Additional Naloxone Research Articles

759: CHARACTERIZATION OF CONTINUOUS-INFUSION NALOXONE DOSING IN OPIOID OVERDOSE

Introduction: Naloxone is a competitive antagonist that is used to reverse the effects of opioid overdose. Due to its short half-life continuous infusions have been indicated in overdose patients. Current recommendations endorse starting naloxone infusions at two-thirds the initial effective dose, however, case reports describe doses ranging from 0.1 mg to 4 mg/hr. The purpose of this medication utilization review is to characterize the utilization and initial dosing of continuous infusion naloxone in adult overdose patients who presented to the emergency department (ED) at a single academic medical center. Methods: This study retrospectively evaluated a cohort of patients 18 years and older who presented to the ED at Virginia Commonwealth University Health and received continuous infusion naloxone for opioid overdose between January 1, 2006, and December 31, 2021. Patients were excluded if the naloxone infusion was not administered, if it was ordered for indications other than opioid overdose, or if the patient required naloxone for iatrogenic overdose. Results: Out of 3056 patient encounters where naloxone was given, only 66 patients were started on a naloxone infusion. On average patients were 46 years old, 65% male, and 73% African American. Heroin was the primary suspected overdose agent in 35% of patients and was unknown in 46% of patients. Seventy-four percent of patients received intravenous naloxone by EMS and 97% received additional naloxone boluses in the ED before starting a continuous infusion. Patients received a median of 3 mg of naloxone as boluses before starting continuous infusion naloxone. Fifty percent of patients were started on naloxone infusions < 2 mg/hr, 39% were started on the institution default of 2 mg/hr, and 11% were started >2 mg/hr with a median infusion rate of 1.5 mg/hr and duration of 7.8 hours. Fifty-four percent of patients who were started on an initial rate of 2 mg/h had an infusion dose decrease before discontinuation, while 31% required a dose increase. Conclusions: Given the current opioid epidemic, the optimal dosing of continuous infusion naloxone is unknown. It is unclear whether the recommendation of two-thirds of initial effective dose is still applicable. Currently, empiric dosing is variable and provider dependent.

682: UNINTENTIONAL PEDIATRIC ORAL INGESTION OF BRIMONIDINE EYE DROPS

Introduction: Brimonidine is a central alpha-2 adrenergic agonist agent chemically similar to clonidine. When used for glaucoma treatment, activation of alpha-2 receptors in the ciliary musculature culminates in decreased intraocular pressure by reducing aqueous humor production and stimulating outflow. While intended use is intraocular, oral ingestion and associated neurological and cardiovascular toxicities are not robustly documented in pediatric literature. In this case report, we present the toxic oral ingestion of brimonidine eye drops in a pediatric patient. Description: A two year old, previously healthy female presented to the emergency department (ED) with acute altered mental status, found dizzy and unresponsive by her grandmother around 9pm; she was last known well before going to bed at 8pm. On arrival to the ED, the patient was crying, intermittently somnolent, and opening her eyes spontaneously. Her vital signs were as follows: temperature 97.2F, heart rate 79 beats per minute, respiratory rate 22 time per minute, blood pressure 126/86 mmHg. Venous blood gas showed respiratory alkalosis and lactate 2.1mmol/L. A urine toxicology screen was negative and serum acetaminophen, salicylate, alcohol, and tricyclic levels were undetectable. Head imaging and electrocardiograms were normal. Upon further review, the patient’s grandmother revealed she recently underwent kidney transplantation. She detailed that none of her oral medications were missing but had found an empty bottle of brimonidine eye drops under the couch. The grandmother was unable to share whether it was a 5mL or 15mL bottle of 0.1% or 0.2% eye drops. With concern that the patient may have ingested brimonidine, she received empiric intravenous naloxone 0.1mg/kg amounting to 1.5mg. Rapid improvement in wakefulness and mental status was observed. The child was admitted for monitoring in an intensive care unit, did not require any additional naloxone, and was discharged after approximately 36 hours. Discussion: Oral ingestion of brimonidine eye drops may cause somnolence and bradycardia in pediatric patients. Additionally, naloxone utilization may not elicit an appropriate response. This case describes the successful identification of toxicity and use of empiric naloxone for diagnostic and treatment purposes in a pediatric patient.

Comparing Projected Fatal Overdose Outcomes and Costs of Strategies to Expand Community-Based Distribution of Naloxone in Rhode Island

In 2021, the state of Rhode Island distributed 10 000 additional naloxone kits compared with the prior year through partnerships with community-based organizations. To compare various strategies to increase naloxone distribution through community-based programs in Rhode Island to identify one most effective and efficient strategy in preventing opioid overdose deaths (OODs). In this decision analytical model study conducted from January 2016 to December 2022, a spatial microsimulation model with an integrated decision tree was developed and calibrated to compare the outcomes of alternative strategies for distributing 10 000 additional naloxone kits annually among all individuals at risk for opioid overdose in Rhode Island. Distribution of 10 000 additional naloxone kits annually, focusing on people who inject drugs, people who use illicit opioids and stimulants, individuals at various levels of risk for opioid overdose, or people who misuse prescription opioids vs no additional kits (status quo). Two expanded distribution implementation approaches were considered: one consistent with the current spatial distribution patterns for each distribution program type (supply-based approach) and one consistent with the current spatial distribution of individuals in each of the risk groups, assuming that programs could direct the additional kits to new geographic areas if required (demand-based approach). Witnessed OODs, cost per OOD averted (efficiency), geospatial health inequality measured by the Theil index, and between-group variance for OOD rates. A total of 63 131 simulated individuals were estimated to be at risk for opioid overdose in Rhode Island based on current population data. With the supply-based approach, prioritizing additional naloxone kits to people who use illicit drugs averted more witnessed OODs by an estimated mean of 18.9% (95% simulation interval [SI], 13.1%-30.7%) annually. Expanded naloxone distribution using the demand-based approach and focusing on people who inject drugs had the best outcomes across all scenarios, averting an estimated mean of 25.3% (95% SI, 13.1%-37.6%) of witnessed OODs annually, at the lowest mean incremental cost of $27 312 per OOD averted. Other strategies were associated with fewer OODs averted at higher costs but showed similar patterns of improved outcomes and lower unit costs if kits could be reallocated to areas with greater need. The demand-based approach reduced geospatial inequality in OOD rates in all scenarios compared with the supply-based approach and status quo. In this decision analytical model study, variations in the effectiveness, efficiency, and health inequality of the different naloxone distribution expansion strategies and approaches were identified. Future efforts should be prioritized for people at highest risk for overdose (those who inject drugs or use illicit drugs) and redirected toward areas with the greatest need. These findings may inform future naloxone distribution priority settings.

Out-of-hospital management of unresponsive, apneic, witnessed opioid overdoses: a case series from a supervised consumption site.

There are conflicting recommendations for lay rescuer management of patients who are unresponsive and apneic due to opioid overdose. We evaluated the management of such patients at an urban supervised consumption site. At a single urban supervised consumption site in Vancouver, BC, we conducted a retrospective chart review and administrative database linkage of consecutive patients who were unresponsive and apneic following witnessed opioid overdose between January 1, 2012 and December 31, 2017. We linked these visits with regional hospital records to define the entire care episode, which concluded when the patient was discharged from the supervised consumption site, ED, or hospital, or died. The primary outcome was successful resuscitation, defined as alive and neurologically intact (ambulatory and speaking coherently, or alert and oriented, or Glasgow Coma Scale 15) at the conclusion of the care episode. Secondary outcomes included mortality and predefined complications of resuscitation. We collected 767 patients, with a median age of 43 and 81.6% male, with complete follow-up on 763 patients (99.5%). All patients were managed with oxygen and ventilation (100%, 95% CI 0.995-1.0); 715 (93.2%, 95% CI 0.911-0.949) received naloxone; no patients underwent chest compressions (0%, 95% CI 0-0.005). All patients with complete follow-up were alive and neurologically intact at the end of their care episode (100%, 95% CI 0.994-1.0). Overall, 191 (24.9%) patients were transported to hospital, and 15 (2.0%) patients required additional naloxone after leaving the supervised consumption site; 16 (2.1%) developed complications, and 1 patient was admitted to hospital. At an urban supervised consumption site, all unresponsive, apneic patients with witnessed opioid overdose were successfully resuscitated with oxygen and/or naloxone. No patients required chest compressions.

Comparison of intranasal and intramuscular naloxone in opioid overdoses managed by ambulance staff: a double-dummy, randomised, controlled trial.

AimsTo measure and evaluate clinical response to nasal naloxone in opioid overdoses in the pre‐hospital environment.DesignRandomised, controlled, double‐dummy, blinded, non‐inferiority trial, and conducted at two centres.SettingParticipants were included by ambulance staff in Oslo and Trondheim, Norway, and treated at the place where the overdose occurred.ParticipantsMen and women age above 18 years with miosis, rate of respiration ≤8/min, and Glasgow Coma Score <12/15 were included. Informed consent was obtained through a deferred‐consent procedure.Intervention and comparatorA commercially available 1.4 mg/0.1 mL intranasal naloxone was compared with 0.8 mg/2 mL naloxone administered intramuscularly.MeasurementsThe primary end‐point was restoration of spontaneous respiration of ≥10 breaths/min within 10 minutes. Secondary outcomes included time to restoration of spontaneous respiration, recurrence of overdose within 12 hours and adverse events.FindingsIn total, 201 participants were analysed in the per‐protocol population. Heroin was suspected in 196 cases. With 82% of the participants being men, 105 (97.2%) in the intramuscular group and 74 (79.6%) in the intranasal group returned to adequate spontaneous respiration within 10 minutes after one dose. The estimated risk difference was 17.5% (95% CI, 8.9%–26.1%) in favour of the intramuscular group. The risk of receiving additional naloxone was 19.4% (95% CI, 9.0%–29.7%) higher in the intranasal group. Adverse reactions were evenly distributed, except for drug withdrawal reactions, where the estimated risk difference was 6.8% (95% CI, 0.2%–13%) in favour of the intranasal group in a post hoc analysis.ConclusionIntranasal naloxone (1.4 mg/0.1 mL) was less efficient than 0.8 mg intramuscular naloxone for return to spontaneous breathing within 10 minutes in overdose patients in the pre‐hospital environment when compared head‐to‐head. Intranasal naloxone at 1.4 mg/0.1 mL restored breathing in 80% of participants after one dose and had few mild adverse reactions.

Naloxone Injections into the Parabrachial Nucleus/ Kölliker‐Fuse Complex, the preBötzinger Complex and the Caudal Medullary Raphe Reverse Remifentanil‐Induced Respiratory Depression

Background We have shown that naloxone microinjections into the Parabrachial Nucleus/ Kölliker-Fuse (PBN/KF) complex and the preBötzinger Complex (preBC) partially reversed remifentanil-induced respiratory rate depression (1). The magnitude of reversal was dose dependent. The goal of this study was to determine whether additional naloxone injection into the caudal medullary raphe (CMR (2)) could completely reverse the opioid effect. Methods The study was approved by the local Animal Care Committee and conformed to NIH standards. Adult New Zealand White rabbits (3-4kg) were anesthetized, tracheotomized, ventilated, decerebrated and vagotomized. Phrenic nerve activity was recorded from the c5 rootlet, time averaged and used to calculate inspiratory and expiratory duration and peak phrenic activity (PPA). Gridwise localized pressure microinjections of AMPA (50 μM, 70 nl) with a multibarrel glass pipette were used to functionally identify the PBN/KF and preBC. The CMR was defined as the area between 2.0mm caudal and 1.5mm rostral to preBC in the midline. We then injected an “apneic” remifentanil IV bolus (12±2mcg), which interrupted inspiratory activity for at least 60 sec. Next, a remifentanil infusion was started at an “analgesic” dose-rate, defined to achieve respiratory rate depression of 50% of control. At steady-state, we sequentially injected naloxone (1mM, 700nl) into the bilateral PBN/KF, the preBC, and the CMR. We repeated the “apneic” remifentanil bolus after naloxone injection into each area. To determine whether injection order affected the naloxone reversal, in separate sets of animals we microinjected naloxone in the reverse order, or solely into the preBC and CMR. Drug effects were compared with Paired t-tests. Results Figure 1 illustrates the effects of sequential naloxone microinjection into the bilateral PBN/KF, preBC, and CMR. At the end of the naloxone injection sequence, respiratory rate depression was completely reversed (A+B) or even increased above baseline (C). Depression of PPA was completely reversed (p=0.756). Conclusion Naloxone injection into the CMR reversed remifentanil-induced respiratory depression in addition to the reversal achieved in the PBN/KF and preBC at “analgesic” and “apneic” remifentanil doses. Further research is needed to determine whether the naloxone effect in the CMR was partially due to reversal of endogenous opioid-receptor activation (see Palkovic B, Endogenous Opioid-Receptor Activation in the Caudal Medullary Raphe Depresses Respiratory Rate in Decerebrate Rabbits, EB 2021). (1) Palkovic et al., Anesthesiology 2020, A3038 (2) Zhang et al., Anesthesiology 2007, 107: 288-97

Outcomes following Naloxone Administration by Bystanders and First Responders

Background: Naloxone is widely available to bystanders and first responders to treat patients with suspected opioid overdose. In these patients, the prognostic factors and potential benefits associated with additional naloxone administered by emergency medical services (EMS) are uncertain. Objectives: We sought to identify prognostic factors for admission to the hospital following prehospital administration of naloxone for suspected opioid overdose by bystanders and first responders. We secondarily examined whether administration of additional naloxone by paramedics after initial treatment by non-EMS personnel was associated with improvement in level of consciousness prior to hospital arrival. Methods: This is a retrospective cross-sectional study of patients treated within a single urban EMS system from 2013 to 2016. Inclusion criteria were administration of naloxone by bystanders or first responders and transport to one of three academic medical centers. For the secondary analysis, only patients with a Glasgow Coma Scale (GCS) score ≤12 on paramedic arrival were included. We performed univariate and multivariable analyses examining a primary outcome of hospital admission and secondary outcome of improvement in consciousness as defined by GCS >12 in patients with initial GCS ≤12. Results: Of 359 patients identified for the primary analysis, 60 were admitted to the hospital. Factors associated with increased rate of admission included higher total naloxone dosage (OR 1.36, 95% CI 1.09–1.70) and presence of alternate/additional non-opioid central nervous system (CNS) depressants (OR 2.51, 95% CI 1.13–5.56). Among 178 patients who had poor neurologic status (GCS ≤12) on paramedic arrival following naloxone administered by bystander or first responder, administration of additional naloxone was not associated with a better rate of neurologic improvement prior to hospital arrival (77% improved with additional naloxone, 81% improved without additional naloxone; OR 0.82, 95% CI 0.39–1.76). Conclusions: Among patients with suspected opioid overdose treated with naloxone by bystanders and first responders, a higher total dose of naloxone and polysubstance intoxication with additional CNS depressants were predictors of admission. Administration of additional naloxone by paramedics was not associated with a higher rate of neurologic improvement prior to hospital arrival, suggesting a ceiling effect on naloxone efficacy in opioid overdose.

Fentanyl-contaminated cocaine outbreak with laboratory confirmation in New York City in 2019.

Illicitly manufactured fentanyl and fentanyl analogues (IMFs) are being increasingly suspected in overdose deaths. However, few prior outbreaks have been reported thus far of patients with laboratory-confirmed IMF toxicity after reporting intent to use only nonopioid substances. Herein we report a case series of nine patients without opioid use disorder who presented to two urban emergency departments (EDs) with opioid toxicity after insufflating a substance they believed to be cocaine. Over a period of under three hours, nine patients from five discrete locations were brought to two affiliated urban academic EDs. All patients denied prior illicit opioid use. All patients endorsed insufflating cocaine shortly prior to ED presentation. Soon after exposure, all developed lightheadedness and/or respiratory depression. Seven patients received naloxone en route to the hospital; all had improvement in respiratory function by arrival to the ED. None of the patients required any additional naloxone administration in the ED. All nine patients were discharged home after observation. Blood +/- urine samples were obtained from eight patients. All patients who provided specimens tested positive for cocaine metabolites and had quantifiable IMF concentrations, as well as several detectable fentanyl derivatives, analogues, and synthetic opioid manufacturing intermediates. IMF-contamination of illicit drugs remains a public health concern that does not appear to be restricted to heroin. This confirmed outbreak demonstrates that providers should elevate their level of suspicion for concomitant unintentional IMF exposure even in cases of non-opioid drug intoxication. Responsive public health apparatuses must prepare for future IMF-contamination outbreaks.

Prehospital Naloxone and Emergency Department Adverse Events: ADose-Dependent Relationship.

The purpose of this study was to evaluate prehospital and emergency department (ED) interventions and outcomes of patients who received prehospital naloxone for a suspected opioid overdose. The primary objective was to evaluate if the individual dose, individual route, total dose, number of prehospital naloxone administrations, or occurrence of a prehospital adverse event (AE) were associated with the occurrence of AEs in the ED. Secondary objectives included a subset analysis of patients who received additional naloxone while in the ED, or were admitted to an intensive care or step-down unit (ICU). This was a retrospective, observational chart review of adult patients who received prehospital naloxone and were transported by ambulance to a suburban academic tertiary care center between 2014 and 2017. Descriptive, univariate, and multivariate statistics were used, with p<0.05 indicating significance. There were 513 patients included in the analysis, with a median age of 29years, and median total prehospital naloxone dose of 2mg. An increasing number of prehospital naloxone doses, an occurrence of a prehospital AE, and a route of administration other than intranasally for the first dose of prehospital naloxone were significantly associated with an increased likelihood of an ED AE. Patients who received < 2mg of prehospital naloxone had the least likelihood of being admitted to an ICU, whereas patients who received at least 6mg had a dramatically increased likelihood of ICU admission. Our results suggest that an increasing number of prehospital naloxone doses was significantly associated with an increased likelihood of an ED adverse event.

Effects of Different Systemic Opioid Doses on Subareas of the Ventral Respiratory Column

BackgroundThe Parabrachial Nucleus (PBN)/Kölliker‐Fuse (KF) complex are important subareas of the ventral respiratory column (VRC) that regulate inspiratory on‐ ( 1) and off‐switch ( 2). We have shown in vagus‐intact rabbits that respiratory rate depression caused by clinical opioid concentrations was in part mediated by the PBN ( 3), and that systemic opioid effects on respiratory phase timing could be partially reversed in the preBötzinger complex (preBC) albeit without reversing respiratory rate depression ( 4). The present study was to determine how much the combination of local microinjections of naloxone into the KF, PBN and preBC could reverse respiratory depression from intravenous remifentanil (REMI).MethodsThe study was approved by the local Animal Care Committee and conformed to NIH standards. Adult New Zealand White rabbits (3–4kg) were anesthetized, tracheotomized, ventilated, decerebrated and vagotomized. Phrenic nerve activity was recorded from the c5 rootlet, time averaged and used to calculate inspiratory and expiratory duration and peak phrenic activity (PPA). Gridwise localized pressure microinjections of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA, 50 μM, 70 nl) utilizing a multibarrel glass pipette into the VRC caudal to the inferior collicle identified the PBN where AMPA injection caused significant tachypnea and the KF where AMPA caused transient bradypnea and a decrease in PPA. The tachypneic response to AMPA injection in the medulla was used to identify the preBC area. After functional identification of the PBN, KF and preBC areas, we injected a bolus of 10mcg REMI IV, which resulted in apnea. On return of the breathing pattern, a REMI infusion was started to achieve a steady‐state respiratory rate depression of 50% of control rate. After reaching steady‐state, we injected naloxone (1mM, 700nl) into the bilateral KF, PBN and preBC. We then repeated the REMI bolus injection with the apneic dose of 10mcg. In a subset of animals, the 10 mcg REMI bolus was repeated after naloxone injection into the KF/PBN and after injection into the preBC. Residual respiratory depression was reversed at the end of the protocol with IV naloxone (300μM). Drug effects were compared with one‐way RM ANOVA. Data are expressed as mean±SD.ResultsIn 11 animals, IV REMI depressed respiratory rate from 39±7 to 18±6 breaths per minute (BPM). Naloxone injection recovered respiratory rate to 20±9 in the KF (p=0.36), to 26±9 after additional injection into the PBN (p&lt;0.001), and to 28±7 bpm after injection into the preBC area (p=0.54). The IV REMI bolus caused apnea &gt;30s at control but only depressed respiratory rate to 12±6 bpm after naloxone injection into the KF/PBN (p&lt;0.001) and to 16±7 after additional naloxone reversal in the preBC area (p=0.21, n=5).ConclusionRespiratory rate depression from IV opioids is mostly mediated by the PBN, however, higher opioid doses may also affect other brainstem areas.Support or Funding InformationSupported by NIH R01GM112960701A1 (Dr. Stucke) and VA merit grant I01BX000721 (Dr. Zuperku)Figure 1

Association between state Medicaid expansion status and naloxone prescription dispensing.

To test whether Medicaid expansion is associated with (a) a greater number of naloxone prescriptions dispensed and (b) a higher proportion of naloxone prescriptions paid by Medicaid. We used the IQVIA National Prescription Audit to obtain data on per state per quarter naloxone prescription dispensing for the period 2011-16. In this quasi-experimental design study, the impact of Medicaid expansion on naloxone prescription dispensing was examined using difference-in-difference estimation models. State-level covariates including pharmacy-based naloxone laws (standing/protocol orders and direct authority to dispense naloxone), third-party prescribing laws, opioid analgesic prescribing rates, opioid-involved overdose death rates, and population size were controlled for in the analysis. Medicaid expansion was associated with 38 additional naloxone prescriptions dispensed per state per quarter compared to nonexpansion controls, on average (P=.030). Also, Medicaid expansion resulted in an average increase of 9.86 percent in the share of naloxone prescriptions paid by Medicaid per state per quarter (P<.001). Our study found that Medicaid expansion increased naloxone availability. This finding suggests that it will be important to consider naloxone access when making federal- and state-level decisions affecting Medicaid coverage.

Do Patients Require Emergency Department Interventions After Prehospital Naloxone?

Patients receiving naloxone for suspected opioid overdose in the prehospital setting are typically transported to the emergency department (ED) for further evaluation, regardless of Glasgow Coma Scale (GCS). The objective of our study is to determine whether patients with GCS ≥14 after receiving prehospital naloxone received additional doses of naloxone and medical interventions in the ED compared with those with GCS <14 after prehospital naloxone. Our retrospective observational study included patients ≥18 years old treated with naloxone and transported by an inner-city hospital-based Emergency Medical Services (EMS) to its affiliated ED from January 2, 2016 to December 31, 2016. Investigators collected demographic data, prehospital interventions, GCS, ED interventions, and dispositions. Institutional Review Board approval was obtained. The main outcome measures were repeat doses of naloxone and ED interventions. In all, 473 patient encounters were reviewed. Most common route of prehospital naloxone administration was intranasal (68%). Nearly two-thirds (n = 473) of patients had GCS ≥14 upon ED arrival. Repeat naloxone was administered to 3.5% (n = 314) of patients with GCS ≥14 versus 14.6% (n = 159) of patients with GCS <14. ED interventions, such as airway maneuvers, laboratory and radiology testing, and cardiac monitoring, were less common among patients who had improved GCS of 14 or higher (n = 314). There were 8 deaths among patients with GCS <14 (n = 159) and no deaths among patients with GCS ≥14 (n = 314). Patients with GCS score ≥14 after administration of prehospital naloxone are less likely to receive additional naloxone doses and medical interventions in the ED compared with those with a GCS score <14 after prehospital naloxone and may present an invaluable opportunity for the ED to initiate an addiction treatment program for patients with nonfatal overdose.

A standardized team-based approach for identifying naloxone-eligible patients in a grocery store pharmacy

ObjectivesTo define a standardized team-based approach to identify naloxone-eligible patients in a community pharmacy and to evaluate the impact of the approach on the number of naloxone orders dispensed. SettingTwo locations within one district of a chain pharmacy. Practice descriptionKroger is a national grocery store pharmacy. Practice innovationA standardized team-based approach was implemented from November 2017 to February 2018 into the dispensing workflow to identify naloxone-eligible patients. Training was provided to team members (e.g., pharmacist, student pharmacist, technician) at the intervention store. Persons age 18 years and older who met more than 1 of the following criteria were included: greater than or equal to 50 morphine milligram equivalents per day, concurrent benzodiazepine and opioid use, fentanyl patch greater than or equal to 25 μg/h, and documented or verbal history of overdose or substance use disorder. Persons were excluded if they were younger than 18 years, did not speak English, or received an opioid prescription of less than 5 days' duration and no opioid exposure during the previous 30 days. EvaluationIf inclusion criteria were met, a clinical flag was placed in the dispensing system, alerting the pharmacist to speak with the patient at pick-up. The pharmacist educated the patient on the risks of opioid medications and the benefits of naloxone and then offered to dispense naloxone. The control store followed standard of practice. Data were evaluated using descriptive statistics. ResultsThe intervention and control store each dispensed 3 naloxone orders from November 2016 to February 2017. During the study period, 39 persons were identified as eligible for naloxone, and 11 naloxone orders were dispensed at the intervention store (28.2%); 2 naloxone orders were dispensed at the control store. A standardized team-based approach resulted in dispensing 8 additional naloxone orders at the intervention store, representing a 367% increase compared with the prior year, when this approach was not used. ConclusionA standardized team-based approach was successfully implemented in a grocery store pharmacy and resulted in increased naloxone dispensing to naloxone-eligible patients.

Association of Naloxone Coprescription Laws With Naloxone Prescription Dispensing in the United States

To mitigate the opioid overdose crisis, states have implemented a variety of legal interventions aimed at increasing access to the opioid antagonist naloxone. Recently, Virginia and Vermont mandated the coprescription of naloxone for potentially at-risk patients. To assess the association between naloxone coprescription legal mandates and naloxone dispensing in retail pharmacies. This was a population-based, state-level cohort study. The sample included all prescriptions dispensed for naloxone in the retail pharmacy setting contained in IQVIA's national prescription audit, which represents 90% of all retail pharmacies in the United States. The unit of observation was state-month and the study period was January 1, 2011, to December 31, 2017. State legal intervention mandating naloxone coprescription. Number of naloxone prescriptions dispensed. State rates of naloxone prescriptions dispensed per month per 100 000 standard population were calculated. The rate of naloxone dispensing increased after implementation of legal mandates for naloxone coprescription. An estimated 88 naloxone prescriptions per 100 000 were dispensed in Virginia and 111 prescriptions per 100 000 were dispensed in Vermont during the first full month the legal requirement was effective. In comparison, 16 naloxone prescriptions per 100 000 were dispensed in the 10 states (including the District of Columbia) with the highest opioid overdose death rates and 6 prescriptions per 100 000 were dispensed in the 39 remaining states. The number of naloxone prescriptions dispensed was associated with the legal mandate for naloxone coprescription (incidence rate ratio [IRR], 7.75; 95% CI, 1.22-49.35). Implementation of the naloxone coprescription mandate was associated with an estimated 214 additional naloxone prescriptions dispensed per month in the period following the mandates, holding all other variables constant. Among covariates, naloxone access laws (IRR, 1.37; 1.05-1.78), opioid overdose death rates (IRR, 1.06; 95% CI, 1.04-1.08), the percentage of naloxone prescriptions paid by third-party payers (IRR 1.009; 1.008-1.010), and time (IRR, 1.06; 95% CI, 1.05-1.07) were significantly associated with naloxone prescription dispensing. These study findings suggest that legally mandated naloxone prescription for those at risk for opioid overdose may be associated with substantial increases in naloxone dispensing and further reduction in opioid-related harm.

Prepacked naloxone administration for suspected opioid overdose in the era of illicitly manufactured fentanyl: a retrospective study of regional poison center data

Background: Prepacked naloxone kits (PNKs) are frequently used to reverse opioid intoxication. It is unknown if the presence of illicitly manufactured fentanyl and its analogs (IMFs) in heroin supply is affecting the PNK doses given by laypersons. We investigated the trend of PNK dose administered to reverse opioid toxicity in suspected/undifferentiated opioid intoxication.Methods: We retrospectively reviewed PNK administrations reported to the Maryland Poison Center between 1 January 2015 and 15 October 2017. Primary outcome was the mean PNK dose administered to reverse opioid-induced central nervous system and ventilatory depression. Secondary outcomes included the reversal rate of opioid toxicity, patient disposition, and survival rate.Results: Our analysis involved 1139 PNK administrations. The mean age of subjects was 34.3 years; 68.8% (n = 781) were male. Ventilatory depression was present in 98.2% (n = 958) of cases, and 97% (n = 1097) were unresponsive. Law enforcement administered the majority of PNK (91.0%; n = 1035); the primary route was intranasal (97.9%; n = 1051). Toxicity was reversed in 79.2% (n = 886) of overdose victims after a mean PNK dose of 3.12 mg. EMS personnel gave 291 subjects additional naloxone (mean: 2.2 mg), reversing opioid toxicity in 94.2% (n = 254). Between 2015 and 2017, the mean PNK dose increased from 2.12 to 3.63 mg (p < .0001) while the reversal rate decreased from 82.1% to 76.4% (p = .04). One hundred and eighty-two patients (15.9%) refused transport; of those transported to a hospital, 73.4% (n = 569) were treated and released and 12.4% (n = 96) required hospitalization. Ninety-six percent (n = 1092) of the subjects survived. Forty subjects were pronounced dead at the scene. Fentanyl or its analog was detected in 36 of 55 opioid-related deaths (65.5%).Conclusions: PNK administration reversed toxicity in the majority of patients with undifferentiated opioid intoxication. Between 2015 and 2017, increasing doses of PNK were administered but the reversal rate decreased. These trends are likely multifactorial, including increasing availability of IMFs.

Retrospective Review of Need for Delayed Naloxone or Oxygen in Emergency Department Patients Receiving Naloxone for Heroin Reversal.

Emergency departments (EDs) are experiencing an increasing number of heroin overdose visits. Currently, there is no generally agreed upon ED observation period for heroin overdose patients who receive naloxone. We aimed to determine the safety of a 2-h observation period for heroin overdose patients who receive naloxone. We performed a chart review of all patients who presented with any opioid-related complaint between 2009 and 2014 to our urban academic trauma center. Subset analysis of patients with isolated heroin overdose who received naloxone was performed, with the intent of excluding patients intoxicated with long-acting/enteral opioids. The primary outcome was the number of patients who required delayed intervention-specifically, additional naloxone or supplemental oxygen. Between 2009 and 2014, we recorded 806 visits to our ED for heroin use after receiving naloxone. Twenty-nine patients (3.6%) received a repeat dose of naloxone, and 17 patients (2%) received oxygen ≥2h after initial naloxone administration. Our 2-h intervention rate was 4.6% (N=37). This decreased to 1.9% (N=15) after 3h and 0.9% (N=7) after 4h. Patients with polysubstance use were more likely to receive repeat naloxone (p<0.01), but not oxygen (p=0.10). Preexisting cardiopulmonary conditions did not correlate with a need for supplemental oxygen (p=0.24) or repeat naloxone (p=0.30). A 2-h ED observation period for heroin overdose patients reversed with naloxone resulted in a delayed intervention rate of 5%. Clinicians may consider a 3-h observation period, with extra scrutiny in polysubstance abuse.

Insights From a Pilot Study of Naloxone Education

Background and Aims: We wanted to test whether introducing an additional Naloxone component into overdose education would affect the willingness and confidence of a potential overdose witness to intervene effectively. A further aim was to test the potential of education to reduce barriers to administering Naloxone and barriers to calling 999 (UK Emergency services). Methods: We used quantitative methods to gather and analyze data from both control (overdose education, n=15) and experimental (overdose and Naloxone education, n=57) participants, facilitated by educators in the North West of England and London, for opioid users (n=5), former users (n=19), carers/support workers (n=29), family members (n=31) or friends (n=12) (multiple response item). We measured self-reported confidence and willingness of participants using evaluation forms with Likert scales, and knowledge using open-ended questions. We ran a focus group with educators about delivery, teaching and/or working with this study population as learners Results: Both the controlled and the experimental sessions increased participants’ confidence to use first aid skills, specific confidence in an overdose situation and willingness to act. The educators reported low levels of learner literacy, which may have affected the reliability of the data gathered. The sessions the benefits of a flexible, workshop-style session, peer-to-peer support. Conclusion: Introducing a Naloxone component to first aid education targeting potential witnesses of an opioid overdose situation does not seem to negatively impact on learners’ confidence or willingness to act, though the methodological challenges of this study limits the conclusiveness of this statement. Overdose or Naloxone education should employ a flexible format that is tailored to the needs of the learners and encourage peer-to-peer support.

Hospital Observation Upon Reversal (HOUR) With Naloxone: A Prospective Clinical Prediction Rule Validation Study.

St. Paul's Early Discharge Rule was derived to determine which patients could be safely discharged from the emergency department after a 1-hour observation period following naloxone administration for opiate overdose. The rule suggested that patients could be safely discharged if they could mobilize as usual and had a normal oxygen saturation, respiratory rate, temperature, heart rate, and Glasgow Coma Scale score. Validation of the St. Paul's Early Discharge Rule is necessary to ensure that these criteria are appropriate to apply to patients presenting after an unintentional presumed opioid overdose in the context of emerging synthetic opioids and expanded naloxone access. In this prospective, observational validation study, emergency medicine providers assessed patients 1hour after administration of prehospital naloxone. Unlike in the derivation study the threshold for normal oxygen saturation was set at 95% and patients were not immediately discharged after a normal 1-hour evaluation. Patients were judged to have a normal 1-hour evaluation if all six criteria of the rule were met. Patients were judged to have an adverse event (AE) if they had one or more of the preestablished AEs. A total of 538 patients received at least one administration of prehospital naloxone, were transported to the study hospital, and had a 1-hour evaluation performed by a provider. AEs occurred in 82 (15.4%) patients. The rule exhibited a sensitivity of 84.1% (95% confidence interval [CI]= 76.2%-92.1%), a specificity of 62.1% (95% CI= 57.6%-66.5%), and a negative predictive value of 95.6% (95% CI= 93.3%-97.9%). Only one patient with a normal 1-hour evaluation subsequently received additional naloxone following a presumed heroin overdose. This rule may be used to risk stratify patients for early discharge following naloxone administration for suspected opioid overdose.

Identifying barriers to dispensing naloxone: A survey of community pharmacists in North Carolina

ObjectivesThe primary objective of this study was to identify barriers to dispensing naloxone under the North Carolina statewide standing order in the community pharmacy setting. Secondary objectives included identifying areas for additional training. MethodsThis study was conducted as a cross-sectional survey distributed to community pharmacists in North Carolina through an Internet-based questionnaire platform. The questions assessed pharmacists' training regarding naloxone, willingness to dispense naloxone, knowledge of naloxone and opioid overdose, perceived barriers to implementing a naloxone distribution program, and demographic information. Descriptive statistics and Pearson correlation coefficient were used in data analysis. ResultsOnly 30% of survey respondents scored greater than 90% on the knowledge assessment portion of the survey. Furthermore, more than 50% of respondents indicated that they were not very comfortable dispensing naloxone, based on their responses to a series of Likert-type scale statements. A statistically significant positive correlation (r = 0.288; P < 0.001) was found between pharmacists' knowledge of naloxone and opioid overdose and willingness to dispense naloxone. The majority of respondents indicated that lack of training was a major barrier to dispensing naloxone. Additional training needs included information regarding naloxone, strategies to initiate patient discussion, identifying eligible patients, and workflow implementation. More than 95% of respondents indicated that the pharmacy in which they are employed would benefit from additional naloxone training. ConclusionCommunity pharmacists in North Carolina would like to receive additional training regarding naloxone and opioid overdose. Given the statistically significant positive correlation between knowledge concerning naloxone and opioid overdose and willingness to dispense naloxone, it is possible that increased pharmacist training could lead to increased willingness to dispense naloxone under the statewide standing order. These results can be used in a meaningful way to determine the best ways to better educate pharmacists on naloxone and improve patient access to this life-saving medication.

Use of Intranasal Naloxone by Basic Life Support Providers

Study Objectives: Intranasal delivery of naloxone to reverse the effects of opioid overdose by Advanced Life Support (ALS) providers has been studied in several prehospital settings. In 2006, in response to the increase in opioid-related overdoses, a special waiver from the state allowed administration of intranasal naloxone by Basic Life Support (BLS) providers in our city. This study aimed to determine: 1) if patients who received a 2-mg dose of nasal naloxone administered by BLS required repeat dosing while in the emergency department (ED), and 2) the disposition of these patients. Methods: This was a retrospective review of patients transported by an inner-city municipal ambulance service to one of three academic medical centers. We included patients aged 18 and older that were transported by ambulance between 1/1/2006 and 12/12/2012 and who received intranasal naloxone by BLS providers as per a state approved protocol. Site investigators matched EMS run data to patients from each hospital's EMR and performed a chart review to confirm that the patient was correctly identified and to record the outcomes of interest. Descriptive statistics were then generated. Results: A total of 793 patients received nasal naloxone by BLS and were transported to three hospitals. ALS intervened and transported 116 (14.6%) patients, and 11 (1.4%) were intubated in the field. There were 724 (91.3%) patients successfully matched to an ED chart. Hospital A received 336 (46.4%) patients, Hospital B received 210 (29.0%) patients, and Hospital C received 178 (24.6%) patients. Mean age was 36.2 (SD 10.5) years and 522 (72.1%) were male; 702 (97.1%) were reported to have abused heroin while 21 (2.9%) used other opioids. Nasal naloxone had an effect per the prehospital record in 689 (95.2%) patients. An additional naloxone dose was given in the ED to 64 (8.8%) patients. ED dispositions were: 507 (70.0%) discharged, 105 (14.5%) admitted, and 112 (15.5%) other (e.g., left against medical advice, left without being seen, or transferred). Conclusions: Only a small percentage of patients receiving prehospital administration of nasal naloxone by BLS providers required additional doses of naloxone in the ED and the majority of patients were discharged.