Perioperative Naltrexone Management: A Scoping Review by the Perioperative Pain and Addiction Interdisciplinary Network.

Substance use disorders, including alcohol use disorder, are a public health concern that affect more than 150 million people globally. The opioid antagonist naltrexone is being increasingly prescribed to treat opioid use disorder, alcohol use disorder, and chronic pain. Perioperative management of patients on naltrexone is inconsistent and remains a controversial topic, with mismanagement posing a significant risk to the long-term health of these patients. This scoping review was conducted to identify human studies in which the perioperative management of naltrexone was described. This review includes a systematic literature search involving Medline, Medline In-Process, Embase, PsycINFO, and Web of Science. Seventeen articles that describe perioperative naltrexone management strategies were included, including thirteen guidelines, one case report, and three randomized trials. Despite its use in patients with alcohol use disorder and chronic pain, no clinical studies, case reports, or guidelines addressed naltrexone use in these clinical populations. All of the guideline documents recommended the preoperative cessation of naltrexone, irrespective of dose, indication, or route of administration. None of these guideline documents were designed on the basis of a systematic literature search or a Delphi protocol. As described by the primary studies, perioperative pain relief varied depending on naltrexone dose and route of administration, time since last naltrexone administration, and underlying substance use disorder. None of the studies commented on the maintenance of recovery for the patient's substance use disorder in the context of perioperative naltrexone management. The current understanding of the risks and benefits of continuing or stopping naltrexone perioperatively is limited by a lack of high-quality evidence. In patients with risk factors for return to use of opioids or alcohol, the discontinuation of naltrexone should have a strong rationale. Future studies and guidelines should seek to address both acute pain management and maintaining recovery when discussing perioperative naltrexone management strategies.

"We don't even know where it's kept": exploring perspectives on naloxone administration by provincial correctional workers in Manitoba, Canada.

PURPOSE: Prisonersare at disproportionate risk of suffering substance-related harms. The administration of naloxone is essential to reversing opioid overdose and minimizing substance-related harms in prison and the community. The purpose of this study is to examine how naloxone administration is practiced and perceived in prison settings. DESIGN/METHODOLOGY/APPROACH: The authors conducted surveys with correctional workers in Manitoba, Canada (n = 257) to examine how they understand and feel about the need for and practice of administering naloxone in their everyday work with criminalized populations. FINDINGS: Respondents reported feeling a great need to administer naloxone, but most did not feel adequately trained to administer naloxone, creating the perception that criminalized populations remain at enhanced risk. ORIGINALITY/VALUE: Findings provide emerging evidence of the need for training and accompanying policies and procedures for correctional workers on how to access and administer naloxone.

The safety and effectiveness of naldemedine for opioid-induced constipation in patients with advanced cancer in real-world palliative care settings: a multicenter prospective observational study.

PURPOSE: In this study, we aimed to evaluate the safety and effectiveness of naldemedine for treating opioid-induced constipation (OIC) in patients with advanced cancer, who are receiving palliative care, and particularly explored its early effects. METHODS: Palliative care teams and inpatient palliative care units across 14 institutions in Japan were included in this multicenter, prospective, observational study. Patients who were newly prescribed a daily oral dose of 0.2 mg naldemedine were enrolled. The spontaneous bowel movement (SBM) within 24 h after the first dose of naldemedine was considered the primary outcome, whereas, the secondary outcomes included weekly changes in SBM frequency and adverse events. RESULTS: A total of 204 patients were enrolled and 184 completed the 7-day study. The average age of the participants (103 males, 101 females) was 63 ± 14 years. The primary cancer was detected in the lungs (23.5%), gastrointestinal tract (13.7%), and urological organs (9.3%). A considerable proportion of patients (34.8%) had ECOG performance status of 3-4. Most patients were undergoing active cancer treatment, however, 40.7% of the patients were receiving the best supportive care. Within 24 h of the first naldemedine dose, 146 patients (71.6%, 95% CI: 65.4-77.8%) experienced SBMs. The weekly SBM counts increased in 62.7% of the participants. The major adverse events included diarrhea and abdominal pain, detected in 17.6% and 5.4% of the patients, respectively. However, no serious adverse events were observed. CONCLUSION: Conclusively, naldemedine is effective and safe for OIC treatments in real-world palliative care settings. TRIAL REGISTRATION NUMBER: UMIN000031381, registered 20/02/2018.

Intranasal Delivery of Medications for the Treatment of Neurologic Conditions: A Pharmacology Update.

ABSTRACT: INTRODUCTION: Nurses have a central role in educating patients and families about treatment options and how to integrate them into action plans for neurologic conditions. In recent years, a growing number of intranasal formulations have become available as rescue therapy for neurologic conditions or symptoms including migraine, opioid overdose, and seizures. Rescue therapies do not replace maintenance medications or emergency care but are designed to enable rapid treatment of urgent or disabling conditions in community settings. Yet, discussion of rescue therapies for neurologic conditions remains limited in nursing literature. CONTENT: Intranasal formulations are specifically formulated for delivery and absorption in the nose and have several characteristics that are well suited as rescue therapies for neurologic conditions. Intranasal formulations include triptans for migraine, naloxone and nalmefene for opioid overdose, and benzodiazepines for seizure clusters in patients with epilepsy. Therapeutic attributes discussed here include ease of use in community settings by nonmedical professionals, relatively rapid onset of action, and favorable safety profile and patient experience. This information is critical for nurses to make informed decisions about rescue therapy options, incorporate these into plans of care, and educate patients, care partners, and other healthcare providers. CONCLUSION: Rescue therapies are increasingly important in the care of people with neurologic conditions. Various formulations are available and continue to evolve, offering easy and quick ways for nurses, patients, and nonmedical care partners to administer critical rescue medications. For nurses overseeing medication management, the attributes of intranasal rescue therapies should be considered in the context of providing patients with the right care at the right time.

Considerations when prescribing opioid agonist therapies for people living with HIV.

INTRODUCTION: Medications for opioid use disorder (MOUD) include opioid agonist therapies (OAT) (buprenorphine and methadone), and opioid antagonists (extended-release naltrexone). All forms of MOUD improve opioid use disorder (OUD) and HIV outcomes. However, the integration of services for HIV and OUD remains inadequate. Persistent barriers to accessing MOUD underscore the immediate necessity of addressing pharmacoequity in the treatment of OUD in persons with HIV (PWH). AREAS COVERED: In this review article, we specifically focus on OAT among PWH, as it is the most commonly utilized form of MOUD. Specifically, we delineate the intersection of HIV and OUD services, emphasizing their integration into the United States Ending the HIV Epidemic (EHE) plan by offering comprehensive screening, testing, and treatment for both HIV and OUD. We identify potential drug interactions of OAT with antiretroviral therapy (ART), address disparities in OAT access, and present the practical benefits of long-acting formulations of buprenorphine, ART, and pre-exposure prophylaxis for improving HIV prevention and treatment and OUD management. EXPERT OPINION: Optimizing OUD outcomes in PWH necessitates careful attention to diagnosing OUD, initiating OUD treatment, and ensuring medication retention. Innovative approaches to healthcare delivery, such as mobile pharmacies, can integrate both OUD and HIV and reach underserved populations.

How Should Harm Reduction Be Included in Care Continua for Patients With Opioid Use Disorder?

Practices and interventions that aim to slow progression or reduce negative consequences of substance use are harm reduction strategies. Often described as a form of tertiary prevention, harm reduction is key to caring well for people who use drugs. Evidence-based harm reduction interventions include naloxone and syringe service programs. Improving equitable outcomes for those with opioid use disorder (OUD) requires access to the continuum of evidence-based OUD care, including harm reduction interventions, as well as dismantling policies that undermine mental health and substance use disorder treatment continuity, housing stability, and education and employment opportunities.

How Should Risks and Benefits of Short-Acting Opioids Be Evaluated in the Care of Inpatients With OUD?

Severe opioid withdrawal, risk of patient-initiated discharge, and some inpatients' use of unregulated substances prompt clinical and ethical questions considered in this commentary on a case. Short-acting opioids can be used to manage inpatients' pain and opioid use disorder (OUD) withdrawal symptoms. Including evidence-based interventions-such as naloxone kits, substance use equipment, and supervised consumption-in some inpatients' care plans may make those patients safer and reduce their risk of death. These and other strategies align with clinicians' ethical duties to minimize harms and maximize benefits for inpatients with OUD.

A pilot study surveying the impact of pharmacist-led counseling on naloxone dispensing.

OBJECTIVE: The purpose of this study was to evaluate the impact of pharmacist counseling on patients purchasing naloxone and to highlight reasons for naloxone purchase refusal. DESIGN: A multisite study that was conducted from September 15, 2022, to January 11, 2023. SETTING: Independent community pharmacies. PATIENTS/PARTICIPANTS: Fifty patients met inclusion criteria. Data collected included demographics, preintervention knowledge assessment, post-intervention naloxone purchase, and reasons for naloxone refusal. OUTCOME MEASURES: The primary outcome was naloxone purchase after pharmacist education intervention. The secondary outcome was reasons for naloxone purchase refusal. RESULTS: The primary outcome showed that 60 percent of patients purchased naloxone after pharmacist intervention. As a secondary outcome, the number of patients who refused to purchase naloxone was 20 percent, with the majority of patients expressing that naloxone was not necessary as a reason for refusal. CONCLUSION: More studies are needed in order to conclude the impact of pharmacist education on the increasing purchase of naloxone.

Extended-Release 7-Day Injectable Buprenorphine for Patients With Minimal to Mild Opioid Withdrawal.

Importance: Buprenorphine is an effective yet underused treatment for opioid use disorder (OUD). Objective: To evaluate the feasibility (acceptability, tolerability, and safety) of 7-day injectable extended-release buprenorphine in patients with minimal to mild opioid withdrawal. Design, Setting, and Participants: This nonrandomized trial comprising 4 emergency departments in the Northeast, mid-Atlantic, and Pacific geographic areas of the US included adults aged 18 years or older with moderate to severe OUD and Clinical Opiate Withdrawal Scale (COWS) scores less than 8 (minimal to mild), in which scores range from 0 to 7, with higher scores indicating increasing withdrawal. Exclusion criteria included methadone-positive urine, pregnancy, overdose, or required admission. Outcomes were assessed at baseline, daily for 7 days by telephone surveys, and in person at 7 days. Patient recruitment occurred between July 13, 2020, and May 25, 2023. Intervention: Injection of a 24-mg dose of a weekly extended-release formulation of buprenorphine (CAM2038) and referral for ongoing OUD care. Main Outcomes and Measures: Primary feasibility outcomes included the number of patients who (1) experienced a 5-point or greater increase in the COWS score or (2) transitioned to moderate or greater withdrawal (COWS score ≥13) within 4 hours of extended-release buprenorphine or (3) experienced precipitated withdrawal within 1 hour of extended-release buprenorphine. Secondary outcomes included injection pain, satisfaction, craving, use of nonprescribed opioids, adverse events, and engagement in OUD treatment. Results: A total of 100 adult patients were enrolled (mean [SD] age, 36.5 [8.7] years; 72% male). Among the patients, 10 (10.0% [95% CI, 4.9%-17.6%]) experienced a 5-point or greater increase in COWS and 7 (7.0% [95% CI, 2.9%-13.9%]) transitioned to moderate or greater withdrawal within 4 hours, and 2 (2.0% [95% CI, 0.2%-7.0%]) experienced precipitated withdrawal within 1 hour of extended-release buprenorphine. A total of 7 patients (7.0% [95% CI, 2.9%-13.9%]) experienced precipitated withdrawal within 4 hours of extended-release buprenorphine, which included 2 of 63 (3.2%) with a COWS score of 4 to 7 and 5 of 37 (13.5%) with a COWS score of 0 to 3. Site pain scores (based on a total pain score of 10, in which 0 indicated no pain and 10 was the worst possible pain) after injection were low immediately (median, 2.0; range, 0-10.0) and after 4 hours (median, 0; range, 0-10.0). On any given day among those who responded, between 29 (33%) and 31 (43%) patients reported no cravings and between 59 (78%) and 75 (85%) reported no use of opioids; 57 patients (60%) reported no days of opioid use. Improving privacy (62%) and not requiring daily medication (67%) were deemed extremely important. Seventy-three patients (73%) were engaged in OUD treatment on day 7. Five serious adverse events occurred that required hospitalization, of which 2 were associated with medication. Conclusions and Relevance: This nonrandomized trial of the feasibility of a 7-day buprenorphine injectable in patients with minimal to mild opioid withdrawal (COWS scores, 0-7) found the formulation to be acceptable, well tolerated, and safe in those with COWS scores of 4 to 7. This new medication formulation could substantially increase the number of patients with OUD receiving buprenorphine. Trial Registration: ClinicalTrials.gov Identifier: NCT04225598.

Therapeutic Potential of Naltrexone in the Niche of Psychopharmacology.

NTX is FDA-approved for opiate and alcohol use disorders as anti-craving agent. It has been used successfully off-label in other psychiatric indications. Here, we shed some light on these while examining the extant evidence.

Bystanders Saving Lives with Naloxone: A Scoping Review on Methods to Estimate Overdose Reversals.

Introduction: People who use drugs in community settings are at risk of a fatal overdose, which can be mitigated by naloxone administered via bystanders. In this study we sought to investigate methods of estimating and tracking opioid overdose reversals by community members with take-home naloxone (THN) to coalesce possible ways of characterizing THN reach with a metric that is useful for guiding both distribution of naloxone and advocacy of its benefits. Methods: We conducted a scoping review of published literature on PubMed on August 15, 2022, using PRISMA-ScR protocol, for articles discussing methods to estimate THN reversals in the community. The following search terms were used: naloxone AND ("take home" OR kit OR "community distribution" OR "naloxone distribution"). We used backwards citation searching to potentially find additional studies. Overdose education and naloxone distribution program-based studies that analyzed only single programs were excluded. Results: The database search captured 614 studies, of which 14 studies were relevant. Backwards citation searching of 765 references did not reveal additional relevant studies. Of the 14 relevant studies, 11 were mathematical models. Ten used Markov models, and one used a system dynamics model. Of the remaining three articles, one was a meta-analysis, and two used spatial analysis. Studies ranged in year of publication from 2013-2022 with mathematical modeling increasing in use over time. Only spatial analysis was used with a focus on characterizing local naloxone use at the level of a specific city. Conclusion: Of existing methods to estimate bystander administration of THN, mathematical models are most common, particularly Markov models. System dynamics modeling, meta-analysis, and spatial analysis have also been used. All methods are heavily dependent upon overdose education and naloxone distribution program data published in the literature or available as ongoing surveillance data. Overall, there is a paucity of literature describing methods of estimation and even fewer with methods applied to a local focus that would allow for more targeted distribution of naloxone.

Patient experiences of buprenorphine dispensing from a mobile medical unit.

BACKGROUND: Overdose deaths continue to rise within the United States, despite effective treatments such as buprenorphine and methadone for opioid use disorder (OUD). Mobile medical units with the ability to dispense buprenorphine have been developed to engage patients and eliminate barriers to accessing OUD treatment. This study reports survey responses of patients of a mobile medical unit dispensing buprenorphine in areas of Chicago, IL with high overdose rates. METHODS: All patients who were dispensed buprenorphine via the mobile medical unit were invited to participate in a 7-item anonymous survey between May 24, 2023, and August 25, 2023. The survey included 5-point satisfaction scale, multiple-choice, and open-ended questions. Outcomes included satisfaction with buprenorphine dispensing from the mobile medical unit, satisfaction with filling buprenorphine at a pharmacy in the past, barriers experienced at pharmacies when filling buprenorphine, and whether the client would have started treatment that day if the mobile medical unit had not been present. Satisfaction scale and multiple-choice question responses were assessed using descriptive statistics. Wilcoxon signed-rank test was used to compare median satisfaction levels between receiving buprenorphine from the mobile medical unit versus filling a buprenorphine prescription at a community pharmacy. Open-ended questions were analyzed qualitatively using inductive thematic analysis. RESULTS: 106 unique patients were dispensed buprenorphine from the mobile unit during the study period. Of these patients, 54 (51%) completed the survey. Respondents reported high satisfaction with the buprenorphine dispensing process as a part of a mobile medical unit. Of those who had previously filled buprenorphine at a pharmacy, 83% reported at least one barrier, with delays in prescription dispensing from a community pharmacy, lack of transportation to/from the pharmacy, and opioid withdrawal symptoms being the most common barriers. 87% reported they would not have started buprenorphine that same day if the mobile medical unit had not been present. Nearly half of survey participants reported having taken buprenorphine that was not prescribed to them. Qualitative analysis of open-ended survey responses noted the importance of convenient accessibility, comprehensive care, and a non-judgmental environment. CONCLUSIONS: Mobile medical units that dispense buprenorphine are an innovative model to reach patients with OUD who have significant treatment access barriers. This study found that patients who experienced barriers to accessing buprenorphine from a pharmacy were highly satisfied with the mobile medical unit's buprenorphine dispensing process. Programs seeking to develop mobile buprenorphine dispensing programs should consider patient priorities of accessibility, comprehensive care, and welcoming, non-judgmental environments.

A case of severe opioid and methamphetamine use disorder in a 14 year old.

We present the case of a 14-year-old who established care at our primary care clinic after hospitalization for unintentional fentanyl overdose. They were diagnosed with severe opioid use disorder (OUD) and stimulant use disorder (StUD) and initiated buprenorphine while inpatient. They were then transitioned to the only known outpatient primary care clinic in her county who was actively providing medications for opioid use disorder (MOUD) in adolescents.At the first visit, they reported a history of 20 overdoses, struggling with adherence to buprenorphine and continued opioid cravings. An overdose safety plan was reviewed with them and their parent including providing them naloxone kits, fentanyl test strips, and education handout sheets. Due to their significant overdose history and adherence challenges with sublingual buprenorphine, they were started on long-acting injectable buprenorphine (LAIB) with weekly provider visits and urine toxicology screening. In collaboration with the treatment team, they initiated behavioral treatment with contingency management (CM), with incentives for appointment completion, expected urine results, and successful medication administration. Over the next 19 months, and to date, they have increasingly engaged with care and have remained abstinent. LAIB may be an appealing alternative for adolescents with OUD to improve adherence and reduce risk of recurrent use and overdose. Adjunctive treatment with CM may improve retention in MOUD and have the benefit of treating StUD. There is a need for further research to explore innovative, community-based treatment for youth with OUD.

Availability and Opportunities for Expansion of Buprenorphine for the Treatment of Opioid Use Disorder.

There is an urgent need to expand access to treatment for persons with opioid use disorder (OUD). As neurologists may frequently encounter patients with chronic pain who have developed OUD, they are in a position to serve as advocates for treatment. Buprenorphine is the most scalable medication for OUD in the United States, yet expansion has plateaued in recent years despite growing treatment needs. Reluctance of providers to establish treatment with new patients, challenges with rural expansion, stigma related to buprenorphine-based care, and pharmacy pressures that incentivize low dispensing and inventories may have stalled expansion. This review introduces these challenges before outlining actionable and evidenced-based strategies that warrant investigation, including methods to improve patient access to care (remotely delivered care, mobile delivery programs, Bridge programs) and provider retention and confidence in prescribing (expert consults, Extension for Community Healthcare Outcomes, a telementoring model, hub-and-spoke services), as well as novel innovations (virtual reality, artificial intelligence, wearable technologies). Overall, fortifying existing delivery systems while developing new transformative models may be necessary to achieve more optimal levels of buprenorphine treatment expansion.

Iontophoresis-coupled rapidly dissolving polymeric microneedle patch of naloxone for its enhanced transdermal delivery.

The transdermal delivery of naloxone for opioid overdose emergency purposes is a challenge due to its poor rate of diffusion through the layers of skin. This results in delayed delivery of an insufficient amount of the drug within minimal time as is desired to save lives. The ability of dissolving polymeric microneedles to shorten the lag time significantly has been explored and shown to have prospects in terms of the transdermal delivery of naloxone. This is an option that offers critical advantages to the ongoing opioid crisis, including ease of distribution and easy administration, with little to no need for intervention by clinicians. Nonetheless, this approach by itself needs augmentation to meet pharmacokinetic delivery attributes desired for a viable clinical alternative to existing market dosage forms. In this study, we report the success of an optimized iontophoresis-coupled naloxone loaded dissolving microneedle patch which had facilitated a 12- fold increase in average cumulative permeation and a 6-fold increase in drug flux over a conventional dissolving microneedle patch within 60 min of application (p < 0.05). This translates to a 30 % decrease in dose requirement in a mechanistically predicted microneedle patch established to be able to achieve the desired early plasma concentration time profile needed in an opioid overdose emergency. Applying a predictive mathematical model, we describe an iontophoresis-coupled microneedle patch design capable of meeting the desired pharmacokinetic profile for a viable naloxone delivery form through skin.

Rapid induction of transdermal buprenorphine to subcutaneous extended-release buprenorphine for the treatment of opioid use disorder.

BACKGROUND: Buprenorphine is an effective and safe treatment for opioid use disorder, but the requirement for moderate opioid withdrawal symptoms to emerge prior to initiation is a significant treatment barrier. CASE PRESENTATION: We report on two cases of hospitalized patients with severe, active opioid use disorder, in which we initiated treatment with transdermal buprenorphine over 48 h, followed by the administration of a single dose of sublingual buprenorphine/naloxone and then extended-release subcutaneous buprenorphine. The patients did not experience precipitated withdrawal and only had mild withdrawal symptoms. CONCLUSIONS: This provides preliminary evidence for a rapid induction strategy that may improve tolerability, caregiver burden, and treatment retention as compared to previous induction strategies.

Low-dose overlap initiation with split tablets of buprenorphine in intubated intensive care unit patients with opioid use disorder.

BACKGROUND: As the opioid public health crisis evolves to include fentanyl and other potent synthetic opioids, more patients are admitted to the hospital with serious complications of drug use and frequently require higher levels of care, including intensive care unit (ICU) admission, for acute and chronic conditions related to opioid use disorder (OUD). This patient population poses a unique challenge when managing sedation and ensuring adequate ventilation while intubated given their high opioid requirements. Starting a patient on medications such as buprenorphine may be difficult for inpatient providers unfamiliar with its use, which may lead to undertreatment of patients with OUD, prolonged mechanical ventilation and length of stay. METHODS: We developed a 7-day buprenorphine low dose overlap initiation (LDOI) schedule for patients with OUD admitted to the ICU (Table 1). Buprenorphine tablets were split by pharmacists and placed into pre-made blister packs as a kit to be loaded into the automated medication dispensing machine for nursing to administer daily. An internal quality review validated the appropriate dosing of split-dose tablets. To simplify order entry and increase prescriber comfort with this new protocol, we generated an order set within our electronic health record software with prebuilt buprenorphine titration orders. This protocol was implemented alongside patient and healthcare team education and counseling on the LDOI process, with follow-up offered to all patients upon discharge. RESULTS: Here we report a series of 6 ICU patients started on buprenorphine using the LDOI schedule with split buprenorphine tablets. None of the 6 patients experienced precipitated withdrawal upon buprenorphine initiation using the LDOI schedule, and 5/6 patients were successfully extubated during the buprenorphine initiation. Four of six patients had a decrease in daily morphine milligram equivalents, with 3 patients transitioning to buprenorphine alone. CONCLUSION: Initiating buprenorphine via LDOI was found to be successful in the development of a protocol for critically ill patients with OUD. We examined LDOI of buprenorphine in intubated ICU patients and found no events of acute precipitated withdrawal. This protocol can be used as a guide for other institutions seeking to start critically ill patients on medication treatment for OUD during ICU admission.

Extended-Release Injection vs Sublingual Buprenorphine for Opioid Use Disorder With Fentanyl Use: A Post Hoc Analysis of a Randomized Clinical Trial.

Importance: Fentanyl has exacerbated the opioid use disorder (OUD) and opioid overdose epidemic. Data on the effectiveness of medications for OUD among patients using fentanyl are limited. Objective: To assess the effectiveness of sublingual or extended-release injection formulations of buprenorphine for the treatment of OUD among patients with and without fentanyl use. Design, Setting, and Participants: Post hoc analysis of a 24-week, randomized, double-blind clinical trial conducted at 35 outpatient sites in the US from December 2015 to November 2016 of sublingual buprenorphine-naloxone vs extended-release subcutaneous injection buprenorphine (CAM2038) for patients with OUD subgrouped by presence vs absence of fentanyl or norfentanyl in urine at baseline. Study visits with urine testing occurred weekly for 12 weeks, then 6 times between weeks 13 and 24. Data were analyzed on an intention-to-treat basis from March 2022 to August 2023. Intervention: Weekly and monthly subcutaneous buprenorphine vs daily sublingual buprenorphine-naloxone. Main Outcomes and Measures: Retention in treatment, percentage of urine samples negative for any opioids (missing values imputed as positive), percentage of urine samples negative for fentanyl or norfentanyl (missing values not imputed), and scores on opiate withdrawal scales and visual analog craving scales. Results: Of 428 participants, 123 (subcutaneous buprenorphine, n = 64; sublingual buprenorphine-naloxone, n = 59; mean [SD] age, 39.1 [10.8] years; 75 men [61.0%]) had evidence of baseline fentanyl use and 305 (subcutaneous buprenorphine, n = 149; buprenorphine-naloxone, n = 156; mean [SD] age, 38.1 [11.1] years; 188 men [61.6%]) did not have evidence of baseline fentanyl use. Study completion was similar between the fentanyl-positive (60.2% [74 of 123]) and fentanyl-negative (56.7% [173 of 305]) subgroups. The mean percentage of urine samples negative for any opioid were 28.5% among those receiving subcutaneous buprenorphine and 18.8% among those receiving buprenorphine-naloxone in the fentanyl-positive subgroup (difference, 9.6%; 95% CI, -3.0% to 22.3%) and 36.7% among those receiving subcutaneous buprenorphine and 30.6% among those receiving buprenorphine-naloxone in the fentanyl-negative subgroup (difference, 6.1%; 95% CI, -1.9% to 14.1%), with significant main associations of baseline fentanyl status and treatment group. In the fentanyl-positive subgroup, the mean percentage of urine samples negative for fentanyl during the study was 74.6% among those receiving subcutaneous buprenorphine vs 61.9% among those receiving sublingual buprenorphine-naloxone (difference, 12.7%; 95% CI, 9.6%-15.9%). Opioid withdrawal and craving scores decreased rapidly after treatment initiation across all groups. Conclusions and Relevance: In this post hoc analysis of a randomized clinical trial of sublingual vs extended-release injection buprenorphine for OUD, buprenorphine appeared to be effective among patients with baseline fentanyl use. Patients with fentanyl use had fewer opioid-negative urine samples during the trial compared with the fentanyl-negative subgroup. These findings suggest that the subcutaneous buprenorphine formulation may be more effective at reducing fentanyl use. Trial Registration: ClinicalTrials.gov Identifier: NCT02651584.

Pulmonary edema after naloxone administration for opioid reversal: a systematic review of case reports and causality assessment using the Naranjo scale.

INTRODUCTION: Pulmonary edema is a rare complication occurring after naloxone administration, but the causal relationship remains insufficiently investigated. We aimed to determine the likelihood of naloxone as the causative agent in published cases of pulmonary edema. METHODS: A literature search was conducted across multiple databases, utilizing database-specific search terms such as "pulmonary edema/chemically induced" and "naloxone/adverse effects." Each case report was evaluated using the Naranjo scale, a standardized causality assessment algorithm. RESULTS: We identified 49 published case reports of pulmonary edema following naloxone administration. The median total dose of naloxone was 0.2 mg for patients presenting following a surgical procedure and 4 mg for out-of-hospital opioid overdoses. Based on the Naranjo scale, the majority of cases were classified as "possible" (n = 38) or "probable" (n = 11) adverse reactions, while no "definite" cases of naloxone-induced pulmonary edema were identified. Many patients were classified as "possible" due to limited patient information or other potential risks, such as fluid administration or airway obstruction. Forty-six of 49 patients survived (94 percent). DISCUSSION: Pulmonary edema may occur after both low and high doses of naloxone; however, low doses were primarily reported in the surgical population. Despite this complication, the majority of patients survived. Furthermore, no case report in our analysis was classified as a "definite" case of naloxone-induced pulmonary edema which limits the establishment of causality. Future studies should explore patient risk factors, including surgical versus outpatient setting and opioid-naïve versus opioid-tolerant for developing pulmonary edema and employ a causality assessment algorithm. CONCLUSIONS: These case reports suggest pulmonary edema can occur following naloxone administration, irrespective of dose. According to the Naranjo scale, there were no definite cases of naloxone-induced pulmonary edema. Overall, we suggest the benefits of naloxone administration outweigh the risks. Naloxone should be administered to treat opioid overdoses while monitoring for the development of pulmonary edema.