Policies, adaptations, and ongoing challenges to naloxone, buprenorphine and nonprescription syringe access across four-states: Findings from an environmental scan and key informant interviews.

Background: As the US opioid-involved morbidity and mortality increase, uptake and implementation of evidence-based interventions remain key policy responses. Respond to Prevent was a multi-component, randomized trial implemented in four states and two large pharmacy chains with the aim of improving the pharmacy's capacity to provide naloxone, dispense buprenorphine, and sell nonprescription syringes (NPS). We sought to provide context and assess how policies and organizational practices affect communities and pharmacies across the study states. Methods: Using a multi-method approach we: 1) conducted an environmental scan of published literature and online materials spanning January 2015 to June 2021, 2) created timelines of key events pertaining to those policies and practices and 3) conducted semi-structured interviews with stakeholders (key informants) at the state and local levels (N=36) to provide further context for the policies and practices we discovered. Results: Key informants discussed state policies, pharmacy policies and local practices that facilitated access to naloxone, buprenorphine and NPSs. Interviewees from all states spoke about the impact of naloxone standing orders, active partnerships with community-based harm reduction organizations, and some federal and state policies like Medicaid coverage for naloxone and buprenorphine, and buprenorphine telehealth permissions as key facilitators. They also discussed patient stigma, access in rural settings, and high cost of medications as barriers. Conclusion: Findings underscore the important role harm reduction-related policies play in boosting and institutionalizing interventions in communities and pharmacies while also identifying structural barriers where more focused state and local attention is needed.

"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.

Comparison of intranasal naloxone and intranasal nalmefene in a translational model assessing the impact of synthetic opioid overdose on respiratory depression and cardiac arrest.

Introduction: Using a validated translational model that quantitatively predicts opioid-induced respiratory depression and cardiac arrest, we compared cardiac arrest events caused by synthetic opioids (fentanyl, carfentanil) following rescue by intranasal (IN) administration of the µ-opioid receptor antagonists naloxone and nalmefene. Methods: This translational model was originally developed by Mann et al. (Clin Pharmacol Ther 2022) to evaluate the effectiveness of intramuscular (IM) naloxone. We initially implemented this model using published codes, reproducing the effects reported by Mann et al. on the incidence of cardiac arrest events following intravenous doses of fentanyl and carfentanil as well as the reduction in cardiac arrest events following a standard 2 mg IM dose of naloxone. We then expanded the model in terms of pharmacokinetic and µ-opioid receptor binding parameters to simulate effects of 4 mg naloxone hydrochloride IN and 3 mg nalmefene hydrochloride IN, both FDA-approved for the treatment of opioid overdose. Model simulations were conducted to quantify the percentage of cardiac arrest in 2000 virtual patients in both the presence and absence of IN antagonist treatment. Results: Following simulated overdoses with both fentanyl and carfentanil in chronic opioid users, IN nalmefene produced a substantially greater reduction in the incidence of cardiac arrest compared to IN naloxone. For example, following a dose of fentanyl (1.63 mg) producing cardiac arrest in 52.1% (95% confidence interval, 47.3-56.8) of simulated patients, IN nalmefene reduced this rate to 2.2% (1.0-3.8) compared to 19.2% (15.5-23.3) for IN naloxone. Nalmefene also produced large and clinically meaningful reductions in the incidence of cardiac arrests in opioid naïve subjects. Across dosing scenarios, simultaneous administration of four doses of IN naloxone were needed to reduce the percentage of cardiac arrest events to levels that approached those produced by a single dose of IN nalmefene. Conclusion: Simulations using this validated translational model of opioid overdose demonstrate that a single dose of IN nalmefene produces clinically meaningful reductions in the incidence of cardiac arrest compared to IN naloxone following a synthetic opioid overdose. These findings are especially impactful in an era when >90% of all opioid overdose deaths are linked to synthetic opioids such as fentanyl.

Health-Related Quality of Life in Chronic Pain Treated With Tapentadol Versus Oxycodone/Naloxone and Its Determinants: A Real-World, Single-Center Retrospective Cohort Study in Spain.

OBJECTIVES: A substantial proportion of patients with chronic noncancer pain (CNCP) are treated with tapentadol (TAP) or oxycodone/naloxone (OXN) to improve their perceived physical and mental health over time. METHODS: A cross-sectional study was conducted in 135 CNCP outpatients with usual prescribing (TAP: n = 58, OXN: n = 77) at a tertiary-care Spanish Hospital to compare health-related quality-of-life (HRQoL) records. Health utility was derived from the EQ-5D-3L. Regression models were performed to search for other HRQoL determinants. Pain intensity, relief, analgesic prescription, adverse events, inpatient stays, emergency department visits, and change to painkiller prescriptions were registered from electronic records. RESULTS: Health utility (0.43 ± 0.24 scores, from -0.654 to 1) was similar for both opioids, although TAP showed a significantly low daily opioid dose requirement, neuromodulators use, and constipation side effect compared with OXN. After multivariable adjustment, the significant predictors of impaired HRQoL were pain intensity (ß = -0.227, 95% CI -0-035 to -0.005), number of adverse events (ß = -0.201, 95% CI -0.024 to -0.004), and opioid daily dose (ß = -0.175, 95% CI -0.097 to -0.012). Male sex (ß = -0.044) and pain relief (ß = 0.158) should be taken into account for future studies. CONCLUSIONS: HRQoL was similar for TAP and OXN in real-world patients with CNCP, albeit with a TAP opioid-sparing effect. More work is needed to explore HRQoL determinants in relation to long-term opioid use in CNCP.

A theoretical explanation of naloxone provision among primary care physicians and community pharmacists in Tennessee.

BACKGROUND: Increasing access to naloxone reduces opioid-related morbidity and mortality. Primary care and community pharmacy settings are critical access points, yet limited theoretical research has examined naloxone prescribing and dispensing behaviors. OBJECTIVES: To determine if the theory of planned behavior (TPB) combined with theoretical constructs from communication science explains intentions to co-prescribe and discuss co-dispensing naloxone among primary care physicians and community pharmacists, respectively. METHODS: This cross-sectional study surveyed cohorts of licensed primary care physicians and community pharmacists in Tennessee in 2017. Intentions were measured using profession-specific case vignettes, whereby they were asked given 10 similar patients, how many times (0-10) would they co-prescribe or discuss co-dispensing naloxone. Bivariate and multivariable analyses were used. RESULTS: The analytic sample included 295 physicians (response rate = 15.6 %) and 423 pharmacists (response rate = 19.4 %). Approximately 65 % of physicians reported never intending to co-prescribe naloxone (0 out of 10 patients), while 47 % of pharmacists reported never intending to discuss co-dispensing. All TPB constructs-attitudes (AOR = 1.32, CI = 1.16-1.50), subjective norms (AOR = 1.17, CI = 1.06-1.30), and perceived behavioral control (AOR 1.16, CI = 1.02-1.33)-were associated with an increased likelihood of pharmacists always (versus never) discussing co-dispensing. Similarly, two TPB constructs-attitudes (AOR = 1.41, CI = 1.19-1.68) and subjective norms (AOR = 1.22, CI = 1.08-1.39)-were associated with an increased likelihood of physicians always co-prescribing. Among physicians only, one communication construct-self-perceived communication competence (AOR = 1.19, CI = 1.01-1.41)-was associated with an increased likelihood of always co-prescribing. CONCLUSION: Findings support the value of theory, particularly TPB, in explaining primary care physician intentions to co-prescribe and community pharmacist intentions to discuss co-dispensing naloxone.

Naloxone prescription fills and use by patients treated for opioid use disorder by telehealth.

Background: It is unknown how many people in treatment for opioid use disorder (OUD) have naloxone, use naloxone, and what their perceptions and barriers to obtaining it are. Methods: This was a survey of patients treated in a large telehealth OUD program. Between December 6, 2023 and January 6, 2024, all patients who had access to the program's phone app (n=17,899 individuals, of whom 12,887 were in active treatment), were invited to complete an anonymous online survey. Results: There were 701 individuals who completed the survey. Nearly all patients (n=693, 99%) knew what naloxone is, and the majority (n=601, 86%) knew how to administer it. A quarter of these patients (n=177, 25%) reported either having naloxone used on themselves or using it on someone else. 161 patients (23%) reported taking a naloxone training course. Of patients who recalled receiving a prescription, 72% (n=382) filled the prescription, and 85% (n=321) reported that insurance paid for all or part of it. If filled, the naloxone was reported as used by 30 (8%) patients. If not filled, reasons were: already had it (n=55, 37%), did not think it was needed (n=54, 37%) or too expensive (n=36, 23%). Patients who reported knowing how to administer naloxone (OR 2.63 (95% CI 1.35-5.00) were more likely to fill the prescription. Conclusions: Patients prescribed naloxone in a telehealth treatment program filled the prescription 72% of the time, and when it was filled, 8% used the naloxone. Education and cost policy changes may reduce barriers to obtaining naloxone.

The association of early naloxone use with outcomes in non-shockable out-of-hospital cardiac arrest.

STUDY OBJECTIVE: Evaluate the association between early naloxone use and outcomes after out-of-hospital cardiac arrest (OHCA) with initial non-shockable rhythms. METHODS: This study was a secondary analysis of data collected in the Portland Cardiac Arrest Epidemiologic Registry, a database containing details of emergency medical services (EMS)-treated OHCA cases in the Portland, Oregon metropolitan region. Eligible patients had non-traumatic OHCA with an initial non-shockable rhythm and received naloxone by EMS or law enforcement prior to IV/IO access (exposure group). The primary outcome was ROSC at emergency department (ED) arrival. Secondary outcomes included survival to admission, survival to hospital discharge, and cerebral performance category score ≤2 at discharge (good neurologic outcome). We performed multivariable logistic regressions adjusting for age, sex, arrest location, witness status, bystander interventions, dispatch to EMS arrival time, initial rhythm, and county of arrest. RESULTS: There were 1807 OHCA cases from 2018 to 2021 meeting eligibility criteria, with 57 receiving naloxone before vascular access. Patients receiving naloxone prior to vascular access attempts had higher adjusted odds (aOR [95% CI]) of ROSC at any time (2.14 [1.20-3.81]), ROSC at ED arrival (2.14 [1.18-3.88]), survival to admission (2.86 [1.60-5.09]), survival to discharge (4.41 [1.78-10.97]), and good neurologic outcome (4.61 [1.74-12.19]). CONCLUSIONS: Patients with initial non-shockable OHCA who received law enforcement or EMS naloxone prior to IV/IO access attempts had higher adjusted odds of ROSC at any time, ROSC at ED arrival, survival to admission, survival to discharge, and good neurologic outcome.

Endogenous and Exogenous Opioids: Role in Substance Use Disorders.

Opioid use disorders have become an epidemic in recent years with rates nearly quadrupling since 1999 according to the US Centers for Disease Control and Prevention (Centers for Disease Control, Wide-ranging online data for epidemiologic research (WONDER). CDC, National Center for Health Statistics, Atlanta. Retrieved December 19, 2017, from http://wonder.cdc.gov, 2016). To understand substance use disorder (SUD) as a disease, many aspects must be studied including the circuitry in the brain, adaptations to neuronal circuitry and neurotransmitters, genetic variations increasing the risk for SUD, and treatments available for SUD. The mechanism in which an exogenous opioid may cause SUD is nearly identical to the mechanism of an endogenous opioid. This chapter reviews the clinical and epidemiological aspects of opioid use disorder, as well as the interactions between endogenous and exogenous opioids. Additionally, this chapter discusses current scientific data regarding genetic variations and mechanisms within brain circuitry and the role of endogenous opioids in substance use disorders generally (and opioid use disorder specifically). Future applications of these data to treatment of substance use disorders are also discussed.

Differential effects of opioid receptor antagonism on the anti-dyskinetic and anti-parkinsonian effects of sub-anesthetic ketamine treatment in a preclinical model.

Sub-anesthetic ketamine treatment has been shown to be an effective therapy for treatment-resistant depression and chronic pain. Our group has previously shown that sub-anesthetic ketamine produces acute anti-parkinsonian, and acute anti-dyskinetic effects in preclinical models of Parkinson's disease (PD). Ketamine is a multifunctional drug and exerts effects through blockade of N-methyl-d-aspartate receptors but also through interaction with the opioid system. In this report, we provide detailed pharmacokinetic rodent data on ketamine and its main metabolites following an intraperitoneal injection, and second, we explore the pharmacodynamic properties of ketamine in a rodent PD model with respect to the opioid system, using naloxone, a pan-opioid receptor antagonist, in unilateral 6-hydroxydopamine-lesioned male rats, treated with 6 mg/kg levodopa (l-DOPA) to establish a model of l-DOPA-induced dyskinesia (LID). As previously reported, we showed that ketamine (20 mg/kg) is highly efficacious in reducing LID and now report that the magnitude of this effect is resistant to naloxone (3 and 5 mg/kg). The higher naloxone dose of 5 mg/kg, however, led to an extension of the time-course of the LID, indicating that opioid receptor activation, while not a prerequisite for the anti-dyskinetic effects of ketamine, still exerts an acute modulatory effect. In contrast to the mild modulatory effect on LID, we found that naloxone added to the anti-parkinsonian activity of ketamine, further reducing the akinetic phenotype. In conclusion, our data show opioid receptor blockade differentially modulates the acute anti-parkinsonian and anti-dyskinetic actions of ketamine, providing novel mechanistic information to support repurposing ketamine for individuals with LID.

Rapid jail-based implementation of overdose education and naloxone distribution in response to the COVID-19 pandemic.

BACKGROUND: People incarcerated in jails are highly impacted by the opioid epidemic, and overdose education and naloxone distribution (OEND) is an effective strategy to reduce opioid overdose deaths. This study examines barriers and facilitators of fast-track OEND implementation within the jails in the Wave 1 Kentucky counties of the HEALing Communities Study during the COVID-19 pandemic. METHODS: Meeting minutes with jail stakeholders were qualitatively coded using the Practical, Robust Implementation and Sustainability Model (PRISM) as the coding framework. The analysis highlighted the top barriers and facilitators to fast-track OEND implementation within the PRISM framework. RESULTS: Space and staffing shortages related to the COVID-19 pandemic, disruptions in interorganizational programming from pandemic-related service suspensions, and a lack of technological solutions (e.g., reliable Internet access) for socially distanced delivery were the top barriers to fast-track OEND implementation. In addition, there were limitations on non-jail staff access to jails during COVID-19. Top facilitators included jail leadership support, the option to prioritize high-risk groups, and the incorporation of OEND processes into existing communications and management software. While the COVID-19 pandemic strained jail infrastructure, jail and partner agency collaboration led to creative implementation strategies for the successful integration of OEND into jail operations. Urban jails were more likely than rural jails to be early adopters of OEND during the public health emergency. CONCLUSIONS: Understanding the barriers to and facilitators of OEND within jails will improve implementation efforts seeking to curb opioid overdose deaths. Jail leadership support and interorganizational efforts were key facilitators to implementation; therefore, it is recommended to increase buy-in with multiple agencies to promote success. Challenges brought on by COVID-19 have resulted in a need for innovative solutions for implementation. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov, NCT04111939, Submitted 30 September 2019, https://clinicaltrials.gov/study/NCT04111939?titles=HEALing%20Communities%20Study&rank=1 .

A new pharmacological approach for tracheal intubation?

Anaesthesia induced with remimazolam and a fentanyl-series opioid can be reversed with flumazenil and naloxone. Concomitant paralysis with rocuronium can facilitate tracheal intubation whilst being reversible with sugammadex. Together, this combination might offer full reversibility of a 'routine' or a 'rapid-sequence' induction anaesthesia. Whether this is useful, or even safe, requires careful evaluation.

Reducing perceived barriers to scaling up overdose education and naloxone distribution and medications for opioid use disorder in the United States in the HEALing (helping end addiction long-term®) communities study.

BACKGROUND: Scaling up overdose education and naloxone distribution (OEND) and medications for opioid use disorder (MOUD) is needed to reduce opioid overdose deaths, but barriers are pervasive. This study examines whether the Communities That HEAL (CTH) intervention reduced perceived barriers to expanding OEND and MOUD in healthcare/behavioral health, criminal-legal, and other/non-traditional venues. METHODS: The HEALing (Helping End Addiction Long-Term®) Communities Study is a parallel, wait-list, cluster randomized trial testing the CTH intervention in 67 communities in the United States. Surveys administered to coalition members and key stakeholders measured the magnitude of perceived barriers to scaling up OEND and MOUD in November 2019-January 2020, May-June 2021, and May-June 2022. Multilevel linear mixed models compared Wave 1 (intervention) and Wave 2 (wait-list control) respondents. Interactions by rural/urban status and research site were tested. RESULTS: Wave 1 respondents reported significantly greater reductions in mean scores for three outcomes: perceived barriers to scaling up OEND in Healthcare/Behavioral Health Venues (-0.26, 95% confidence interval, CI: -0.48, -0.05, p = 0.015), OEND in Other/Non-traditional Venues (-0.53, 95% CI: - 0.84, -0.22, p = 0.001) and MOUD in Other/Non-traditional Venues (-0.34, 95% CI: -0.62, -0.05, p = 0.020). There were significant interactions by research site for perceived barriers to scaling up OEND and MOUD in Criminal-Legal Venues. There were no significant interactions by rural/urban status. DISCUSSION: The CTH Intervention reduced perceived barriers to scaling up OEND and MOUD in certain venues, with no difference in effectiveness between rural and urban communities. More research is needed to understand facilitators and barriers in different venues.

Overdose deaths before and during the COVID-19 pandemic in a US county.

Introduction: Globally, overdose deaths increased near the beginning of the COVID-19 pandemic, which created availability and access barriers to addiction and social services. Especially in times of a crisis like a pandemic, local exposures, service availability and access, and system responses have major influence on people who use drugs. For policy makers to be effective, an understanding at the local level is needed. Methods: This retrospective epidemiologic study from 2019 through 2021 compares immediate and 20-months changes in overdose deaths from the pandemic start to 16 months before its arrival in Pinellas County, FL We examine toxicologic death records of 1,701 overdoses to identify relations with interdiction, and service delivery. Results: There was an immediate 49% increase (95% CI 23-82%, p < 0.0001) in overdose deaths in the first month following the first COVID deaths. Immediate increases were found for deaths involving alcohol (171%), heroin (108%), fentanyl (78%), amphetamines (55%), and cocaine (45%). Overdose deaths remained 27% higher (CI 4-55%, p = 0.015) than before the pandemic through 2021.Abrupt service reductions occurred when the pandemic began: in-clinic methadone treatment dropped by two-thirds, counseling by 38%, opioid seizures by 29%, and drug arrests by 56%. Emergency transport for overdose and naloxone distributions increased at the pandemic onset (12%, 93%, respectively) and remained higher through 2021 (15%, 377%,). Regression results indicate that lower drug seizures predicted higher overdoses, and increased 911 transports predicted higher overdoses. The proportion of excess overdose deaths to excess non-COVID deaths after the pandemic relative to the year before was 0.28 in Pinellas County, larger than 75% of other US counties. Conclusions: Service and interdiction interruptions likely contributed to overdose death increases during the pandemic. Relaxing restrictions on medical treatment for opioid addiction and public health interventions could have immediate and long-lasting effects when a major disruption, such as a pandemic, occurs. County level data dashboards comprised of overdose toxicology, and interdiction and service data, can help explain changes in overdose deaths. As a next step in predicting which policies and practices will best reduce local overdoses, we propose using simulation modeling with agent-based models to examine complex interacting systems.

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.

Missouri's overdose field report: descriptive analysis, survival trends, and naloxone dosing patterns from a community-based survey tool, 2018-2022.

Background: Missouri's Overdose Field Report (ODFR) is a community-based reporting system which intends to capture overdoses which may not be otherwise recorded.Objectives: Describe the factors related to non-fatal overdoses reported to Missouri's ODFR.Methods: This study used a descriptive epidemiological approach to examine the demographics and circumstances of overdoses reported to the ODFR. We used binary logistic regression to evaluate factors associated with survival and ordinal logistic regression to evaluate factors associated with number of doses used. Factors were chosen based on their relevance to overdose education and survival, and naloxone distribution.Results: Between 2018 and 2022, 12,225 overdoses (67% male; 78% White) were reported through the ODFR, with a 96% (n = 11,225) survival rate. Overdose survival (ps < .02) was associated with younger age (OR = .58), no opioid and stimulant co-involvement (OR = .61), and private location (OR = .48). Intramuscular naloxone in particular was associated with a significantly higher odds of survival compared to nasal naloxone (OR = 2.11). An average of 1.6 doses of naloxone per incident were administered. Additional doses were associated (ps < .02) with being older (OR = .45), female (OR = .90), nasal naloxone (versus intravenous) (OR = .65), and the belief fentanyl was present (OR = 1.49).Conclusion: Our reporting form provides a comprehensive picture of the events surrounding reported overdoses, including factors associated with survival, how much naloxone was used, and the effects of respondents believing fentanyl was involved. Missouri's report can provide support for current naloxone dosing, contextualize refusing post-overdose transport, and can be used to improve overdose response by community and first responders.

Navigating Care Refusal and Noncompliance in Patients with Opioid Use Disorder.

BACKGROUND: For many emergency physicians (EPs), deciding whether or not to allow a patient suffering the ill effects of opioid use to refuse care is the most frequent and fraught situation in which they encounter issues of decision-making capacity, informed refusal, and autonomy. Despite the frequency of this issue and the well-known impacts of opioid use disorder on decision-making, the medical ethics community has offered little targeted analysis or guidance regarding these situations. DISCUSSION: As a result, EPs demonstrate significant variability in how they evaluate and respond to them, with highly divergent understandings and application of concepts such as decision-making capacity, informed consent, autonomy, legal repercussions, and strategies to resolve the clinical dilemma. In this paper, we seek to provide more clarity to this issue for the EPs. CONCLUSIONS: Successfully navigating this issue requires that EPs understand the specific effects that opioid use disorder has on decision-making, and how that in turn bears on the ethical concepts of autonomy, capacity, and informed refusal. Understanding these concepts can lead to helpful strategies to resolve these commonly-encountered dilemmas.

Gestational buprenorphine-naloxone exposure and fetal neurobehavior.

BACKGROUND: Buprenorphine-naloxone treatment may confer substantial benefits for the treatment of opioid use disorder (OUD) during pregnancy including lower risk for overdose/death, less diversion potential and reduced use of other substances. Treatment may also result in less severe Neonatal Abstinence Syndrome (NAS), but little is known about the effects of this medication on fetal neurodevelopment. METHODS: The purpose of the current study is to evaluate neurobehaviors among fetuses exposed to buprenorphine-naloxone at four time points over the second and third trimesters of gestation in pregnant women with OUD on buprenorphine-naloxone therapy. Sixty minutes of continuous fetal monitoring via fetal actocardiograph with a single wide array abdominal transducer took place at times of peak and trough buprenorphine-naloxone levels in 24 pregnant women. Data collection, which included measures of fetal heart rate and motor activity, was conducted between 24 and 36 weeks gestation, with the majority (84.6%) monitored at two or more gestational ages. Medication dose and other substance use was monitored throughout the study and infant NAS severity was assessed. RESULTS: Fetal heart rate (FHR), FHR variability, accelerations in FHR, and motor activity were suppressed when buprenorphine-naloxone levels were at pharmacologic peak as compared to trough concentrations at 36 weeks, but not earlier in gestation. Maternal medication dose was unrelated to infant NAS severity. CONCLUSIONS: Conclusions: There were evident subclinical fetal neurophysiological responses at times of peak maternal buprenorphine/naloxone levels in later gestation, similar to those previously described for buprenorphine only. Further studies evaluating the effects of these changes in fetal neurobehaviors on the longer-term infant development are needed.

At a Crossroads: Opioid Use Disorder, the X-Waiver, and the Road Ahead.

Background: Buprenorphine/naloxone (Suboxone) is widely considered the first-line treatment for opioid use disorder (OUD), which causes significant morbidity and mortality in the United States, but prior to 2023, practitioners interested in prescribing buprenorphine/naloxone for OUD needed a special Drug Enforcement Administration certification (the X-Waiver) that imposed a patient cap and other limitations. The Consolidated Appropriations Act of 2023 considerably decreased the restrictions on prescribing practitioners. Buprenorphine/naloxone can now be prescribed like any other prescription opioid, excluding methadone. The historic context for the opioid crisis, OUD, the X-Waiver, and additional initiatives that may be needed beyond legislative change to effectively address OUD are the subjects of this review. Methods: To develop this review of the opioid crisis, OUD, and OUD treatment, we conducted a literature search of the PubMed database and constructed a timeline of the opioid crisis and changes in OUD treatment, specifically the X-Waiver, to characterize the historic context of OUD and the X-Waiver against the background of the opioid crisis. Results: The opioid crisis has had pervasive public health and economic impacts in the United States. Major changes to the treatment of OUD have occurred as a result of the Drug Addiction Treatment Act of 2000 that imposed the X-Waiver and the Consolidated Appropriations Act of 2023 that repealed the X-Waiver. Conclusion: The repeal of the X-Waiver is predicted to increase the accessibility of buprenorphine/naloxone in the United States. However, additional work beyond legislative change, including institutional support and reduction of stigma and disparities, is needed to substantially improve outcomes for OUD patients.

From Friend to Foe: A Case of Naloxone-Induced Pulmonary Edema.

Naloxone, an opioid receptor antagonist, effectively reverses opioid overdose and opioid-induced respiratory depression. A few side effects were reported after naloxone administration, including arrhythmia and pulmonary edema. Although rare, naloxone-induced pulmonary edema can be a severe and sometimes life-threatening complication requiring mechanical ventilation. This condition is predominantly linked to an upsurge in catecholamines after opioid reversal as part of acute withdrawal syndrome, especially seen in patients who chronically use opioids. In this report, we present a case of a 66-year-old patient who developed pulmonary edema following the administration of multiple doses of intravenous and intranasal naloxone for opioid overdose. This case highlights the potential adverse effects associated with naloxone use and discusses how to employ this life-saving medication with minimal side effects.

Fentanyl activates opposing opioid and non-opioid receptor systems that control breathing.

Fentanyl elicits profound disturbances in ventilatory control processes in humans and experimental animals. The traditional viewpoint with respect to fentanyl-induced respiratory depression is that once the effects on the frequency of breathing (Freq), tidal volume (TV), and minute ventilation (MV = Freq × TV) are resolved, then depression of breathing is no longer a concern. The results of the present study challenge this concept with findings, as they reveal that while the apparent inhibitory effects of fentanyl (75 µg/kg, IV) on Freq, TV, and MV in adult male rats were fully resolved within 15 min, many other fentanyl-induced responses were in full effect, including opposing effects on respiratory timing parameters. For example, although the effects on Freq were resolved at 15 min, inspiratory duration (Ti) and end inspiratory pause (EIP) were elevated, whereas expiratory duration (Te) and end expiratory pause (EEP) were diminished. Since the effects of fentanyl on TV had subsided fully at 15 min, it would be expected that the administration of an opioid receptor (OR) antagonist would have minimal effects if the effects of fentanyl on this and other parameters had resolved. We now report that the intravenous injection of a 1.0 mg/kg dose of the peripherally restricted OR antagonist, methyl-naloxone (naloxone methiodide, NLXmi), did not elicit arousal but elicited some relatively minor changes in Freq, TV, MV, Te, and EEP but pronounced changes in Ti and EIP. In contrast, the injection of a 2.5 mg/kg dose of NLXmi elicited pronounced arousal and dramatic changes in many variables, including Freq, TV, and MV, which were not associated with increases in non-apneic breathing events such as apneas. The two compelling conclusions from this study are as follows: 1) the blockade of central ORs produced by the 2.5 mg/kg dose of NLXmi elicits pronounced increases in Freq, TV, and MV in rats in which the effects of fentanyl had apparently resolved, and 2) it is apparent that fentanyl had induced the activation of two systems with counter-balancing effects on Freq and TV: one being an opioid receptor inhibitory system and the other being a non-OR excitatory system.