18 mg administration in 47 non-treatment-seeking adults with moderate to severe OUD in a phase 2 study. Analysis used non-|linear mixed-effects modeling (NONMEM®). The final Imax model adequately described the PK/PD relationship between buprenorphine plasma concentration and drug liking Emax VAS score. Simulations showed drug liking was effectively blocked at low buprenorphine plasma concentrations (0.4 ng/mL) where the upper 95% confidence interval of the drug liking Emax VAS score was below the pre-defined 11-point complete blockade threshold. The buprenorphine plasma concentration required to achieve 90% of the maximal effect (IC90) of drug liking was 0.675 ng/mL. Interindividual variability in responses to buprenorphine was observed; some participants experienced fluctuating responses, and a few did not achieve drug liking blockade even with higher buprenorphine plasma concentrations. This affirms the need to individualize treatment and titrate doses for optimal treatment outcomes. PK/PD models were also developed for desire to use VAS and Clinical Opiate Withdrawal Scale (COWS) scores, with results aligned to those for drug liking.

Availability of Long-Acting Injectable Buprenorphine at Substance Use Treatment Facilities in 2021.

This study assesses the proportion of US substance use and mental health care facilities that offered any medications for opioid use disorder and, specifically, long-acting injectable buprenorphine in 2021.

Assessment of a naloxone distribution plan in a veteran population who experienced an opioid-related overdose event.

BACKGROUND: The Veteran Health Administration prioritizes the distribution of naloxone to veterans diagnosed with opioid use disorder (OUD) to prevent deaths due to opioid-related overdose. The Overdose Education and Naloxone Distribution (OEND) program was created with tools to supplement efforts in identifying veterans at risk of opioid-related adverse events secondary to OUD or other comorbidities and increase access, education, and distribution of naloxone. Utilizing the OEND tool, Veteran Health Indiana (VHI) employed two different distribution initiatives to increase access to naloxone. OBJECTIVE: The purpose of this study is to assess naloxone distribution efforts at a VA medical center and evaluate outcomes in patients who experienced opioid overdose events before and after the OEND initiatives were implemented. The primary outcome is to assess the distribution of naloxone within the year prior to the documented overdose event before and after the OEND initiatives. Secondary outcomes include assessment of the number of naloxone doses administered during the overdose event, substances involved in the overdose, and distribution of outpatient naloxone prescriptions after the overdose event. METHODS: This study was a retrospective electronic chart review of all patients who experienced an opioid-related overdose event at VHI from March 1, 2019, to March 1, 2022. RESULTS: Of the 59 opioid-overdose events analyzed, the percentage of patients with a naloxone prescription within 12 months prior to an opioid-overdose event was similar between the pre- and post-OEND initiatives. Within 12 months following the overdose event, naloxone was dispensed to nearly 10% more patients in the post-OEND group compared to the pre-OEND group. CONCLUSIONS: The OEND initiatives increased naloxone distribution amongst patients who ultimately experienced an opioid-related overdose. Additional research is needed to assess if these efforts prevented further overdoses.